Interest in Over-the-Counter Access to a Progestin-Only Pill among Women in the United States.

PubMed

Grindlay, Kate; Grossman, Daniel

A progestin-only pill may be the first pill formulation to become available over the counter in the United States; however, no research on over-the-counter (OTC) pill interest has focused on progestin-only pills or a representative sample of teens. The objective of this study was to assess U.S. women and teens' interest in OTC progestin-only pill use. In October 2015, we conducted a nationally representative, cross-sectional, online survey with 2,026 sexually active adult women aged 18 to 44 not currently desiring pregnancy, and 513 female teens aged 15 to 17. Logistic regression was used to identify characteristics associated with likely OTC progestin-only pill use. We also assessed reasons for use or nonuse, duration of use, and willingness to pay. Thirty-nine percent of adults and 29% of teens reported likely use, with a greater likelihood if covered by insurance. Adults were willing to pay $15 per month and teens $10 per month on average. Among adults, women who were never married or living alone (vs. married), uninsured (vs. privately insured), current pill or less effective method users (vs. ring, patch, injectable, or intrauterine device), tried to get a birth control prescription in the past year, or ever used an oral contraceptive pill or progestin-only pill had higher odds of likely use. Among teens, Spanish speakers and those who ever had sex had higher odds of likely use; Black teens (vs. White) had lower odds. Teens and adults are interested in using an OTC progestin-only pill. These findings indicate a large pool of interested users and the potential for improved contraceptive access by making an OTC progestin-only pill available. Copyright © 2017 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.

Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin.

PubMed

Wiehle, Ronald D; Christov, Konstantin; Mehta, Rajendra

2007-07-01

In this report, we evaluate the effects of a 21-substituted-19-nor-progestin, CDB-4124, on 7,12,-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats in comparison with RU486. Sprague-Dawley female rats were treated with DMBA at 50 days of age in order to induce mammary tumors. When the tumors reached the size of 10-12 mm, the animals were treated for 28 days with the vehicle, RU486, progesterone, CDB-4124 at various doses, or CDB-4124 plus progesterone. Anti-progestins resulted in the regression in the size of the existing tumors, and in the suppressed development of new tumors and tumor multiplicity. Progesterone treatment, however, increased the size and multiplicity. Progesterone rendered an increased number of growing tumors as compared to the regression in the anti-progesterone treatment groups. The combination of CDB-4124 and high doses of progesterone opposed the efficacy of CDB-4124. The growth inhibitory effects of the anti-progestins were correlated with increased apoptosis and reduced cell proliferation. These results indicate that anti-progestins should be developed for the chemoprevention and treatment of hormone-responsive breast cancer.

Oral progestin induces rapid, reversible suppression of ovarian activity in the cat

PubMed Central

Stewart, R.A.; Pelican, K.M.; Brown, J.L.; Wildt, D.E.; Ottinger, M.A.; Howard, J.G.

2010-01-01

The influence of oral progestin (altrenogest; ALT) on cat ovarian activity was studied using non-invasive fecal steroid monitoring. Queens were assigned to various ALT dosages: 1) 0 mg/kg (control; n = 5 cats); 2) 0.044 mg/kg (LOW; n = 5); 3) 0.088 mg/kg (MID; n = 6); or 4) 0.352 mg/kg (HIGH; n = 6). Fecal estrogen and progestagen concentrations were quantified using enzyme immunoassays for 60 days before, 38 days during and 60 days after ALT treatment. Initiation of follicular activity was suppressed in all cats during progestin treatment, whereas controls continued to cycle normally. Females (n = 6) with elevated fecal estrogens at treatment onset completed a normal follicular phase before returning to baseline and remained suppressed until treatment withdrawal. All cats receiving oral progestin reinitiated follicular activity after treatment, although MID cats experienced the most synchronized return (within 10-16 days). Mean baseline fecal estrogens and progestagens were higher (P < 0.05) after treatment in HIGH, but not LOW or MID cats compared to pre-treatment values. Results demonstrate that: 1) oral progestin rapidly suppresses initiation of follicular activity in the cat, but does not influence a follicular phase that exists before treatment initiation; and 2) queens return to normal follicular activity after progestin withdrawal. This study provides foundational information for research aimed at using progestin priming to improve ovarian response in felids scheduled for ovulation induction and assisted breeding. PMID:20051246

Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study.

PubMed

Byrne, Elizabeth H; Anahtar, Melis N; Cohen, Kathleen E; Moodley, Amber; Padavattan, Nikita; Ismail, Nasreen; Bowman, Brittany A; Olson, Gregory S; Mabhula, Amanda; Leslie, Alasdair; Ndung'u, Thumbi; Walker, Bruce D; Ghebremichael, Musie S; Dong, Krista L; Kwon, Douglas S

2016-04-01

The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract. In this prospective cohort, we enrolled HIV-negative South African women aged 18-23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods. Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12·06 per 100 person-years, 95% CI 6·41-20·63) than women using no long-term contraception (3·71 per 100 person-years, 1·36-8·07; adjusted hazard ratio [aHR] 2·93, 95% CI 1·09-7·868, p=0·0326). HIV-negative injectable progestin-only contraceptive users had 3·92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0·0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3·25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0·0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives. Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure. The Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radiosequence analysis of the human progestin receptor charged with ( sup 3 H)promegestone. A comparison with the glucocorticoid receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stroemstedt, P.E.B.; Berkenstam, A.; Joernvall, H.G.

1990-08-05

Partially purified preparations of the human progestin receptor and the human and rat glucocorticoid receptor proteins were covalently charged with the synthetic progestin, ({sup 3}H)promegestone, by photoaffinity labeling. After labeling, the denaturated protein was cleaved and the mixture of peptides subjected to radiosequence analysis as previously described for the rat glucocorticoid receptor protein. The radioactivity labels identified, corresponded to Met-759 and Met-909 after photoaffinity labeling of the human progestin receptor, and Met-622 and Cys-754 after labeling of the rat glucocorticoid receptor. The residues labeled in the glucocorticoid receptor are the same as those previously reported to bind triamcinolone actonide. Themore » corresponding residues were also labeled in the human glucocorticoid receptor. Met-759 of the progestin receptor and Met-622 of the rat glucocorticoid receptor are positioned within a segment with an overall high degree of sequence similarity and are equivalent. However, Met-909 (progestin receptor) and Cys-754 (glucocorticoid receptor) do not occur within equivalent segments of the two proteins. Thus, although the two classes of steroid hormone share a common structure within the A-ring, there are subtle differences in their interaction with the two separate receptor proteins.« less

Studies on the synergistic effect of androgen on the stimulation of progestin secretion by FSH in cultured rat granulosa cells: a search for the mechanism of action.

PubMed

Nimrod, A

1977-09-01

Cultures of granulosa cells from immature hypophysectomized DES-treated rats were unable to maintain progestin production of more than 48 h in medium without hormone supplementation or in the presence of FSH only. Production of progestin (20alpha-dihydroprogesterone, as measured by radioimmunoassay) remained unimpaired in the presence of androstenedione (Ad) and was markedly increased in the presence of both Ad and FSH. The combined treatment with FSH and Ad during the first 48 h of culture brought about persistent changes in the cultured cells, since progestin accumulation did not decline upon subsequent removal of these hormones during days 3 and 4 of culture. Dibutyryl cyclic AMP (DBC) was able to mimic the changes in steroidogenic capability induced by the combined action of FSH and Ad. The extent of [125I]-FSH binding, FSH-stimulable cAMP accumulation and cyclic 3',5'-nucleotide phosphodiesterase activity were not affected by addition of Ad to the culture medium. Ad synergized with DBC in the stimulation of progestin accumulation in granulosa cell cultures. It is suggested that androgen acts at a step in the regulation of progestin biosynthesis distal to cAMP production.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis.

PubMed

Farris, Manuela; Bastianelli, Carlo; Rosato, Elena; Brosens, Ivo; Benagiano, Giuseppe

2017-10-01

The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.

Progestins in the menopause in healthy women and breast cancer patients.

PubMed

Pasqualini, Jorge R

2009-04-20

At present, more than 200 progestin compounds are synthetized, but their biological effects are different: this is function of their structure, receptor affinity, metabolic transformations, the target tissues considered, dose. The action of progestins in breast cancer is controversial; some studies indicate an increase in breast cancer incidence, others show no differences, and yet others indicate a decrease. Many studies agree that treatment with progestins plus estrogens at a low dose and during a limited period (less than 5 years) can have beneficial effects in peri- and post-menopausal women. It was demonstrated that various progestins (e.g. nomegestrol acetate, medrogestone, promegestone), as well as tibolone and its metabolites, can block the enzymes involved in estradiol bioformation (sulfatase, 17beta-hydroxysteroid dehydrogenase) in breast cancer. Progesterone is converted into various metabolic products: in normal breast tissue the transformation is mainly to 4-ene derivatives, whereas in the tumor tissue 5alpha-pregane derivatives are predominant. Aromatase activity is the last step in the formation of estrogens by the conversion of androgens. In recent studies it was shown that 20alpha-dihydroprogesterone, a metabolite found mainly in normal breast tissue and having anti-proliferative properties, can act as an anti-aromatase agent. The data suggest the possible utilization of this compound in breast cancer prevention. In conclusion, in order to clarify and better understand the response of progestins in breast cancer (incidence and mortality), as well as in hormone replacement therapy or in endocrine dysfunction, new clinical trials are necessary using other progestins in function of the dose and period of treatment.

Characterization of the estrous cycle and assessment of reproductive status in Matschie's tree kangaroo (Dendrolagus matschiei) with fecal progestin profiles.

PubMed

North, Lindsay A; Harder, John D

2008-03-01

The population of Matschie's tree kangaroos (Dendrolagus matschiei) held in North American zoos has declined to critically low numbers, and information on the reproductive biology of tree kangaroos is limited. The objectives of this study were to (1) characterize the temporal features of the estrous cycle through the measurement of fecal progesterone metabolite (i.e., progestin) concentrations and (2) determine the reproductive status of female tree kangaroos in the captive population of North America through the identification of estrous cyclicity. Fecal pellets and observations of estrous behaviors were collected from 16 captive female tree kangaroos. Fecal pellets were sampled and extracted with methanol, and progestin concentrations were quantified using a radioimmunoassay (RIA) for progesterone and its metabolites. A progestin profile was obtained for each female by plotting fecal progestin concentrations for every third day over a 120-day period. Profiles for 12 of 16 females showed evidence of estrous cyclicity (P<0.01). The mean length of the estrous cycle was estimated at 58.9+/-2.4 days (n=11). Progestin concentrations were low during the first 15-20 days of the luteal phase and remained elevated above baseline only during the last 30.2+/-3.2 days of the luteal phase, which averaged 46.6+/-2.5 days in duration. The progestin profile observed in the estrous cycle of Matschie's tree kangaroos in this study is very similar to that seen in the non-pregnant cycle of several other species in the family Macropodidae.

[Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in human and nude mouse ectopic endometrium and the effect of estrogen and progestin on their expression].

PubMed

Lou, Yan-hui; Guo, Xin-hua; Jiang, Hua; Xia, Yu-fang

2010-04-01

To explore the roles of matrix metalloproteinase-1(MMP-1) and tissue inhibitor of metalloproteinase-1(TIMP-1) in the pathogenesis of endometriosis and the effects of estrogen and progestin on their expression. Immunohistochemistry and RT-PCR were employed to detect the expression of MMP-1 and TIMP-1 in the ectopic tissues of 35 patients with endometriosis, 22 eutopic endometrium tissues from women with endometriosis and 28 normal controls. Fifty-nine nude mice were injected with human late secretory endometrial chippings and randomized into estrogen group, progestin group, estrogen-progestin group and control group with corresponding treatments. The implantation rates and graft morphology were observed and MMP-1 and TIMP-1 expressions in the grafts detected by immunohistochemistry. Typical endometrial glands and stroma were observed in all the groups with comparable implantation rates. The administration of progestin was associated with multiple peritoneal implantation sites and significantly larger implants. The transplanted endometria showed proliferative or secretory changes with estrogen or progestin administration. MMP-1 expression significantly increased and TIMP-1 expression decreased with increased MMP-1/TIMP-1 ratio in human and nude mouse ectopic endometria in comparison with those in normal endometria (P<0.05, P<0.01). MMP-1 expression was higher in estrogen and estrogen-progestin groups than in the control group, and was lower in the 3 sexual hormone-treated groups than in the control group. MMP-1 mRNA expression in the eutopic endometrium was significantly higher than that in the normal endometria. Progestrin can not inhibit MMP-1 expression or the effect of estrogen on ectopic endometrium known as progestin resistance. The high expression of MMP-1 and low expression of TIMP-1 in endometriotic tissues confer strong invasiveness of ectopic endometrial tissue, especially in eutopic endometrial tissue, and may play an important role in the pathogenesis of endometriosis.

Oral Progestin Priming Increases Ovarian Sensitivity to Gonadotropin Stimulation and Improves Luteal Function in the Cat1

PubMed Central

Stewart, Rosemary A.; Pelican, Katharine M.; Crosier, Adrienne E.; Pukazhenthi, Budhan S.; Wildt, David E.; Ottinger, Mary Ann; Howard, JoGayle

2012-01-01

ABSTRACT As the only domesticated species known to exhibit both induced and spontaneous ovulation, the cat is a model for understanding the nuances of ovarian control. To explore ovarian sensitivity to exogenous gonadotropins and the influence of progestin priming, we conducted a study of queens that were down-regulated with oral progestin or allowed to cycle normally, followed by low or high doses of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). Our metrics included 1) fecal steroid metabolite profiles before and after ovulation induction, 2) laparoscopic examination of ovarian follicles and corpora lutea (CL) on Days 2 and 17 (Day 0 = hCG administration), and 3) ovariohysterectomy (Day 17) to assess CL progesterone concentrations, morphometrics, and histology. Reproductive tracts from time-matched, naturally mated queens (n = 6) served as controls. Every progestin-primed cat (n = 12) produced the desired response of morphologically similar, fresh CL (regardless of eCG/hCG dose) by Day 2, whereas 41.7% of unprimed counterparts (n = 12) failed to ovulate or had variable-aged CL suggestive of prior spontaneous ovulation (P < 0.05). The ovarian response to low, but not high, eCG/hCG was improved (P < 0.05) in primed compared to unprimed cats, indicating increased sensitivity to gonadotropin in the progestin-primed ovary. Progestin priming prevented hyperelevated fecal steroid metabolites and normalized CL progesterone capacity, but only when combined with low eCG/hCG. However, priming failed to prevent ancillary CL formation, smaller CL mass, or abnormal luteal cell density, which were common to all eCG/hCG-treated cats. Thus, the domestic cat exposed to eCG/hCG produces CL with structural and functional aberrations. These anomalies can be partially mitigated by progestin priming, possibly due to a protective effect of progestin associated with enhanced ovarian sensitivity to gonadotropins. PMID:23100619

CDC2 Mediates Progestin Initiated Endometrial Stromal Cell Proliferation: A PR Signaling to Gene Expression Independently of Its Binding to Chromatin

PubMed Central

Vallejo, Griselda; Mestre-Citrinovitz, Ana C.; Ballaré, Cecilia; Beato, Miguel; Saragüeta, Patricia

2014-01-01

Although non-genomic steroid receptor pathways have been studied over the past decade, little is known about the direct gene expression changes that take place as a consequence of their activation. Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. We showed that picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERb) and without transcriptional activity of endogenous PR and ER. Here we identify early downstream targets of cytoplasmic PR signaling and their possible role in endometrial stromal cell proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors and regulatory factors associated with cell proliferation and cell cycle, a large fraction of which were repressors down-regulated by hormone. Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR-mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding. ChIP experiments show that progestin promoted the interaction of USF1 with the proximal promoter of the Cdc2 gene. Usf1 knockdown abolished Cdc2 progestin-dependent transcriptional regulation and cell proliferation, which also blocked Cdc2 knockdown. We conclude that progestin-induced proliferation of endometrial stromal cells is mediated by ERK1-2 and AKT dependent early regulation of USF1, which directly induces Cdc2. To our knowledge, this is the first description of early target genes of progestin-activated classical PR via crosstalk with protein kinases and independently of hormone receptor binding to the genomic targets. PMID:24859236

Hemodynamic and metabolic effects of estrogen plus progestin therapy in hypertensive postmenopausal women treated with an ACE-inhibitor or a diuretic.

PubMed

Posadzy-Malaczynska, Anna; Rajpold, Katarzyna; Woznicka-Leskiewicz, Lucyna; Marcinkowska, Justyna

2015-01-01

The aim of the study was to assess the hemodynamic and metabolic actions of estrogen plus progestin therapy (EPT) in hypertensive, postmenopausal women treated with perindopril (ACEI) or hydrochlorothiazide (HCTZ). A group of normotensive postmenopausal women was also studied. 100 hypertensive and 40 normotensive postmenopausal women were recruited for the study. The hypertensive females were randomly assigned to receive ACEI or HCTZ for 12 months. The patients of the ACEI group and the patients of the HCTZ group, as well as normotensives, were further subdivided into two subgroups each. One subgroup received estrogen plus progestin therapy (EPT+), the other subgroup received no hormone replacement (EPT-). Combined hormone replacement with transdermal patches releasing 17β-estradiol and norethisterone was used. Office and 24-hour ambulatory blood pressure was measured at baseline and during follow-up. Renal plasma flow (RPF) was measured using the clearance of [125I]-iodohippuran. Pulse wave velocity (PWV) was determined with an automatic device. In normotensive postmenopausal women, transdermal estrogen plus progestin therapy increases RPF and insulin sensitivity, decreases PWV, decreases total and LDL cholesterol, and decreases uric acid serum levels. Perindopril (4 mg/day) and hydrochlorothiazide (25 mg/day) were equally effective in reducing blood pressure in postmenopausal, hypertensive subjects. In these females, perindopril increased RPF and decreased PWV and plasma insulin levels. These effects of the ACEI were not altered by estrogen plus progestin therapy. Hydrochlorothiazide decreased RPF and increased plasma insulin and uric acid concentrations in hypertensive subjects whom were not receiving estrogen plus progestin therapy. The unfavorable metabolic and hemodynamic actions of the diuretic were counteracted by estrogen plus progestin therapy. Concomitant estrogen plus progestin therapy may be a method to avoid unfavorable hemodynamic and metabolic effects of thiazide diuretics in hypertensive, postmenopausal women.

Several synthetic progestins disrupt the glial cell specific-brain aromatase expression in developing zebra fish

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cano-Nicolau, Joel

The effects of some progestins on fish reproduction have been recently reported revealing the hazard of this class of steroidal pharmaceuticals. However, their effects at the central nervous system level have been poorly studied until now. Notwithstanding, progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. Herein, we investigated the effects of a large set of synthetic ligands of the nuclear progesterone receptor on the glial-specific expression of the zebrafish brain aromatase (cyp19a1b) using zebrafish mechanism-based assays. Progesterone and 24 progestins were first screened on transgenic cyp19a1b-GFP zebrafish embryos. Wemore » showed that progesterone, dydrogesterone, drospirenone and all the progesterone-derived progestins had no effect on GFP expression. Conversely, all progestins derived from 19-nortesterone induced GFP in a concentration-dependent manner with EC{sub 50} ranging from the low nM range to hundreds nM. The 19-nortestosterone derived progestins levonorgestrel (LNG) and norethindrone (NET) were further tested in a radial glial cell context using U251-MG cells co-transfected with zebrafish ER subtypes (zfERα, zfERβ1 or zfERβ2) and cyp19a1b promoter linked to luciferase. Progesterone had no effect on luciferase activity while NET and LNG induced luciferase activity that was blocked by ICI 182,780. Zebrafish-ERs competition assays showed that NET and LNG were unable to bind to ERs, suggesting that the effects of these compounds on cyp19a1b require metabolic activation prior to elicit estrogenic activity. Overall, we demonstrate that 19-nortestosterone derived progestins elicit estrogenic activity by inducing cyp19a1b expression in radial glial cells. Given the crucial role of radial glial cells and neuro-estrogens in early development of brain, the consequences of exposure of fish to these compounds require further investigation. - Highlights: • P4 + 24 progestins were tested on embryonic brain aromatase expression in zebrafish. • 19 nor-testosterone derivatives induced cyp19a1b expression. • cyp19a1b up-regulation involved functional zfERs. • 19 nor-testosterone derivatives are pro-estrogenic compounds. • Effect of progestins should be further investigated at the brain level.« less

Progestins and breast cancer.

PubMed

Pasqualini, Jorge R

2007-10-01

Progestins exert their progestational activity by binding to the progesterone receptor (form A, the most active and form B, the less active) and may also interact with other steroid receptors (androgen, glucocorticoid, mineralocorticoid, estrogen). They can have important effects in other tissues besides the endometrium, including the breast, liver, bone and brain. The biological responses of progestins cover a very large domain: lipids, carbohydrates, proteins, water and electrolyte regulation, hemostasis, fibrinolysis, and cardiovascular and immunological systems. At present, more than 200 progestin compounds have been synthesized, but the biological response could be different from one to another depending on their structure, metabolism, receptor affinity, experimental conditions, target tissue or cell line, as well as the biological response considered. There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E(2)) from circulating precursors. Two principal pathways are implicated in the final steps of E(2) formation in breast cancer tissue: the 'aromatase pathway', which transforms androgens into estrogens, and the 'sulfatase pathway', which converts estrone sulfate (E(1)S) into estrone (E(1)) via estrone sulfatase. The final step is the conversion of weak E(1) to the potent biologically active E(2) via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. It has been demonstrated that various progestins (e.g. nomegestrol acetate, medrogestone, promegestone) as well as tibolone and their metabolites can block the enzymes involved in E(2) bioformation (sulfatase, 17beta-hydroxysteroid dehydrogenase) in breast cancer cells. These substances can also stimulate the sulfotransferase activity which converts estrogens into the biologically inactive sulfates. The action of progestins in breast cancer is very controversial; some studies indicate an increase in breast cancer incidence, others show no difference and still others a significant decrease. Progestin action can also be a function of combination with other molecules (e.g. estrogens). In order to clarify and better understand the response of progestins in breast cancer (incidence, mortality), as well as in hormone replacement therapy or endocrine dysfunction, new clinical trials are needed studying other progestins as a function of the dose and period of treatment.

Ovarian cycle of southern brown howler monkey (Alouatta guariba clamitans) through fecal progestin measurement.

PubMed

Silvestre, Thiago; Zanetti, Eveline S; Duarte, José M B; Barriento, Fernando G; Hirano, Zelinda M B; Souza, Júlio C; Passos, Fernando C

2017-01-01

The ovarian cycle in howler monkeys (genus Alouatta) has beean investigated through several biological parameters (ranging between 16.3 and 29.5 days); however, no data exist concerning the ovarian activity of the southern brown howler monkey (Alouatta guariba clamitans). This study aimed to describe the ovarian cycle of A. g. clamitans by profiling fecal progestin concentrations. Over 20 weeks, fecal samples of eight captive adult females of A. g. clamitans were collected. The collections were made at dawn, 5 days a week, and the samples were frozen immediately following collection. Next, they were dried, pulverized and hormonal metabolites were extracted to determine progestin concentrations by enzyme immunoassay. Of the 758 samples tested, the mean concentration of fecal progestins was 2866.40 ± 470.03 ng/g of dry feces, while the mean concentration at baseline was 814.47 ± 164.36 ng/g of dry feces. Among the eight females, one showed no ovarian cyclicity and three presented periods of probable absence of cyclicity and low progestin concentrations. A mean duration of 16 ± 0.52 days was observed for the 35 cycles studied. The interluteal phase lasted 4 ± 0.37 days on average, with a mean concentration of fecal progestins of 467.98 ± 29.12 ng/g of dry feces, while the luteal phase lasted 11 ± 0.50 days, with a mean concentration of 4283.27 ± 193.31 ng/g of dry feces. Besides describing the characteristics of the ovarian cycle, possible causes for the low concentrations of fecal progestins and periods of absence of cyclicity are also discussed.

Trace analysis of 61 natural and synthetic progestins in river water and sewage effluents by ultra-high performance liquid chromatography-tandem mass spectrometry.

PubMed

Shen, Xiaoyan; Chang, Hong; Sun, Dezhi; Wang, Linxia; Wu, Fengchang

2018-04-15

A broad number of natural and synthetic progestins are widely used in human and veterinary therapies. Although progestins exhibit adverse effects in aquatic organisms, information about environmental occurrence and fate have been limited to several compounds, hampering the accuracy of risk assessments of the compounds. In this study, a selective and sensitive analytical method was established to simultaneously determine 19 natural and 42 synthetic progestins in environmental waters, and the synthetic progestins included 19-nortestosterone, 17α-hydroxyprogesterone and progesterone derivatives. All of the target compounds were effectively separated using an HSS T3 column, and the recoveries for effluent and river samples were 80-115% and 75-105%, respectively. The detection limits for the 61 analytes were in the range of 0.05-0.60 ng/L and 0.03-0.40 ng/L for the effluent and river samples, respectively. The developed method is applied to analyze the target progestogens in sewage effluent and river water samples from Beijing. The detected concentrations of natural progesterone metabolites (3α-hydroxy-5β-tetrahydroprogesterone) were up to 63 times higher than those of the parent compound. Of the three groups of synthetic progestins, the progesterone derivatives were detected for the first time and had the highest concentrations followed by the 19-nortestosterone and 17α-hydroxyprogesterone derivatives. In contrast to previous studies, the predominant derivative compounds of 19-nortestosterone were found to be 19-nortestosterone, gestodene and mifepristone, and those of 17α-hydroxyprogesterone were 6-epi-medroxy progesterone 17-acetate and melengestrol acetate. The toxicities and environmental risk of these emerging progestins deserves more attention in the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role?

PubMed

Botteri, Edoardo; Støer, Nathalie C; Sakshaug, Solveig; Graff-Iversen, Sidsel; Vangen, Siri; Hofvind, Solveig; Ursin, Giske; Weiderpass, Elisabete

2017-11-01

The association between use of menopausal hormone therapy (HT) and occurrence of skin malignant melanoma (SMM) is controversial. We investigated the issue in a nationwide cohort of 684,696 Norwegian women, aged 45-79 years, followed from 2004 to 2008. The study was based on linkage between Norwegian population registries. Multivariable Poisson regression models were used to estimate the effect of HT use, different HT types, routes of administration and doses of estrogen and progestin on the risk of SMM. During the median follow-up of 4.8 years, 178,307 (26%) women used HT, and 1,476 incident SMM cases were identified. Current use of HT was associated with increased risk of SMM (rate ratios (RR) = 1.19; 95% confidence interval (CI) 1.03-1.37). Plain estrogen therapy was associated with an increased risk of SMM (RR 1.45; 95% CI 1.21-1.73), both for oral (RR 1.45; 95% CI 1.09-1.93) and vaginal (RR 1.44; 95% CI 1.14-1.84) formulations, while combined estrogen and progestin therapy (EPT) was not (RR 0.91; 95% CI 0.70-1.19). We performed a dose-response analysis of estrogen and progestin in women using tablets, and found that use of estrogens was associated with increased risk (RR 1.24; 95% CI 1.00-1.53 per 1 mg/day) and use of progestins with decreased risk (RR 0.71; 95% CI 0.57-0.89 per 10 mg/month) of SMM. In conclusion, estrogens were associated with increased risk of SMM, while combinations of estrogens and progestins were not. Our results suggest that estrogens and progestins might affect the risk of SMM in opposite ways. © 2017 UICC.

Birth control - slow release methods

MedlinePlus

Contraception - slow-release hormonal methods; Progestin implants; Progestin injections; Skin patch; Vaginal ring ... might want to consider a different birth control method. SKIN PATCH The skin patch is placed on ...

Cervical mucus and serum estradiol as predictors of response to progestin challenge.

PubMed

Rarick, L D; Shangold, M M; Ahmed, S W

1990-08-01

The present study was undertaken to assess the correlation between and relative predictive value of each of the following variables and progestin-induced withdrawal bleeding: cervical mucus appearance, serum E2 level, patient age, duration of amenorrhea, smoking and exercise habits, and body composition. Of 120 oligomenorrheic and amenorrheic women evaluated, only cervical mucus appearance and serum E2 level were significantly associated with response to progestin challenge. A multivariate logistical regression analysis showed cervical mucus to be the most predictive variable followed by serum E2 level. No absolute E2 level was found to discriminate between those who did and those who did not have withdrawal bleeding after progestin challenge. These data suggest that office examination of cervical mucus may be a useful indicator and guideline in planning therapy.

Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial.

PubMed

Zitzmann, M; Rohayem, J; Raidt, J; Kliesch, S; Kumar, N; Sitruk-Ware, R; Nieschlag, E

2017-05-01

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone ® (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 μg/day absorbed, NETA 5 mg/10 mg, LNG 120 μg/240 μg. From an andrology outpatient clinic, 56 healthy men aged 18-50 years, with body mass index ≤33 kg × m -2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception. © 2017 American Society of Andrology and European Academy of Andrology.

Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women

PubMed Central

Chlebowski, Rowan T.; Anderson, Garnet L.; Gass, Margery; Lane, Dorothy S.; Aragaki, Aaron K.; Kuller, Lewis H.; Manson, JoAnn E.; Stefanick, Marcia L.; Ockene, Judith; Sarto, Gloria E.; MD, Karen C. Johnson; Wactawski-Wende, Jean; Ravdin, Peter M.; Schenken, Robert; Hendrix, Susan L.; Rajkovic, Aleksandar; Rohan, Thomas E.; Yasmeen, Shagufta; Prentice, Ross L.

2016-01-01

Context In the Women's Health Initiative estrogen plus progestin trial, after mean (SD) intervention of 5.6 (1.3) years (range 3.7 to 8.6 years) and mean follow-up of 7.9 (1.4) years, breast cancer incidence was increased by combined hormone therapy. However, breast cancer mortality results have not been previously reported. Objective To determine estrogen plus progestin effects on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (2.7) years thru August 14, 2009. Design, Setting, and Participants 16,608 postmenopausal women, aged 50-79 years with no prior hysterectomy, were randomly assigned to combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo. After the original trial completion date (March 31, 2005) re-consent was required for continued follow-up for breast cancer incidence and was obtained in 83%. Main outcome measures Invasive breast cancer incidence and breast cancer mortality. Results In intent-to-treat analyses including all randomized participants, censoring those on March 31, 2005 not-consenting for additional follow-up, estrogen plus progestin increased invasive breast cancers compared with placebo (385 [0.42%/yr] vs 293 [0.34%/yr] cases; hazard ratio [HR] 1.25, 95% confidence interval (CI) 1.07-1.46; P=.004). The breast cancers in the estrogen plus progestin group were similar in histology and grade but were more likely to be node positive (81 [23.7%] vs 43 [16.2%], respectively; P=0.03). Deaths directly attributed to breast cancer were greater in the estrogen plus progestin group (25 [0.03%/yr] vs 12 [0.01%/yr] deaths; HR, 1.96; 95% CI 1.00-4.04, P=.049) as were deaths from all causes occurring after a breast cancer diagnosis (51 [0.05%/yr] vs 31 [0.03%/yr] deaths; HR 1.57, 95% CI 1.01-2.48; P=.045). Conclusions Estrogen plus progestin increases breast cancer incidence with cancers more commonly node positive. Breast cancer mortality also appears to be increased with combined estrogen plus progestin use. PMID:20959578

High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials.

PubMed

Maltoni, M; Nanni, O; Scarpi, E; Rossi, D; Serra, P; Amadori, D

2001-03-01

The aim of the present study was to summarise evidence from scientific studies on cancer anorexia-cachexia syndrome in order to assess and highlight the efficacy of high-dose progestins (megestrol acetate and medroxyprogesterone acetate) compared with placebo in patients with hormone-independent tumors. A systematic review of published randomised clinical trials was carried out by an extensive electronic and hand search through databases, relevant journals and books, congress, proceedings, reference lists, without any language or year of publication restriction. The research was conducted by two independent operators who collected the data in a form specifically designed for this review. Among the several possible outcomes, appetite and body weight were chosen. Fifteen randomised clinical trials (more than 2000 patients) were retrieved for the review. There was a statistically significant advantage for high-dose progestins as regards improved appetite: pooled odds ratio (OR) = 4.23, 95% confidence interval (CI): 2.53-7.04. Although the effect of high-dose progestins on body weight was less impressive, statistical significance was also reached for this outcome: pooled OR = 2.66, 95% CI: 1.80-3.92. Treatment morbidity was very low, due to the brief period of the treatment in most of the studies. The effects of high-dose progestins on appetite and body weight were clearly demonstrated. However, further studies are undoubtedly warranted to investigate other aspects of progestin activity, especially as regards dosage, duration and timing with best therapeutic index.

[Oral contraception and carbohydrate metabolism--the physiopathological explanation].

PubMed

Hilal, M

1985-12-01

On the basis of observation of the effects on glucose metabolism of estrogens and progestins administered alone or in combination, it is believed that deterioration of glucose tolerance in the 1st trimester of oral contraceptive (OC) use is due to the synthetic estrogen, while hyperinsulinism after the 6th month of use is due to the progestin component. Either the estrogen-induced deterioration of glucose tolerance or the progestin-induced insulin resistence may lead to poor glucose tolerance or diabetes in predisposed individuals. The early deterioration of glucose tolerance with synthetic estrogens is probably due to a direct action of estrogens on the pancreas, where specific estrogen receptors have been identified, but the regression of this effect has not been explained. The reduction of fasting glucose levels by synthetic estrogens is due to a reduction of glucogenolysis and of gluconeogenesis with an increase of hepatic gluconeogenesis. These 3 effects may be explained by the action of estrogens on insulin and glucagon: estrogens inhibit the secretion of glucagon induced by arginine, an effect not obtained by progestins. A daily injection of estradiol for 6 weeks in overiectomized rats results in a lowered level of insulin and glucagon with an elevated insulin/glucagon ratio in the portal vein; this results in a decline in gluconeogenesis with a particular decline in phospho-enol-pyruvate-carboxy-kinase activity. Progestins on the other hand augment insulin and glucagon secretion without modifying their ratio in the portal vein. Hyperinsulinism in the basal state and after stimulation is observed in women using combined OCs or progestins only, whether or not there is a deterioration of glucose tolerance. The effect appears after 3 months of use and continues as long as OCs are used. This hyperinsulinism is due to a hypersecretion and not to a diminution in degradation of insulin. The insulin/glucose ratio is elevated; the hypersecretion of insulin compensates for a lowered peripheral sensitivity to the hormone. Pill-induced insulin resistence is comparable to that of pregnancy. Although all progestins used in contraception induce insulin resistence with hyperinsulinism, the effect is more marked with 19 nortestosterone derivatives than with those of 17 alpha hydroxyprogesterone, because of the structural similarity of 19 norsteroids to anabolic androgens. 2 arguments suggest a potentialization of the effects of progestins by the estrogens in combined OCs: estrogens diminish the biliary flow and may therefore diminish progesterone secretion, and progestin catabolism is diminished by estrogens. Theories have been proposed to explain the diabetogenic effect of combined OCs through indirect mechanisms involving cortisol, growth hormone, or tryptophane metabolism.

Progestin treatment of atypical hyperplasia and well-differentiated adenocarcinoma of the endometrium to preserve fertility.

PubMed

Koskas, Martin; Azria, Elie; Walker, Francine; Luton, Dominique; Madelenat, Patrick; Yazbeck, Chadi

2012-03-01

To evaluate the outcome of a cohort of young women treated with progestin for fertility-sparing management of endometrial atypical hyperplasia (AH) and endometrial carcinoma (EC). This retrospective multicentre cohort study included women under the age of 40 years treated conservatively for AH and EC to preserve fertility using progestin for at least 3 months. Four inclusion criteria were defined: (i) the presence of AH or grade 1 EC confirmed by two pathologists (including a reference pathologist); (ii) the use of conservative management for fertility sparing; (iii) adequate radiological examination before conservative management; and (iv) a minimal follow-up time of one year. Twenty-two patients fulfilled the inclusion criteria (8 had EC, and 14 had AH). After progestin treatment, 17 patients responded. Among the 17 patients who experienced remission, three also experienced disease relapse. One patient initially diagnosed with AH experienced progression of her disease to stage IIIA EC. Ten pregnancies were achieved in eight patients. Fertility-sparing management using progestin offers the opportunity to fulfil maternal desires in young patients diagnosed with AH and EC. However, progression of the disease is possible and close follow-up is needed.

Reproductive responses in fathead minnow and Japanese medaka following exposure to a synthetic progestin, Norethindrone.

PubMed

Paulos, Peter; Runnalls, Tamsin J; Nallani, Gopi; La Point, Tom; Scott, Alexander P; Sumpter, John P; Huggett, Duane B

2010-08-15

Synthetic progestins, such as Norethindrone (NET), are common ingredients in oral contraceptives and in treatment for post-menopausal problems. Given the widespread use of oral contraceptives and post-menopausal treatments, several reports have targeted and identified progestins in aquatic environments. In fish, progestins play an important role in the stimulation of oocyte final maturation and ovulation in females, stimulation of spermiation and sperm motility in males, and the initiation of meiosis in both sexes. They also have a role as pheromones in some species. Given the pivotal role that progestins play in reproduction, their appreciable daily dose (i.e. microg to mg range in contraceptives and hormone replacement therapies) and continuous use pattern, it is important to understand the potential risk these compounds pose once discharged into the aquatic environment. Since little published data are available on this class of compounds, our research focused on the reproductive effects of NET on the fathead minnow and Japanese medaka. A 28 day static-renewal reproduction study with Japanese medaka indicated that NET produces a significant decrease in fecundity at aqueous concentrations >or=25 ng/L. A 21 day flow-though fathead minnow reproduction study also demonstrated that NET causes a significant decrease in fecundity in the low ng/L range. Fathead minnow morphological changes (i.e. female fin spots) suggest that NET exposure may have a potent androgenic effect on fish; however, plasma 11-Ketotestosterone (11-KT) concentrations were reduced in males at the highest exposure concentration. Collectively, these data indicate that further investigation of reproductive responses associated with synthetic progestins is warranted.

Uterine glands: development, function and experimental model systems

PubMed Central

Cooke, Paul S.; Spencer, Thomas E.; Bartol, Frank F.; Hayashi, Kanako

2013-01-01

Development of uterine glands (adenogenesis) in mammals typically begins during the early post-natal period and involves budding of nascent glands from the luminal epithelium and extensive cell proliferation in these structures as they grow into the surrounding stroma, elongate and mature. Uterine glands are essential for pregnancy, as demonstrated by the infertility that results from inhibiting the development of these glands through gene mutation or epigenetic strategies. Several genes, including forkhead box A2, beta-catenin and members of the Wnt and Hox gene families, are implicated in uterine gland development. Progestins inhibit uterine epithelial proliferation, and this has been employed as a strategy to develop a model in which progestin treatment of ewes for 8 weeks from birth produces infertile adults lacking uterine glands. More recently, mouse models have been developed in which neonatal progestin treatment was used to permanently inhibit adenogenesis and adult fertility. These studies revealed a narrow and well-defined window in which progestin treatments induced permanent infertility by impairing neonatal gland development and establishing endometrial changes that result in implantation defects. These model systems are being utilized to better understand the molecular mechanisms underlying uterine adenogenesis and endometrial function. The ability of neonatal progestin treatment in sheep and mice to produce infertility suggests that an approach of this kind may provide a contraceptive strategy with application in other species. Recent studies have defined the temporal patterns of adenogenesis in uteri of neonatal and juvenile dogs and work is underway to determine whether neonatal progestin or other steroid hormone treatments might be a viable contraceptive approach in this species. PMID:23619340

The preclinical biology of a new potent and selective progestin: trimegestone.

PubMed

Winneker, Richard C; Bitran, Daniel; Zhang, Zhiming

2003-11-01

Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.

Estrogen plus Progestin and Risk of Benign Proliferative Breast Disease

PubMed Central

Rohan, Thomas E; Negassa, Abdissa; Chlebowski, Rowan T; Lasser, Norman L.; McTiernan, Anne; Schenken, Robert S.; Ginsberg, Mindy; Wassertheil-Smoller, Sylvia; Page, David L.

2008-01-01

Women with benign proliferative breast disease are at increased risk of subsequent breast cancer. Estrogens and progesterone exert proliferative effects on mammary epithelium and combined hormone replacement therapy has been associated with increased breast cancer risk. We tested the effect of conjugated equine estrogen plus progestin on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. In the WHI trial of estrogen plus progestin, 16608 postmenopausal women were randomly assigned either to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate or to placebo. Baseline and annual breast exams and mammograms were required. The trial was terminated early (average follow-up, 5.5 years). We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. Overall, 178 incident cases of benign proliferative breast disease were ascertained in the estrogen plus progestin group and 99 in the placebo group. Use of estrogen plus progestin was associated with a 74% increase in risk of benign proliferative breast disease (hazard ratio 1.74, 95% CI 1.35-2.25). For benign proliferative breast disease without atypia the hazard ratio was 2.00 (95% CI 1.50-2.66), while for atypical hyperplasia it was 0.76 (95% CI 0.38-1.52). Risk varied little by levels of baseline characteristics. The results of this study suggest that use of estrogen plus progestin may increase the risk of benign proliferative breast disease. PMID:18725513

ESC expert statement on the effects on mood of the natural cycle and progestin-only contraceptives.

PubMed

Merki-Feld, G S; Apter, D; Bartfai, G; Grandi, G; Haldre, K; Lech, M; Lertxundi, R; Lete, I; Lobo Abascal, P; Raine, S; Roumen, F; Serfaty, D; Shulman, L P; Skouby, S; Bitzer, J

2017-08-01

Hormonal fluctuations during the natural cycle, as well as progestins used for hormonal contraception, can exert effects on mood especially in vulnerable women. Negative effects of levonorgestrel-releasing intrauterine contraception on mood are rare.

A comparison of progestins within three classes: Differential effects on learning and memory in the aging surgically menopausal rat.

PubMed

Braden, B Blair; Andrews, Madeline G; Acosta, Jazmin I; Mennenga, Sarah E; Lavery, Courtney; Bimonte-Nelson, Heather A

2017-03-30

For decades, progestins have been included in hormone therapies (HT) prescribed to women to offset the risk of unopposed estrogen-induced endometrial hyperplasia. However, the potential effects on cognition of subcategories of clinically used progestins have been largely unexplored. In two studies, the present investigation evaluated the cognitive effects of norethindrone acetate (NETA), levonorgestrel (LEVO), and medroxyprogesterone acetate (MPA) on the water radial-arm maze (WRAM) and Morris water maze (MM) in middle-aged ovariectomized rats. In Study 1, six-weeks of a high-dose NETA treatment impaired learning and delayed retention on the WRAM, and impaired reference memory on the MM. Low-dose NETA treatment impaired delayed retention on the WRAM. In Study 2, high-dose NETA treatment was reduced to four-weeks and compared to MPA and LEVO. As previously shown, MPA impaired working memory performance during the lattermost portion of testing, at the highest working memory load, impaired delayed retention on the WRAM, and impaired reference memory on the MM. NETA also impaired performance on these WRAM and MM measures. Interestingly, LEVO did not impair performance, but instead enhanced learning on the WRAM. The current study corroborates previous evidence that the most commonly prescribed FDA-approved progestin for HT, MPA, impairs learning and memory in the ovariectomized middle-aged rat. When progestins from two different additional subcategories were investigated, NETA impaired learning and memory similarly to MPA, but LEVO enhanced learning. Future research is warranted to determine LEVO's potential as an ideal progestin for optimal health in women, including for cognition. Copyright © 2016 Elsevier B.V. All rights reserved.

Rapid Steroid Hormone Actions Initiated at the Cell Surface and the Receptors that Mediate Them with an Emphasis on Recent Progress in Fish Models

PubMed Central

Thomas, Peter

2011-01-01

In addition to the classic genomic mechanism of steroid action mediated by activation of intracellular nuclear receptors, there is now extensive evidence that steroids also activate receptors on the cell surface to initiate rapid intracellular signaling and biological responses that are often nongenomic. Recent progress in our understanding of rapid, cell surface-initiated actions of estrogens, progestins, androgens and corticosteroids and the identities of the membrane receptors that act as their intermediaries is briefly reviewed with a special emphasis on studies in teleost fish. Two recently discovered novel proteins with seven-transmembrane domains, G protein-coupled receptor 30 (GPR30), and membrane progestin receptors (mPRs) have the ligand binding and signaling characteristics of estrogen and progestin membrane receptors, respectively, but their functional significance is disputed by some researchers. GPR30 is expressed on the cell surface of fish oocytes and mediates estrogen inhibition of oocyte maturation. mPRα is also expressed on the oocyte cell surface and is the intermediary in progestin induction of oocyte maturation in fish. Recent results suggest there is cross-talk between these two hormonal pathways and that there is reciprocal down-regulation of GPR30 and mPRα expression by estrogens and progestins at different phases of oocyte development to regulate the onset of oocyte maturation. There is also evidence in fish that mPRs are involved in progestin induction of sperm hypermotility and anti-apoptotic actions in ovarian follicle cells. Nonclassical androgen and corticosteroid actions have also been described in fish models but the membrane receptors mediating these actions have not been identified. PMID:22154643

Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body Composition and Bone Metabolism.

PubMed

Tack, Lloyd J W; Craen, Margarita; Lapauw, Bruno; Goemaere, Stefan; Toye, Kaatje; Kaufman, Jean-Marc; Vandewalle, Sara; T'Sjoen, Guy; Zmierczak, Hans-Georg; Cools, Martine

2018-06-01

Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth. To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively. Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones. Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [-2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: -0.765 to -1.145 (P = 0.002)]. L did not affect physiological bone development. Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy.

Apigenin prevents development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats

PubMed Central

Mafuvadze, Benford; Benakanakere, Indira; Lopez, Franklin; Besch-Williford, Cynthia; Ellersieck, Mark R.; Hyder, Salman M.

2011-01-01

The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins. PMID:21505181

Postmenopausal estrogen and progestin effects on the serum proteome

PubMed Central

2009-01-01

Background Women's Health Initiative randomized trials of postmenopausal hormone therapy reported intervention effects on several clinical outcomes, with some important differences between estrogen alone and estrogen plus progestin. The biologic mechanisms underlying these effects, and these differences, have yet to be fully elucidated. Methods Baseline serum samples were compared with samples drawn 1 year later for 50 women assigned to active hormone therapy in both the estrogen-plus-progestin and estrogen-alone randomized trials, by applying an in-depth proteomic discovery platform to serum pools from 10 women per pool. Results In total, 378 proteins were quantified in two or more of the 10 pooled serum comparisons, by using strict identification criteria. Of these, 169 (44.7%) showed evidence (nominal P < 0.05) of change in concentration between baseline and 1 year for one or both of estrogen-plus-progestin and estrogen-alone groups. Quantitative changes were highly correlated between the two hormone-therapy preparations. A total of 98 proteins had false discovery rates < 0.05 for change with estrogen plus progestin, compared with 94 for estrogen alone. Of these, 84 had false discovery rates <0.05 for both preparations. The observed changes included multiple proteins relevant to coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors, and osteogenesis. Evidence of differential changes also was noted between the hormone preparations, with the strongest evidence in growth factor and inflammation pathways. Conclusions Serum proteomic analyses yielded a large number of proteins similarly affected by estrogen plus progestin and by estrogen alone and identified some proteins and pathways that appear to be differentially affected between the two hormone preparations; this may explain their distinct clinical effects. PMID:20034393

Effects of Norethindrone and Levonorgestrel on Reproductive Parameters in a Marine Fish

EPA Science Inventory

Progestins and other hormones are continuously added to surface and ground waters through waste water treatment plant (WWTP) effluent in concentrations of low to hundreds of ng/L (Orlando and Ellestad 2014). The exposure effects of pharmaceutical progestins from oral contraceptiv...

Clinical experience with trimegestone as a new progestin in HRT.

PubMed

Grubb, Gary; Spielmann, Daniele; Pickar, James; Constantine, Ginger

2003-11-01

Trimegestone (TMG) is a novel, 19-norpregnane progestin, which demonstrates endometrial selectivity with a reduced progestin-related side effect profile when compared to several other currently marketed progestins. TMG has been studied in combination with 17beta-estradiol (17beta-E2) and conjugated equine estrogens (CEE). TMG-containing HRT agents were effective in relieving vasomotor symptoms and providing protection from endometrial hyperplasia with < or =1% hyperplasia. In clinical trials with sequential regimens, TMG provided predictable withdrawal bleeding associated with a low incidence of irregular and prolonged bleeding. Clinical studies of continuous combined regimens of estrogen/TMG combinations demonstrated high levels of amenorrhea. Both 17beta-E2 and CEE/TMG combinations have shown improved bone mineral density and quality-of-life assessments. Both continuous combined and sequential regimens of 17beta-E2/TMG and CEE/TMG have a favorable clinical profile. TMG provides an important new option for the treatment of postmenopausal symptoms and the prevention of osteoporosis.

Change to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunction.

PubMed

Davis, Susan R; Bitzer, Johannes; Giraldi, Annamaria; Palacios, Santiago; Parke, Susanne; Serrani, Marco; Mellinger, Uwe; Nappi, Rossella E

2013-12-01

It is a commonly held belief that combined oral contraceptive (COC) pills containing an androgenic progestin may be less likely to impair sexual function than COCs containing an anti-androgenic progestin. The study aims to compare the effects of a COC containing a progestin with an anti-androgenic profile (estradiol valerate [E2 V]/dienogest [DNG]) to that of one with an androgenic progestin (ethinyl estradiol [EE]/levonorgestrel [LNG]) on sexual function in women with COC-associated sexual dysfunction. In this multicenter, randomized, double-blind, noninferiority study, women with COC-associated female sexual dysfunction (FSD) were randomized to E2 V/DNG or EE/LNG for six cycles. The primary outcome was the change in the sum of Female Sexual Function Index (FSFI) desire and arousal component scores between baseline and cycle 6. Secondary outcome measures included changes to the FSFI domains, the Female Sexual Distress Scale (FSDS-R), Vaginal Health Assessment, the Atrophy Symptom Questionnaire, and the Psychological General Well Being Index over six treatment cycles. The main outcome is the change in the sum of FSFI desire and arousal component scores between baseline and cycle 6. Of 276 women screened, 213 received treatment and 191 completed the study. The mean increase in the sum of FSFI desire and arousal component scores was 5.90 (standard deviation [SD] 5.45) for E2 V/DNG and 5.79 (SD 6.17) for EE/LNG (change from baseline P < 0.0001, both groups). Both treatments showed equal efficacy and were associated with improvements in all domains of the FSFI, with no between-group differences. Both COCs reduced the distress associated with FSD, as indicated by reduced FSDS-R scores. In women with COC-associated FSD, switching to either E2 V/DNG or EE/LNG was associated with equivalent improvements in symptoms, challenging the perception that COCs containing anti-androgenic progestins have a detrimental effect on sexual function relative to those containing androgenic progestins. © 2013 International Society for Sexual Medicine.

Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.

PubMed

Chlebowski, Rowan T; Anderson, Garnet L; Gass, Margery; Lane, Dorothy S; Aragaki, Aaron K; Kuller, Lewis H; Manson, JoAnn E; Stefanick, Marcia L; Ockene, Judith; Sarto, Gloria E; Johnson, Karen C; Wactawski-Wende, Jean; Ravdin, Peter M; Schenken, Robert; Hendrix, Susan L; Rajkovic, Aleksandar; Rohan, Thomas E; Yasmeen, Shagufta; Prentice, Ross L

2010-10-20

In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants. Invasive breast cancer incidence and breast cancer mortality. In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. clinicaltrials.gov Identifier: NCT00000611.

Comparison of estrus synchronization by controlled internal drug release device (CIDR) and adhesive transdermal progestin patch in postpartum beef cows.

PubMed

Kajaysri, Jatuporn; Chumchoung, Chaiwat; Wutthiwitthayaphong, Supphathat; Suthikrai, Wanvipa; Sangkamanee, Praphai

2017-09-15

Estrous synchronization with progesterone based protocols has been essentially used in cattle industry. Although intravaginal devices have been commonly used, this technique may induce vaginitis. This study aimed at examining the efficiency of novel transdermal progestin patch on follicle development and comparing the progestin patch versus CIDR device on estrous synchronization, complication at treated site and pregnancy in beef cattle. In experiment 1, seven beef cows were treated with an adhesive transdermal progestin patch on the ventral surface of the proximal part of the tail for 7 days. The cows were daily examined the follicular development using ultrasonography starting on Day 0 till 3 days after hormone removal. Experiment 2, forty beef cows were divided into two equal groups (20 cows per group). The cows randomly allocated to received either vaginal insertion of CIDR (n = 20) or treated with an adhesive transdermal progestin patch (n = 20). The levels of plasma progesterone during the experiment and the numbers of standing estrous cows were recorded. Timed artificial inseminated (TAI) was performed at 60 h after CIDR or patch termination. Pregnancy rates were determined at 60 days after TAI. Experiment 1 revealed that the novel transdermal progestin patch could efficiently control follicular growth. All the seven treated cows had dominant follicle upon dermal patch removal indicating the effectiveness of the progestin patch. In experiment 2, the percentages of cows exhibited standing estrus were similar between transdermal patch (72.22%) and CIDR (70.00%). The levels of plasma progesterone during CIDR treatment were significantly higher (4.06 ± 1.65 ng/mL on Day 1 and 3.62 ± 1.60 ng/mL on Day 7) compared with transdermal patch (2.60 ± 1.43 ng/mL on Day 1 and 1.81 ± 1.57 ng/mL on Day 7). Three cows treated with CIDR (15%) developed vaginitis while none of cows had physically dermal reaction at adhesive site. Cows synchronized with these two protocols had similar pregnancy rates (50.00%) following fixed time artificial insemination. It is concluded that transdermal progestin patch was equally effective in estrus synchronization as compared with traditional CIDR. However, the transdermal patch demonstrated less complication. This device should therefore be considered as an alternative method for estrus synchronization in postpartum beef cattle. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of progestin vs. combined oral contraceptive pills on lactation: A double-blind randomized controlled trial

PubMed Central

Espey, Eve; Ogburn, Tony; Leeman, Larry; Singh, Rameet; Schrader, Ronald

2013-01-01

Objective To estimate the effect of progestin-only vs. combined hormonal contraceptive pills on rates of breastfeeding continuation in postpartum women. Secondary outcomes include infant growth parameters, contraceptive method continuation and patient satisfaction with breastfeeding and contraceptive method. Methods In this randomized controlled trial, postpartum breastfeeding women who desired oral contraceptives were assigned to progestin-only vs. combined hormonal contraceptive pills. At two and eight weeks postpartum, participants completed in-person questionnaires that assessed breastfeeding continuation and contraceptive use. Infant growth parameters including weight, length and head circumference were assessed at eight weeks postpartum. Telephone questionnaires assessing breastfeeding, contraceptive continuation and satisfaction were completed at 3-7 weeks and 4 and 6 months. Breastfeeding continuation was compared between groups using Cox proportional hazards regression. Differences in baseline demographic characteristics and in variables between the two intervention groups were compared using chi-square tests, Fisher’s Exact test, or two-sample t-tests as appropriate. Results Breastfeeding continuation rates, contraceptive continuation, and infant growth parameters did not differ between users of progestin-only and combined hormonal contraceptive pills. Infant formula supplementation and maternal perception of inadequate milk supply were associated with decreased rates of breastfeeding in both groups. Conclusions Choice of combined or progestin-only birth control pills administered two weeks postpartum did not adversely affect breastfeeding continuation. PMID:22143258

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martel, Peter M.; Norris Cotton Cancer Center, Dartmouth Medical School; Bingham, Chad M.

Most breast cancers exhibit brisk lipogenesis, and require it for growth. S14 is a lipogenesis-related nuclear protein that is overexpressed in most breast cancers. Sterol response element-binding protein-1c (SREBP-1c) is required for induction of lipogenesis-related genes, including S14 and fatty acid synthase (FAS), in hepatocytes, and correlation of SREBP-1c and FAS expression suggested that SREBP-1c drives lipogenesis in tumors as well. We directly tested the hypothesis that SREBP-1c drives S14 expression and mediates lipogenic effects of progestin in T47D breast cancer cells. Dominant-negative SREBP-1c inhibited induction of S14 and FAS mRNAs by progestin, while active SREBP-1c induced without hormone andmore » superinduced in its presence. Changes in S14 mRNA were reflected in protein levels. A lag time and lack of progestin response elements indicated that S14 and FAS gene activation by progestin is indirect. Knockdown of S14 reduced, whereas overexpression stimulated, T47D cell growth, while nonlipogenic MCF10a mammary epithelial cells were not growth-inhibited. These data directly demonstrate that SREBP-1c drives S14 gene expression in breast cancer cells, and progestin magnifies that effect via an indirect mechanism. This supports the prediction, based on S14 gene amplification and overexpression in breast tumors, that S14 augments breast cancer cell growth and survival.« less

[Customization of hormonal contraception].

PubMed

DE Leo, Vincenzo; Cianci, Antonio; DI Carlo, Costantino; Cappelli, Valentina; Fruzzetti, Franca

2018-02-01

In the last few years new oral contraceptives have been marketed showing a better safety profile for women. They are the result of important changes made to the old compounds. As far as the estrogenic component, with the aim of decreasing side effects, the dose of ethinyl estradiol has been reduced and synthetic estrogens have been replaced by natural estradiol, further improving the safety profile. Also the progestin component in the last years has been changed in terms of dose, endocrine and metabolic characteristics. Levonorgestrel is an androgenic progestin, but now there is the possibility of choosing progestins without androgenic effect (gestodene and desogestrel) or progestins with antiandrogenic effect (cyproterone acetate, dienogest, drospirenone, chlormadinone acetate), very useful in patients with hyperandrogenism. Some of these progestins, like Drospirenone, represented the real held contributing, because of its antimineralcorticoid action, to reduce an important side effect like fluid retention; moreover there is the possibility to choose products with high progestogen effect on endometrium (dienogest, nomegestrole acetate), resulting very effective in women with abnormal uterine bleedings. Also the regimens of administration have been changed, by shortening or eliminating the tablet-free period; in this way the women may avoid premenstrual symptoms. The oral is not the only route of administration, but today there are alternative routes like transdermal, transvaginal, intrauterine and subcutaneous, reducing gastro-intestinal interferences and possible mistakes in pill intake.

Progesterone-Based Contraceptives Reduce Adaptive Immune Responses and Protection against Sequential Influenza A Virus Infections.

PubMed

Hall, Olivia J; Nachbagauer, Raffael; Vermillion, Meghan S; Fink, Ashley L; Phuong, Vanessa; Krammer, Florian; Klein, Sabra L

2017-04-15

In addition to their intended use, progesterone (P4)-based contraceptives promote anti-inflammatory immune responses, yet their effects on the outcome of infectious diseases, including influenza A virus (IAV) infection, are rarely evaluated. To evaluate their impact on immune responses to sequential IAV infections, adult female mice were treated with placebo or one of two progestins, P4 or levonorgestrel (LNG), and infected with a mouse-adapted H1N1 (maH1N1) virus. Treatment with P4 or LNG reduced morbidity but had no effect on pulmonary virus titers during primary H1N1 infection compared to placebo treatment. In serum and bronchoalveolar lavage fluid, total anti-IAV IgG and IgA titers and virus-neutralizing antibody titers but not hemagglutinin stalk antibody titers were lower in progestin-treated mice than placebo-treated mice. Females were challenged 6 weeks later with either an maH1N1 drift variant (maH1N1dv) or maH3N2 IAV. The level of protection following infection with the maH1N1dv was similar among all groups. In contrast, following challenge with maH3N2, progestin treatment reduced survival as well as the numbers and activity of H1N1- and H3N2-specific memory CD8 + T cells, including tissue-resident cells, compared with placebo treatment. In contrast to primary IAV infection, progestin treatment increased the titers of neutralizing and IgG antibodies against both challenge viruses compared with those achieved with placebo treatment. While the immunomodulatory properties of progestins protected immunologically naive female mice from the severe outcomes from IAV infection, it made them more susceptible to secondary challenge with a heterologous IAV, despite improving their antibody responses against a secondary IAV infection. Taken together, the immunomodulatory effects of progestins differentially regulate the outcome of infection depending on exposure history. IMPORTANCE The impact of hormone-based contraceptives on the outcome of infectious diseases outside the reproductive tract is rarely considered. Using a mouse model, we have made the novel observation that treatment with either progesterone or a synthetic analog found in hormonal contraceptives, levonorgestrel, impacts sequential influenza A virus infection by modulating antibody responses and decreasing the numbers and activity of memory CD8 + T cells. Progestins reduced the antibody responses during primary H1N1 virus infection but increased antibody titers following a sequential infection with either an H1N1 drift variant or an H3N2 virus. Following challenge with an H3N2 virus, female mice treated with progestins experienced greater mortality with increased pulmonary inflammation and reduced numbers and activity of CD8 + T cells. This study suggests that progestins significantly affect adaptive immune responses to influenza A virus infection, with their effect on the outcome of infection depending on exposure history. Copyright © 2017 American Society for Microbiology.

Differential effects of estrogen and progestin on apolipoprotein B100 and B48 kinetics in postmenopausal women

USDA-ARS?s Scientific Manuscript database

The distinct effects of the estrogen and progestin components of hormonal therapy on the metabolism of apolipoprotein (apo) B-containing lipoproteins have not been studied. We enrolled eight healthy postmenopausal women in a placebo-controlled, randomized, double-blind, crossover study. Each subject...

Biological characterization of non-steroidal progestins from botanicals used for women’s health

PubMed Central

Toh, MF; Sohn, J; Chen, SN; Yao, P; Bolton, JL; Burdette, JE

2012-01-01

Progesterone plays a central role in women’s reproductive health. Synthetic progestins, such as medroxyprogesterone acetate (MPA) are often used in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Although MPA is clinically effective, it also promiscuously binds to androgen and glucocorticoid receptors (AR/GR) leading to many undesirable side effects including cardiovascular diseases and breast cancers. Therefore, identifying alternative progestins is clinically significant. The purpose of this study was to biologically characterize non-steroidal progestins from botanicals by investigating their interaction and activation of progesterone receptor (PR). Eight botanicals commonly used to alleviate menopausal symptoms were investigated to determine if they contain progestins using a progesterone responsive element (PRE) luciferase reporter assay and a PR polarization competitive binding assay. Red clover extract stimulated PRE-luciferase and bound to PR. A library of purified compounds previously isolated from red clover was screened using the luciferase reporter assay. Kaempferol identified in red clover and a structurally similar flavonoid, apigenin, bound to PR and induced progestegenic activity and P4 regulated genes in breast epithelial cells and human endometrial stromal cells (HESC). Kaempferol and apigenin demonstrated higher progestegenic potency in the HESC compared to breast epithelial cells. Furthermore, phytoprogestins were able to activate P4 signaling in breast epithelial cells without downregulating PR expression. These data suggest that botanical extracts used for women’s health may contain compounds capable of activating progesterone receptor signaling. PMID:22484153

Effects of synthetic gestagens on fish reproduction.

PubMed

Zeilinger, Jana; Steger-Hartmann, Thomas; Maser, Edmund; Goller, Stephan; Vonk, Richardus; Länge, Reinhard

2009-12-01

Although it is well known that estrogenic steroidal hormones are able to affect the sexual development and reproduction of fish at low concentrations, no data on environmental effects of the class of progestogenic hormones are available yet. Synthetic gestagens (progestins) are a component in oral contraceptives. Upon their use, a fraction of the progestins will be excreted via urine into the aquatic environment. On the basis of their pharmacological action in mammals, it is supposed that fish reproduction is the most sensitive endpoint for the progestin treatment. In order to test this assumption, the effects of two progestins currently marketed in contraceptive formulations, levonorgestrel (LNG) and drospirenone (DRSP), were investigated in adult fathead minnows (Pimephales promelas) following an Organization for Economic Cooperation and Development 21-d fish reproduction screening assay draft protocol with additional end points. Levonorgestrel was tested at measured concentrations of 0.8, 3.3, and 29.6 ng/L, and DRSP at concentrations of 0.66, 6.5, and 70 microg/L. Both tested progestins caused an inhibition of reproduction. For LNG, this occurred at concentrations of >or=0.8 ng/L, no no-observed-effect concentration (NOEC) could be defined. Higher concentrations resulted in masculinization of females with de novo synthesis of nuptial tubercles. Drospirenone treatment, however, affected the reproductive success of fathead minnow at concentrations of 6.5 microg/L and higher with a clear dose-response relationship and a NOEC of 0.66 microg/L, which is above environmentally relevant concentrations.

Progestin Exposure Before Gonadotropin Stimulation Improves Embryo Development after In Vitro Fertilization in the Domestic Cat1

PubMed Central

Pelican, Katharine M.; Spindler, Rebecca E.; Pukazhenthi, Budhan S.; Wildt, David E.; Ottinger, Mary A.; Howard, JoGayle

2010-01-01

This study investigated the influence of progestin priming and ovarian quiescence on response to exogenous gonadotropin stimulation in the cat. Because a subpopulation of cats routinely ovulated spontaneously, there also was the opportunity to examine the ovary's reaction to the added impact of endogenously secreted progestagen. Queens were given 1) equine chorionic gonadotropin (eCG) plus human chorionic gonadotropin (hCG) only (control; n = 9 cats), 2) GnRH antagonist (antide) injections followed by eCG and hCG (n = 9), and 3) a progestin implant (levonorgestrel) followed by eCG and hCG (n = 9). Laparoscopy was used to assess ovarian activity and aspirate follicular oocytes that were graded on the basis of morphology. In five cats per treatment, half of the high-quality oocytes were assessed for glucose, pyruvate, and lactate metabolism as well as nuclear maturation. Remaining oocytes were inseminated in vitro, cultured, and examined at 72 h after insemination for cleavage. In the remaining four cats per treatment, all oocytes were inseminated in vitro and assessed at 72, 120, and 168 h after insemination for embryo developmental stage. Cats pretreated with progestin had more follicles and produced more embryos per donor (including at the combined morula/blastocyst stage) than controls or females treated with GnRH antagonist (P < 0.05). There were no differences among groups (P > 0.05) in oocyte carbohydrate metabolism, nuclear maturation metrics, or fertilization success, although there was a tendency toward improvements in all three (P < 0.2) in progestin-treated females. Interestingly, cats that spontaneously ovulated within 60 days of treatment onset also produced more embryos per cat than induced-ovulation counterparts (P < 0.05). Results indicate that prior exposure to exogenous progestin (via implant) or endogenous progestagen (via spontaneous ovulation) improves ovarian responsiveness to gonadotropins in the cat through a mechanism that is independent of the induction of ovarian quiescence. PMID:20463355

Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells

PubMed Central

Swarbrick, Alexander; Lee, Christine S. L.; Sutherland, Robert L.; Musgrove, Elizabeth A.

2000-01-01

The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G1 cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27Kip1 among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27Kip1 and few were bound to p21Cip1. In vitro, recombinant His6-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His6-p27 in vitro or p27Kip1 in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18INK4c and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18INK4c led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27Kip1 and p18INK4c cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor β and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation. PMID:10713180

Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome.

PubMed

Lu, Karen H; Loose, David S; Yates, Melinda S; Nogueras-Gonzalez, Graciela M; Munsell, Mark F; Chen, Lee-May; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M; Broaddus, Russell R

2013-08-01

Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population.

Prospective, Multi-center Randomized Intermediate Biomarker Study of Oral Contraceptive vs. Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome

PubMed Central

Lu, Karen H.; Loose, David S.; Yates, Melinda S.; Nogueras-Gonzalez, Graciela M.; Munsell, Mark F.; Chen, Lee-may; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S.; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M.; Broaddus, Russell R.

2013-01-01

Women with Lynch syndrome have a 40–60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have demonstrated that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown if they are effective in women with Lynch syndrome. Asymptomatic women age 25–50 with Lynch syndrome were randomized to receive the progestin compounds depo-Provera (depoMPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were performed before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depoMPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results demonstrate that women with Lynch syndrome do show an endometrial response to short term exogenous progestins, suggesting that OCP and depoMPA may be reasonable chemopreventive agents in this high-risk patient population. PMID:23639481

Hormonal induction of transfected genes depends on DNA topology.

PubMed Central

Piña, B; Haché, R J; Arnemann, J; Chalepakis, G; Slater, E P; Beato, M

1990-01-01

Plasmids containing the hormone regulatory element of mouse mammary tumor virus linked to the thymidine kinase promoter of herpes simplex virus and the reporter gene chloramphenicol acetyltransferase of Escherichia coli respond to glucocorticoids and progestins when transfected into appropriate cells. In the human mammary tumor cell line T47D, the response to progestins, but not to glucocorticoids, is highly dependent on the topology of the transfected DNA. Although negatively supercoiled plasmids respond optimally to the synthetic progestin R5020, their linearized counterparts exhibit markedly reduced progestin inducibility. This is not due to changes in the efficiency of DNA transfection, since the amount of DNA incorporated into the cell nucleus is not significantly dependent on the initial topology of the plasmids. In contrast, cotransfection experiments with glucocorticoid receptor cDNA in the same cell line show no significant influence of DNA topology on induction by dexamethasone. A similar result was obtained with fibroblasts that contain endogenous glucocorticoid receptors. When the distance between receptor-binding sites or between the binding sites and the promoter was increased, the dependence of progestin induction on DNA topology was more pronounced. In contrast to the original plasmid, these constructs also revealed a similar topological dependence for induction by glucocorticoids. The differential influence of DNA topology is not due to differences in the affinity of the two hormone receptors for DNA of various topologies, but probably reflects an influence of DNA topology on the interaction between different DNA-bound receptor molecules and between receptors and other transcription factors. Images PMID:2153920

Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study.

PubMed

Squadrito, Francesco; Altavilla, Domenica; Crisafulli, Alessandra; Saitta, Antonino; Cucinotta, Domenico; Morabito, Nunziata; D'Anna, Rosario; Corrado, Francesco; Ruggeri, Pietro; Frisina, Nicola; Squadrito, Giovanni

2003-04-15

Genistein, a phytoestrogen found in soybeans, corrects endothelial dysfunction induced by oophorectomy in animals. Using a double-blind, controlled, randomized design, we evaluated its effects on endothelial function in women. We enrolled 79 healthy postmenopausal women (mean [+/- SD] age, 56 +/- 4 years) and randomly assigned them to receive continuous estrogen/progestin therapy (n = 26; 17beta-estradiol [1 mg/d] combined with norethisterone acetate [0.5 mg/d]), genistein (n = 27; 54 mg/d), or placebo (n = 26). Brachial artery flow-mediated, endothelium-dependent vasodilation and plasma levels of nitrites/nitrates (a marker of nitric oxide metabolism) and endothelin-1 were measured at baseline and after 1 year of therapy. Treatment with genistein increased levels of nitrites/nitrates (mean increase, 21 micromol/L; 95% confidence interval [CI]: 15 to 26 micromol/L; P <0.001 vs. placebo); estrogen/progestin therapy caused similar changes (P <0.001 vs. placebo). Plasma endothelin-1 levels decreased following 12 months of genistein (mean decrease, 7 pg/mL; 95% CI: 3 to 10 pg/mL; P <0.001 vs. placebo) and after 12 months of estrogen/progestin (P <0.001 vs. placebo). When compared with placebo, brachial artery flow-mediated dilation was improved by genistein (mean increase, 5.5%; 95% CI: 3.9% to 7.0%; P <0.001) and by estrogen/progestin (P <0.001). There were no significant differences between estrogen and genistein for any of these parameters (all P >0.4). One year of genistein therapy improves endothelium function in postmenopausal women to a similar extent as does an estrogen/progestin regimen.

Effects of progestational agents on serum lipids and lipoproteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauss, R.M.

1982-08-01

Though progestins with relatively strong androgenic or antiestrogenic effects (e.g., levonorgestrel and norethindrone acetate) tend to have the greatest capacity to offset the major estrogen effects (e.g., on serum triglyceride and, to a greater extent, HDL-cholesterol), this association is not sufficiently strong to allow prediction of the effects of other progestins on lipid and lipoprotein metabolism.

Progestin-based contraceptive on the same day as medical abortion.

PubMed

Park, Jeanna; Robinson, Nuriya; Wessels, Ursula; Turner, James; Geller, Stacie

2016-05-01

To determine the success rate of medical abortion when a progestin-based contraceptive-either an etonogestrel implant or depot medroxyprogesterone acetate (DMPA) injection-is given on the same day as mifepristone for medical abortion. In a retrospective chart review, data were assessed for women aged 15-49years who underwent medical abortion (≤63days of pregnancy) at two hospitals in KwaZulu Natal, South Africa, between August 2013 and July 2014. The women were given oral mifepristone (200mg) and buccal misoprostol (800μg), and received an etonogestrel implant or DMPA injection on the same day as mifepristone. The primary outcome was the success rate of medical abortion. Comparative data were obtained through a PubMed search. A total of 89 women were included. Complete termination was achieved in 87 (98%, 95% confidence interval 95%-100%) women. This success rate is similar to that reported in a previous systematic review of the rate of medical abortion success without progestin contraceptive administration (94.8%). Administration of a progestin-based contraceptive such as an etonogestrel implant or DMPA injection on the same day as mifepristone for medical abortion did not alter the success rates. Published by Elsevier Ireland Ltd.

Patterns of fecal gonadal hormone metabolites in the maned wolf (Chrysocyon brachyurus).

PubMed

Songsasen, N; Rodden, M; Brown, J L; Wildt, D E

2006-10-01

Ex situ populations of maned wolves are not viable due to low reproductive efficiency. The objective of this study was to increase knowledge regarding the reproductive physiology of maned wolves to improve captive management. Fecal samples were collected 3-5 d/wk from 12 females of various reproductive age classes (young, prime breeding and aged) and reproductive histories (conceived and raised pups, conceived but lost pups, pseudo-pregnant and unpaired). Ovarian steroids were extracted from feces and assessed by enzyme immunoassay. Concentrations of estrogen metabolites gradually increased, beginning 2-5 d before breeding, and declined to baseline on the day of lordosis and copulation. Fecal progestin metabolite concentrations increased steadily during the periovulatory period, when sexual receptivity was observed, and remained elevated during pregnancy and pseudo-pregnancy. During the luteal phase, young and prime breeding-age females excreted larger amounts of progestins than those of older age classes. Furthermore, progestin concentrations were higher during the luteal phase of pregnant versus pseudo-pregnant bitches. Profiles of fecal progestin metabolites for three singleton females were unchanged throughout the breeding season, suggesting ovulation is induced in this species. However, this finding could be confounded by age, as these females were either young or aged.

[Hormonal contraception and thromboembolic disease--pathophysiologic findings and practical recommendations].

PubMed

Dulícek, P

2001-09-01

Review the knowledge about changes in hemostatic system in combined oral contraceptives users (focused on studies published between 1997 and 2000). Review of literature. Department of Clinical Hematology, University Hospital Hradec Králové, Czech Republic. Summary of the results of substantial studies published on this topic. Studies were identified by Medline database search. Hemostatic changes were described in all subsystems (in both procoagulant and fibrinolytic systems, in natural inhibitors of coagulation) and could be seen also in molecular marks of coagulation and fibrinolysis activity. Substantial differences were not described for ethinylestradiol doses 20-50 micrograms and up to 1997 also not for different progestins. More expressed acquired resistance to activated protein C at 3rd generation progestins in comparison with levonorgestrel was described recently as well as greater inhibition of fibrinolysis at desogestrel users. The results of recent studies indicate the differences in hemostatic changes between users of 3rd generation progestins, respective desogestrel, and users of levonorgestrel. However, the practical recommendations (aiming at minimalization of VTE risk) are focused on personal and family history and on patient counseling. The choice of progestin could be important but it is not crucial.

Contraceptives with novel benefits.

PubMed

Su, Ying; Lian, Qing-Quan; Ge, Ren-Shan

2012-01-01

Progesterone receptor (PR) agonists (progestins) and antagonists are developed for female contraceptives. However, non-contraceptive applications of newer progestins and PR modulators are being given more attention. The newer PR agonists including drospirenone, nomegestrol, trimegestone, dienogest and nestorone are being evaluated as contraceptives with health benefits because of their unique pharmacological properties. The selective PR modulators (SPRM; PR antagonists with PR agonistic properties) are under development not only for emergency contraception but also for other health benefits such as the treatment of endometritis and leiomyoma. After searching the literature from PubMed, clinicaltrials.gov and patent database, this review focuses on the effects and mechanisms of these progestins, and SPRMs as contraceptives with other health benefits. PR agonists and antagonists that have novel properties may generate better contraceptive effects with other health benefits.

Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials.

PubMed

Abu Hashim, Hatem; Ghayaty, Essam; El Rakhawy, Mohamed

2015-10-01

We sought to evaluate the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH). Searches were conducted on PubMed, SCOPUS, and CENTRAL databases to August 2014, and reference lists of relevant articles were screened. The search was limited to articles conducted on human beings and females. The PRISMA Statement was followed. Seven randomized controlled trials (n = 766 women) were included. Main outcome measures were the therapeutic effect rate (histological response) after 3, 6, 12, and 24 months of treatment; rate of irregular vaginal bleeding; and the hysterectomy rate per woman randomized. The Cochrane Collaboration risk of bias tool was used for quality assessment. Metaanalysis was performed with fixed effects model. LNG-IUS achieved a highly significant therapeutic response rate compared with oral progestins after 3 months of treatment (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.39-3.82; P = .001, 5 trials, I(2) = 0%, n = 376), after 6 months of treatment (OR, 3.16; 95% CI, 1.84-5.45; P < .00001, 4 trials, I(2) = 0%, n = 397), after 12 months of treatment (OR, 5.73; 95% CI, 2.67-12.33; P < .00001, 2 trials, I(2) = 0%, n = 224), and after 24 months of treatment (OR, 7.46; 95% CI, 2.55-21.78; P = .0002, 1 trial, n = 104). Subgroup analysis showed evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins for non-atypical simple as well as complex EH (OR, 2.51; 95% CI, 1.14-5.53; P = .02, 6 trials, I(2) = 0%, n = 290; and OR, 3.31; 95% CI, 1.62-6.74; P = .001, 4 trials, I(2) = 0%, n = 216, respectively). Compared with oral progestins, LNG-IUS achieved significantly fewer hysterectomies (OR, 0.26; 95% CI, 0.15-0.45; P < .00001, 3 trials, n = 362, I² = 42%). No difference was observed in the rate of irregular vaginal bleeding between both groups (OR, 1.12; 95% CI, 0.54-2.32; P = .76, 2 trials, n = 207, I² = 77%). Funnel plot analysis was not performed because of the relatively small number of included studies. For treatment of non-atypical EH, LNG-IUS achieves higher therapeutic effect rates and lower hysterectomy rates than oral progestins and should be offered as an alternative to oral progestins in these cases. Copyright © 2015 Elsevier Inc. All rights reserved.

Biological Basis for Chemoprevention of Ovarian Cancer

DTIC Science & Technology

1999-10-01

potent apoptotic effect on ovarian epithelial cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and...women. A chemoprevention trial is ongoing in chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian...subsequent studies performed in vitro, we have induced apoptosis in epithelial cells treated with the progestin levonorgestrel . Progestin mediated apoptotic

Mid-aged and aged wild-type and progestin receptor knockout (PRKO) mice demonstrate rapid progesterone and 3alpha,5alpha-THP-facilitated lordosis.

PubMed

Frye, C A; Sumida, K; Lydon, J P; O'Malley, B W; Pfaff, D W

2006-05-01

Progesterone (P) and its 5alpha-reduced metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP), facilitate sexual behavior of rodents via agonist-like actions at intracellular progestin receptors (PRs) and membrane GABA(A)/benzodiazepine receptor complexes (GBRs), respectively. Given that ovarian secretion of progestins declines with aging, whether or not senescent mice are responsive to progestins was of interest. Homozygous PR knockout (PRKO) or wild-type mice that were between 10-12 (mid-aged) or 20-24 (aged) months of age were administered P or 3alpha,5alpha-THP, and the effect on lordosis were examined. Effects of a progestin-priming regimen that enhances PR-mediated (experiment 1) or more rapid, PR-independent effects of progestins (experiments 2 and 3) on sexual behavior were examined. Levels of P, 3alpha,5alpha-THP, and muscimol binding were examined in tissues from aged mice (experiment 4). Wild-type, but not PRKO, mice were responsive when primed with 17beta-estradiol (E(2); 0.5 microg) and administered P (500 microg, subcutaneously). Mid-aged wild-type mice demonstrated greater increases in lordosis 6 h later compared to their pre-P, baseline test than did aged wild-type mice (experiment 1). Lordosis of younger and older wild-type, but not PRKO, mice was significantly increased within 5 min of intravenous (IV) administration of P (100 ng), compared with E(2)-priming alone (experiment 2). However, wild-type and PRKO mice demonstrated significant increases in lordosis 5 min after IV administration of 3alpha,5alpha-THP, an effect which was more pronounced in mid-aged than in aged animals (100 ng-experiment 3). In tissues from aged wild-type and PRKO mice, levels of P, 3alpha,5alpha-THP, and muscimol binding were increased by P administration (experiment 4). PR binding was lower in the cortex of PRKO than that of wild-type mice. Mid-aged and aged PRKO and wild-type mice demonstrated rapid P or 3alpha,5alpha-THP-facilitated lordosis that may be, in part, independent of activity at PRs.

The effect of prothrombotic blood abnormalities on risk of deep vein thrombosis in users of hormone replacement therapy: a prospective case-control study.

PubMed

Douketis, Jim D; Julian, Jim A; Crowther, Mark A; Kearon, Clive; Bates, Shannon M; Barone, Marisa; Piovella, Franco; Middeldorp, Saskia; Prandoni, Paolo; Johnston, Marilyn; Costantini, Lorrie; Ginsberg, Jeffrey S

2011-01-01

Few studies have assessed the effect of prothrombotic blood abnormalities on the risk of deep vein thrombosis (DVT) with hormone replacement therapy (HRT). We studied postmenopausal women with suspected DVT in whom HRT use and prothrombotic blood abnormalities were sought. Cases had unprovoked DVT and controls had no DVT and without DVT risk factors. The risk of DVT was determined in women with and without prothrombotic abnormalities. A total of 510 postmenopausal women with suspected DVT were assessed; 57 cases and 283 controls were identified. Compared to HRT, nonusers without the factor V Leiden mutation, the risk of DVT was increased in estrogen-progestin HRT users (odds ratio [OR], 3.2; 95% confidence interval [CI]: 1.2-8.6) and in nonusers with the factor V Leiden mutation (OR, 5.3; 1.9-15.4) and appears multiplied in users of estrogen-progestin HRT with the factor V Leiden mutation (OR, 17.1; 3.7-78). Compared to HRT, nonusers with normal factor VIII, the risk of DVT was increased in estrogen-progestin HRT users with normal factor VIII (OR, 2.8; 1.0-7.9) and in HRT nonusers with the highest factor VIII quartile (OR, 6.0; 2.1-17), and appears to be multiplied in women who are users of estrogen-progestin HRT with the highest factor VIII quartile (OR, 17.0; 3.6-80). In postmenopausal women who are estrogen-progestin HRT users, the presence of the factor V Leiden mutation or an elevated factor VIII level appears to have a multiplicative effect on their overall risk of DVT, increasing it 17-fold compared to women without these blood abnormalities who are HRT nonusers.

Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks

PubMed Central

Paris, Jason J; Frye, Cheryl A

2008-01-01

Ovarian hormone elevations are associated with enhanced learning/memory. During behavioral estrus or pregnancy, progestins, such as progesterone (P4) and its metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP), are elevated due, in part, to corpora luteal and placental secretion. During ‘pseudopregnancy’, the induction of corpora luteal functioning results in a hormonal milieu analogous to pregnancy, which ceases after about 12 days, due to the lack of placental formation. Multiparity is also associated with enhanced learning/memory, perhaps due to prior steroid exposure during pregnancy. Given evidence that progestins and/or parity may influence cognition, we investigated how natural alterations in the progestin milieu influence cognitive performance. In Experiment 1, virgin rats (nulliparous) or rats with two prior pregnancies (multiparous) were assessed on the object placement and recognition tasks, when in high-estrogen/P4 (behavioral estrus) or low-estrogen/P4 (diestrus) phases of the estrous cycle. In Experiment 2, primiparous or multiparous rats were tested in the object placement and recognition tasks when not pregnant, pseudopregnant, or pregnant (between gestational days (GDs) 6 and 12). In Experiment 3, pregnant primiparous or multiparous rats were assessed daily in the object placement or recognition tasks. Females in natural states associated with higher endogenous progestins (behavioral estrus, pregnancy, multiparity) outperformed rats in low progestin states (diestrus, non-pregnancy, nulliparity) on the object placement and recognition tasks. In earlier pregnancy, multiparous, compared with primiparous, rats had a lower corticosterone, but higher estrogen levels, concomitant with better object placement performance. From GD 13 until post partum, primiparous rats had higher 3α,5α-THP levels and improved object placement performance compared with multiparous rats. PMID:18390689

Micro-RNA-181a suppresses progestin-promoted breast cancer cell growth.

PubMed

Gu, Muqing; Wang, Lijuan; Yang, Chun; Li, Xue; Jia, Chanwei; Croteau, Stephane; Ruan, Xiangyan; Hardy, Pierre

2018-08-01

Recent investigations have indicated that hormone therapy may increase the risk of breast cancer (BC), and the addition of synthetic progestins may play a critical role in this. Several studies have pointed out the important role of progesterone receptor membrane component 1 (PGRMC1) in the development of BC, especially with hormone therapy using progestins. Although the deregulation of microRNA-181a (miR-181a) is often associated with human BC, the effect of miR-181a on PGRMC1 expression during hormone therapy has not been investigated. Cell viability assay and apoptosis assay were performed to investigate the pro-BC effect of progestin (norethisterone, NET) and anti-BC effect of miR-181a on MCF-7 cells. Quantitative RT-PCR and Western blot analysis were used to evaluate gene expressions in the NET-treated MCF-7 cells. NET dose-dependently increased BC cell viability and this effect was accompanied by increased expression of PGRMC1. Overexpression of miR-181a strongly reduced the cell viability of MCF-7 cells, mainly through increased apoptosis, which was evidenced by substantially increased gene expression of pro-apoptosis factors such as BAX and CASPASE 9 in miR-181a overexpressed cells. Importantly, miR-181a abrogated NET-stimulated cell viability and PGRMC1 expression. We provide evidence that miR-181a promotes MCF-7 cell apoptosis. Moreover, miR-181a suppressed NET-provoked cell viability and PGRMC1 expression in MCF-7 cells. These data may suggest a therapeutic strategy of using miR-181a to reduce BC risk in progestin hormone replacement therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming

PubMed Central

Diep, Caroline H.; Knutson, Todd P.; Lange, Carol A.

2015-01-01

Progesterone promotes differentiation coupled to proliferation and pro-survival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform-specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target-gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B). Chromatin immunoprecipitation (ChIP) assays performed on PR-isoform specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin marks. Overexpression of constitutively active FOXO1 in PR-A-expressing cells conferred robust ligand-dependent upregulation of the PR-B target genes GZMA, IGFBP1, and p21, and induced cellular senescence. In the presence of endogenous active FOXO1, PR-A was phosphorylated on Ser294 and transactivated PR-B at PR-B target genes; these events were blocked by the FOXO1 inhibitor (AS1842856). PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin; loss of progestin sensitivity correlated with high AKT activity. PMID:26577046

Incidence of endometrial spotting or bleeding during continuous-combined estrogen-progestin therapy in postmenopausal women with and without hypertension.

PubMed

Sriprasert, Intira; Beydoun, Hind; Barnabei, Vanessa; Nassir, Rami; LaCroix, Andrea Z; Archer, David F

2015-10-01

Endometrial spotting or bleeding is a common adverse effect among women taking continuous-combined estrogen-progestin therapy. The renin-angiotensin-aldosterone system plays a major role in hypertension and is present in the endometrium. We hypothesized that postmenopausal women with hypertension would have a higher incidence of bleeding compared with postmenopausal women without hypertension. A multivariate mixed-effects logistic model estimated the odds ratios for the relationship of hypertension status or use of antihypertensive drugs with endometrial bleeding using the Women's Health Initiative database. The incidence of spotting or bleeding in the first 12 months of estrogen-progestin use was 42% in women aged 50 to 79 years. Women with hypertension were more likely to experience bleeding than women without hypertension (odds ratio, 1.07; 95% CI, 1.02-1.13). Overall antihypertensive medication use increased bleeding with an odds ratio of 1.24, whereas angiotensin II receptor antagonists had a reduced odds ratio (0.53). Postmenopausal women with hypertension are more likely to bleed than postmenopausal women without hypertension when taking continuous estrogen-progestin, with less bleeding in women using angiotensin II receptor antagonists. This finding is novel and supports our hypothesis that the endometrial renin-angiotensin-aldosterone system may contribute to endometrial bleeding.

The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures.

PubMed

Loiseau, Camille; Osinski, Diane; Joubert, Fanny; Straus, Christian; Similowski, Thomas; Bodineau, Laurence

2014-05-01

Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H(+) chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H(+) chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[Effects of pathological assessment of endometrial tissue in fertility-sparing treatment with progestin for endometrial carcinoma of stage I a and complex atypical hyperplasia].

PubMed

Gong, Qinglin; Chen, Xiaoduan; Xie, Xing

2014-09-01

To assess the efficacy and pathological change of fertility-sparing treatment with progestin for endometrial carcinoma (EC) of stage I a and complex atypical hyperplasia (CAH) and to observe the prognosis of the treatment. Nine EC patients of stage I a and 21 CAH patients aged under 40 years who desired childbearing and retaining their fertility were enrolled into this study. All patients were given a daily oral high-dose of progestin with duration of treatment ranging from 6 to 9 months. Diagnostic curettage was performed every 3 months as a modality for seeing the histologic change of neoplastic tissues and endometrial tissue. A careful and long- term follow- up is necessary for patients with complete response (CR). During the first period of fertility-sparing management, according to histologic change, 5 EC patients and 18 CAH patients showed CR with no evidence of endometrial adenocarcinoma or hyperplasia, 2 EC patients and 2 CAH patients showed partial response with a regression to complex or simple hyperplasia without atypia, 2 EC patients and 1 CAH patient showed stable disease or progressive disease. Accordingly, a total of 26 patients showed CR (26 of 30 patients). The median time to CR was 6 months (range, 3 to 21 months) of progestin treatment. The median follow-up time was 55.5 months (range, 24 to 104 months) and all patients were alive. During follow-up, among the 26 patients with CR, 3 of 6 EC patients achieved CR recurred disease after a median time interval of 10 months (range, 6 to 51 months), 7 of 20 CAH patients achieved CR had recurrent disease after a median time interval of 12 months (range, 6 to 55 months). Four of 7 CAH with recurrent disease achieved CR to progestin re-treatment. Eight of 26 patients achieved CR continued a further 3 or 6 months of consolidation therapy, 3 of them had recurrent disease, the remaining 18 stopped progesterone treatment after CR and 7 patients had recurrent disease; there was no significant statistical difference between the two groups (P = 1.000). EC patients succeeded in 4 pregnancies, CAH patients succeeded in 10 pregnancies, they gave birth to 16 healthy babies in all. EC of stage I a and CAH had slow progression of symptoms. Progestin treatment in EC of stage I a and CAH patients was effective. A careful and long-term follow-up is required because of the substantial high rate of recurrence. Progestin re-treatment in most patients with recurrent endometrial cancer is effective and safe.

[Combined estrogen-progestagen contraception and glucid and water-sodium metabolism].

PubMed

Belaisch, J; Hommais-loufrani, B

1988-02-01

Although combined oral contraceptives (OCs) do not create a true cardiovascular risk, they may increase the impact of existing vascular risk factors. Pill use disturbs metabolism of lipids and carbohydrates as well as the balance of water and sodium. New combinations with lower doses of steroids have significantly reduced these risks, and the development of new and less androgenic progestins for low dose pills is expected to reduce them further. The diabetogenic effect of OCs has been noted since 1963. Among normal women, the observed modifications in carbohydrate metabolism are minor and temporary, with increases in levels of blood sugar maximal at the beginning of use and normalizing after 12 months. Among women with family histories of diabetes or who have had gestational diabetes, use of combined OCs can entail irreversible deterioration of glucose tolerance or diabetes. The number of women with poor glucose tolerance increases with the duration of pill use. Reversibility of the condition decreases with duration of use. The proportion of women with poor glucose tolerance who develop diabetes is higher than among normal subjects. Women with poor glucose tolerance must be considered at risk of diabetes. Ethinyl estradiol is responsible for the early modification of glucose tolerance, which regresses after about 6 months of use. Hyperinsulinemia is caused by the direct stimulation of progestins on insulin secretion by the pancreas as well as by the development of peripheral resistence to glucose utilization resulting from a decrease of insulin receptors. The effect on insulin resistence is among the most androgenic progestins. Chronic hyperinsulinism represents a classic risk factor for atherosclerosis because of the effects on the arterial wall: proliferation of smooth muscle fibers, inhibition of lipolysis, and development of lesions of the intima analogous to those of atheroma. Estrogen is primarily responsible for the increased blood pressure of pill users, but the development of hypertension is also correlated with the progestin content. Progestins have an antidiuretic effect which contributes to increases in blood pressure when added to the estrogen stimulation of the renin-aldosterone-angiotensin system. Gestodene, a new progestin in the gonane series, is the most powerful synthetic progesterone yet known. Its uniqueness derives from the dissociation between its very powerful antigonadotropic activity even at small doses and its androgenic effects which only appear at considerably higher doses. Most of the metabolic effects of progestins are linked to their degree of androgenicity. Different studies of gestodene tolerance in a triphasic formulation have concluded that it is innocuous. The use of gestodene in a low-dose triphasic formulation may result in a combined OC that does not increase the individual atheromatous risk of the user.

Characterization and manipulation of reproductive cycles in the jaguar (Panthera onca).

PubMed

Barnes, Serena A; Andrew Teare, J; Staaden, Sheryl; Metrione, Lara; Penfold, Linda M

2016-01-01

Basic reproductive information in female jaguars (Panthera onca) is lacking, thus longitudinal fecal samples from seven females were analyzed via enzyme immunoassay to measure estradiol and progestin metabolites throughout the year. Mean estrus length of 194 estrus periods measured hormonally was 6.5±0.3d, mean peak fecal estradiol concentration was 138.7±5.7ng/g; and in one female, estrus resumption occurred approximately 15d post-partum. Ovulation, as indicted by sustained elevated progestin concentrations (>20d), was successfully induced one time by treatment with exogenous hormones in one female and by physical vaginal stimulation in two females a combined total of three times. Elevated fecal progestin was observed outside exogenous stimulation on five occasions, suggesting ovulation occurred spontaneously. Mean length of physically induced and spontaneous pseudopregnancies was 24.7±4.2d and 29.6±2.6d, respectively, and mean length of pregnancy (n=2) was 98.0±0.0d. Mean peak progestin concentration for spontaneous and induced pseudopregnancies, and pregnancy was 7.4±1.4μg/g, 6.4±1.2μg/g, and 13.7±1.0μg/g, respectively. This data suggests jaguars are polyestrous and generally induced ovulators, with a moderate incidence of spontaneous ovulation. Additionally, two protocols to successfully stimulate ovarian activity in jaguars are described. Copyright © 2015 Elsevier Inc. All rights reserved.

Vasodilating effect of norethisterone and its 5 alpha metabolites: a novel nongenomic action.

PubMed

Perusquía, Mercedes; Villalón, Carlos M; Navarrete, Erika; García, Gustavo A; Pérez-Palacios, Gregorio; Lemus, Ana E

2003-08-15

Estrogens are generally administered in hormone replacement therapy in combination with synthetic progestins. Studies of cardiovascular risk factors in postmenopausal women have shown a variety of responses according to the molecular structure of the progestin used in hormone replacement therapy schemes. The present study sets out to determine the vasoactive effects of norethisterone and its 5alpha-dihydro (5alpha-norethisterone) and -tetrahydro (3alpha,5alpha-norethisterone and 3beta,5alpha-norethisterone) metabolites in isolated precontracted rat thoracic aorta. The addition of norethisterone and 3alpha,5alpha-norethisterone in rat aorta exhibited a potent, concentration-response inhibition of noradrenaline-induced contraction, while 5alpha- and 3beta,5alpha-norethisterone had very little, if any, vasorelaxing effect. Relaxation to norethisterone and 3alpha,5alpha-norethisterone had very rapid time-courses and it was neither affected by the absence of endothelium nor by the inhibitor of nitric oxide synthase, Nomega-nitro-L-arginine methyl ester (L-NAME). The addition of specific anti-androgen, anti-progestin and anti-estrogen compounds and protein synthesis inhibitors did not preclude the vasorelaxing effect of norethisterone and its 3alpha,5alpha-reduced metabolite. The results strongly suggest that these effects are not mediated by nuclear sex steroid hormone receptors. The overall data document a novel nongenomic endothelium-independent vasorelaxing action of a 19-nor synthetic progestin and one of its A-ring-reduced derivatives.

Progesterone's 5 alpha-reduced metabolite, 3 alpha,5 alpha-THP, mediates lateral displacement of hamsters.

PubMed

Frye, Cheryl A; Rhodes, Madeline E

2005-03-15

5 alpha-Pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP), progesterone (P4)'s 5 alpha-reduced, 3 alpha-hydroxysteroid oxidoreduced product, facilitates lordosis of rodents in part via agonist-like actions at GABA(A)/benzodiazepine receptor complexes in the ventral tegmental area (VTA). Whether 3 alpha,5 alpha-THP influences another reproductively-relevant behavior, lateral displacement, of hamsters was investigated. Lateral displacement is the movement that female hamsters make with their perineum towards male-like tactile stimulation. This behavior facilitates, and is essential for, successful mating. Hamsters in behavioral estrus had greater lateral displacement responses when endogenous progestin levels were elevated compared to when progestin levels were lower. Administration of P4, a prohormone for 3 alpha,5 alpha-THP, dose-dependently (500 > 200 > 100, 50, or 0 microg) enhanced lateral displacement of ovariectomized hamsters that had been primed with SC estradiol benzoate (5 or 10 microg). Inhibiting P4's metabolism to 3 alpha,5 alpha-THP by co-administering finasteride, a 5 alpha-reductase inhibitor, or indomethacin, a 3 alpha-hydroxysteroid oxidoreductase inhibitor, either systemically or to the VTA, significantly decreased lateral displacement and midbrain progestin levels of naturally receptive or hormone-primed hamsters compared to controls. These data suggest that lateral displacement is progestin-sensitive and requires the formation of 3 alpha,5 alpha-THP in the midbrain VTA.

Cortisol and progestin release, heart rate and heart rate variability in the pregnant and postpartum mare, fetus and newborn foal.

PubMed

Nagel, C; Erber, R; Bergmaier, C; Wulf, M; Aurich, J; Möstl, E; Aurich, C

2012-09-01

The mechanisms leading to parturition in the horse in many aspects differ from those in other species. Pregnancy is maintained not by progesterone but by 5α-pregnanes and the progestin precursor pregnenolone originates from the fetus. As parturition approaches, the fetal adrenal switches from pregnenolone to cortisol synthesis but it is not known whether cortisol crosses the placenta. We hypothesized that in parallel to fetal cortisol release, cortisol in the maternal circulation increases before foaling and this increase can be determined in both saliva and plasma. In addition, maternal, fetal and neonatal heart rate and heart rate variability were measured. In 25 pregnant mares, saliva for cortisol analysis was collected 4 times daily from 15 days before to 5 days after foaling. In 13 mares, in addition, fetomaternal electrocardiogram (ECG) recordings were made and blood samples for progestin and cortisol analysis were collected once daily. Heart rate (HR) was recorded until 5 days after foaling. The heart rate variability (HRV) variables standard deviation of the beat-to-beat (RR) interval (SDRR) and root mean square of successive RR differences (RMSSD) were calculated. From Days 15 to 4 before parturition, progestin concentration increased (peak 267 ± 42 ng/mL) and decreased thereafter (P < 0.05, day of foaling 113 ± 18 ng/mL). A prepartum increase in maternal cortisol concentrations was evident in blood (P < 0.05) and saliva (P < 0.05) and paralleled the decrease in progestin concentrations. In mares, HR remained constant during the last days of pregnancy but decreased within one day after parturition (P < 0.05) while maternal HRV did not change. In the fetus and neonate, HR increased from before to after birth (P < 0.05) indicating increasing demands on the cardiovascular system with adaptation to extrauterine life. Copyright © 2012 Elsevier Inc. All rights reserved.

Progestin implants can rescue demi-embryo pregnancies in goats: a case study.

PubMed

Beckett, D M; Oppenheim, S M; Moyer, A L; BonDurant, R H; Rowe, J D; Anderson, G B

1999-06-01

Survival after transfer of demi-embryos (i.e., half-embryos produced by embryo splitting) to recipients usually is lower than survival after transfer of intact embryos. Reduced survival after demi-embryo transfer could be due to loss of viability after splitting, failure of a viable demi-embryo to prevent corpus luteum (CL) regression in the recipient female, or a combination of factors. From a retrospective analysis of pregnancy and embryo survival rates after demi-embryo transfer in sheep and goats, we report the rescue of caprine demi-embryo pregnancies in which CL regression occurred at the end of diestrus despite the presence of a viable conceptus in the uterus with progestin implants. Day 5 or 6 morulae and blastocysts were flushed from superovulated ewes and does and split into demi-embryos of approximately equal halves. Demi-embryos were either transferred fresh to synchronized recipients of the homologous species or frozen in liquid nitrogen. Approximately half of the recipient does and ewes were treated with norgestomet implants on Day 10 of the embryo transfer cycle and again 2 wk later. Serum collected on Day 25 from recipients with implants was assayed for progesterone to determine if a CL of pregnancy had been maintained. Pregnancy was diagnosed by ultrasonography on Day 35 of gestation. Corpus luteum regression occurred despite the presence of a viable conceptus in the uterus in 6 of 55 progestin-treated caprine demi-embryo recipients and in 0 of 66 ovine demi-embryo recipients. Five of the caprine pregnancies were maintained to term with norgestomet implants and produced 5 live kids. The sixth fetus, which was carried by a progestin implant-treated 8-mo-old doeling, died at approximately 50 d of gestation. These results suggest that, at least in goats, some demi-embryos may provide inadequate signaling for maternal recognition of pregnancy, and such pregnancies can be rescued with progestin treatment to the doe.

Progestin withdrawal at parturition in the mare.

PubMed

Legacki, Erin L; Corbin, C J; Ball, B A; Wynn, M; Loux, S; Stanley, S D; Conley, A J

2016-10-01

Mammalian pregnancies need progestogenic support and birth requires progestin withdrawal. The absence of progesterone in pregnant mares, and the progestogenic bioactivity of 5α-dihydroprogesterone (DHP), led us to reexamine progestin withdrawal at foaling. Systemic pregnane concentrations (DHP, allopregnanolone, pregnenolone, 5α-pregnane-3β, 20α-diol (3β,20αDHP), 20α-hydroxy-5α-dihydroprogesterone (20αDHP)) and progesterone) were monitored in mares for 10days before foaling (n=7) by liquid chromatography-mass spectrometry. The biopotency of dominant metabolites was assessed using luciferase reporter assays. Stable transfected Chinese hamster ovarian cells expressing the equine progesterone receptor (ePGR) were transfected with an MMTV-luciferase expression plasmid responsive to steroid agonists. Cells were incubated with increasing concentrations (0-100nM) of progesterone, 20αDHP and 3α,20βDHP. The concentrations of circulating pregnanes in periparturient mares were (highest to lowest) 3α,20βDHP and 20αDHP (800-400ng/mL respectively), DHP and allopregnanolone (90 and 30ng/mL respectively), and pregnenolone and progesterone (4-2ng/mL). Concentrations of all measured pregnanes declined on average by 50% from prepartum peaks to the day before foaling. Maximum activation of the ePGR by progesterone occurred at 30nM; 20αDHP and 3α,20βDHP were significantly less biopotent. At prepartum concentrations, both 20αDHP and 3α,20βDHP exhibited significant ePGR activation. Progestogenic support of pregnancy declines from 3 to 5days before foaling. Prepartum peak concentrations indicate that DHP is the major progestin, but other pregnanes like 20αDHP are present in sufficient concentrations to play a physiological role in the absence of DHP. The authors conclude that progestin withdrawal associated with parturition in mares involves cessation of pregnane synthesis by the placenta. © 2016 Society for Reproduction and Fertility.

Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

PubMed Central

Dai, Donghai; Meng, Xiangbing; Thiel, Kristina W.; Leslie, Kimberly K.; Yang, Shujie

2016-01-01

Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term “molecularly enhanced progestin therapy.” What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a previously unanticipated inverse relationship between the tumor suppressor PR and the oncogene Myc in endometrial cancer. PMID:26859414

Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women’s Health Initiative Randomized Trial

PubMed Central

Anderson, G. L.; Sarto, G. E.; Haque, R.; Runowicz, C. D.; Aragaki, A. K.; Thomson, C. A.; Howard, B. V.; Wactawski-Wende, J.; Chen, C.; Rohan, T. E.; Simon, M. S.; Reed, S. D.; Manson, J. E.

2016-01-01

Background: While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women’s Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use. Methods: The WHI enrolled 16 608 postmenopausal women into a randomly assigned, double-blind, placebo-controlled trial. Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were randomly assigned to once-daily 0.625mg conjugated equine estrogen plus 2.5mg medroxyprogesterone acetate (n = 8506) as a single pill or matching placebo (n = 8102). Follow-up beyond the original trial completion date required reconsent, obtained from 12 788 (83%) of surviving participants. Analyses were by intent-to-treat. All statistical tests were two-sided. Results: After 5.6 years’ median intervention and 13 years’ median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group (66 vs 95 case patients, yearly incidence, 0.06% vs 0.10%; hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). While there were somewhat fewer endometrial cancers during intervention (25 vs 30, respectively; HR = 0.77, 95% CI = 0.45 to 1.31), the difference became statistically significant postintervention (41 vs 65, respectively; HR = 0.59, 95% CI = 0.40 to 0.88, P = .008), but hazard ratios did not differ between phases (P difference = .46). There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group (5 vs 11 deaths, HR = 0.42, 95% CI = 0.15 to 1.22). Conclusion: In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. PMID:26668177

Oral contraceptives and cardiovascular risk in women with polycystic ovary syndrome.

PubMed

Carmina, E

2013-05-01

Because women affected by polycystic ovary syndrome (PCOS) present an increased cardiovascular risk, the safety of estroprogestin treatment is debated and contrasting data have been reported. However, cardiovascular risk is not the same in all PCOS women and individual cardiovascular risk should be assessed before staring any estroprogestin treatment. The available data show that products containing both 2nd-generation and 3rd-generation progestins (including drospirenone and cyproterone acetate) represent a safe treatment in PCOS patients with regular cardiovascular risk. In PCOS patients with increased cardiovascular risk, a careful choice of estroprogestin product is needed and cardiovascular risk should be monitored during treatment. In obese PCOS patients with normal glucose tolerance and lipid profile, products containing 2nd-generation progestins may be preferred because of lower venous thromboembolism risk. In PCOS patients with altered lipid profile or glucose intolerance, 3rd-generation progestins should be used but, during treatment, cardiovascular risk should be periodically re-assessed. In special situations, metformin or statins may be added to estroprogestin treatment.

Dienogest in the treatment of endometriosis.

PubMed

Bizzarri, Nicolò; Remorgida, Valentino; Leone Roberti Maggiore, Umberto; Scala, Carolina; Tafi, Emanuela; Ghirardi, Valentina; Salvatore, Stefano; Candiani, Massimo; Venturini, Pier Luigi; Ferrero, Simone

2014-09-01

Dienogest (DNG) is an oral progestin, derivative of 19-nortestosterone, that has recently been introduced for the treatment of endometriosis. This review examines the clinical efficacy, safety and tolerability of DNG in the treatment of endometriosis. The material included in the current manuscript was searched and obtained via Medline, Pubmed and EMBASE, from inception until February 2014. The term 'dienogest' was associated with the following search terms: 'endometriosis', 'pharmacokinetics', 'safety' and 'efficacy'. Several trials demonstrated the clinical efficacy, safety and tolerability of DNG. However the use of DNG is associated with some limitations. So far, no study investigated the potential of contraceptive effect of this treatment and therefore, it should be recommended with other methods of contraception (e.g., barrier methods). A further limitation of the use of DNG as daily therapy in the long term is that the cost of the therapy is higher than other progestins available on the market and combined oral contraceptives. Therefore, future studies should be designed to compare the efficacy and safety of DNG with other progestins.

Comparing the Effects of Oral Contraceptives Containing Levonorgestrel With Products Containing Antiandrogenic Progestins on Clinical, Hormonal, and Metabolic Parameters and Quality of Life in Women With Polycystic Ovary Syndrome: Crossover Randomized Controlled Trial Protocol

PubMed Central

Amiri, Mina; Nahidi, Fatemeh; Khalili, Davood; Bidhendi-Yarandi, Razieh

2017-01-01

Background Oral contraceptives (OCs) have been used as a first-line option for medical treatment in women with polycystic ovary syndrome (PCOS). Despite theoretical superiority of products containing antiandrogenic progestins compared to OCs containing levonorgestrel (LNG), the clinical advantage of these compounds remains unclear. Objective The aim of this study was to compare the effects of OCs containing LNG with products containing antiandrogenic progestins including cyproterone acetate, drospirenone, and desogestrel on clinical, hormonal, and metabolic parameters and quality of life in women with PCOS. Methods We conducted a 6-arm crossover randomized controlled trial with each arm including OCs containing LNG and one of those 3 OCs containing antiandrogenic progestins. The anthropometric and clinical manifestations and hormonal and biochemical parameters of participants were assessed at 6 time points including baseline, after washout period, and 3 and 6 months after intervention. Results The study is ongoing and follow-up of recruited women will continue until 2018. Conclusions This study will provide scientific evidence on comparability of OCs with the various progesterones that will assist in decision making taking into account cost effectiveness. Trial Registration Iranian Registry of Clinical Trials IRCT201702071281N2; http://www.irct.ir/searchresult.php? keyword=&id=1281&number=2&prt=12869&total=10&m=1 (Archived by WebCite at http://www.webcitation.org/6tSP8FNWo) PMID:28963092

Studies on the synergistic effect of androgen on the stimulation of progestin secretion by FSH in cultured rat granulosa cells: progesterone metabolism and the effect of androgens.

PubMed

Nimrod, A

1977-09-01

Metabolic transformations of progesterone in cultures of granulosa cells from immature hypophysectomized rats treated with diethylstilbestrol were studied in relation to the synergistic action of exogenous androgen and FSH on progestin (progesterone and 20alpha-dihydroprogesterone) accumulation. Androstenedione (Ad; 10 ng/ml) enhanced the sensitivity of rat granulosa cells to this steroidogenic action of FSH, lowering the threshold of the response from greater than 4 ng/ml (FSH alone) to 0.8 ng/ml in the presence of Ad. A synergistic effect with FSH was also shown by various 5alpha-androstane derivatives. They were, however, less effective than the parent delta4-3 keto androstenes. Progesterone underwent extensive 5alpha-reduction during culture, leading to accumulation of endogenous 5alpha-pregnane compounds, and to transformation of labelled progesterone into 5 alpha-reduced radiometabolites. These compounds corresponded in gas-liquid and thin-layer chromatographic behaviour to 3alpha-hydroxy-5alpha-pregnan-20-one, 20alpha-hydroxy-5alpha-pregnan-3-one and 5alpha-pregnane-3alpha,20alpha-diol. The rate of 5alpha-reduction of progestins was not affected by the presence of exogenous Ad (1 microgram/ml), ruling out the possibility that the effect of androgen on progestin accumulation depends on competitive inhibition of 5alpha-reductase. An involvement of androgen of thecal origin in the enhancement of the sensitivity of the FSH-responsive mechanism in granulosa cells is suggested.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism.

PubMed

Bastianelli, Carlo; Farris, Manuela; Rosato, Elena; Brosens, Ivo; Benagiano, Giuseppe

2017-03-01

The risk-benefit profile of any pharmacologic agent must be evaluated against risks connected with the events to be avoided. This is especially true in the case of hormonal contraception, not intended to combat a disease. Over the six decades during which their use has progressively expanded, the risk-benefit profile of combined oral contraceptives (COC) has substantially changed, with new combinations, dosages and mode of administration appearing on the market. Area covered: In a series of articles, recent information on the complex issue of COC risks and benefits will be reviewed in the hope of providing an updated picture. The present article reviews metabolic changes occurring during use of modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), often compared to classic compounds, such as levonorgestrel. Three categories of metabolic effects in healthy women are detailed: on carbohydrates, lipid and bone mineral content. Expert commentary: Overall, the picture is reassuring: the new generations of progestins are basically devoid of androgenic, estrogenic or glucocorticoid related side-effects. This should result in an improved safety profile, although past history teaches us that that large comparative and surveillance studies are required before firm conclusions can be drawn. At any rate, available evidence indicates that metabolic effects of third and fourth generation progestins, especially when they are combined with natural estrogens, are minimal and, if used in healthy women, should not cause concern.

Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal pregnancy outcomes compared with the standard progestin-primed ovarian stimulation in infertile women with polycystic ovarian syndrome.

PubMed

Ye, Hongjuan; Tian, Hui; He, Wen; Lyu, Qifeng; Kuang, Yanping; Chen, Qiuju; Sun, Lihua

2018-05-28

Oral progestin has recently been used to prevent premature LH surges in ovarian stimulation, and this progestin-primed ovarian stimulation (PPOS) is effective and safe in patients with different ovarian reserves. The current data are lacking regarding how to individualize the gonadotropin dose and regimen for women with polycystic ovarian syndrome (PCOS). A retrospective cohort trial was performed to evaluate the efficacy of progestin-primed milder stimulation with clomiphene citrate (CC) compared to the standard progestin-primed ovarian stimulation (PPOS) protocol for infertile women with PCOS. A total of 220 PCOS women were collected and classified into the study group (HMG 150 IU/d + CC 50 mg/d + MPA 10 mg/d) and control group (HMG 225 IU/d + MPA 10 mg/d). Ovulation was triggered by GnRH agonist 0.1 mg and hCG 1000 IU when dominant follicles matured. Viable embryos were cryopreserved for later transfer. The primary endpoint was the ongoing pregnancy rate. Secondary outcomes included the cycle characteristics and the live birth rate. The study group consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± 372.0 IU, P < 0.001) and harvested fewer oocytes than the control group (12.2 ± 7.4 vs 18.2 ± 9.7, P < 0.001). The study group showed a higher mid-follicular LH concentration (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 mIU/ml, P < 0.05) but no endogenous LH surge. No between-group difference was found in the incidence of ovarian hyperstimulation syndrome (OHSS) (0.91% vs 0.91%, P > 0.05). The cumulative ongoing pregnancy rate and live birth rate per patient were lower but did not reach significance compared with the control group (71.8% vs 81.8 and 64.5% vs 75.5%, respectively, both P > 0.05). The milder PPOS with CC in PCOS women led to lower oocyte yields and suboptimal pregnancy outcomes compared to the standard PPOS treatment. The two regimens both achieved a low incidence of OHSS. The results from the CC combination regimen provide a new insight for developing a more patient-friendly protocol for PCOS women.

Progestins to control feline reproduction: Historical abuse of high doses and potentially safe use of low doses.

PubMed

Romagnoli, Stefano

2015-09-01

The high fertility rate of cats means that methods to control feline reproduction are a requirement for cat breeders and pet owners, as well as for those involved in the management of feral cat populations. Progestins continue to be used to prevent queens from cycling, and also as an adjunct or alternative to surgical sterilization within trap-neuter-return (TNR) programs. A considerable body of information exists on megestrol acetate (MA) and medroxyprogesterone acetate (MPA), thanks to the many studies and case reports published in the scientific literature over the past 50 years documenting their clinical use in cats. Comparatively less is known about the use in cats of more recent progestins such as levonorgestrel, proligestone, delmadinone, chlormadinone and altrenogest. Based on a combination of dose, frequency and duration of treatment, MA can be categorized into low (0.625 mg/kg/week for up to 30 weeks), medium (0.625 mg/kg q24h for 1 week or q48h for up to 2 weeks) and high (0.625 mg/kg q24h or q48h for several weeks, or weekly for months or years) dosages. Studies suggest that low dosages can be used relatively safely in cats, while higher dosages increase the risk and severity of adverse reactions. Early work showing that an oral MPA dosage of 0.01 mg/kg administered q24h for 12 months suppresses oestrus in queens effectively and safely has not been considered, and much higher MPA dosages (>6.25 mg/kg q24h) have been used in cats over the past 40 years. Progestins should always be used with caution. Using the lowest possible dosages, MA and MPA may, however, continue to be used safely in pet queens as well as (in conjunction with TNR programs) for the control of feral cat colonies. More recent progestins appear to be effective and safe, albeit their efficacy and safety need to be further investigated. © The Author(s) 2015.

Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus).

PubMed

Svensson, Johan; Fick, Jerker; Brandt, Ingvar; Brunström, Björn

2014-02-01

Synthetic steroid hormones from contraceptive pharmaceuticals have become global aquatic contaminants. Progestins, the synthetic analogs to progesterone, are receiving increasing attention as contaminants and have been shown to impair reproduction in fish and amphibians at low ng L(-1) concentrations. Certain progestins, such as levonorgestrel have androgenic properties and seem to be several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins and progestagens. We recently reported that levonorgestrel has strong androgenic effects in female three-spined sticklebacks (Gasterosteus aculeatus), including induction of the normally male-specific glue protein spiggin and suppression of vitellogenesis. In light of this we investigated if exposure to levonorgestrel could disrupt the highly androgen-dependent seasonal reproductive cycle in male sticklebacks. Male sticklebacks that were in the final stage of a breeding period were exposed to various concentrations of levonorgestrel for six weeks in winter conditions in terms of light and temperature, after which reproductive status was evaluated from gross morphology, histology and key gene transcript levels. During the experimental period the controls had transitioned from full breeding condition into the non-breeding state, including regression of secondary sex characteristics, cessation of spiggin production in the kidney, and resumption of spermatogenesis in the testes. This is ascribed to the natural drop in plasma androgen levels after breeding. However, in the groups concurrently exposed to levonorgestrel, transition to the non-breeding condition was dose-dependently inhibited. Our results show that levonorgestrel can disrupt the seasonal breeding cycle in male sticklebacks. The fitness costs of such an effect could be detrimental to natural stickleback populations. Some effects occurred at a levonorgestrel concentration of 6.5 ng L(-1), well within the range of levonorgestrel levels in surface waters and may therefore occur in progestin-contaminated waters. Furthermore, the effects by levonorgestrel in the present study were likely mediated mainly by its androgenic activity, and the low concentration at which they occurred makes levonorgestrel one of the most potent androgenic contaminants known. Copyright © 2013 Elsevier B.V. All rights reserved.

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

PubMed Central

Singhal, Hari; Greene, Marianne E.; Tarulli, Gerard; Zarnke, Allison L.; Bourgo, Ryan J.; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G.; Raj, Ganesh V.; Hickey, Theresa E.; Tilley, Wayne D.; Greene, Geoffrey L.

2016-01-01

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored. PMID:27386569

Progesterone increases resistance of ophthalmic and central retinal arteries in climacteric women.

PubMed

Souza, M A M De; Souza, B M De; Geber, S

2013-04-01

To evaluate the effect of a synthetic progestin on the vascular resistance of the ophthalmic and central retinal arteries in climacteric women, compared to placebo, using transorbital ultrasound with Doppler velocimetry. We performed a prospective, randomized, double-blinded, placebo-controlled study with 216 climacteric women. Subjects were randomly allocated to one of two groups: either the group receiving placebo (one pill/day for 30 days) (n = 108) or the group receiving progestin (5 mg medroxyprogesterone acetate/day for 30 days) (n = 108). Transorbital Doppler velocimetric ultrasound was performed, before and after treatment; we measured the pulsatility index, resistance index and systole/diastole ratio. The mean ages of the participants in the study group and the control group were 54 ± 6.2 years (range 48-59 years) and 55 ± 6.8 years (range 46-60 years), respectively. When we compared the effect of the progestin on the central retinal artery before and after treatment, we observed a significant increase after the treatment in all Doppler indices. The same was observed when we compared the effect of the progestin on the ophthalmic artery. In the group of women receiving placebo, the Doppler indices were similar before and after treatment. Our results demonstrate the existence of a progestogenic vasoconstrictive effect in the ophthalmic and central retinal arteries. As this study provides new data, the observed effect needs further investigations to better elucidate its extent. Moreover, our findings may be particularly useful to others interested in understanding the vascular dynamics of the cerebral vessels and to researchers running clinical trials related to hormone replacement therapy.

Ovarian ultrasonography correlated with fecal progestins and estradiol during the estrous cycle and early pregnancy in giraffes (Giraffa camelopardalis rothschildi).

PubMed

Lueders, Imke; Hildebrandt, Thomas B; Pootoolal, Jason; Rich, Peter; Gray, Charlie S; Niemuller, Cheryl A

2009-11-01

Fecal and urinary progestin analyses have shown that giraffes express a short reproductive cycle, averaging 15 days, compared with other large ruminants. However, actual ovarian events have not been correlated with the hormonal pattern. In this study, mature cycling female Rothschild giraffes (Giraffa camelopardalis rothschildi) were repeatedly examined by transrectal ultrasonography to correlate ovarian function with changes in fecal progestin (fP4 [n(c) = 6]) and estradiol (fE2 [n(c) = 6]) and serum progestin (n(c) = 2) as measured by enzyme immunoassay. Five females became pregnant and were monitored during early gestation. In this study, we discovered that hormone values for fP4 in cycling giraffes do not correlate with the classic profile of follicular development, ovulation, and luteogenesis. The corpus luteum (CL) and the next dominant follicle were forming simultaneously. A mean +/- SD peak in fE2 of 254.92 +/- 194.76 ng/g and subsequent ovulation occurred as early as 1 day after the fall in fP4. In pregnant giraffes, the CL reached a diameter significantly larger (mean +/- SD, 41.02 +/- 2.70 mm; P = 0.0126) than that during the cycle (33.48 +/- 2.80 mm), while follicular activity and fluctuating fE2 were still present. With this research, we demonstrated that the progesterone profile typically used to characterize the ovarian cycle does not correlate with luteal development in the ovaries of this species. Furthermore, we conclude that the giraffe could have evolved a short reproductive cycle because of the almost parallel order of ovarian events.

The use of faecal progestin measurements to monitor reproductive activity in Mashona cows in a smallholder farming area of Zimbabwe.

PubMed

Masunda, B; Mutisi, C; Hamudikuwanda, H; Agumbah, J G O

2002-07-01

The objectives of this study were to investigate the relationship between the concentrations of progesterone (P4) in the peripheral circulation and progestins in the faeces of cows in a smallholder farming area and to monitor the ovarian activity of such cows. The study was carried out in Sanyati smallholder farming area, located 250 km southwest of Harare. Blood and faecal samples for P4 and progestin determination, respectively, were obtained once a week from 35 Mashona type cows that belonged to farmers from three different villages. The cows were weighed once every month and all births were recorded. The concentrations of progestins in faeces and P4 in plasma were positively correlated (r = 0.72, p < 0.01). Most of the non-pregnant cows (65%) cycled during the rainy season. Most of those that were acyclic at this time were undergoing post-partum anoestrus. During the dry season, most cows (58%) became acyclic as forage became scarce and of poor quality. Thirty-two calves were born during the study period, mostly during the first or last two months of the year, when there was enough forage. The mean calving to first oestrus in 14 cows that recalved was 71 +/- 49 days. Eight of these 14 cows conceived again, the calving to conception interval being 173 +/- 94 days. The cows' liveweights were highest in April, at the end of the rainy season. By the end of the dry season, the cows had lost, on average, 15% of their peak weight.

The influence of exogenous progestin on the occurrence of proestrous or estrous signs, plasma concentrations of luteinizing hormone and estradiol in deslorelin (GnRH agonist) treated anestrous bitches.

PubMed

Sung, M; Armour, A F; Wright, P J

2006-10-01

The objectives of this study were to confirm: (i) whether progestin treatment suppressed GnRH agonist-induced estrus in anestrous greyhound bitches; and (ii) the site of progestin action (i.e. pituitary, ovary). All bitches received a deslorelin implant on Day 0 and blood samples were taken from -1 h to +6 h. Five bitches were treated with megestrol acetate (2 mg/kg orally once daily) from -7 d to +6 d (Group 1) and 10 bitches were untreated controls (Group 2). Proestrous or estrous signs were observed in 4 of 5 bitches in Group 1, and 4 of 10 bitches in Group 2 (P = 0.28). The plasma LH responses (area under the curve from 0 to 6h after implantation) were higher (P = 0.008) in Group 2 than in Group 1. Plasma LH responses were similar (P = 0.59) in bitches showing signs of proestrus or estrus (responders) and in non-responders. The plasma estradiol responses (calculated as for LH response) were greater in Group 1 than in Group 2 (P = 0.048), and in responders than in non-responders (P = 0.02). (i) progestin treatment (a) did not suppress the incidence of bitches showing deslorelin-induced proestrus or estrus, and (b) was associated with a reduced pituitary responsiveness and an increased ovarian responsiveness to deslorelin treatment; (ii) the occurrence of proestrous or estrous signs reflected increased ovarian responsiveness to induced gonadotrophin secretion and not increased pituitary responsiveness to deslorelin.

Comparative Study of the Effects of Combined Oral Contraceptives in Hemostatic Variables

PubMed Central

Stocco, Bianca; Fumagalli, Helen F.; Franceschini, Silvio A.; Martinez, Edson Z.; Marzocchi-Machado, Cleni M.; de Sá, Marcos Felipe S.; Toloi, Maria Regina T.

2015-01-01

Abstract Thrombotic risk is associated with the estrogen dose and type of progestin in combined oral contraceptives. Studies published since 1990 showed that third-generation progestins have larger risk to contribute to thrombosis development than the second-generation. However, there are conflicts in the literature regarding the thrombotic risk associated to the drospirenone progestin. So, this study aimed to evaluate the effects of 3 formulations of contraceptives containing ethinylestradiol (EE) (20 and 30 μg) combined with drospirenone versus levonorgestrel combined with EE (30 μg) in hemostatic parameters. This cross-sectional study included 70 healthy women between 18 and 30 years, BMI 19 to 30 kg/m2, not pregnant, non-smokers, and users or non-users (control) of contraceptives for a minimum period of 6 months. The following parameters were assessed: prothrombin time (PT), Factor VII, activated partial thromboplastin time (aPTT), Factor XII, fibrinogen, Factor 1 + 2, Protein C, Protein S, antithrombin, D-dimers, and plasminogen activator inhibitor-1. Significant alterations were found in PT, aPTT, fibrinogen, D-dimers, and protein S, all favoring a state of hypercoagulation for contraceptive containing DRSP/20EE. Both contraceptives containing DRSP/30EE and LNG/30EE promoted changes that favor the hypercoagulability in the coagulant variable PT and in the anticoagulant variables Protein S and Protein C, respectively. We suggest that the progestin drospirenone can contribute to an inadequate balance among procoagulant, anticoagulant, and fibrinolytic factors, since that the contraceptive containing the lowest dose of estrogen and drospirenone (DRSP/20EE) caused a higher number of hemostatic changes. PMID:25634167

Progesterone potentiates the growth inhibitory effects of calcitriol in endometrial cancer via suppression of CYP24A1.

PubMed

Bokhari, Amber A; Lee, Laura R; Raboteau, Dewayne; Turbov, Jane; Rodriguez, Isabel V; Pike, John Wesley; Hamilton, Chad A; Maxwell, George Larry; Rodriguez, Gustavo C; Syed, Viqar

2016-11-22

Here, we evaluated the expression of CYP24A1, a protein that inactivates vitamin D in tissues. CYP24A1 expression was increased in advanced-stage endometrial tumors compared to normal tissues. Similarly, endometrial cancer cells expressed higher levels of CYP24A1 than immortalized endometrial epithelial cells. RT-PCR and Western blotting were used to examine CYP24A1 mRNA and protein levels in endometrial cancer cells after 8, 24, 72, and 120 h of exposure to progesterone, progestin derivatives and calcitriol, either alone or in combination. Progestins inhibited calcitriol-induced expression of CYP24A1 and splice variant CYP24SV mRNA and protein in cancer cells. Furthermore, actinomycin D, but not cycloheximide, blocked calcitriol-induced CYP24A1 splicing. siRNA-induced knockdown of CYP24A1 expression sensitized endometrial cancer cells to calcitriol-induced growth inhibition. These data suggest that CYP24A1 overexpression reduces the antitumor effects of calcitriol in cancer cells and that progestins may be beneficial for maintaining calcitriol's anti-endometrial cancer activity.

Hormonal Contraceptives Differentially Suppress TFV and TAF Inhibition of HIV Infection and TFV-DP in Blood and Genital Tract CD4+ T cells.

PubMed

Shen, Zheng; Rodriguez-Garcia, Marta; Patel, Mickey V; Bodwell, Jack; Kashuba, Angela D M; Wira, Charles R

2017-12-18

HIV prevention research is focused on combining antiretrovirals (ARV) and progestin contraceptives to prevent HIV infection and pregnancy. The possibility that progestins compromise ARV anti-HIV activity prompted us to evaluate the effects of progestins on tenofovir (TFV) and TFV-alafenamide (TAF) on HIV infection and intracellular TFV-diphosphate (TFV-DP) concentrations in blood and genital CD4+ T cells. Following incubation of blood CD4+ T cells with TFV or TAF, Medroxyprogesterone acetate (MPA), but not Levonorgestrel, Norethisterone or progesterone, suppressed the anti-HIV effect of TFV by reducing intracellular TFV-DP, but had no effect on TAF inhibition of infection or TFV-DP. In contrast, with genital CD4+ T cells, MPA suppressed TAF inhibition of HIV infection and lowered of TFV-DP concentrations without affecting TFV protection. These findings demonstrate that MPA selectively compromises TFV and TAF protection in blood and genital CD4+ T cells and suggests that MPA may decrease ARV protection in individuals who use ARV intermittently for prevention.

Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.

PubMed

Wei, Daimin; Shi, Yuhua; Li, Jing; Wang, Ze; Zhang, Lin; Sun, Yun; Zhou, Hong; Xu, Yuping; Wu, Chunxiang; Liu, Ling; Wu, Qiongfang; Zhuang, Lili; Du, Yanzhi; Li, Weiping; Zhang, Heping; Legro, Richard S; Chen, Zi-Jiang

2017-02-01

Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)? OCs used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs. Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth. This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014. At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups. With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66-0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61-0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28-3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth. The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study. Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings. This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures. Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome

PubMed Central

Wei, Daimin; Shi, Yuhua; Li, Jing; Wang, Ze; Zhang, Lin; Sun, Yun; Zhou, Hong; Xu, Yuping; Wu, Chunxiang; Liu, Ling; Wu, Qiongfang; Zhuang, Lili; Du, Yanzhi; Li, Weiping; Zhang, Heping; Legro, Richard S.; Chen, Zi-Jiang

2017-01-01

Abstract STUDY QUESTION Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER OCs used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs. WHAT IS KNOWN ALREADY Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth. STUDY DESIGN, SIZE, DURATION This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups. MAIN RESULTS AND THE ROLE OF CHANCE With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66–0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61–0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28–3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth. LIMITATIONS, REASONS FOR CAUTION The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures. TRIAL REGISTRATION NUMBER Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528. PMID:27999118

Aqueous exposure to the progestin, levonorgestrel, alters anal fin development and reproductive behavior in the eastern mosquitofish (Gambusia holbrooki)

USGS Publications Warehouse

Frankel, Tyler E.; Meyer, Michael T.; Orlando, Edward F.

2016-01-01

Endogenous progestogens are important regulators of vertebrate reproduction. Synthetic progestins are components of human contraceptive and hormone replacement pharmaceuticals. Both progestogens and progestins enter the environment through a number of sources, and have been shown to cause profound effects on reproductive health in various aquatic vertebrates. Progestins are designed to bind human progesterone receptors, but they also have been shown to strongly activate androgen receptors in fish. Levonorgestrel (LNG) activates fish androgen receptors and induces development of male secondary sex characteristics in females of other species. Although behavior has been postulated to be a sensitive early indicator of exposure to certain environmental contaminants, no such research on the reproductive behavior of gestagen-exposed fish has been conducted to date. The goal of our study was to examine the exposure effects of a human contraceptive progestin, LNG, on the reproductive development and behavior of the viviparous eastern mosquitofish (Gambusia holbrooki). Internal fertilization is a requisite characteristic of viviparous species, and is enabled by an androgen driven elongation of the anal fin into the male gonopodium (i.e., phallus). In this study, we exposed adult mosquitofish to ethanol (EtOH control), 10 ng/L, and 100 ng/L LNG for 8 d using a static replacement exposure design. After 8 d, a subset of males and females from each treatment were examined for differences in the 4:6 anal fin ratio. In addition, paired social interaction trials were performed using individual control males and control females or females treated 10 ng/L or 100 ng/L LNG. Female mosquitofish exposed to LNG were masculinized as evidenced by the elongation of the anal fin rays, a feature normal to males and abnormal to females. LNG caused significant increases in the 4:6 anal fin ratios of female mosquitofish in both the 10 ng/L and 100 ng/L treatments, although these differences were not significant between the two treatments. LNG caused significant increases in the 4:6 anal fin ratio of males exposed to 100 ng/L, with no effects observed in the 10 ng/L treatment. In addition, the reproductive behavior of control males paired with female mosquitofish exposed to 100 ng/L LNG was also altered, for these males spent more time exhibiting no reproductive behavior, had decreased attending behavior, and a lower number of gonopodial thrusts compared to control males paired to control female mosquitofish. Given the rapid effects on both anal fin morphology and behavior observed in this study, the mosquitofish is an excellent sentinel species for the detection of exposure to LNG and likely other 19-nortestosterone derived contraceptive progestins in the environment.

Effects of estrogens and progestins on high density lipoproteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauss, R.M.; Lindgren, F.T.; Wingerd, J.

High density lipoprotein (HDL) levels are knwon to be higher in women than in men, and to increase with estrogen use. To assess the effects of estrogens on HDL subspecies, analytic ultracentrifuge measurements of HDL were compared in 11 menopausal estrogen users and 16 controls. The difference in mean schlieren patterns between the groups showed a significantly higher level of HDL with flotation rate (F/sub 1/ /sub 20//sup 0/) > 1.5 (predominantly HDL/sub 2/) in the users. This was similar to the difference in HDL seen between nonusers of hormones and age-matched males. A previous study had shown that usersmore » of combination oral contraceptives had increased levels of HDL with F/sub 1/ /sub 20//sup 0/ less than or equal to 3.5 (primarily HDL/sub 3/) suggesting that the estrogen effect on HDL is altered by the presence of added progestin. The progestin effect was studied here in detail in two women with type V hyperlipoproteinemia treated with norethindrone acetate. Reduction in serum triglyceride was accompanied by a reduction in HDL, predominantly in the less dense species (HDL/sub 2/). Among groups of oral contraceptive and noncontraceptive estrogen and progestin users whose HDL-cholesterol levels have been reported recently, there was a direct correlation (r = 0.86, p < .001) between mean HDL-cholesterol and triglyceride levels. Endogenous hormonal influences on HDL were assessed by serum hormone and lipoprotein measurements at weekly intervals during two consecutive menstrual cycles in four healthy females. An increase in HDL of highest flotation rate (F/sub 1/ /sub 20//sup 0/ 5 to 9) was seen, which corresponded with the time of ovulation, raising the possibility of pituitary as well as gonadal hormone effects on HDL.« less

Comparison of 7α-methyl-19-nortestosterone effectiveness alone or combined with progestins on androgen receptor mediated-transactivation.

PubMed

García-Becerra, Rocío; Ordaz-Rosado, David; Noé, Gabriela; Chávez, Bertha; Cooney, Austin J; Larrea, Fernando

2012-02-01

7α-methyl-19-nortestosterone (MENT) is an androgen with potent gonadotropin inhibitory activity and prostate-sparing effects. These attributes give MENT advantages over testosterone as a male contraceptive, but, as in the case of testosterone, a partial dose-dependent suppression of spermatogenesis has been observed. Combination of testosterone or MENT with synthetic progestins improves the rate of azoospermia; however, it is unknown whether these combinations affect hormone androgenicity or exert synergistic effects via progestational or androgenic interaction. Herein, using transactivation assays, we examined the ability of MENT alone or combined with several 19-nor-derived synthetic progestins to activate androgen receptor (AR)-dependent gene transcription. In addition, the capability of 7α-methyl-estradiol (7α-methyl-E(2)), an aromatized metabolite of MENT, to transactivate gene transcription via estrogen receptor α (ERα; ESR1) or ERβ (ESR2) was also investigated. As expected, MENT induced gene transactivation through either the progesterone receptor (PGR) or the AR. MENT was as efficient as progesterone in activating PGR-mediated reporter gene expression, but it was ten times more potent than testosterone and dihydrotestoterone in activating of AR-driven gene expression. The addition of increasing concentrations of other 19-nortestosterone derivatives (norethisterone or levonorgestrel) did not affect, in a significant manner, the ability of MENT to activate AR-dependent reporter gene transcription. The same results were obtained with different cell lines. 7α-Methyl-E(2) resulted in potent estrogen activity via both ER subtypes with efficiency similar to natural E(2). These results suggest that the addition of 19-nortestosterone-derived progestins, as a hormonal adjuvant in male fertility strategies for effective spermatogenic suppression, does not display any detrimental effect that would interfere with MENT androgenic transcriptional activity.

Postmenopausal Hormone Use and the Risk of Nephrolithiasis

PubMed Central

Maalouf, Naim M.; Sato, Alicia H.; Welch, Brian J.; Howard, Barbara V.; Cochrane, Barbara B.; Sakhaee, Khashayar; Robbins, John A.

2012-01-01

Background Observational studies examining the role of estrogen in the risk of kidney stone formation have shown conflicting results. However, randomized trial evidence on nephrolithiasis risk with estrogen therapy in postmenopausal women is lacking. Methods We reviewed the incidence of nephrolithiasis in the Women’s Health Initiative estrogen-alone and estrogen plus progestin trials conducted at 40 US clinical centers. A total of 10 739 postmenopausal women with hysterectomy were randomized to receive 0.625 mg/d of conjugated equine estrogens (CEE) or placebo, and 16 608 postmenopausal women without hysterectomy were randomized to receive placebo or estrogen plus progestin given as CEE plus medroxyprogesterone acetate (2.5 mg/d). The incidence of nephrolithiasis was determined for an average follow-up of 7.1 years for the CEE trial and 5.6 years for the estrogen plus progestin trial. Results Baseline demographic characteristics and risk factors for nephrolithiasis were similar in the placebo and treatment arms. Estrogen therapy was associated with a significant increase in nephrolithiasis risk from 34 to 39 cases per 10 000 person-years (hazard ratio, 1.21; 95% confidence interval, 1.03-1.44). Censoring data from women when they ceased to adhere to study medication increased the hazard ratio to 1.39 (95% confidence interval, 1.08-1.78). The increased nephrolithiasis risk was independent of progestin coadministration, and effects did not vary significantly according to prerandomization history of nephrolithiasis. Conclusions These data suggest that estrogen therapy increases the risk of nephrolithiasis in healthy postmenopausal women. These findings should be considered in decision making regarding postmenopausal estrogen use. The mechanisms underlying this higher susceptibility remain to be determined. PMID:20937929

Endoplasmic reticulum stress in complex atypical hyperplasia as a possible predictor of occult carcinoma and progestin response.

PubMed

Tierney, Katherine E; Ji, Lingyun; Dralla, Shannon S; Yoo, Eunjeong; Yessaian, Annie; Pham, Huyen Q; Roman, Lynda; Sposto, Richard; Mhawech-Fauceglia, Paulette; Lin, Yvonne G

2016-12-01

Glucose-regulated protein (GRP)-78, the key regulator of endoplasmic reticulum (ER) stress, is associated with endometrial cancer (EC) development and progression. However, its role in the continuum from complex atypical hyperplasia (CAH) to EC is unknown and the focus of this study. 252 formalin-fixed, paraffin-embedded endometrial biopsies from patients with CAH diagnosed between 2003 and 2011 were evaluated for GRP78 expression by immunohistochemistry. Expression was also evaluated in subsequent biopsies from those patients treated with progestins. Differences in GRP78 expression were assessed using standard statistical methods. GRP78 expression was undetectable in 45(18%) patients with CAH, while 120(48%) CAH cases showed moderate/strong expression. Among women who ultimately underwent hysterectomy for CAH (n=134), 54(40%) had occult EC while 57(43%) had persistent CAH. Those with occult EC upon hysterectomy had significantly stronger GRP78 expression than those who did not have occult EC (p=0.007). Greater GRP78 expression within CAH remained independently associated with the presence of an occult EC (p=0.017). Thirty-four of 54 (63%) patients with occult EC had moderate/strong GRP78 expression compared to 36 of 80 (45%) patients with persistent CAH, benign or non-atypical hyperplastic endometrium. In those treated with progestins, samples with persistent CAH and EC were more likely to have high levels of GRP78 expression in the initial biopsies than those who responded (p=0.014). Increased GRP78 expression in untreated CAH correlates with the presence of an occult EC. In addition, CAH specimens with greater GRP78 expression may identify patients who are less likely to respond to progestin therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Additive effects of levonorgestrel and ethinylestradiol on brain aromatase (cyp19a1b) in zebrafish specific in vitro and in vivo bioassays.

PubMed

Hinfray, N; Tebby, C; Garoche, C; Piccini, B; Bourgine, G; Aït-Aïssa, S; Kah, O; Pakdel, F; Brion, F

2016-09-15

Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-transfected with zebrafish estrogen receptors (zfERs) and the luciferase gene under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentration-response relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures. Copyright © 2016 Elsevier Inc. All rights reserved.

Are hormonal components of oral contraceptives associated with impaired female sexual function? A questionnaire-based online survey of medical students in Germany, Austria, and Switzerland.

PubMed

Wallwiener, Christian W; Wallwiener, Lisa-Maria; Seeger, Harald; Schönfisch, Birgitt; Mueck, Alfred O; Bitzer, Johannes; Zipfel, Stephan; Brucker, Sara Y; Taran, Florin-Andrei; Wallwiener, Markus

2015-10-01

To investigate in a large cohort of young university women whether different progestins and different ethinyl estradiol (EE) dosages in oral hormonal contraceptives (OHCs) adversely affect sexual function. Female medical students from German, Austrian, and Swiss universities (14/1/1) completed an anonymous online questionnaire comprising the 19 Female Sexual Function Index (FSFI) questions and 17 additional questions concerning demographics, lifestyle, sexual activity, and contraceptive use. OHCs were categorized by EE dose (≤20, <20 to ≤30, and >30 µg) and partially androgenic or antiandrogenic progestins. FSFI scores were analyzed by contraceptive method using descriptive statistics and standard nonparametric tests. We analyzed 2612 questionnaires submitted by respondents aged ≤30 years [mean age (SD) 23.5 (2.5) years]. Of 2126 contraceptive users, 1535 (72.2 %) used OHCs. Median FSFI total scores (ranges) were 28.2 (2.0-36.0) for all respondents. Median FSFI was significantly lower in non-users (24.4) versus users (28.7) of contraception (p < 0.001). Stratified analysis showed that 279/486 (57.4 %) respondents using no contraceptives, 563/1535 (36.7 %) using OHCs, 71/227 (31.3 %) using non-oral hormonal contraceptives, and 96/351 (27.4 %) using non-hormonal contraceptives were at risk for female sexual dysfunction (FSFI total score <26.55). FSFI scores for the three EE dosage categories and progestin components did not differ significantly. For OHCs, the FSFI score was lower than for other contraceptives but there was no significant association with EE dose or progestins, possibly due to small sample sizes. Further research needs to clarify the role of OHCs in female sexual function.

Choosing the Right Oral Contraceptive Pill for Teens.

PubMed

Powell, Anne

2017-04-01

Oral contraceptive pills (OCPs) continue to be the most commonly used form of prescription contraceptives used by adolescents in the United States. With proper use, oral contraceptives provide safe and effective birth control. Broad categories of OCPs include progestin-only pills (POPs) and combined oral contraceptive pills (COCs). Certain types of progestins have more potent antiandrogenic properties and are more effective in treating acne, hirsutism, and polycystic ovary syndrome. This article reviews types of OCPs, discusses risks and benefits of OCPs, and provides guidance for how to choose the most beneficial and appropriate OCP for individual adolescent patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Preclinical and clinical properties of trimegestone: a potent and selective progestin.

PubMed

Sitruk-Ware, Regine; Bossemeyer, Ronald; Bouchard, Phillipe

2007-06-01

Trimegestone (TMG) is a novel, 19-norpregnane progestin with potent and selective properties. In preclinical studies, TMG has been shown to provide high endometrial selectivity. Further, TMG has high affinity and selectivity for the progesterone receptor and lacks the agonist effects of other steroid hormones. In clinical studies, TMG has been shown to have high endometrial safety and an improved bleeding profile along with improved tolerability compared with other progestins. In addition, TMG also does not impede the beneficial effects of estrogen, especially on bone, and does not compromise quality of life. The preclinical findings of lack of mineralocorticoid activity of TMG were supported in clinical findings, with neutral effect on body weight. Similarly, the smaller effect of TMG on the GABA-ergic (gamma-aminobutyric acid) system in preclinical studies is consistent with the improvement of central nervous system-related effects on depressed mood and sleep quality in clinical studies. Low-dose estradiol/TMG regimens provide rapid relief from menopausal symptoms, reducing the number and severity of hot flushes as effectively as 2 mg 17beta-estradiol/1 mg norethisterone acetate. Therefore, it may be concluded that TMG provides a clinically proven option in hormone therapy for both clinicians and patients.

Progesterone from maternal circulation binds to progestin receptors in fetal brain.

PubMed

Wagner, Christine K; Quadros-Mennella, Princy

2017-06-01

Steroid hormones activate nuclear receptors which, as transcription factors, can regulate critical aspects of neural development. Many regions of the rat forebrain, midbrain and hindbrain express progestin receptors (PR) during perinatal life, suggesting that progesterone may play an important role in the development of the brain. An immunohistochemical approach using two antibodies with differential recognition of ligand-bound PR was used to examine whether fetuses are exposed to maternal progesterone during pregnancy and whether progesterone from maternal circulation can bind to PR within the fetal brain. Findings demonstrate that maternal and fetal serum progesterone levels are positively correlated at the end of gestation, suggesting a common source of progesterone in mothers and fetuses (e.g., the maternal ovary). Additional findings suggest that administration of exogenous progesterone to mothers not only increases fetal serum progesterone levels within 2 h, but appears to increase ligand-bound PR in fetal brain. These findings suggest that progesterone of maternal origin may play a previously overlooked role in neural development. In addition, there are implications for the ongoing prophylactic use of synthetic progestins in pregnant women for the prevention of premature birth. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 767-774, 2017. © 2016 Wiley Periodicals, Inc.

Increased cleavage and blastocyst rate in ewes treated with bovine somatotropin 5 days before the end of progestin-based estrous synchronization.

PubMed

Montero-Pardo, A; Hernández-Cerón, J; Rojas-Maya, S; Valencia, J; Rodríguez-Cortez, A; Gutiérrez, C G

2011-05-01

Treatment with bovine somatotropin (bST) during estrous synchronization increased fertility and prolificacy in sheep. In the present study, a single dose of bST 5 days before the end of progestin treatment improved cleavage and embryo development. Stage of estrous cycle was synchronized in ewes (n=32) with progestin and superovulation was induced by use of FSH. Five days before the end of progestin treatment, ewes were randomly assigned to two groups: bST group (n=16) received a depot injection of 125 mg of bST sc (Lactotropina, Elanco, México) and the control group (n=16) received saline solution. Estrous was detected with rams fitted with an apron every 2 h and estrous sheep were mated every 8 h whilst in estrous. Embryos were recovered on Day 7 post mating, assessed microscopically and fixed in 4% paraformaldehyde. Cell number in blastocysts was counted after Hoechst 33342 staining. Plasma concentrations of IGF-I, insulin and progesterone were determined in eight sheep per group from the day of bST treatment to the day of embryo recovery. Cleavage rate, percentage of transferable embryos (transferable embryos/cleaved) and percentage of embryos reaching the blastocyst stage (blastocyst/cleaved) were compared between groups by logistic regression. IGF-I, insulin and progesterone plasma concentrations were analyzed by ANOVA for repeated measurements and cell number by ANOVA. Cleavage rate was greater (P<0.01) in bST treatment group (86%) than in the control group (62%). Similarly, the proportion of embryos reaching the blastocyst stage (bST=68.7 vs control=42.5) and the number of cells per blastocyst (bST group 91.8±5.5 compared to control group 75±6) were greater (P<0.01) in the bST-treated sheep. Plasma concentrations of IGF-I and insulin were greater (P<0.01) in the bST-treated group. No changes were observed in progesterone concentrations (P=0.5). It is concluded that bST injection 5 days before progestin removal increases cleavage rate and the proportion of embryos that reach the blastocyst stage. These effects are associated with an increase in IGF-I and insulin concentrations. Copyright © 2011 Elsevier B.V. All rights reserved.

Progestin effects on expression of AKR1C1-AKR1C3, SRD5A1 and PGR in the Z-12 endometriotic epithelial cell line.

PubMed

Beranič, Nataša; Lanišnik Rižner, Tea

2013-02-25

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. This disease is associated with diminished protective effects of progesterone, which are usually explained by inadequate activation of progesterone receptors and also enhanced pre-receptor metabolism of progesterone. Endometriosis is often treated with progestins, which act as progesterone receptor agonists, although their exact mechanisms of action are not completely understood. The aim of the present study was to investigate how the progestins medroxyprogesterone acetate, dydrogesterone and dienogest, as well as progesterone, impact on the expression of genes of pre-receptor progesterone metabolism in Z-12 epithelial cell line, a model system of peritoneal endometriosis. Our data demonstrate that these progestins affect local pre-receptor metabolism to a different extent. The most favorable effects were seen for dydrogesterone and dienogest, where the first, dydrogesterone, significantly reduced SRD5A1, AKR1C2 and AKR1C3 expression, and additionally had a nonsignificant impact on progesterone receptor B (PR-B) protein levels. This might slow down the first step of pre-receptor metabolism, the conversion of progesterone to 5α-dihydroprogestrone by SRD5A1, and it might also affect further reduction of 3-keto and 20-keto groups catalyzed by AKR1C2 and AKR1C3. Similarly favorable effects were seen for dienogest, which promoted significant reduction of AKR1C1 and AKR1C2 expression and also showed no effect on PR-B protein levels. Different effects were seen for progesterone, which significantly decreased SRD5A1, PR-B and HSD17B2 protein levels. In contrast, treatment with medroxyprogesterone acetate resulted in increased AKR1C1 expression and decreased levels of PR-B, which might lead to enhanced progesterone metabolism and reduced signaling through progesterone receptors. Altogether, our data in this Z-12 cell model suggest that the beneficial effects of treatment with progestin observed in endometriosis patients might arise from decreased pre-receptor metabolism of the protective progesterone by the SRD5A1 and AKR1C enzymes. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Exposure to the contraceptive progestin, gestodene, alters reproductive behavior, arrests egg deposition, and masculinizes development in the fathead minnow (Pimephales promelas)

USGS Publications Warehouse

Frankel, Tyler E.; Meyer, Michael T.; Kolpin, Dana W.; Gillis, Amanda B.; Alvarez, David A.; Orlando, Edward F.

2016-01-01

Endogenous progestogens and pharmaceutical progestins enter the environment through wastewater treatment plant effluent and agricultural field runoff. Lab studies demonstrate strong, negative exposure effects of these chemicals on aquatic vertebrate reproduction. Behavior can be a sensitive, early indicator of exposure to environmental contaminants associated with altered reproduction yet is rarely examined in ecotoxicology studies. Gestodene is a human contraceptive progestin and a potent activator of fish androgen receptors. Our objective was to test the effects of gestodene on reproductive behavior and associated egg deposition in the fathead minnow. After only 1 day, males exposed to ng/L of gestodene were more aggressive and less interested in courtship and mating, and exposed females displayed less female courtship behavior. Interestingly, 25% of the gestodene tanks contained a female that drove the male out of the breeding tile and displayed male-typical courtship behaviors toward the other female. Gestodene decreased or arrested egg deposition with no observed gonadal histopathology. Together, these results suggest that effects on egg deposition are primarily due to altered reproductive behavior. The mechanisms by which gestodene disrupts behavior are unknown. Nonetheless, the rapid and profound alterations of the reproductive biology of gestodene-exposed fish suggest that wild populations could be similarly affected.

Hormonal contraceptive use and women's risk of HIV acquisition: priorities emerging from recent data.

PubMed

Ralph, Lauren J; Gollub, Erica L; Jones, Heidi E

2015-12-01

Understanding whether hormonal contraception increases women's risk of HIV acquisition is a public health priority. This review summarizes recent epidemiologic and biologic data, and considers the implications of new evidence on research and programmatic efforts. Two secondary analyses of HIV prevention trials demonstrated increased HIV risk among depot medroxyprogesterone acetate (DMPA) users compared with nonhormonal/no method users and norethisterone enanthate (NET-EN) users. A study of women in serodiscordant partnerships found no significant association for DMPA or implants. Two meta-analyses found elevated risks of HIV among DMPA users compared with nonhormonal/no method users, with no association for NET-EN or combined oral contraceptive pills. In-vitro and animal model studies identified plausible biological mechanisms by which progestin exposure could increase risk of HIV, depending on the type and dose of progestin, but such mechanisms have not been definitively observed in humans. Recent epidemiologic and biologic evidence on hormonal contraception and HIV suggests a harmful profile for DMPA but not combined oral contraceptives. In limited data, NET-EN appears safer than DMPA. More research is needed on other progestin-based methods, especially implants and Sayana Press. Future priorities include updating modeling studies with new pooled estimates, continued basic science to understand biological mechanisms, expanding contraceptive choice, and identifying effective ways to promote dual method use.

A longitudinal study of disturbances of the hypothalamic-pituitary-adrenal axis in women with progestin-negative functional hypothalamic amenorrhea.

PubMed

Kondoh, Y; Uemura, T; Murase, M; Yokoi, N; Ishikawa, M; Hirahara, F

2001-10-01

To longitudinally evaluate disturbances of the hypothalamic-pituitary-adrenal (HPA) axis in women with secondary progestin-negative hypothalamic amenorrhea. Retrospective cohort study. Yokohama City University, Yokohama, Japan. Twenty-four women with progestin-negative hypothalamic amenorrhea. Administration of human corticotropin-releasing hormone (hCRH) and treatment with a combination of estrogen and progesterone. Plasma cortisol and ACTH concentrations and period required for recovery from amenorrhea. Plasma ACTH concentrations 30 and 60 minutes after injection of hCRH and the percent maximum increment (%Cmax) of ACTH were significantly lower in the amenorrheic patients compared with the control group patients. The basal cortisol was significantly higher, and the %Cmax of cortisol was significantly lower. In the 16 patients who recovered from amenorrhea, there was a significant positive correlation (Y = 1.93X-10.8, r = 0.629) between the basal cortisol concentrations (X) and the period for recovery (Y). The serum E2 gradually increased before recovery, and this E2 increase was preceded by changes in the plasma cortisol concentration and the %Cmax values of cortisol and ACTH. The CRH test might be useful for evaluating the roles of stress and for estimating the period required for recovery in hypothalamic amenorrhea.

Progesterone and synthetic progestin, dienogest, induce apoptosis of human primary cultures of adenomyotic stromal cells.

PubMed

Yamanaka, Akiyoshi; Kimura, Fuminori; Kishi, Yohei; Takahashi, Kentaro; Suginami, Hiroshi; Shimizu, Yutaka; Murakami, Takashi

2014-08-01

To investigate the direct effects of progesterone receptor (PR) agonists on proliferation and apoptosis of human adenomyotic cells. Human primary cultures of adenomyotic stromal cells (ASCs) from 24 patients with adenomyosis were co-treated with estradiol (E2) plus the PR agonists, endogenous progesterone (P) or the synthetic progestin dienogest (DNG), which is used to treat endometriosis. In ASCs, anti-proliferative effects and induction of apoptosis were evaluated in the presence or absence of P (10(-8)-10(-6)M) or DNG (10(-8)-10(-6)M) in culture medium containing E2. Cellular proliferation was analyzed with bromodeoxyuridine incorporation and flow cytometry. Apoptosis was detected with annexin V/7-amino-actinomycin D (7-AAD) staining with flow cytometry and cellular caspase 3/7 activity. P and DNG significantly decreased the proportion of cells in the S phase. In addition, both P and DNG increased apoptosis as measured by annexin V-positive/7-AAD -negative cells and caspase 3/7 activity. Both endogenous P and synthetic progestin directly inhibited cellular proliferation and induced apoptosis in human ASCs. These pharmacological features of progestational compounds provide insight into the therapeutic strategy for the treatment of adenomyosis. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Oral contraceptives cause evolutionarily novel increases in hormone exposure

PubMed Central

Lovett, Jennie L; Chima, Margo A; Wexler, Juliana K; Arslanian, Kendall J; Friedman, Andrea B; Yousif, Chantal B; Strassmann, Beverly I

2017-01-01

Abstract Background and objectives In the evolutionary past, women spent most of their reproductive lives either pregnant or in lactational amenorrhea, and rarely menstruated. The current pattern of frequent menses, and the associated increase in endogenous hormonal exposure, has been implicated in the current breast cancer epidemic. It is not known, however, whether oral contraceptives further increase, or actually decrease, hormonal exposure over one menstrual cycle. Here, we examined variation in hormonal exposure across seven oral contraceptive (OC) formulations, and produced the first quantitative comparison of exogenous versus endogenous hormone exposure. Methodology Data from 12 studies of serum estradiol (E2) and progesterone (P4) were aggregated to create a composite graph of endogenous hormone levels over one menstrual cycle in European or American women (age 19–40 years). Pharmacokinetic package insert data, also from Western women, were used to calculate exposures for hormones in seven different OC formulations. Endogenous and exogenous hormone levels were compared after adjusting for the relative binding affinity (RBA) of progestin to the progesterone receptor and ethinyl estradiol (EE) to the estrogen receptor. Results After adjusting for RBA, median ethinyl estradiol exposure across 28 days in the OCs was 11.4 nmol/l, similar to median E2 exposure. One formulation, however, was 40% higher in ethinyl estradiol exposure relative to median endogenous estradiol. Median exposure from progestins in OCs (1496 nmol/l) was 4-fold higher than the median endogenous exposure from P4 (364 nmol/l). Exposure from OC progestins ranged from one sixtieth to 8-fold median endogenous P4 over 28 days. Conclusions and implications Given that breast cancer risk increases with hormonal exposure, our finding that four widely prescribed formulations more than quadruple progestin exposure relative to endogenous progesterone exposure is cause for concern. As not all formulations produce the same exposures, these findings are pertinent to contraceptive choice. We also identify critical gaps in the provision of relevant data on pharmacokinetics and carcinogenicity by drug manufacturers. PMID:28685096

Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium

PubMed Central

Flannery, Clare A.; Fleming, Andrew G.; Choe, Gina H.; Naqvi, Hanyia; Zhang, Margaret; Sharma, Anu

2016-01-01

Endometrial cancer develops during exposure to estrogen unopposed by progesterone. Traditional formulations for menopausal hormone therapy include a progestin in women with a uterus. However, progestin exposure increases breast cancer risk in postmenopausal women. Alternatives to progestin include bazedoxifene (BZA), a selective estrogen receptor modulator, which prevents estrogen induced endometrial hyperplasia in clinical trials. Molecular mechanisms responsible for BZA's antiproliferative effect are not fully elucidated. We profiled endometrial adenocarcinoma, hyperplasia, and normal proliferative endometrium for differential expression in genes known to be regulated by estrogens or progesterone. Fibroblast growth factor (FGF)18, a paracrine growth factor promoting epithelial proliferation, was significantly increased in adenocarcinoma. Progesterone represses FGF18 by inducing heart and neural crest derivatives expressed transcript 2 (HAND2) in stromal cells. Notably, we confirmed lower HAND2 mRNA in adenocarcinoma, along with higher FGF tyrosine kinase receptor 2 and E74-like factor 5, collectively promoting FGF18 activity. We hypothesized BZA reduces epithelial proliferation by inhibiting FGF18 synthesis in stromal cells. To determine whether BZA regulates FGF18, we treated primary stromal cells with BZA or vehicle. In vitro, BZA reduced FGF18, but did not affect, HAND2. CD1 female mice received either BZA, conjugated estrogen (CE), or combined BZA/CE for 8 weeks. CE-treated mice had nearly 3-fold higher FGF18 expression. In contrast, BZA-treated mice, alone or with CE, had similar FGF18 as controls. Unexpectedly, BZA, alone or with CE, reduced HAND2 more than 80%, differing from progesterone regulation. Reduction of FGF18 is a potential mechanism by which BZA reduces endometrial proliferation and hyperplasia induced by estrogens. However, BZA works independently of HAND2, revealing a novel mechanism for progestin-free hormone therapy in postmenopausal women. PMID:27267714

The progestin norethisterone affects thyroid hormone-dependent metamorphosis of Xenopus laevis tadpoles at environmentally relevant concentrations.

PubMed

Lorenz, Claudia; Krüger, Angela; Schöning, Viola; Lutz, Ilka

2018-04-15

Previously, levonorgestrel (LNG) has been shown to be an endocrine disruptor of the amphibian thyroid system. In the present study, we investigated whether anti-thyroidal effects are a common property of progestins other than LNG. Premetamorphic Xenopus laevis tadpoles were exposed to norethisterone (NET) and dienogest DIE (each at 0.1-10nM) and LNG (10nM) until completion of metamorphosis. LNG and NET at all concentrations caused a significant developmental retardation whereas DIE did not impair time to metamorphosis. In LNG and 10nM NET exposed animals, tsh mRNA levels increased considerably later than the developmental delay occurred and thyroid histopathology showed no signs of TSH-hyperstimulation. Instead, thyroid glands from these treatments appeared inactive in producing thyroid hormones. Thyroidal transcript levels of dio2 and dio3 were increased by treatments with LNG and NET at 1nM and 10nM, whereas iyd mRNA was reduced by LNG and 10nM NET. Expression of slc5α5 was not changed by any treatment. Effects of DIE differed from those induced by LNG and NET. No developmental delay was measurable; however, tshβ and dio2 mRNAs were increased in pituitary glands of tadpoles exposed to 1.0nM and 10nM DIE. Thyroid histopathology displayed no abnormalities and thyroidal mRNA expression of the genes analyzed (slc5α5, iyd, dio2, dio3) was not changed by DIE. Overall, our results provide evidence that the anti-thyroidal effects already known from LNG are also present in another progestin, namely NET, even at environmentally relevant concentrations. In conclusion we suggest that progestins do not only pose an environmental risk in terms of their impact on reproductive success of aquatic vertebrates, but also with respect to their anti-thyroidal properties affecting amphibian metamorphosis. Copyright © 2017 Elsevier Inc. All rights reserved.

A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder.

PubMed

Rapkin, Andrea

2003-08-01

Severe premenstrual syndrome (PMS) and, more recently, premenstrual dysphoric disorder (PMDD) have been studied extensively over the last 20 years. The defining criteria for diagnosis of the disorders according to the American College of Obstetricians and Gynecologists (ACOG) include at least one moderate to severe mood symptom and one physical symptom for the diagnosis of PMS and by DSM IV criteria a total of 5 symptoms with 1 severe mood symptom for the diagnosis of PMDD. There must be functional impairment attributed to the symptoms. The symptoms must be present for one to two weeks premenstrually with relief by day 4 of menses and should be documented prospectively for at least two cycles using a daily rating form. Nonpharmacologic management with some evidence for efficacy include cognitive behavioral relaxation therapy, aerobic exercise, as well as calcium, magnesium, vitamin B(6) L-tryptophan supplementation or a complex carbohydrate drink. Pharmacologic management with at least ten randomized controlled trials to support efficacy include selective serotonin reuptake inhibitors administered daily or premenstrually and serotonergic tricyclic antidepressants. Anxiolytics and potassium sparing diuretics have demonstrated mixed results in the literature. Hormonal therapy is geared towards producing anovulation. There is good clinical evidence for GnRH analogs with addback hormonal therapy, danocrine, and estradiol implants or patches with progestin to protect the endometrium. Oral contraceptive pills prevent ovulation and should be effective for the treatment of PMS/PMDD. However, limited evidence does not support efficacy for oral contraceptive agents containing progestins derived from 19-nortestosterone. The combination of the estrogen and progestin may produce symptoms similar to PMS, such as water retention and irritability. There is preliminary evidence that a new oral contraceptive pill containing low-dose estrogen and the progestin drospirenone, a spironolactone analog, instead of a 19-nortestosterone derivative can reduce symptoms of water retention and other side effects related to estrogen excess. The studies are in progress, however, preliminary evidence suggests that the drospirenone-containing pill called Yasmin may be effective the treatment of PMDD.

Determination of two progestin metabolites (17α-hydroxypregnanolone and pregnanediol) and different classes of steroids (androgens, estrogens, corticosteroids, progestins) in rivers and wastewaters by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

PubMed

Zhang, Kun; Fent, Karl

2018-01-01

A highly sensitive and robust method was developed for routine analysis of two progestin metabolites, 17α-hydroxypregnanolone (17OH-Δ5P) and pregnanediol (PD), and 31 other natural and synthetic steroids and related metabolites (estrogens, androgens, corticosteroids, progestins) in river water, as well as influents and effluents of municipal wastewater treatment plants (WWTP) using HPLC-MS/MS combined with solid-phase extraction. For the various matrixes considered, the optimized method showed satisfactory performance with recoveries of 70-120% for most of target steroids. The method detection limits (MDLs) ranged from 0.01 to 3ng/L for river water, 0.02 to 10ng/L for WWTP effluents, and 0.1 to 40ng/L for influents with good linearity and reproducibility. The developed method was successfully applied for the analysis of steroids in rivers and WWTP influent and effluents. WWTP influents concentrations of 17OH-Δ5P and PD were 51-256ng/L and up to 400ng/L, respectively, along with androstenedione (concentration range: 38-220ng/L), testosterone (11-26ng/L), estrone (2.3-37ng/L), 17β-estradiol (N.D.-8.7ng/L), 17α-hydroxyprogesterone (N.D.-66ng/L), medroxyprogesterone acetate (N.D.-5.3ng/L), and progesterone (2.0-22ng/L), while only androstenedione (ADD), estrone (E1), and estriol (E3) were detected in effluent with concentrations ranging up to 1.7ng/L, 0.90ng/L and 0.8ng/L, respectively. In river water samples, only ADD and E1 were detected with concentrations up to 1.0ng/L and 0.91ng/L. Our procedure represents the first method for analyzing 17OH-Δ5P and PD in environmental samples along with a large series of steroids. Copyright © 2017 Elsevier B.V. All rights reserved.

[Sex hormones and the metabolism of carbohydrates].

PubMed

Boukhris, R

1987-12-01

Sex hormones play an important role in the control of glucose metabolism and insulin. Decreased glucose tolerance observed at the end of pregnancy in most cases remains within normal limits. Pregnancy has an important effect on the islets of Langerhans and on the growth of beta cellules. At the end of pregnancy, assimilation of glucose and triglycerides by maternal tissues is slowed and transfer to the fetus is favored. Hyperinsulinism persists but insulin resistance at the level of maternal tissue becomes very strong and the number of receptors declines. This late pregnancy insulin resistance has not been satisfactorily explained. The declining number of receptors may be a mechanism, or the "antiinsulin" pregnancy hormones which includes estrogens and progesterone may play a major role. Although other mechanisms have been proposed to explain the antiinsulin effect, the role of sex hormones and especially of progesterone (and synthetic progestins used in contraception) appears crucial. The presence of estrogen and progesterone receptors in the beta cellules of the islets of Langerhans suggests a direct effect of these hormones on the cellules. Estrogens however work by other mechanisms than insulin secretion. Experimental evidence indicates that during pregnancy, progesterone increases insulin release while human placental lactogen stimulates hyperplasia of the islets. The progestins derived from progesterone used in contraception have a parallel action. A slight elevation of blood sugar and insulinemia have been observed in oral contraceptive (OC) users. Only 3-5% of OC users develop true hyperglycemia. The changes are usually transitory and disappear on termination of OC use except in the small number of women predisposed to diabetes. The decreased glucose tolerance of OC users differs from true diabetes. Combined OCs favor vascular accidents and myocardial infarct in insulin-dependent diabetics. The mechanisms involved include deteriorating control of diabetes; effects on the serum lipids, coagulation factors, and blood pressure; and direct effects of estrogen on the vascular wall. Venous but not arterial vascular accidents decline with lower estrogen doses. Progestins probably play a more significant role from estrogens in decreasing glucose tolerance. Pregnanes, progestins derived from progesterone, do not appear to affect glucose tolerance. Among testosterone derivatives, the entrances decrease glucose tolerance slightly and the gonanes more strongly, also causing hyperinsulinism. But the new triphasic OCs with low levonorgestrel doses cause no significant changes in glucose tolerance even in women with histories of gestational diabetes. Long-acting progestin implants, vaginal rings, and injectables appear thus far to have minimal or no effects on glucose tolerance.

Circumventing the natural, frequent oestrogen waves of the female cheetah (Acinonyx jubatus) using oral progestin (Altrenogest).

PubMed

Crosier, Adrienne E; Comizzoli, Pierre; Koester, Diana C; Wildt, David E

2017-08-01

Cheetah are induced ovulators, experiencing short, variable oestrogen waves year-round. Exogenous gonadotrophin administration induces ovulation, but success is variable and often improves if ovaries are quiescent. After affirming the presence of short-term oestrogenic waves, we examined the effect of the timing of administration of exogenous equine and human chorionic gonadotrophins (eCG-hCG) within the oestrogen concentration pattern on subsequent follicle development and oocyte and corpus luteum quality. We also investigated ovarian suppression using an oral progestin (Altrenogest, 7 days) and assessed whether Altrenogest moderated adrenal activity by reducing glucocorticoid metabolites. All cheetahs exhibited short (every ~7-10 days), sporadic, year-round increases in faecal oestradiol punctuated by unpredictable periods (4-10 weeks) of baseline oestradiol (anoestrous). Gonadotrophin (eCG-hCG) efficacy was not affected by oestradiol 'wave' pattern if administered ≥3 days after an oestrogen peak. Such cheetahs produced normative faecal progestagen patterns and higher numbers (P<0.06) of mature oocytes than females given gonadotrophins ≤2 days after an oestradiol peak. Altrenogest supplementation expanded the interval between oestradiol peaks to 12.9 days compared with 7.3 days without progestin pretreatment. Altrenogest-fed females excreted less (P<0.05) glucocorticoid metabolites than non-supplemented counterparts. Results show that Altrenogest is effective for suppressing follicular activity, may contribute to reduced glucocorticoid production and may result in more effective ovulation induction via gonadotrophin therapy.

Environmental Progestins Progesterone and Drospirenone Alter the Circadian Rhythm Network in Zebrafish (Danio rerio).

PubMed

Zhao, Yanbin; Castiglioni, Sara; Fent, Karl

2015-08-18

Progestins alter hormone homeostasis and may result in reproductive effects in humans and animals. Thus far, studies in fish have focused on the hypothalamic-pituitary-gonadal (HPG)-axis and reproduction, but other effects have little been investigated. Here we report that progesterone (P4) and drospirenone (DRS) interfere with regulation of the circadian rhythm in fish. Breeding pairs of adult zebrafish were exposed to P4 and DRS at concentrations between 7 and 13 650 ng/L for 21 days. Transcriptional analysis revealed significant and dose-dependent alterations of the circadian rhythm network in the brain with little effects in the gonads. Significant alterations of many target transcripts occurred even at environmental relevant concentrations of 7 ng/L P4 and at 99 ng/L DRS. They were fully consistent with the well-described circadian rhythm negative/positive feedback loops. Transcriptional alterations of the circadian rhythm network were correlated with those in the HPG-Liver-axis. Fecundity was decreased at 742 (P4) and 2763 (DRS) ng/L. Dose-dependent alterations in the circadian rhythm network were also observed in F1 eleuthero-embryos. Our results suggest a potential target of environmental progestins, the circadian rhythm network, in addition to the adverse reproductive effects. Forthcoming studies should show whether the transcriptional alterations in circadian rhythm translate into physiological effects.

Ethinyl estradiol-to-desogestrel ratio impacts endothelial function in young women✩

PubMed Central

Meendering, Jessica R.; Torgrimson, Britta N.; Miller, Nicole P.; Kaplan, Paul F.; Minson, Christopher T.

2010-01-01

Background Ethinyl estradiol (EE) and progestins have the ability to alter endothelial function. The type of progestin and the ratio of EE to progestin used in oral contraceptive pills (OCPs) may determine how they affect the arterial vasculature. Study Design In this study, we investigated endothelial function across a cycle in very low dose (VLD) and low dose (LD) combination EE and desogestrel (DSG) OCP users during two phases: active (VLD=20 mcg EE/150 mcg DSG; LD=30 mcg EE/150 mcg DSG) and pill-free. Endothelial function was also measured during an EE-only hormone phase (10 mcg EE) in group VLD. Results Endothelium-dependent vasodilation was greater during the active phase compared to the pill-free phase in group LD (9.02±0.72% vs. 7.33±0.84%; p=.029). This phase difference was not observed in group VLD (5.86±0.63% vs. 6.56±0.70%; p=.108). However, endothelium-dependent vasodilation was higher during the EE-only phase, compared to the active and pill-free phases (8.92±0.47% vs. 5.86±0.63%, and 6.56±0.70%; pb.001) in group VLD. Conclusions These data suggest DSG may antagonize the vasodilatory activity of EE and that this effect is further modulated by the EE-toDSG ratio. PMID:19041440

The medical management of abnormal uterine bleeding in reproductive-aged women.

PubMed

Bradley, Linda D; Gueye, Ndeye-Aicha

2016-01-01

In the treatment of women with abnormal uterine bleeding, once a thorough history, physical examination, and indicated imaging studies are performed and all significant structural causes are excluded, medical management is the first-line approach. Determining the acuity of the bleeding, the patient's medical history, assessing risk factors, and establishing a diagnosis will individualize their medical regimen. In acute abnormal uterine bleeding with a normal uterus, parenteral estrogen, a multidose combined oral contraceptive regimen, a multidose progestin-only regimen, and tranexamic acid are all viable options, given the appropriate clinical scenario. Heavy menstrual bleeding can be treated with a levonorgestrel-releasing intrauterine system, combined oral contraceptives, continuous oral progestins, and tranexamic acid with high efficacy. Nonsteroidal antiinflammatory drugs may be utilized with hormonal methods and tranexamic acid to decrease menstrual bleeding. Gonadotropin-releasing hormone agonists are indicated in patients with leiomyoma and abnormal uterine bleeding in preparation for surgical interventions. In women with inherited bleeding disorders all hormonal methods as well as tranexamic acid can be used to treat abnormal uterine bleeding. Women on anticoagulation therapy should consider using progestin-only methods as well as a gonadotropin-releasing hormone agonist to treat their heavy menstrual bleeding. Given these myriad options for medical treatment of abnormal uterine bleeding, many patients may avoid surgical intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

[Oral contraception].

PubMed

Montloin, A

1990-11-01

This brief discussion of the different types of oral contraceptives (OCs) makes abundant use of flow charts, tables, and diagrams to present information and stress specific points. The work begins by defining the different hypothalamic, pituitary, and ovarian hormones and diagramming and describing the menstrual cycle. A discussion of combined OCs defines and diagrams monophasic, biphasic, and triphasic pills, distinguishes between different dose levels, and describes the mechanisms of action of OCs. Sequential pills and their mechanism of action are briefly discussed. The discussion of OCs containing progestins distinguishes between low does pills and high dose pills and describes the use of injectable progestins. A table then lists the dose-dependent side effects of estrogens and progestins. Simple instructions are provided for administering pills beginning on the 1st cycle day and for actions to take in the event a pill is forgotten. A flow chart taking into account age and presence or absence of vascular and gynecologic risk factors indicates which type of OC should be selected. Some advantages of OCs are identified, including maximum effectiveness and prevention of benign breast disease and perhaps of some type of rheumatoid arthritis. Another flow chart, on patient monitoring, identifies the contraindications that should be ruled out before OCs are prescribed and the routine follow-up examinations required for safe use. Other charts list absolute and relative contraindications and possible drug interferences.

Progestins alter photo-transduction cascade and circadian rhythm network in eyes of zebrafish (Danio rerio)

NASA Astrophysics Data System (ADS)

Zhao, Yanbin; Fent, Karl

2016-02-01

Environmental progestins are implicated in endocrine disruption in vertebrates. Additional targets that may be affected in organisms are poorly known. Here we report that progesterone (P4) and drospirenone (DRS) interfere with the photo-transduction cascade and circadian rhythm network in the eyes of zebrafish. Breeding pairs of adult zebrafish were exposed to P4 and DRS for 21 days with different measured concentrations of 7-742 ng/L and 99-13´650 ng/L, respectively. Of totally 10 key photo-transduction cascade genes analyzed, transcriptional levels of most were significantly up-regulated, or normal down-regulation was attenuated. Similarly, for some circadian rhythm genes, dose-dependent transcriptional alterations were also observed in the totally 33 genes analyzed. Significant alterations occurred even at environmental relevant levels of 7 ng/L P4. Different patterns were observed for these transcriptional alterations, of which, the nfil3 family displayed most significant changes. Furthermore, we demonstrate the importance of sampling time for the determination and interpretation of gene expression data, and put forward recommendations for sampling strategies to avoid false interpretations. Our results suggest that photo-transduction signals and circadian rhythm are potential targets for progestins. Further studies are required to assess alterations on the protein level, on physiology and behavior, as well as on implications in mammals.

Hormonal approaches to male contraception.

PubMed

Wang, Christina; Swerdloff, Ronald S

2010-11-01

Condoms and vasectomy are male-controlled family planning methods but suffer from limitations in compliance (condoms) and limited reversibility (vasectomy); thus many couples desire other options. Hormonal male contraceptive methods have undergone extensive clinical trials in healthy men and shown to be efficacious, reversible and appear to be well tolerated. The success rate of male hormonal contraception using injectable testosterone alone is high and comparable to methods for women. Addition of progestins to androgens improved the rate of suppression of spermatogenesis. Supported by government or nongovernment organizations, current studies aim to find the best combination of testosterone and progestins for effective spermatogenesis suppression and to explore other delivery methods for these hormones. Translation of these advances to widespread use in the developed world will need the manufacturing and marketing skills of the pharmaceutical industry. Availability of male contraceptives to the developing world may require commitments of governmental and nongovernmental agencies. In a time when imbalance of basic resources and population needs are obvious, this may prove to be a very wise investment. Male hormonal contraception is efficacious, reversible and well tolerated for the target population of younger men in stable relationships. Suppression of spermatogenesis is achieved with a combination of an androgen and a progestin. Partnership with industry will accelerate the marketing of a male hormonal contraceptive. Research is ongoing on selective androgen and progesterone receptor modulators that suppress spermatogenesis, minimize potential adverse events while retaining the androgenic and gonadotropin suppressive actions.

Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments

PubMed Central

Rajkumar, Lakshmanaswamy; Guzman, Raphael C; Yang, Jason; Thordarson, Gudmundur; Talamantes, Frank; Nandi, Satyabrata

2004-01-01

Introduction Women who have undergone a full-term pregnancy before the age of 20 have one-half the risk of developing breast cancer compared with women who have never gone through a full-term pregnancy. This protective effect is observed universally among women of all ethnic groups. Parity in rats and mice also protects them against chemically induced mammary carcinogenesis. Methods Seven-week-old virgin Lewis rats were given N-methyl-N-nitrosourea. Two weeks later the rats were treated with natural or synthetic estrogens and progestins for 7–21 days by subcutaneous implantation of silastic capsules. Results In our current experiment, we demonstrate that short-term sustained exposure to natural or synthetic estrogens along with progestins is effective in preventing mammary carcinogenesis in rats. Treatment with 30 mg estriol plus 30 mg progesterone for 3 weeks significantly reduced the incidence of mammary cancer. Short-term exposure to ethynyl estradiol plus megesterol acetate or norethindrone was effective in decreasing the incidence of mammary cancers. Tamoxifen plus progesterone treatment for 3 weeks was able to confer only a transient protection from mammary carcinogenesis, while 2-methoxy estradiol plus progesterone was effective in conferring protection against mammary cancers. Conclusions The data obtained in the present study demonstrate that, in nulliparous rats, long-term protection against mammary carcinogenesis can be achieved by short-term treatments with natural or synthetic estrogen and progesterone combinations. PMID:14680498

[Potential advantages of triphasic combined oral contraceptives in the light of recent epidemiological and endocrinometabolic data].

PubMed

Gaspard, U; Dubois, M

1982-09-01

New epidemiologic data on the vascular risks of oral contraceptives (OCs) were assessed to determine whether the recently introduced low dose triphasic pills offer greater potential safety for OC users than previous formulations. Epidemiologic studies have demonstrated that vascular accidents are less frequent with OCs containing lower doses of both estrogens and progestins. The new triphasic pills have the lowest steroid content of any pills yet developed and less of a progestin climate than low dose monophasic pills. The gradual increases in the progestin dose, from 50 mcg on days 1-6 to 75 mcg on days 7-11 and 125 mcg on days 12-21 and of ethinyl estradiol from 30 mcg on days 1-6 to 40 on days 7-11 and back to 30 on days 12-21 reflect the natural cycle of steroid secretion. The endometrial mucus is better developed than under low dose monophasic pills, permitting better cycle control. Triphasic pills have been shown in all studies to block secretion by the hypothalamus and pituitary of the gonadotropins follicle stimulating hormone and luteinizing hormone, resulting in absence of follicular maturation and of ovulation. Even with the small dose of levonorgestrel, the cervical mucus is rendered inhospitable to capacitation and passage of sperm. The impact on glucose tolerance of low doses of ethinyl estradiol, even after long use, is minimal, but the 19 norsteroids used in most combined pills have a more significant impact. To the directly stimulating effect of progestins on pancreatic insulin secretion is added the development of increased peripheral resistence apparently due to a decrease in the number of insulin receptors in the target tissue. The decrease appears to be dose dependent and proportional to the androgenicity of the progestin. A recent study indicated that triphasic pills caused less of a deterioration in glucose tolerance than standard or low-dose combined OCs or a biphasic formulation. This finding was significant because of the possibility that disturbances in carbohydrate metabolism can favor development of vascular diseases. Triphasic OCs have a slight estrogen dominance, which allows them to maintain favorable levels of high density lipoprotein cholesterol, the fraction believed to provide cardiovascular protection. Similarly, they caused minimal variation on the order of 10-15% in the levels of fibrinogen, factors VII, VIII, and X, plasminogen, and antithrombine III. It has not yet been established with certainty however that changes in the levels of these coagulation factors correspond to changes in actual risk of thromboembolic accidents. Triphasics cause a minimal increase in renin substrate and activity of 12-30% compared to the 30-40% at higher estrogen doses. No significant variation in blood pressure has been observed in triphasic OC users.

Additive effects of levonorgestrel and ethinylestradiol on brain aromatase (cyp19a1b) in zebrafish specific in vitro and in vivo bioassays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinfray, N., E-mail: nathalie.hinfray@ineris.fr

Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-transfected with zebrafish estrogen receptors (zfERs) and the luciferase genemore » under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentration-response relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures. - Highlights: • Combined effects of EE2 and LNG were assessed on ER-dependent cyp19a1b expression. • EE2 and LNG alone induced brain aromatase in zebrafish specific bioassays. • Experimental ray design allowed complete concentration-response surfaces modeling. • EE2 and LNG exerted additive effects on brain aromatase in radial glial cells.« less

Progestin treatment does not affect expression of cytokines, steroid receptors, oxytocin receptor, and cyclooxygenase 2 in fetal membranes and endometrium from pony mares at parturition.

PubMed

Palm, F; Walter, I; Nowotny, N; Budik, S; Helmreich, M; Aurich, C

2013-01-01

In most mammalian species, progestins have a major function in maintaining pregnancy. In humans, the physiologic initiation of parturition bears similarities with inflammatory processes and anti-inflammatory effects of progestins have been suggested to postpone birth until term. To examine if comparable effects exist in the horse, mares were treated with the synthetic progestin altrenogest from day 280 of gestation until parturition (N = 5) or were left untreated as controls (N = 7). Tissue from the amnion (AMN), allantochorion (AC), and endometrium (EM) was collected at foaling and mRNA expression of interleukin (IL)-6 and -8, cyclooxygenase 2 (COX2), estrogen receptor (ER) α, progesterone receptor, and oxytocin receptor (OTR) was analyzed. Leukocytes, steroid receptors, COX2, and OTR were also investigated by histology and immunohistochemistry. Expression of mRNA for IL-6 was higher in AMN and EM versus AC (P < 0.01). Expression of IL-8 was higher in AMN than AC and EM (P < 0.001). Steroid receptors and OTR were highly expressed in EM but not in AMN and AC (P < 0.001). Expression of COX2 was most pronounced in AC whereas IL expression was not upregulated in AC. No differences in mRNA expression existed between altrenogest-treated and control animals. Endometrial polymorphonuclear leukocytes were increased in altrenogest-treated mares. Epithelial cells of all tissues, except AC chorionic villi stained progesterone receptor-positive. Staining for ER was more pronounced in the amnion facing epithelium of the AC in altrenogest-treated versus control animals (P < 0.01). In conclusion, COX2 is highly expressed in the AC. The fetal membranes thus might play a role in the onset of labor in the horse. Altrenogest did not affect gene expression in the AMN, AC, and EM but had localized effects on inflammatory cells and ER expression. No anti-inflammatory effects of altrenogest in healthy, late pregnant pony mares could be detected. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of oral contraceptives on metabolic profile in women with polycystic ovary syndrome: A meta-analysis comparing products containing cyproterone acetate with third generation progestins.

PubMed

Amiri, Mina; Ramezani Tehrani, Fahimeh; Nahidi, Fatemeh; Kabir, Ali; Azizi, Fereidoun; Carmina, Enrico

2017-08-01

Although oral contraceptives (OCs) are the most common treatment in women with polycystic ovary syndrome (PCOS), their effects and safety on the metabolic profiles of these patients are relatively unknown. In this meta-analysis the effects of the different durations (from 3months to 1year) of OC treatment using cyproterone acetate (CA) or third generation progestins on metabolic profile of patients with PCOS were assessed. PubMed, Scopus, Google Scholar and ScienceDirect databases (2001-2015) were searched to identify clinical trials investigating the effects of OC containing CA or third generation progestins on metabolic profiles of women with PCOS. Both fixed and random effect models were used. Subgroup analyses were performed based on the progestin compounds used and on duration of treatment. Oral contraceptive (OC) use was found to be associated with a worsening in lipid profiles but no changes were observed in other metabolic outcomes, including body mass index (BMI), fasting blood glucose (FBG), fasting insulin, homeostatic model for measuring insulin resistance (HOMA-IR) and in blood pressure (BP) values. All studied OCs showed similar effects on lipid profiles but with different timings, with products containing CA, requiring 6months to raise high density lipoprotein-cholesterol (HDL-C) levels and 12months to increase triglycerides (TG). On the contrary, products containing drospirenone (DRSP) or desogestrel (DSG) increased HDL-C after only 3months but determined elevations of TG after 6months. All OCs induced an increase in low density lipoprotein-cholesterol (LDL-C) after 12months of use. The study shows that, in women with PCOS, OC use is associated with significant changes in lipid profiles, including elevation not only in HDL-C but also in TG and LDL-C. All OCs studied showed similar effects but with different timings, with products containing CA generally requiring more prolonged use to increase serum lipids. Instead, OC use does not affect body weight, BP or glucose levels, with only some minor increase of fasting insulin levels. Copyright © 2017 Elsevier Inc. All rights reserved.

Estrogen and Progestin (Oral Contraceptives)

MedlinePlus

... from entering. Oral contraceptives are a very effective method of birth control, but they do not prevent ... tell you whether you need to use another method of birth control during the first 7 to ...

Progestin-Only Oral Contraceptives

MedlinePlus

... oral contraceptives are a very effective method of birth control, but they do not prevent the spread of ... on another day, use a backup method of birth control (such as a condom and/or a spermicide) ...

The relationship of the oestrogen and progestin receptors in the abnormal uterus of the adult anovulatory rat. Effects of neonatal treatment with testosterone propionate or clomiphene citrate.

PubMed Central

White, J O; Moore, P A; Elder, M G; Lim, L

1981-01-01

The neonatal administration of testosterone propionate to Wistar rats resulted in anovulatory adults in persistent vaginal oestrus. Clomiphene citrate had a similar effect. In both groups of adults, hyperplasia of the uterine epithelium and occasional metaplasia was observed. The uterine nuclear and cytosol oestrogen and progestin receptors of these anovulatory rats were found to have affinities for their respective ligands similar to those of normal females. The nuclear oestrogen receptor comprised occupied and unoccupied components, as in normal females. The content of the nuclear oestrogen receptor was comparable with that of females in the late dioestrous or pro-oestrous phase. This content was higher in the clomiphene-treated group. Despite the relatively high nuclear oestrogen receptor content the content of progestin receptors, a putative index of the oestrogenic response, was lower in the treated rats than in normal adult females throughout the cycle. Administration of oestradiol to both treatment groups resulted in depletion of cytosol oestrogen receptor content 1 h later, which, however, was not reflected by an increase in the content of nuclear oestrogen receptors. There was no measurable increase in progesterone receptor content in treated rats after daily administration of oestrogen (5 microgram/rat) for 3 days. These changes in sex-hormone-receptor interactions involving an impairment of the normal oestrogenic response may be associated with the abnormal differentiation of the uterus in these sterile, anovulatory animals. Images Fig. 1. Fig. 2. PMID:7316994

Hormonal Approaches to Male contraception

PubMed Central

Wang, Christina; Swerdloff, Ronald S.

2010-01-01

Purpose of review Condoms and vasectomy are male controlled family planning methods but suffer from limitations in compliance (condoms) and limited reversibility (vasectomy); thus many couples desire other options. Hormonal male contraceptive methods have undergone extensive clinical trials in healthy men and shown to be efficacious, reversible and appear to be safe. Recent Findings The success rate of male hormonal contraception using injectable testosterone alone is high and comparable to methods for women. Addition of progestins to androgens improved the rate of suppression of spermatogenesis. Supported by government or non-government organizations, current studies aim to find the best combination of testosterone and progestins for effective spermatogenesis suppression and to explore other delivery methods for these hormones. Translation of these advances to widespread use in the developed world will need the manufacturing and marketing skills of the pharmaceutical industry. Availability of male contraceptives to the developing world may require commitments of governmental and non-governmental agencies. In a time when imbalance of basic resources and population needs are obvious, this may prove to be a very wise investment. Summary Male hormonal contraception is efficacious, reversible and safe for the target population of younger men in stable relationships. Suppression of spermatogenesis is achieved with a combination of an androgen and a progestin. Partnership with industry will accelerate the marketing of a male hormonal contraceptive. Research is ongoing on selective androgen and progesterone receptor modulators that suppress spermatogenesis, minimize potential adverse events while retaining the androgenic actions. PMID:20808223

Lordosis facilitated by GPER-1 receptor activation involves GnRH-1, progestin and estrogen receptors in estrogen-primed rats.

PubMed

Domínguez-Ordóñez, R; Garcia-Juárez, M; Lima-Hernández, F J; Gómora-Arrati, P; Domínguez-Salazar, E; Blaustein, J D; Etgen, A M; González-Flores, O

2018-02-01

The present study assessed the participation of membrane G-protein coupled estrogen receptor 1 (GPER-1) and gonadotropin releasing hormone 1 (GnRH-1) receptor in the display of lordosis induced by intracerebroventricular (icv) administration of G1, a GPER-1 agonist, and by unesterified 17β-estradiol (free E 2 ). In addition, we assessed the participation of both estrogen and progestin receptors in the lordosis behavior induced by G1 in ovariectomized (OVX), E 2 -benzoate (EB)-primed rats. In Experiment 1, icv injection of G1 induced lordosis behavior at 120 and 240min. In Experiment 2, icv injection of the GPER-1 antagonist G15 significantly reduced lordosis behavior induced by either G1 or free E 2 . In addition, Antide, a GnRH-1 receptor antagonist, significantly depressed G1 facilitation of lordosis behavior in OVX, EB-primed rats. Similarly, icv injection of Antide blocked the stimulatory effect of E 2 on lordosis behavior. In Experiment 3, systemic injection of either tamoxifen or RU486 significantly reduced lordosis behavior induced by icv administration of G1 in OVX, EB-primed rats. The results suggest that GnRH release activates both estrogen and progestin receptors and that this activation is important in the chain of events leading to the display of lordosis behavior in response to activation of GPER-1 in estrogen-primed rats. Copyright © 2018 Elsevier Inc. All rights reserved.

Modulatory Effects of Sex Steroids Progesterone and Estradiol on Odorant Evoked Responses in Olfactory Receptor Neurons

PubMed Central

Scholz, Paul; Mohrhardt, Julia; Gisselmann, Günter; Hatt, Hanns

2016-01-01

The influence of the sex steroid hormones progesterone and estradiol on physiology and behavior during menstrual cycles and pregnancy is well known. Several studies indicate that olfactory performance changes with cyclically fluctuating steroid hormone levels in females. Knowledge of the exact mechanisms behind how female sex steroids modulate olfactory signaling is limited. A number of different known genomic and non-genomic actions that are mediated by progesterone and estradiol via interactions with different receptors may be responsible for this modulation. Next generation sequencing-based RNA-Seq transcriptome data from the murine olfactory epithelium (OE) and olfactory receptor neurons (ORNs) revealed the expression of several membrane progestin receptors and the estradiol receptor Gpr30. These receptors are known to mediate rapid non-genomic effects through interactions with G proteins. RT-PCR and immunohistochemical staining results provide evidence for progestin and estradiol receptors in the ORNs. These data support the hypothesis that steroid hormones are capable of modulating the odorant-evoked activity of ORNs. Here, we validated this hypothesis through the investigation of steroid hormone effects by submerged electro-olfactogram and whole cell patch-clamp recordings of ORNs. For the first time, we demonstrate that the sex steroid hormones progesterone and estradiol decrease odorant-evoked signals in the OE and ORNs of mice at low nanomolar concentrations. Thus, both of these sex steroids can rapidly modulate the odor responsiveness of ORNs through membrane progestin receptors and the estradiol receptor Gpr30. PMID:27494699

Does ethnicity matter in male hormonal contraceptive efficacy?

PubMed Central

Ilani, Niloufar; Liu, Peter Y; Swerdloff, Ronald S; Wang, Christina

2011-01-01

The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy. PMID:21317912

Birth control pills - progestin only

MedlinePlus

... pregnant right away. When to Use a Backup Method Use a backup method of birth control, such as a condom, diaphragm, ... body may not absorb it. Use a backup method of birth control, and call your provider. You ...

Therapeutic Amenorrhea in Patients at Risk for Thrombocytopenia

PubMed Central

Martin-Johnston, Meredith K.; Okoji, Olanma Y.; Armstrong, Alicia

2016-01-01

To examine the need for and evaluate the method of menses suppression in women at risk for thrombocytopenia. A systematic review of the published literature in MEDLINE using the search terms thrombocytopenia, menorrhagia, therapeutic amenorrhea, progestin intrauterine device, combination oral contraceptive—extended and cyclic, gonadotropin releasing hormone agonist, danazol, and progestins. There are an increased number of reproductive age women at risk for thrombocytopenia who would benefit from menses suppression. A number of effective medical regimens are available. In patients who fail medical therapy, endometrial ablation appears to be effective in women with thrombocytopenia. As a result of the increased number of women at risk for thrombocytopenia, there is a need for therapeutic amenorrhea. The type of regimen selected depends upon the patients need for contraception and the ability to tolerate estrogen-containing medications. For women who fail medical therapy, there are surgical options, which are associated with less morbidity than hysterectomy. PMID:18492296

Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome

PubMed Central

Mathur, Ruchi; Levin, Olga; Azziz, Ricardo

2008-01-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrine/metabolic disorders found in women, affecting approximately 105 million women worldwide. It is characterized by ovulatory dysfunction, often presenting as oligomenorrhea or amenorrhea and either clinical or biochemical hyperandrogenism. Combined oral contraceptive (COC) therapy has long been a cornerstone of care for women with PCOS. COC therapy often provides clinical improvement in the areas of excessive hair growth, unpredictable menses, acne, and weight gain. One of the main issues in COC therapy is choosing the most appropriate progestin component to provide the greatest anti androgenic effects. Drospirenone, a relatively new progestin, has shown benefit in the PCOS population when used in conjunction with ethinyl estradiol. We now review the role of COCs in PCOS, focusing specifically on drospirenone. Controversy over metabolic effects of COCs in PCOS is also discussed. PMID:18728832

Drospirenone/ethinyl estradiol 3 mg/20 μg (24/4 day regimen): hormonal contraceptive choices – use of a fourth-generation progestin

PubMed Central

Bachmann, Gloria; Kopacz, Sharon

2009-01-01

The combined oral contraceptive pill (COC) consisting of drospirenone 3 mg/ethinyl estradiol 20 μg (3 mg DRSP/20 μg EE-24/4) supplies 24 days of pills with hormones followed by 4 days of hormone-free pills. This regimen is called the 24/4 regimen. The progesterone component of this oral contraceptive pill (OCP), drospirenone (DRSP), is a fourth-generation progestin that has potent progestogenic, antimineralocorticoid, and antiandrogenic activity, which are unique characteristics compared with the other progestogens contained in most of the other OCPs currently marketed. This formulation, in addition to being an effective long-term OCP, has the additional medical benefit of providing a good parallel treatment for premenstrual dysphoric disorder and moderate acne. The effectiveness of 3 mg DRSP/20 μg EE-24/4, its tolerability and safety, and its additional non-contraceptive benefits are discussed. PMID:19936169

Cancer risk and PCOS.

PubMed

Dumesic, Daniel A; Lobo, Rogerio A

2013-08-01

Women with polycystic ovary syndrome (PCOS) have a 2.7-fold increased risk for developing endometrial cancer. A major factor for this increased malignancy risk is prolonged exposure of the endometrium to unopposed estrogen that results from anovulation. Additionally, secretory endometrium of some women with PCOS undergoing ovulation induction or receiving exogenous progestin exhibits progesterone resistance accompanied by dysregulation of gene expression controlling steroid action and cell proliferation. Endometrial surveillance includes transvaginal ultrasound and/or endometrial biopsy to assess thickened endometrium, prolonged amenorrhea, unopposed estrogen exposure or abnormal vaginal bleeding. Medical management for abnormal vaginal bleeding or endometrial hyperplasia consists of estrogen-progestin oral contraceptives, cyclic or continuous progestins or a levonorgestrel-releasing (Mirena) intrauterine device. Lifestyle modification with caloric restriction and exercise is appropriate to treat obesity as a concomitant risk factor for developing endometrial disease. An increased risk of ovarian cancer may also exist in some women with PCOS. There are strong data to suggest that oral contraceptive use is protective against ovarian cancer and increases with the duration of therapy. The mechanism of this protection may be through suppression of gonadotropin secretion rather than the prevention of "incessant ovulation". There is no apparent association of PCOS with breast cancer, although the high prevalence of metabolic dysfunction from obesity is a common denominator for both conditions. Recent data suggest that the use of metformin may be protective for both endometrial and breast cancer. There are insufficient data to evaluate any association between PCOS and vaginal, vulvar and cervical cancer or uterine leiomyosarcoma. Copyright © 2013 Elsevier Inc. All rights reserved.

Expression of HOXA10 in endometrial hyperplasia and adenocarcinoma and regulation by sex hormones in vitro.

PubMed

Zhong, Gang; Wang, Yan; Liu, Xuemei

2011-07-01

The objective of the study was to determine the expression of HOXA10 in human endometrial tissue in endometrial hyperplasia and carcinomas, and regulation by sex steroids in Ishikawa cells. Endometrial tissue was obtained from 133 subjects with normal endometria, endometrial hyperplasia, or endometrial adenocarcinoma. Among 133 specimens, 20 were normal endometria, 19 were simple hyperplasias without atypia, 20 were complex hyperplasias without atypia, 33 were atypical hyperplasias, and 41 were endometrial adenocarcinomas. The expression of HOXA10 was analyzed by immunohistochemistry. Ishikawa cell lines were incubated with 17β estradiol (10⁻⁸ mol/L) alone, medroxyprogesterone acetate (10⁻⁶ mol/L) alone, or the combination of estrogen and progesterone for 48 hours, respectively. In certain experiments, the antiprogestin antagonist, RU486 (10⁻⁵ mol/L), was also added to Ishikawa cells along with estradiol and medroxyprogesterone acetate for 48 hours. The expression of HOXA10 gene was detected by reverse transcriptase-polymerase chain reaction and Western blotting. HOXA10 was expressed in both normal and neoplastic endometria. No significant difference in HOXA10 expression was found between normal and hyperplastic endometrial tissues. The expression of HOXA10 was decreased in endometrial adenocarcinomas compared with normal endometria. Estrogen alone, progestin alone, or progestin combined with estrogen could significantly increase the expression of HOXA10 gene (P<0.05). RU486 could inhibit the effect of up-regulation of HOXA10 expression by progestin. The expression of HOXA10 was deregulated in endometrial carcinomas and up-regulated by sex hormones.

Period Prevalence and Perceived Side Effects of Hormonal Contraceptive Use and the Menstrual Cycle in Elite Athletes.

PubMed

Martin, Daniel; Sale, Craig; Cooper, Simon B; Elliott-Sale, Kirsty J

2017-12-28

To identify the period prevalence of hormonal contraceptive (HC) use and characterise the perceived side effects associated with the menstrual cycle and HC use. 430 elite female athletes completed a questionnaire to assess; the period prevalence of HC use, the reasons for initiation and discontinuation of HCs and the side effects experienced by HC and non-HC users. Descriptive statistics, between-group comparisons and associations between categorical variables were calculated. 49.5% of athletes were currently using HCs and 69.8% had used HCs at some point. Combined oral contraceptives were most commonly used (68.1%), with 30.0% using progestin-only contraceptives (implant = 13.1%; injection = 3.7%; intrauterine system = 2.8%). Perceived negative side effects were more common with progestin-only HC use (39.1%) compared to combined HC use (17.8%; P = 0.001) and were most prevalent in implant users (53.6%; P = 0.004). HC users reported perceived positive side effects relating to the ability to predict and/or manipulate the timing, frequency and amount of menstrual bleeding. Non-HC users had a menstrual cycle length of 29 ± 5 d and 77.4% reported negative side effects during their menstrual cycle, primarily during days 1-2 of menstruation (81.6%). Approximately half of elite athletes used HCs and progestin-only contraceptive users reported greater incidences of negative side effects, especially with the implant. Due to the high inter-individual variability in reported side effects, athletes and practitioners should maintain an open dialogue to pursue the best interests of the athlete.

ck2-dependent phosphorylation of progesterone receptors (PR) on Ser81 regulates PR-B isoform-specific target gene expression in breast cancer cells.

PubMed

Hagan, Christy R; Regan, Tarah M; Dressing, Gwen E; Lange, Carol A

2011-06-01

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G(1)/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments.

ck2-Dependent Phosphorylation of Progesterone Receptors (PR) on Ser81 Regulates PR-B Isoform-Specific Target Gene Expression in Breast Cancer Cells ▿

PubMed Central

Hagan, Christy R.; Regan, Tarah M.; Dressing, Gwen E.; Lange, Carol A.

2011-01-01

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. Herein, we show that phosphorylation of PR Ser81 is ck2 dependent and progestin regulated in intact cells but also occurs in the absence of PR ligands when cells enter the G1/S phase of the cell cycle. T47D breast cancer cells stably expressing a PR-B mutant receptor that cannot be phosphorylated at Ser79/81 (S79/81A) formed fewer soft agar colonies. Regulation of selected genes by PR-B, but not PR-A, also required Ser79/81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF) expression. Additionally, wild-type (wt) PR-B, but not S79/81A mutant PR, was robustly recruited to a progesterone response element (PRE)-containing transcriptional enhancer region of BIRC3; abundant ck2 also associated with this region in cells expressing wt but not S79/81A PR. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR-B target genes. Understanding how ligand-independent PRs function in the context of high levels of kinase activities characteristic of breast cancer is critical to understanding the basis of tumor-specific changes in gene expression and will speed the development of highly selective treatments. PMID:21518957

Progestin-Only Birth Control Pills

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... Emotional Well-Being Mental Health Sex and Birth Control Sex and Sexuality Birth Control Family Health Infants and Toddlers Kids and Teens ... Provera: An Injectable ContraceptiveTubal Sterilization (Tubal Ligation)Birth Control OptionsNatural Family PlanningBirth Control: How to Use Your ...

Infertility Research at the NICHD

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... on this finding, visit PubMed ID: 21719000 . Previous experimental evidence has suggested a possible link between persistent ... in which uterine lining tissue grows out of control, including endometrial cancer and ... in all the groups whether or not women were treated with progestin ...

Birth Control: How to Use Your Diaphragm

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Hormonal therapy for women with stage IA endometrial cancer of all grades.

PubMed

Park, Jeong-Yeol; Kim, Dae-Yeon; Kim, Tae-Jin; Kim, Jae Weon; Kim, Jong-Hyeok; Kim, Yong-Man; Kim, Young-Tak; Bae, Duk-Soo; Nam, Joo-Hyun

2013-07-01

To estimate the oncologic and pregnancy outcomes after oral progestin treatment of women of reproductive age with stage IA endometrial adenocarcinoma with stage IA, grade 1 differentiation with superficial myometrial invasion or stage IA, grade 2-3 differentiation with or without superficial myometrial invasion. Medical records of 48 women (age 40 years or younger) with endometrioid adenocarcinoma of the uterus who met inclusion criteria and were treated conservatively with oral progestin were reviewed. Follow-up was performed primarily with imaging techniques followed by endometrial biopsy when indicated. The median age was 30 years (range, 23-40 years). Fourteen patients (29.2%) received daily oral megestrol acetate (median dose 160 mg per day, range 40-240 mg per day) and 34 (70.8%) received daily oral medroxyprogesterone acetate (median dose 500 mg per day, range 80-1,000 mg per day). Complete responses were observed for 37 patients (77.1%) after the median treatment duration of 10 months (range 3-20 months). Complete response rates were 76.5%, 73.9%, and 87.5% for patients with stage IA, grade 2-3 without myometrial invasion (n=17), for patients with stage IA, grade 1 with superficial myometrial invasion (n=23), and for patients with stage IA, grade 2-3 with superficial myometrial invasion (n=8), respectively (P=.731). Recurrence rates for 37 patients who achieved complete response after a median follow-up time of 48 months (range 7-136 months) were 23.1%, 47.1%, and 71.4%, respectively (P=.104). None experienced disease progression or died of the disease. Nine patients gave birth to 10 healthy newborns. Progestin treatment appears to be reasonably effective for patients with stage IA, grade 2-3 differentiation without myometrial invasion and patients with stage IA grade 1 differentiation with superficial myometrial invasion. III.

Engaging in paced mating, but neither exploratory, anti-anxiety, nor social behavior, increases 5α-reduced progestin concentrations in midbrain, hippocampus, striatum, and cortex

PubMed Central

Frye, Cheryl A; Paris, Jason J; Rhodes, Madeline E

2010-01-01

Sequential actions of 17β-estradiol (E2) and progesterone (P4) in the hypothalamus and the P4 metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), in the midbrain ventral tegmental area (VTA) respectively mediate the initiation and intensity of lordosis of female rats and mayalso modulate anxiety and social behaviors, through actions in these, and/or other brain regions. Biosynthesis of E2, P4, and 3α,5α-THP can also occur in brain, independent of peripheral gland secretion, in response to environmental/behavioral stimuli. The extent to which engaging in tasks related to reproductive behaviors and/or mating increased E2 or progestin concentrations in brain was investigated. In Experiment 1, proestrous rats were randomly assigned to be tested in individual tasks, including the open field, elevated plus maze, partner preference, social interaction, or no test control, in conjunction with paced mating or no mating. Engaging in paced mating, but not other behaviors, significantly increased dihydroprogesterone (DHP) and 3α,5α-THP levels in midbrain, hippocampus, striatum, and cortex. In Experiment 2, proestrous rats were tested in the combinations of the above tasks (open field and elevated plus maze, partner preference, and social interaction) with or without paced mating. As in Experiment 1, only engaging in paced mating increased DHP and 3α,5α-THP concentrations in midbrain, hippocampus, striatum, and cortex. Thus, paced mating enhances concentrations of 5α-reduced progestins in brain areas associated with reproduction (midbrain), as well as exploration/anxiety (hippocampus and striatum) and social behavior (cortex). PMID:17379660

Treatment Considerations for the Cardiometabolic Signs of Polycystic Ovary Syndrome: A Review of the Literature Since the 2013 Endocrine Society Clinical Practice Guidelines.

PubMed

Fields, Errol L; Trent, Maria E

2016-05-01

Polycystic ovary syndrome is characterized by an excess in androgen levels, ovarian dysfunction, and polycystic ovarian morphology but is also associated with metabolic dysfunction and risk factors for cardiovascular disease. To our knowledge, there are few therapeutic recommendations for these cardiometabolic risk factors and little evidence of their long-term clinical relevance to cardiovascular health. To determine metabolic and/or cardiovascular outcomes in polycystic ovary syndrome treatment literature since the publication of the most recent Endocrine Society clinical practice guidelines in 2013. We searched PubMed using a string of variations of polycystic ovary syndrome, therapy/treatment, and adolescence, and we included English-language original research articles published while the 2013 clinical practice guidelines were disseminated (ie, articles published from January 1, 2011, to June 1, 2015). Articles that appeared relevant based on a review of titles and abstracts were read in full to determine relevancy. References from relevant articles were reviewed for additional studies. Four topic areas emerged: (1) lifestyle modification, (2) metformin vs placebo or estrogen-progestin oral contraceptives, (3) insulin-sensitizing agents, and (4) estrogen-progestin formulations. Most studies assessed the role of metformin as a monotherapy or dual therapy supplement and found significant benefit when including metformin in polycystic ovary syndrome treatment regimens. Studies showed improvements in cardiometabolic risk factors and, in several, androgen excess and cutaneous and menstrual symptoms. Studies were limited by sample size (range, 22-171), few adolescent participants, and short-term outcomes. Findings show potential for metformin and estrogen-progestin dual therapy but warrant longitudinal studies examining outcomes from adolescence through middle age to determine the effect on long-term cardiovascular health.

Soy foods and soybean isoflavones and menopausal health.

PubMed

Messina, Mark J

2002-01-01

Soybeans are a natural dietary source of isoflavones, which have estrogen-like properties. Therefore, it is worthwhile to consider the implications for soy of the recently published findings of the Heart and Estrogen/Progestin Replacement Study (HERS) I/II and the Women's Health Initiative (WHI). The WHI found coronary heart disease (CHD) risk to be increased in women receiving hormone replacement therapy, and both studies found increases in venous thromboembolic disease in such women. Additionally, stroke and breast cancer risk were increased in the WHI, although risk of colorectal cancer and fracture was decreased. Because research suggests that it is the combination of estrogen plus progestin, and not estrogen alone, that increases breast cancer risk, soy seems unlikely to increase risk because it has no progestin activity. Similarly, there is no evidence to suggest that soy will increase venous thromboembolic disease or stroke; however, only limited data are available in this area. There are promising data suggesting that soy may decrease CHD risk, although studies conducted thus far have examined only markers of risk and not actual CHD events. Similarly, short-term studies generally suggest that soy reduces bone loss in postmenopausal women; however, such effects have been noted primarily only at the spine, and longer-term studies are needed. Finally, very limited human research suggests that soy may decrease colon cancer risk, but this is highly speculative. The results of HERS I/II and WHI suggest that soy may have some of the advantages, but not the disadvantages, of combined hormone replacement therapy (at least with respect to the specific hormones and doses used in the HERS I/II and WHI), but that large, long-term intervention studies examining disease outcome are needed before definitive conclusions can be drawn. Nevertheless, the evidence warrants recommendations that menopausal women include soy in their diets.

The display of sexual behaviors by female rats administered ICI 182,780.

PubMed

Clark, Ann S; Guarraci, Fay A; Megroz, Alison B; Porter, Donna M; Henderson, Leslie P

2003-04-01

ICI 182,780 (ICI) is a pure antiestrogen that when administered systemically does not cross the blood-brain barrier, thus its actions are limited to the periphery. Four experiments were conducted to test the effects of ICI on the display of sexual behaviors in ovariectomized rats. Experiment 1 examined the effects of three doses of ICI (250, 500, and 750 micro g/rat) on sexual receptivity and paced mating behavior in rats primed with estradiol benzoate (EB) in combination with progesterone (P). Experiments 2 and 3 compared the display of sexual behaviors in rats primed with EB+P or EB alone and administered either 250 micro g ICI (Experiment 2) or 500 micro g ICI (Experiment 3). Experiment 4 tested the effects of ICI (250 and 500 micro g) on the expression of estrogen-induced progestin receptors in the uterus. ICI did not affect the display of sexual receptivity in any experiment. In rats primed with EB+P, paced mating behavior was altered by the 500 and 750 micro g, but not the 250 micro g, doses of ICI. The lowest (250 micro g) dose of ICI did alter paced mating behavior in rats primed with EB alone. The effects of ICI on paced mating behavior were manifested by a substantial lengthening of contact-return latencies following intromissions and ejaculations. The percentage of exits were not affected by ICI. Estrogen stimulation of uterine weight and induction of uterine progestin receptors was suppressed by ICI (250 and 500 micro g). ICI effects on paced mating behavior in hormone-primed female rats are likely to reflect antiestrogenic actions in the periphery, including interference with the estrogen induction of progestin receptors.

Emergency contraception in a public health emergency: exploring pharmacy availability in Brazil.

PubMed

Tavares, Marilia P; Foster, Angel M

2016-08-01

Dedicated progestin-only emergency contraceptive pills (ECPs) have been available with a prescription in Brazil since 1999. However, utilization of emergency contraception has been limited. We conducted a mystery client study at retail pharmacies in three regions to assess current availability. Using a predetermined client profile, we approached a random sample of chain and independent pharmacies in urban areas in the southeastern, northeastern and central-west regions. We documented product availability, price and the client-pharmacy representative interaction at each site. We analyzed these data with descriptive statistics and for content and themes. We visited 122 pharmacies in early 2016. All but three pharmacies (97.5%) had ECPs in stock at the time of the interaction and offered our client the medication without a prescription. In general, pharmacy representatives did not ask questions or provide our client with information about emergency contraception. When prompted, over one third of the pharmacy representatives (37.7%) inaccurately reported that levonorgestrel ECPs could only be used immediately or within 12, 24 or 48h from the time of intercourse. Despite the current regulatory status, our findings suggest that progestin-only ECPs are widely available without a prescription. Additional efforts to ensure that women have up-to-date and medically accurate information about progestin-only ECPs appear warranted. Our findings suggest that more work needs to be done to align national regulatory policies with international standards and evidence-based practices. The Zika virus epidemic has shined a spotlight on the importance of providing timely access to emergency contraception in Latin America. This public health emergency offers a window of opportunity to advance national policies and practices to ensure that Brazilian women have access to a full range of reproductive health services. Copyright © 2016 Elsevier Inc. All rights reserved.

Dilatation and curettage is more accurate than endometrial aspiration biopsy in early-stage endometrial cancer patients treated with high dose oral progestin and levonorgestrel intrauterine system

PubMed Central

2017-01-01

Objective To determine whether less invasive endometrial (EM) aspiration biopsy is adequately accurate for evaluating treatment outcomes compared to the dilatation and curettage (D&C) biopsy in early-stage endometrial cancer (EC) patients treated with high dose oral progestin and levonorgestrel intrauterine system (LNG-IUS). Methods We conducted a prospective observational study with patients younger than 40 years who were diagnosed with clinical stage IA, The International Federation of Gynecology and Obstetrics grade 1 or 2 endometrioid adenocarcinoma and sought to maintain their fertility. The patients were treated with medroxyprogesterone acetate 500 mg/day and LNG-IUS. Treatment responses were evaluated every 3 months. EM aspiration biopsy was conducted after LNG-IUS removal followed D&C. The tissue samples were histologically compared. The diagnostic concordance rate of the two tests was examined with κ statistics. Results Twenty-eight pairs of EM samples were obtained from five patients. The diagnostic concordance rate of D&C and EM aspiration biopsy was 39.3% (κ value=0.26). Of the seven samples diagnosed as normal with D&C, three (42.8%) were diagnosed as normal by using EM aspiration biopsy. Of the eight samples diagnosed with endometrioid adenocarcinoma by using D&C, three (37.5%) were diagnosed with endometrioid adenocarcinoma by using EM aspiration biopsy. Of the 13 complex EM hyperplasia samples diagnosed with the D&C, five (38.5%) were diagnosed with EM hyperplasia by using EM aspiration biopsy. Of the samples obtained through EM aspiration, 46.4% were insufficient for histological evaluation. Conclusion To evaluate the treatment responses of patients with early-stage EC treated with high dose oral progestin and LNG-IUS, D&C should be conducted after LNG-IUS removal. PMID:27670255

The progestin levonorgestrel induces endothelium-independent relaxation of rabbit jugular vein via inhibition of calcium entry and protein kinase C: role of cyclic AMP

PubMed Central

Herkert, Olaf; Kuhl, Herbert; Busse, Rudi; Schini-Kerth, Valérie B

2000-01-01

The progestin and oestrogen component of oral contraceptives have been involved in the development of venous thromboembolic events in women. In the present study we determined the vasoactive effects of sex steroids used in oral contraceptives in isolated preconstricted rabbit jugular veins in the presence of diclofenac and examined the underlying mechanisms.The natural hormone progesterone, the synthetic progestins levonorgestrel, 3-keto-desogestrel, gestodene and chlormadinone acetate, and the synthetic estrogen 17 α-ethinyloestradiol induced concentration-dependent relaxations of endothelium-intact veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K+) solution or phorbol myristate acetate (PMA) in the absence and presence of extracellular calcium (Ca2+). In addition, levonorgestrel depressed contractions evoked by Ca2+ and reduced 45Ca2+ influx in depolarized veins.Relaxations to levonorgestrel in U46619-constricted veins were neither affected by the presence of the endothelium nor by the inhibitor of soluble guanylyl cyclase, NS2028, but were significantly improved either by the selective cyclic AMP phosphodiesterase inhibitor rolipram or in the absence of diclofenac, and decreased by the protein kinase A inhibitor, Rp-8-CPT-cAMPS. Rolipram also potentiated relaxations to levonorgestrel in PMA-constricted veins in the presence, but not in the absence of extracellular Ca2+. Levonorgestrel increased levels of cyclic AMP and inhibited PMA-induced activation of protein kinase C in veins.These findings indicate that levonorgestrel caused endothelium-independent relaxations of jugular veins via inhibition of Ca2+ entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contributes to the levonorgestrel-induced relaxation possibly by depressing Ca2+ entry. PMID:10952682

Postmenopausal hormone therapy-also use of estradiol plus levonorgestrel-intrauterine system is associated with an increased risk of primary fallopian tube carcinoma.

PubMed

Koskela-Niska, Virpi; Pukkala, Eero; Lyytinen, Heli; Ylikorkala, Olavi; Dyba, Tadeusz

2015-10-15

Data on the possible impact of postmenopausal hormone therapy (HT) on the incidence of rare primary fallopian tube carcinoma (PFTC) are scarce. Therefore, we conducted a nationwide case-control study analyzing the association between the use of different HTs and PFTC. All women aged 50 years or older with an incident PFTC (n = 360) during 1995-2007 were identified from the Finnish Cancer Registry. For each case of PFTC, ten age- and place of residence-matched controls were selected from the Finnish National Population Register, which also provided information on parity. Data on HT purchases were received from the Prescription Register, and data on hysterectomies and sterilizations from the National Care Register. Controls with a salpingectomy before the PFTC diagnosis of the respective case were excluded. The PFTC risk in relation to different HTs was estimated with a conditional logistic regression model, adjusted for parity, age at last delivery, hysterectomy and sterilization. The use for five years or more of estradiol combined with levonorgestrel-releasing-intrauterine system (odds ratio 2.84, 95% confidence interval 1.10-7.38) and sequential estradiol-progestin therapy (EPT; 3.37; 2.23-5.08) were both linked with increases in the risk of PFTC, while the risk with use of estradiol-only therapy or continuous EPT was not statistically significantly increased. The OR for the use of tibolone for one year or more was 1.56 (0.55-4.41). The use of HT is related to an increased risk of PFTC, particularly when a progestin component is intrauterine or systemic progestin is given in sequential manner. © 2015 UICC.

Dilatation and curettage is more accurate than endometrial aspiration biopsy in early-stage endometrial cancer patients treated with high dose oral progestin and levonorgestrel intrauterine system.

PubMed

Kim, Da Hee; Seong, Seok Ju; Kim, Mi Kyoung; Bae, Hyo Sook; Kim, Mi La; Yun, Bo Seong; Jung, Yong Wook; Shim, Jeong Yun

2017-01-01

To determine whether less invasive endometrial (EM) aspiration biopsy is adequately accurate for evaluating treatment outcomes compared to the dilatation and curettage (D&C) biopsy in early-stage endometrial cancer (EC) patients treated with high dose oral progestin and levonorgestrel intrauterine system (LNG-IUS). We conducted a prospective observational study with patients younger than 40 years who were diagnosed with clinical stage IA, The International Federation of Gynecology and Obstetrics grade 1 or 2 endometrioid adenocarcinoma and sought to maintain their fertility. The patients were treated with medroxyprogesterone acetate 500 mg/day and LNG-IUS. Treatment responses were evaluated every 3 months. EM aspiration biopsy was conducted after LNG-IUS removal followed D&C. The tissue samples were histologically compared. The diagnostic concordance rate of the two tests was examined with κ statistics. Twenty-eight pairs of EM samples were obtained from five patients. The diagnostic concordance rate of D&C and EM aspiration biopsy was 39.3% (κ value=0.26). Of the seven samples diagnosed as normal with D&C, three (42.8%) were diagnosed as normal by using EM aspiration biopsy. Of the eight samples diagnosed with endometrioid adenocarcinoma by using D&C, three (37.5%) were diagnosed with endometrioid adenocarcinoma by using EM aspiration biopsy. Of the 13 complex EM hyperplasia samples diagnosed with the D&C, five (38.5%) were diagnosed with EM hyperplasia by using EM aspiration biopsy. Of the samples obtained through EM aspiration, 46.4% were insufficient for histological evaluation. To evaluate the treatment responses of patients with early-stage EC treated with high dose oral progestin and LNG-IUS, D&C should be conducted after LNG-IUS removal.

Thrombin impairs human endometrial endothelial angiogenesis; implications for progestin-only contraceptive-induced abnormal uterine bleeding.

PubMed

Shapiro, John P; Guzeloglu-Kayisli, Ozlem; Kayisli, Umit A; Semerci, Nihan; Huang, S Joseph; Arlier, Sefa; Larsen, Kellie; Fadda, Paolo; Schatz, Frederick; Lockwood, Charles J

2017-06-01

Progestin-only contraceptives induce abnormal uterine bleeding, accompanied by prothrombin leakage from dilated endometrial microvessels and increased thrombin generation by human endometrial stromal cell (HESC)-expressed tissue factor. Initial studies of the thrombin-treated HESC secretome identified elevated levels of cleaved chondroitin sulfate proteoglycan 4 (CSPG4), impairing pericyte-endothelial interactions. Thus, we investigated direct and CSPG4-mediated effects of thrombin in eliciting abnormal uterine bleeding by disrupting endometrial angiogenesis. Liquid chromatography/tandem mass spectrometry, enzyme-linked immunosorbent assay (ELISA) and quantitative real-time-polymerase chain reaction (PCR) evaluated conditioned medium supernatant and cell lysates from control versus thrombin-treated HESCs. Pre- and post-Depo medroxyprogesterone acetate (DMPA)-administered endometria were immunostained for CSPG4. Proliferation, apoptosis and tube formation were assessed in human endometrial endothelial cells (HEECs) incubated with recombinant human (rh)-CSPG4 or thrombin or both. Thrombin induced CSPG4 protein expression in cultured HESCs as detected by mass spectrometry and ELISA (p<.02, n=3). Compared to pre-DMPA endometria (n=5), stromal cells in post-DMPA endometria (n=5) displayed stronger CSPG4 immunostaining. In HEEC cultures (n=3), total tube-formed mesh area was significantly higher in rh-CSPG4 versus control (p<.05). However, thrombin disrupted HEEC tube formation by a concentration- and time-dependent reduction of angiogenic parameters (p<.05), whereas CSPG4 co-treatment did not reverse these thrombin-mediated effects. These results suggest that disruption of HEEC tube formation by thrombin induces aberrant angiogenesis and abnormal uterine bleeding in DMPA users. Mass spectrometry analysis identified several HESC-secreted proteins regulated by thrombin. Therapeutic agents blocking angiogenic effects of thrombin in HESCs can prevent or minimize progestin-only contraceptive-induced abnormal uterine bleeding. Copyright © 2017. Published by Elsevier Inc.

Progesterone and Neuroprotection

PubMed Central

Singh, Meharvan; Su, Chang

2012-01-01

Summary Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals have, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer’s disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone’s neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women’s Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function. PMID:22732134

Optimal routes of administration, vehicles and timing of progesterone treatment for inhibition of delivery during pregnancy.

PubMed

Fang, Dajun; Moreno, Mario; Garfield, Robert E; Kuon, Ruben; Xia, Huimin

2017-09-01

Progestins, notably progesterone (P4) and 17 alpha hydroxyprogesterone caproate, are presently used to treat pregnant women at risk of preterm birth. The aim of this study was to assess the optimal treatment options for progesterone (P4) to delay delivery using a sensitive bioassay for progesterone. Pregnant rats, known to be highly sensitive to progestins, were treated with P4, including Prochieve ® (also known as Crinone ® ), in various vehicles from day 13 of gestation and in late gestation, days 19 to 22, and delivery times noted. Various routes of administration of P4 and various treatment periods were studied. Use of micronized P4 by rectal, subcutaneous injection (sc) and topical (transdermal) administration in various oils all significantly (P<0.05-<0.001) delay delivery, but vaginal Prochieve ® did not. Administration of P4 in late gestation also prevented (P<0.001) delivery even when given 8h before delivery. Prochieve ® possesses little biological activity to suppress delivery in a sensitive bioassay system and suggests that this preparation may be of little value in prevention and inhibition of preterm birth. Further, this study shows: 1) Inhibition of delivery is increased with P4 treatments when given subcutaneously or topically. 2) P4 in fish oil provides the best vehicle for topical treatment and may be an effective treatment of preterm birth. 3) P4 in fish oil also delays delivery even when treatment begins just prior to normal delivery. 4) To prevent preterm birth in pregnant women, randomized controlled studies are needed with a potent progestin using better formulations and routes of administration. Copyright © 2017. Published by Elsevier B.V.

Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

PubMed

Mahabadi, Vahid; Amory, John K; Swerdloff, Ronald S; Bremner, William J; Page, Stephanie T; Sitruk-Ware, Regine; Christensen, Peter D; Kumar, Narender; Tsong, Yun-Yen; Blithe, Diana; Wang, Christina

2009-07-01

Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. The randomized, unblinded clinical trial was conducted at two academic medical centers. A total of 140 healthy male volunteers participated. One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis.

Effects of Norethindrone and Metabolite Ethynylestradiol on Reproductive Parameters in a Marine Fish

EPA Science Inventory

Norethindrone (NOR) is a progestin used in human contraceptives and has been detected in low concentrations (ng/L) in aquatic environments. Laboratory experiments were conducted with the marine fish cunner (Tautogolabrus adspersus) to evaluate whether NOR could affect reproductiv...

Effects of Two Progestins, Norethindrone and Levonorgestrel, On Reproduction in a Marine Fish, Tautogolabrus adspersus.

EPA Science Inventory

Endocrine-active pharmaceuticals that enter the aquatic environment through sewage effluent may have unintended impacts on reproduction in fish, which in turn may affect the sustainability of exposed populations. Laboratory experiments were conducted with the marine fish cunner (...

Effects of Two Progestins, Norethindrone and Levonorgestrel, on Reproduction in a Marine Fish, Tautogolabrus adspersus

EPA Science Inventory

Endocrine-active pharmaceuticals that enter the aquatic environment through sewage effluent may have unintended impacts on reproduction in fish, which in turn may affect the sustainability of exposed populations. Laboratory experiments were conducted with the marine fish cunner (...

Cloning and initial characterization of nuclear and four membrane progesterone receptors in the fathead minnow(Pimephales promelas)

EPA Science Inventory

Both native progestagens and synthetic progestins have important effects on reproduction that are mediated through progesterone receptors (PRs). Progestagens regulate gamete maturation in vertebrates, are critical regulators of placental mammal pregnancy, and act as reproductive ...

Practice Bulletin No. 152: Emergency Contraception.

PubMed

2015-09-01

Emergency contraception, also known as postcoital contraception, is therapy used to prevent pregnancy after an unprotected or inadequately protected act of sexual intercourse. Common indications for emergency contraception include contraceptive failure (eg, condom breakage or missed doses of oral contraceptives) and failure to use any form of contraception (). Although oral emergency contraception was first described in the medical literature in the 1960s, the U.S. Food and Drug Administration (FDA) approved the first dedicated product for emergency contraception in 1998. Since then, several new products have been introduced. Methods of emergency contraception include oral administration of combined estrogen-progestin, progestin only, or selective progesterone receptor modulators and insertion of a copper intrauterine device (IUD). Many women are unaware of the existence of emergency contraception, misunderstand its use and safety, or do not use it when a need arises (). The purpose of this Practice Bulletin is to review the evidence for the efficacy and safety of available methods of emergency contraception and to increase awareness of these methods among obstetrician-gynecologists and other gynecologic providers.

Assessment of ovarian cycles in the African elephant (Loxodonta africana) by measurement of salivary progesterone metabolites.

PubMed

Illera, Juan-Carlos; Silván, Gema; Cáceres, Sara; Carbonell, Maria-Dolores; Gerique, Cati; Martínez-Fernández, Leticia; Munro, Coralie; Casares, Miguel

2014-01-01

Monitoring ovarian cycles through hormonal analysis is important in order to improve breeding management of captive elephants, and non-invasive collection techniques are particularly interesting for this purpose. However, there are some practical difficulties in collecting proper samples, and easier and more practical methods may be an advantage for some institutions and/or some animals. This study describes the development and validation of an enzymeimmunoassay (EIA) for progestins in salivary samples of African elephants, Loxodonta africana. Weekly urinary and salivary samples from five non-pregnant elephant cows aged 7-12 years were obtained for 28 weeks and analyzed using EIA. Both techniques correlated positively (r = 0.799; P < 0.001), and the cycle characteristics obtained were identical. The results clearly show that ovarian cycles can be monitored by measuring progestins from salivary samples in the African elephant. This is a simple and non-invasive method that may be a practical alternative to other sampling methods used in the species. © 2014 Wiley Periodicals, Inc.

Cloning and initial characterization of nuclear and membrane progesterone receptors in the Fathead Minnow, Pimephales promelas

EPA Science Inventory

Both native progestagens and synthetic progestins have important effects on reproduction that are mediated through progesterone receptors (PRs). They regulate gamete maturation and can serve as precursors for other steroid hormones in vertebrates and act as reproductive pheromone...

Progestin-only contraceptives: effects on weight

PubMed Central

Lopez, Laureen M; Edelman, Alison; Chen-Mok, Mario; Trussell, James; Helmerhorst, Frans M

2015-01-01

Background Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users. Objectives The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight. Search strategy We searched MEDLINE, CENTRAL, POPLINE, EMBASE, LILACS, ClinicalTrials.gov, and ICTRP, and contacted investigators to identify other trials. Selection criteria All comparative studies were eligible that examined a POC versus another method or no contraceptive. The primary outcome was mean change in body weight or body composition. Data collection and analysis Two authors extracted the data. We computed the mean difference with 95% confidence interval (CI) for continuous variables and odds ratio with 95% CI for dichotomous variables. Main results We did not conduct meta-analysis due to the various contraceptive methods and weight change measures. Fifteen studies examined progestin-only pills (N=1), Norplant (N=4), and depot medroxyprogesterone acetate (DMPA) (N=10). Comparison groups were similar for weight change in 11 studies. Four studies showed differences in weight or body composition change for POCs compared to no hormonal method. Adolescents using DMPA had a greater increase in body fat (%) versus a group using no hormonal method (mean difference 11.00; 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (mean difference −4.00; 95% CI −6.93 to −1.07). In another study, weight gain (kg) was greater for the DMPA group than an IUD group (mean difference 2.28, 2.71, 3.17, respectively). The differences were notable within the normal weight and overweight subgroups. One study showed the Norplant (six-capsule) group had greater weight gain (kg) than a non-hormonal IUD group (mean difference 0.47 (95% CI 0.29 to 0.65) and a group using non-hormonal or no method (mean difference 0.74; 95% CI 0.52 to 0.96). Another study also showed a Norplant group also had greater weight gain (kg) than an IUD group (mean difference 1.10; 95% CI 0.36 to 1.84). Authors’ conclusions We found little evidence of weight gain when using POCs. Mean gain was less than 2 kg for most studies up to 12 months, and usually similar for the comparison group using another contraceptive. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain. PMID:21491411

Comparing the Effects of Combined Oral Contraceptives Containing Progestins With Low Androgenic and Antiandrogenic Activities on the Hypothalamic-Pituitary-Gonadal Axis in Patients With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis

PubMed Central

Amiri, Mina; Nahidi, Fatemeh; Kabir, Ali; Azizi, Fereidoun

2018-01-01

Background Different products of combined oral contraceptives (COCs) can improve clinical and biochemical findings in patients with polycystic ovary syndrome (PCOS) through suppression of the hypothalamic-pituitary-gonadal (HPG) axis. Objective This systematic review and meta-analysis aimed to compare the effects of COCs containing progestins with low androgenic and antiandrogenic activities on the HPG axis in patients with PCOS. Methods We searched PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science databases (1980-2017) to identify randomized controlled trials or nonrandomized studies investigating the effect of COCs containing progestins with low androgenic and antiandrogenic activities, including the products containing desogestrel, cyproterone acetate, and drospirenone, on the HPG axis in patients with PCOS. In this meta-analysis, fixed and random effect models were used. Outcomes of interest were weighted mean differences (WMD) of hormonal parameters, including the follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH-to-FSH ratio, estradiol, total testosterone, and sex hormone–binding globulin. Potential sources of heterogeneity were investigated using meta-regression and subgroup analyses. Subgroup analyses were performed based on the used progestin compound and treatment duration. We assessed quality of included studies and their risk of bias using Cochrane guidelines. Publication bias was assessed using Egger test and funnel plot. Results COC use was significantly associated with a decrease in gonadotropin levels, including FSH and LH. Use of products containing cyproterone acetate was associated with a decrease in FSH levels after 3 months (WMD=−0.48; 95% CI −0.81 to −0.15), 6 months (WMD=−2.33; 95% CI −3.48 to −1.18), and 12 months (WMD=−4.70; 95% CI −4.98 to −4.42) and a decrease in LH levels after 3 months (WMD=−3.57; 95% CI −5.14 to −1.99), 6 months (WMD=−5.68; 95% CI −9.57 to −1.80), and 12 months (WMD=−11.60; 95% CI −17.60 to −5.60). Use of COCs containing drospirenone for 6 months decreased FSH (WMD=−0.93; 95% CI −1.79 to −0.08) and LH (WMD=−4.59; 95% CI −7.53 to −1.66) levels. Data for products containing desogestrel were few, but this compound generally had no statistically significant influence on gonadotropin levels similar to that observed with COCs containing cyproterone acetate and drospirenone. Use of COCs was not associated with any significant change in LH-to-FSH ratio. COCs containing cyproterone acetate showed maximum effect on gonadotropin suppression. COCs containing cyproterone acetate significantly decreased estradiol concentrations, whereas those containing drospirenone exhibited no such effect. All COCs demonstrated improvement in androgenic profile and had the same effects on total testosterone and sex hormone–binding globulin concentrations. Progestin compound and treatment duration had no statistically significant effects on changing total testosterone and sex hormone–binding globulin levels. Conclusions COCs containing cyproterone acetate can effectively suppress gonadotropins, leading to a decrease in androgenic parameters. Although different products of COCs could significantly suppress the androgenic profile, it seems that products containing cyproterone acetate are more effective in suppressing gonadotropin and estradiol levels in patients with PCOS. PMID:29695378

Comparing the Effects of Combined Oral Contraceptives Containing Progestins With Low Androgenic and Antiandrogenic Activities on the Hypothalamic-Pituitary-Gonadal Axis in Patients With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis.

PubMed

Amiri, Mina; Ramezani Tehrani, Fahimeh; Nahidi, Fatemeh; Kabir, Ali; Azizi, Fereidoun

2018-04-25

Different products of combined oral contraceptives (COCs) can improve clinical and biochemical findings in patients with polycystic ovary syndrome (PCOS) through suppression of the hypothalamic-pituitary-gonadal (HPG) axis. This systematic review and meta-analysis aimed to compare the effects of COCs containing progestins with low androgenic and antiandrogenic activities on the HPG axis in patients with PCOS. We searched PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science databases (1980-2017) to identify randomized controlled trials or nonrandomized studies investigating the effect of COCs containing progestins with low androgenic and antiandrogenic activities, including the products containing desogestrel, cyproterone acetate, and drospirenone, on the HPG axis in patients with PCOS. In this meta-analysis, fixed and random effect models were used. Outcomes of interest were weighted mean differences (WMD) of hormonal parameters, including the follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH-to-FSH ratio, estradiol, total testosterone, and sex hormone-binding globulin. Potential sources of heterogeneity were investigated using meta-regression and subgroup analyses. Subgroup analyses were performed based on the used progestin compound and treatment duration. We assessed quality of included studies and their risk of bias using Cochrane guidelines. Publication bias was assessed using Egger test and funnel plot. COC use was significantly associated with a decrease in gonadotropin levels, including FSH and LH. Use of products containing cyproterone acetate was associated with a decrease in FSH levels after 3 months (WMD=-0.48; 95% CI -0.81 to -0.15), 6 months (WMD=-2.33; 95% CI -3.48 to -1.18), and 12 months (WMD=-4.70; 95% CI -4.98 to -4.42) and a decrease in LH levels after 3 months (WMD=-3.57; 95% CI -5.14 to -1.99), 6 months (WMD=-5.68; 95% CI -9.57 to -1.80), and 12 months (WMD=-11.60; 95% CI -17.60 to -5.60). Use of COCs containing drospirenone for 6 months decreased FSH (WMD=-0.93; 95% CI -1.79 to -0.08) and LH (WMD=-4.59; 95% CI -7.53 to -1.66) levels. Data for products containing desogestrel were few, but this compound generally had no statistically significant influence on gonadotropin levels similar to that observed with COCs containing cyproterone acetate and drospirenone. Use of COCs was not associated with any significant change in LH-to-FSH ratio. COCs containing cyproterone acetate showed maximum effect on gonadotropin suppression. COCs containing cyproterone acetate significantly decreased estradiol concentrations, whereas those containing drospirenone exhibited no such effect. All COCs demonstrated improvement in androgenic profile and had the same effects on total testosterone and sex hormone-binding globulin concentrations. Progestin compound and treatment duration had no statistically significant effects on changing total testosterone and sex hormone-binding globulin levels. COCs containing cyproterone acetate can effectively suppress gonadotropins, leading to a decrease in androgenic parameters. Although different products of COCs could significantly suppress the androgenic profile, it seems that products containing cyproterone acetate are more effective in suppressing gonadotropin and estradiol levels in patients with PCOS. ©Mina Amiri, Fahimeh Ramezani Tehrani, Fatemeh Nahidi, Ali Kabir, Fereidoun Azizi. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 25.04.2018.

Practice Bulletin Summary No. 152: Emergency Contraception.

PubMed

2015-09-01

Emergency contraception, also known as postcoital contraception, is therapy used to prevent pregnancy after an unprotected or inadequately protected act of sexual intercourse. Common indications for emergency contraception include contraceptive failure (eg, condom breakage or missed doses of oral contraceptives) and failure to use any form of contraception (1-3). Although oral emergency contraception was first described in the medical literature in the 1960s, the U.S. Food and Drug Administration (FDA) approved the first dedicated product for emergency contraception in 1998. Since then, several new products have been introduced. Methods of emergency contraception include oral administration of combined estrogen-progestin, progestin only, or selective progesterone receptor modulators and insertion of a copper intrauterine device (IUD). Many women are unaware of the existence of emergency contraception, misunderstand its use and safety, or do not use it when a need arises (4-6). The purpose of this Practice Bulletin is to review the evidence for the efficacy and safety of available methods of emergency contraception and to increase awareness of these methods among obstetrician-gynecologists and other gynecologic providers.

Effect of saxagliptin on the pharmacokinetics of the active components of Ortho-Cyclen(®), a combined oral contraceptive containing ethinyl estradiol and norgestimate, in healthy women.

PubMed

Upreti, V V; Hsiang, C B; Li, L; Xu, X; LaCreta, F P; Boulton, D W

2012-12-01

Saxagliptin (Onglyza™) is a dipeptidyl peptidase-4 (DPP4) inhibitor for treating type 2 diabetes mellitus. This open-label, randomized, two-way crossover study in 20 healthy female subjects investigated the effect of saxagliptin on the pharmacokinetics (PK) of the active components of a combined oral contraceptive (COC). Subjects received either COC (Ortho-Cyclen(®)) once daily (QD) for 21 days, then 5 mg saxagliptin QD + COC QD for 21 days, or vice versa. Coadministration of saxagliptin and COC did not alter the steady-state PK of the primary active oestrogen (ethinyl estradiol) or progestin (norelgestromin) COC components. The area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) of an active metabolite of norelgestromin (norgestrel) were increased by 13 and 17%, respectively, a magnitude that was not considered clinically meaningful. Coadministration of saxagliptin and COC in this study was generally well-tolerated. Saxagliptin can be co-prescribed with an oestrogen/progestin combination for women taking oral contraceptive. © 2012 Blackwell Publishing Ltd.

Mifepristone inhibits extracellular matrix formation in uterine leiomyoma.

PubMed

Patel, Amrita; Malik, Minnie; Britten, Joy; Cox, Jeris; Catherino, William H

2016-04-01

To characterize the efficacy of mifepristone treatment on extracellular matrix (ECM) production in leiomyomas. Laboratory study. University research laboratory. None. Treatment of human immortalized two-dimensional (2D) and three-dimensional (3D) leiomyoma and myometrial cells with mifepristone and the progestin promegestone (R5020). Expression of COL1A1, fibronectin, versican variant V0, and dermatopontin in treated leiomyoma cells by Western blot analysis and confirmatory immunohistochemistry staining of treated 3D cultures. Treatment with progestin stimulated production of COL1A1, fibronectin, versican, and dermatopontin. Mifepristone treatment inhibited protein production of these genes, most notably with versican expression. Combination treatment with both the agonist and antagonist further inhibited protein expression of these genes. Immunohistochemistry performed on 3D cultures demonstrated generalized inhibition of ECM protein concentration. Our study demonstrated that the progesterone agonist R5020 directly stimulated extracellular matrix components COL1A1, fibronectin, versican, and dermatopontin production in human leiomyoma cells. Progesterone antagonist mifepristone decreased protein production of these genes to levels comparable with untreated leiomyoma cells. Published by Elsevier Inc.

The effects of levonorgestrel on FSH-stimulated primary rat granulosa cell cultures through gene expression profiling are associated to hormone and folliculogenesis processes.

PubMed

Lira-Albarrán, Saúl; Larrea-Schiavon, Marco F; González, Leticia; Durand, Marta; Rangel, Claudia; Larrea, Fernando

2017-01-05

Levonorgestrel (LNG), a synthetic progestin, is used in emergency contraception (EC). The mechanism is preventing or delaying ovulation at the level of the hypothalamic pituitary unit; however, little knowledge exists on LNG effects at the ovary. The aim of this study was to identify the effects of LNG on FSH-induced 17β-estradiol (E 2 ) production, including LNG-mediated changes on global gene expression in rat granulosa cells (GC). Isolated GC from female Wistar rats were incubated in vitro in the presence or absence of human FSH and progestins. At the end of incubations, culture media and cells were collected for E 2 and mRNA quantitation. The results showed the ability of LNG to inhibit both hFSH-induced E 2 production and aromatase gene expression. Microarray analysis revealed that LNG treatment affects GC functionality particularly that related to folliculogenesis and steroid metabolism. These results may offer additional evidence for the mechanisms of action of LNG as EC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation

PubMed Central

Meendering, Jessica R.; Torgrimson, Britta N.; Miller, Nicole P.; Kaplan, Paul F.; Minson, Christopher T.

2010-01-01

Background Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination OCPs have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers, and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone. Study Design Twelve women were studied during two hormone phases of their OCP cycle; once at the end of three weeks of active pills (30 mcg EE and 3.0 mg drospirenone), and once at the end of a week of placebo pills (no exogenous hormones). Results Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p < 0.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases. Conclusion These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase. PMID:20851231

Comparative effects of a contraceptive vaginal ring delivering a nonandrogenic progestin and continuous ethinyl estradiol and a combined oral contraceptive containing levonorgestrel on hemostasis variables.

PubMed

Rad, Mandana; Kluft, Cornelis; Ménard, Joël; Burggraaf, Jacobus; de Kam, Marieke L; Meijer, Piet; Sivin, Irving; Sitruk-Ware, Regine L

2006-07-01

This study aimed to compare the effects on hemostasis variables of a contraceptive vaginal ring with those of an oral contraceptive. Twenty-three and 22 healthy premenopausal women were randomized to the contraceptive vaginal ring (150 microg Nestorone and 15 microg ethinyl estradiol) or Stediril 30 during 3 cycles. Analysis of covariance was performed with baseline values as covariate. The contraceptive vaginal ring changed most hemostasis variables similarly but raised (95% confidence intervals of percent treatment differences) Factor VIIt (28% to 49%), extrinsic activated protein C resistance (14% to 65%), and sex hormone-binding globulin (117% to 210%) and lowered Protein S (-32% to -16%) and the global activated partial thromboplastin time-based activated protein C resistance (-12% to -2%) more than the oral contraceptive. The contraceptive vaginal ring affected some measured hemostasis variables and sex hormone-binding globulin differently from the oral contraceptive, most likely because of difference in androgenicity of the progestins. The results suggest that the contraindications for oral contraceptive use would also apply to the tested contraceptive vaginal ring.

Aromatase inhibitors: the next generation of therapeutics for endometriosis?

PubMed

Attar, Erkut; Bulun, Serdar E

2006-05-01

To review the role of aromatase inhibitors (AIs) in the treatment of endometriosis. Endometriosis is a common estrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. Approximately only half of women with endometriosis get pain relief from existing medical or surgical treatments. Medical treatments usually are directed at inhibiting estrogen action or its production from the ovaries and do not address local estrogen biosynthesis by the aromatase enzyme in endometriotic lesions. A single gene encodes aromatase, which is the final enzyme in the estrogen biosynthesis pathway, and its inhibition effectively eliminates estrogen production. The recently introduced highly specific AIs have successfully treated pelvic pain and significantly reduced the lesion size. In premenopausal women, an AI alone may induce ovarian folliculogenesis, and thus AIs are combined with a progestin, a combination oral contraceptive, or a GnRH analogue. The side-effect profile of AIs administered in combination with an oral contraceptive or a progestin is remarkably benign. We review herein the published clinical evidence for the use of AIs in the treatment of endometriosis.

Progesterone regulation of stem and progenitor cells in normal and malignant breast

PubMed Central

Axlund, Sunshine Daddario; Sartorius, Carol A.

2011-01-01

Progesterone plays an important, if not controversial, role in mammary epithelial cell proliferation and differentiation. Evidence supports that progesterone promotes rodent mammary carcinogenesis under some conditions, progesterone receptors (PR) are necessary for murine mammary gland tumorigenesis, and exogenous progestin use in post-menopausal women increases breast cancer risk. Thus, the progesterone/PR signaling axis can promote mammary tumorigenesis, albeit in a context dependent manner. A mechanistic basis for the tumor promoting actions of progesterone has thus far remained unknown. Recent studies, however, have identified a novel role for progesterone in controlling the number and function of stem and progenitor cell populations in the normal human and mouse mammary glands, and in human breast cancers. These discoveries promise to reshape our perception of progesterone function in the mammary gland, and have spawned new hypotheses for how progestins may increase the risk of breast cancer. Here we review studies on progesterone regulation of mammary stem cells in normal and malignant tissue, and their implications for breast cancer risk, tumorigenesis, and tumor behavior. PMID:21945473

A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation.

PubMed

Meendering, Jessica R; Torgrimson, Britta N; Miller, Nicole P; Kaplan, Paul F; Minson, Christopher T

2010-10-01

Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination oral contraceptive pills (OCPs) have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone. Twelve women were studied during two hormone phases of their OCP cycle: once at the end of 3 weeks of active pills (30 mcg EE and 3.0 mg drospirenone) and once at the end of a week of placebo pills (no exogenous hormones) Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p<.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases. These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase. Copyright © 2010 Elsevier Inc. All rights reserved.

A single dose of bovine somatotropin 5 days before the end of progestin-based estrous synchronization increases prolificacy in sheep.

PubMed

Carrillo, F; Hernández-Cerón, J; Orozco, V; Hernández, J A; Gutiérrez, C G

2007-11-01

Bovine somatotropin (bST) enhances ovarian follicular and embryonic development in sheep and cattle. In the present study, the objective was to assess whether bST given 5 days before the end of progestin-based estrous synchronization improves prolificacy and lambing rate in sheep. Pelibuey ewes (n=92) exhibiting estrous cycles at regular intervals received an intravaginal sponge containing 45mg of FGA for 12 days. Five days before sponge withdrawal, ewes were treated with either 125mg of bST sc (bST group; n=47) or saline solution (control; n=45). After the sponge was removed, ewes were observed for estrus and subsequently mated twice. Lambing rate and prolificacy was determined at birth. Blood samples were taken from the time of treatment until day 15 after estrus in eight ewes from the bST group and nine from the control group. Concentrations of IGF-I were determined by immunoradiometric assay and progesterone by RIA. Treatment with bST increased (P<0.01) the proportion of ewes with more than one lamb (bST, 56% compared with control, 26%) and prolificacy (bST, 1.6 compared with control, 1.3). Treatment with bST increased (P<0.05) the lambing rate of multiparous (bST, 92% compared with control, 67%) but not in ewes at the first time they were mated (bST, 71% compared with control, 87%; P>0.05). IGF-I concentrations were greater (P<0.01) in ewes treated with bST than in control ewes from 2 days after treatment. Progesterone concentrations did not vary (P>0.05) between groups. It is concluded that a single dose of bST 5 days before progestin withdrawal increases lambing rate and prolificacy in sheep. These effects are associated with an increase in circulating concentrations of IGF-I.

The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells

PubMed Central

Ghatge, Radhika P; Jacobsen, Britta M; Schittone, Stephanie A; Horwitz, Kathryn B

2005-01-01

Introduction Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells. Method A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor. Results In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous. Conclusion Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor. PMID:16457685

Estrogen response of MCF-7 cells grown on diverse substrates and in suspension culture: promotion of morphological heterogeneity, modulation of progestin receptor induction; cell-substrate interactions on collagen gels.

PubMed

Pourreau-Schneider, N; Berthois, Y; Mittre, H; Charpin, C; Jacquemier, J; Martin, P M

1984-12-01

In this study we observed the incidence of hormone sensitivity in the response of MCF-7 cells to estrogen stimulation when the cells were cultured in different contact environments (hydrophilic plastic, bovine corneal extracellular matrix, type I collagen and in suspension culture). The major purpose was to describe the influence of cell to cell and cell to substrate contacts on the morphological response to estrogen treatment. However, other parameters including growth and induction of progestin receptor were also explored, keeping in mind that the MCF-7 cell line, although representative of normal mammary epithelium in that it contains a similar hormone receptivity, was selected in vitro from a metastatic population in a pleural effusion. Although substrate conditions did not modify growth enhancement by estrogens, progestin receptor levels were significantly higher in three-dimensional spheroid cultures in which cell to cell contacts were optimal due to elimination of basal contact. A careful morphological survey of large surfaces lead to an objective opinion of the overall effect of the hormone treatment on the non-cloned cell line in which a marked heterogeneity in the response of individual cells was observed. In terms of morphofunctional differentiation, the edification of acini with dense microvillus coating was best in suspension culture. When sections were made perpendicular to the plane of cultures on collagen gel rafts two other phenomena were noted: decrease in intercellular junctions, resulting in reduced cell to cell cohesion, and accumulation biodegradation products in the collagen lattice. This suggested a hormone-mediated interaction between the metastatic cells and the fibrillar substrate, collagen I, one of the major constituents of tissue stroma. This estrogen response might be related to the metastatic phenotype and must be distinct from their hormone sensitivity in terms of growth and differentiation since hormone receptivity is generally considered to be a favorable prognosis for breast cancer.

Clinical monograph: hormone replacement therapy.

PubMed

Deady, Joan

2004-01-01

For decades, hormone replacement therapy (HRT), which includes both estrogen and progestin, has been administered to postmenopausal women to mainly treat the symptoms of menopause and help prevent osteoporosis, with the added benefit of preventing coronary heart disease (CHD). Recently released study results have left clinicians wondering if HRT should be used at all, and, if so, with whom and under what circumstances. To provide readers with an example of the real-world operation of a pharmacy and therapeutics (P&T) committee in its use of a concise clinical monograph to guide its formulary decisions. The most relevant information for this committee, interested in evidence, was an analysis of the most current pivotal trials and observational studies that help define the place in therapy of HRT and provide information on product efficacy and safety. These included the Heart and Estrogen/progestin Replacement Study (HERS) and its extension trial, HERS II, in postmenopausal women with CHD and an average age of 67 years. The Women's Health Initiative (WHI) study, where the mean age of postmenopausal women was 63 years was also reviewed. The U.S. Food and Drug Administration (FDA) statements through January 8, 2003, on the appropriate use of these agents were also included in this clinical monograph for P&T committee review. HERS and HERS II provided evidence that HRT does not provide secondary prevention in women with CHD. Data from the WHI study concluded that HRT promotes CHD and breast cancer in this age group. The Women's Health, Osteoporosis, Progestin, Estrogen study concluded that lower doses of conjugated estrogens (0.3 mg) are just as effective in treating postmenopausal symptoms as higher doses (0.625 mg) and result in fewer side effects. The risk of breast cancer outweighs the benefits of osteoporosis prevention from HRT. According to labeling changes recommended by the FDA, HRT (or estrogen replacement therapy) should be limited to the shortest possible duration. Alternatives to HRT should be considered for the prevention of postmenopausal osteoporosis.

Oral contraceptives and the risk of gallbladder disease: a comparative safety study

PubMed Central

Etminan, Mahyar; Delaney, Joseph A.C.; Bressler, Brian; Brophy, James M.

2011-01-01

Background Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives. Methods We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease. Results We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate). Interpretation In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant. PMID:21502354

The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive

PubMed Central

Simonson, Steven G; Martin, Paul D; Warwick, Mike J; Mitchell, Patrick D; Schneck, Dennis W

2004-01-01

Aims To assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed. Methods This open-label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri-Cyclen®) on Days 1–21 and placebo OCS on Days 22–28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1–21 of Cycle B. Results Co-administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co-administration increased AUC[0–24] for ethinyl oestradiol (26%; 90% CI ratio 1.19–1.34), 17-desacetyl norgestimate (15%; 90% CI 1.10–1.20), and norgestrel (34%; 90% CI 1.25–1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17–1.33) and norgestrel (23%; 90% CI 1.14–1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle-stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6β-hydroxycortisol. Rosuvastatin significantly decreased low-density lipoprotein cholesterol [-55%], total cholesterol [-27%], and triglycerides [-12%], and significantly increased high-density lipoprotein cholesterol[11%]. Co-administration was well tolerated. Conclusions Rosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid-regulating effect was observed in this study, and there was no evidence of an altered lipid-regulating effect with OCS coadministration. PMID:14998424

Menopausal hormone usage and breast cancer in Saskatchewan: a record-linkage cohort study.

PubMed

Risch, H A; Howe, G R

1994-04-01

The association between the occurrence of carcinoma of the breast and previous usage of menopausal estrogens, progestins, and oral contraceptives is examined in a record-linkage study using the Saskatchewan Health Prescription-Drug-Plan Database. Saskatchewan Health is a governmental agency that funds publicly insured health care for essentially all residents of the province. For this study, all women aged 43-49 years in 1976 resident in Saskatchewan were identified from the Saskatchewan Health master registration file. These women were linked by registration beneficiary number to the Drug-Plan Database for the period from January 1976 to June 1987 and to the Provincial Cancer Registry Database for the period from March 1960 to December 1990. The fact and date of death or emigration from the province were obtained through the annual updates of the health plan. Of the 33,003 women initially in the cohort, 213 had a breast cancer diagnosed before 1976 and were omitted from this analysis. Between 1976 and 1990, 742 new primary breast cancer cases occurred. Women taking estrogens unopposed by progestins had an elevated risk of breast cancer, the risk increasing by 7% (relative risk = 1.072, 95% confidence interval 1.02-1.13; p = 0.008) for each 252 tablets used (approximately 1 year of use). Usage of estrogens opposed by progestins showed no association with risk (p = 0.48). Women taking oral contraceptives during this follow-up period also had a higher risk, increasing by 14% (relative risk = 1.144, 95% confidence interval 1.05-1.24; p = 0.002) for every 252 tablets used. These 1-year risk elevations are small but become appreciable at longer durations. For example, at 5 years of unopposed estrogen use, the relative risk is 1.42; for 5 years of oral contraceptive use, it is 1.96.

Progesterone induces progesterone receptor gene (PGR) expression via rapid activation of protein kinase pathways required for cooperative estrogen receptor alpha (ER) and progesterone receptor (PR) genomic action at ER/PR target genes.

PubMed

Diep, Caroline H; Ahrendt, Hannah; Lange, Carol A

2016-10-01

Progesterone Receptors (PRs) are critical effectors of estrogen receptor (ER) signaling required for mammary gland development and reproductive proficiency. In breast and reproductive tract malignancies, PR expression is a clinical prognostic marker of ER action. While estrogens primarily regulate PR expression, other factors likely contribute to a dynamic range of receptor expression across diverse tissues. In this study, we identified estrogen-independent but progestin (R5020)-dependent regulation of ER target genes including PGR in ER+/PR+ cancer cell lines. R5020 (10nM-10μM range) induced dose-dependent PR mRNA and protein expression in the absence of estrogen but required both PR and ERα. Antagonists of either PR (RU486, onapristone) or ERα (ICI 182,780) attenuated R5020 induction of TFF1, CTSD, and PGR. Chromatin immunoprecipitation (ChIP) assays performed on ER+/PR+ cells demonstrated that both ERα and PR were recruited to the same ERE/Sp1 site-containing region of the PGR proximal promoter in response to high dose progestin (10μM). Recruitment of ERα and PR to chromatin and subsequent PR mRNA induction were dependent upon rapid activation of MAPK/ERK and AKT; inhibition of these kinase pathways via U0126 or LY294002 blocked these events. Overall, we have identified a novel mechanism of ERα activation initiated by rapid PR-dependent kinase pathway activation and associated with phosphorylation of ERα Ser118 for estrogen-independent but progestin-dependent ER/PR cross talk. These studies may provide insight into mechanisms of persistent ER-target gene expression during periods of hormone (i.e. estrogen) ablation and suggest caution following prolonged treatment with aromatase or CYP17 inhibitors (i.e. contexts when progesterone levels may be abnormally elevated). Copyright © 2016 Elsevier Inc. All rights reserved.

Detection and identification of plasma progesterone metabolites in the female Florida manatee (Trichechus manatus latirostris) using GC/MS/MS.

PubMed

Tripp, K M; Dubois, M; Delahaut, P; Verstegen, J P

2009-08-01

Florida manatees (Trichechus manatus latirostris) have relatively low peripheral concentrations of progesterone (P4). The objective of this study was to determine if these relatively low P4 concentrations are associated with a high ratio of progestin metabolites and to document metabolite concentrations from individual blood samples obtained from manatees during diestrus or pregnancy. Metabolites known to exist in elephants-terrestrial manatee relatives-were targeted. These included 5alpha-reduced progestins (5alpha-pregnane-3,20-dione [5alpha-DHP] and 3alpha-hydroxy-5alpha-pregnan-20-one [5alpha-P3-OH]) and 17alpha-hydroxyprogesterone (17alpha-OHP), which occurs in Asian elephants. An additional, inactive metabolite, 20alpha-hydroxyprogesterone (20alpha-OHP), indicative of P4 overproduction, was also targeted. Progesterone itself was the predominant progestin detected in pregnant and nonpregnant manatee plasma (n = 10) using gas chromatography-mass spectrometry with tandem quadrupole detectors (GC/MS/MS). Progesterone concentrations in pregnant females varied from early (moderate to high) through mid and late (low) pregnancy. Progesterone concentrations ranged from low to high in nonpregnant, nonlactating females. The most commonly detected metabolite was 5alpha-P3-OH (n = 7), which occurred in pregnant (lower limit of detection [LLOD] to high) and nonpregnant (trace to high) females. The 5alpha-DHP metabolite was also detected in pregnant (LLOD to moderate) and nonpregnant (low) females. The 17alpha-OHP metabolite was not detected in any tested female. The 20alpha-OHP metabolite was detected in one nonpregnant, nonlactating, captive female (LLOD). Metabolites were most prevalent during early pregnancy, concurrent with maximum P4 concentrations. Based on their concentrations in peripheral circulation, we inferred that these metabolites may have, opposite to elephants, a limited physiologic role during luteal, pregnant, and nonpregnant phases in the manatee.

Mammary Hypertrophy in an Ovariohysterectomized Cat

PubMed Central

Pukay, B.P.; Stevenson, D.A.

1983-01-01

A four year old ovariohysterectomized domestic short-haired cat under treatment for behavioral urine spraying and idiopathic alopecia developed mammary gland hypertrophy following treatment with megestrol acetate. Withdrawal of the progestin and treatment with androgen failed to cause regression of the hypertrophy. The affected mammary gland was surgically excised and recovery was uneventful. ImagesFigure 1. PMID:17422254

Birth Control Pills and Nonprofessional Voice: Acoustic Analyses

ERIC Educational Resources Information Center

Amir, Ofer; Biron-Shental, Tal; Shabtai, Esther

2006-01-01

Purpose: Two studies are presented here. Study 1 was aimed at evaluating whether the voice characteristics of women who use birth control pills that contain different progestins differ from the voice characteristics of a control group. Study 2 presents a meta-analysis that combined the results of Study 1 with those from 3 recent studies that…

Effect of Levonorgestrel (NORPLANT) on the Immune Regulation of Bone Morphogenesis in Calvarial Cultures from the Laboratory Mouse (Mus muscularis).

DTIC Science & Technology

1995-10-01

continually releases a synthetic progestin, levonorgestrel , for five years. In order to assess the impact of levonorgestrel on bone cells, murine calvarial...cell cultures were harvested, grown to confluence and treated with levonorgestrel , progesterone and estrogen. The majority of the cells grown in these

Progesterone receptor membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine-induced matrix metalloproteinase 9 activity in vitro.

PubMed

Allen, Terrence K; Feng, Liping; Grotegut, Chad A; Murtha, Amy P

2014-02-01

Progesterone (P4) and the progestin, 17α-hydroxyprogesterone caproate, are clinically used to prevent preterm births (PTBs); however, their mechanism of action remains unclear. Cytokine-induced matrix metalloproteinase 9 (MMP-9) activity plays a key role in preterm premature rupture of the membranes and PTB. We demonstrated that the primary chorion cells and the HTR8/SVneo cells (cytotrophoblast cell line) do not express the classical progesterone receptor (PGR) but instead a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), whose role remains unclear. Using HTR8/SVneo cells in culture, we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate (MPA) and dexamethasone (Dex) but not P4 or 17α-hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α-induced MMP-9 activity after a 24-hour incubation period. The inhibitory effect of MPA, but not Dex, was attenuated when PGRMC1 expression was successfully reduced by PGRMC1 small interfering RNA. Our findings highlight a possible novel role of PGRMC1 in mediating the effects of MPA and in modulating cytokine-induced MMP-9 activity in cytotrophoblast cells in vitro.

Association between hormone replacement therapy and dementia: is it time to forget?

PubMed

Almeida, Osvaldo P; Flicker, Leon

2005-06-01

The results of in vitro and animal studies provide a strong rationale for the use of hormone replacement therapy (HRT) to prevent dementia and Alzheimer's disease (AD). In humans, the results of 16 observational studies are consistent with the hypothesis that estrogen use reduces the risk of AD by 10 to 60%. However, women who are prescribed HRT are less likely to have hypertension, diabetes and history of stroke than nonusers. As all of these factors have been associated with increased risk of dementia (including AD), this "prescription bias" may have a significant impact on the results of observational studies. Randomized trials are designed with the aim of avoiding many of the potential biases and confounding (measured or unmeasured) of observational studies. The results of the Women's Health Initiative Memory Study (WHIMS) indicate that HRT (estrogen plus progestin or estrogen alone) increases the risk of dementia (hazard ratio, HR = 1.8, 95% CI = 1.2-2.6). Taking into account the results of the WHIMS and the adverse health events associated with the use of estrogen plus progestin or estrogen alone, we conclude that HRT cannot be recommended as a safe and effective strategy to prevent dementia.

Progress and prospects in male hormonal contraception

PubMed Central

Amory, John K.

2009-01-01

Purpose of review Testosterone functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary. Low concentrations of these hormones deprive the testes of the signals required for spermatogenesis and results in markedly decreased sperm concentrations and effective contraception in a majority of men. Male hormonal contraception is well tolerated and acceptable to most men. Unfortunately, testosterone-alone regimens fail to completely suppress spermatogenesis in all men, meaning that in some the potential for fertility remains. Recent findings Because of this, novel combinations of testosterone and progestins, which synergistically suppress gonadotropins, have been studied. Two recently published testosterone/progestin trials are particularly noteworthy. In the first, a long-acting injectable testosterone ester, testosterone decanoate, was combined with etonogestrel implants and resulted in 80–90% of subjects achieving a fewer than 1 million sperm per milliliter. In the second, a daily testosterone gel was combined with 3-monthly injections of depot medroxyprogesterone acetate producing similar results. Summary Testosterone-based hormone combinations are able to reversibly suppress human spermatogenesis; however, a uniformly effective regimen has remained elusive. Nevertheless, improvements, such as the use of injectable testosterone undecanoate, may lead to a safe, reversible and effective male contraceptive. PMID:18438174

Influence of an oral contraceptive containing drospirenone on insulin sensitivity of healthy women.

PubMed

Cagnacci, Angelo; Piacenti, Ilaria; Zanin, Renata; Xholli, Anjeza; Tirelli, Alessandra

2014-07-01

Oral contraceptives (OCs) containing androgenic second and third generation progestins decrease insulin sensitivity (SI). In this study we investigated whether an oral contraceptive containing the anti-androgenic progestin drospirenone (DRSP) still alters SI. Lipid modifications were investigated as well. Eleven young healthy women were allocated to receive for 6 months ethinyl-estradiol (EE) 30μg plus DRSP (3mg). SI and glucose utilization independent of insulin (Sg) was investigated by the minimal model method. Lipid modifications were also analyzed. SI did not vary during EE/DRSP (from 3.72±2.62 to 3.29±2.93; p=0.73). Similarly, values of Sg did not vary (from 0.03±0.02 to 0.032±0.014; p=0.87). An increase was observed in HDL cholesterol (9.4±9.8mg/dl; p=0.05) and triglycerides (46.9±75.1mg/dl; p=0.046), with no modification in LDL cholesterol (-4.64±1.704mg/dl; p=0.6). EE/DRSP does not deteriorate SI. These results are reassuring for the long-term use of this association. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of Norethindrone-Containing OCPs to Desogestrel OCPs and Depro-Provera in Women

DTIC Science & Technology

2001-10-01

servicewomen requesting contraception have been prescribed a monophasic norethindrone-containing birth control pill (NOCA). In 1992, injectable depot...medroxyprogesterone acetate (DMPA) received approval and more recently, birth control pills using the new progestin, desogestrel (DOCA), have been made...an injectable progestational agent that offers a highly effective, safe, convenient, reversible and almost user-independent method of birth control (12

Warming modulates the effects of the endocrine disruptor progestin levonorgestrel on the zebrafish fitness, ovary maturation kinetics and reproduction success.

PubMed

Cardoso, P G; Rodrigues, D; Madureira, T V; Oliveira, N; Rocha, M J; Rocha, E

2017-10-01

Interactive effects between multiple stressors, namely climate drivers (e.g., temperature) and chemical pollution (e.g., endocrine disruptors) are poorly studied. Here, it was for the first time evaluated the combinatory effects of temperature and a synthetic progestin, levonorgestrel (LNG), on the fitness and reproductive-related endpoints of zebrafish (Danio rerio). A multi-factorial design was implemented by manipulating both temperature [setting as baseline an ambient temperature of 27 °C, against warming (+3 °C)] and LNG levels (10 ngL -1 and 1000 ngL -1 ). Groups of males and females were exposed sub-acutely, for 21-days. Increased temperature caused an overall decrease in the females' gonadosomatic index (GSI), during the pre-reproduction phase, LNG did not affect GSI. In addition, fecundity (number of ovulated eggs) was negatively affected by both temperature and LNG, being the effect of the latter more intense. Fish exposed to the highest LNG concentration (at both temperatures) did not reproduce, but also in those exposed to the lowest dose of progestin at a higher temperature, a complete reproductive failure occurred. These results reflect what was observed in the stereological analysis of the ovary maturation stages prior to reproduction. Accordingly, the higher the LNG concentration, the lower the degree of maturation of the ovary. This was exacerbated by the higher temperature. As to embryonated eggs, they hatched significantly faster at higher temperatures, but exposure to 10 ngL -1 of LNG (at 27 °C) reduced significantly the hatching rate, comparing to control. Further, the recrudescence of the ovary 48 h after spawning seems to be not affected by both stressors. Our data suggest that in a future scenario of global warming and synthetic hormones exposure, the reproduction of fish species, such as the zebrafish, can be endangered, which can put at risk their success, and consequently affect the structure and functioning of associated aquatic ecosystems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Monitoring ovarian cycles, pregnancy and post-partum in captive marsh deer (Blastocerus dichotomus) by measuring fecal steroids

PubMed Central

Polegato, Bruna Furlan; Duarte, José Maurício Barbanti

2018-01-01

Abstract The marsh deer is an endangered species from the marshlands of central South America. This study aimed to characterize certain aspects of the reproductive physiology of marsh deer hinds, including the duration and fecal progestins profile of the estrous cycle, pregnancy and post-partum periods, and evaluate the effect of cloprostenol administration on this species. The experimental group consisted of six females and one fertile male marsh deer. During monitoring of the estrous cycle, the fresh fecal samples were collected daily and, during pregnancy, they were collected twice weekly. The hormonal profile obtained from daily fecal samples indicated that the mean duration of the estrous cycle was 21.3 ± 1.3 days (6.4 days inter-luteal phase and 14.8 days luteal phase; n = 16 estrous cycles). The mean concentration of fecal progestins in the inter-luteal phase was 834 ± 311 ng g−1, in the luteal phase was 3979 ± 1611 ng g−1, value between them was 1457 ng g−1. No significant difference in fecal estrogen concentrations was determined during the estrous cycle. The corpora luteum was not responsive to cloprostenol until Day 6 of the estrous cycle, the period previously described as the inter-luteal phase. Half the females became pregnant following treatment with cloprostenol and two others were fertilized in their natural estrous cycle. Four females delivered fawns, and the mean duration of pregnancy was 253 ± 4 days. Fecal progestin concentrations were similar to those of the estrous cycle during the first 11 weeks of pregnancy and increased significantly ( > 15250 ng g−1) thereafter, providing a presumptive diagnosis guideline. Within 60 days of post-partum analyses, 75% of the deer exhibited behavioural estrus and/or ovarian activity. This study generated a broader understanding of the marsh deer species concerning the production of consistent data related to its reproduction. This knowledge can be used to assist the reproductive management of this species and, consequently, to promote its conservation. PMID:29383254

Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding.

PubMed

Guzeloglu Kayisli, Ozlem; Kayisli, Umit A; Basar, Murat; Semerci, Nihan; Schatz, Frederick; Lockwood, Charles J

2015-01-01

Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription. The resultant PR and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding.

The Progestin-Only Contraceptive Medroxyprogesterone Acetate, but Not Norethisterone Acetate, Enhances HIV-1 Vpr-Mediated Apoptosis in Human CD4+ T Cells through the Glucocorticoid Receptor

PubMed Central

Tomasicchio, Michele; Avenant, Chanel; Du Toit, Andrea; Ray, Roslyn M.; Hapgood, Janet P.

2013-01-01

The glucocorticoid receptor (GR) regulates several physiological functions, including immune function and apoptosis. The HIV-1 virus accessory protein, viral protein R (Vpr), can modulate the transcriptional response of the GR. Glucocorticoids (GCs) and Vpr have been reported to induce apoptosis in various cells, including T-cells. We have previously shown that the injectable contraceptive, medroxyprogesterone acetate (MPA) is a partial to full agonist for the GR, unlike norethisterone acetate (NET-A). We investigated the functional cross talk between the GR and Vpr in inducing apoptosis in CD4+ T-cells, in the absence and presence of GCs and these progestins, as well as progesterone. By using flow cytometry, we show that, in contrast to NET-A and progesterone, the synthetic GR ligand dexamethasone (Dex), cortisol and MPA induce apoptosis in primary CD4+ T-cells. Furthermore, the C-terminal part of the Vpr peptide, or HIV-1 pseudovirus, together with Dex or MPA further increased the apoptotic phenotype, unlike NET-A and progesterone. By a combination of Western blotting, PCR and the use of receptor- selective agonists, we provide evidence that the GR and the estrogen receptor are the only steroid receptors expressed in peripheral blood mononuclear cells. These results, together with the findings that RU486, a GR antagonist, prevents Dex-, MPA- and Vpr-mediated apoptosis, provide evidence for the first time that GR agonists or partial agonists increase apoptosis in primary CD4+ T-cells via the GR. We show that apoptotic induction involves differential expression of key apoptotic genes by both Vpr and GCs/MPA. This work suggests that contraceptive doses of MPA but not NET-A or physiological doses of progesterone could potentially accelerate depletion of CD4+ T-cells in a GR-dependent fashion in HIV-1 positive women, thereby contributing to immunodeficiency. The results imply that choice of progestin used in contraception may be critical to susceptibility and progression of diseases such as HIV-1. PMID:23658782

The pregnancy outcome of progestin-primed ovarian stimulation using 4 versus 10 mg of medroxyprogesterone acetate per day in infertile women undergoing in vitro fertilisation: a randomised controlled trial.

PubMed

Dong, J; Wang, Y; Chai, W R; Hong, Q Q; Wang, N L; Sun, L H; Long, H; Wang, L; Tian, H; Lyu, Q F; Lu, X F; Chen, Q J; Kuang, Y P

2017-06-01

To investigate the clinical outcome and endocrinological characteristics of progestin-primed ovarian stimulation (PPOS) using 4 versus 10 mg of medroxyprogesterone acetate (MPA) per day in infertile women with normal ovary reserve. A randomised parallel controlled trial. Tertiary-care academic medical centre. A cohort of 300 infertile women undergoing in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Human menopausal gonadotropin (hMG; 225 iu per day) and MPA (group A, 10 mg per day; group B, 4 mg per day) were started simultaneously from cycle day 3 onwards. Ovulation was co-triggered by human chorionic gonadotropin (hCG; 1000 iu) and gonadotropin-releasing hormone agonist (GnRH agonist; 0.1 mg) when dominant follicles matured. Viable embryos were cryopreserved for later frozen embryo transfer (FET) in both groups. The primary outcome measure was the number of oocytes retrieved. Secondary outcomes included the incidence of a premature surge in luteinising hormone (LH), the number of viable embryos, and clinical pregnancy outcomes. The number of oocytes retrieved and viable embryos were similar between two groups (9.8 ± 6.3 versus 9.6 ± 5.9; 4.2 ± 2.6 versus 3.7 ± 3.0; P > 0.05). No significant difference was found in clinical pregnancy rate (58.0 versus 48.7%) and live birth rate per participant (48.7 versus 42.0%; P > 0.05). No premature LH surge and ovarian hyperstimulation syndrome (OHSS) occurred in either group. Progestin-primed ovarian stimulation (PPOS) using 4 or 10 mg of MPA per day was comparable in terms of the number of oocytes retrieved and pregnancy outcome after FET. The administration of 4 mg of MPA per day was sufficient to prevent an untimely LH rise in women undergoing IVF/ICSI treatment. An RCT confirmed similar pregnancy outcome in P-primed ovarian stimulation with a daily dose of 4 or 10 mg MPA. © 2017 Royal College of Obstetricians and Gynaecologists.

Progesterone increases ex vivo testosterone production and decreases the expression of progestin receptors and steroidogenic enzymes in the fathead minnow (Pimephales promelas) ovary.

PubMed

Chishti, Yasmin Z; Feswick, April; Martyniuk, Christopher J

2014-04-01

Progesterone (P4) is a metabolic precursor for a number of steroids, including estrogens and androgens. P4 also has diverse roles within the vertebrate ovary that include oocyte growth and development. The objectives of this study were to measure the effects of P4 on testosterone (T) and 17β-estradiol (E2) production in the fathead minnow (FHM) ovary and on the mRNA abundance of transcripts involved in steroidogenesis and steroid receptor signaling. Ovary explants were treated with P4 (10(-6)M) for 6 and 12h. P4 administration significantly increased T production ∼3-fold at both 6 and 12h, whereas E2 production was not affected, consistent with the hypothesis that excess P4 is not converted to terminal estrogens in the mature ovary. Nuclear progesterone receptor mRNA was decreased at 6h and membrane progesterone receptor gamma-2 mRNA was significantly down-regulated at both 6 and 12h; however there was no change in membrane progesterone receptor alpha or beta mRNA levels. Androgen receptor (ar) and estrogen receptor 2a (esr2a) mRNA were significantly reduced at 6h with P4 treatment, but there was no change in esr2b mRNA at either time point. Transcripts for enzymes in the steroid pathway (star, hsd11b2) were significantly lower at 6h compared to controls, whereas cyp17a and cyp19a mRNA abundance did not change with treatments at either time point. These data suggest that P4 incubation can lead to increased T production in the FHM ovary without a concomitant change in E2, and that the membrane bound progestin receptors are differentially regulated by P4 in the teleost ovary. As environmental progestins have received increased attention due to their suspected role as endocrine disruptors, mechanistic data on the role of exogenous P4 treatments in the male and female gonad is warranted. Copyright © 2014 Elsevier Inc. All rights reserved.

[Studies of progestin specific binding protein in the human prostate. [III]; Sodium molybdate effect on SDG analysis].

PubMed

Imai, K; Kumasaka, F; Kobayashi, M; Takahashi, Y; Takahashi, E; Yamanaka, H

1985-08-20

The effect of sodium molybdate on the specific binding protein (SBP) of synthetic progestin 17 alpha-methyl-[3H]-promegestone (R5020) in the cytosol of the human prostate was studied. In a sucrose density gradient analysis, two R5020 SBP components at 4S and 7-8S were observed. It was apparent that the 4S component was reduced and the 7-8S component increased with the addition of 10mM sodium molybdate into the cytosol. Therefore, the molybdate enhancement degree on total SBP amount (4S plus 7-8S) was decided by the relationship between the decreasing rate at 4S and the increasing one at 7-8S. It was shown that the molybdate effect was time-dependent and was not related to the SBP state, whether it was bounded with steroid or not. Moreover, it was estimated that the molybdate effect was not related to phosphatase inhibition since R5020 SBP in SDG was not enhanced by the addition of sodium fluoride which was a phosphatase inhibitor. In this report, the possibility of the existence of the 7-8S forming factor in the human prostate and the relationship between it and sodium molybdate was also discussed through an experiment on a Sephadex G-25.

An efficient model of human endometriosis by induced unopposed estrogenicity in baboons.

PubMed

Nair, Hareesh B; Baker, Robert; Owston, Michael A; Escalona, Renee; Dick, Edward J; VandeBerg, John L; Nickisch, Klaus J

2016-03-08

Endometriosis is a chronic estrogen-dependent disease that occurs in approximately 10% of reproductive age women. Baboons offer a clear benefit for studying the initiation and progression of endometriosis since baboon is very close to humans phylogenetically. Progestins are used in the treatment of endometriosis. The therapeutic window of progestins depends on the ratio of its affinity towards progesterone receptor agonism verses antagonism. The present study is to determine the role of pure antiprogestin in baboon endometriosis. We hypothesize that pure antiprogestin will induce unopposed estrogenicity and spontaneous endometriosis in baboons. The rate of endometrial invasion and attachment through modeled peritoneum in the presence and absence of progesterone and antiprogestin was evaluated in this study. A baboon model of endometriosis induced by unopposed estrogenicity using progesterone receptor antagonist (EC304) was used in this study. We observed EC304 has induced unopposed estrogenicity that deregulated proteins involved in attachment, invasion, cell growth, and steroid hormone receptors in this model. Our data suggest that depleting progesterone levels in the endometrium will increase estrogen hyper-responsiveness that leads to increased endometriotic lesion progression in the baboon (Papio anubis) model. This study reports a refined model of human endometriosis in baboons that could potentially be used to develop new diagnostic and therapeutic strategies for the benefit of women suffering from endometriosis.

Effects of sex steroids on women's health: implications for practitioners.

PubMed

Derman, R J

1995-01-16

Androgen excess in women is manifested typically by clinical features that may include hirsutism, acne, central obesity, male-pattern baldness, upper torso widening, increased waist-to-hip ratio, clitoral hypertrophy, and deepening of the voice. The differential diagnosis includes androgen-producing ovarian and adrenal neoplasms, Cushing's syndrome, polycystic ovary syndrome, and the intake of exogenous androgens. Physicians treating patients for one symptom of androgen excess must be alert for other symptoms and signs. The cosmetic manifestations of androgen excess belie the serious health risks associated with this condition, including cardiovascular disease, intravascular thrombosis, and insulin resistance. Prompt clinical recognition of androgen excess, understanding of the androgen-related biochemical abnormalities underlying the risks associated with this condition, and implementation of risk modification can reduce the incidence of associated morbidity and mortality. An interdisciplinary approach to management is strongly recommended. Risk reduction strategies include correction of dyslipidemias, low-dose aspirin for primary prevention of myocardial infarction, maintenance of ideal weight, smoking cessation, exercise, use of oral contraceptives containing a low-androgenic progestin, and postmenopausal estrogen replacement. Combination oral contraceptives containing low-androgenic progestins are effective not only in reducing signs of androgen excess but also in potentially retarding the progression of long-term sequelae such as cardiovascular disease.

Blockage of progestin physiology disrupts ovarian differentiation in XX Nile tilapia (Oreochromis niloticus).

PubMed

Zhou, Linyan; Luo, Feng; Fang, Xuelian; Charkraborty, Tapas; Wu, Limin; Wei, Jing; Wang, Deshou

2016-04-22

Previous studies indicated that maturation inducing hormone, 17α, 20β-Dihydroxy-4-pregnen-3-one (DHP), probably through nuclear progestin receptor (Pgr), might be involved in spermatogenesis and oogenesis in fish. To further elucidate DHP actions in teleostean ovarian differentiation, we analyzed the expression of pgr in the ovary of Nile tilapia (Oreochromis niloticus), and performed RU486 (a synthetic Pgr antagonist) treatment in XX fish from 5 days after hatching (dah) to 120 dah. Tilapia Pgr was abundantly expressed in the follicular cells surrounding oocytes at 30 and 90 dah. Continuous RU486 treatment led to the blockage of oogenesis and masculinization of somatic cells in XX fish. Termination of RU486 treatment and maintenance in normal condition resulted in testicular differentiation, and estrogen compensation in RU486-treated XX fish successfully restored oogenesis. In RU486-treated XX fish, transcript levels of female dominant genes were significantly reduced, while male-biased genes were evidently augmented. Meanwhile, both germ cell mitotic and meiotic markers were substantially reduced. Consistently, estrogen production levels were significantly declined in RU486-treated XX fish. Taken together, our data further proved that DHP, possibly through Pgr, might be essential in the ovarian differentiation and estrogen production in fish. Copyright © 2016 Elsevier Inc. All rights reserved.

Src kinase signaling mediates estrous behavior induced by 5β-reduced progestins, GnRH, prostaglandin E2 and vaginocervical stimulation in estrogen-primed rats.

PubMed

Lima-Hernández, Francisco J; Beyer, Carlos; Gómora-Arrati, Porfirio; García-Juárez, Marcos; Encarnación-Sánchez, José L; Etgen, Anne M; González-Flores, Oscar

2012-11-01

The progesterone receptor (PR) is a dual function protein that acts in the nucleus as a transcriptional factor and at the cytoplasm as a scaffold for the Src-MAPK signaling pathway. Several agents lacking affinity for the PR, such as 5β-reduced progestins, GnRH or prostaglandin E(2) (PGE(2)) facilitate estrous behavior in ovariectomized (ovx), estrogen-primed rats yet their action is blocked by the antiprogestin RU486. We hypothesize that these agents act by using the PR-Src-mitogen activated protein kinase alternative pathway. To test this hypothesis we used PP2, a specific inhibitor of the Src kinase family. Intraventricular infusion of 30 μg of PP2, 30 min before behavioral testing, significantly attenuated estrous behaviors induced in estradiol benzoate (E(2)B)-primed rats by 5β-dihydroprogesterone (5β-DHP), 5β-pregnan-3β-ol-20-one (5β,3β-Pgl), GnRH, PGE(2) and by manual flank/vaginocervical stimulation. These results suggest that the Src signaling system, by activating mitogen-activated protein kinases, participates in the facilitation of estrous behavior in E(2)B-primed rats induced by agents lacking affinity for the PR. Copyright © 2012 Elsevier Inc. All rights reserved.

Persistence of an intact endometrial matrix and vessels structure in women exposed to VA-2914, a selective progesterone receptor modulator.

PubMed

Ravet, S; Munaut, C; Blacher, S; Brichant, G; Labied, S; Beliard, A; Chabbert-Buffet, N; Bouchard, P; Foidart, J-M; Pintiaux, A

2008-11-01

VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity that induces amenorrhea, whereas progestins cause endometrial spotting and bleeding. This abnormal bleeding due to progestins is a consequence of focal stromal proteolysis by an increase in naked vessel size and density. Our objective was to quantify the effects of VA-2914 on endometrial vascularization, fibrillar matrix, and vascular endothelial growth factor (VEGF)-A expression in endometrial biopsies from 41 women before and after 12 wk daily treatment with a placebo, or 2.5, 5, or 10 mg VA-2914. Collagen fibrillar network was stained by silver impregnation. Vessel area, density, and structure were quantified with a computer-assisted image analysis system after double immunostaining using an anti-von Willebrand factor (endothelial cells) and an anti-alpha smooth muscle actin (vascular smooth muscle cells) marker antibody. VEGF-A mRNAs were quantified by RT-PCR and localized by immunohistochemistry. The endometrial vessels, collagen network, and mRNA levels of VEGF-A were identical during the luteal phase at baseline and in VA-2914 treated women. VEGF-A distribution was unchanged. VA-2914 does not alter the endometrial matrix and cells, and does not modify the endometrial vessel morphology as compared with baseline biopsies.

Depot-medroxyprogesterone acetate: an update.

PubMed

Bakry, Sayed; Merhi, Zaher O; Scalise, Trudy J; Mahmoud, Mohamad S; Fadiel, Ahmed; Naftolin, Frederick

2008-07-01

Depo-Provera is a contraceptive approved by the US Food and Drug Administration (FDA) since 1992 and used worldwide by more than 90 million women. Despite the fact that progestins are endogenous hormones that are secreted by the body, its excess might lead to detrimental health effects. Whether progestins as contraceptives are friends or foes is a questionable matter. In this manuscript, we drive the attention to both usage and side effects Depo-Provera. Depot-medroxyprogesterone acetate (DMPA) is a highly effective, convenient non-daily hormonal contraceptive option that has been available worldwide for many years. The experience with DMPA provides a large body of long-term data regarding the efficacy and safety of this contraceptive method; this long-term experience has established that the use of DMPA does not increase the risk of cardiovascular events, breast cancer, other gynecologic malignancy, or postmenopausal fracture; however, patients are often more concerned about the relatively immediate effects of contraceptives such as potential changes in menstrual cycle, body weight, and mood disturbances. Concerns about such issues may lead to reluctance to initiate therapy or premature discontinuation. Counseling and understanding of women's concerns and experiences using Depo-Provera is important and could help health care providers redesign counseling strategies to improve contraceptive continuation and improve patient adherence.

Estrogen sulfotransferases in breast and endometrial cancers.

PubMed

Pasqualini, Jorge Raul

2009-02-01

Estrogen sulfotransferase is significantly more active in the normal breast cell (e.g., Human 7) than in the cancer cell (e.g., MCF-7). The data suggest that in breast cancer sulfoconjugated activity is carried out by another enzyme, the SULT1A, which acts at high concentration of the substrates. In breast cancer cells sulfotransferase (SULT) activity can be stimulated by various progestins: medrogestone, promegestone, and nomegestrol acetate, as well as by tibolone and its metabolites. SULT activities can also be controlled by other substances including phytoestrogens, celecoxib, flavonoids (e.g., quercetin, resveratrol), and isoflavones. SULT expression was localized in breast cancer cells, which can be stimulated by promegestone and correlated with the increase of the enzyme activity. The estrogen sulfotransferase (SULT1E1), which acts at nanomolar concentration of estradiol, can inactivate most of this hormone present in the normal breast; however, in the breast cancer cells, the sulfotransferase denoted as SULT1A1 is mainly present, and this acts at micromolar concentrations of E(2). A correlation was postulated among breast cancer cell proliferation, the effect of various progestins, and sulfotransferase stimulation. In conclusion, it is suggested that factors involved in the stimulation of the estrogen sulfotransferases could provide new possibilities for the treatment of patients with hormone-dependent breast and endometrial cancers.

Hippocampal 3alpha,5alpha-THP may alter depressive behavior of pregnant and lactating rats.

PubMed

Frye, Cheryl A; Walf, Alicia A

2004-07-01

The 5alpha-reduced metabolite of progesterone (P), 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), may mediate progestins' effects to reduce depressive behavior of female rats in part through actions in the hippocampus. To investigate, forced swim test behavior and plasma and hippocampal progestin levels were assessed in groups of rats expected to differ in their 3alpha,5alpha-THP levels due to endogenous differences (pregnant and postpartum), administration of a 5alpha-reductase inhibitor (finasteride; 50 mg/kg sc), and/or gestational stress [prenatal stress (PNS)], an animal model of depression. Pregnant rats had higher plasma and hippocampal 3alpha,5alpha-THP levels and less depressive behavior (decreased immobility, increased struggling and swimming) in the forced swim test than did postpartum rats. Finasteride, compared to vehicle-administration, reduced plasma and hippocampal 3alpha,5alpha-THP levels and increased depressive behavior (increased immobility, decreased struggling and swimming). PNS was associated with lower hippocampal, but not plasma, 3alpha,5alpha-THP levels and increased swimming compared to that observed in control rats. Together, these data suggest that 3alpha,5alpha-THP in the hippocampus may mediate antidepressive behavior of female rats.

Progesterone-induced Neuroprotection: Factors that may predict therapeutic efficacy

PubMed Central

Singh, Meharvan; Su, Chang

2013-01-01

Both progesterone and estradiol have well-described neuroprotective effects against numerous insults in a variety of cell culture models, animal models and in humans. However, the efficacy of these hormones may depend on a variety of factors, including the type of hormone used (ex. progesterone versus medroxyprogesterone acetate), the duration of the postmenopausal period prior to initiating the hormone intervention, and potentially, the age of the subject. The latter two factors relate to the proposed existence of a “window of therapeutic opportunity” for steroid hormones in the brain. While such a window of opportunity has been described for estrogen, there is a paucity of information to address whether such a window of opportunity exists for progesterone and its related progestins. Here, we review known cellular mechanisms likely to underlie the protective effects of progesterone and furthermore, describe key differences in the neurobiology of progesterone and the synthetic progestin, medroxyprogesterone acetate (MPA). Based on the latter, we offer a model that defines some of the key cellular and molecular players that predict the neuroprotective efficacy of progesterone. Accordingly, we suggest how changes in the expression or function of these cellular and molecular targets of progesterone with age or prolonged duration of hormone withdrawal (such as following surgical or natural menopause) may impact the efficacy of progesterone. PMID:23340161

The 9-day CIDR-PG protocol: Incorporation of PGF2α pretreatment into a long-term progestin-based estrus synchronization protocol for postpartum beef cows.

PubMed

Thomas, Jordan M; Bishop, Brianne E; Abel, Jillian M; Ellersieck, Mark R; Smith, Michael F; Patterson, David J

2016-06-01

A pilot experiment was designed to test the hypothesis that administration of PGF2α before progestin treatment would allow for a reduced duration of progestin treatment in a long-term progestin-based estrus synchronization protocol. A modified presynchronization treatment was compared with a standard long-term controlled internal drug release (CIDR) treatment, and treatments were compared on the basis of ovarian follicular dynamics, estrous response rate, synchrony of estrus expression, and pregnancy rates resulting from timed artificial insemination (TAI) in postpartum beef cows. Estrous was synchronized for 85 cows, with cows assigned to one of two treatments based on age, days postpartum, and body condition score. Cows assigned to the 14-day CIDR-PG protocol received a CIDR insert (1.38 g progesterone) on Day 0, CIDR removal on Day 14, and administration of PGF2α (25 mg im) on Day 30. Cows assigned to the 9-day CIDR-PG protocol received PGF2α concurrent with CIDR insertion on Day 5, PGF2α concurrent with CIDR removal on Day 14, and administration of PGF2α on Day 30. In both treatments, split-time AI was performed based on estrous response. At 72 hours after PGF2α (Day 33), cows having expressed estrus received TAI; cows that failed to express estrus by 72 hours received TAI 24 hours later (96 hours after PGF2α on Day 34), with GnRH (100 μg im) administered to nonestrous cows. Estrus-detection transmitters were used from CIDR removal until AI to determine onset time of estrus expression both after CIDR removal and after PGF2α. Ovarian ultrasonography was performed at CIDR removal on Day 14, PGF2α on Day 30, and AI on Days 33 or 34. At CIDR removal on Day 14, diameter of the largest follicle present on the ovary was similar between treatments. The proportion of cows expressing estrus after CIDR removal tended to be higher (P = 0.09) among cows assigned to the 9-day CIDR-PG treatment (93%; 40 of 43) than among cows assigned to the 14-day CIDR-PG treatment (81%; 34 of 42). After PGF2α, a significantly higher proportion (P = 0.02) of cows expressed estrus after synchronization with the 9-day CIDR-PG treatment (91%; 39 of 43) than the 14-day CIDR-PG treatment (69%; 29 of 42). Consequently, pregnancy rate to TAI tended to be increased (P = 0.09) among the 9-day CIDR-PG treatment (76.7%; 33 of 43) compared with the 14-day CIDR-PG treatment (59.5%; 25 of 42). In summary, a long-term CIDR-based estrous synchronization protocol for postpartum beef cows was enhanced through administration of PGF2α at CIDR insertion and CIDR removal. Copyright © 2016 Elsevier Inc. All rights reserved.

New Drugs for Anemia Treatment Based on a New Understanding of the Mechanisms of Stress Erythropoiesis

DTIC Science & Technology

2013-09-01

were hydrocortisone , other corticosteroids, and the estrogen receptor agonist 1,3,5(10)-estratrien-3-ol-17-one 3-sulfate potassium. Importantly, all of... Hydrocortisone hemisuccinate, a corticosteroid used in creams for the treatment of various skin disorders 3. Beclomethasone is used for the prophylaxis of...medroxyprogesterone, a steroidal progestin drug that is not marketed for use in humans; hydrocortisone hemisuccinate, a corticosteroid used in creams for

Vascular Endothelial Growth Factor (VEGF) mRNA Isoforms are Altered in Bovine Granulosa Cells (GC) by Circulating Progestin Concentrations (P4) and May Indicate Follicle Status and Oocyte Competence

USDA-ARS?s Scientific Manuscript database

Previously, Melengestrol Acetate (MGA) fed for 14 d (0.5mg/cow/d; < 1 ng/ml P4) resulted in persistent follicles with increased size, decreased number of GC/follicular fluid (FF) volume, and less fertile oocytes. An experiment was conducted to determine effects of circulating P4 on amount of mRNA fo...

S14 as a Therapeutic Target in Breast Cancer

DTIC Science & Technology

2005-08-01

dimethylthiazol-2yl)-5-(3-carboxymethyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (Promega). Oxidation of MTS by viable mitochondria yields a...potential mediators of the observed superinduction. The amplified signal could not be attributed to progestin induction of PPAR Gamma Coactivator-113 (PGC-lf3...quantitation of siRNA transfection efficiency, verification of localization of the siRNA to the interior of the cells, using more than one siRNA, and the

Uterine Artery Embolization: A Systematic Review of the Literature and Proposal for Research.

DTIC Science & Technology

1999-01-01

examined the literature review. Using a modified Delphi process, the panelists rated a comprehensive list of outcomes with regard to their importance...accounts for the bulk of symptoms) is medical, and includes the use of hormonal agents such as progestins, combined oral contraceptives , and (less...leiomyomata. At the meeting, panelists used a modified Delphi process, to independently and anonymously rate the importance of measuring each of these

Increased body condition score through increased lean muscle, but not fat deposition, is associated with reduced reproductive response to oestrus induction in beef cows.

PubMed

Guzmán, A; Gonzalez-Padilla, E; Garcés-Yepez, P; Rosete-Fernández, J V; Calderón-Robles, R C; Whittier, W D; Keisler, D H; Gutierrez, C G

2016-10-01

Energy reserve, estimated as body condition score (BCS), is the major determinant of the re-initiation of ovarian activity in postpartum cows. Leptin, IGF-I and insulin are positively related to BCS and are putative mediators between BCS and reproductive function. However, when BCS and body composition dissociates, concentrations of these metabolic hormones are altered. We hypothesized that increasing lean muscle tissue, but not fat tissue, would diminish the reproductive response to oestrus induction treatments. Thirty lactating beef cows with BCS of 3.10±1.21 and 75.94±12 days postpartum were divided in two groups. Control cows (n=15) were supplemented with 10.20 kg of concentrate daily for 60 days. Treated cows (n=15) were supplemented equally, and received a β-adrenergic receptor agonist (β-AA; 0.15 mg/kg BW) to achieve accretion of lean tissue mass and not fat tissue mass. Twelve days after ending concentrate supplementation/β-AA treatment, cows received a progestin implant to induce oestrus. Cows displaying oestrus were inseminated during the following 60 days, and maintained with a fertile bull for a further 21 days. Cows in both groups gained weight during the supplementation period (Daily weight gain: Control=0.75 kg v. β-AA=0.89 kg). Cows treated with β-AA had a larger increase in BCS (i.e. change in BCS: control=1 point (score 4.13) v. β-AA=2 points (score 5.06; P0.05) did not differ between groups. However, the number of cows displaying oestrus (control 13/15 v. β-AA 8/15; P<0.05) and the percentage cycling (control 6/8 v. β-AA 3/10; P=0.07) after progestin treatment and the pregnancy percentage at the end of the breeding period (control 13/15 v. β-AA 8/15; P<0.05) were lower in β-AA than control cows. In summary, the increase BCS through muscle tissue accretion, but not through fat tissue accretion, resulted in a lower response to oestrus induction, lower percentage of cycling animals and lower pregnancy percentage after progestin treatment; which was associated with a decrease in serum concentrations of leptin and IGF-I.

Pharmacologic development of male hormonal contraceptive agents.

PubMed

Roth, M Y; Amory, J K

2011-01-01

The world population continues to increase dramatically despite the existence of contraceptive technology. The use of male hormonal contraception may help in preventing un intended pregnancies and managing future population growth. Male hormonal contraception relies on the administration of exogenous hormones to suppress spermatogenesis. Clinical trials have tested several regimens using testosterone, alone or in combination with a progestin. These regimens were shown to be >90% effective in preventing conception and were not associated with serious adverse events.

COX-1 Suppression and Follicle Depletion in the Etiology of Menopause-Associated Ovarian Cancer

DTIC Science & Technology

2008-10-01

form (8), and cause growth inhibition and apoptosis in ovarian cancer cell lines (9). However, the link between morphological inhibition and...of the c-kit receptor. Genes Dev 1990;4:390-400. 2. Mintz B. Embryological development of primordial germ-cells in the mouse: influence of a new...708–14. 12 Rodriguez GC, Walmer DK, Cline M, et al. Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis

The Role of DNA Methyltransferase in the Progression of Breast Cancer of a Hormone Independent Phenotype

DTIC Science & Technology

1999-09-01

cycle with alternating rounds of proliferation and apoptosis. The greatest increase in mitotic index occurs during the luteal phase of the cycle...for the mitogenic actions of progesterone on breast tissue during the luteal phase of the reproductive cycle (72, 95). Progestins induce growth hormone...antagonist show ductal hyperplasia. Ablation of the GH/IGF1 axis in mice with human breast cancer xenografts, or transplant of xenografts into GH- deficient

COX-1 Suppression and Follicle Depletion in the Etiology of Menopause-Associated Ovarian Cancer

DTIC Science & Technology

2009-10-01

Increased parity and oral contraceptive use are the clearest examples of factors that decrease ovarian cancer risk, both of which limit ovulation. Two...act by suppressing ovulation decrease the risk of ovarian cancer by about 40% after 3 years of use .10,11 Why pregnancy and oral contraceptives ...regular use of progestin-containing oral contraceptives is a protective factor, and the benefi t decreases after time.13 Gonadotropin stimulation in

Mammary fibroadenomatous hyperplasia in a male cat.

PubMed

Mayayo, Saray Lorna; Bo, Stefano; Pisu, Maria Carmela

2018-01-01

Mammary fibroadenomatous hyperplasia (MFH) is a benign pathology characterised by extensive proliferation of the ductal epithelium and mammary stroma. It typically occurs in young female cats, and seems to result from hypersensitivity to progesterone. A 2-year-old entire male European Shorthair cat presented to the veterinary clinic with enlargement of several mammary glands, which had developed within the previous 10 days. There was no prior administration of progestin in the cat's medical history. Diagnostic tests were performed to assess the basal progesterone concentration and the concentration after stimulation with gonadotropin-releasing hormone, which ruled out the presence of functional ovarian tissue. Histological examination of the testes excluded hormone-secreting testicular tumours. Histological examination of the mammary gland confirmed the diagnosis of MFH. Treatment was started with aglepristone, a selective competitor for progesterone receptors, administered subcutaneously at 15 mg/kg at days 1, 2, 8 and 15. A reduction in the size of the mammary glands was evident 6 days after the first administration, with complete remission observed after 4 weeks. To the best of our knowledge, this is the first full report of MFH in a male cat. Although the origin of the progestins responsible for MFH in this case could not be confirmed, in the light of the diagnostic tests performed and the results obtained, accidental contact with hormone-like substances seems to be the only plausible explanation for the cat's clinical signs. Inhibitor therapy was successful.

Comparison of levonorgestrel-releasing intrauterine device with oral progestins in heavy menstrual bleeding (HMB) cases with uterine leiomyoma (LNG-IUD and oral progestin usage in myoma uteri).

PubMed

Tosun, Ayse Kavasoglu; Tosun, Ismet; Suer, Necdet

2014-07-01

To compare the effectiveness and acceptability of LNG-IUD with oral progesterone (norethisterone acetate; NETA) in achieving a reduction in volume of the myomas, hemoglobin levels, satisfaction of the women. This study includes randomized 30 women treated by LNG-IUD and randomized 30 women treated by oral norethisterone (NETA). All these participants in the study have received medical treatment and had been registered as patients in Istanbul Medeniyet University Göztepe Education and Research Hospital. Leiomyoma volumes and hemoglobin levels have been determined. In the third and sixth months, these measurements have been done again. We examined the adverse effects and the treatment continuity. For the statistical analysis of the findings NCSS [Number Cruncher Statistical System] 2007 & PASS 2008 program; student t, Mann Whitney U, Paired Samples t, Wilcoxon Signed Ranks, Ki-Kare, Fisher's Exact Ki-Kare tests have been used. After six months treatment, the reduction of bleeding determined by Visual Bleeding Score (VBS) in LNG-IUD group is 80% and in oral norethisteron group is 56%; in both groups leiomyoma volumes and hemoglobin levels were significantly high. LNG-IUD is a good alternative treatment to the oral progesterone in long term minimizing the hysterectomy for myoma uteri because of the good patient tolerance and easy usage.

Synthetic progestins medroxyprogesterone acetate and dydrogesterone and their binary mixtures adversely affect reproduction and lead to histological and transcriptional alterations in zebrafish (Danio rerio).

PubMed

Zhao, Yanbin; Castiglioni, Sara; Fent, Karl

2015-04-07

Medroxyprogesterone acetate (MPA) and dydrogesterone (DDG) are synthetic progestins widely used in human and veterinary medicine. Although aquatic organisms are exposed to them through wastewater and animal farm runoff, very little is known about their effects in the environment. Here we provide a comprehensive analysis of the responses of zebrafish (Danio rerio) to MPA, DDG, and their binary mixtures at measured concentrations between 4.5 and 1663 ng/L. DDG and both mixtures impaired reproductive capacities (egg production) of breeding pairs and led to histological alterations of ovaries and testes and increased gonadosomatic index. Transcriptional analysis of up to 28 genes belonging to different pathways demonstrated alterations in steroid hormone receptors, steroidogenesis enzymes, and specifically, the circadian rhythm genes, in different organs of adult zebrafish and eleuthero-embryos. Alterations occurred even at environmentally relevant concentrations of 4.5-4.8 ng/L MPA, DDG and the mixture in eleuthero-embryos and at 43-89 ng/L in adult zebrafish. Additionally, the mixtures displayed additive effects in most but not all parameters in adults and eleuthero-embryos, suggesting concentration addition. Our data suggest that MPA and DDG and their mixtures induce multiple transcriptional responses at environmentally relevant concentrations and adverse effects on reproduction and gonad histology at higher levels.

The use of hormonal contraceptive agents and mood disorders in women.

PubMed

Svendal, Gjertrud; Berk, Michael; Pasco, Julie A; Jacka, Felice N; Lund, Anders; Williams, Lana J

2012-09-01

Mood disorders are a major cause of disability in developed countries, and contraceptive agents among the most widely used medications. The relationship between contraceptive agents and mood is unclear. The aim of this study was therefore to investigate the association between current contraception use and mood disorders in a random population-based sample of women. This study examined epidemiological data obtained from 498 women aged 20-50year participating in the Geelong Osteoporosis Study (GOS). Mood disorders were diagnosed using a clinical interview (SCID-I/NP) and information on medication use and other lifestyle factors were documented. After adjusting for age and socioeconomic status (SES), women taking progestin-only contraceptive agents had an increased likelihood of a current mood disorder (OR 3.0 95%CI: 1.1-7.8, p=0.03). In contrast, women taking combined contraceptive agents had a decreased likelihood of a current mood disorder, adjusting this for age and SES (OR 0.3 95%CI: 0.1, 0.9 p=0.03). These findings were not explained by weight, physical activity level, past depression, number of medical conditions or cigarette smoking. This study is cross-sectional, which precludes any determination regarding the direction of the relationships. These data suggest a protective effect of the combined contraceptive pill, and a deleterious effect of progestin only agents in regards to mood disorders. Copyright © 2012 Elsevier B.V. All rights reserved.

Male hormonal contraception: concept proven, product in sight?

PubMed

Matthiesson, Kati L; McLachlan, Robert I

2006-01-01

Current male hormonal contraceptive (MHC) regimens act at various levels within the hypothalamic pituitary testicular axis, principally to induce the withdrawal of the pituitary gonadotrophins and in turn intratesticular androgen production and spermatogenesis. Azoospermia or severe oligozoospermia result from the inhibition of spermatogonial maturation and sperm release (spermiation). All regimens include an androgen to maintain virilization, while in many the suppression of gonadotrophins/spermatogenesis is augmented by the addition of another anti-gonadotrophic agent (progestin, GnRH antagonist). The suppression of sperm concentration to 1 x 10(6)/ml appears to provide comparable contraceptive efficacy to female hormonal methods, but the confidence intervals around these estimates remain relatively large, reflecting the limited number of exposure years reported. Also, inconsistencies in the rapidity and depth of spermatogenic suppression, potential for secondary escape of sperm into the ejaculate and onset of fertility return not readily explainable by analysis of subject serum hormone levels, germ cell number or intratesticular steroidogenesis, are apparent. As such, a better understanding of the endocrine and genetic regulation of spermatogenesis is necessary and may allow for new treatment paradigms. The development of an effective, consumer-friendly male contraceptive remains challenging, as it requires strong translational cooperation not only between basic scientists and clinicians but also between public and private sectors. At present, a prototype MHC product using a long-acting injectable testosterone and depot progestin is well advanced.

Exposure to levonorgestrel increases nest acquisition success and decreases sperm motility in the male fathead minnow (Pimephales promelas).

PubMed

Frankel, Tyler; Yonkos, Lance; Ampy, Franklin; Frankel, Jack

2018-04-01

Progestins are utilized as a component of human contraceptives, and commonly enter the environment via wastewater treatment plant effluent. Certain progestins activate fish androgen receptors and cause decreases in fecundity and masculinization of females. We used a nest acquisition assay and computer-assisted sperm analysis to examine the effects of levonorgestrel on male fathead minnow (Pimephales promelas) reproductive fitness. Males were exposed to 0, 10, or 100 ng/L levonorgestrel for 14 d. Combinations of a control male and a male from one of the treatments were placed into a competitive nesting assay, and the time each male spent holding the nest and time spent exhibiting aggressive behaviors were analyzed at 48 h postexposure. Semen samples were analyzed for total motility, straight-line velocity, curvilinear velocity, average path velocity, linearity, beat cross frequency, and wobble at 0, 30, 60, 90, and 120 s postactivation. Males exposed to either 10 or 100 ng/L of levonorgestrel exhibited increased nest acquisition success and lower levels of aggression compared with control-control pairings, as well as decreases in multiple sperm motion characteristics. Our results suggest that further research is required to ascertain the effects of levonorgestrel on male gamete quality and reproductive behaviors. Environ Toxicol Chem 2018;37:1131-1137. © 2017 SETAC. © 2017 SETAC.

Flutamide-metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity.

PubMed

Ibáñez, Lourdes; De Zegher, Francis

2004-08-01

Low-dose flutamide-metformin has been developed as a background therapy for non-obese adolescents and young women with hyperinsulinaemic hyperandrogenism, a variant of polycystic ovary syndrome (PCOS). We verified whether the lipolytic efficacy of flutamide-metformin in women with PCOS is enhanced by giving an oral contraceptive (OC) co-therapy that contains drospirenone, instead of gestodene, as progestin. An open-labelled study was carried out in which non-obese women with PCOS (n = 29; age approximately 20 years), who had been on a combination of flutamide (62.5 mg/day), metformin (850 mg/day) and ethinylestradiol-gestodene for 8-15 months, were randomized for replacement of the gestodene OC by a drospirenone OC. Assessments of endocrine-metabolic state and body composition (by dual-energy X-ray absorptiometry) were performed at randomization and after 6 months. The switch to drospirenone OC was accompanied by a reduction of total and abdominal fat (mean -0.8 and -0.5 kg) and by an increment of lean body mass (+0.6 kg; all P < 0.01), so that body adiposity was strikingly reduced without changing body weight. In non-obese women with PCOS, low-dose flutamide-metformin reduces total and abdominal fat excess more effectively if contraceptive co-therapy contains drospirenone, instead of gestodene, as progestin. Copyright 2004 European Society of Human Reproduction and Embryology

Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: a nationwide population-based study with age-specific analyses.

PubMed

Lindberg, Malou; Foldemo, Anniqa; Josefsson, Ann; Wiréhn, Ann-Britt

2012-04-01

To examine, among young women, the association of individual hormonal contraceptives, within two broad groupings, with antidepressant therapy. In a nationwide register-based study, we examined the prescription rates of antidepressant drugs in relation to individual combined hormonal and progestin-only contraceptives among Swedish women aged 16-31 years (N = 917,993). Drug data were obtained from the Swedish Prescribed Drug Register for the period 1 July 2005-30 June 2008. Data on the total population of women aged 16-31 in 2008 were obtained from the Total Population Register of Statistics Sweden. The proportion of women using both hormonal contraception and antidepressants, and odds ratios (ORs) for antidepressant use for hormonal contraceptive users versus non-users, were calculated, the latter by logistic regression, for each formulation. The highest antidepressant OR in all age groups, particularly in the 16-19 years age group, related to medroxyprogesterone-only, followed by etonogestrel-only, levonorgestrel-only and ethinylestradiol/norelgestromin formulations. Oral contraceptives containing ethinylestradiol combined with lynestrenol or drospirenone had considerably higher ORs than other pills. ORs significantly lower than 1 were observed when ethinylestradiol was combined with norethisterone, levonorgestrel or desogestrel. The association between use of hormonal contraceptives and antidepressant drugs varies considerably within both the combined hormonal contraceptive and the progestin-only groups.

Psychosexual well-being in women using oral contraceptives containing drospirenone.

PubMed

Nappi, Rossella E; Albani, Francesca; Tonani, Silvia; Santamaria, Valentina; Pisani, Carla; Terreno, Erica; Martini, Ellis; Polatti, Franco

2009-01-01

Considerable advances have been made in hormonal contraception in recent years, geared at maximizing compliance and minimizing discontinuation. In oral contraceptive (OC) formulations, the estrogenic component, generally ethinyl estradiol (EE), has been reduced significantly and newer progestins like dienogest and drospirenone (DRSP), compounds with different molecular structures, have been introduced; in addition, new regimens (extended, flexible, 24/4 formats instead of the standard 21/7 format) and innovative delivery systems (vaginal rings, transdermal patches, subcutaneous implants and intrauterine devices) are available. The multitude of choices allows hormonal contraception to be tailored to the individual woman in order to obtain non-contraceptive benefits, without significant side effects, and also a favorable risk/benefit profile for her general and reproductive health. Over the past few years, new OC formulations combining DRSP (3 mg), a unique progestin with both antimineralocorticoid and antiandrogenic activities, with estrogen (30 mcg or 20 mcg EE), in two regimens (24/4 and 21/7) of active pills in a 28-day cycle, have shown positive effects on water retention-related weight gain and physical, emotional and psychosexual well-being. It seems likely that the use of a low-dose, well-balanced OC and the shorter 4-day hormone-free interval may minimize the side effects that can impair quality of life and thus increase women's compliance with hormonal contraception therapy.

Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection.

PubMed

Quispe Calla, N E; Vicetti Miguel, R D; Boyaka, P N; Hall-Stoodley, L; Kaur, B; Trout, W; Pavelko, S D; Cherpes, T L

2016-11-01

Depot-medroxyprogesterone acetate (DMPA) is a hormonal contraceptive especially popular in areas with high prevalence of HIV and other sexually transmitted infections (STI). Although observational studies identify DMPA as an important STI risk factor, mechanisms underlying this connection are undefined. Levonorgestrel (LNG) is another progestin used for hormonal contraception, but its effect on STI susceptibility is much less explored. Using a mouse model of genital herpes simplex virus type 2 (HSV-2) infection, we herein found that DMPA and LNG similarly reduced genital expression of the desmosomal cadherin desmoglein-1α (DSG1α), enhanced access of inflammatory cells to genital tissue by increasing mucosal epithelial permeability, and increased susceptibility to viral infection. Additional studies with uninfected mice revealed that DMPA-mediated increases in mucosal permeability promoted tissue inflammation by facilitating endogenous vaginal microbiota invasion. Conversely, concomitant treatment of mice with DMPA and intravaginal estrogen restored mucosal barrier function and prevented HSV-2 infection. Evaluating ectocervical biopsy tissue from women before and 1 month after initiating DMPA remarkably revealed that inflammation and barrier protection were altered by treatment identically to changes seen in progestin-treated mice. Together, our work reveals DMPA and LNG diminish the genital mucosal barrier; a first-line defense against all STI, but may offer foundation for new contraceptive strategies less compromising of barrier protection.

Risk factors for recurrence of venous thromboembolism associated with the use of oral contraceptives.

PubMed

Vaillant-Roussel, Hélène; Ouchchane, Lemlih; Dauphin, Claire; Philippe, Pierre; Ruivard, Marc

2011-11-01

Combined oral contraceptives (COC) increase the risk of venous thromboembolism (VTE), but the risk of recurrent VTE is not precisely determined. In this retrospective cohort study, we sought the risk factors for recurrence after a first VTE that occurred in women taking COC. Time-to-event analysis was done with Kaplan-Meier estimates. In total, 172 patients were included (43% with pulmonary embolism): 82% had no other clinical risk factor for VTE. Among the 160 patients who stopped anticoagulation, the cumulative incidence of recurrent VTE was 5.1% after 1 year and 14.2% after 5 years. Significant factors associated with recurrence were renewed use of COC [hazard ratio (HR)=8.2 (2.1-32.2)], antiphospholipid syndrome [HR=4.1 (1.3-12.5)] and protein C deficiency or factor II G20210A [HR=2.7 (1.1-7)]. Pure-progestin contraception [HR=1.3 (0.5-3.0)] or factor V Leiden [HR=1.3 (0.5-3.4)] did not increase recurrence. Postsurgical VTE had a lower risk of recurrence [HR=0.1 (0.0-0.9)]. Further studies are warranted to determine whether testing for antiphospholipid syndrome, protein C deficiency or the factor II G20210A could modify the duration of anticoagulation. This study confirms the safety of pure-progestin contraception. Copyright © 2011 Elsevier Inc. All rights reserved.

Emergency contraception for prevention of adolescent pregnancy.

PubMed

Lindberg, Claire E

2003-01-01

Adolescent pregnancy remains a significant problem in the United States today, despite availability of effective contraceptive methods. Not all sexually active adolescents use contraception, and even those who do use contraception sometimes use it incorrectly. Emergency contraception, which refers to methods of pregnancy prevention used after unprotected intercourse, has the potential to prevent most unplanned adolescent pregnancies. Emergency contraceptive pills (ECP) containing estrogen and progestin or progestin alone are more than 75% effective when the first dose is taken within 72 hours after unprotected sex and the second dose is taken 12 hours later. However, barriers to accessing ECPs include lack of knowledge of the method, fear of loss of privacy, difficulties in finding a provider, and cost. Another barrier is that controversy exists about the mechanisms of action of emergency contraception about its role in pregnancy prevention. As a result, some nurses are not comfortable with suggesting emergency contraception to their patients. Nurses can play a critical role in providing ECPs to adolescents by developing programs to streamline distribution of ECPs, while maintaining adolescent privacy. Other essential roles for nurses include providing education about ECPs to parents, other healthcare providers and community members, and advocating for political and legal changes that will ease restrictions on ECP distribution. Nurses who are personally uncomfortable discussing emergency contraception can refer their patients to other providers for information and access to this method.

[Medical treatment of endometriosis: Hormonal treatment of pain, impact on evolution and future perspectives].

PubMed

Geoffron, Sophie; Legendre, Guillaume; Daraï, Emile; Chabbert-Buffet, Nathalie

2017-12-01

Endometriosis is a chronic painful disease, for which hormone therapy is usually offered as a first line option to women not willing to conceive. To analyse and synthesize the literature, from 2006 onwards, on pain control, and disease evolution in oemn using combined hormonal contraceptives, progestins and GnRH analogs. Data on other current and future treatment perspectives is included as well. Medline (Pubmed), the Cochrane Library, and endometriosis treatment recommendations published by European Society of Human Reproduction and Embryology (ESHRE), National Institute for health and Care Excellence (NICE), American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG) and Société des Obstétriciens et Gynécologues du Canada (SOGC). Meta-analysis and clinical trials are included. Study quality is heterogeneous in general. Hormone therapy inconstantly allows pain relief and prevention of endometrioma and rectovaginal wall nodules recurrence. Available molecules and routes of administration as well as risk benefit balance are evaluated. Data on future perspectives are limited to date and do not allow use in routine. Hormonal treatment of endometriosis relies on combined hormonal contraceptives (using different routes of administration), progestins and particularly the levonorgestrel-releasing IUS, and GnRH analogs as a last option, in combination with an add-back therapy. Promising alternatives are currently under preclinical and clinical evaluation. Copyright © 2017. Published by Elsevier Masson SAS.

Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model

PubMed Central

Patil, Avinash S.; Swamy, Geeta K.; Murtha, Amy P.; Heine, R. Phillips; Zheng, Xiaomei; Grotegut, Chad A.

2015-01-01

Objective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility. PMID:26037300

Selective progesterone receptor modulators 2: use in reproductive medicine.

PubMed

Benagiano, Giuseppe; Bastianelli, Carlo; Farris, Manuela

2008-10-01

Synthetic compounds can bind to progesterone receptors and these progesterone receptor ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. These substances have been classified as antiprogestins or as selective progesterone receptor modulators. There are several hundred selective progesterone receptor modulators available, although only a dozen or so have been evaluated to any significant extent. The best-known selective progesterone receptor modulators are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex() (CDB 4124), ORG 33628 and ORG 31710. A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone, but also on those other selective progesterone receptor modulators for which data are available. Outside pregnancy, selective progesterone receptor modulators are used or have been tested clinically for a number of indications in reproductive medicine: as oral contraceptives, alone or in combination with a progestin, to improve cycle control in users of progestin-only contraceptives, as emergency contraceptives, for the medical treatment of uterine fibroids, in cases of endometriosis and premenstrual syndrome and to improve ovarian stimulation prior to in vitro fertilisation. In the authors' opinion, as of today, few applications outside pregnancy seem worthy of large-scale use: emergency contraception and long-term medical management of uterine fibroids and possibly of endometriosis.

Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate (17-OHPC), and related progestins

PubMed Central

Attardi, Barbara J.; Zeleznik, Anthony; Simhan, Hyagriv; Chiao, Jye Ping; Mattison, Donald R; Caritis, Steve N

2007-01-01

Condensation 17-hydroxyprogesterone caproate is not better than progesterone in binding to progesterone or glucocorticoid receptors or eliciting gene expression in progesterone responsive genes. Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate (17-OHPC), and related progestins. Objective To determine whether the reduction in premature birth attributable to 17-OHPC occurs because of a greater affinity for progesterone (PR) or glucocorticoid (GR) receptors or by enhanced stimulation of progestogen responsive genes when compared with progesterone. Study Design We performed competitive steroid hormone receptor binding assays using cytosols expressing either recombinant human PR-A (rhPR-A) or B (rhPR-B) or rabbit uterine or thymic cytosols. We used four different carcinoma cell lines to assess transactivation of reporter genes or induction of alkaline phosphatase. Results Relative binding affinity of 17-OHPC for rhPR-B, rhPR-A and rabbit PR was 26–30% that of progesterone. Binding of progesterone to rabbit thymic GR was weak. 17-OHPC was comparable to progesterone in eliciting gene expression in all cell lines studied. Conclusions Binding to PR, GR or expression of progesterone-responsive genes is no greater with 17-OHPC than with progesterone. Other mechanisms must account for the beneficial effect of 17-OHPC on preterm birth rates. PMID:18060946

[Analysis of prescriptions associated to hormone replacement therapy in Midi-Pyrénées region].

PubMed

Gass-Jégu, Florence; Damase-Michel, Christine; Hurault-Delarue, Caroline; Bourrel, Robert; Montastruc, Jean-Louis

2012-01-01

The aim of the present study was 1- to describe hormone replacement therapy (HRT) prescription in Midi-Pyrénées region (South West France) and 2- to compare the prescriptions of associated drugs to those of women who took HRT with prescriptions to women who did not take HRT. From 2004 to 2008, HRT prescription decreased for women aged 50 to 59 years in Midi-Pyrénées: 13.95% to 10.33% estradiol/progestin association consumers. During the first 6 months of 2008, 20,161 women took the association estradiol/progestin. Transdermal/percutaneous forms of estradiol (71.21%) and natural progesterone were mainly prescribed. The number of different dispensed drugs was significantly higher in the HRT group: 5.18 versus 2.82 in the control group (p < 0.0001). All classes were concerned except antineoplastic drugs and immunomodulators, drugs for diabetes and raloxifene which were more prescribed to controls. In the period of the study, 7,035 patients took estrogen alone (25.87% of HRT consumers). The same phenomena were observed in this group. Women exposed to HRT in Midi-Pyrénées, great consumers of drugs, represent a population who require particular medical supervision, because of the risks of HRT and pathologies and/or numerous associated drugs. © 2012 Société Française de Pharmacologie et de Thérapeutique.

Novel strategies in the management of polycystic ovary syndrome.

PubMed

Spritzer, P M; Motta, A B; Sir-Petermann, T; Diamanti-Kandarakis, E

2015-09-01

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting reproductive-aged women. PCOS has been recognized as a syndrome combining reproductive and metabolic abnormalities with lifelong health implications. Cardiometabolic alterations require regular screening and effective and targeted lifestyle advice to lose weight as well as to prevent weight gain. Pharmacological therapy includes insulin-sensitizer drugs and agents that act directly on metabolic comorbidities, such as statins and antiobesity drugs. Bariatric surgery may be an option for severely obese women with PCOS Regarding reproductive aspects, ovulation induction with antiestrogens such as clomiphene citrate or letrozole is the first-line medical treatment. Exogenous gonadotropins and in vitro fertilization (IVF) are recommended as second-line treatment for anovulatory infertility. Laparoscopic ovarian diathermy may be used in special cases and metformin is no longer recommended for ovulation induction. Combined oral contraceptives (OCs) are the first-line treatment for the management of menstrual irregularities in women not seeking pregnancy, also providing endometrial protection and contraception. Progestin-only pills or cyclical progestins are recommended for those with contraindications to OCs. Metformin is also considered a second-line choice for improving menstrual cycles in women presenting insulin-resistance and dysglicemia. Hirsutism requires cosmetic procedures and medical treatment with OCs. More severe cases may need anti-androgen drugs added to the OCs. In conclusion, strategies regarding the management of reproductive issues in PCOS encompass a tailored approach to individual needs of each patient.

Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder.

PubMed

Breech, Lesley L; Braverman, Paula K

2010-08-09

Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%-8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality.

Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder

PubMed Central

Breech, Lesley L; Braverman, Paula K

2010-01-01

Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%–8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality. PMID:21072278

Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation

PubMed Central

Le Dily, François; Baù, Davide; Pohl, Andy; Vicent, Guillermo P.; Serra, François; Soronellas, Daniel; Castellano, Giancarlo; Wright, Roni H.G.; Ballare, Cecilia; Filion, Guillaume; Marti-Renom, Marc A.

2014-01-01

The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ∼2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as “regulons” to enable spatially proximal genes to be coordinately transcribed in response to hormones. PMID:25274727

Dysfunctional uterine bleeding in ovulatory women.

PubMed

Strickler, R C

1985-01-01

Ovulatory dysfunctional uterine bleeding (DUB), a disease prevalent in the latter half of the reproductive years, is diagnosed when organic causes for bleeding have been excluded by clinical, laboratory, and surgical diagnostic means. Disordered prostaglandin metabolism within the endometrium explains most cases of DUB. Nonsteroidal antiinflammatory drugs, oral contraceptives, and oral progestin are effective medical alternatives for women who wish to retain their uterus or to avoid surgery. Hysterectomy is a rapid cure for DUB and is a therapy that is acceptable to many, if not most, women.

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

DTIC Science & Technology

2013-06-01

pulmonary embolism , colorectal cancer, hip fractures , and death from other causes. After a mean follow-up of 6.8 years, no signifi- cant effect of ET...20 The benefits of HT include a signifi- cantly decreased incidence of bone fractures .21 Seven hundred thirty-three women (8.6%) in the estrogen-plus...progestin group and 896 women (11.1%) in the placebo group developed a fracture (HR, 0.76; 95% CI, 0.69-0.83). Total hip bone mineral density increased

An Analysis of Prescription Claims for Medications from Retail Pharmacies in TRICARE Region 2

DTIC Science & Technology

2000-05-01

RECOMMENDATIONS 34 REFERENCES 36 APPENDIX A APPENDIX B APPENDIX C Retail Pharmacy Prescription Analysis 5 List of Tables Table 1. Pharmacy Beneficiary Categories...All claims data used in this analysis was obtained from the Region 2 Managed Care Support Contractor (MCSC), Anthem Alliance Health Insurance Company ...66,297.76 $17,084,273.96 92.73% $39.04 PROGESTINS 3148 454684 85.78% $60,831.60 $17,145,105.56 93.06% $86.92 ANTITUSSIVES 8324 463008 87.35% $60,616.97

Cyclin D1 and Cyclin E as Markers of Therapeutic Responsiveness in Breast Cancer

DTIC Science & Technology

2002-05-01

address whether cyclin D1 and cyclin E were predictive markers for therapeutic responsiveness in breast cancer. Both estrogen and progesterone ...although whether progesterone is tion of p 18 N K4c and increased association of the CDK stimulatory or inhibitory for normal breast epithelium remains...steroid progesterone and its synthetic ana- p2 7Ki pl and p21 ip 1 available to bind other proteins (8). Thus, logues, progestins, have complex effects

Mammary fibroadenomatous hyperplasia in a male cat

PubMed Central

Mayayo, Saray Lorna; Bo, Stefano; Pisu, Maria Carmela

2018-01-01

Case summary Mammary fibroadenomatous hyperplasia (MFH) is a benign pathology characterised by extensive proliferation of the ductal epithelium and mammary stroma. It typically occurs in young female cats, and seems to result from hypersensitivity to progesterone. A 2-year-old entire male European Shorthair cat presented to the veterinary clinic with enlargement of several mammary glands, which had developed within the previous 10 days. There was no prior administration of progestin in the cat’s medical history. Diagnostic tests were performed to assess the basal progesterone concentration and the concentration after stimulation with gonadotropin-releasing hormone, which ruled out the presence of functional ovarian tissue. Histological examination of the testes excluded hormone-secreting testicular tumours. Histological examination of the mammary gland confirmed the diagnosis of MFH. Treatment was started with aglepristone, a selective competitor for progesterone receptors, administered subcutaneously at 15 mg/kg at days 1, 2, 8 and 15. A reduction in the size of the mammary glands was evident 6 days after the first administration, with complete remission observed after 4 weeks. Relevance and novel information To the best of our knowledge, this is the first full report of MFH in a male cat. Although the origin of the progestins responsible for MFH in this case could not be confirmed, in the light of the diagnostic tests performed and the results obtained, accidental contact with hormone-like substances seems to be the only plausible explanation for the cat’s clinical signs. Inhibitor therapy was successful. PMID:29568542

New low-dose, extended-cycle pills with levonorgestrel and ethinyl estradiol: an evolutionary step in birth control.

PubMed

Nelson, Anita

2010-08-09

To review milestones in development of oral contraceptive pills since their introduction in the US 50 years ago in order to better understand how a new formulation with low-dose estrogen in an extended-cycle pattern fits into the evolution of birth control pills. This is a review of trends in the development of various birth controls pills and includes data from phase III clinical trials for this new formulation. The first birth control pill was a very high-dose monophasic formulation with the prodrug estrogen mestranol and a first-generation progestin. Over the decades, the doses of hormones have been markedly reduced, and a new estrogen and several different progestins were developed and used in different dosing patterns. The final element to undergo change was the 7-day pill-free interval. Many of these same changes have been made in the development of extended-cycle pill formulation. The newest extended-cycle oral contraceptive formulation with 84 active pills, each containing 20 μg ethinyl estradiol and 100 μg levonorgestrel, represents an important evolution in birth control that incorporates lower doses of estrogen (to reduce side effects and possibly reduce risk of thrombosis), fewer scheduled bleeding episodes (to meet women's desires for fewer and shorter menses) and the use of low-dose estrogen in place of placebo pills (to reduce the number of days of unscheduled spotting and bleeding). Hopefully, this unique formation will motivate women to be more successful contraceptors.

Daily fecal sex steroid hormonal changes and mating success in captive female cheetahs (Acinonyx jubatus) in Japan.

PubMed

Kinoshita, Kodzue; Ohazama, M; Ishida, R; Kusunoki, H

2011-05-01

Daily fecal estrogen and progestin concentrations were measured by enzyme immunoassay in five female cheetahs (Acinonyx jubatus) for 4-6 months. The animals were housed under different conditions: (1) a female always housed in a group including one or more males; (2) two females isolated individually for short or long periods; (3) the other two females housed together. These females were separately housed with males for mating around the time of the estrogen peaks. The hormone profiles were similar in all five females regardless of the housing conditions. However, only the female that had been isolated from other cheetahs for over a year mated and reproduce cubs successfully, whereas the remaining four did not (one was isolated for only 6 weeks, another was always housed with males and the other two were housed together). In all females, the estrogen peaks were obtained at regular intervals of approximately 8-15 days. Unlike estrogen, the progestin concentrations were always low in all females except during pregnancy and they did not increase following the estrogen surges. These results showed that female cheetahs are typically reflex ovulators and female receptiveness may not be reflected to her hormonal states. It was also suspected that individual housing and long-term separation are advantageous for breeding this wild cat in captivity, mimicking the ecological/behavioral patterns in the wild, though housing condition might have no effect on the estrous cycle. Copyright © 2011 Elsevier B.V. All rights reserved.

Prescriptions for category D and X drugs during pregnancy in Taiwan: a population-based study.

PubMed

Kao, Li-Ting; Chen, Yi-Hua; Lin, Herng-Ching; Chung, Shiu-Dong

2014-10-01

This study aimed to investigate the most prescribed medications and principle diagnoses for category D and X drugs during pregnancy using a population-based dataset in Taiwan. The data for the present study were sourced from the Taiwan Longitudinal Health Insurance Database 2000. We selected 14 125 women who had live singleton births between 1 January 2009 and 31 December 2011. In total, 217 226 prescriptions prescribed to these pregnant women were identified. Of the total 217 226 prescriptions, 1.1% were category D or X drugs; in the first, second, and third trimesters of pregnancy, 1.8%, 0.7%, and 0.5% of prescriptions were category D or X drugs, respectively. Progestins (15.3%) and propylthiouracil (10.7%) were the two most frequently prescribed category D or X drugs during pregnancy. In particular, progestins (20.4%) and estrogens (15.6%) were the most frequently prescribed category D or X drug in the first trimester of pregnancy. Propylthiouracil was the most prescribed category D or X drug in the second (20.3%) and third trimesters (23.1%) of pregnancy, respectively. The most common principal diagnosis during pregnancy was "disorders of menstruation and other abnormal bleeding from the female genital tract" (22% of all principal diagnoses for prescribing category D and X drugs). Our study found that the physicians obviously reduced the use of category D and X drugs for women after becoming aware that they were pregnant. Copyright © 2014 John Wiley & Sons, Ltd.

Progesterone Impairs Social Recognition in Male Rats

PubMed Central

Auger, Catherine J.

2012-01-01

The influence of progesterone in the brain and on the behavior of females is fairly well understood. However, less is known about the effect of progesterone in the male system. In male rats, receptors for progesterone are present in virtually all vasopressin (AVP) immunoreactive cells in the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). This colocalization functions to regulate AVP expression, as progesterone and/or progestin receptors (PR)s suppresses AVP expression in these same extrahypothalamic regions in the brain. These data suggest that progesterone may influence AVP-dependant behavior. While AVP is implicated in numerous behavioral and physiological functions in rodents, AVP appears essential for social recognition of conspecifics. Therefore, we examined the effects of progesterone on social recognition. We report that progesterone plays an important role in modulating social recognition in the male brain, as progesterone treatment lead to a significant impairment of social recognition in male rats. Moreover, progesterone appears to act on PRs to impair social recognition, as progesterone impairment of social recognition is blocked by a PR antagonist, RU-486. Social recognition is also impaired by a specific progestin agonist, R5020. Interestingly, we show that progesterone does not interfere with either general memory or olfactory processes, suggesting that progesterone seems critically important to social recognition memory. These data provide strong evidence that physiological levels of progesterone can have an important impact on social behavior in male rats. PMID:22366506

A high-content assay to identify small-molecule modulators of a cancer stem cell population in luminal breast cancer.

PubMed

Yoo, Byong Hoon; Axlund, Sunshine Daddario; Kabos, Peter; Reid, Brian G; Schaack, Jerome; Sartorius, Carol A; LaBarbera, Daniel V

2012-10-01

Breast cancers expressing hormone receptors for estrogen (ER) and progesterone (PR) represent ~70% of all cases and are treated with both ER-targeted and chemotherapies, with near 40% becoming resistant. We have previously described that in some ER(+) tumors, the resistant cells express cytokeratin 5 (CK5), a putative marker of breast stem and progenitor cells. CK5(+) cells have lost expression of ER and PR, express the tumor-initiating cell surface marker CD44, and are relatively quiescent. In addition, progestins, which increase breast cancer incidence, expand the CK5(+) subpopulation in ER(+)PR(+) breast cancer cell lines. We have developed models to induce and quantitate CK5(+)ER(-)PR(-) cells, using CK5 promoter-driven luciferase (Fluc) or green fluorescent protein (GFP) reporters stably transduced into T47D breast cancer cells (CK5Pro-GFP or CK5Pro-Luc). We validated the CK5Pro-GFP-T47D model for high-content screening in 96-well microplates and performed a pilot screen using a focused library of 280 compounds from the National Institutes of Health clinical collection. Four hits were obtained that significantly abrogated the progestin-induced CK5(+) cell population, three of which were members of the retinoid family. Hence, this approach will be useful in discovering small molecules that could potentially be developed as combination therapies, preventing the acquisition of a drug-resistant subpopulation.

Exposure effects of levonorgestrel on oogenesis in the fathead minnow (Pimephales promelas).

PubMed

Frankel, Tyler; Yonkos, Lance; Frankel, Jack

2017-12-01

The synthetic progestin levonorgestrel is commonly utilized in human oral contraceptives. It enters the environment as a component of wastewater treatment plant effluent, and has been measured at low ng/L concentrations in surface waters. It has been shown to activate fish androgen receptors, causing the physical masculinization of females, changes in reproductive behavior, and decreases in fecundity. In the present study, the effects of levonorgestrel exposure on early-stage oogenesis in the fathead minnow (Pimephales promelas) was examined. Adult females were exposed to 0, 10, or 100 ng/L levonorgestrel for 14 d using a flow-through exposure system. The ovaries from each female were then removed via dissection and weighed for gonadosomatic index (GSI) calculations, and oocytes from one lobe preserved in Serra's fixative. Total numbers of late-stage vitellogenic oocytes exhibiting a germinal vesicle were then quantified. In a second exposure, blood plasma samples were collected from adult females and analyzed for vitellogenin concentrations using enzyme-linked immunosorbent assay. Females exposed to both concentrations of levonorgestrel developed male secondary sexual characteristics in a dose-dependent manner, and ovaries contained significantly fewer late stage oocytes. Exposure to 100 ng/L of levonorgestrel resulted in decreased GSI and blood plasma vitellogenin concentrations. The results suggest that female exposure to levonorgestrel alone may have profound effects on reproduction in progestin-contaminated environments. Environ Toxicol Chem 2017;36:3299-3304. © 2017 SETAC. © 2017 SETAC.

Evaluation and management of abnormal uterine bleeding in premenopausal women.

PubMed

Sweet, Mary Gayle; Schmidt-Dalton, Tarin A; Weiss, Patrice M; Madsen, Keith P

2012-01-01

Up to 14 percent of women experience irregular or excessively heavy menstrual bleeding. This abnormal uterine bleeding generally can be divided into anovulatory and ovulatory patterns. Chronic anovulation can lead to irregular bleeding, prolonged unopposed estrogen stimulation of the endometrium, and increased risk of endometrial cancer. Causes include polycystic ovary syndrome, uncontrolled diabetes mellitus, thyroid dysfunction, hyperprolactinemia, and use of antipsychotics or antiepileptics. Women 35 years or older with recurrent anovulation, women younger than 35 years with risk factors for endometrial cancer, and women with excessive bleeding unresponsive to medical therapy should undergo endometrial biopsy. Treatment with combination oral contraceptives or progestins may regulate menstrual cycles. Histologic findings of hyperplasia without atypia may be treated with cyclic or continuous progestin. Women who have hyperplasia with atypia or adenocarcinoma should be referred to a gynecologist or gynecologic oncologist, respectively. Ovulatory abnormal uterine bleeding, or menorrhagia, may be caused by thyroid dysfunction, coagulation defects (most commonly von Willebrand disease), endometrial polyps, and submucosal fibroids. Transvaginal ultrasonography or saline infusion sonohysterography may be used to evaluate menorrhagia. The levonorgestrel-releasing intrauterine system is an effective treatment for menorrhagia. Oral progesterone for 21 days per month and nonsteroidal anti-inflammatory drugs are also effective. Tranexamic acid is approved by the U.S. Food and Drug Administration for the treatment of ovulatory bleeding, but is expensive. When clear structural causes are identified or medical management is ineffective, polypectomy, fibroidectomy, uterine artery embolization, and endometrial ablation may be considered. Hysterectomy is the most definitive treatment.

Unscheduled bleeding with continuous oral contraceptive pills: a comparison of progestin dose.

PubMed

Kaneshiro, Bliss; Edelman, Alison; Carlson, Nichole E; Nichols, Mark; Jensen, Jeffrey

2012-07-01

Although the use of continuous oral contraceptive pills (OCPs) eliminates scheduled uterine bleeding, unscheduled bleeding is common. The objective of this study was to determine whether progestin dose influences bleeding with use of continuous OCPs. This was a secondary data analysis of two other studies of continuous OCPs. Women were eligible if they were switching from a cyclic hormonal contraceptive to a continuous OCP. Women took a 20-mcg ethinyl estradiol (EE)/100-mcg levonorgestrel (LNG) pill or a 20-mcg EE/90-mcg LNG pill for 112 days. The number of bleeding/spotting days was compared between groups using a t test. Sample size was adequate to detect a difference of 8 days of bleeding/spotting over the 112 day study period (β=0.80, α=0.05). Sixty-six subjects were enrolled, 33 in each group. There were no differences in baseline characteristic, missed OCPs or side effects. There were no differences in the mean number of bleeding/spotting days in the first 84 days of the study (90 mcg LNG mean 20.8 (SE 3.6) days versus 100 mcg LNG 17.8 (SE 2.3) days, p=.48), nor was there a difference in the time to amenorrhea (p=.35). Our results do not support the use of one LNG dose over another to decrease the amount of unscheduled bleeding women experience when initiating a continuous OCP. Copyright © 2012 Elsevier Inc. All rights reserved.

Progesterone impairs social recognition in male rats.

PubMed

Bychowski, Meaghan E; Auger, Catherine J

2012-04-01

The influence of progesterone in the brain and on the behavior of females is fairly well understood. However, less is known about the effect of progesterone in the male system. In male rats, receptors for progesterone are present in virtually all vasopressin (AVP) immunoreactive cells in the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). This colocalization functions to regulate AVP expression, as progesterone and/or progestin receptors (PR)s suppress AVP expression in these same extrahypothalamic regions in the brain. These data suggest that progesterone may influence AVP-dependent behavior. While AVP is implicated in numerous behavioral and physiological functions in rodents, AVP appears essential for social recognition of conspecifics. Therefore, we examined the effects of progesterone on social recognition. We report that progesterone plays an important role in modulating social recognition in the male brain, as progesterone treatment leads to a significant impairment of social recognition in male rats. Moreover, progesterone appears to act on PRs to impair social recognition, as progesterone impairment of social recognition is blocked by a PR antagonist, RU-486. Social recognition is also impaired by a specific progestin agonist, R5020. Interestingly, we show that progesterone does not interfere with either general memory or olfactory processes, suggesting that progesterone seems critically important to social recognition memory. These data provide strong evidence that physiological levels of progesterone can have an important impact on social behavior in male rats. Copyright © 2012 Elsevier Inc. All rights reserved.

Tracking Progesterone Receptor-Mediated Actions in Breast Cancer

PubMed Central

Knutson, Todd P.; Lange, Carol A.

2014-01-01

Ovarian steroid hormones contribute to breast cancer initiation and progression primarily through the actions of their nuclear transcription factors, the estrogen receptor alpha (ERα) and progesterone receptors (PRs). These receptors are important drivers of the luminal A and B subtypes of breast cancer, where estrogen-blocking drugs have been effective endocrine therapies for patients with these tumors. However, many patients do not respond, or become resistant to treatment. When endocrine therapies fail, the luminal subtypes of breast cancer are more difficult to treat because these subtypes are among the most heterogeneous in terms of mutation diversity and gene expression profiles. Recent evidence suggests that progestin and PR actions may be important drivers of luminal breast cancers. Clinical trial data has demonstrated that hormone replacement therapy with progestins drives invasive breast cancer and results in greater mortality. PR transcriptional activity is dependent upon cross-talk with growth factor signaling pathways that alter PR phosphorylation, acetylation, or SUMOylation as mechanisms for regulating PR target gene selection required for increased cell proliferation and survival. Site-specific PR phosphorylation is the primary driver of gene-selective PR transcriptional activity. However, PR phosphorylation and heightened transcriptional activity is coupled to rapid PR protein degradation; the range of active PR detected in tumors is likely to be dynamic. Thus, PR target gene signatures may provide a more accurate means of tracking PR’s contribution to tumor progression rather than standard clinical protein-based (IHC) assays. Further development of antiprogestin therapies should be considered along side antiestrogens and aromatase inhibitors. PMID:24291072

Contraindications to progestin-only oral contraceptive pills among reproductive aged women

PubMed Central

White, Kari; Potter, Joseph E.; Hopkins, Kristine; Fernández, Leticia; Amastae, Jon; Grossman, Daniel

2012-01-01

Background Progestin-only oral contraceptive pills (POPs) have fewer contraindications to use compared to combined pills. However, the overall prevalence of contraindications to POPs among reproductive aged women has not been assessed. Study Design We collected information on contraindications to POPs in two studies: 1) the Self-Screening Study, a sample of 1,267 reproductive aged women in the general population in El Paso, Texas, and 2) the Prospective Study of Oral Contraceptive (OC) Users, a sample of current OC users who obtained their pills in El Paso clinics (n=532) or over the counter (OTC) in Mexican pharmacies (n=514). In the Self-Screening Study, we also compared women’s self-assessment of contraindications using a checklist to a clinician’s evaluation. Results Only 1.6% of women in the Self-Screening Study were identified as having at least one contraindication to POPs. The sensitivity of the checklist for identifying women with at least one contraindication was 75.0% (95% CI: 50.6–90.4%), and the specificity was 99.4% (95% CI: 98.8–99.7%). In total, 0.6% of women in the Prospective Study of OC Users reported having any contraindication to POPs. There were no significant differences between clinic and OTC users. Conclusion The prevalence of contraindications to POPs was very low in these samples. POPs may be the best choice for the first OTC oral contraceptive in the US. PMID:22364816

Role of medical therapy in the management of deep rectovaginal endometriosis.

PubMed

Vercellini, Paolo; Buggio, Laura; Somigliana, Edgardo

2017-12-01

Defining whether medical therapy is effective in women with deep rectovaginal endometriosis and in which circumstances it can be considered an alternative to surgery is important for patients and physicians. Numerous observational and some randomized controlled studies demonstrated that different hormonal drugs improved pain and other symptoms in approximately two-thirds of women with deep rectovaginal endometriosis. Because major differences in the effect size of various compounds were not observed, much importance should be given to safety, tolerability, and cost of medications when counseling patients. Progestins seem to offer the best therapeutic balance when long-term treatments are planned. Women should be informed that hormonal drugs control but do not cure endometriosis and that, to avoid surgery, they should be used for years. Medical therapy is not an alternative to surgery in women with hydronephrosis, severe subocclusive bowel symptoms, and in those wishing a natural conception. A progestin should systematically be chosen as a comparator in future randomized trials on novel medications for deep endometriosis. In the meantime, the use of existing drugs should be optimized, and medical and surgical treatments could be viewed as subsequent stages of a stepwise approach. In general, there is no absolute "best" choice, and women must be thoroughly informed of potential benefits, potential harms, and costs of different therapeutic options and allowed to choose what they deem is better for them. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Formulation and performance characterization of radio-sterilized "progestin-only" microparticles intended for contraception.

PubMed

Puthli, Shivanand; Vavia, Pradeep

2009-01-01

The aim of this study was to formulate and characterize a microparticulate system of progestin-only contraceptive. Another objective was to evaluate the effect of gamma radio-sterilization on in vitro and in vivo drug release characteristics. Levonorgestrel (LNG) microspheres were fabricated using poly(lactide-co-glycolide) (PLGA) by a novel solvent evaporation technique. The formulation was optimized for drug/polymer ratio, emulsifier concentration, and process variables like speed of agitation and evaporation method. The drug to polymer ratio of 1:5 gave the optimum encapsulation efficiency. Speed of agitation influenced the spherical shape of the microparticles, lower speeds yielding less spherical particles. The speed did not have a significant influence on the drug payloads. A combination of stabilizers viz. methyl cellulose and poly vinyl alcohol with in-water solvent evaporation technique yielded microparticles without any free drug crystals on the surface. This aspect significantly eliminated the in vitro dissolution "burst effect". The residual solvent content was well within the regulatory limits. The microparticles passed the test for sterility and absence of pyrogens. In vitro dissolution conducted on the product before and after gamma radiation sterilization at 2.5 Mrad indicated no significant difference in the drug release patterns. The drug release followed zero-order kinetics in both static and agitation conditions of dissolution testing. The in vivo studies conducted in rabbits exhibited LNG release up to 1 month duration with drug levels maintained within the effective therapeutic window.

A Single Glycine-Alanine Exchange Directs Ligand Specificity of the Elephant Progestin Receptor

PubMed Central

Wierer, Michael; Schrey, Anna K.; Kühne, Ronald; Ulbrich, Susanne E.

2012-01-01

The primary gestagen of elephants is 5α-dihydroprogesterone (DHP), which is unlike all other mammals studied until now. The level of DHP in elephants equals that of progesterone in other mammals, and elephants are able to bind DHP with similar affinity to progesterone indicating a unique ligand-binding specificity of the elephant progestin receptor (PR). Using site-directed mutagenesis in combination with in vitro binding studies we here report that this change in specificity is due to a single glycine to alanine exchange at position 722 (G722A) of PR, which specifically increases DHP affinity while not affecting binding of progesterone. By conducting molecular dynamics simulations comparing human and elephant PR ligand-binding domains (LBD), we observed that the alanine methyl group at position 722 is able to push the DHP A-ring into a position similar to progesterone. In the human PR, the DHP A-ring position is twisted towards helix 3 of PR thereby disturbing the hydrogen bond pattern around the C3-keto group, resulting in a lower binding affinity. Furthermore, we observed that the elephant PR ligand-binding pocket is more rigid than the human analogue, which probably explains the higher affinity towards both progesterone and DHP. Interestingly, the G722A substitution is not elephant-specific, rather it is also present in five independent lineages of mammalian evolution, suggesting a special role of the substitution for the development of distinct mammalian gestagen systems. PMID:23209719

Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations.

PubMed

Nelson, Heidi D; Walker, Miranda; Zakher, Bernadette; Mitchell, Jennifer

2012-07-17

Menopausal hormone therapy to prevent chronic conditions is currently not recommended because of its adverse effects. To update evidence about the effectiveness of hormone therapy in reducing risk for chronic conditions and adverse effects, and to examine whether outcomes vary among women in different subgroups. MEDLINE (January 2002 to November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the 3rd quarter of 2011), Scopus, and reference lists. Randomized, placebo-controlled trials of menopausal hormone therapy published in English since 2002 that assessed primary prevention of chronic conditions. Investigators extracted data on participants, study design, analysis, follow-up, and results; 2 investigators independently rated study quality by using established criteria. 9 fair-quality trials met the inclusion criteria. The Women's Health Initiative reported most of the results, had 11 years of follow-up, and had data most applicable to postmenopausal women in the United States. It showed that estrogen plus progestin therapy reduced fractures (46 fewer per 10 000 woman-years) and increased invasive breast cancer (8 more per 10 000 woman-years), stroke (9 more per 10 000 woman-years), deep venous thrombosis (12 more per 10 000 woman-years), pulmonary embolism (9 more per 10 000 woman-years), lung cancer death (5 more per 10 000 woman-years), gallbladder disease (20 more per 10 000 woman-years), dementia (22 more per 10 000 woman-years), and urinary incontinence (872 more per 10 000 woman-years). Estrogen-only therapy reduced fractures (56 fewer per 10 000 woman-years), invasive breast cancer (8 fewer per 10 000 woman-years), and death (2 fewer per 10 000 woman-years) and increased stroke (11 more per 10 000 woman-years), deep venous thrombosis (7 more per 10 000 woman-years), gallbladder disease (33 more per 10 000 woman-years), and urinary incontinence (1271 more per 10 000 woman-years). Outcomes did not consistently differ by age or comorbid conditions. Limitations of the trials included low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens. Estrogen plus progestin and estrogen alone decreased risk for fractures but increased risk for stroke, thromboembolic events, gallbladder disease, and urinary incontinence. Estrogen plus progestin increased risk for breast cancer and probable dementia, whereas estrogen alone decreased risk for breast cancer. Agency for Healthcare Research and Quality.

Hox proteins activate the IGFBP-1 promoter and suppress the function of hPR in human endometrial cells.

PubMed

Gao, Jiaguo; Mazella, James; Tseng, Linda

2002-11-01

Previous studies have shown that progestin activates the transcription of IGFBP-1 (insulin-like growth factor binding protein-1). Four regions in the IGFBP-1 promotor have been identified to enhance the transcription. Two of the regions, located at -73 to -65 bp and -319 to -311 bp formed identical DNA-protein complexes with the nuclear extracts of endometrial stromal/decidual cells. To identify the binding protein(s) in endometrial cells that interact with these two regions, we have used the TGTCAATTA repeats (-319 to -11 bp of the IGFBP-1 promoter) to screen the human decidual cDNA library by yeast one-hybrid system. We found that Hox A10, HoxA11, HoxB2, HoxB4, and HoxD11 interacted with the TGTCAATTA repeats in yeast cells. Among these hox genes, the full-length coding region of HoxA10, HoxA11, and HoxB4 were used for functional analysis in three types of endometrial cells, undifferentiated endometrial stromal cells, decidual cells (differentiated stromal cells) and endometrial adenocarcinoma cell line (HEC1-B). All these endometrial cells produce IGFBP-1. Transient transfection assay showed that HoxA10 expression vector increased the promoter activity (the IGFBP-1 proximal promoter containing TGC/TCAATTA and two functional PRE sites) in endometrial stromal cells and in HEC-1B cells, but not in decidual cells. HoxB4 enhanced the promoter activity only in decidual cells, while HoxA11 had no apparent effect in all three types of cells. To evaluate whether Hox proteins would interact with progesterone receptor (hPR), cells were transfected with the promoter construct, Hox and hPR expression vectors. hPR alone activated the IGFBP-1 promoter activity, but expression of Hox gene suppressed the activation. Hox proteins also suppressed the hPR enhanced promoter activities of MMTV (containing consensus-PRE sites) and glycodelin (GdA, containing Sp1 site which mediates the hPR function). These data showed that Hox genes selectively activate the transcription of the IGFBP-1 and GdA genes in different types of endometrial cells. Hox genes, however, suppress the hPR enhanced activities. In addition, we found that HoxB4 expression was induced by estrogen and progestin. Other investigators have shown that HoxA10 and 11 were stimulated by progestin. These findings show that Hox proteins are molecular mediators of the steroid hormones during endometrial cell development.

Progesterone Receptor Scaffolding Function in Breast Cancer

DTIC Science & Technology

2010-10-28

regulated (BIRC3, HSD11β2, and HbEGF ) expression. We conclude that phospho-Ser81 PR provides a platform for ck2 recruitment and regulation of selected PR...of a subset of PR target genes known to be involved in cell growth and prevention of apoptosis, including BIRC3, HSD11β2 and HbEGF (Appendix A, Fig...genes by PR-B also required Ser81 phosphorylation for basal and/or progestin-regulated (BIRC3, HSD11β2, and HbEGF ) expression. We conclude that phospho

A comparison of progestin and androgen receptor binding using the CoMFA technique

NASA Astrophysics Data System (ADS)

Loughney, Deborah A.; Schwender, Charles F.

1992-12-01

A series of 48 steroids has been studied with the SYBYL QSAR module using Relative Binding Affinities (RBAs) to progesterone and androgen receptors obtained from the literature. Models for the progesterone and androgen data were developed. Both models show regions where sterics and electrostatics correlate to binding affinity but are different for androgen and progesterone which suggests differences possibly important for receptor selectivity. The progesterone model is more predictive than the androgen (predictive r2 of 0.725 vs. 0.545 for progesterone and androgen, respectively).

New low-dose, extended-cycle pills with levonorgestrel and ethinyl estradiol: an evolutionary step in birth control

PubMed Central

Nelson, Anita

2010-01-01

Aim: To review milestones in development of oral contraceptive pills since their introduction in the US 50 years ago in order to better understand how a new formulation with low-dose estrogen in an extended-cycle pattern fits into the evolution of birth control pills. Methods: This is a review of trends in the development of various birth controls pills and includes data from phase III clinical trials for this new formulation. Results: The first birth control pill was a very high-dose monophasic formulation with the prodrug estrogen mestranol and a first-generation progestin. Over the decades, the doses of hormones have been markedly reduced, and a new estrogen and several different progestins were developed and used in different dosing patterns. The final element to undergo change was the 7-day pill-free interval. Many of these same changes have been made in the development of extended-cycle pill formulation. Conclusion: The newest extended-cycle oral contraceptive formulation with 84 active pills, each containing 20 μg ethinyl estradiol and 100 μg levonorgestrel, represents an important evolution in birth control that incorporates lower doses of estrogen (to reduce side effects and possibly reduce risk of thrombosis), fewer scheduled bleeding episodes (to meet women’s desires for fewer and shorter menses) and the use of low-dose estrogen in place of placebo pills (to reduce the number of days of unscheduled spotting and bleeding). Hopefully, this unique formation will motivate women to be more successful contraceptors. PMID:21072303

Role of Estrogens in the Regulation of Liver Lipid Metabolism.

PubMed

Palmisano, Brian T; Zhu, Lin; Stafford, John M

2017-01-01

Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride, and cholesterol metabolism to influence cardiovascular risk.The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increases VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides.Many aspects of sex differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in the muscle, adipose, and liver. In humans, 17β-estradiol (E2) is the predominant circulating estrogen and signals through estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled estrogen receptor (GPER). Over 1000 human liver genes display a sex bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues or specific aspects of the signaling pathways in order to recapitulate the protective physiology of premenopause therapeutically after menopause.

The Complex Interaction Between Polycystic Ovary Syndrome and Hereditary Angioedema: Case Reports and Review of the Literature.

PubMed

Iahn-Aun, Marina; Aun, Marcelo Vivolo; Motta, Antonio Abílio; Kalil, Jorge; Giavina-Bianchi, Pedro; Hayashida, Sylvia Asaka; Baracat, Edmund Chada; Maciel, Gustavo Arantes

2017-07-01

Hereditary angioedema (HAE) is a rare but severe disease, with high risk of death, and attacks have been associated to high estrogen levels. Polycystic ovary syndrome (PCOS) is a common hyperandrogenic condition, which is frequently treated with combined oral contraceptives. The aim of this study was to describe 2 clinical cases of young women diagnosed as having PCOS who developed HAE attacks after the introduction of combined estrogen-progestin pills to treat PCOS symptoms. Literature review of sex hormones' role in genesis of HAE attacks and possible mechanisms involved. In the cases reported, after initiation of combined contraceptives, patients presented with facial swelling with airway involvement (laryngeal edema) and abdominal pain. They had a familial history of angioedema and normal C1 inhibitor (C1-INH) levels, leading to the diagnosis of HAE with normal C1-INH (HAEnC1-INH) or HAE type III. After suspension of exogenous estrogen, patients remained asymptomatic from HAE. HAEnC1-INH is an estrogen-dependent form of HAE. It is well established that exogenous estrogen triggers attacks of all types of HAE. However, this is the first description of the association between PCOS and HAE, in which PCOS could be masking HAE symptoms. We propose that PCOS might have a protective role regarding HAE attacks, because of its particular hormonal features, that is, hyperandrogenism and relative stable levels of estradiol. The use of combined estrogen-progestin compounds in women with PCOS and HAE must be avoided, and treatment must be individualized.

Blockage of progestin physiology disrupts ovarian differentiation in XX Nile tilapia (Oreochromis niloticus)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Linyan; Luo, Feng; Fang, Xuelian

Previous studies indicated that maturation inducing hormone, 17α, 20β-Dihydroxy-4-pregnen-3-one (DHP), probably through nuclear progestin receptor (Pgr), might be involved in spermatogenesis and oogenesis in fish. To further elucidate DHP actions in teleostean ovarian differentiation, we analyzed the expression of pgr in the ovary of Nile tilapia (Oreochromis niloticus), and performed RU486 (a synthetic Pgr antagonist) treatment in XX fish from 5 days after hatching (dah) to 120dah. Tilapia Pgr was abundantly expressed in the follicular cells surrounding oocytes at 30 and 90dah. Continuous RU486 treatment led to the blockage of oogenesis and masculinization of somatic cells in XX fish. Terminationmore » of RU486 treatment and maintenance in normal condition resulted in testicular differentiation, and estrogen compensation in RU486-treated XX fish successfully restored oogenesis. In RU486-treated XX fish, transcript levels of female dominant genes were significantly reduced, while male-biased genes were evidently augmented. Meanwhile, both germ cell mitotic and meiotic markers were substantially reduced. Consistently, estrogen production levels were significantly declined in RU486-treated XX fish. Taken together, our data further proved that DHP, possibly through Pgr, might be essential in the ovarian differentiation and estrogen production in fish. - Highlights: • DHP plays a critical role in early stage oogenesis of XX tilapia. • Blockage of DHP actions by RU486 treatment led to masculinization and/or sex reversal in XX tilapia. • Both DHP and estrogen are indispensable for ovarian differentiation.« less

Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI

PubMed Central

Mao, Chengjian; Livezey, Mara; Kim, Ji Eun; Shapiro, David J.

2016-01-01

Outgrowth of metastases expressing ERα mutations Y537S and D538G is common after endocrine therapy for estrogen receptor α (ERα) positive breast cancer. The effect of replacing wild type ERα in breast cancer cells with these mutations was unclear. We used the CRISPR-Cas9 genome editing system and homology directed repair to isolate and characterize 14 T47D cell lines in which ERαY537S or ERαD538G replace one or both wild-type ERα genes. In 2-dimensional, and in quantitative anchorage-independent 3-dimensional cell culture, ERαY537S and ERαD538G cells exhibited estrogen-independent growth. A progestin further increased their already substantial proliferation in micromolar 4-hydroxytamoxifen and fulvestrant/ICI 182,780 (ICI). Our recently described ERα biomodulator, BHPI, which hyperactivates the unfolded protein response (UPR), completely blocked proliferation. In ERαY537S and ERαD538G cells, estrogen-ERα target genes were constitutively active and partially antiestrogen resistant. The UPR marker sp-XBP1 was constitutively activated in ERαY537S cells and further induced by progesterone in both cell lines. UPR-regulated genes associated with tamoxifen resistance, including the oncogenic chaperone BiP/GRP78, were upregulated. ICI displayed a greater than 2 fold reduction in its ability to induce ERαY537S and ERαD538G degradation. Progestins, UPR activation and perhaps reduced ICI-stimulated ERα degradation likely contribute to antiestrogen resistance seen in ERαY537S and ERαD538G cells. PMID:27713477

The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women.

PubMed

Sevinsky, Heather; Eley, Timothy; Persson, Anna; Garner, Dennis; Yones, Cynthia; Nettles, Richard; Krantz, Kathryn; Bertz, Richard; Zhang, Jenny

2011-01-01

Women of childbearing age represent a growing proportion of people living with HIV. Preventing pregnancy is important in HIV-infected women receiving efavirenz as part of their antiretroviral therapy. The effects of coadministration of efavirenz (600 mg once daily) on the pharmacokinetics (PK) of the active components (ethinyl estradiol [EE] and 17-deacetyl norgestimate [NGMN]) of Ortho Cyclen(®) (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) were investigated in 28 healthy HIV-negative women. The peak plasma concentration (C(max)), area under the concentration-time curve for a dosing interval (AUC([τ])), and lowest plasma concentration (C(min)) for EE and NGMN during cycles of treatment with Ortho Cyclen with and without coadministration of efavirenz were compared. Additionally, a post hoc exploratory analysis was conducted to assess the effect of efavirenz on the PK of an additional progestin, levonorgestrel (LNG). Exposures to EE were similar during coadministration of efavirenz and Ortho Cyclen to those during administration of Ortho Cyclen alone. Exposures to NGMN were substantially decreased following coadministration of efavirenz and Ortho Cyclen (adjusted geometric means for C(max), AUC([τ]) and C(min) decreased by 46%, 64% and 82%, respectively) compared with Ortho Cyclen alone. Consistent with NGMN, LNG exposures were decreased 80-86% by efavirenz. Although efavirenz had no significant effect on the PK of EE, exposures to the progestin components of Ortho Cyclen, NGMN and LNG, were substantially reduced. The results reinforce the need to use reliable methods of barrier contraception, even when taking oral contraceptives and efavirenz.

Steroid hormone receptors: long- and short-term integrators of the internal milieu and the external environment.

PubMed

Blaustein, J D

2012-07-01

Many of the influences of estrogens and progestins on the brain and behavior are mediated by estrogen receptors and progestin receptors, acting as transcriptional regulators. The homologous and heterologous regulation of the concentrations of these receptors by cognate hormones is well established. However, although they were discovered and characterized based on their binding to cognate hormone and their role in transcriptional regulation, steroid hormone receptors have a more complex role and serve many more functions than originally suspected. First, besides being regulated by steroid hormones, the intracellular concentrations of brain steroid hormone receptors are regulated by neurotransmitters, a pathway by which stimuli from the environment, including from conspecific animals, can modulate the concentration of particular steroid hormone receptors in subsets of cells. Further, besides being activated by cognate steroid hormones, the receptors can be activated by a variety of neurotransmitters and phosphorylation pathways, providing a route through which environmental stimulation can activate steroid-receptor-dependent functions in specific cells. In addition, the transcription factor, estrogen receptor-α, produced from the estrogen receptor-α gene, can be modified to be targeted to membranes, where it can signal via kinase pathways. Finally, developmental experiences, such as particular stressors during the pubertal period, can permanently remodel the brain's response to ovarian hormones, most likely by long-term changes in regulation of the receptors mediating those responses. In addition to their function in responding to cognate ligand, it is now more appropriate to think of steroid hormone receptors as integrators of a wide variety of signaling pathways. © Georg Thieme Verlag KG Stuttgart · New York.

Medroxyprogesterone Acetate Antagonizes Estrogen Up-Regulation of Brain Mitochondrial Function

PubMed Central

Irwin, Ronald W.; Yao, Jia; Ahmed, Syeda S.; Hamilton, Ryan T.; Cadenas, Enrique

2011-01-01

The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy. PMID:21159850

Mechanisms of Normal and Abnormal Endometrial Bleeding

PubMed Central

Lockwood, Charles J.

2011-01-01

Expression of tissue factor (TF), the primary initiator of coagulation, is enhanced in decidualized human endometrial stromal cells (HESC) during the progesterone-dominated luteal phase. Progesterone also augments a second HESC hemostatic factor, plasminogen activator inhibitor-1 (PAI-1). In contrast, progestins inhibit HESC matrix metalloproteinase (MMP)-1, 3 and 9 expression to stabilize endometrial stromal and vascular extracellular matrix. Through these mechanisms decidualized endometrium is rendered both hemostatic and resistant to excess trophoblast invasion in the mid-luteal phase and throughout gestation to prevent hemorrhage and accreta. In non-fertile cycles, progesterone withdrawal results in decreased HESC TF and PAI-expression and increased MMP activity and inflammatory cytokine production promoting the controlled hemorrhage of menstruation and related tissue sloughing. In contrast to these well ordered biochemical processes, unpredictable endometrial bleeding associated with anovulation reflects absence of progestational effects on TF, PAI-1 and MMP activity as well as unrestrained angiogenesis rendering the endometrium non-hemostatic, proteolytic and highly vascular. Abnormal bleeding associated with long-term progestin-only contraceptives results not from impaired hemostasis but from unrestrained angiogenesis leading to large fragile endometrial vessels. This abnormal angiogenesis reflects progestational inhibition of endometrial blood flow promoting local hypoxia and generation of reactive oxygen species that increase production of angiogenic factors such as vascular endothelial growth factor (VEGF) in HESCs and Angiopoietin-2 (Ang-2) in endometrial endothelial cells while decreasing HESC expression of angiostatic, Ang-1. The resulting vessel fragility promotes bleeding. Aberrant angiogenesis also underlies abnormal bleeding associated with myomas and endometrial polyps however there are gaps in our understanding of this pathology. PMID:21499503

Identification of 17,20beta,21-trihydroxy-4-pregnen-3-one as an oocyte maturation-inducing steroid in black porgy, Acanthopagrus schlegeli.

PubMed

Yueh, Wen-Shiun; Thomas, Peter; Chang, Ching-Fong

2005-02-01

The identity of the maturation-inducing steroid (MIS) in black porgy, Acanthopagrus schlegeli, a marine protandrous teleost, is unknown. Previous studies demonstrated that two teleost MISs, the progestins 17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S) and 17,20beta-dihydroxy-4-pregnen-3-one (DHP) can induce maturation of black porgy oocytes in vitro. The purpose of the present study was to identify the major progestin produced during oocyte maturation (OM) in black porgy and investigate whether its secretion increases during this process. Females were injected twice with a LHRH analog to induce OM. Ovarian follicles undergoing OM were incubated in vitro with tritiated [3H]pregnenolone precursor and the tritiated products were extracted, purified, and identified by HPLC, TLC, acetylation, and recrystallization. Significant amounts of tritiated products were biosynthesized from [3H]pregnenolone that co-migrated with 20beta-S but not with DHP on HPLC and TLC. Similar TLC profiles were obtained with the tritiated products isolated from the HPLC/TLC 20beta-S fraction and standard 20beta-S after the acetylation reaction. The identity of the tritiated products as 20beta-S was confirmed by recrystallization. 20beta-S had a slightly higher potency than DHP in the inducing in vitro final oocyte maturation. Plasma 20beta-S concentrations increased significantly during the oocyte maturation after injection with a LHRH analog. The present data suggest that 20beta-S is the MIS in black porgy.

Lipidomic Components Alterations of Human Follicular Fluid Reveal the Relevance of Improving Clinical Outcomes in Women Using Progestin-Primed Ovarian Stimulation Compared to Short-Term Protocol.

PubMed

Wen, Xiaowei; Kuang, Yanping; Zhou, Lixia; Yu, Baofeng; Chen, Qiuju; Fu, Yonglun; Yan, Zheng; Guo, Haiyan; Lyu, Qifeng; Xie, Jun; Chai, Weiran

2018-05-21

BACKGROUND Increasing the success rate of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) is a duty of clinicians that has made many seek a variety of protocols. This study was undertaken to use a liquid chromatography-mass spectrometry (LC-MS) to define the alterations of follicular fluid (FF) lipid metabolites in patients undergoing progestin-primed ovarian stimulation (PPOS) compared with short-term protocol, revealing potential correlations between the differentially expressed lipids and ameliorative clinical outcomes. MATERIAL AND METHODS Ninety-three infertile women undergoing IVF/ICSI treatment with PPOS (n=62) or a short-term protocol (n=31) were prospectively enrolled in a randomized controlled trial. FF samples were obtained from dominant follicles at the time of oocyte retrieval. Lipid metabolism profiles were analyzed using LC-MS. RESULTS Twelve lipids were found to be higher in patients treated with the PPOS protocol than in those receiving the short-term protocol, including triacylglycerols (TAG-34: 1+NH4, TAG-58: 0+NH4, TAG-64: 3+NH4, and TAG-64: 8+NH4), diacylglycerol DAG-38: 6+NH4, phosphatidylglycerols (PG-26: 0, PG-30: 2, and PG-40: 5), phosphatidylethanolamine PE-32: 2, lysophosphatidylethanolamine LPE-14: 1, lysophosphatidylinositol LPI-12: 0, and lysophosphatidylcholine LPC-16: 0. CONCLUSIONS Our data demonstrate that the PPOS protocol increases the levels of 12 lipids in FF, which reveals a strong association between the differentially elevated lipids and better IVF/ICSI outcomes.

ALLOPREGNANOLONE’S ATTENUATION OF THE LORDOSIS-INHIBITNG EFFECTS OF RESTRAINT IS BLOCKED BY THE ANTIPROGESTIN, CDB-4124

PubMed Central

Uphouse, Lynda; Hiegel, Cindy

2014-01-01

A brief restraint experience reduces lordosis behavior in ovariectomized females that have been hormonally primed with estradiol benzoate. The addition of progesterone to the priming prevents the lordosis inhibition. Based on prior studies with an inhibitor of progesterone metabolism, we have implicated the intracellular progesterone receptor, rather than progesterone metabolites, as responsible for this protection. However, the progesterone metabolite, allopregnanolone (3α-hydroxy-5α-pregnan-20-one), also prevents lordosis inhibition after restraint. In a prior study, we reported that the progestin receptor antagonist, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), attenuated the effect of allopregnanolone. Because RU486 can also block the glucocorticoid receptor, in the current studies, we evaluated the effect of the progestin receptor antagonist, CDB-4124 (17 α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione), which is relatively devoid of antiglucocorticoid activity. Ovariectomized, Fischer rats were injected with 10 μg estradiol benzoate. Two days later, rats received either 60 mg/kg CDB-4124 or the 20% DMSO/propylene glycol vehicle 1 hr before injection with 4 mg/kg allopregnanolone. After a pretest to confirm sexual receptivity, rats were restrained for 5 min and immediately tested for sexual behavior. Lordosis behavior was reduced by the restraint and attenuated by allopregnanolone. Pretreatment with CDB-4124 reduced allopregnanolone’s effect. These findings support prior suggestions that allopreganolone reduces the response to restraint by mechanisms that require activation of the intracellular progesterone receptor. PMID:24650591

Allopregnanolone's attenuation of the lordosis-inhibiting effects of restraint is blocked by the antiprogestin, CDB-4124.

PubMed

Uphouse, Lynda; Hiegel, Cindy

2014-07-01

A brief restraint experience reduces lordosis behavior in ovariectomized females that have been hormonally primed with estradiol benzoate. The addition of progesterone to the priming prevents the lordosis inhibition. Based on prior studies with an inhibitor of progesterone metabolism, we have implicated the intracellular progesterone receptor, rather than progesterone metabolites, as responsible for this protection. However, the progesterone metabolite, allopregnanolone (3α-hydroxy-5α-pregnan-20-one), also prevents lordosis inhibition after restraint. In a prior study, we reported that the progestin receptor antagonist, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), attenuated the effect of allopregnanolone. Because RU486 can also block the glucocorticoid receptor, in the current studies, we evaluated the effect of the progestin receptor antagonist, CDB-4124 (17α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione), which is relatively devoid of antiglucocorticoid activity. Ovariectomized, Fischer rats were injected with 10 μg estradiol benzoate. Two days later, rats received either 60 mg/kg CDB-4124 or 20% DMSO/propylene glycol vehicle 1 h before injection with 4 mg/kg allopregnanolone. After a pretest to confirm sexual receptivity, rats were restrained for 5min and immediately tested for sexual behavior. Lordosis behavior was reduced by the restraint and attenuated by allopregnanolone. Pretreatment with CDB-4124 reduced allopregnanolone's effect. These findings support prior suggestions that allopreganolone reduces the response to restraint by mechanisms that require activation of the intracellular progesterone receptor. Copyright © 2014 Elsevier Inc. All rights reserved.

The effect of human chorionic gonadotrophin contained in human menopausal gonadotropin on the clinical outcomes during progestin-primed ovarian stimulation

PubMed Central

Fu, Yonglun; Ai, Ai; Cai, Renfei; Wang, Yun; Hong, Qingging; Hui, Tian; Lyu, Qifeng; Chen, Qiuju; Kuang, Yanping

2017-01-01

Progestin-primed ovarian stimulation (PPOS) protocol has recently been demonstrated to be an novel regimen for preventing premature LH surges during controlled ovarian hyperstimulation (COH) in combination with frozen-thawed embryo transfer (FET). Our prospective controlled study was to explore the effect of human chorionic gonadotropin (hCG) contained in human menopausal gonadotropin (hMG) on the clinical outcomes in normalovulatory women undergoing COH with PPOS. A total of 180 patients were allocated into three groups according to the gonadotropin (Gn) used: group A (human menopausal gonadotropin, hMG-A), group B (hMG-B) or group C (follicle stimulating hormone, FSH). The primary outcome measured was the number of oocytes retrieved. The number of oocytes retrieved in group A B C was 10.72±5.78 11.33±5.19and13.38±8.97, respectively, with no statistic significance (p>0.05). Other embryological indicators were also similar (p>0.05). The concentration of serum and urinary β-hCG on the trigger day in group A and B were not associated with embryo results (p>0.05). There was no significant differences in the clinical pregnancy rate (41.67% vs. 51.56% vs. 39.51%, p>0.05) and implantation rate (31.58%vs. 34.75%vs.25.33%) after FET among the three groups. Thus the clinical characteristics were not affected by the hCG contained in hMG in normalovulatory women treated with PPOS. PMID:29152085

Progesterone resistance in endometriosis: origins, consequences and interventions.

PubMed

Patel, Bansari G; Rudnicki, Martin; Yu, Jie; Shu, Yimin; Taylor, Robert N

2017-06-01

Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital "preconditioning", whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

Chronic administration of tibolone modulates anxiety-like behavior and enhances cognitive performance in ovariectomized rats.

PubMed

Espinosa-Raya, Judith; Neri-Gómez, Teresa; Orozco-Suárez, Sandra; Campos, María G; Guerra-Araiza, Christian

2012-01-01

Hormone replacement therapy (HRT) may be prescribed to prevent the symptoms of menopause. This therapy may include estrogenic and/or progestin components and may increase the incidence of endometrial and breast cancers. Tibolone (TIB), which is also made up of estrogen and progestin components, is often used to reduce the impact of HRT. However, the effect of TIB on the processes of learning, memory and anxiety has yet to be fully elucidated. The aim of this study was to evaluate the long-term effect on learning, memory processes and anxiety in ovariectomized rats caused by different doses of TIB (0 mg/kg, 0.01 mg/kg, 0.1 mg/kg 1.0 mg/kg and 10 mg/kg, administered daily via the oral route for 18 weeks). Two behavioral animal models, the autoshaping and T maze models were employed. The concentrations of acetyl choline transferase (ChAT) and tryptophan hydroxylase (TPH) in the hippocampus were directly measured by Western blot. No significant changes were observed in the autoshaping model and spontaneous activity test. In the T maze, increased latency was observed with TIB doses of 1 and 10 mg/kg compared to the vehicle. We observed that the ChAT content decreased with increasing doses of TIB, whereas TPH content increased with doses of 1 and 10 mg/kg of TIB. These data indicate that high doses of TIB improved emotional learning, which may be related to the modulation of the cholinergic and serotonergic systems by TIB. Copyright © 2011 Elsevier Inc. All rights reserved.

Oral contraceptives in polycystic ovary syndrome.

PubMed

Helvaci, N; Yildiz, B O

2014-09-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age and combined oral contraceptives (OCs) are often the first-line treatment of the syndrome by improving hyperandrogenism and regulating menstrual cycles. Oral contraceptives have some cardiovascular and metabolic effects that varies among different formulations depending upon the dose and type of the both estrogen and progestin components. These cardiometabolic effects of OCs raise some concerns about their long-term use in PCOS, but available data suggest that the benefits outweigh the risks. More studies are needed to clarify the safety of long-term use of OCs in PCOS.

Clinical trials in male hormonal contraception.

PubMed

Nieschlag, Eberhard

2010-11-01

Research has established the principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis. All hormonal male contraceptives use testosterone, but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Clinical trials concentrate on testosterone combined with norethisterone, desogestrel, etonogestrel or depot-medroxyprogesterone acetate. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of testosterone undecanoate and etonogestrel in suppressing spermatogenesis in volunteers. Copyright © 2010 Elsevier Inc. All rights reserved.

The male contraceptive regimen of testosterone and levonorgestrel significantly increases lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced by testosterone alone.

PubMed

Herbst, Karen L; Anawalt, Bradley D; Amory, John K; Matsumoto, Alvin M; Bremner, William J

2003-03-01

In hypogonadal men, testosterone (T) in replacement dosages is known to increase fat-free mass (lean mass) and decrease fat mass. In young eugonadal men, similar dosages of T increase lean mass, but much higher dosages of T are required to decrease total body fat mass. Current T-based male hormonal contraceptive regimens include a second agent, such as a progestin, to maximize inhibition of pituitary gonadotropins and improve efficacy. To study the effect of such combinations on body composition, we randomized healthy, young, eugonadal men into four combinations of exogenous T and the progestin, levonorgestrel (LNG): 1) 100 mg T enanthate, im, weekly plus 125 micro g LNG, orally, daily (T+LNG); 2) T plus placebo LNG (T alone); 3) placebo T plus LNG (LNG alone); and 4) placebo T plus placebo LNG (placebo). We then analyzed body composition by dual energy x-ray absorptiometry after 4 and 8 wk of treatment. T+LNG significantly increased total lean mass after 4 and 8 wk of treatment (3.5 +/- 0.9% and 4.2 +/- 1.2%, respectively; P < 0.05) and truncal lean mass after 4 and 8 wk of treatment (4.7 +/- 0.9% and 5.0 +/- 0.9%, respectively; P < 0.05) compared with baseline and placebo. T alone also increased total and truncal lean mass significantly compared with placebo after 4 wk of treatment, but not compared with baseline (3.3 +/- 1.4% and 3.2 +/- 2.3%, respectively; P < 0.05 vs. placebo), suggesting an additive effect of T and LNG to increase lean mass. Fat mass significantly decreased in the abdomen in men administered T alone compared with LNG alone (-4.9 +/- 2.8%; P < 0.05). Fat mass significantly increased in the abdomen with LNG alone (4.1 +/- 1.0%; P < 0.05) compared with baseline and was unchanged with the combination of T+LNG, suggesting that LNG attenuates the decrease in fat mass seen with T alone. There was no change in weight or body mass index in any group during the study. This study shows that in young eugonadal men 1) T alone rapidly increases lean mass and decreases fat mass in 4-8 wk; 2) T+LNG rapidly increases lean mass, but has no effect on fat mass; and 3) LNG alone increases fat mass. The favorable profile on body composition by T is, therefore, partially attenuated by the progestin, LNG. These findings suggest that androgen-based male hormonal contraceptives might have favorable effects on body composition. The impact of these changes on cardiovascular risk in normal men needs further study.

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

PubMed

Chlebowski, Rowan T; Schwartz, Ann G; Wakelee, Heather; Anderson, Garnet L; Stefanick, Marcia L; Manson, JoAnn E; Rodabough, Rebecca J; Chien, Jason W; Wactawski-Wende, Jean; Gass, Margery; Kotchen, Jane Morley; Johnson, Karen C; O'Sullivan, Mary Jo; Ockene, Judith K; Chen, Chu; Hubbell, F Allan

2009-10-10

In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. National Heart, Lung and Blood Institute, National Institutes of Health.

New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF.

PubMed

Massin, Nathalie

2017-03-01

The advent of embryo and oocyte vitrification today gives reproductive specialists an opportunity to consider new strategies for improving the practice and results of IVF attempts. As the freezing of entire cohorts does not compromise, and may even improve, the results of IVF attempts, it is possible to break away from the standard sequence of stimulation-retrieval-transfer. The constraints associated with ovarian stimulation in relation to the potential harmful effects of the hormonal environment on endometrial receptivity can be avoided. This review will look at the new stimulation protocols where progesterone is used to block the LH surge. Thanks to 'freeze all' strategies, the increase in progesterone could actually be no longer a cause for concern. There are two ways of using progesterone, whether it be endogenous, as in luteal phase stimulation, or exogenous, as in the use of progesterone in the follicular phase i.e. progestin primed ovarian stimulation. A literature search was carried out (until September 2016) on MEDLINE. The following text words were utilized to generate the list of citations: progestin primed ovarian stimulation, luteal phase stimulation, luteal stimulation, duostim, double stimulation, random start. Articles and their references were then examined in order to identify other potential studies. All of the articles are reported in this review. The use of progesterone during ovarian stimulation is effective in blocking the LH surge, whether endogenous or exogenous, and it does not affect the number of oocytes collected or the quality of the embryos obtained. Its main constraint is that it requires total freezing and delayed transfer. A variety of stimulation protocols can be derived from these two methods, and their implications are discussed, from fertility preservation to ovarian response profiles to organization for the patients and clincs. These new regimens enable more flexibility and are of emerging interest in daily practice. However, their medical and economic significance remains to be demonstrated. The use of luteal phase or follicular phase protocols with progestins could rapidly develop in the context of oocyte donation and fertility preservation not related to oncology. Their place could develop even more in the general population of patients in IVF programs. The strategy of total freezing continues to develop, thanks to technical improvements, in particular vitrification and PGS on blastocysts, and thanks to studies showing improvements in embryo implantation when the transfer take place far removed from the hormonal changes caused by ovarian stimulation. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

The future of male contraception: a fertile ground

PubMed Central

Zillioux, Jacqueline; Eisenfrats, Kevin; Foley, Daniel; Smith, Ryan

2018-01-01

The continued and rapid expansion of the Earth’s population mandates the need for safe and effective measures of contraception. While a plethora of options exist for women, methods of contraception for the male partner are limited to condoms and vasectomy. The sequela of this discrepancy has led to the family planning burden falling disproportionately on the female partner. For the past several decades, extensive research has been undertaken exploring the feasibility of hormonal male contraception. This proposed method of contraception has focused on suppressing spermatogenesis by exploiting the hypothalamic-pituitary-gonadal (HPG) axis. Beginning with proof of concept studies in the early nineties, administration of testosterone in healthy male subjects has been shown to be an efficacious method of inducing sterility. Owing to ethnic differences in spermatogenesis suppression and the comparatively low rate of azoospermia in Caucasian men with androgen-only regimens, investigators have explored the addition of progestins to further enhance the efficacy of hormonal contraception. Though studies have revealed promise with androgen-progestin regimens, the lack of long-term studies has precluded the development of a marketable product. Recently, more research has been directed towards identifying non-hormonal alternatives to male contraception. These non-hormonal options have ranged from the development of devices facilitating reversible occlusion of the vas deferens lumen to medications disrupting various pathways in the process of spermatogenesis. Underlying the development of hormonal and non-hormonal strategies is the shared enthusiasm men and women have towards these male directed methods. The willingness of couples to pursue these alternatives combined with the global need to reduce the psychological and socioeconomic implications of unintended pregnancy ensures that research will continue to bring this goal to fruition.

Is there a need for better sexual education of young men? Sexual behaviour and reproductive health in Swiss university students: a questionnaire-based pilot study.

PubMed

Merki-Feld, Gabriele Susanne; Felder, Stephanie; Roelli, Conrad; Imthurn, Bruno; Stewart, Mary; Bateson, Deborah

2018-04-01

There is evidence that men's perception of contraceptive methods and of their effectiveness and health risks have a major impact on couples contraceptive choices. Engaging men in decision making improves reproductive health outcomes. If they are better informed, men can potentially contribute to more effective use of contraception, thus reducing the rate of sexually transmitted infections and abortion. In Central European countries, few data are available on male contraceptive knowledge and behaviour. To collect more data we conducted an anonymous survey among young men studying at Zürich University in Switzerland. A questionnaire was distributed to 1500 male students which included a broad range of items addressing sexual behaviour, condom use and knowledge, and attitudes regarding contraceptive methods. Three hundred and sixty-one questionnaires were eligible for evaluation. Condoms and the combined oral contraceptive pill were the most frequently used methods. However, at last intercourse 15.6% of respondents had not used any method of contraception. Many respondents (37%) had had a one-night stand without protection. Contraceptive methods most regarded as unhealthy for women were the combined oral contraceptive pill, progestin-only methods, intrauterine devices (IUDs) and emergency contraception. Characteristics considered by young men to be important in determining contraceptive method choice were: efficacy, partner satisfaction and no impact on fertility and libido. Awareness among male Swiss students about contraceptive methods is high, but in-depth knowledge is limited. Myths were expressed about the combined oral contraceptive pill, progestin-only methods, IUDs and the emergency contraceptive pill. High-risk behaviour occurs frequently. The internet was reported to be the most important source of information about contraception.

Protective actions of progesterone in the cardiovascular system: potential role of membrane progesterone receptors (mPRs) in mediating rapid effects.

PubMed

Thomas, Peter; Pang, Yefei

2013-06-01

The protective functions of progesterone in the cardiovascular system have received little attention even though evidence has accumulated that progesterone lowers blood pressure, inhibits coronary hyperactivity and has powerful vasodilatory and natriuretic effects. One possible reason why potential beneficial actions of progesterone on cardiovascular functions have not been extensively studied is that divergent effects to those of progesterone have been observed in many clinical trials with synthetic progestins such as medroxyprogesterone acetate which are associated with increased risk of coronary disease. Evidence that progesterone exerts protective effects on cardiovascular functions is briefly reviewed. The finding that progesterone administration decreases blood vessel vasoconstriction in several animal models within a few minutes suggests that rapid, nongenomic progesterone mechanisms are of physiological importance in regulating vascular tone. Rapid activation of second messenger pathways by progesterone has been observed in vascular endothelial and smooth muscle cells, resulting in alterations in endothelial nitric oxide synthase (eNOS) activity and calcium influx, respectively. Both nuclear progesterone receptors (PRs) and novel membrane progesterone receptors (mPRs) are candidates for the intermediaries in these rapid, cell-surface initiated progesterone actions in endothelial and smooth muscle vascular cells. PRs have been detected in both cell types. New data are presented showing mPRα, mPRβ and mPRγ are also present in human endothelial and smooth muscle vascular cells. Preliminary evidence suggests mPRs mediate rapid progestin signaling in these endothelial cells, resulting in down-regulation of cAMP production and increased nitric oxide synthesis. The role of mPRs in progesterone regulation of cardiovascular functions warrants further investigation. Copyright © 2013 Elsevier Inc. All rights reserved.

Metabolism of the Synthetic Progestogen Norethynodrel by Human Ketosteroid Reductases of the Aldo-Keto Reductase Superfamily

PubMed Central

Jin, Yi; Duan, Ling; Chen, Mo; Penning, Trevor M; Kloosterboer, Helenius J.

2012-01-01

Human ketosteroid reductases of the aldo-keto reductase (AKR) superfamily, i.e. AKR1C1-4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17α-ethynyl-17β-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3α- and 3β-hydroxy metabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3β-hydroxy NOR, while AKR1C3 gave 3β-hydroxy NOR as the main product and AKR1C4 predominantly formed 3α-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Δ4-isomer of NOR and the most commonly used synthetic progestin, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7α-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7α-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3α- and 3β-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB. PMID:22210085

Long-Term Outcome of Aromatase Inhibitor Therapy With Letrozole in Patients With Advanced Low-Grade Endometrial Stromal Sarcoma.

PubMed

Yamaguchi, Munekage; Erdenebaatar, Chimeddulam; Saito, Fumitaka; Motohara, Takeshi; Miyahara, Yo; Tashiro, Hironori; Katabuchi, Hidetaka

2015-11-01

There has been no consensus on the indications for the treatment of advanced low-grade endometrial stromal sarcoma (LGESS), and the possible effects of hormonal treatment including progestins and aromatase inhibitors have been reported. The aim of this study was to investigate the efficacy of aromatase inhibitor therapy with letrozole for patients with residual or recurrent LGESS. We retrospectively reviewed the clinical response of patients with advanced LGESS who had been treated with letrozole. We also analyzed the adverse effects after the administration of letrozole. The expression levels of estrogen receptor and aromatase in the tumors were immunohistochemically examined. In 5 patients who had been treated for unresectable LGESS lesions after initial or repeat surgical procedures, residual lesions in 3 patients and recurrence lesions in 2 patients were the indications for hormonal therapy with letrozole. The median duration of letrozole exposure at retrospective analysis was 53 (10-96) months. The clinical outcomes were classified as complete response in 2 patients, partial response in 1 patient, and stable disease in 2 patients. Myalgias, hot flashes, and arthralgias were not observed during the follow-up period in any patients. The median serum levels of estradiol were <5.0 (cutoff value, <0.5-11.8) pg/mL. The median age-matched bone mineral densities were 92% (79%-123%). The LGESS tissues in all 5 patients were positive for estrogen receptor and aromatase expression. Letrozole as well as progestins could be the first choice of treatment for patients with recurrent or residual LGESS, which is difficult to resect surgically because of its efficacy and minimal adverse effects.

Economic return from the Women's Health Initiative estrogen plus progestin clinical trial: a modeling study.

PubMed

Roth, Joshua A; Etzioni, Ruth; Waters, Teresa M; Pettinger, Mary; Rossouw, Jacques E; Anderson, Garnet L; Chlebowski, Rowan T; Manson, Joann E; Hlatky, Mark; Johnson, Karen C; Ramsey, Scott D

2014-05-06

The findings of the Women's Health Initiative (WHI) estrogen plus progestin (E+P) trial led to a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States. The economic effect of this shift has not been evaluated relative to the trial's $260 million cost (2012 U.S. dollars). To estimate the economic return from the WHI E+P trial. Decision model to simulate health outcomes for a "WHI scenario" with observed cHT use and a "no-WHI scenario" with cHT use extrapolated from the pretrial period. Primary analyses of WHI outcomes, peer-reviewed literature, and government sources. Postmenopausal women in the United States, aged 50 to 79 years, who did not have a hysterectomy. 2003 to 2012. Payer. Combined hormone therapy. Disease incidence, expenditure, quality-adjusted life-years, and net economic return. The WHI scenario resulted in 4.3 million fewer cHT users, 126,000 fewer breast cancer cases, 76,000 fewer cardiovascular disease cases, 263,000 more fractures, 145,000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100,000 per quality-adjusted life-year. The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion. No evaluation of indirect costs or outcomes beyond 2012. The WHI E+P trial made high-value use of public funds with a substantial return on investment. These results can contribute to discussions about the role of public funding for large, prospective trials with high potential for public health effects. National Heart, Lung, and Blood Institute.

Reproduction control in cats: new developments in non-surgical methods.

PubMed

Goericke-Pesch, Sandra

2010-07-01

Reproduction control is an area of feline medicine that is assuming increasing importance in companion animal practice. Signs of oestrus such as increased vocalisation, rolling on the ground and a very short interoestrous interval may negatively influence the relationship between cat and owner, and prompt the owner to seek a method of reproduction control. In breeding catteries, control of reproduction may be needed as part of a planned breeding programme. Surgical contraception is not always the owner's wish - especially when a cat may be intended for future breeding. Besides, ethical principles and animal welfare legislation in an increasing number of countries are imposing restrictions on this 'classical approach' to reproduction control. Progestins are routinely used as non-surgical alternatives in cases where fertility is to be preserved, but the associated risks of uterine disease, mammary tumours, fibroadenomatosis or diabetes mellitus have to be taken into account - especially in predisposed animals. Modern, effective pharmacological alternatives are available for managing oestrous suppression and unwanted pregnancy. Detailed knowledge of the physiology of the oestrous cycle in the cat is necessary to ensure that the appropriate treatment is chosen for the individual animal and its owner. This article presents an update for small animal practitioners on these alternative methods; specifically, the use of slow-release GnRH agonists or melatonin implants for hormonal contraception, and the antiprogestin aglepristone for pregnancy termination. Several studies have documented the mode of action and risk of side effects of the traditional alternative to surgical castration - treatment with progestins. Evidence underpinning the safety and efficacy of GnRH agonists and melatonin implants for suppression of fertility in queens and toms is reviewed. Copyright 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Reproductive and oncologic outcomes after progestin therapy for endometrial complex atypical hyperplasia or carcinoma.

PubMed

Kudesia, Rashmi; Singer, Tomer; Caputo, Thomas A; Holcomb, Kevin Michael; Kligman, Isaac; Rosenwaks, Zev; Gupta, Divya

2014-03-01

This study evaluated fertility and oncological outcomes in women with complex atypical hyperplasia (CAH) or nonmyoinvasive grade 1 endometrioid endometrial carcinoma (EM) who desired fertility-sparing therapy. The retrospective cohort study included women younger than 45 years with CAH or EM who desired fertility-sparing treatment at our institution. Only patients for whom both oncological treatment and pregnancy outcomes were available were included. Statistical analyses were performed using a Fisher exact test, Pearson χ(2) test, and Spearman rank correlation test, as appropriate. Seventy-five patients were identified, and 23 (13 CAH, 10 EM) met the inclusion criteria. All 23 patients had at least 1 prior pregnancy. Treatment was split between oral progesterone only (38.5% CAH, 40% EM), levonorgestrel intrauterine device only (30.8% CAH, 20% EM), and both (30.8% CAH, 40% EM). After a median follow-up of 13 months (range, 3-74 months), 9 patients (46.2% CAH, 30% EM, P = .39) had persistent/progressive disease. Eight patients (30.8% CAH, 40% EM, P = .69) ultimately had a hysterectomy, and 3 of these (13.0%) were found to have persistent/progressive disease. Median time from diagnosis to hysterectomy was 13 months (range, 4-56 months). Fourteen of the 23 patients utilized assisted reproductive techniques (60.9%); 12 underwent IVF and 2 chose a gestation carrier. Seven clinical intrauterine pregnancies (30.4%) resulting in 6 live births (26.1%) were found in the entire cohort. Fertility-sparing treatment for CAH and grade 1 endometrial cancer is feasible with progestin therapy and leads to clinically meaningful rates of pregnancy in young women who desire fertility. Copyright © 2014 Mosby, Inc. All rights reserved.

Menopausal Symptom Relief and Side Effects Experienced by Women Using Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 1.

PubMed

Deleruyelle, Laura J

2016-01-01

The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, large-scale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women's menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t -test, two-sample t -test, and f tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh's Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. The results of this study will be summarized in forthcoming articles in this series. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Effects of hormonal contraceptives on mental rotation and verbal fluency.

PubMed

Griksiene, Ramune; Ruksenas, Osvaldas

2011-09-01

Cognitive abilities, such as verbal fluency and mental rotation, are most sensitive to changes in sex steroids but poorly studied in the context of hormonal contraceptive usage. Therefore, we investigated the performance of mental rotation and verbal fluency in young (21.5±1.8 years) healthy oral contraceptive (OC) users (23 women) and non-users (20 women) during the follicular, ovulatory and luteal phases of the menstrual cycle. Salivary 17β-estradiol, progesterone and testosterone levels were assayed to evaluate hormonal differences between groups and the phases of the menstrual cycle. To assess the effects of progestins having androgenic/anti-androgenic properties, OC users were subdivided into the third and new generation OC users. In addition, positive and negative affects as factors possibly affecting cognitive performance were evaluated. Salivary 17β-estradiol and progesterone levels were significantly lower in hormonal contraception users. Level of salivary testosterone was slightly lower in the OC users group with significant difference only during ovulatory phase. Naturally cycling women performed better on verbal fluency task as compared to OC users. Subjects who used the third generation (androgenic) OCs generated significantly fewer words as compared to new generation (anti-androgenic) OC users and non-users. The third generation OC users demonstrated significantly longer RT in MRT task as compared to non-users. The MRT, verbal fluency and mood parameters did not depend on the phase of menstrual cycle. The parameters of the PANAS (Positive and Negative Affect Schedule) scales did not differ between OC users and non-users. Our findings show that hormonal contraception has an impact on verbal and spatial abilities. Different performances between users of oral contraceptives with androgenic and anti-androgenic properties suggest an essential role for the progestins contained in OCs on cognitive performance. Copyright © 2011 Elsevier Ltd. All rights reserved.

Injectable contraception. New and existing options.

PubMed

Kaunitz, A M

2000-12-01

DMPA and MPA/E2C contraception offer women safe, effective, convenient, and reversible birth control choices. The use of DMPA, a 3-month injectable, is characteristically associated with amenorrhea. Lactating women and women in whom contraceptive doses of estrogen are contraindicated can use this progestin-only birth control method. Return of fertility can be delayed in women discontinuing DMPA to become pregnant. In some cases, the use of DMPA also confers important noncontraceptive and therapeutic benefits. A monthly estrogen/progestin injectable contraceptive, MPA/E2C should appeal to women who are concerned about daily pill taking, who prefer regular cycles to amenorrhea, and who find monthly injections acceptable and accessible. As is true for oral contraceptives, MPA/E2C represents an appropriate choice for women who prefer a rapidly reversible contraceptive. Currently, the proposed contraindications for MPA/E2C parallel those for combined oral contraceptives. As MPA/E2C contraception becomes available for American women, clinicians will learn how to best include this new method among the array of contraceptive choices. By individualizing contraceptive selection, counseling, and management approaches based on the relevant behavioral and medical considerations reviewed herein, clinicians can maximize their patients' success with injectable contraceptives. The more innovative that clinicians, family planning agencies, and insurers are in facilitating access to care (including reinjections), the more women will be able to avail themselves of safe, effective, and reversible methods of contraception. In addition to the physician's office or health clinic, other sites at which women might receive contraceptive injections include employee health clinics, college health clinics, or perhaps the pharmacy where the prescription is filled. Self-administration may become an appropriate option for some users of injectable contraception.

Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study.

PubMed

Duijkers, Ingrid J M; Klipping, Christine; Zimmerman, Yvette; Appels, Nicole; Jost, Maud; Maillard, Catherine; Mawet, Marie; Foidart, Jean-Michel; Coelingh Bennink, Herjan J T

2015-01-01

The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women. This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use

PubMed Central

Lensing, Anthonie W. A.; Middeldorp, Saskia; Levi, Marcel; Beyer-Westendorf, Jan; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A.; Cohen, Alexander T.; Trajanovic, Mila; Gebel, Martin; Lam, Phuong; Wells, Philip S.; Prins, Martin H.

2016-01-01

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an “unacceptable health risk” during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration. PMID:26696010

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.

PubMed

Martinelli, Ida; Lensing, Anthonie W A; Middeldorp, Saskia; Levi, Marcel; Beyer-Westendorf, Jan; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A; Cohen, Alexander T; Trajanovic, Mila; Gebel, Martin; Lam, Phuong; Wells, Philip S; Prins, Martin H

2016-03-17

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration. © 2016 by The American Society of Hematology.

Endocrine diseases in dogs and cats: similarities and differences with endocrine diseases in humans.

PubMed

Rijnberk, Ad; Kooistra, Hans S; Mol, Jan A

2003-08-01

Over several millennia, humans have created hundreds of dog and cat breeds by selective breeding, including fixation of mutant genes. The domestic dog is unique in the extent of its variation in height, weight and shape as well as its behavior. It is primarily the relatively long persistence of high levels of growth hormone (GH) release at a young age that accounts for the large body size in giant breeds of dogs. Several of the endocrine diseases of humans are also known to occur as similar entities in dogs and cats. With some variations, this is true for conditions such as diabetes mellitus and the hypofunction syndromes of the thyroid and adrenal cortex. Also, the hyperfunction syndromes of hypercortisolism and hyperparathyroidism in dogs and cats have many similarities with their human counterparts. The exception seems to be Graves' disease. This condition, which is due to production of thyroid-stimulating hormone (TSH)-receptor antibodies, has not been observed in dogs and cats. The very common form of hyperthyroidism in cats is due to toxic adenomas. In the 1980s it was discovered that in dogs exogenous progestins and endogenous progesterone can induce GH excess. This GH excess originates form the mammary gland and may give rise to acromegaly and insulin resistance. GH production by the mammary gland is not unique to the dog. It has become clear that cats and humans also express the GH gene in the mammary gland. There is increasing evidence that this locally produced GH not only plays a role in the morphologic changes of the mammary gland associated with the ovarian cycle and gestation, but that it is also involved in the development of breast cancer. In dogs, induction of mammary GH production by progestin administration allows for treatment of GH deficiency.

Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats

PubMed Central

Molenda-Figueira, Heather A.; Williams, Casey A.; Griffin, Andreana L.; Rutledge, Eric M.; Blaustein, Jeffrey D.; Tetel, Marc J.

2008-01-01

The ovarian hormones, estradiol (E) and progesterone (P) facilitate the expression of sexual behavior in female rats. E and P mediate many of these behavioral effects by binding to their respective intracellular receptors in specific brain regions. Nuclear receptor coactivators, including Steroid Receptor Coactivator-1 (SRC-1) and CREB Binding Protein (CBP), dramatically enhance ligand-dependent steroid receptor transcriptional activity in vitro. Previously, our lab has shown that SRC-1 and CBP modulate estrogen receptor (ER)-mediated induction of progestin receptor (PR) gene expression in the ventromedial nucleus of the hypothalamus (VMN) and hormone-dependent sexual receptivity in female rats. Female sexual behaviors can be activated by high doses of E alone in ovariectomized rats, and thus are believed to be ER-dependent. However, the full repertoire of female sexual behavior, in particular, proceptive behaviors such as hopping, darting and ear wiggling, are considered to be PR-dependent. In the present experiments, the function of SRC-1 and CBP in distinct ER- (Exp. 1) and PR- (Exp. 2) dependent aspects of female sexual behavior was investigated. In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior. In Exp. 2, antisense to SRC-1 and CBP mRNA around the time of P administration reduced PR-dependent ear wiggling and hopping and darting. Taken together, these data suggest that SRC-1 and CBP modulate ER and PR action in brain and influence distinct aspects of hormone-dependent sexual behaviors. These findings support our previous studies and provide further evidence that SRC-1 and CBP function together to regulate ovarian hormone action in behaviorally-relevant brain regions. PMID:16769066

Progesterone inhibits proliferation and modulates expression of proliferation-Related genes in classical progesterone receptor-negative human BxPC3 pancreatic adenocarcinoma cells.

PubMed

Goncharov, Alexey I; Maslakova, Aitsana A; Polikarpova, Anna V; Bulanova, Elena A; Guseva, Alexandra A; Morozov, Ivan A; Rubtsov, Petr M; Smirnova, Olga V; Shchelkunova, Tatiana A

2017-01-01

Recent studies suggest that progesterone may possess anti-tumorigenic properties. However, a growth-modulatory role of progestins in human cancer cells remains obscure. With the discovery of a new class of membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor gene family, it becomes important to study the effect of this hormone on proliferation of tumor cells that do not express classical nuclear progesterone receptors (nPRs). To identify a cell line expressing high levels of mPRs and lacking nPRs, we examined mRNA levels of nPRs and three forms of mPRs in sixteen human tumor cell lines of different origin. High expression of mPR mRNA has been found in pancreatic adenocarcinoma BxPC3 cells, while nPR mRNA has not been detected in these cells. Western blot analysis confirmed these findings at the protein level. We revealed specific binding of labeled progesterone in these cells with affinity constant similar to that of human mPR expressed in yeast cells. Progesterone at high concentration of 20 μM significantly reduced the mRNA levels of proliferation markers Ki67 and PCNA, as well as of cyclin D1, and increased the mRNA levels of cyclin dependent kinase inhibitors p21 and p27. Progesterone (1 μM and 20 μM) significantly inhibited proliferative activity of BxPC3 cells. These results point to anti-proliferative effects of the progesterone high concentrations on BxPC3 cells and suggest that activation of mPRs may mediate this action. Our data are a starting point for further investigations regarding the application of progesterone in pancreatic cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Clinical efficacy and metabolic impact of two different dosages of ethinyl-estradiol in association with drospirenone in normal-weight women with polycystic ovary syndrome: a randomized study.

PubMed

Romualdi, D; De Cicco, S; Busacca, M; Gagliano, D; Lanzone, A; Guido, M

2013-09-01

The estrogenic component of estro- progestin (EP) is responsible for a negative impact on the metabolic and lipid assessment in women with polycystic ovary syndrome (PCOS). To evaluate the risk/benefit ratio of two EP combinations, containing the same progestin (3 mg drospirenone) and a different dose of ethinyl-estradiol (EE) (20 vs 30 μg) and to compare their effects on the clinical and endocrine-metabolic parameters in normal-weight PCOS women. In this randomized pilot study, we enrolled 30 young normal-weight PCOS women. Fifteen subjects were allocated to group A (20 μg EE) and 15 PCOS subjects to group B (30 μg EE). Hirsutism score, hormonal assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp and lipid profile were performed at baseline, and after 6 and 12 months of therapy. Main outcome measures were signs of hyperandrogenism, glucose and insulin metabolism, lipid profile. Both treatment regimens induced a significant improvement in hirsutism score, testosterone, DHEAS, and SHBG levels. Androstenedione significantly dropped only in patients of Group A, while 17(OH)P only in those from Group B. Both the formulations did not significantly modify gluco-insulinemic metabolism. Total cholesterol, LDL cholesterol, and HDL cholesterol levels significantly increased in both groups. Triglycerides levels, which increased as well, resulted more markedly influenced by the formulation with 30 μg EE. In association with drospirenone, 20 μg EE results as effective as 30 μg in improving clinical and hormonal features of normal-weight PCOS women, while exhibiting a milder influence on lipidic parameters.

Contraceptive use in the Nordic countries.

PubMed

Lindh, Ingela; Skjeldestad, Finn E; Gemzell-Danielsson, Kristina; Heikinheimo, Oskari; Hognert, Helena; Milsom, Ian; Lidegaard, Øjvind

2017-01-01

The aim was to compare contraceptive use in the Nordic countries and to assess compliance with recommendations from the European Medicines Agency regarding the use of combined oral contraception containing low-dose estrogen and levonorgestrel, norethisterone or norgestimate. Data on hormonal contraceptive prescriptions and sales figures for copper intrauterine devices were obtained from national databases and manufacturers in Denmark, Finland, Iceland, Norway and Sweden in 2010-2013. Contraceptive use was highest in Denmark (42%) and Sweden (41%), followed by Finland (40%). Combined oral contraception was the most used method in all countries, with the highest use in Denmark (26%). The second most used method was the levonorgestrel-releasing intrauterine system, with the highest use in Finland (15%) and ≈10% in the other countries. Copper intrauterine devices (7%) and the progestin-only pill (7%) were most often used in Sweden. Combined oral contraception use decreased with increasing age and levonorgestrel-releasing intrauterine system and progestin-only pills use increased. The use of long-acting reversible methods of contraception (=levonorgestrel-releasing intrauterine system, copper intrauterine devices, and implants) increased with time and was highest in Sweden (20%) and Finland (18%). The highest use of European Medicines Agency recommended combined oral contraception was in Denmark, increasing from 13 to 50% between 2010 and 2013. In Finland, recommended combined oral contraception remained below 1%. Contraceptive use was highest in Denmark and Sweden, levonorgestrel-releasing intrauterine system use was highest in Finland and all long-acting methods were most common in Sweden. The use of combined oral contraception recommended by the European Medicines Agency was highest in Denmark. © 2016 Nordic Federation of Societies of Obstetrics and Gynecology.

Towards an understanding of the evolution of the chorioallantoic placenta: steroid biosynthesis and steroid hormone signaling in the chorioallantoic membrane of an oviparous reptile.

PubMed

Cruze, Lori; Kohno, Satomi; McCoy, Michael W; Guillette, Louis J

2012-09-01

Amniotes, mammals, reptiles, and birds form common extraembryonic membranes during development to perform essential functions, such as protection, nutrient transfer, gas exchange, and waste removal. Together with the maternal uterus, extraembryonic membranes of viviparous (live-bearing) amniotes develop as an endocrine placenta that synthesizes and responds to steroid hormones critical for development. The ability of these membranes to synthesize and respond to steroid hormone signaling has traditionally been considered an innovation of placental amniotes. However, our laboratory recently demonstrated that this ability extends to the chorioallantoic membrane (CAM) of an oviparous (egg-laying) amniote, the domestic chicken, and we hypothesized that steroidogenic extraembryonic membranes could be an evolutionarily conserved characteristic of all amniotes because of similarities in basic structure, function, and shared evolutionary ancestry. In this study, we examined steroid hormone synthesis and signaling in the CAM of another oviparous amniote, the American alligator (Alligator mississippiensis). We quantified mRNA expression of a steroidogenic factor involved in the regulation of steroidogenesis (NR5A1), the key steroidogenic enzymes involved in the synthesis of progestins (HSD3B1), androgens (CYP17A1), and estrogens (CYP19A1), and the receptors involved in the signaling of progestins (PR), androgens (AR), estrogens (ESR1 and ESR2), and glucocorticoids (GR). Furthermore, we performed protein immunolocalization for PR and ESR1. Collectively, our findings indicate that the alligator CAM has the capability to regulate, synthesize, and respond to steroid hormone signaling, thus, supporting our hypothesis that the extraembryonic membranes of Amniota share a unifying characteristic, that is, the ability to synthesize and respond to steroid hormones.

Sometimes You Do Get a Second Chance: Emergency Contraception for Adolescents.

PubMed

Rome, Ellen S; Issac, Veronica

2017-04-01

Unplanned or unintended pregnancy remains a significant challenge for adolescents; many teens who plan ahead but opt not to choose long-acting reversible contraceptive methods have high failure rates with condom usage, oral contraceptives, and other less long-acting methods. Emergency contraception (EC) remains a necessity for those adolescents seeking a second chance to prevent the unintended consequences of unplanned sexual activity. At present, 5 postcoital methods remain available as EC globally: intrauterine devices, ulipristal acetate, a selective progesterone modulator, mifepristone; levonorgestrel, and ethinyl estradiol plus levonorgestrel or norgestrel (rarely used now that progestin only methods are more readily available). Copyright © 2017 Elsevier Inc. All rights reserved.

Use of Exogenous Progestins and Risk or In Situ and Invasive Breast Cancer

DTIC Science & Technology

2011-10-01

will be funded by the parent R01 (NCI) grant, and not by the Era of Hope Scholar Award. Table 1: Participant enrollment report Project 2 Project 1...of lobular tumors that were node positive, PR+, e-cadherin negative , and had low p21 expression (Table 6). No differences were seen across the other...Node negative 61% 1.2 (0.8-2.0) 63% 1.9 (1.04-3.4) Node positive 31% 0.9 (0.5-1.7) 37% 3.7 (1.8-7.8) PR+ 89% 1.2 (0.8-1.9) 84% 2.9 (1.7-5.1) PR- 11

Control of estrus and ovulation in beef heifers.

PubMed

Patterson, David J; Thomas, Jordan M; Martin, Neal T; Nash, Justin M; Smith, Michael F

2013-11-01

Expanded use of artificial insemination (AI) and/or adoption of emerging reproductive technologies for beef heifers and cows require precise methods of estrous-cycle control. New protocols for inducing and synchronizing a fertile estrus in replacement beef heifers and postpartum beef cows in which progestins are used provide new opportunities for beef producers to synchronize estrus and ovulation and to facilitate fixed-time AI. This article reviews the various estrous synchronization protocols currently available for use in replacement beef heifers. New methods of inducing and synchronizing estrus now create the opportunity to significantly expand the use of AI in the United States cowherd. Copyright © 2013 Elsevier Inc. All rights reserved.

The selective estrogen enzyme modulators in breast cancer: a review.

PubMed

Pasqualini, Jorge R

2004-06-07

It is well established that increased exposure to estradiol (E(2)) is an important risk factor for the genesis and evolution of breast tumors, most of which (approximately 95-97%) in their early stage are estrogen-sensitive. However, two thirds of breast cancers occur during the postmenopausal period when the ovaries have ceased to be functional. Despite the low levels of circulating estrogens, the tissular concentrations of these hormones are significantly higher than those found in the plasma or in the area of the breast considered as normal tissue, suggesting a specific tumoral biosynthesis and accumulation of these hormones. Several factors could be implicated in this process, including higher uptake of steroids from plasma and local formation of the potent E(2) by the breast cancer tissue itself. This information extends the concept of 'intracrinology' where a hormone can have its biological response in the same organ where it is produced. There is substantial information that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of E(2) from circulating precursors. Two principal pathways are implicated in the last steps of E(2) formation in breast cancer tissues: the 'aromatase pathway' which transforms androgens into estrogens, and the 'sulfatase pathway' which converts estrone sulfate (E(1)S) into E(1) by the estrone-sulfatase. The final step of steroidogenesis is the conversion of the weak E(1) to the potent biologically active E(2) by the action of a reductive 17beta-hydroxysteroid dehydrogenase type 1 activity (17beta-HSD-1). Quantitative evaluation indicates that in human breast tumor E(1)S 'via sulfatase' is a much more likely precursor for E(2) than is androgens 'via aromatase'. Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of E(2) biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In recent years, it was demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone, dydrogesterone, norelgestromin), tibolone and its metabolites, as well as other steroidal (e.g. sulfamates) and non-steroidal compounds, are potent sulfatase inhibitors. Various progestins can also block 17beta-hydroxysteroid dehydrogenase activities. In other studies, it was shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of 'Selective Estrogen Enzyme Modulators' (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase and consequently on the levels of tissular levels of E(2), will provide a new possibility in the treatment of this disease.

The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.

PubMed

Schatz, Frederick; Guzeloglu-Kayisli, Ozlem; Arlier, Sefa; Kayisli, Umit A; Lockwood, Charles J

2016-06-01

Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the decidualized endometrium, modification of spiral arteries and post-partum processes. However, decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. Progestin-induced decidualization of estradiol-primed human endometrial stromal cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. Perivascular decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding

PubMed Central

Schatz, Frederick; Guzeloglu-Kayisli, Ozlem; Arlier, Sefa; Kayisli, Umit A.; Lockwood, Charles J.

2016-01-01

BACKGROUND Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the decidualized endometrium, modification of spiral arteries and post-partum processes. However, decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. METHODS We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. RESULTS Progestin-induced decidualization of estradiol-primed human endometrial stromal cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. CONCLUSION Perivascular decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms. PMID:26912000

Progestin-only contraceptives: effects on weight

PubMed Central

Lopez, Laureen M; Ramesh, Shanthi; Chen, Mario; Edelman, Alison; Otterness, Conrad; Trussell, James; Helmerhorst, Frans M

2016-01-01

Background Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. POCs include injectables, intrauterine contraception, implants, and oral contraceptives. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users. Objectives The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight. Search methods Until 4 August 2016, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP. For the initial review, we contacted investigators to identify other trials. Selection criteria We considered comparative studies that examined a POC versus another contraceptive method or no contraceptive. The primary outcome was mean change in body weight or mean change in body composition. We also considered the dichotomous outcome of loss or gain of a specified amount of weight. Data collection and analysis Two authors extracted the data. Non-randomized studies (NRS) need to control for confounding factors. We used adjusted measures for the primary effects in NRS or the results of matched analysis from paired samples. If the report did not provide adjusted measures for the primary analysis, we used unadjusted outcomes. For RCTs and NRS without adjusted measures, we computed the mean difference (MD) with 95% confidence interval (CI) for continuous variables. For dichotomous outcomes, we calculated the Mantel-Haenszel odds ratio (OR) with 95% CI. Main results We found 22 eligible studies that included a total of 11,450 women. With 6 NRS added to this update, the review includes 17 NRS and 5 RCTs. By contraceptive method, the review has 16 studies of depot medroxyprogesterone acetate (DMPA), 4 of levonorgestrel-releasing intrauterine contraception (LNG-IUC), 5 for implants, and 2 for progestin-only pills. Comparison groups did not differ significantly for weight change or other body composition measure in 15 studies. Five studies with moderate or low quality evidence showed differences between study arms. Two studies of a six-rod implant also indicated some differences, but the evidence was low quality. Three studies showed differences for DMPA users compared with women not using a hormonal method. In a retrospective study, weight gain (kg) was greater for DMPA versus copper (Cu) IUC in years one (MD 2.28, 95% CI 1.79 to 2.77), two (MD 2.71, 95% CI 2.12 to 3.30), and three (MD 3.17, 95% CI 2.51 to 3.83). A prospective study showed adolescents using DMPA had a greater increase in body fat (%) compared with a group not using a hormonal method (MD 11.00, 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD −4.00, 95% CI −6.93 to −1.07). A more recent retrospective study reported greater mean increases with use of DMPA versus Cu IUC for weight (kg) at years 1 (1.3 vs 0.2), 4 (3.5 vs 1.9), and 10 (6.6 vs 4.9). Two studies reported a greater mean increase in body fat mass (%) for POC users versus women not using a hormonal method. The method was LNG-IUC in two studies (reported means 2.5 versus −1.3; P = 0.029); (MD 1.60, 95% CI 0.45 to 2.75). One also studied a desogestrel-containing pill (MD 3.30, 95% CI 2.08 to 4.52). Both studies showed a greater decrease in lean body mass among POC users. Authors’ conclusions We considered the overall quality of evidence to be low; more than half of the studies had low quality evidence. The main reasons for downgrading were lack of randomizations (NRS) and high loss to follow-up or early discontinuation. These 22 studies showed limited evidence of change in weight or body composition with use of POCs. Mean weight gain at 6 or 12 months was less than 2 kg (4.4 lb) for most studies. Those with multiyear data showed mean weight change was approximately twice as much at two to four years than at one year, but generally the study groups did not differ significantly. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain. PMID:27567593

Progestin-only contraceptives: effects on weight

PubMed Central

Lopez, Laureen M; Edelman, Alison; Chen, Mario; Otterness, Conrad; Trussell, James; Helmerhorst, Frans M

2013-01-01

Background Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users. Objectives The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight. Search methods Through May 2013, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP. The 2010 search also included EMBASE. For the initial review, we contacted investigators to identify other trials. Selection criteria All comparative studies were eligible that examined a POC versus another contraceptive method or no contraceptive. The primary outcome was mean change in body weight or mean change in body composition. We also considered the dichotomous outcome of loss or gain of a specified amount of weight. Data collection and analysis Two authors extracted the data. We computed the mean difference (MD) with 95% confidence interval (CI) for continuous variables. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated. Main results We found 16 studies; one examined progestin-only pills, one studied the levonorgestrel-releasing intrauterine system (LNG-IUS), four examined an implant, and 10 focused on depot medroxyprogesterone acetate (DMPA). Outcomes examined were changes in body weight only (14 studies), changes in both body weight and body composition (1 study), and changes in body composition only (1 study). We did not conduct meta-analysis due to the various contraceptive methods and weight change measures. Comparison groups did not differ significantly for weight change in 12 studies. However, three studies showed weight change differences for POC users compared to women not using a hormonal method. In one study, weight gain (kg) was greater for the DMPA group than the group using a non-hormonal IUD in years one through three [(MD 2.28; 95% CI 1.79 to 2.77), (MD 2.71, 95% CI 2.12 to 3.30), and (MD 3.17; 95% CI 2.51 to 3.83), respectively]. The differences were notable within the normal weight and overweight subgroups. Two implant studies also showed differences in weight change. The implant group (six-capsule) had greater weight gain (kg) compared to the group using a non-hormonal IUD in both studies [(MD 0.47 (95% CI 0.29 to 0.65); (MD 1.10; 95% CI 0.36 to 1.84)]. In one of those studies, the implant group also had greater weight gain than a group using a barrier method or no contraceptive (MD 0.74; 95% CI 0.52 to 0.96). The two studies that assessed body composition change showed differences between POC users and women not using a hormonal method. Adolescents using DMPA had a greater increase in body fat (%) compared to a group not using a hormonal method (MD 11.00; 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD −4.00; 95% CI −6.93 to −1.07). The other study reported differences between an LNG-IUS group and a non-hormonal IUD group in percent change in body fat mass (2.5% versus −1.3%, respectively; reported P value = 0.029) and percent change in lean body mass (−1.4% versus 1.0%, respectively; reported P value = 0.027). Authors’ conclusions The overall quality of evidence was moderate to low, given that the studies were evenly divided across the evidence quality groups (high, moderate, low, or very low quality). We found limited evidence of weight gain when using POCs. Mean gain was less than 2 kg for most studies up to 12 months. Weight change for the POC group generally did not differ significantly from that of the comparison group using another contraceptive. Two studies that assessed body composition showed that POC users had greater increases in body fat and decreases in lean body mass compared to users of non-hormonal methods. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain. PMID:23821307

The use of testosterone as a male contraceptive.

PubMed

Amory, J K; Bremner, W J

1998-10-01

Testosterone functions as a contraceptive by suppressing secretion of the pituitary gonadotropins luteinizing hormone and follicle stimulating hormone. Low levels of these hormones decrease endogenous testosterone secretion from the testis and deprive developing sperm of the signals required for normal maturation. Interference with sperm maturation causes a decline in sperm production and can lead to reversible infertility in men, raising the possibility that testosterone could be utilized in a commercially available contraceptive. To this end, testosterone has been studied alone and in combination with either gonadotropin releasing hormone analogues or progestins in efforts to improve its contraceptive efficacy. In this chapter, we will review efforts to use testosterone to create a safe, convenient, efficacious contraceptive method for men.

Clarification of contraceptive drug pharmacokinetics in obesity☆

PubMed Central

Jusko, William J.

2017-01-01

Related to concerns about the role of obesity in the efficacy of contraceptive drugs, a review of the literature was carried out in regard to the pharmacokinetics of ethinyl estradiol and various progestins given by various routes of administration. Most studies show that obese women exhibit modestly lower plasma concentrations of these drugs (circa 30%) when given the same doses as normal-weight women. While the mechanism is uncertain, precedence in the literature suggests that this is due to body weight-related differences in metabolism rates. Confusing in some of the literature is that a few studies have reported erroneously calculated pharmacokinetic parameters after multiple dosing of oral contraceptives. A demonstration of appropriate pharmacokinetic methodology is provided. PMID:27542520

Emergency contraception in Albania: a multimethods qualitative study of awareness, knowledge, attitudes and practices.

PubMed

Doci, Florida; Thaci, Jonida; Foster, Angel M

2018-04-11

Contraceptive prevalence is relatively low in Albania, and abortion is the mainstay of family planning. Although levonorgestrel-only emergency contraceptive pills are available, uptake of this method is minimal. Emergency contraception (EC) could play a significant role in addressing women's need for an effective and discreet pregnancy prevention method. However, information about the dynamics surrounding EC is limited. In 2016-2017, we conducted a multimethods qualitative study that aimed to explore awareness, knowledge, attitudes and practices toward EC in Albania. This project comprised four components: a community-based survey with 115 respondents, six focus group discussions with women of reproductive age, 19 semistructured key informant interviews, and 16 structured interviews with retail pharmacists. We analyzed our data using descriptive statistics and for content and themes. Our findings suggest that EC is widely available in pharmacies in Albania. However, a quarter of our survey participants did not know whether EC was available, and more than a third did not think EC was safe to use. Women face numerous barriers to accessing this form of contraception. Misconceptions about hormonal contraceptives, in general, and about progestin-only EC in particular, lack of training among providers, and stigma and fear of judgment were common obstacles identified by participants. Misinformation and lack of knowledge about EC among women and providers in Albania appears common. Training health service providers, raising awareness among women, and developing linguistically and culturally resonant materials for distribution could be keys to improving access to and use of EC. Although the availability of progestin-only EC is widespread in Albania, our findings suggest that more work needs to be done to align national regulatory policies with international standards, facilitate evidence-based service delivery, and increase access to medically accurate information in Albanian. Copyright © 2018 Elsevier Inc. All rights reserved.

Progesterone Directly and Rapidly Inhibits GnRH Neuronal Activity via Progesterone Receptor Membrane Component 1

PubMed Central

Bashour, Nicholas Michael

2012-01-01

GnRH neurons are essential for reproduction, being an integral component of the hypothalamic-pituitary-gonadal axis. Progesterone (P4), a steroid hormone, modulates reproductive behavior and is associated with rapid changes in GnRH secretion. However, a direct action of P4 on GnRH neurons has not been previously described. Receptors in the progestin/adipoQ receptor family (PAQR), as well as progesterone receptor membrane component 1 (PgRMC1) and its partner serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1) mRNA binding protein 1 (SERBP1), have been shown to mediate rapid progestin actions in various tissues, including the brain. This study shows that PgRMC1 and SERBP1, but not PAQR, are expressed in prenatal GnRH neurons. Expression of PgRMC1 and SERBP1 was verified in adult mouse GnRH neurons. To investigate the effect of P4 on GnRH neuronal activity, calcium imaging was used on primary GnRH neurons maintained in explants. Application of P4 significantly decreased the activity of GnRH neurons, independent of secretion of gamma-aminobutyric acidergic and glutamatergic input, suggesting a direct action of P4 on GnRH neurons. Inhibition was not blocked by RU486, an antagonist of the classic nuclear P4 receptor. Inhibition was also maintained after uncoupling of the inhibitory regulative G protein (Gi/o), the signal transduction pathway used by PAQR. However, AG-205, a PgRMC1 ligand and inhibitor, blocked the rapid P4-mediated inhibition, and inhibition of protein kinase G, thought to be activated downstream of PgRMC1, also blocked the inhibitory activity of P4. These data show for the first time that P4 can act directly on GnRH neurons through PgRMC1 to inhibit neuronal activity. PMID:22822163

Age and the metabolic syndrome affect salivary cortisol rhythm: data from a community sample.

PubMed

Ceccato, Filippo; Barbot, Mattia; Zilio, Marialuisa; Ferasin, Sergio; De Lazzari, Paola; Lizzul, Laura; Boscaro, Marco; Scaroni, Carla

2015-01-01

Measurement of cortisol levels in saliva is a marker of free hormone. How salivary cortisol rhythm is affected by age, gender, the metabolic syndrome and estrogen-progestin therapy was evaluated in a community sample of adults. One hundred twenty volunteers recruited from the Hospital staff and family members of the Endocrinology Unit were instructed to collect 7 salivary samples: the first on awakening (F(0)) and 6 more (F(1.5), F(5), F(6), F(10), F(11.5) and F(14)) over the next 14 hours. Each volunteer also underwent a complete physical evaluation and a comprehensive medical history was taken. Salivary cortisol was measured using a radioimmunometric assay. Daily cortisol secretion was evaluated computing the Area Under the Curve (AUC(F0)(→)(F14)); the F(14)/F(0) ratio was calculated as a marker of cortisol rhythm. Median F(14) levels were higher in the subjects in the third tertile of age than in those falling in the second or in the first age tertile (respectively, 2.09 vs 1.33 vs 1.25 ng/mL, p=0.023 and p=0.006), in the hypertensive volunteers (2.44 vs 1.44 ng/mL, p=0.030) and in those with the metabolic syndrome (2.95 vs 1.4 ng/mL, p=0.002), with an elevated median F(14)/F(0) ratio (0.48 vs 0.19, p=0.006). According to the Kruskal-Wallis analysis of variance, the most important factor affecting F(14) value was age (p=0.001). AUC(F0)(→)(F14) was not influenced by gender, age, metabolic syndrome or estrogen-progestin therapy. While it did not affect the daily cortisol rate, late-night salivary cortisol levels were found to be increased in the subjects in the higher age tertile and in those with the metabolic syndrome.

Positive association between mammographic breast density and bone mineral density in the Postmenopausal Estrogen/Progestin Interventions Study

PubMed Central

Crandall, Carolyn; Palla, Shana; Reboussin, Beth A; Ursin, Giske; Greendale, Gail A

2005-01-01

Introduction Mammographic breast density is a strong independent risk factor for breast cancer. We hypothesized that demonstration of an association between mammographic breast density and bone mineral density (BMD) would suggest a unifying underlying mechanism influencing both breast density and BMD. Methods In a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions Study (PEPI), participants were aged 45 to 64 years and were at least 1 year postmenopausal. Mammographic breast density (percentage of the breast composed of dense tissue), the outcome, was assessed with a computer-assisted percentage-density method. BMD, the primary predictor, was measured with dual-energy X-ray absorptiometry. Women quitting menopausal hormone therapy to join PEPI were designated recent hormone users. Results The mean age of the 594 women was 56 years. The average time since menopause was 5.6 years. After adjustment for age, body mass index, and cigarette smoking, in women who were not recent hormone users before trial enrollment (n = 415), mammographic density was positively associated with total hip (P = 0.04) and lumbar (P = 0.08) BMD. Mammographic density of recent hormone users (n = 171) was not significantly related to either total hip (P = 0.51) or lumbar (P = 0.44) BMD. In participants who were not recent hormone users, mammographic density was 4% greater in the highest quartile of total hip BMD than in the lowest. In participants who were not recent hormone users, mammographic density was 5% greater in the highest quartile of lumbar spine BMD than in the lowest. Conclusion Mammographic density and BMD are positively associated in women who have not recently used postmenopausal hormones. A unifying biological mechanism may link mammographic density and BMD. Recent exogenous postmenopausal hormone use may obscure the association between mammographic density and BMD by having a persistent effect on breast tissue. PMID:16280044

Pharmacologic Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.

PubMed

Fink, Howard A; Jutkowitz, Eric; McCarten, J Riley; Hemmy, Laura S; Butler, Mary; Davila, Heather; Ratner, Edward; Calvert, Collin; Barclay, Terry R; Brasure, Michelle; Nelson, Victoria A; Kane, Robert L

2018-01-02

Optimal treatment to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia is uncertain. To summarize current evidence on the efficacy and harms of pharmacologic interventions to prevent or delay cognitive decline, MCI, or dementia in adults with normal cognition or MCI. Several electronic databases from January 2009 to July 2017, bibliographies, and expert recommendations. English-language trials of at least 6 months' duration enrolling adults without dementia and comparing pharmacologic interventions with placebo, usual care, or active control on cognitive outcomes. Two reviewers independently rated risk of bias and strength of evidence; 1 extracted data, and a second checked accuracy. Fifty-one unique trials were rated as having low to moderate risk of bias (including 3 that studied dementia medications, 16 antihypertensives, 4 diabetes medications, 2 nonsteroidal anti-inflammatory drugs [NSAIDs] or aspirin, 17 hormones, and 7 lipid-lowering agents). In persons with normal cognition, estrogen and estrogen-progestin increased risk for dementia or a combined outcome of MCI or dementia (1 trial, low strength of evidence); high-dose raloxifene decreased risk for MCI but not for dementia (1 trial, low strength of evidence); and antihypertensives (4 trials), NSAIDs (1 trial), and statins (1 trial) did not alter dementia risk (low to insufficient strength of evidence). In persons with MCI, cholinesterase inhibitors did not reduce dementia risk (1 trial, low strength of evidence). In persons with normal cognition and those with MCI, these pharmacologic treatments neither improved nor slowed decline in cognitive test performance (low to insufficient strength of evidence). Adverse events were inconsistently reported but were increased for estrogen (stroke), estrogen-progestin (stroke, coronary heart disease, invasive breast cancer, and pulmonary embolism), and raloxifene (venous thromboembolism). High attrition, short follow-up, inconsistent cognitive outcomes, and possible selective reporting and publication. Evidence does not support use of the studied pharmacologic treatments for cognitive protection in persons with normal cognition or MCI. Agency for Healthcare Research and Quality.

Economic Return From the Women’s Health Initiative Estrogen Plus Progestin Clinical Trial

PubMed Central

Roth, Joshua A.; Etzioni, Ruth; Waters, Teresa M.; Pettinger, Mary; Rossouw, Jacques E.; Anderson, Garnet L.; Chlebowski, Rowan T.; Manson, JoAnn E.; Hlatky, Mark; Johnson, Karen C.; Ramsey, Scott D.

2014-01-01

Background The findings of the Women’s Health Initiative (WHI) estrogen plus progestin (E+P) trial led to a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States. The economic effect of this shift has not been evaluated relative to the trial’s $260 million cost (2012 U.S. dollars). Objective To estimate the economic return from the WHI E+P trial. Design Decision model to simulate health outcomes for a “WHI scenario” with observed cHT use and a “no-WHI scenario” with cHT use extrapolated from the pretrial period. Data Sources Primary analyses of WHI outcomes, peer-reviewed literature, and government sources. Target Population Postmenopausal women in the United States, aged 50 to 79 years, who did not have a hysterectomy. Time Horizon 2003 to 2012. Perspective Payer. Intervention Combined hormone therapy. Outcome Measures Disease incidence, expenditure, quality-adjusted life-years, and net economic return. Results of Base-Case Analysis The WHI scenario resulted in 4.3 million fewer cHT users, 126 000 fewer breast cancer cases, 76 000 fewer cardiovascular disease cases, 263 000 more fractures, 145 000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100 000 per quality-adjusted life-year. Results of Sensitivity Analysis The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion. Limitation No evaluation of indirect costs or outcomes beyond 2012. Conclusion The WHI E+P trial made high-value use of public funds with a substantial return on investment. These results can contribute to discussions about the role of public funding for large, prospective trials with high potential for public health effects. Primary Funding Source National Heart, Lung, and Blood Institute. PMID:24798522

Hormonal Contraception and Risk of Psychiatric and Other Noncommunicable Diseases in HIV-Infected Women

PubMed Central

Jenkins, Cathy A.; Shepherd, Bryan E.; Bebawy, Sally S.; Turner, Megan; Sterling, Timothy R.; Melekhin, Vlada V.

2015-01-01

Abstract Background: Hormonal contraception use is common among human immunodeficiency virus (HIV)-infected women. Risk of psychiatric and other noninfectious complications of hormonal contraception use has not been described in this population. Methods: We performed a retrospective cohort study of HIV-infected women receiving care in Tennessee from 1998 to 2008 to examine the risks of incident psychiatric and other noncommunicable diseases (NCDs), including cardiovascular, hepatic, renal, and malignant diseases, and hormonal contraception use, including depot medroxyprogesterone acetate (DMPA) and combined estrogen- and progestin-containing hormonal contraceptives. We used marginal structural models with inverse probability weights to account for time-varying confounders associated with hormonal contraception use. Results: Of the 392 women included, 94 (24%) used hormonal contraception during the study period. Baseline psychiatric disease was similar between women who received and did not receive hormonal contraception. There were 69 incident psychiatric diagnoses and 72 NCDs. Only time-varying DMPA use was associated with increased risk of psychiatric disease (adjusted odds ratio [aOR] 3.70; 95% confidence interval [95% CI] 1.32–10.4) and mood disorders, specifically (aOR 4.70 [1.87–11.8]). Time-varying and cumulative combined hormonal contraception use were not statistically associated with other NCDs (aOR 1.64, 95% CI 0.64–4.12 and aOR 1.16, 95% CI 0.86–1.56, respectively). However, risk of incident NCDs was increased with cumulative DMPA exposure (per year exposure aOR 1.45, 95% CI 1.01–2.08). Conclusions: Among HIV-infected women, DMPA was associated with risk of incident psychiatric diseases, particularly mood disorders, during periods of use. Cumulative DMPA exposure was also associated with risk of other NCDs. However, combined estrogen and progestin-containing hormonal contraception use was not statistically associated with risk of any NCDs. PMID:25751720

Insights into the epidemiology of postmenopausal osteoporosis: the Women's Health Initiative.

PubMed

Jackson, Rebecca D; Mysiw, W Jerry

2014-11-01

Osteoporosis and its associated increased risk for fragility fracture is one of the most disabling consequences of aging in women. To successfully reduce the public health burden of this pervasive disease, it is necessary to develop strategies that permit the earlier identification of women at risk for fracture and ensure that preventive interventions to reduce the risk for fracture are both safe and effective. The Women's Health Initiative offers the unprecedented opportunity to systematically address both of these issues. Eleven clinically available risk factors (age, race/ethnicity, self-reported health, weight, height, physical activity, parental hip fracture, fracture history after age 54, current smoking, corticosteroid use, and history of treated diabetes), have been identified to predict 5-year hip fracture risk in white women. Two of these factors (age and fracture history) also predict risk for total fractures in women irrespective of race-ethnicity. Biomarkers including low vitamin D or bioavailable testosterone and/or high cystatin C, pro-inflammatory cytokines, osteoprotegerin and sex hormone-binding globulin also predict risk for hip fracture independent of clinical risk factors. Two cornerstones of therapy for postmenopausal osteoporosis-postmenopausal hormone therapy and calcium plus vitamin D supplementation- were rigorously studied. Estrogen with or without a progestin was effective at preventing bone loss and reducing risk for hip, clinical vertebral and total fractures but the balance of risks and benefits failed to show an overall benefit of taking estrogen-alone or estrogen plus progestin as a preventive strategy for skeletal health. Calcium plus vitamin D supplementation also demonstrated a small but significant favorable effect on hip bone density but in contrast, the modest effect did not translate into a significant reduction in the risk of fractures in intent-to-treat analyses. Data such as these have helped to lay a foundation for the more effective management of postmenopausal osteoporosis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

[To bleed or not--a new dogma or a real choice in contraception?].

PubMed

Renteria, Saira-Christine

2008-10-22

Let's talk about it Suppression of menstruation, by extending the duration of contraceptives containing estro-progestins (oral contraception, patch or vaginal ring) to long cycles, is a new approach in the field of contraception. These extended cycles aim at obtaining prolonged amenorrhea, interrupted periodically by a free interval of 7 days without hormone intake and thus causing breakthrough bleeding. Pathologies, which are supposed to get some benefit from the suppression of menstruation and of hormone level variations related to ovarian activity, are widely recognized as an indication. Some interest is also coming up for so called life style indications. Treatment issues, advantages and disadvantages are examined in the light of women's expectations and right to access to informed consent and independent choice.

Exogenous and endogenous hormones and breast cancer

PubMed Central

ChenMD, Wendy Y.

2008-01-01

Exposure to higher levels of both exogenous and endogenous hormone is associated with breast cancer risk. Because of the association between breast cancer and HRT, only the minimal duration of HRT use is recommended for symptom control, and it is not recommended for chronic disease management. Current research issues include the role of progestins, other types of HRT, duration of unopposed estrogen use, and characteristics of cancers that develop on HRT. Circulating sex steroid levels are associated with breast cancer risk, but multiple issues need to be addressed before they are used routinely in clinical practice. Current research issues include measurement of levels for routine clinical practice, integration with standard breast cancer risk models and genetic polymorphism data, and applicability to estrogen-receptor-negative cancers. PMID:18971119

Of conflicts, conspiracies, red herrings, and black swans.

PubMed

Wactawski-Wende, J; Anderson, G L

2015-06-01

The impact of the findings from the Women's Health Initiative trial of estrogen plus progestin cannot be attributed to any real or imagined conflicts of interest between government, researchers, and journals. Rather, the findings overturned decades of dogma in part promoted by the pharmaceutical industry, and the reaction to these unexpected findings was in direct proportion to their importance in reversing a misguided practice of prescribing the drug for chronic disease prevention. The findings have been widely accepted, as shown by the sustained subsequent reduction in prescriptions. However, conflicts of interest may influence a minority unwilling to accept the findings. The decrease in the use of a drug with an adverse risk profile for prevention of chronic disease is a public good.

Immunology of term and preterm labor

PubMed Central

Peltier, Morgan R

2003-01-01

During pregnancy there is an alteration in maternal immunity within the uterus where innate, proinflammatory immune responses are tightly regulated to prevent immunological rejection of the fetal allograft. Disruption of the delicate balance of cytokines by bacteria or other factors increases the production of proinflammatory cytokines at the maternal-fetal interface and activates the parturition mechanism prematurely. Despite years of searching, there is still no broadly effective strategy for preventing preterm labor and most therapies are directed at inhibiting myometrial contractions and improving neonatal outcome. Recent studies with progestins and interleukin-10 (IL-10), however, are showing promise in randomized clinical trials and animal studies. Furthermore, the identification of the Toll-like receptors as upstream mediators of inflammation may offer alternative therapeutic targets for preventing this common pregnancy complication. PMID:14651749

Dysmenorrhea and related disorders

PubMed Central

Bernardi, Mariagiulia; Lazzeri, Lucia; Perelli, Federica; Reis, Fernando M.; Petraglia, Felice

2017-01-01

Dysmenorrhea is a common symptom secondary to various gynecological disorders, but it is also represented in most women as a primary form of disease. Pain associated with dysmenorrhea is caused by hypersecretion of prostaglandins and an increased uterine contractility. The primary dysmenorrhea is quite frequent in young women and remains with a good prognosis, even though it is associated with low quality of life. The secondary forms of dysmenorrhea are associated with endometriosis and adenomyosis and may represent the key symptom. The diagnosis is suspected on the basis of the clinical history and the physical examination and can be confirmed by ultrasound, which is very useful to exclude some secondary causes of dysmenorrhea, such as endometriosis and adenomyosis. The treatment options include non-steroidal anti-inflammatory drugs alone or combined with oral contraceptives or progestins. PMID:28944048

Human Endometrial Adenocarcinoma Transplanted into Nude Mice: Growth Regulation by Estradiol

NASA Astrophysics Data System (ADS)

Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R.

1983-01-01

A model for studying the growth of primary tumors of human endometrium and its regulation by 17β -estradiol has been developed in which ovariectomized nude mice are used as recipients. The receptors for sex steroids are maintained during serial transplantation of the tumor in this system. Although the rate of growth of receptor-negative endometrial tumors transplanted into ovariectomized nude mice is unaffected by the sustained presence or absence of estradiol, the growth of receptor-positive tumors is significantly increased by estradiol. Receptor-positive tumors treated with estradiol produced elevated concentrations of progesterone receptor. That the progesterone receptor is functional in this tumor is evident from the induction of estradiol 17β -dehydrogenase activity upon progestin administration. These findings are consistent with receptor-mediated regulation of growth of endometrial carcinoma.

Endometrial adenocarcinoma in a 13-year-old girl.

PubMed

Kim, Sung Mee; Shin, So Jin; Bae, Jin Gon; Kwon, Kun Young; Rhee, Jeong Ho

2016-03-01

Endometrial cancer is the third most common gynecologic cancer in the Korea and occurs mainly in menopausal women. Although it can develop in young premenopausal women cancer as well, an attack in the adolescent girl is very rare. A 13-year-old girl visited gynecology department with the complaint of abnormal uterine bleeding. An endometrial biopsy revealed FIGO (International Federation of Gynecology and Obstetrics) grade II endometrial adenocarcinoma. In the treatment of endometrial cancer, conservative management should be considered if the patient is nulliparous or wants the fertility preservation. Therefore, we decided to perform a hormonal therapy and a follow-up endometrial biopsy after progestin administration for eight months revealed no residual tumor. We report a case of endometrial cancer occurred in a 13-year-old girl with a brief review of the literature.

Vascular Effects of Estrogenic Menopausal Hormone Therapy

PubMed Central

Reslan, Ossama M.; Khalil, Raouf A.

2011-01-01

Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the ‘timing hypothesis’, which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of an appropriate MHT dose, route of administration, and estrogen/progestin combination could maximize the vascular benefits of MHT and minimize other adverse effects, especially if given within a reasonably short time after menopause to women that seek MHT for the relief of menopausal symptoms. PMID:21864249

Clinical practice guidelines on menorrhagia: management of abnormal uterine bleeding before menopause.

PubMed

Marret, H; Fauconnier, A; Chabbert-Buffet, N; Cravello, L; Golfier, F; Gondry, J; Agostini, A; Bazot, M; Brailly-Tabard, S; Brun, J-L; De Raucourt, E; Gervaise, A; Gompel, A; Graesslin, O; Huchon, C; Lucot, J-P; Plu-Bureau, G; Roman, H; Fernandez, H

2010-10-01

Normal menstrual periods last 3-6 days and involve blood loss of up to 80ml. Menorrhagia is defined as menstrual periods lasting more than 7 days and/or involving blood loss greater than 80ml. The prevalence of abnormal uterine bleeding (AUB) is estimated at 11-13% in the general population and increases with age, reaching 24% in those aged 36-40 years. A blood count for red cells+platelets to test for anemia is recommended on a first-line basis for women consulting for AUB whose history and/or bleeding score justify it. A pregnancy test by an hCG assay should be ordered. A speculum examination and Pap smear, according to the French High Health Authority guidelines should be performed early on to rule out any cervical disease. Pelvic ultrasound, both abdominal (suprapubic) and transvaginal, is recommended as a first-line procedure for the etiological diagnosis of AUB. Hysteroscopy or hysterosonography can be suggested as a second-line procedure. MRI is not recommended as a first-line procedure. In idiopathic AUB, the first-line treatment is medical, with efficacy ranked as follows: levonorgestrel IUD, tranexamic acid, oral contraceptives, either estrogens and progestins or synthetic progestins only, 21 days a month, or NSAIDs. When hormone treatment is contraindicated or immediate pregnancy is desired, tranexamic acid is indicated. Iron must be included for patients with iron-deficiency anemia. For women who do not wish to become pregnant in the future and who have idiopathic AUB, the long-term efficacy of conservative surgical treatment is greater than that of oral medical treatment. Placement of a levonorgestrel IUD (or administration of tranexamic acid by default) is recommended for women with idiopathic AUB. If this fails, a conservative surgical technique must be proposed; the choices include second-generation endometrial ablation techniques (thermal balloon, microwave, radiofrequency), or, if necessary, first-generation techniques (endometrectomy, roller-ball). A first-line hysterectomy is not recommended in this context. Should a hysterectomy be selected for functional bleeding, it should be performed by the vaginal or laparoscopic routes. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Control of the estrous cycle to improve fertility for fixed-time artificial insemination in beef cattle: a review.

PubMed

Lamb, G C; Dahlen, C R; Larson, J E; Marquezini, G; Stevenson, J S

2010-04-01

Early estrus-synchronization protocols focused on regressing the corpus luteum (CL) with an injection of PGF(2alpha) followed by detection of estrus or involved the use of exogenous progestins that prevent estrus from occurring. Later, protocols combining the use of PGF(2alpha) and exogenous progestins were developed. Gonadotropin-releasing hormone was utilized to control follicular waves, synchronize ovulation, or to luteinize large dominant follicles. Our research aimed to develop reliable protocols that 1) relied solely on fixed-timed AI (TAI); 2) required a maximum of 3 animal handlings, and 3) were successful in estrous-cycling and noncycling females. In cows, insertion of an intravaginal progesterone insert during the 7-d interval between the initial GnRH and PGF(2alpha) injections enhanced pregnancy rates by 9 to 10%. In a multi-location study, a TAI protocol yielded pregnancy rates similar to a protocol involving detection of estrus plus a fixed-time clean-up AI for females not detected in estrus (54 vs. 58%, respectively, for cows and 53 vs. 57%, respectively, for heifers). Initiation of estrous cycles in noncycling cows is likely the primary manner in which beef producers may improve fertility in response to estrus synchronization and TAI protocols. Treatment of noncycling females with progesterone and GnRH increases the percentage of cycling females and improves fertility to a TAI, but inducing cyclicity with hCG failed to enhance fertility in TAI protocols. Supplementing progesterone after TAI failed to increase pregnancy rates in beef cattle. In contrast, administration of hCG 7 d after TAI induced an accessory CL, increased progesterone, and tended to enhance pregnancy rates. Development of TAI protocols that reduce the hassle factors associated with ovulation synchronization and AI provide cattle producers efficient and effective tools for capturing selective genetic traits of economic consequences. Location variables, however, which may include differences in pasture and diet, breed composition, body condition, postpartum interval, climate, and geographic location, affect the success of TAI protocols.

Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 2.

PubMed

Deleruyelle, Laura J

2016-01-01

The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, large-scale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women's menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t-test, two-sample t-test, and f-tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh's Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. Included in part 1 of this series of articles was the introduction to the study conducted and the results of the literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy. Part 2 provides a brief discussion on the significance of this study to nursing and provides the methods used in this study. The results of this study will be summarized in forthcoming articles in this series. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 3.

PubMed

Deleruyelle, Laura J

2017-01-01

The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, large-scale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women's menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t-test, two-sample t-test, and f-tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh's Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. Included in part 1 of this series of articles was the introduction to the study conducted and the results of the literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy. Part 2 provided a brief discussion on the significance of this study to nursing and provided the methods used in this study. The results and conclusion of this study are provided within this article. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Thromboembolic adverse event study of combined estrogen-progestin preparations using Japanese Adverse Drug Event Report database

PubMed Central

Hasegawa, Shiori; Matsui, Toshinobu; Hane, Yuuki; Abe, Junko; Hatahira, Haruna; Motooka, Yumi; Sasaoka, Sayaka; Fukuda, Akiho; Naganuma, Misa; Hirade, Kouseki; Takahashi, Yukiko; Kinosada, Yasutomi

2017-01-01

Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3–71.4), 29.1 (23.5–35.9), 42.9 (32.3–57.0), 44.7 (32.7–61.1), and 38.6 (26.3–56.7), respectively. The medians (25%–75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3–314.0), 128.0 (27.0–279.0), 204.0 (44.0–660.0), 142.0 (41.3–344.0), and 16.5 (8.8–32.0) days, respectively. The 95% CIs of the WSP-β for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning. PMID:28732067

Reducing low-value care in endometriosis between limited evidence and unresolved issues: a proposal.

PubMed

Vercellini, Paolo; Giudice, Linda C; Evers, Johannes L H; Abrao, Mauricio S

2015-09-01

Quantification of benefits and harms of medical interventions should be based on high-quality evidence, which is not always the case in the endometriosis field. In many clinical circumstances, healthcare decisions in women with endometriosis are taken based on suboptimal evidence or on evidence of coexistence of benefits and harms that must be balanced. In these conditions, it is important to avoid or reduce the use of low-value care, i.e. interventions with defined harms and uncertain benefits, or whose effectiveness is comparable with less expensive alternatives. In particular, we suggest that: (i) non-surgical diagnosis based on symptoms, physical findings and transvaginal ultrasonography is possible in most women with symptomatic endometriosis. Thus, except in doubtful cases, laparoscopy should be intended for surgical treatment, not for diagnostic purposes: early diagnosis and diagnostic laparoscopy are not synonymous; (ii) future trials on new drugs for endometriosis should address those outcomes that are most important to patients, should be designed as superiority trials and should include a progestin or an estrogen-progestin as a comparator. Moreover, limitation of repetitive surgery for recurrent endometriosis is among the objectives of long-term medical treatment; (iii) indications for surgery should be the result of a balance between demonstrated benefits in terms of fertility enhancement and pain relief, specific risks associated with excision of different types of endometriotic lesions, cost-effectiveness and patient preference after detailed information; (iv) physicians, health professionals and policy makers should discriminate between screening for and diagnosis of endometriosis. Limited peritoneal foci, which are frequently observed also in asymptomatic women, regress or remain stable in about two thirds of cases. Therefore, the theoretical premises for a screening campaign are currently unclear; (v) physicians should develop the ability to effectively communicate quantitative information based on international guidelines and systematic literature reviews. This will assist a woman's understanding of the interaction between the evidence and her priorities, facilitating the transition towards value-based medicine. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The use of altrenogest to avoid hyperestrogenism after eCG-hCG ovulation induction in southern tigrina (Leopardus guttulus).

PubMed

Micheletti, Tatiane; Brown, Janine L; Walker, Susan L; Cubas, Zalmir S; Furtado, Priscila V; Putman, Sarah B; de Moraes, Wanderlei; de Oliveira, Marcos J; de Oliveira, Claudio A; Moreira, Nei

2015-09-01

The goal of this study was to optimize an ovulation induction protocol for use with artificial insemination in the southern tigrina (Leopardus guttulus). The specific aims were to report the efficacy of using altrenogest, an oral progestin (Regumate, MSD Animal Health, Merck Animal Health), to suppress ovarian activity and prevent follicular hyperstimulation and hyperestrogenism after the administration of exogenous eCG and hCG. To monitor ovarian responses, fecal estrogen and progestogen metabolites were quantified by enzyme immunoassay in females before and after intramuscular administration of 200-IU eCG and 150-IU hCG in two trials, 4 months apart. During the first trial, there was no use of altrenogest, only the eCG-hCG ovulation induction protocol. In the second trial, the ovulation induction protocol was preceded by the administration of oral altrenogest for 14 days (minimum of 0.192 mg per kg per day). Altrenogest administration resulted in a suppression of follicular activity in three out of six females before eCG-hCG administration on the basis of lower mean estrogen concentrations (P < 0.05). It also resulted in four out of six females presenting lower fecal estrogen metabolite concentrations (P < 0.05) after ovulation induction, and two out of six individuals showed a reduction (P < 0.05) in postovulatory fecal progestogen metabolite concentrations, all when compared to the same female's cycles without the progestin. Fecal estrogen metabolite concentrations were closer to baseline in 50% of these individuals after altrenogest and eCG-hCG treatments when compared to basal concentrations before gonadotropins without the use of altrenogest. This study reported that use of altrenogest in southern tigrina can suppress ovarian activity and avoid hyperestrogenism after administration of eCG and hCG treatment. However, not all females responded uniformly, so more studies are needed to increase the efficacy of ovulation induction for use with artificial insemination in this species. Copyright © 2015 Elsevier Inc. All rights reserved.

Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement.

PubMed

Grossman, David C; Curry, Susan J; Owens, Douglas K; Barry, Michael J; Davidson, Karina W; Doubeni, Chyke A; Epling, John W; Kemper, Alex R; Krist, Alex H; Kurth, Ann E; Landefeld, C Seth; Mangione, Carol M; Phipps, Maureen G; Silverstein, Michael; Simon, Melissa A; Tseng, Chien-Wen

2017-12-12

Menopause occurs at a median age of 51.3 years, and the average US woman who reaches menopause is expected to live another 30 years. The prevalence and incidence of most chronic conditions, such as coronary heart disease, dementia, stroke, fractures, and breast cancer, increase with age; however, the excess risk for these conditions that can be attributed to menopause alone is uncertain. Since the publication of findings from the Women's Health Initiative that hormone therapy use is associated with serious adverse health effects in postmenopausal women, use of menopausal hormone therapy has declined. To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on the use of menopausal hormone therapy for the primary prevention of chronic conditions. The USPSTF reviewed the evidence on the benefits and harms of systemic (ie, oral or transdermal) hormone therapy for the prevention of chronic conditions in postmenopausal women and whether outcomes vary among women in different subgroups or by timing of intervention after menopause. The review did not address hormone therapy for preventing or treating menopausal symptoms. Although the use of hormone therapy to prevent chronic conditions in postmenopausal women is associated with some benefits, there are also well-documented harms. The USPSTF determined that the magnitude of both the benefits and the harms of hormone therapy in postmenopausal women is small to moderate. Therefore, the USPSTF concluded with moderate certainty that combined estrogen and progestin has no net benefit for the primary prevention of chronic conditions for most postmenopausal women with an intact uterus and that estrogen alone has no net benefit for the primary prevention of chronic conditions for most postmenopausal women who have had a hysterectomy. The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal women. (D recommendation) The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal women who have had a hysterectomy. (D recommendation).

Role of G-protein-coupled estrogen receptor (GPER/GPR30) in maintenance of meiotic arrest in fish oocytes.

PubMed

Thomas, Peter

2017-03-01

An essential role for GPER (formerly known as GPR30) in regulating mammalian reproduction has not been identified to date, although it has shown to be involved in the regulation a broad range of other estrogen-dependent functions. In contrast, an important reproductive role for GPER in the maintenance of oocyte meiotic arrest has been identified in teleost fishes, which is briefly reviewed here. Recent studies have clearly shown that ovarian follicle production of estradiol-17β (E 2 ) maintains meiotic arrest in several teleost species through activation of GPER coupled to a stimulatory G protein (G s ) on oocyte plasma membranes resulting in stimulation of cAMP production and maintenance of elevated cAMP levels. Studies with denuded zebrafish oocytes and with microinjection of GPER antisense oligonucleotides into oocytes have demonstrated the requirement for both ovarian follicle production of estrogens and expression of GPER on the oocyte surface for maintenance of meiotic arrest. This inhibitory action of E 2 on the resumption of meiosis is mimicked by the GPER-selective agonist G-1, by the GPER agonists and nuclear ER antagonists, ICI 182,780 and tamoxifen, and also by the xenoestrogen bisphenol-A (BPA) and related alkylphenols. GPER also maintains meiotic arrest of zebrafish oocytes through estrogen- and BPA-dependent GPER activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling. Interestingly, progesterone receptor component 1 (PGRMC1) is also involved in estrogen maintenance of meiotic arrest through regulation of EGFR expression on the oocyte plasma membrane. The preovulatory surge in LH secretion induces the ovarian synthesis of progestin hormones that activate a membrane progestin receptor alpha (mPRα)/inhibitory G protein (Gi) pathway. It also increases ovarian synthesis of the catecholestrogen, 2-hydroxy-estradiol-17β (2-OHE 2 ) which inhibits the GPER/Gs/adenylyl cyclase pathway. Both of these LH actions cause declines in oocyte cAMP levels resulting in the resumption of meiosis. GPER is also present on murine oocytes but there are no reports of studies investigating its possible involvement in maintaining meiotic arrest in mammals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reprint of "Role of G protein-coupled estrogen receptor (GPER/GPR30) in maintenance of meiotic arrest in fish oocytes".

PubMed

Thomas, Peter

2018-02-01

An essential role for GPER (formerly known as GPR30) in regulating mammalian reproduction has not been identified to date, although it has shown to be involved in the regulation a broad range of other estrogen-dependent functions. In contrast, an important reproductive role for GPER in the maintenance of oocyte meiotic arrest has been identified in teleost fishes, which is briefly reviewed here. Recent studies have clearly shown that ovarian follicle production of estradiol-17β (E 2 ) maintains meiotic arrest in several teleost species through activation of GPER coupled to a stimulatory G protein (G s ) on oocyte plasma membranes, resulting in stimulation of cAMP production and maintenance of elevated cAMP levels. Studies with denuded zebrafish oocytes and with microinjection of GPER antisense oligonucleotides into oocytes have demonstrated the requirement for both ovarian follicle production of estrogens and expression of GPER on the oocyte surface for maintenance of meiotic arrest. This inhibitory action of E 2 on the resumption of meiosis is mimicked by the GPER-selective agonist G-1, by the GPER agonists and nuclear ER antagonists, ICI 182,780 and tamoxifen, and also by the xenoestrogen bisphenol-A (BPA) and related alkylphenols. GPER also maintains meiotic arrest of zebrafish oocytes through estrogen- and BPA-dependent GPER activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling. Interestingly, progesterone receptor component 1 (PGRMC1) is also involved in estrogen maintenance of meiotic arrest through regulation of EGFR expression on the oocyte plasma membrane. The preovulatory surge in LH secretion induces the ovarian synthesis of progestin hormones that activate a membrane progestin receptor alpha (mPRα)/inhibitory G protein (Gi) pathway. It also increases ovarian synthesis of the catecholestrogen, 2-hydroxy-estradiol-17β (2-OHE 2 ) which inhibits the GPER/Gs/adenylyl cyclase pathway. Both of these LH actions cause declines in oocyte cAMP levels resulting in the resumption of meiosis. GPER is also present on murine oocytes but there are no reports of studies investigating its possible involvement in maintaining meiotic arrest in mammals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain.

PubMed

Ezzati, Mohammad; Carr, Bruce R

2015-01-01

Suppression of estrogen production and reduction of menstrual blood flow are the mainstays of medical treatment of endometriosis-related pain and have been traditionally achieved by methods such as combined hormonal contraception, progestins and GnRH analogs, all with comparable efficacies, though different side-effect profiles. Elagolix is the frontrunner among an emerging class of GnRH antagonists, which unlike their peptide predecessors has a nonpeptide structure resulting in its oral bioavailability. Phase I and II clinical trials have demonstrated safety of elagolix and its efficacy in partial and reversible suppression of ovarian estrogen production resulting in improvements in endometriosis-related pain. Phase III clinical trials are currently underway and elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

Evaluation and Management of Adolescents with Abnormal Uterine Bleeding.

PubMed

Mullins, Tanya L Kowalczyk; Miller, Rachel J; Mullins, Eric S

2015-09-01

The International Federation of Gynecology and Obstetrics and the American Congress of Obstetricians and Gynecologists support the use of new terminology for abnormal uterine bleeding (AUB) to consistently categorize AUB by etiology. The term AUB can be further classified as AUB/heavy menstrual bleeding (HMB) (replacing the term "menorrhagia") or AUB/intermenstrual bleeding (replacing the term "metrorrhagia"). Although many cases of AUB in adolescent women are attributable to immaturity of the hypothalamic-pituitary-ovarian axis, underlying bleeding disorders should be considered in women with AUB/HMB. This article reviews the new terminology for AUB, discusses important relevant features of history and examination, presents the laboratory evaluation of HMB, and describes hormonal (oral contraceptive pills, progestin-only methods, long-acting reversible contraceptives including intrauterine systems), hematologic (tranexamic acid and desmopressin), and surgical management options for AUB/HMB. Copyright 2015, SLACK Incorporated.

Psychosexual development: an examination of the role of prenatal hormones.

PubMed

Ehrhardt, A A; Meyer-Bahlburg, H F

Naturally occurring endocrine syndromes and the offspring from steroid-treated pregnancies are the major sources of evidence for a role of prenatal hormones in psychosexual development in man. Effects of prenatal androgens have been established for the sex-dimorphic behaviour clusters of energy expenditure (increased), parenting rehearsal (decreased), peer associations (shifted to male), and grooming-related behaviour (decreased); most of the information was obtained on the syndrome of congenital adrenal hyperplasia and in progestin-induced female hermaphroditism. Studies of children and adults exposed prenatally to exogenous oestrogens and/or progestagens suggest slight demasculinizing effects but cannot yet be considered conclusive. Gender identity is largely dependent on the sex of rearing; a direct role of prenatal hormones in its formation has not been shown. The evidence for the role of prenatal hormones in the development of sexual orientation is inconclusive.

Prevention and treatment of postmenopausal osteoporosis

PubMed Central

Gallagher, J Christopher; Tella, Sri Harsha

2014-01-01

In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen + the progestin medroxyprogesterone acetate and actually reduced breast cancer. PMID:24176761

Effects of menstrual cycle on creativity.

PubMed

Krug, R; Stamm, U; Pietrowsky, R; Fehm, H L; Born, J

1994-01-01

Seventeen healthy women (21-31 years) not taking oral contraceptives were tested at three phases of the menstrual cycle distinctly differing in hormonal patterns (menses, preovulatory phase, and midluteal phase). Phase detection was assured by determination of blood hormone concentrations. Another 17 women taking oral contraceptives (combined preparation of estrogen and progestin) served as age-matched controls, and were tested during menses and during phases corresponding to preovulatory and midluteal phase. On each test occasion, aspects of creativity were assessed by a battery of six tests measuring "semantic" and "figural" abilities of divergent thinking. Additionally, a test of motor perseveration (Mittenecker-Zeigeversuch) was presented. During the preovulatory phase, creativity was in general improved when serum concentrations of estrogen (E2) and luteinizing hormone (LH) were highest whereas motor perseveration decreased. In control women, there was no preovulatory improvement of divergent thinking and no preovulatory decrease in motor perseveration.

Novel [corrected] medical management of primary bladder endometriosis with dienogest: a case report.

PubMed

Takagi, H; Matsunami, K; Ichigo, S; Imai, A

2011-01-01

Because of its low incidence, medical treatment of has not yet been well established although surgical excision is generally considered effective. We report the first case of primary bladder endometriosis successfully managed with a novel progestin dienogest. A 39-year-old woman, nulligravida, presented with lower urinary tract symptoms, especially during menstruation. Cystoscopy, with subsequent cold cup biopsy, revealed a solitary submucosal mass (2 x 2 cm) in the bladder on the posterior wall; histopathology revealed the diagnosis of extraperitoneal endometriosis. MRI and laparoscopy confirmed no peritoneal endometriosis implants or adenomyosis. She was treated with oral 2 mg/day dienogest for six months. The measurable lesion exhibited a remarkable reduction in its size, accompanied with immediate relief of the lesion-related symptoms. At one year after medication cessation, she is well and symptom-free. Dienogest may be a novel conservative alternative for bladder endometriosis, in particular for women who wish to avoid surgical intervention.

[Hypertension and pregnancy: Post-partum period].

PubMed

Hugon-Rodin, Justine; Plu-Bureau, Geneviève

2016-01-01

Post-partum period is associated with specific characteristics in women with gestational disorders or preeclampsia. For breastfeeding women, the choice of antihypertensive treatment should take into account the impact on child health. The impact of breastfeeding on health mother must be also discussed. Moreover, for lactation inhibition, bromocriptine should not be used, especially in the context of gestational disorders. In post-partum period, the best contraceptive strategy is only-progestin contraception or non-hormonal contraceptives use. However, this choice will depend on the stabilization or normalization of blood pressure in early post-partum period. Finally, several consultations should be suggested: an information and announcement to explain the consequences of these gestational disorders and organize their multidisciplinary management and follow-up. A preconceptional consultation takes its place to anticipate potential recurrent preeclampsia or gestational hypertension and to schedule a future pregnancy in optimal conditions. Copyright © 2016. Published by Elsevier Masson SAS.

Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors.

PubMed

Natale, Christopher A; Duperret, Elizabeth K; Zhang, Junqian; Sadeghi, Rochelle; Dahal, Ankit; O'Brien, Kevin Tyler; Cookson, Rosa; Winkler, Jeffrey D; Ridky, Todd W

2016-04-26

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.

Feed-forward transcriptional programming by nuclear receptors: regulatory principles and therapeutic implications.

PubMed

Sasse, Sarah K; Gerber, Anthony N

2015-01-01

Nuclear receptors (NRs) are widely targeted to treat a range of human diseases. Feed-forward loops are an ancient mechanism through which single cell organisms organize transcriptional programming and modulate gene expression dynamics, but they have not been systematically studied as a regulatory paradigm for NR-mediated transcriptional responses. Here, we provide an overview of the basic properties of feed-forward loops as predicted by mathematical models and validated experimentally in single cell organisms. We review existing evidence implicating feed-forward loops as important in controlling clinically relevant transcriptional responses to estrogens, progestins, and glucocorticoids, among other NR ligands. We propose that feed-forward transcriptional circuits are a major mechanism through which NRs integrate signals, exert temporal control over gene regulation, and compartmentalize client transcriptomes into discrete subunits. Implications for the design and function of novel selective NR ligands are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Oral contraceptives and mood in women with and without premenstrual dysphoria: a theoretical model.

PubMed

Kurshan, N; Neill Epperson, C

2006-01-01

Despite numerous studies on the topic, there is no consensus to date on the effects of oral contraceptives on mood or the mechanism(s) by which they exert these effects. This review article presents a theoretical model to explain the way in which oral contraceptives may affect mood. Specifically, it is argued that progestins exert differential effects on endogenous levels of neurosteroids, thereby altering mood. After providing an overview of the effects of estrogen, progesterone, and progesterone's metabolites on cortical excitability and the role of neurosteroids in depression and premenstrual dysphoria, this article reviews the research that has been conducted on the relationship between oral contraceptives and neurosteroids. Finally, suggestions for future research are made with the dual aim of improving existing studies on the relationship between oral contraceptives and mood and further investigating the possibility that fluctuations in neurosteroid levels are responsible for the effects of oral contraceptives on mood.

Controlling levonorgestrel binding and release in a multi-purpose prevention technology vaginal ring device.

PubMed

Murphy, Diarmaid J; Boyd, Peter; McCoy, Clare F; Kumar, Sandeep; Holt, Jonathon D S; Blanda, Wendy; Brimer, Andrew N; Malcolm, R Karl

2016-03-28

Despite a long history of incorporating steroids into silicone elastomers for drug delivery applications, little is presently known about the propensity for irreversible drug binding in these systems. In this study, the ability of the contraceptive progestin levonorgestrel to bind chemically with hydrosilane groups in addition-cure silicone elastomers has been thoroughly investigated. Cure time, cure temperature, levonorgestrel particle size, initial levonorgestrel loading and silicone elastomer type were demonstrated to be key parameters impacting the extent of levonorgestrel binding, each through their influence on the solubility of levonorgestrel in the silicone elastomer. Understanding and overcoming this levonorgestrel binding phenomenon is critical for the ongoing development of a number of drug delivery products, including a multi-purpose technology vaginal ring device offering simultaneous release of levonorgestrel and dapivirine - a lead candidate antiretroviral microbicide - for combination HIV prevention and hormonal contraception. Copyright © 2016 Elsevier B.V. All rights reserved.

Modulation of the cytosolic androgen receptor in striated muscle by sex steroids

NASA Technical Reports Server (NTRS)

Rance, N. E.; Max, S. E.

1982-01-01

The influence of orchiectomy (GDX) and steroid administration on the level of the cytosolic androgen receptor in the rat levator ani muscle and in rat skeletal muscles (tibialis anterior and extensor digitorum longus) was studied. Androgen receptor binding to muscle cytosol was measured using H-3 methyltrienolone (R1881) as ligand, 100 fold molar excess unlabeled R1881 to assess nonspecific binding, and 500 fold molar excess of triamcinolone acetonide to prevent binding to glucocorticoid and progestin receptors. Results demonstrate that modification of the levels of sex steroids can alter the content of androgen receptors of rat striated muscle. Data suggest that: (1) cytosolic androgen receptor levels increase after orchiectomy in both levator ani muscle and skeletal muscle; (2) the acute increase in receptor levels is blocked by an inhibitor of protein synthesis; and (3) administration of estradiol-17 beta to castrated animals increases receptor binding in levator ani muscle but not in skeletal muscle.

Effects of oral contraceptive agents and sex steroids on carbohydrate metabolism.

PubMed

Kalkhoff, R K

1972-01-01

The article offers a general interpretation of the influence of oral contraceptive agents on glucose tolerance, emphasizing comparisons of synthetic sex hormones. Although there are conflicting reports on steroid-induced diabetes in normal women, their glucose curves are often higher when under oral contraceptive treatment, suggesting that oral contraceptives may induce a form of subclinical diabetes melitus that is reversible. Evidence from diabetic women suggests definite deliterious effects from contraceptive administration. Estradiol, estriol, and estrone may improve glucose tolerance in nondiabetic women and reduce insulin requirements in diabetics. Progesterone has little effect on carbohydrate tolerance, as did synthetic progestin. Conjugated equine estrogens (equilenine or Premarin) may provoke mild to moderate deterioration of carbohydrate tolerance. Parenterally administered natural estrogens and orally administered synthetic derivatives appear to differ sharply in their effects. Sex hormones' effects on carbohydrate metabolism likely involve interactions with insulin and endogenous glucocorticoids.

Endometrioid endometrial carcinoma indirectly caused by pituitary prolactinoma: a case report.

PubMed

Nishino, Kimihiro; Niwa, Yuri; Mizutani, Teruyuki; Shimizu, Ken; Hayashi, Kazumasa; Chaya, Jyunya; Kato, Noriko; Yamamuro, Osamu

2013-01-01

We present the case of a 44-year-old nulliparous woman who experienced irregular menstrual cycles for about 10 years and developed both pituitary prolactinoma and endometrioid endometrial carcinoma. In premenopausal women, hyperprolactinemia causes hypogonadism by inhibiting secretion of gonadotropin-releasing hormone and thus suppressing luteinizing hormone levels, which can cause menstrual disorders ranging from amenorrhea, oligomenorrhea and chronic anovulatory cycle to short luteal phase of the menstrual cycle. A chronic anovulatory menstrual cycle is the most common cause of long-term exposure of the endometrium to endogenous estrogen without adequate opposition from progestins, which can lead to endometrioid endometrial carcinoma. In this case, pituitary prolactinoma may have caused the chronic anovulatory cycle and indirectly led to the endometrioid endometrial carcinoma. In patients for whom the cause of irregular menstruation and chronic anovulatory cycle is suspected to be hyperprolactinemia, explorations of both the hypophysis and endometrium are essential.

Estrogen replacement therapy, Alzheimer's disease, and mild cognitive impairment.

PubMed

Mulnard, Ruth A; Corrada, Marìa M; Kawas, Claudia H

2004-09-01

This article highlights the latest findings regarding estrogen replacement therapy in the treatment and prevention of Alzheimer's disease (AD) and mild cognitive impairment in women. Despite considerable evidence from observational studies, recent randomized clinical trials of conjugated equine estrogens, alone and in combination with progestin, have shown no benefit for either the treatment of established AD or for the short-term prevention of AD, mild cognitive impairment, or cognitive decline. Based on the evidence, there is no role at present for estrogen replacement therapy in the treatment or prevention of AD or cognitive decline, despite intriguing results from the laboratory and from observational studies. However, numerous questions remain about the biologic effects of estrogens on brain structure and function. Additional basic and clinical investigations are necessary to examine different forms and dosages of estrogens, other populations, and the relevance of timing and duration of exposure.

[Somatostatin analogs for the treatment of advanced, hormone-refractory prostate cancer: a possibility for secondary hormonal ablation?].

PubMed

Schilling, D; Küfer, R; Kruck, S; Stenzl, A; Kuczyk, M A; Merseburger, A S

2008-10-01

Almost all patients with hormone-refractory prostate cancer under primary androgen deprivation therapy will develop progression, frequently initially marked by an asymptomatic increase of prostate-specific antigen (PSA). Recent data showed that taxane-based chemotherapy offers significant survival benefit to patients with advanced prostate cancer; however, the toxic side effects frequently exert a significant negative impact on the quality of life. At the androgen-independent stage of the cancer, before becoming hormone refractory, progression might still be delayed by secondary manipulation of either androgen or confounding receptors and their signaling pathways. Secondary hormonal manipulations traditionally included antiandrogen withdrawal, second-line antiandrogens, direct adrenal androgen inhibitors, estrogens, and progestins.We discuss the mode of action and application of somatostatin analogs as an emerging secondary hormonal treatment concept in patients with advanced prostate cancer on the basis of the current literature.

Endometrioid Endometrial Carcinoma Indirectly Caused by Pituitary Prolactinoma: A Case Report

PubMed Central

Nishino, Kimihiro; Niwa, Yuri; Mizutani, Teruyuki; Shimizu, Ken; Hayashi, Kazumasa; Chaya, Jyunya; Kato, Noriko; Yamamuro, Osamu

2013-01-01

We present the case of a 44-year-old nulliparous woman who experienced irregular menstrual cycles for about 10 years and developed both pituitary prolactinoma and endometrioid endometrial carcinoma. In premenopausal women, hyperprolactinemia causes hypogonadism by inhibiting secretion of gonadotropin-releasing hormone and thus suppressing luteinizing hormone levels, which can cause menstrual disorders ranging from amenorrhea, oligomenorrhea and chronic anovulatory cycle to short luteal phase of the menstrual cycle. A chronic anovulatory menstrual cycle is the most common cause of long-term exposure of the endometrium to endogenous estrogen without adequate opposition from progestins, which can lead to endometrioid endometrial carcinoma. In this case, pituitary prolactinoma may have caused the chronic anovulatory cycle and indirectly led to the endometrioid endometrial carcinoma. In patients for whom the cause of irregular menstruation and chronic anovulatory cycle is suspected to be hyperprolactinemia, explorations of both the hypophysis and endometrium are essential. PMID:23467393

Expression of placental protein 14 by the new endometrial cancer cell line MFE-280 in vitro and by endometrial carcinomas in vivo.

PubMed

Hackenberg, R; Loos, S; Nia, A H; Kunzmann, R; Schulz, K D

1998-01-01

MFE-280 endometrial cancer cells express PP14 (placental protein 14) in vitro. PP14 is normally found in the secretory endometrium and in placental tissue. MFE-280 cells, which are tumorigenic in nude mice, were derived from a recurrent, poorly differentiated endometrial carcinoma. The cells were initially grown in suspension culture and later transferred to monolayer cultures. Karyotyping revealed near-diploidy with a complex heterogeneous aberration pattern. MFE-280 cells were positive for the cytokeratins 7, 8, 18 and 19 as well as for vimentin. The expression of PP14 in MFE-280 cells was demonstrated by immunochemistry and reverse transcriptase--polymerase chain reaction. PP14-mRNA was also detected in one out of five endometrial cancer specimen. In tumor tissue the expression of PP14 was not dependent on progestins.

Emergency contraception: which is the best?

PubMed

Mittal, Suneeta

2016-12-01

Emergency contraception is a safe and effective method to prevent an unwanted pregnancy after an unprotected or inadequately protected sexual intercourse. Several methods for emergency contraception (EC) are currently registered in many countries for use in an emergency to prevent a pregnancy following an unprotected, possibly fertile intercourse or after a contraceptive accident like condom rupture. Different methods have varying modes of action, time frame of efficacy, dosage schedule and unwanted effects. Since several methods are available it is important to decide the best method. In this article the available literature on emergency contraception has been reviewed and an attempt has been made to discuss the need for emergency contraception and compare different options for emergency contraception in terms of their efficacy in pregnancy prevention, their safety profile and unwanted side effects. EC repeated use and initiating a regular method after EC use are also discussed. Emergency contraceptive methods include copper Intra-uterine devices (IUD) and different types of pills like estrogen progestin combination pill (Yuzpe Regimen), Progestin only pill (LNG), antiprogestin pill (Mifepristone), and progesterone modulator Uripristal Acetate (UPA). There is a marginal difference in the mechanism of action, efficacy including time frame and ability to protect from pregnancy with regular doses in obese women, drug interactions and side effects. These are discussed in detail. Copper IUD is the most effective emergency contraceptive with advantage of providing continued contraception. However, it cannot be used universally due to lack of infrastructure and a trained provider as well as not being suitable option for women at risk of sexually transmitted infections. Amongst different pills LNG is more effective with fewer side effects than Yuzpe regimen. LNG and UPA are comparable with similar efficacy and side effect profile. UPA has a wider window of efficacy, in LNG efficacy declines after 72 hours. UPA is more suitable for obese women. Mifepristone is effective but is registered as EC pill only in few countries and use is limited as it is also used as an abortion pill. Yuzpe regimen is the least effective of all contraceptive pills as EC, and works only till 72 hours of unprotected sex, but is useful in places where dedicated methods are not available, as it is easily accessible. Any combined pill can be used in this regimen except triphasic pill.

Concomitant contraceptive implant and efavirenz use in women living with HIV: perspectives on current evidence and policy implications for family planning and HIV treatment guidelines

PubMed Central

Patel, Rena C.; Morroni, Chelsea; Scarsi, Kimberly K.; Sripipatana, Tabitha; Kiarie, James; Cohen, Craig R.

2017-01-01

Abstract Introduction: Preventing unintended pregnancies is important among all women, including those living with HIV. Increasing numbers of women, including HIV-positive women, choose progestin-containing subdermal implants, which are one of the most effective forms of contraception. However, drug–drug interactions between contraceptive hormones and efavirenz-based antiretroviral therapy (ART) may reduce implant effectiveness. We present four inter-related perspectives on this issue. Discussion: First, as a case study, we discuss how limited data prompted country-level guidance against the use of implants among women concomitantly using efavirenz in South Africa and its subsequent negative effects on the use of implants in general. Second, we discuss the existing clinical data on this topic, including the observational study from Kenya showing women using implants plus efavirenz-based ART had three-fold higher rates of pregnancy than women using implants plus nevirapine-based ART. However, the higher rates of pregnancy in the implant plus efavirenz group were still lower than the pregnancy rates among women using common alternative contraceptive methods, such as injectables. Third, we discuss the four pharmacokinetic studies that show 50–70% reductions in plasma progestin concentrations in women concurrently using efavirenz-based ART as compared to women not on any ART. These pharmacokinetic studies provide the biologic basis for the clinical findings. Fourth, we discuss how data on this topic have marked implications for both family planning and HIV programmes and policies globally. Conclusion: This controversy underlines the importance of integrating family planning services into routine HIV care, counselling women appropriately on increased risk of pregnancy with concomitant implant and efavirenz use, and expanding contraceptive method mix for all women. As global access to ART expands, greater research is needed to explore implant effectiveness when used concomitantly with newer ART regimens. Data on how HIV-positive women and their partners choose contraceptives, as well as information from providers on how they present and counsel patients on contraceptive options are needed to help guide policy and service delivery. Lastly, greater collaboration between HIV and reproductive health experts at all levels are needed to develop successful strategies to ensure the best HIV and reproductive health outcomes for women living with HIV. PMID:28530033

Distinct lipid/lipoprotein profiles and hormonal responsiveness in nine ethnic groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study.

PubMed

Taechakraichana, N; Holinka, C F; Haines, C J; Subramaniam, R; Tian, X W; Ausmanas, M K

2007-06-01

Lipid/lipoprotein profiles, among other factors, are associated with risk of cardiovascular disease. Because cardiovascular disease varies in Asian countries, we hypothesized that lipid profiles differ in ethnic groups of postmenopausal Asian women. To add to the limited body of information currently available, we also investigated the effects of estrogen/progestin therapy on lipid/lipoprotein profiles in postmenopausal Asian women. The Pan-Asia Menopause (PAM) study was a prospective, randomized, double-blind clinical trial evaluating 1028 postmenopausal women at 22 investigational centers in 11 Asian countries/territories. Subjects were randomly assigned to one of three doses of continuous combined conjugated estrogens (CE)/medroxyprogesterone acetate (MPA): CE/MPA (in mg/day) = 0.625/2.5, 0.45/1.5 or 0.3/1.5. The treatment period, following baseline evaluations, consisted of six continuous 28-day cycles. Analysis of lipid profiles was a secondary objective of the PAM study. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), very low density cholesterol (VLDC-C), triglycerides and lipoprotein(a) were analyzed at a central laboratory by state-of-the-art methods. Mean concentrations of total cholesterol, LDL-C, VLDL-C and triglycerides differed significantly among the nine ethnic groups of postmenopausal women. This difference was independent of body mass index and age, two factors that also influenced lipid/lipoprotein profiles. Mean HDL-C concentrations also differed, but this difference was influenced by body mass index in a weak interaction. All three doses of CE/MPA significantly lowered total cholesterol. Treatment with the high and middle doses significantly lowered LDL-C, and increased HDL-C, VLDL-C and triglycerides. The high dose produced a significant decrease in lipoprotein(a). The different lipid/lipoprotein profiles in the nine ethnic groups of postmenopausal Asian women evaluated here suggest a relationship to differences in the prevalence of cardiovascular disease reported for different regions in Asia. However, the reported prevalence data on cardiovascular disease morbidity and mortality in the regions corresponding to the nine ethnic groups are insufficient to allow qualitative comparisons with the lipid profiles shown in our study. The lipid/lipoprotein changes in response to estrogen/progestin therapy observed here are consistent with those reported for Western women.

[Oral contraception, glucid metabolism and monitoring criteria].

PubMed

Gaspard, U

1988-02-01

Combined oral contraceptives (OCs) entail insulin resistence and decreased glucose tolerance proportional to their dose and type of progestin. Derivatives of 19-nortestosterone have more deleterious effects than do derivatives of 17-acetoxy progesterone. The effects are usually reversible and limited, and the diabetogenic role of currently available low-dose OCs is small. Metabolic and vascular risks must still be taken into account in prescribing OCs because hyperglycemia and hyperinsulinemia are significant vascular risk factors. Women with histories of OC use have increased risks of fatal and nonfatal myocardial infarct, cerebrovascular accidents, and peripheral vascular disease, but the increases are not always significant. Age and smoking are known to be primary risk factors whose effects are increased by OCs. Reduction of the estrogen dose of OCs may have resulted in a significant reduction of the venous thromboembolic risk, while reduction of the progestin dose may have resulted in a decreased incidence of venous accidents. The mechanisms of action by which OCs amplify existing vascular risks are largely unknown. Research with methods capable of quantifying insulin resistence suggests that a post-receptor intracellular effect is responsible for insulin resistence and diminished intracellular metabolism of glucose in users of OCs. Because OCs are ordinarily used by healthy young women over long periods of time with minimal medical supervision, it is desirable to identify cases in which cardiovascular and other undesirable secondary effects are likely. OCs are contraindicated for any woman with a history of cardiac accidents, venous or arterial vascular problems, or hypertension. Obesity is a relative contraindication because it may coexist with a problem of glucose metabolism and constitute a diabetic risk factor. Other diabetic risk factors that must be evaluated are age, family or personal history of gestational diabetics, and transitory problems of glucose tolerance. Low dose combined OCs have little effect on carbohydrate metabolism or glucose tolerance, but women with diabetic risk factors may be more sensitive to the vascular impact of OCs than other women. Weight, blood pressure, and fasting or nonfasting blood sugar should be assessed annually OC users. Obese women should undergo an endocrinologic and metabolic examination in the interests of general prevention before receiving a prescription for combined OCs. Women with family or personal histories of diabetic risk should be evaluated from a metabolic and vascular standpoint.

Re-Evaluating the Possible Increased Risk of HIV Acquisition With Progestin-Only Injectables Versus Maternal Mortality and Life Expectancy in Africa: A Decision Analysis.

PubMed

Rodriguez, Maria Isabel; Gaffield, Mary E; Han, Leo; Caughey, Aaron B

2017-12-28

The association between increased risk of HIV acquisition and use of progestin-only injectables (POIs) is controversial. We sought to compare the competing risks of maternal mortality and HIV acquisition with use of POIs using updated data on this association and considering an expanded number of African countries. We designed a decision-analytic model to compare the benefits and risks of POIs on the competing risks of maternal mortality and HIV acquisition on life expectancy for women in 9 African countries. For the purposes of this analysis, we assumed that POIs were associated with an increased risk of HIV acquisition (hazards ratio of 1.4). Our primary outcome was life-years and the population was women of reproductive age (15-49 years) in these countries, who did not have HIV infection and were not currently planning a pregnancy. Probabilities for each variable included in the model, such as HIV incidence, access to antiretroviral therapy, and contraceptive prevalence, were obtained from the literature. Univariate and multivariate sensitivity analyses were performed to check model assumptions and explore how uncertainty in estimates would affect the model results. In all countries, discontinuation of POIs without replacement with an equally effective contraceptive method would result in decreased life expectancy due to a significant increase in maternal deaths. While the removal of POIs from the market would result in the prevention of some new cases of HIV, the life-years gained from this are mitigated due to the marked increase in neonatal HIV cases and maternal mortality with associated life-years lost. In all countries, except South Africa, typical-use contraceptive failure rates with POIs would need to exceed 39%, and more than half of women currently using POIs would have to switch to another effective method, for the removal of POIs to demonstrate an increase in total life-years. Women living in sub-Saharan Africa cope with both high rates of HIV infection and high rates of pregnancy-related maternal death relative to the rest of the world. Based on the most current estimates, our model suggests that removal of POI contraception from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality under a variety of scenarios. © Rodriguez et al.

Contemporary Hormonal Contraception and the Risk of Breast Cancer.

PubMed

Mørch, Lina S; Skovlund, Charlotte W; Hannaford, Philip C; Iversen, Lisa; Fielding, Shona; Lidegaard, Øjvind

2017-12-07

Little is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer. We assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast-cancer diagnoses, and potential confounders. Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen-progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year. The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.).

Concomitant contraceptive implant and efavirenz use in women living with HIV: perspectives on current evidence and policy implications for family planning and HIV treatment guidelines.

PubMed

Patel, Rena C; Morroni, Chelsea; Scarsi, Kimberly K; Sripipatana, Tabitha; Kiarie, James; Cohen, Craig R

2017-05-11

Preventing unintended pregnancies is important among all women, including those living with HIV. Increasing numbers of women, including HIV-positive women, choose progestin-containing subdermal implants, which are one of the most effective forms of contraception. However, drug-drug interactions between contraceptive hormones and efavirenz-based antiretroviral therapy (ART) may reduce implant effectiveness. We present four inter-related perspectives on this issue. First, as a case study, we discuss how limited data prompted country-level guidance against the use of implants among women concomitantly using efavirenz in South Africa and its subsequent negative effects on the use of implants in general. Second, we discuss the existing clinical data on this topic, including the observational study from Kenya showing women using implants plus efavirenz-based ART had three-fold higher rates of pregnancy than women using implants plus nevirapine-based ART. However, the higher rates of pregnancy in the implant plus efavirenz group were still lower than the pregnancy rates among women using common alternative contraceptive methods, such as injectables. Third, we discuss the four pharmacokinetic studies that show 50-70% reductions in plasma progestin concentrations in women concurrently using efavirenz-based ART as compared to women not on any ART. These pharmacokinetic studies provide the biologic basis for the clinical findings. Fourth, we discuss how data on this topic have marked implications for both family planning and HIV programmes and policies globally. This controversy underlines the importance of integrating family planning services into routine HIV care, counselling women appropriately on increased risk of pregnancy with concomitant implant and efavirenz use, and expanding contraceptive method mix for all women. As global access to ART expands, greater research is needed to explore implant effectiveness when used concomitantly with newer ART regimens. Data on how HIV-positive women and their partners choose contraceptives, as well as information from providers on how they present and counsel patients on contraceptive options are needed to help guide policy and service delivery. Lastly, greater collaboration between HIV and reproductive health experts at all levels are needed to develop successful strategies to ensure the best HIV and reproductive health outcomes for women living with HIV.

Ovulation induction and artificial insemination of a captive polar bear (Ursus maritimus) using fresh semen.

PubMed

Curry, Erin; Wyatt, Jeff; Sorel, Lawrence J; MacKinnon, Katherine M; Roth, Terri L

2014-09-01

In 2008, polar bears were listed as a species threatened with extinction by the U.S. Endangered Species Act. Unfortunately, reproductive success has been poor despite breeding recommendations for almost every reproductively viable bear by the Species Survival Plan. Assisted reproductive technologies could complement breeding efforts by overcoming the challenges of behavioral incompatibilities and deficiencies, facilitating genetic management and increasing cub production. The goal of this study was to artificially inseminate a female polar bear after inducing ovarian activity and ovulation with exogenous hormones (equine chorionic gonadotropin and porcine luteinizing hormone). Fresh semen collected from an adult male via electroejaculation/urethral catheterization was used for the insemination. Fecal steroid monitoring indicated that the female ovulated following the exogenous hormone treatment. Progestin concentrations increased in late summer, at the time implantation was expected to occur; however, no cubs were produced. To the authors' knowledge, this is the first report of ovulation induction and artificial insemination in a polar bear.

Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors

PubMed Central

Natale, Christopher A; Duperret, Elizabeth K; Zhang, Junqian; Sadeghi, Rochelle; Dahal, Ankit; O'Brien, Kevin Tyler; Cookson, Rosa; Winkler, Jeffrey D; Ridky, Todd W

2016-01-01

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics. DOI: http://dx.doi.org/10.7554/eLife.15104.001 PMID:27115344

The breast cancer epidemic: 10 facts

PubMed Central

Schneider, A. Patrick; Zainer, Christine M.; Kubat, Christopher Kevin; Mullen, Nancy K.; Windisch, Amberly K.

2014-01-01

Breast cancer, affecting one in eight American women, is a modern epidemic. The increasing frequency of breast cancer is widely recognized. However, the wealth of compelling epidemiological data on its prevention is generally not available, and as a consequence, is largely unknown to the public. The purpose of this report is to review the epidemiological evidence of preventable causes of breast cancer. TABLE 1 Frequently used abbreviations and terms (listed alphabetically)AbbreviationsTermsABC linkAbortion–breast cancer linkCEE(s)Conjugated equine estrogen(s)CHDCoronary heart diseaseCHRTCombined hormone replacement therapyCIConfidence IntervalCOC(s)Combined oral contraceptive(s)ECEmergency contraceptionECP(s)Emergency contraception pill(s)ERTEstrogen replacement therapyFDAFood and Drug AdministrationFFTPFirst full-term pregnancyHRTHormone replacement therapyIA(s)Induced abortion(s)IARCInternational Agency for Research on CancerMPAMedroxyprogesterone acetateOC(s)Oral contraceptive(s)OROdds ratioOTCOver-the-counterPOC(s)Progestin-only contraceptive(s)RRRelative RiskWHIWomen's Health InitiativeWHOWorld Health Organization PMID:25249706

Recent methodological advances in male hormonal contraception

PubMed Central

Liu, Peter Y.; Swerdloff, Ronald S.; Wang, Christina

2010-01-01

Landmark WHO-sponsored trials showed decades ago that male hormonal contraception (MHC) is an effective male-directed contraceptive approach. Considerable progress has been made particularly in the last 5 years, establishing for the first time the reversibility of MHC and its short-term safety. Methodological advances in recent years include: the pooling of information and individual-level integrated analysis; the first-time use of centralized semen analysis and fluorescence to detect low sperm concentrations; the establishment of sperm quality reference ranges in fertile men; the measurement of blood steroid concentrations by gas or chromatography/mass spectrometry; and the inclusion of placebo groups to delineate clearly possible adverse effects of androgens and progestins in men. We report integrated analyses of factors that are important in predicting suppression and recovery of spermatogenesis after MHC clinical trials for the past 15 years. These are the best data available and will provide guidance and reassurance for the larger scale Phase III specific regimen efficacy studies that will be required to bring MHC to the population (market). PMID:20933121

Polycystic ovary syndrome (PCOS), insulin resistance and insulin-like growth factors (IGfs)/IGF-binding proteins (IGFBPs).

PubMed

Wang, Hsin-Shih; Wang, Tzu-Hao

2003-08-01

Polycystic ovary syndrome (PCOS) is the most frequent androgen disorder of ovarian function. Hyperinsulinemia with insulin resistance is believed to be a key link in the enigmatic generation of the symptoms of PCOS such as anovulatory infertility and hyperandrogenism. Regression of these symptoms may be achieved by reducing the hyperinsulinemia. A growing body of evidence suggests that PCOS patients with hyperinsulinemia have a higher risk to develop diabetes mellitus, hypertension and cardiovascular disease as compared to age-matched women. Although oral contraceptives, progestins, antiandrogens, and ovulation induction agents remain standard therapies, weight loss should also be vigorously encouraged to ameliorate the metabolic consequences of PCOS. In addition, insulin-sensitizing agents are now being shown to be useful alone or combined with standard therapies to alleviate hyperinsulinemia in PCOS. Finally and most importantly, early identification of patients at risk and prompt initiation of therapies, followed by long-term surveillance and management, may promote the patient's long-term health.

Location and removal of deslorelin acetate implants in female African lions (Panthera leo).

PubMed

Moresco, Anneke; Dadone, Liza; Arble, Jason; Klaphake, Eric; Agnew, Dalen W

2014-06-01

Contraception is necessary to manage zoo animal populations and to be able to house animals in groups without producing additional unwanted offspring. In felids and canids, an association between exposure to progestins and the occurrence of endometrial and mammary gland pathology has been documented. Therefore, the Association of Zoos and Aquariums (AZA) Wildlife Contraceptive Center recommends the use of deslorelin acetate for long-term contraception in carnivores. Return to cyclicity after deslorelin treatment has been variable; some individuals show ovarian suppression for long periods after the expected end of the deslorelin efficacy. In an attempt to reduce the time to reversal, techniques to locate and remove previous implants are being developed. This report documents the successful implementation of high-frequency ultrasonography in lions (Panthera leo) to locate and direct surgical removal of multiple deslorelin implants placed at least 2 yr previously as well as the return of follicular activity in both females at 7 months post-removal of implants.

Food Versus Pharmacy: Assessment of Nutritional and Pharmacological Strategies to Improve Bone Health in Energy-Deficient Exercising Women.

PubMed

Southmayd, Emily A; Hellmers, Adelaide C; De Souza, Mary Jane

2017-10-01

The review aims to summarize our current knowledge surrounding treatment strategies aimed at recovery of bone mass in energy-deficient women suffering from the Female Athlete Triad. The independent and interactive contributions of energy status versus estrogen status on bone density, geometry, and strength have recently been reported, highlighting the importance of addressing both energy and estrogen in treatment strategies for bone health. This is supported by reports that have identified energy-related features (low body weight and BMI) and estrogen-related features (late age of menarche, oligo/amenorrhea) to be significant risk factors for low bone mineral density and bone stress injury in female athletes and exercising women. Nutritional therapy is the recommended first line of treatment to recover bone mass in energy-deficient female athletes and exercising women. If nutritional therapy fails after 12 months or if fractures or significant worsening in BMD occurs, pharmacological therapy may be considered in the form of transdermal estradiol with cyclic oral progestin (not COC).

Case of ovarian hyperstimulation and oocyte pick-up during very early period of unnoticed pregnancy followed by ongoing normal pregnancy.

PubMed

Takenaka, Hiroshi; Nakao, Kazuki; Horikawa, Michiharu; Negishi, Hiroaki

2016-04-01

We report a case of unnoticed pregnancy that was maintained during low estrogen and progesterone circumstances, that showed menses-like bleeding, and was then discovered after ovarian hyperstimulation during the next period. The patient was 39 years old and primigravid. She underwent intrauterine insemination, followed by luteal support with human chorionic gonadotrophin and progestin; however, she experienced menstruation-like bleeding 15 days later. As low estradiol and progesterone levels were confirmed on the 2nd day of bleeding, ovarian hyperstimulation of short protocol for in vitro fertilization was commenced. Although 13 mature follicles were observed, only six oocytes were retrieved and one developed into a blastocyst. Four days after oocyte pick-up, a gestational sac was seen in utero. The fetus is currently growing uneventfully. This case suggests that pregnancy can be maintained during ovarian hyperstimulation, even if menstruation-like bleeding is shown in low-progesterone circumstances. © 2016 Japan Society of Obstetrics and Gynecology.

Decidualized Human Endometrial Stromal Cells Mediate Hemostasis, Angiogenesis, and Abnormal Uterine Bleeding

PubMed Central

Lockwood, Charles J.; Krikun, Graciela; Hickey, Martha; Huang, S. Joseph; Schatz, Frederick

2011-01-01

Factor VII binds trans-membrane tissue factor to initiate hemostasis by forming thrombin. Tissue factor expression is enhanced in decidualized human endometrial stromal cells during the luteal phase. Long-term progestin only contraceptives elicit: 1) abnormal uterine bleeding from fragile vessels at focal bleeding sites, 2) paradoxically high tissue factor expression at bleeding sites; 3) reduced endometrial blood flow promoting local hypoxia and enhancing reactive oxygen species levels; and 4) aberrant angiogenesis reflecting increased stromal cell-expressed vascular endothelial growth factor, decreased Angiopoietin-1 and increased endothelial cell-expressed Angiopoietin-2. Aberrantly high local vascular permeability enhances circulating factor VII to decidualized stromal cell-expressed tissue factor to generate excess thrombin. Hypoxia-thrombin interactions augment expression of vascular endothelial growth factor and interleukin-8 by stromal cells. Thrombin, vascular endothelial growth factor and interlerukin-8 synergis-tically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding. PMID:19208784

Emergency Contraception in Post-Conflict Somalia: An Assessment of Awareness and Perceptions of Need.

PubMed

Gure, Faduma; Dahir, Mohammed Koshin; Yusuf, Marian; Foster, Angel M

2016-03-01

In conflict-affected settings such as Somalia, emergency contraception (EC) has the potential to serve as an important means of pregnancy prevention. Yet Somalia remains one of the few countries without a registered progestin-only EC pill. In 2014, we conducted a qualitative, multi-methods study in Mogadishu to explore awareness of and perceptions of need for EC. Our project included 10 semi-structured key informant interviews, 20 structured in-person interviews with pharmacists, and four focus group discussions with married and unmarried Somali women. Our findings reveal a widespread lack of knowledge of both existing family planning methods and EC. However, once we described EC, participants expressed enthusiasm for expanding access to post-coital contraception. Our results shed light on why Somalia continues to be a global exception with respect to an EC product and suggest possible politically and culturally acceptable and effective avenues for introducing EC into the health system. © 2016 The Population Council, Inc.

Malignant neoplasms of decidual origin (deciduosarcomas) induced by estrogen-progestin-releasing intravaginal devices in rabbits.

PubMed

Zook, B C; Spiro, I; Hertz, R

1987-08-01

A combination of estrogen and levonorgestrel was continuously delivered to 23 adult rabbits for up to 2 years via a Silastic ring device sutured into the vagina. Twenty-one control rabbits were given similar rings devoid of drugs. A marked decidual reaction of the endometrium occurred in 16 of 23 test rabbits. In 14 test rabbits (61%) malignant tumors developed of decidual type cells not heretofore described. The deciduosarcomas were composed of anaplastic cells that invaded the uterine walls, uterine lymphatics, and in 4 of 13 (31%) rabbits that survived 2 years of treatment, the tumors metastasized to the lungs. Several deciduosarcomas appeared to arise within the spleen or other abdominal organs. Other drug-related lesions included uterine or vaginal polyps, endometrial atrophy, and focal necrosis and mineralization of the uterine wall. Cells from several deciduosarcomas failed to produce tumors in nude mice or to colonize on soft agar. No decidualization or decidual neoplasms were seen in the controls.

Antiprogestin-releasing intrauterine devices

PubMed Central

Nayak, NR; Slayden, OD; Mah, K; Chwalisz, K; Brenner, Robert M

2007-01-01

Intrauterine devices (IUDs) that release progestins are highly effective contraceptives, but they induce breakthrough bleeding that some women find unacceptable. Because progesterone (P) antagonists (AP) are known to suppress the endometrium, induce amenorrhea, and inhibit fertility, AP IUDs may provide an effective contraceptive that also controls endometrial bleeding. Here we assessed the effects of empty (blank) vs AP-releasing (ZK 230 211) IUDs on bleeding patterns and endometrial growth in ovariectomized, artificially cycled macaques. The AP IUDs (but not the blank controls) induced extended, frank menstruation when inserted during the late luteal phase, an indication of local AP action. Over time, endometrial glandular and arterial proliferation were inhibited, steroid receptors were elevated, spiral arteries showed degenerative changes, progesterone withdrawal bleeding was prevented and estradiol-dependent proliferation was suppressed by the AP IUDs. In sum, AP IUDs suppressed the effects of P on endometrial progestational development and blocked the effects of estradiol on endometrial proliferation as previously shown for systemic treatment with APs. Therefore, AP IUDs may provide novel contraceptive devices with minimal breakthrough bleeding. PMID:17531599

Identification of hormone-interacting amino acid residues within the steroid-binding domain of the glucocorticoid receptor in relation to other steroid hormone receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carlstedt-Duke, J.; Stroemstedt, P.E.; Persson, B.

1988-05-15

Purified rat liver glucocorticoid receptor was covalently charged with (/sup 3/H)glucocorticoid by photoaffinity labeling (UV irradiation of (/sup 3/H)triamcinolone acetonide-glucocorticoid receptor) or affinity labeling (incubation with (/sup 3/H)dexamethasone mesylate). After labeling, separate samples of the denatured receptor were cleaved with trypsin (directly or after prior succinylation), chymotrypsin, and cyanogen bromide. Labeled residues in the peptides obtained were identified by radiosequence analysis. The peaks of radioactivity corresponded to Met-622 and Cys-754 after photoaffinity labeling with (/sup 3/H)triamcinolone acetonide and Cys-656 after affinity labeling with (/sup 3/H)dexamethasone mesylate. The labeled residues are all positioned within hydrophobic segments of the steroid-binding domain. Themore » patterns of hydropathy and secondary structure for the glucocorticoid receptor are highly similar to those for the progestin receptor and similar but less so to those for the estrogen receptor and to those for c-erb A.« less

Impaired gamete production and viability in Atlantic croaker collected throughout the 20,000 km(2) hypoxic region in the northern Gulf of Mexico.

PubMed

Thomas, Peter; Rahman, Md Saydur; Picha, Matthew E; Tan, Wenxian

2015-12-15

The long-term impacts of recent marked increases in the incidence and extent of hypoxia (dissolved oxygen <2 mg/L) in coastal regions worldwide on fisheries and ecosystems are unknown. Reproductive impairment was investigated in Atlantic croaker collected in 2010 from the extensive coastal hypoxic region in the northern Gulf of Mexico. Potential fecundity was significantly lower in croaker collected throughout the ~20,000 km(2) hypoxic region than in croaker from normoxic sites. In vitro bioassays of gamete viability showed reductions in oocyte maturation and sperm motility in croaker collected from the hypoxic sites in response to reproductive hormones which were accompanied by decreases in gonadal levels of membrane progestin receptor alpha, the receptor regulating these processes. The finding that environmental hypoxia exposure reduces oocyte viability in addition to decreasing oocyte production in croaker suggests that fecundity estimates need to be adjusted to account for the decrease in oocyte maturation. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Management of assisted reproductive technology (ART) in case of endometriosis related infertility: CNGOF-HAS Endometriosis Guidelines].

PubMed

Santulli, P; Collinet, P; Fritel, X; Canis, M; d'Argent, E M; Chauffour, C; Cohen, J; Pouly, J L; Boujenah, J; Poncelet, C; Decanter, C; Borghese, B; Chapron, C

2018-03-01

The management of endometriosis related infertility requires a global approach. In this context, the prescription of an anti-gonadotropic hormonal treatment does not increase the rate of non-ART (assisted reproductive technologies) pregnancies and it is not recommended. In case of endometriosis related infertility, the results of IVF management in terms of pregnancy and birth rates are not negatively affected by the existence of endometriosis. Controlled ovarian stimulation during IVF does not increase the risk of endometriosis associated symptoms worsening, nor accelerate the intrinsic progression of endometriosis and does not increase the rate of recurrence. However, in the context of IVF management for women with endometriosis, pre-treatment with GnRH agonist or with oestrogen/progestin contraception improve IVF outcomes. There is currently no evidence of a positive or negative effect of endometriosis surgery on IVF outcomes. Information on the possibilities of preserving fertility should be considered, especially before surgery. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Progestin Concentrations Are Increased following Paced Mating in Midbrain, Hippocampus, Diencephalon, and Cortex of Rats in Behavioral Estrus, but Only in Midbrain of Diestrous Rats

PubMed Central

Frye, Cheryl A.; Rhodes, Madeline E.

2013-01-01

Background The progesterone (P4 ) metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), acts in the midbrain ventral tegmental area (VTA) to modulate the intensity and duration of lordosis. 3α,5α-THP can also have anti-anxiety and anti-stress effects in part through actions in the hippocampus. Separate reports indicate that manipulating 3α,5α-THP levels in the VTA or hippocampus respectively can influence lordosis and affective behavior. 3α,5α-THP levels can also be altered by behavioral experiences, such as mating or swim stress. Whether endogenous levels of 3α,5α-THP modulate and/or are increased in response to affective and/or reproductively-relevant behaviors was investigated. Methods In Experiment 1, rats in behavioral estrus or diestrus were individually tested sequentially in the open field, elevated plus maze, partner preference, social interaction, and paced mating tasks and levels of 17 β-estradiol (E2), P4, dihydroprogesterone (DHP), and 3α,5α-THP in serum, midbrain, hippocampus, diencephalon, and cortex were examined. In Experiments 2 and 3, rats in behavioral estrus or diestrus, were individually tested in the battery indicated above, with, or without, paced mating and tissues were collected immediately after testing for later assessment of endocrine measures. Results In Experiment 1, behavioral estrous, compared to diestrous, rats demonstrated more exploratory, anti-anxiety, social, and reproductive behaviors, and had higher levels of E2 and progestins in serum, midbrain, hippocampus, diencephalon, and cortex. In Experiment 2, in midbrain and hippocampus, levels of 3α,5α-THP and its precursor DHP were increased among rats in behavioral estrus that were mated. In diencephalon, and cortex, DHP levels were increased by mating. In Experiment 3, in midbrain, levels of 3α,5α-THP and its precursor DHP were increased among diestrous rats that were tested in the behavioral battery with mating as compared to those tested in the behavioral battery without mating. Conclusions Increased levels of 3α,5α-THP in behavioral estrus versus diestrous rats are associated with enhanced exploratory, anti-anxiety, social, and reproductive behaviors. Rats in behavioral estrus that are mated have further increases in 3α,5α-THP and/or DHP levels in midbrain, hippocampus, diencephalon, and cortex than do non-mated rats in behavioral estrus, whereas diestrous rats only show 3α,5α-THP increases in midbrain in response to behavioral testing that included mating. PMID:17028418

Combined hormonal versus nonhormonal versus progestin-only contraception in lactation.

PubMed

Lopez, Laureen M; Grey, Thomas W; Stuebe, Alison M; Chen, Mario; Truitt, Sarah T; Gallo, Maria F

2015-03-20

Postpartum contraception improves the health of mothers and children by lengthening birth intervals. For lactating women, contraception choices are limited by concerns about hormonal effects on milk quality and quantity and passage of hormones to the infant. Ideally, the contraceptive chosen should not interfere with lactation or infant growth. Timing of contraception initiation is also important. Immediately postpartum, most women have contact with a health professional, but many do not return for follow-up contraceptive counseling. However, immediate initiation of hormonal methods may disrupt the onset of milk production. To determine the effects of hormonal contraceptives on lactation and infant growth We searched for eligible trials until 2 March 2015. Sources included the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, POPLINE, Web of Science, LILACS, ClinicalTrials.gov, and ICTRP. We also examined review articles and contacted investigators. We sought randomized controlled trials in any language that compared hormonal contraception versus another form of hormonal contraception, nonhormonal contraception, or placebo during lactation. Hormonal contraception includes combined or progestin-only oral contraceptives, injectable contraceptives, implants, and intrauterine devices.Trials had to have one of our primary outcomes: breast milk quantity or biochemical composition; lactation initiation, maintenance, or duration; infant growth; or timing of contraception initiation and effect on lactation. Secondary outcomes included contraceptive efficacy while breastfeeding and birth interval. For continuous variables, we calculated the mean difference (MD) with 95% confidence interval (CI). For dichotomous outcomes, we computed the Mantel-Haenszel odds ratio (OR) with 95% CI. Due to differing interventions and outcome measures, we did not aggregate the data in a meta-analysis. In 2014, we added seven trials for a new total of 11. Five reports were published before 1985 and six from 2005 to 2014. They included 1482 women. Four trials examined combined oral contraceptives (COCs), and three studied a levonorgestrel-releasing intrauterine system (LNG-IUS). We found two trials of progestin-only pills (POPs) and two of the etonogestrel-releasing implant. Older studies often lacked quantified results. Most trials did not report significant differences between the study arms in breastfeeding duration, breast milk composition, or infant growth. Exceptions were seen mainly in older studies with limited information.For breastfeeding duration, two of eight trials indicated a negative effect on lactation. A COC study reported a negative effect on lactation duration compared to placebo but did not quantify results. Another trial showed a lower percentage of the LNG-IUS group breastfeeding at 75 days versus the nonhormonal IUD group (reported P < 0.05) but no significant difference at one year.For breast milk volume, two older studies indicated lower volume for the COC group versus the placebo group. One trial did not quantify results. The other showed lower means (mL) for the COC group, e.g. at 16 weeks (MD -24.00, 95% CI -34.53 to -13.47) and at 24 weeks (MD -24.90, 95% CI -36.01 to -13.79). Another four trials did not report any significant difference between the study groups in milk volume or composition with two POPs, a COC, or the etonogestrel implant.Seven trials studied infant growth; one showed greater weight gain (grams) for the etonogestrel implant versus no method for six weeks (MD 426.00, 95% CI 58.94 to 793.06) but less compared with depot medroxyprogesterone acetate (DMPA) from 6 to 12 weeks (MD -271.00, 95% CI -355.10 to -186.90). The others studied POPs, COCs versus POPs, or an LNG-IUS. Results were not consistent across the 11 trials. The evidence was limited for any particular hormonal method. The quality of evidence was moderate overall and low for three of four placebo-controlled trials of COCs or POPs. The sensitivity analysis included six trials with moderate quality evidence and sufficient outcome data. Five trials indicated no significant difference between groups in breastfeeding duration (etonogestrel implant insertion times, COC versus POP, and LNG-IUS). For breast milk volume or composition, a COC study showed a negative effect, while an implant trial showed no significant difference. Of four trials that assessed infant growth, three indicated no significant difference between groups. One showed greater weight gain in the etonogestrel implant group versus no method but less versus DMPA.

Oral contraceptives in polycystic ovary syndrome: risk-benefit assessment.

PubMed

Yildiz, Bulent O

2008-01-01

Combined oral contraceptive pills (OCPs) have been a key component of the chronic treatment of polycystic ovary syndrome (PCOS) by improving androgen excess and regulating menstrual cycles. Earlier epidemiologic studies with second- and third-generation OCPs in the general population have raised important questions regarding long-term cardiometabolic effects of these agents. In PCOS, there are only a few short-term studies with contradictory results evaluating potential adverse effects of OCPs on cardiovascular risk factors and glucose homeostasis. These studies included a small number of participants and did not take into account several confounding factors that might influence the outcome. Nevertheless, limited available data support the benefits of long-term OCP use in PCOS. By contrast, solid evidence for cardiometabolic adverse outcome with the use of these agents, especially with newer OCPs containing antiandrogenic progestins, is lacking. More studies are needed to resolve controversies regarding the safety of long-term OCP use in PCOS. Meanwhile, assessment of each PCOS patient's personal cardiometabolic risk profile should be an essential component of the evaluation before prescribing OCPs and also during follow-up.

Bridging progestogens in pregnancy and pregnancy prevention

PubMed Central

Micks, Elizabeth; Raglan, Greta B; Schulkin, Jay

2015-01-01

Steroid hormones have been in use for more than a half a century as contraceptive agents, and only now are researchers elucidating the biochemical mechanisms of action and non-target effects. Progesterone and synthetic progestins, critical for women's health in the US and internationally, appear to have important effects on immune functioning and other diverse systems. Apart from the contraceptive world is a separate field that is devoted to understanding progesterone in other contexts. Based on research following a development timeline parallel to hormonal contraception, progesterone and 17-hydroxyprogesterone caproate are now administered to prevent preterm birth in high-risk pregnant women. Preterm birth researchers are similarly working to determine the precise biochemical actions and immunological effects of progesterone. Progesterone research in both areas could benefit from increased collaboration and bringing these two bodies of literature together. Progesterone, through actions on various hormone receptors, has lifelong importance in different organ systems and researchers have much to learn about this molecule from the combination of existing literatures, and from future studies that build on this combined knowledge base. PMID:26581227

[Male hormonal contraception: past, present, future].

PubMed

Pásztor, Norbert; Hegyi, Borbála Eszter; Badó, Attila; Németh, Gábor

2017-11-01

In certain regions of the world the enormous rate of population growth raises economic and public health concerns and widely accessible contraceptive methods would be desired. In contrast, in other countries the use of effective contraception is a question of individual preferences. Today, most of the reliable contraceptive methods are applied by women, while the options for male methods are quite limited. It is well known that significant portion of pregnancies are still unplanned and several data revealed men's willingness to take part in family planning. Based on these needs, remarkable efforts have been made to develop a suitable hormonal contraceptive agent for men. With the exogenous suppression of follicle stimulating hormone and luteinizing hormone secretion, the inhibition of the testicular testosterone production and the spermatogenesis can be achieved. In the beginning, testosterone-derivatives, or testosterone-progestin combinations were administered, later synthetic androgen agents were developed. Despite of these efforts, unfortunately, there is no safe, widely feasible male hormonal contraception to date, but in the future this goal can be achieved by solving the key hurdles. Orv Hetil. 2017; 158(46): 1819-1830.

Recent methodological advances in male hormonal contraception.

PubMed

Liu, Peter Y; Swerdloff, Ronald S; Wang, Christina

2010-11-01

Landmark WHO-sponsored trials showed decades ago that male hormonal contraception (MHC) is an effective male-directed contraceptive approach. Considerable progress has been made particularly in the last 5 years, establishing for the first time the reversibility of MHC and its short-term safety. Methodological advances in recent years include the pooling of information and individual-level integrated analysis; the first-time use of centralized semen analysis and fluorescence to detect low sperm concentrations; the establishment of sperm quality reference ranges in fertile men; the measurement of blood steroid concentrations by gas chromatography/mass spectrometry; and the inclusion of placebo groups to delineate clearly possible adverse effects of androgens and progestins in men. We report integrated analyses of factors that are important in predicting suppression and recovery of spermatogenesis after MHC clinical trials for the past 15 years. These are the best data available and will provide guidance and reassurance for the larger-scale Phase III specific regimen efficacy studies that will be required to bring MHC to the population (market). Copyright © 2010 Elsevier Inc. All rights reserved.

Update on Research and Treatment of Premenstrual Dysphoric Disorder

PubMed Central

Cunningham, Joanne; Yonkers, Kimberly Ann; O'Brien, Shaughn; Eriksson, Elias

2011-01-01

Many women in their reproductive years experience some mood, behavioral. or physical symptoms in the week prior to menses. Variability exists in the level of symptom burden in that some women experience mild symptoms, whereas a small minority experience severe and debilitating symptoms. For an estimated 5%–8% of premenopausal women, work or social functioning are affected by severe premenstrual syndrome. Many women in this group meet diagnostic criteria for premenstrual dysphoric disorder (PMDD). Among women who suffer from PMDD, mood and behavioral symptoms such as irritability, depressed mood, tension, and labile mood dominate. Somatic complaints, including breast tenderness and bloating, also can prove disruptive to women's overall functioning and quality of life. Recent evidence suggests that individual sensitivity to cyclical variations in levels of gonadal hormones may predispose certain women to experience these mood, behavioral, and somatic symptoms. Treatments include: antidepressants of the serotonin reuptake inhibitor class, taken intermittently or throughout the menstrual cycle; medications that suppress ovarian cyclicity; and newer oral contraceptives with novel progestins. (Harv Rev Psychiatry 2009;17:120–137.) PMID:19373620

PAQR3 Inhibits the Proliferation and Tumorigenesis in Esophageal Cancer Cells.

PubMed

Zhou, Fang; Wang, Shunchang; Wang, Jianjun

2017-05-24

Progestin and adipoQ receptor family member III (PAQR3), a member of the PAQR family, is frequently downregulated in different types of human cancer. However, its expression and functions in esophageal cancer are still unknown. This study aimed to explore the expression of PAQR3 in esophageal cancer cell lines and to investigate the role of PAQR3 in the development of esophageal cancer. Our data showed that PAQR3 is expressed in low amounts in human esophageal cancer cell lines. Overexpression of PAQR3 significantly suppressed the proliferation, migration, and invasion of esophageal cancer cells. In addition, overexpression of PAQR3 downregulated the protein expression levels of RAF1, p-MEK1, and p-ERK1/2 in esophageal cancer cells. Furthermore, overexpression of PAQR3 attenuated the tumor growth in a tumor xenograft model. In conclusion, we demonstrated that overexpression of PAQR3 suppresses cell proliferation, migration, and invasion in esophageal cancer in vitro and in vivo. Therefore, PAQR3 may act as a therapeutic target for human esophageal cancer.

Alternative splicing and the progesterone receptor in breast cancer

PubMed Central

Cork, David MW; Lennard, Thomas WJ; Tyson-Capper, Alison J

2008-01-01

Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions. PMID:18557990

Progesterone Signaling Inhibits Cervical Carcinogenesis in Mice

PubMed Central

Yoo, Young A; Son, Jieun; Mehta, Fabiola F.; DeMayo, Francesco J.; Lydon, John P.; Chung, Sang-Hyuk

2014-01-01

Human papillomavirus is the main cause of cervical cancer, yet other nonviral cofactors are also required for the disease. The uterine cervix is a hormone-responsive tissue, and female hormones have been implicated in cervical carcinogenesis. A transgenic mouse model expressing human papillomavirus oncogenes E6 and/or E7 has proven useful to study a mechanism of hormone actions in the context of this common malignancy. Estrogen and estrogen receptor α are required for the development of cervical cancer in this mouse model. Estrogen receptor α is known to up-regulate expression of the progesterone receptor, which, on activation by its ligands, either promotes or inhibits carcinogenesis, depending on the tissue context. Here, we report that progesterone receptor inhibits cervical and vaginal epithelial cell proliferation in a ligand-dependent manner. We also report that synthetic progestin medroxyprogesterone acetate promotes regression of cancers and precancerous lesions in the female lower reproductive tracts (ie, cervix and vagina) in the human papillomavirus transgenic mouse model. Our results provide the first experimental evidence that supports the hypothesis that progesterone signaling is inhibitory for cervical carcinogenesis in vivo. PMID:24012679

Combined hormonal contraceptive trials: variable data collection and bleeding assessment methodologies influence study outcomes and physician perception.

PubMed

Mishell, Daniel R; Guillebaud, John; Westhoff, Carolyn; Nelson, Anita L; Kaunitz, Andrew M; Trussell, James; Davis, Ann Jeanette

2007-01-01

Initially approved for use in the United States nearly 50 years ago, oral hormonal contraceptives containing both estrogen and progestin have undergone steady improvements in safety and convenience. Concurrent with improvements in safety associated with decreasing doses of both steroids, there has been an increased incidence of unscheduled bleeding and spotting. There exist no standards regarding data collection techniques and methods, and reporting and analysis of bleeding and spotting events during combined hormonal contraceptive (CHC) trials. For the regulatory review of hormonal contraceptives, data regarding the incidence of bleeding and spotting events are not included in either of the traditional categories of efficacy and safety. Standardization of methods for collecting and analyzing data about cycle control in all clinical trials of CHCs is long overdue. Until such standards are developed and implemented, clinicians need to familiarize themselves with the techniques used in each study in order to provide correct information to their patients about the frequency of bleeding and spotting associated with different formulations and delivery systems.

Lactation and reproduction*

PubMed Central

Thomson, A. M.; Hytten, F. E.; Black, A. E.

1975-01-01

The authors review the literature on the effect of lactation on fertility in the absence of contraception and on the effects of contraceptive measures on lactation. They examine data from several countries on the intervals between births and on the return of menstruation and ovulation after childbirth, comparing lactating with nonlactating women. They conclude that lactation is an inefficient contraceptive for the individual, but that in populations sustained lactation is associated with reduced fertility. Possible physiological mechanisms causing lactation amenorrhoea are discussed. Though much of the literature on the effect of contraceptives on lactation is inadequate, there is general agreement that the estrogen component of hormonal preparations has an adverse effect on lactation, but that progestins alone do not. Many questions remain. Is this effect seen in established lactation, or only in the puerperal period? Is it a direct pharmacological effect, or are pill-users the mothers least motivated to maintain breast-feeding? Does a close relationship exist between hormones given and lactation performance? The authors comment on some of the technical deficiencies of previous studies in this field and discuss practical possibilities of, and limitations to, obtaining adequate scientific information in the future. PMID:1084804

Ethynilestradiol 20 mcg plus Levonorgestrel 100 mcg: Clinical Pharmacology.

PubMed

Lello, Stefano; Cavani, Andrea

2014-01-01

Estroprogestins (EPs) are combinations of estrogen and progestin with several actions on women's health. The different pharmacological composition of EPs is responsible for different clinical effects. One of the most used low-dose EP associations is ethinylestradiol 20 mcg plus levonorgestrel 100 mcg in monophasic regimen (EE20/LNG100). This review summarizes clinical pharmacology, cycle control, and effects on lipid and glucose metabolism, coagulation, body weight/body composition, acne, and sexuality of EE20/LNG100. Overall, EE20/LNG100 combination is safe and well tolerated, and in several studies the incidence of adverse events in the treated group was comparable to that of the placebo group. Cycle control was effective and body weight/body composition did not vary among treated and untreated groups in most studies. The EE20/LNG100 combination shows mild or no effect on lipid and glucose metabolism. Lastly, EE20/LNG100 is associated with a low risk of venous thromboembolism (VTE). In conclusion, in the process of decision making for the individualization of EPs choice, EE20/LNG100 should be considered for its favorable clinical profile.

Effects of Sex Steroids on Fish Leukocytes

PubMed Central

Cabas, Isabel

2018-01-01

In vertebrates, in addition to their classically reproductive functions, steroids regulate the immune system. This action is possible mainly due to the presence of steroid receptors in the different immune cell types. Much evidence suggests that the immune system of fish is vulnerable to xenosteroids, which are ubiquitous in the aquatic environment. In vivo and in vitro assays have amply demonstrated that oestrogens interfere with both the innate and the adaptive immune system of fish by regulating the main leukocyte activities and transcriptional genes. They activate nuclear oestrogen receptors and/or G-protein coupled oestrogen receptor. Less understood is the role of androgens in the immune system, mainly due to the complexity of the transcriptional regulation of androgen receptors in fish. The aim of this manuscript is to review our present knowledge concerning the effect of sex steroid hormones and the presence of their receptors on fish leukocytes, taking into consideration that the studies performed vary as regard the fish species, doses, exposure protocols and hormones used. Moreover, we also include evidence of the probable role of progestins in the regulation of the immune system of fish. PMID:29315244

In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone.

PubMed

Attardi, Barbara J; Burgenson, Janet; Hild, Sheri A; Reel, Jerry R

2004-03-01

In determining the biological profiles of various antiprogestins, it is important to assess the hormonal and antihormonal activity, selectivity, and potency of their proximal metabolites. The early metabolism of mifepristone is characterized by rapid demethylation and hydroxylation. Similar initial metabolic pathways have been proposed for CDB-2914 (CDB: Contraceptive Development Branch of NICHD) and CDB-4124, and their putative metabolites have been synthesized. We have examined the functional activities and potencies, in various cell-based assays, and relative binding affinities (RBAs) for progesterone receptors (PR) and glucocorticoid receptors (GR) of the putative mono- and didemethylated metabolites of CDB-2914, CDB-4124, and mifepristone and of the 17alpha-hydroxy and aromatic A-ring derivatives of CDB-2914 and CDB-4124. The binding affinities of the monodemethylated metabolites for rabbit uterine PR and human PR-A and PR-B were similar to those of the parent compounds. Monodemethylated mifepristone bound to rabbit thymic GR with higher affinity than monodemethylated CDB-2914 or CDB-4124. T47D-CO cells were used to assess inhibition of R5020-stimulated endogenous alkaline phosphatase activity and transactivation of the PRE(2)-thymidine kinase (tk)-luciferase (LUC) reporter plasmid in transient transfections. The antiprogestational potency was as follows: mifepristone/CDB-2914/CDB-4124/monodemethylated metabolites (IC(50)'s approximately 10(-9)M) > aromatic A-ring derivatives (IC(50)'s approximately 10(-8)M) > didemethylated/17alpha-hydroxy derivatives (IC(50)'s approximately 10(-7)M). Antiglucocorticoid activity was determined by inhibition of dexamethasone-stimulated transcriptional activity in HepG2 cells. The mono- and didemethylated metabolites of CDB-2914 and CDB-4124 had less antiglucocorticoid activity (IC(50)'s approximately 10(-6)M) than monodemethylated mifepristone (IC(50) approximately 10(-8)M) or the other test compounds. At 10(-6)M in transcription assays, none of these compounds showed progestin agonist activity, whereas mifepristone and its monodemethylated metabolite manifested slight glucocorticoid agonist activity. The reduced antiglucocorticoid activity of monodemethylated CDB-2914 and CDB-4124 was confirmed in vivo by the thymus involution assay in adrenalectomized male rats. The aromatic A-ring derivatives-stimulated transcription of an estrogen-responsive reporter plasmid in MCF-7 and T47D-CO human breast cancer cells but were much less potent than estradiol. Taken together, these data suggest that the proximal metabolites of mifepristone, CDB-2914, and CDB-4124 contribute significantly to the antiprogestational activity of the parent compounds in vivo. Furthermore, the reduced antiglucocorticoid activity of CDB-2914 and CDB-4124 compared to mifepristone in vivo may be due in part to decreased activity of their putative proximal metabolites.

Benefits and risks of ovarian function and reproduction for cancer development and prevention.

PubMed

Schindler, Adolf E

2011-12-01

Ovarian function and menstrual cycle disturbances, pregnancy, and reproductive medicine procedures can either increase gynecological cancer risk or prevent cancer development. For ovarian cancer development, there are two hypotheses, which are connected with ovulation and gonadotropin secretion. Most of the ovarian cancers seem to be derived from displaced ovarian surfice epithelial cells. One year of ovulatory cycles increases the ovarian cancer risk by 6%. Ovulation between 22 and 29 years of age causes the highest risk increase per year. In contrast, progesterone or progestins appear to create protection. Lifestyle can affect or modify ovarian cancer risk. Breast cancer risk is very much related to age of menarche and menopause, pregnancy, and breast feeding. All of which are related to ovarian function and progestogenic impact that translates either into breast cancer risk increase or decrease. This is modified by body mass index, physical activity, and lifestyle in general. The risk of endometrial cancer is most closely related to endogenous progesterone during the menstrual cycle and pregnancy or by exogenous progestogens as in oral contraceptives. These effects are progestogen dose and time dependent. Endometrial cancer risk can also be increased by estrogen-producing tumors or long-term estrogen treatment.

Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men.

PubMed

Meriggiola, M Cristina; Cerpolini, S; Bremner, W J; Mbizvo, M T; Vogelsong, K M; Martorana, G; Pelusi, G

2006-08-01

We assessed attitudes towards and acceptability of male hormonal contraception among volunteers participating in a clinical trial of a prototype regimen, consisting of progestin and testosterone injections. After completing screening, eligible men were randomly assigned to the no-treatment group (n = 40) or to receive injections of norethisterone enanthate and testosterone undecanoate or placebo at different intervals (n = 50) according to a blocked randomization list. They underwent self-administered questionnaires. The average age of the participants was approximately 28 years; most were involved in a stable relationship and had no children. Ninety-two percentage of the respondents thought that men and women should share responsibility for contraception and 75% said they would try a hormonal contraceptive if available. At the end of the treatment phase, 66% of the participants said that they would use such a method, and most rated its acceptability very highly; none reported it to be unacceptable. The injections themselves were indicated as the biggest disadvantage. No significant changes in sexual function or mood states were detected among the men who underwent hormone injections. The contraceptive tested in this study was well accepted by the participants over the course of 1 year.

Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development.

PubMed

Nelson, Anita L

2015-01-01

As efforts are made to continue to increase the safety of contraceptive methods, those without estrogen have attracted new attention. Progestin-only options are available in many delivery systems, but most cause disturbed bleeding patterns. For gynecologic patients, selective progesterone receptor modulators (SPRMs) have been approved for medical abortion, for ovulation suppression in emergency contraception, and for the treatment of heavy menstrual bleeding due to leiomyoma. This article discusses the role of SPRMs in controlling fertility on an ongoing basis with particular emphasis on mifepristone and ulipristal acetate (UPA), since none of the other compounds has progressed out of early Phase I - II testing. It also discusses important information about the mechanisms of action and safety of these two SPRMs. Of all the investigational hormone agonist/antagonists, SPRMs have demonstrated the greatest potential as ongoing female contraceptives. They have the ability to suppress ovulation after initiation of the luteinizing hormone (LH) surge without affecting ovarian production of estrogen or inducing any significant metabolic changes. SPRMs may well be able to provide longer term contraception as oral agents, vaginal rings, and perhaps even intrauterine devices. UPA has the greatest promise. Current research needs to be expanded.

Longitudinal fecal steroid excretion in maned wolves (Chrysocyon brachyurus).

PubMed

Velloso, A L; Wasser, S K; Monfort, S L; Dietz, J M

1998-10-01

This study used a fecal steroid monitoring technique to evaluate reproductive cycles in male (4) and female (15) maned wolves, endangered South American canids. A radiolabeled testosterone infusion on a male revealed a fast and predominantly fecal route of excretion for this steroid. Testosterone was also excreted as eight unidentified metabolites, which was not the primary form of this steroid quantified in our assays. Fecal steroid concentrations (estradiol, E2; progestins, P; testosterone, T) in males and acyclic, nonpregnant (pseudo-pregnant), and pregnant females were monitored over four breeding seasons (October-January). Significant differences were detected between longitudinal P profiles of cyclic and acyclic females during estrus, luteal phase, and after birth/end of pseudo-pregnancy. Concentrations of P were also significantly higher in pregnant, compared to nonpregnant females, from proestrus to the end of the pregnant luteal phase. Although levels of T were higher in males than in females throughout the breeding season, no cyclicity in male fecal T concentrations was detected. Values of fecal P, T, and the ratio P/T were useful for differentiating gender and detecting pregnancy in females. Similarities to available data on other canids and the management and conservation implications of these findings were discussed. Copyright 1998 Academic Press.

Therapeutic options for management of endometrial hyperplasia

PubMed Central

2016-01-01

Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH. PMID:26463434

Therapeutic options for management of endometrial hyperplasia.

PubMed

Chandra, Vishal; Kim, Jong Joo; Benbrook, Doris Mangiaracina; Dwivedi, Anila; Rai, Rajani

2016-01-01

Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.

[Male contraception - the current state of knowledge].

PubMed

Zdrojewicz, Zygmynt; Kasperska, Karolina; Lewandowska, Marta

2016-08-01

Contraception is important from a health, psychological and socioeconomic point of view. Due to the fact that male-based contraceptive methods are mostly represented by condoms and vasectomy, researchers are working on the new solutions, which could let the men be more involved in a conscious family planning. In this review we will present the current state of knowledge on this subject. There is a lot going on in the field of hormonal contraception. Studies including testosterone, progestins, synthetic androgens and other derivatives are on a different stages of clinical trials and mostly demonstrate high efficacy rates. Recent discovers of Izumo and Juno proteins, essential for the fertilization process, give hope for an easily reversible, non-hormonal method. Researchers are also trying to interfere with the process of spermatogenesis using BRDT inhibitor - JQ1, or neutralize the sperm by injecting styrene maleic anhydride (SMA) into the lumen of the vas deferens. The other studies explore processes involved in proper sperm motility. A vaccine which induces an immune response to the reproductive system is also an interesting method. The latest research use ultrasound waves and mechanical device which blocks the patency of vas deferens. The aim of the study current state of knowledge male contraception. © 2016 MEDPRESS.

Use of progesterone and progestin analogs for inhibition of preterm birth and other uterine contractility disorders

PubMed Central

Garfield, R.E.; Shi, L.; Shi, S-Q.

2012-01-01

In this paper we focus on preterm birth as a uterine contractility disorder caused by hypercontractility of the myometrium. We describe changes in uterine function during term and preterm labor and delivery. We also examine the usefulness of measurement of uterine electromyographic (EMG) activity, noninvasively monitored from the abdominal surface of pregnant patients. The use of progesterone treatment for preterm birth is discussed and we conclude that present therapies with progesterone could be improved by changing the route of administration. Finally we show the results of recent studies that show that progesterone injections completely inhibit uterine EMG activity when given several days to hours before normal delivery. These studies illustrate how progesterone suppresses labor at term or preterm, probably through repression of genes which control excitability and conduction of electrical activity. However, direct profusion of soluble progesterone into the uterine cavity has little immediate inhibitory action and this may demonstrate that progesterone has no direct, nongenomic effects, at least in the rat model used. Further studies are required to determine the effects of progesterone on human uterine EMG activity and whether progesterone treatments will prevent preterm birth. PMID:24753915

Metabolic changes in serum steroids induced by total-body irradiation of female C57B/6 mice.

PubMed

Moon, Ju-Yeon; Shin, Hee-June; Son, Hyun-Hwa; Lee, Jeongae; Jung, Uhee; Jo, Sung-Kee; Kim, Hyun Sik; Kwon, Kyung-Hoon; Park, Kyu Hwan; Chung, Bong Chul; Choi, Man Ho

2014-05-01

The short- and long-term effects of a single exposure to gamma radiation on steroid metabolism were investigated in mice. Gas chromatography-mass spectrometry was used to generate quantitative profiles of serum steroid levels in mice that had undergone total-body irradiation (TBI) at doses of 0Gy, 1Gy, and 4Gy. Following TBI, serum samples were collected at the pre-dose time point and 1, 3, 6, and 9 months after TBI. Serum levels of progestins, progesterone, 5β-DHP, 5α-DHP, and 20α-DHP showed a significant down-regulation following short-term exposure to 4Gy, with the exception of 20α-DHP, which was significantly decreased at each of the time points measured. The corticosteroids 5α-THDOC and 5α-DHB were significantly elevated at each of the time points measured after exposure to either 1 or 4Gy. Among the sterols, 24S-OH-cholestoerol showed a dose-related elevation after irradiation that reached significance in the high dose group at the 6- and 9-month time points. Copyright © 2014 Elsevier Ltd. All rights reserved.

An ethinyl estradiol-levonorgestrel containing oral contraceptive does not alter cytochrome P4502C9 in vivo activity.

PubMed

Cherala, Ganesh; Pearson, Jacob; Maslen, Cheryl; Edelman, Alison

2014-03-01

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C24) was measured using liquid chromatography-mass spectrometry. The natural logarithm of tolbutamide C24, a metric for CYP2C9 phenotype, was found to be equivalent (within 80%-125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to co-administer levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs.

Ethinyl estradiol and levonorgestrel in a transdermal contraceptive delivery system.

PubMed

Sriprasert, Intira; Stanczyk, Frank Z; Archer, David F

2015-01-01

The new transdermal contraceptive delivery system (TCDS) developed by Agile Therapeutics containing ethinyl estradiol and levonorgestrel (EE/LNG) is a reversible contraceptive method that maintains stable serum levels of both estrogen and progestin, and has efficacy similar to that of combination oral contraceptives (COC). We provided information of this new TCDS compared with the only TCDS available on the market that contains EE and norelgestromin, and has a higher EE exposure than a COC with 35 µg of EE potentially increasing the risk of venous thromboembolism. The article will summarize finding from clinical studies Phase I, II and III of EE/LNG TCDS. The development of the lower dose EE/LNG TCDS has demonstrated less EE exposure. The serum levels of EE and LNG were stable and comparable between various application sites and daily life conditions. Moreover, the EE/LNG TCDS showed comparable efficacy among obese and non-obese users. However, the Pearl index of this EE/LNG TCDS is questionable and the problem of compliance is a potential confounder of the results. The current Phase III efficacy study will contribute to a further evaluation of compliance and efficacy and will be completed in 2016.

An Ethinyl Estradiol-Levonorgestrel Containing Oral Contraceptive Does Not Alter Cytochrome P4502C9 In Vivo Activity

PubMed Central

Pearson, Jacob; Maslen, Cheryl; Edelman, Alison

2014-01-01

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug–drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C24) was measured using liquid chromatography–mass spectrometry. The natural logarithm of tolbutamide C24, a metric for CYP2C9 phenotype, was found to be equivalent (within 80%–125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to coadminister levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs. PMID:24368832

Lipoprotein Particle Concentrations May Explain the Absence of Coronary Protection in the Women's Health Initiative Hormone Trials

PubMed Central

Hsia, Judith; Otvos, James D.; Rossouw, Jacques E.; Wu, LieLing; Wassertheil-Smoller, Sylvia; Hendrix, Susan L.; Robinson, Jennifer G.; Lund, Bernedine; Kuller, Lewis H.

2009-01-01

Objective The Women's Health Initiative randomized hormone trials unexpectedly demonstrated an increase in early coronary events. In an effort to explain this finding, we examined lipoprotein particle concentrations and their interactions with hormone therapy in a case–control substudy. Methods and Results We randomized 16 608 postmenopausal women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10 739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo, and measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy at baseline and year 1 in 354 women with early coronary events and matched controls. Postmenopausal hormone therapy raised high-density lipoprotein cholesterol and particle concentration and reduced low-density lipoprotein cholesterol (LDL-C; all P<0.001 versus placebo). In contrast, neither unopposed estrogen nor estrogen with progestin lowered low-density lipoprotein particle concentration (LDL-P). Conclusions Postmenopausal hormone therapy–induced reductions in LDL-C were not paralleled by favorable effects on LDL-P. This finding may account for the absence of coronary protection conferred by estrogen in the randomized hormone trials. PMID:18599797

PAQR3 inhibits the proliferation, migration and invasion in human glioma cells.

PubMed

Tang, Shi-Lei; Gao, Yuan-Lin; Hu, Wen-Zhong

2017-08-01

Progestin and AdipoQ Receptor 3 (PAQR3), a member of the PAQR family, is down-regulated in several types of cancers and has been closely associated with tumor progression and development. However, little is known about the functions of PAQR3 in the tumorigenesis of human glioma. Therefore, in this report, we investigated the role of PAQR3 in human glioma. Our results showed that the expression of PAQR3 was significantly reduced in human glioma tissues and cell lines. PAQR3 overexpression inhibited the proliferation of glioma cells in vitro and attenuated tumor xenograft growth in vivo. In addition, PAQR3 overexpression suppressed the migration and invasion of glioma cells, as well as prevented the EMT process. Mechanistic studies demonstrated that PAQR3 overexpression significantly down-regulated the levels of phosphorylated PI3K and Akt in U251 cells. In conclusion, these results demonstrated that PAQR3 inhibited the proliferation, migration and invasion in glioma cells, at least in part, through the inactivation of PI3K/Akt signaling pathway. Therefore, PAQR3 may be a therapeutic target for the treatment of glioma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Characterizing the Growth Kinetics in Estrogen Responsive ...

EPA Pesticide Factsheets

There is a need to develop high-throughput screening (HTS) tests capable of testing thousands of environmental chemicals for endocrine disrupting potential. The estrogen signaling pathway is a known xenobiotic target that has been implicated in a variety of adverse health effects including reproductive deficits and cancer promotion. Using real-time measurements of growth kinetics by electrode impedance, the estrogen-responsive human ductal carcinoma cell line, T47D, was treated with 2000 chemicals of environmental relevance. Cells were treated in concentration response and measurements of cellular impedance were recorded every hour for six days. Exponential impedance, signifying increased proliferation, was observed by prototypical estrogen receptor agonists (17β-estradiol, genestein, bisphenol-A, nonylphenol, 4-tert-octylphenol). Several compounds, including bisphenol-A and genestein, induced cell proliferation at comparable levels to 17β-estradiol, although at much higher concentrations. Progestins, and mineralocortocoids (progesterone, dihydrotestosterone, aldosterone) invoked a biphasic impedance signature. In conclusion, the real-time nature of this assay allows for rapid detection of differential growth characteristics shows potential, in combination with other ToxCast HTS assays, to detect environmental chemicals with potential endocrine activity. [This abstract does not necessarily reflect Agency policy]. Several compounds, including bisphenol-A and

Cyclic stretch augments production of neutrophil chemokines and matrix metalloproteinase-1 in human uterine smooth muscle cells.

PubMed

Zhao, Yin; Koga, Kaori; Osuga, Yutaka; Izumi, Gentaro; Takamura, Masashi; Harada, Miyuki; Hirata, Tetsuya; Hirota, Yasushi; Yoshino, Osamu; Fujii, Tomoyuki; Kozuma, Shiro

2013-03-01

The aim of this study was to investigate the impact of uterine contraction on the immune environment within the uterus during parturition. Uterine smooth muscle cells (USMC) were isolated from uterine myometrial tissues and cultured. The effects of cyclic stretch on mRNA and/or protein expression of IL-8, Groα, and pro-MMP-1 by USMC were measured using RT-PCR and ELISA. Neutrophil chemotactic activity in conditioned media was evaluated using migration assays. To evaluate the effect of progesterone (P(4) ), USMC were pretreated with P(4) for 24 hr. Cyclic stretch increased IL-8 and Groα mRNA and protein and pro-MMP-1 production significantly. Supernatants from stretched cells induced neutrophil chemotactic activity significantly; these effects were abrogated by anti-IL-8 or Groα neutralizing antibodies. Stretch effects were reduced by P(4) . These results suggest that uterine contraction may induce neutrophil infiltration and MMP-1 production, which may contribute to cervical ripening and rupture of membrane. The inhibitory effects of P(4) may explain the mechanism by which progestin prevents preterm labor. © 2012 John Wiley & Sons A/S.

Progesterone and progesterone receptor modulators in the management of symptomatic uterine fibroids.

PubMed

Talaulikar, Vikram Sinai; Manyonda, Isaac

2012-12-01

The majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolisation or focussed ultrasound surgery). None of these treatments is a panacea, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age. It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids and this has raised the possibility that anti-progestins and (PRMs) could be useful in the medical management of fibroids. Some of the compounds which have produced promising results in recent clinical trials or research studies include mifepristone, CDB-4124 (telapristone), CP-8947, J-867 (asoprisnil) and CDB-2914 (ulipristal acetate or UA). UA has recently completed Phase III clinical trials with very encouraging results, and has now acquired a licence for clinical use in Europe. While considerable research has yet to be done on the long-term safety and efficacy of UA there is nevertheless good reason for optimism on the emergence of effective medical therapy in the form of UA and possibly other PRMs. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pituitary and ovarian hormone activity during the 7-day hormone-free interval of various combined oral contraceptive regimens.

PubMed

Cho, Michael; Atrio, Jessica; Lim, Aaron H; Azen, Colleen; Stanczyk, Frank Z

2014-07-01

The objective was to investigate changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and progesterone (P) during the hormone-free interval (HFI) of 6 combined oral contraceptives (COCs). Blood samples were obtained from 62 women. When COCs were grouped by ethinyl estradiol (EE) dose, there was a significant positive mean slope for LH and FSH during the HFI for the 30- and 35 mcg-EE doses, whereas 20 showed a gradual nonsignificant slope. All E2 slopes were significant. P remained suppressed with all doses. A more rapid rebound of gonadotropin levels is found with higher doses of EE during the HFI. This study showed a more rapid rebound of pituitary hormone levels among women using higher-EE-dosage formulations, which was demonstrated by the statistically significant slope for mean LH and FSH from day 1 to day 7 of the HFI. The degree of suppression did not vary across progestin generations. It remains to be established whether women who experience side effects during their HFI may benefit from using a COC with a lower EE dose to minimize changes in endogenous pituitary hormone levels. Copyright © 2014 Elsevier Inc. All rights reserved.

Medroxyprogesterone acetate-treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV-1 susceptibility.

PubMed

Woods, Matthew W; Zahoor, Muhammad Atif; Dizzell, Sara; Verschoor, Chris P; Kaushic, Charu

2018-01-01

Medroxyprogesterone acetate (MPA), a progestin-based hormonal contraceptive designed to mimic progesterone, has been linked to increased human immunodeficiency virus (HIV-1) susceptibility. Genital epithelial cells (GECs) form the mucosal lining of the female genital tract (FGT) and provide the first line of protection against HIV-1. The impact of endogenous sex hormones or MPA on the gene expression profile of GECs has not been comprehensively documented. Using microarray analysis, we characterized the transcriptional profile of primary endometrial epithelial cells grown in physiological levels of E2, P4, and MPA. Each hormone treatment altered the gene expression profile of GECs in a unique manner. Interestingly, although MPA is a progestogen, the gene expression profile induced by it was distinct from P4. MPA increased gene expression of genes related to inflammation and cholesterol synthesis linked to innate immunity and HIV-1 susceptibility. The analysis of gene expression profiles provides insights into the effects of sex hormones and MPA on GECs and allows us to posit possible mechanisms of the MPA-mediated increase in HIV-1 acquisition. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Androgen responsiveness of the new human endometrial cancer cell line MFE-296.

PubMed

Hackenberg, R; Beck, S; Filmer, A; Hushmand Nia, A; Kunzmann, R; Koch, M; Slater, E P; Schulz, K D

1994-04-01

MFE-296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, are derived from a moderately differentiated human endometrial adenocarcinoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near-tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE-296 cells was inhibited by the progestin R5020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole-cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below 5 fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter-gene construct, containing an androgen-responsive element. In MFE-296 cells the content of the androgen receptor was up-regulated by its own ligand.

Suppression of fertility in adult cats.

PubMed

Goericke-Pesch, S; Wehrend, A; Georgiev, P

2014-06-01

Cats are animals with highly efficient reproduction, clearly pointing to a need for suppression of fertility. Although surgical contraception is highly effective, it is not always the method of choice. This is predominantly because it is cost-intensive, time-consuming and irreversible, with the latter being of major importance for cat breeders. This article reviews the use of progestins, scleroting agents, immunocontraception, melatonin, GnRH antagonists and finally, GnRH agonists, in adult male and female cats in detail, according to the present state of the art. By now, various scientific and clinical options are available for the suppression of fertility in adult cats and the decision as to which should be chosen - independent of the legal registration of any state - depends on different facts: (i) feral or privately owned animal? (ii) temporary or permanent suppression of fertility wanted/needed? (iii) sex of the animal? New effective and available methods for hormonal contraception include melatonin implants for short-term post ponement of oestrus in adult queens and slow-release GnRH-agonist implants containing deslorelin (Suprelorin(®) ) for short- and long-term contraception in male and female companion and breeding cats. © 2014 Blackwell Verlag GmbH.

Activation of endothelial nitric oxide synthase by dietary isoflavones: role of NO in Nrf2-mediated antioxidant gene expression.

PubMed

Mann, Giovanni E; Rowlands, David J; Li, Francois Y L; de Winter, Patricia; Siow, Richard C M

2007-07-15

The endothelium plays a key role in the maintenance of vascular homeostasis, and increased oxidative stress in vascular disease leads to reduced nitric oxide bioavailability and impaired endothelium-dependent relaxation of resistance vessels. Although epidemiological evidence suggests that diets containing high amounts of natural antioxidants afford protection against coronary heart disease (CHD), antioxidant supplementation trials have largely reported only marginal health benefits. There is controversy concerning the cardiovascular benefits of prolonged estrogen/progestin or soy isoflavone therapy for postmenopausal women and patients with an increased risk of CHD. Research on the potential health benefits of soy isoflavones and other polyphenols contained in red wine, green and black tea and dark chocolate developed rapidly during the 1990's, and recent clinical trials and studies in animal models and cultured endothelial cells provide important and novel insights into the mechanisms by which dietary polyphenols afford protection against oxidative stress. In this review, we highlight that NO and reactive oxygen radicals may mediate dietary polyphenol induced activation of Nrf2, which in turn triggers antioxidant response element (ARE) driven transcription of phase II detoxifying and antioxidant defense enzymes in vascular cells.

Embryo-fetal toxicity signals for 17alpha-hydroxyprogesterone caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with progestins.

PubMed

Christian, M S; Brent, R L; Calda, P

2007-02-01

A large National Institutes of Health (NIH) study showed that pharmacy-compounded 17alpha-hydroxyprogesterone caproate (17-OHP-C) reduced the incidence of preterm birth. The study results included a signal that 17-OHP-C may be associated with an increase in the rate of miscarriages and stillbirths. The most probable cause of an increased incidence of miscarriage/stillbirths may be the use of 17-OHP-C in high-risk patients. The current search of the non-clinical literature was performed to identify whether there were any signals from studies in animals that might suggest concerns for the safe use of progestins generally, and 17-OHP-C specifically, in the prevention of preterm birth in humans. An extensive literature search was performed for progesterone, 17-hydroxyprogesterone, and 17-OHP-C, using Medline and Toxline databases, textbooks, and then the obtained publications. Because 17-OHP-C does not have a standardized clinical formulation or optimal route of administration identified, all formulations, vehicles, routes and doses were included in the search, as well as treatment during any stage of pregnancy. All publications obtained were reviewed for relevancy; those in German, French, Italian or Russian were translated. None of the relevant non-clinical studies conducted in mice, rats, rabbits, guinea pigs, horses or non-human primates met current standards for determining reproductive and developmental effects as part of the process of drug development. Most studies focused on the potential of 17-OHP-C for teratogenicity. Many studies used supra-pharmacologic and/or high multiples of human exposure in their study design. Overall, 17-OHP-C was consistently shown to be less potent than progesterone, and neither progesterone nor 17-OHP-C consistently adversely affected maternal weight, embryo-fetal viability or caused malformations. One study in rhesus monkeys raises concerns because resorption/abortion occurred at the human equivalent dose of 17-OHP-C, 10 mg/kg; this finding did not occur in cynomolgus monkeys. The absence of information regarding the serum levels of both progesterone and 17-OHP-C in the animal studies and in humans, as well as presumed inter-species metabolic differences, make it difficult to conclude that the findings with 17-OHP-C in rhesus monkeys and the signal in the NIH trial are related. A few studies in rats raised questions regarding potential effects on postnatal development, but in the absence of better study designs, the relevancy of these findings to human risk are also questionable at best. There is a signal for embryo-fetal toxicity associated with 17-OHP-C in the two largest clinical trials conducted to date; there is also a signal for embryo-fetal toxicity with 17-OHP-C in rhesus monkeys and possibly one in rodent species. The relationship between these signals is unclear given the absence of state-of-the-art reproductive toxicology studies and human pharmacokinetic studies.

Contraception today.

PubMed

Benagiano, Giuseppe; Bastianelli, Carlo; Farris, Manuela

2006-12-01

Modern contraceptive methods represent more than a technical advance: they are the instrument of a true social revolution-the "first reproductive revolution" in the history of humanity, an achievement of the second part of the 20th century, when modern, effective methods became available. Today a great diversity of techniques have been made available and-thanks to them, fertility rates have decreased from 5.1 in 1950 to 3.7 in 1990. As a consequence, the growth of human population that had more than tripled, from 1.8 to more than 6 billion in just one century, is today being brought under control. At the turn of the millennium, all over the world, more than 600 million married women are using contraception, with nearly 500 million in developing countries. Among married women, contraceptive use rose in all but two developing countries surveyed more than once since 1990. Among unmarried, sexually active women, it grew in 21 of 25 countries recently surveyed. Hormonal contraception, the best known method, first made available as a daily pill, can today be administered through seven different routes: intramuscularly, intranasally, intrauterus, intravaginally, orally, subcutaneously, and transdermally. In the field of oral contraception, new strategies include further dose reduction, the synthesis of new active molecules, and new administration schedules. A new minipill (progestin-only preparation) containing desogestrel has been recently marketed in a number of countries and is capable of consistently inhibiting ovulation in most women. New contraceptive rings to be inserted in the vagina offer a novel approach by providing a sustained release of steroids and low failure rates. The transdermal route for delivering contraceptive steroids is now established via a contraceptive patch, a spray, or a gel. The intramuscular route has also seen new products with the marketing of improved monthly injectable preparations containing an estrogen and a progestin. After the first device capable of delivering progesterone directly into the uterus was withdrawn, a new system releasing locally 20 microg evonorgestrel is today marketed in a majority of countries with excellent contraceptive and therapeutic performance. Finally, several subcutaneously implanted systems have been developed: contraceptive "rods," where the polymeric matrix is mixed with the steroid and "capsules" made of a hollow polymer tube filled with free steroid crystals. New advances have also been made in nonhormonal intrauterine contraception with the development of "frameless" devices. The HIV/AIDS pandemic forced policy makers to look for ways to protect young people from sexually transmitted diseases as well as from untimely pregnancies. This led to the development of the so-called dual protection method, involving the use of a physical barrier (condom) as well as that of a second, highly effective contraceptive method. More complex is the situation with antifertility vaccines, still at a preliminary stage of development and unlikely to be in widespread use for years to come. Last, but not least, work is in progress to provide effective emergency contraception after an unprotected intercourse. Very promising in this area is the use of selective progesterone receptor modulators (antiprogestins).

When can a woman resume or initiate contraception after taking emergency contraceptive pills? A systematic review.

PubMed

Salcedo, Jennifer; Rodriguez, Maria I; Curtis, Kathryn M; Kapp, Nathalie

2013-05-01

Hormonal emergency contraception can postpone ovulation, making a woman vulnerable to pregnancy later in the same cycle. However, concern exists as to whether concurrently administered emergency contraception pills (ECP) and other hormonal methods of contraception may affect the effectiveness of both medications. A systematic review of the literature using PubMed and the Cochrane databases was performed to identify articles concerning the resumption or initiation of regular contraception within the same cycle as ECP use. We searched for articles in any language, published between 1980 and April 2012 and included all methods of emergency contraception pills available in the USA. The search strategy identified 184 articles in the PubMed and Cochrane databases, of which none met inclusion criteria. The drug manufacturer advises continuation or initiation of routine contraception as soon as possible after use of ulipristal acetate, with concomitant use of a reliable barrier method until next menses. However, a theoretical concern exists that given ulipristal acetate's function as a selective progesterone receptor modulator, coadministration of a progestin could decrease its effectiveness as an emergency contraceptive. Initiation of hormonal contraception following levonorgestrel or the Yuzpe regimen for emergency contraception carries no similar concern for decreased method effectiveness. Copyright © 2013 Elsevier Inc. All rights reserved.

Gamma irradiated micro system for long-term parenteral contraception: An alternative to synthetic polymers.

PubMed

Puthli, S; Vavia, P

2008-11-15

An injectable system of levonorgestrel (LNG) was developed using biodegradable polymer of natural origin. The parenteral system was optimized for particle size and higher drug loading. The microparticulate system was characterised by scanning electron microscopy, encapsulation efficiency, moisture content, IR, DSC, XRD, residual solvent content, sterility testing, test of abnormal toxicity and test for pyrogens. The microparticles were sterilised by gamma irradiation (2.5Mrad). The system was injected intramuscularly in rabbits and the blood levels of LNG were determined using radioimmunoassay technique. An optimized drug to polymer ratio of 0.3-1.0 (w/w ratio) gave improved drug loading of about 52%. In vivo studies in rabbits showed that the drug was released in a sustained manner for a period of 1 month. The AUC(0-t) was found to be 9363.6+/-2340pg/mLday(-1) with MRT calculated to be about 16 days and Kel of 0.01day(-1). LNG levels were maintained between 200 and 400pg/mL. In vivo release exhibited an initial burst effect which was not observed in the in vitro dissolution. This promising "Progestin-only" long-term contraceptive with improved user compliance is an alternative to the synthetic expensive polymeric carriers.

Effects of tibolone on sulfatase pathway of estrogens metabolism and on growth of MCF-7 human breast tumors implanted in ovariectomized nude mice.

PubMed

Desreux, Joëlle; Kloosterboer, Helenius; Noël, Agnès; Frankenne, Francis; Lemaire, Madeleine; Putman, Monique; Foidart, Jean-Michel

2007-01-01

The benefits of estrogen plus progestin in healthy post-menopausal women remain uncertain. Tibolone, with its in vitro documented inhibitory effects on estrogens metabolism and its selective action on breast, may be an alternative that could favorably influence the health benefit of hormone replacement therapy. We studied the effect of tibolone on the tumor growth of MCF-7 cells implanted in 40 ovariectomized nude mice, receiving subcutaneous pellets of 17beta-estradiol, estrone, estrone-sulfate or vehicle, and daily gavages of tibolone or placebo. Tibolone, although used at high dose, did not stimulate nor inhibit the estrogen-induced tumors, nor the tumors in estrogen-deprived mice. Measurements of plasma levels of estrogens indicated that tibolone potently stimulated sulfotransferase activity, but intra-tumor levels of estrogens were not significantly modified by tibolone. This in vivo study performed with high dose of orally administered tibolone that allowed its hepatic conversion into active metabolites has shown no significant effect on breast tumors growth. Tibolone increased the circulating sulfated estrogens by its activity on the hepatic sulfation but not the intra-tumor levels of estrogens (free or sulfated). However, further studies of dose-response curve and molecular markers are needed to exclude definitely a stimulatory effect of tibolone on tumor growth.

Fertility-sparing treatment of endometrial cancer precursors among young women: a reproductive point of view.

PubMed

Ricciardi, E; Maniglio, P; Frega, A; Marci, R; Caserta, D; Moscarini, M

2012-12-01

Early-stage endometrial cancer and complex atypical hyperplasia are treated with hysterectomy and bilateral salpingo-oophorectomy. An emerging issue among younger women affected is the possibility of a fertility-sparing treatment with progestative therapy and close follow-up. To assess the possibility of conceiving after a diagnosis of atypical endometrial hyperplasia among women younger than 40 years old, in term of delaying definitive treatment and achieving pregnancy. 15 women younger than 40 years old with complex CAH or early carcinoma of the endometrium and a wish to preserve fertility. Progestins were administered orally for at least a 12 weeks period. Endometrial biopsies were used at follow-up. In 11 women, a complete pathological remission of the disease was observed. 4 pregnancies were attained in 4 women. 3 showed progression and underwent definitive surgery at 18 months. 1 showed no response at 24 months and 3 cycles and was counseled to receive a hysterectomy. A conservative approach in patients younger than 40 years appears a valid option, and a progestative therapy trial should be attempted whether a valid consensus is attained. Considering the risk to find AEH at biopsies and eventually a carcinoma at hysterectomy (25% of cases) a careful management is strictly required.

Reproductive factors, exogenous estrogen use and risk of Parkinson’s disease

PubMed Central

Simon, Kelly Claire; Chen, Honglei; Gao, Xiang; Schwarzschild, Michael A.; Ascherio, Alberto

2009-01-01

To determine if reproductive factors or exogenous estrogen are associated with risk of Parkinson’s disease (PD), we conducted a prospective study with 22 years of follow-up among post-menopausal participants in the Nurses’ Health Study. Relative risks (RRs) and 95% confidence intervals (CIs) of PD were estimated from a Cox proportional hazards model adjusting for potential confounders. Risk of PD was not significantly associated with any of the reproductive factors measured or exogenous estrogen use. Use of post-menopausal hormones, however, may modify the associations of smoking and caffeine intake with PD risk. The inverse relation between smoking and PD risk was attenuated among ever users of post-menopausal hormones (p for interaction = 0.05). Similar results were obtained for caffeine (p for interaction = 0.09). In exploratory analyses, women using progestin-only hormones were found to have an increased PD risk, but this result was based on a very small number of cases (n=4). In this large longitudinal study, we found no evidence of a beneficial effect of exogenous or endogenous estrogens on risk of PD. The use of post-menopausal hormone use may interact with other risk factors, but findings are preliminary and need confirmation in other populations. PMID:19424986

Therapeutic approach for metabolic disorders and infertility in women with PCOS.

PubMed

Morgante, G; Massaro, M G; Di Sabatino, A; Cappelli, V; De Leo, V

2018-01-01

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10% of women of reproductive age. It generally shows with oligo/amenorrhea, anovulatory cycles, clinical o biochemical hirsutism, polycystic ovaries and, in a significant percentage of cases, insulin resistance. PCOS is defined as a multifactorial pathology, determined by the association of many factors: genetic, endocrine and environmental. The first and most effective treatment of PCOS is to change life-style and lose weight. The use of oral contraceptives has been shown effective in reducing acne and hirsutism and regulates the menstrual cycle. For women with severe hirsutism, the addition of antiandrogens to estrogen-progestin therapy has significantly improved the results. In cases of anovulatory infertility, the drug of first choice is clomiphene citrate, followed by low-dose gonadotropins. Recently, insulin-sensitizing drugs have been widely prescribed for PCOS patients. They are particularly effective in reducing insulin resistance and improving ovulatory performance. Besides insulin-sensitizing drugs, natural substances, such as inositol, seems to have good efficacy, similar to metformin with fewer side effects. New substances that could be used include statins and natural statins, such as monakolin, alone or combined with myo-inositol. These substances do not have side effects and greatly reduce the hyperandrogenic component in these patients.

Medical Treatments for Endometriosis-Associated Pelvic Pain

PubMed Central

Luppi, Stefania; Ricci, Giuseppe

2014-01-01

The main sequelae of endometriosis are represented by infertility and chronic pelvic pain. Chronic pelvic pain causes disability and distress with a very high economic impact. In the last decades, an impressive amount of pharmacological agents have been tested for the treatment of endometriosis-associated pelvic pain. However, only a few of these have been introduced into clinical practice. Following the results of the controlled studies available, to date, the first-line treatment for endometriosis associated pain is still represented by oral contraceptives used continuously. Progestins represent an acceptable alternative. In women with rectovaginal lesions or colorectal endometriosis, norethisterone acetate at low dosage should be preferred. GnRH analogues may be used as second-line treatment, but significant side effects should be taken into account. Nonsteroidal anti-inflammatory drugs are widely used, but there is inconclusive evidence for their efficacy in relieving endometriosis-associated pelvic pain. Other agents such as GnRH antagonist, aromatase inhibitors, immunomodulators, selective progesterone receptor modulators, and histone deacetylase inhibitors seem to be very promising, but there is not enough evidence to support their introduction into routine clinical practice. Some other agents, such as peroxisome proliferator activated receptors-γ ligands, antiangiogenic agents, and melatonin have been proven to be efficacious in animal studies, but they have not yet been tested in clinical studies. PMID:25165691

Postplacental or delayed levonorgestrel intrauterine device insertion and breastfeeding duration

PubMed Central

Chen, Beatrice A.; Reeves, Matthew F.; Creinin, Mitchell D.; Schwarz, E. Bimla

2011-01-01

BACKGROUND The objective was to assess the effect of timing of postpartum levonorgestrel-releasing IUD insertion on breastfeeding continuation. STUDY DESIGN Women interested in using a levonorgestrel IUD postpartum were randomized to immediate postplacental insertion (postplacental group) or insertion 6–8 weeks after vaginal delivery (delayed group). Duration and exclusivity of breastfeeding were assessed at 6–8 weeks, 3 months, and 6 months postpartum. Only women who received an IUD were included in this analysis. RESULTS Breastfeeding was initiated by 32/50 (64%) of women receiving a postplacental IUD and 27/46 (58.7%) of women receiving a delayed IUD (p=0.59). More women in the delayed group compared to the postplacental group continued to breastfeed at 6–8 weeks (16/46 vs 15/50, p=0.62), 3 months (13/46 vs 7/50, p=0.13), and 6 months postpartum (11/46 vs 3/50, p=0.02). The results did not differ when only women who initiated breastfeeding or only primiparous women with no prior breastfeeding experience were analyzed. CONCLUSIONS Immediate postplacental insertion of the levonorgestrel IUD is associated with shorter duration of breastfeeding and less exclusive breastfeeding. Further studies are needed of the effects of early initiation of progestin-only methods on women’s lactation experience. PMID:22018124

Neonatal RU-486 (mifepristone) exposure increases androgen receptor immunoreactivity and sexual behavior in male rats.

PubMed

Forbes-Lorman, Robin; Auger, Anthony P; Auger, Catherine J

2014-01-16

Progesterone and progestin receptors (PRs) are known to play a role in the development of brain physiology and behavior in many different species. The distribution and regulation of PRs within the developing brain suggest that they likely contribute to the organization of the brain and behavior in a sex-specific manner. We examined the role of PR signaling during development on the organization of adult sexual behavior and androgen receptor (AR) expression in the brain. We administered the PR antagonist, RU-486, subcutaneously to male and female rats on postnatal days 1-7 (0=day of birth) and examined adult sexual behavior and AR-immunoreactivity (AR-ir) in the adult brain. A typical sex difference in lordosis quotient (LQ) was observed and neonatal RU-486 treatment did not alter this behavior. In contrast, neonatal RU-486 treatment increased adult male sexual behavior and AR-ir in several brain areas in males. These data indicate that a transient disruption in PR signaling during development can have lasting consequences on the male brain and may increase male sexual behavior in part by increasing AR expression, and therefore androgen sensitivity, in adulthood. © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Parenteral oil-based drospirenone microcrystal suspensions-evaluation of physicochemical stability and influence of stabilising agents.

PubMed

Nippe, Stefanie; General, Sascha

2011-09-15

Drospirenone (DRSP) is a contraceptive drug substance with challenging physicochemical properties, due to insufficient solubility in aqueous and oil-based vehicles as well as low chemical stability in aqueous fluids. Although it is one of the most popular orally used progestins, no parenteral long-acting contraceptive containing the drug substance is marketed. An oil-based DRSP microcrystal suspension (MCS) might be an attractive formulation option. The main focus of this study was to investigate the physicochemical stability of such preparations. Moreover, syringeability and injectability via autoinjector were analysed using a materials testing machine. A high chemical stability of DRSP was found in oil-based vehicles. Span(®) 83, cholesteryl oleate, lecithin, methyl cholate, Aerosil(®) R972 and 200 Pharma were tested for increasing the physical stability of DRSP dispersions. Changes in viscosity, rheological properties, and solubility were analysed. The intention was to show a stabilising effect of the excipients without increasing viscosity and solubility. To evaluate the physical stability of DRSP MCS with and without addition of stabilising agents, sedimentation and particle growth after storage were examined. Especially, the silica derivatives Aerosil(®) 200 and R972 Pharma influenced the physical stability positively. Copyright © 2011 Elsevier B.V. All rights reserved.

Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis.

PubMed

Miyashita, Mariko; Koga, Kaori; Takamura, Masashi; Izumi, Gentaro; Nagai, Miwako; Harada, Miyuki; Hirata, Tetsuya; Hirota, Yasushi; Fujii, Tomoyuki; Osuga, Yutaka

2014-09-01

Dienogest is a novel progestin that is highly selective for progesterone receptors and inhibits endometriosis. However, it remains unknown how the administration of dienogest to patients with endometriosis impacts on their lesion tissues. The aim of this study was to evaluate the in vivo effect of dienogest on endometriosis tissue. We collected endometrioma tissues from patients treated with dienogest (N = 7) or not treated (N = 11, controls). Cell proliferation, aromatase expression and blood vessel density were evaluated by staining for Ki67, aromatase and the von Willebrand factor, respectively. Apoptosis was detected using the TUNEL assay. The proportion of Ki67 and aromatase positive epithelial cells was significantly lower in the dienogest group than in controls (p < 0.05, respectively). The number of TUNEL positive cells was significantly higher in the dienogest group (p < 0.05). The density of blood vessels in endometrioma was marginally lower in the dienogest group compared with controls (p = 0.20). Our study demonstrates that endometrioma taken from patients treated with dienogest show remarkable histological features such as reduction of proliferation, aromatase expression and angiogenesis, and increase of apoptosis. This study clarified the impact of dienogest on local histological events that explain its therapeutic effect on endometriosis.

Comparison of ovariectomy and retinyl acetate on the growth of established 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gandlihon, P.; Melancon, R.; Djiane, J.

1982-08-01

Prolonged exposure to retinyl acetate (RA) in the diet inhibits the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary cancers in rats. The effectiveness of RA was examined when given 6 months after the administration of DMBA. Non-inbred female Sprague-Dawley rats with DMBA-induced mammary tumors were divided into 3 groups and treated for 4 weeks as follows: Group 1 served as controls, group 2 was ovariectomized, and group 3 received 328 mg RA/kg diet. Ovariectomy (OVX) markedly reduced both the number and size of the tumors. RA administration failed to induce any significant regression in tumor number but significantly retarded tumor growth whenmore » compared to tumor growth in group 1 controls. The levels of estradiol, progestin, and prolactin (PRL) receptors were significantly reduced after OVX, whereas only the levels of PRL receptors declined significantly after RA administration. Circulating progesterone concentrations were not affected in the RA-treated group but the plasma PRL level was significantly increased. The present studies show that if treatment with RA is delayed until 6 months after carcinogen administration, the protective effect of RA can still be observed although its effectiveness is less dramatic than when it is administered earlier.« less

Ovarian function in the Nile hippopotamus and the effects of Depo-Provera administration.

PubMed

Graham, L H; Webster, T; Richards, M; Reid, K; Joseph, S

2002-01-01

The preliminary results of an investigation into the reproductive endocrinology of the hippopotamus (Hippopotamus amphibius) and the effects of the progestin Depo-Provera on ovarian function are presented. Faecal progestagen analysis indicated that hippos have an oestrous cycle of 29.2 +/- 0.9 days and faecal progestagen concentrations of 323.6 +/- 31.4 ng g(-1) during the luteal phase. Concentrations were higher (765.9 +/- 162.4 ng g(-1); P < 0.05) during pregnancy than during the luteal phase and remained high until parturition. A lactational anoestrus was usually, but not always, observed during nursing. The onset of puberty was observed in three animals and started at 2.5-3.5 years of age. After Depo-Provera treatment, increases in faecal progestagens indicative of ovulation were observed and were not significantly different from luteal concentrations observed before treatment (236.3 +/- 24.4 versus 340.1 +/- 47.9 ng g(-1), respectively); however, the duration of the luteal phase was shorter (P < 0.05) than before treatment (11.3 +/- 1.0 versus 18.9 +/- 1.0 days, respectively). Females returned to normal cyclicity at day 100.7 +/- 15.3 (range 70-116 days) after administration and one female conceived on day 100 after administration.

Is it possible to predict office hysteroscopy failure?

PubMed

Cobellis, Luigi; Castaldi, Maria Antonietta; Giordano, Valentino; De Franciscis, Pasquale; Signoriello, Giuseppe; Colacurci, Nicola

2014-10-01

The purpose of this study was to develop a clinical tool, the HFI (Hysteroscopy Failure Index), which gives criteria to predict hysteroscopic examination failure. This was a retrospective diagnostic test study, aimed to validate the HFI, set at the Department of Gynaecology, Obstetric and Reproductive Science of the Second University of Naples, Italy. The HFI was applied to our database of 995 consecutive women, who underwent office based to assess abnormal uterine bleeding (AUB), infertility, cervical polyps, and abnormal sonographic patterns (postmenopausal endometrial thickness of more than 5mm, endometrial hyperechogenic spots, irregular endometrial line, suspect of uterine septa). Demographic characteristics, previous surgery, recurrent infections, sonographic data, Estro-Progestins, IUD and menopausal status were collected. Receiver operating characteristic (ROC) curve analysis was used to assess the ability of the model to identify patients who were correctly identified (true positives) divided by the total number of failed hysteroscopies (true positives+false negatives). Positive and Negative Likelihood Ratios with 95%CI were calculated. The HFI score is able to predict office hysteroscopy failure in 76% of cases. Moreover, the Positive likelihood ratio was 11.37 (95% CI: 8.49-15.21), and the Negative likelihood ratio was 0.33 (95% CI: 0.27-0.41). Hysteroscopy failure index was able to retrospectively predict office hysteroscopy failure. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium.

PubMed Central

Osteen, K G; Rodgers, W H; Gaire, M; Hargrove, J T; Gorstein, F; Matrisian, L M

1994-01-01

The hallmark of the menstrual cycle is extensive steroid-dependent tissue turnover. Estrogen mediates endometrial cell growth and structural remodeling, whereas progesterone suppresses estrogen-dependent proliferation and promotes cellular differentiation. In nonfertile cycles, tissue degradation and menstruation occur as a consequence of steroidal deprivation as the ovarian corpus luteum fails. Stromal-epithelial interactions are recognized as a necessary component in mediating steroid-induced endometrial turnover. Specific mRNAs for metalloproteinases of the stromelysin family are expressed during endometrial growth and menstrual breakdown but are absent in the progestin-dominated secretory phase. This expression pattern suggests involvement of stromelysins in remodeling the extracellular matrix of the endometrium during tissue growth and breakdown and implicates progesterone in the suppression of these enzymes. We examined the regulation of endometrial stromelysins in explant cultures and found no acute effect of estradiol on their expression, whereas progesterone was a potent inhibitor of stromelysin expression. Progesterone also suppressed stromelysin expression in cultures of isolated stromal cells, but epithelial cells were progesterone insensitive. Coculture of recombined stromal and epithelial cells restored steroidal suppression of the epithelial-specific metalloproteinase. Our data confirm that progesterone inhibits endometrial stromelysins and further demonstrate the necessity for a stromal-derived factor(s) as a mediator of steroid suppression of an epithelial metalloproteinase. Images PMID:7937850

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause

PubMed Central

Manson, JoAnn E.; Langer, Robert D.; Anderson, Garnet L.; Pettinger, Mary; Jackson, Rebecca D.; Johnson, Karen C.; Kuller, Lewis H.; Lane, Dorothy S.; Wactawski-Wende, Jean; Brzyski, Robert; Allison, Matthew; Ockene, Judith; Sarto, Gloria; Rossouw, Jacques E.

2009-01-01

The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered. PMID:19468079

ESTROGENS AND AGE-RELATED MEMORY DECLINE IN RODENTS: WHAT HAVE WE LEARNED AND WHERE DO WE GO FROM HERE?

PubMed Central

Frick, Karyn M.

2009-01-01

The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline. PMID:18835561

Bone accretion in adolescents using the combined estrogen and progestin transdermal contraceptive method Ortho Evra: a pilot study.

PubMed

Harel, Zeev; Riggs, Suzanne; Vaz, Rosalind; Flanagan, Patricia; Harel, Dalia; Machan, Jason T

2010-02-01

To date, there are no data regarding the effect of the transdermal combined estrogen and progestin contraceptive Ortho Evra on bone mineral content (BMC) and bone mineral density (BMD). We examined the effects of transdermally delivered ethinyl estradiol and norelgestromin on whole body (WB) BMC and BMD of the hip and lumbar spine (LS) of adolescent girls. In a matched case-control study, girls (n = 5) who applied Ortho Evra for days 1-21 followed by days 22-28 free of medication for 13 cycles (about 12 months) were compared with 5 age- and ethnicity-matched control girls. Evaluations of calcium intake; bone-protective physical activity; bone densitometry (DXA, QDR 4500A, Hologic); bone formation markers serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP); bone resorption marker urinary N-telopeptide (uNTX); insulin growth factor-1 (IGF-1); and sex hormone binding globulin (SHBG) were carried out at initiation, 6 months, and 12 months. Changes from baseline were compared using mixed models, adjusting for follow-up comparisons using the Holm Test (sequential Bonferroni). There were no significant differences (SD) between groups at baseline in age, gynecologic age, WBBMC, hip BMD, and LSBMD. Girls on Ortho Evra did not change significantly in WBBMC (12-month mean increase 0.2% +/- 0.8%), whereas controls did (3.9% +/- 1.8%, P < or = .001, adjusted P = .002), with SD between the 2 groups (P = .007, adjusted P = .036). Adolescents on Ortho Evra did not change significantly in hip BMD (12-month mean increase 0.5% +/- 0.6%), whereas controls did (2.7% +/- 0.6%, P < or = .001, adjusted P = .004), with SD between the 2 groups (P = .024) prior to adjustment for multiple comparisons, but no SD after adjustment (P = .096). Similarly, although the increase in LSBMD within the control group after 12 months (mean increase 2.8% +/- 1.0%) was statistically significant (P = .009, adjusted P = .044), the change within the treatment group (12-month mean increase 0.8% +/- 0.8%) was not. However, percent LSBMD changes after 12 months did not significantly differ between the 2 groups before or after adjustment for multiple comparisons. Calcium intake and bone-protective physical activity did not significantly predict BMC and BMD changes of study participants. There was a significantly greater increase in SHBG levels in the treatment group after 6 months (P = .003, adjusted P = .013) and 12 months (P < or = .001, adjusted P < or = .001) than in controls. Changes in levels of OC, BAP, uNTX, and IGF-1 were not significantly different between the 2 groups. Ortho Evra use attenuates bone mass acquisition in young women who are still undergoing skeletal maturation. This attenuation may be attributed in part to increased SHBG levels, which reduce the concentrations of free estradiol and free testosterone that are available to interact with receptors on the bone. Clinical implications remain to be determined in studies with a larger number of adolescents. Copyright 2010 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Effects of P.G. 600 on the onset of estrus and ovulation rate in gilts treated with Regu-mate.

PubMed

Estienne, M J; Harper, A F; Horsley, B R; Estienne, C E; Knight, J W

2001-11-01

Three experiments assessed the onset of estrus and ovulation rate in gilts treated with gonadotropins after the withdrawal of an orally active progestin. In Exp. 1, all cycling gilts received the progestin (Regu-mate; Intervet America Inc., Millsboro, DE) at a rate of 15 mg/d for 18 d. Twenty-four hours after the last feeding of Regu-mate, 32 gilts received an i.m. injection of 400 I.U. PMSG and 200 I.U. hCG (P.G. 600, Intervet America, Inc.), and 32 gilts received an i.m. injection of deionized water. The percentage of gilts displaying estrus < or = 7 d (P = 0.64) and the injection-to-estrus interval (P = 0.37) were similar for P.G. 600-treated gilts (93.8% and 4.1 +/- 0.1 d) and controls (90.6% and 4.3 +/- 0.1 d). Ovulation rate was greater (P < 0.01) in P.G. 600-treated gilts (28.8 +/- 1.1) compared with controls (17.4 +/- 1.1). In Exp. 2, 58 cycling gilts received Regu-mate (15 mg/d) for 18 d. Twenty-four hours after Regu-mate withdrawal, gilts received i.m. P.G. 600 or water (n = 29/treatment). Gilts were bred via AI 12 and 24 h after first detection of estrus. The percentage of gilts displaying estrus < or = 7 d (P = 0.45) and the injection-to-estrus interval (P = 0.27) were similar for P.G. 600-treated gilts (82.7% and 4.0 +/- 0.1 d) and controls (89.7% and 4.2 +/- 0.1 d). Ovulation rate was greater (P < 0.01) in P.G. 600-treated gilts (26.2 +/- 1.8) compared with controls (18.1 +/- 1.7). Pregnancy rate (P = 0.71) and the number of live embryos at d 30 postmating (P = 0.40) were similar for P.G. 600-treated gilts (91.7% and 15.6 +/- 1.2) and controls (88.5% and 14.1 +/- 1.2). In Exp. 3, prepubertal gilts (142.6 +/- 0.7 d of age) received Regumate (15 mg/d) (n = 20) or a control diet not including Regu-mate (n = 20) for 18 d. Twenty-four hours after Regu-mate withdrawal, all gilts received i.m. P.G. 600. The percentage of gilts displaying estrus < or = 7 d (P = 0.49) and the P.G. 600-to-estrus interval (P = 0.69) were similar for Regu-mate-fed gilts (95% and 4.3 +/- 0.2 d) and controls (88.9% and 4.2 +/- 0.2 d). Ovulation rate was similar (P = 0.38) for Regu-mate fed gilts (16.6 +/-1.6) and controls (14.4 +/- 1.8). In cycling gilts, administration of P.G. 600 after withdrawal of Regu-mate increased ovulation rate, but not litter size at d 30 postmating. There was no beneficial effect of Regu-mate pretreatment on the response to P.G. 600 in prepubertal gilts.

Decrease of body temperature after aglepristone treatment in bitches.

PubMed

Corrada, Y; García, P; de la Sota, P E; Huzman, M; Landoni, M F; Gobello, C

2005-07-01

Body temperature responses and the timing of abortions were evaluated in pregnant bitches with the anti-progestin aglepristone. Fifteen purebred and crossbred, 25-45 days pregnant, were included in this study and seven untreated bitches at the same stage of pregnancy served as controls. Treated bitches were administered two applications of aglepristone (10 mg/kg SC) 24 h apart for pregnancy termination. Pregnancy termination was confirmed by ultrasonographic assessment. Body temperature was rectally measured three times a day for 6 days beginning 24 h before treatment or pregnancy diagnosis in the treated and control bitches, respectively. Additionally, serum progesterone concentrations were assessed at time points during the study in the treated bitches. Pregnancy was terminated in 14 treated bitches in a mean+/-S.E.M. of 4.3+/-0.7 days after treatment. Control bitches remained pregnant. In the treated bitches, but not in the controls, body temperature significantly decreased 24 h after the beginning of the treatments (P < 0.01) and then gradually returned to pre-treatment values. Correlation between the day of mean minimum body temperature and the day of pregnancy termination was low (0.07; > 0.05). Progesterone did not show significant change throughout the study. Body temperature does not seem to be a suitable variable to clinically monitor the aborting effect of aglepristone. Decrease of body temperature after aglepristone treatment could represent further evidence of its hypothalamic effects.

Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome.

PubMed

De Leo, Vincenzo; Morgante, Giuseppe; Piomboni, Paola; Musacchio, Maria Concetta; Petraglia, Felice; Cianci, Antonio

2007-07-01

To investigate whether the administration of an oral contraceptive containing the new antiandrogenic drospirenone is associated with reduced adrenal androgen synthesis in hyperandrogenic women with diagnosis of polycystic ovary syndrome. Drospirenone, an analogue of spironolactone and aldosterone antagonist, is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. Prospective study. Healthy volunteers in University Department of Obstetrics and Gynecology. Fifteen women ages 18 to 28 years with the diagnosis of polycystic ovary syndrome. Three months of contraceptive use (30 mcg ethinylestradiol, 3 mg drospirenone). An adrenocorticotropic hormone test was performed before and after the study. Adrenal production of cortisol was unchanged after therapy with oral contraceptives. An interesting observation was reduced basal concentrations of androgens such as androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone during therapy. The ratios of the areas of substrates to products before and after oral contraceptive administration were compared for differences in 17alpha-hydroxylase (17-hydroxyprogesterone/progesterone) and 17,20-lyase (androstenedione/17-hydroxyprogesterone); activities were significantly reduced, indicating a reduction in the activities of these enzymes. The present results show for the first time that oral contraceptives containing drospirenone affect adrenal steroidogenesis by reducing synthesis and release of androgens in response to adrenocorticotropic hormone, leaving adrenal production of cortisol unchanged.

Noncontraceptive use of oral combined hormonal contraceptives in polycystic ovary syndrome-risks versus benefits.

PubMed

Dokras, Anuja

2016-12-01

The use of steroid sex hormones for noncontraceptive benefits has been endorsed by several medical societies. In women with polycystic ovary syndrome (PCOS), hormonal contraceptives are first-line therapy for concurrent treatment of menstrual irregularity, acne, and hirsutism. The association of PCOS with obesity, diabetes, and dyslipidemia frequently brings up the debate regarding risks versus benefits of hormonal contraceptives in this population. In women with PCOS, the lack of large-scale studies evaluating the risks with varying doses of ethinyl estradiol, types of progestins, and presence of confounding factors such as obesity, smoking, and other cardiometabolic comorbidities is a significant limitation in these deliberations. Although it is important to assess the absolute risk for major morbidities including cardiovascular events, currently, there are a paucity of long-term data for these outcomes in PCOS. Most of the current studies do not suggest an increase in risk of prediabetes/diabetes, clinically significant dyslipidemia, inflammatory changes, or depressive/anxiety symptoms with oral contraceptive pill use. Screening of women with PCOS for cardiometabolic and psychiatric comorbidities is routinely recommended. This information should be used by health care providers to individualize the choice of hormonal contraceptive treatment, adequately counsel patients regarding risks and benefits, and formulate an appropriate follow-up plan. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model

PubMed Central

Bøttger, Pernille; Glerup, Simon; Gesslein, Bodil; Illarionova, Nina B.; Isaksen, Toke J.; Heuck, Anders; Clausen, Bettina H.; Füchtbauer, Ernst-Martin; Gramsbergen, Jan B.; Gunnarson, Eli; Aperia, Anita; Lauritzen, Martin; Lambertsen, Kate L.; Nissen, Poul; Lykke-Hartmann, Karin

2016-01-01

Migraine is a complex brain disorder, and understanding the complexity of this prevalent disease could improve quality of life for millions of people. Familial Hemiplegic Migraine type 2 (FHM2) is a subtype of migraine with aura and co-morbidities like epilepsy/seizures, cognitive impairments and psychiatric manifestations, such as obsessive-compulsive disorder (OCD). FHM2 disease-mutations locate to the ATP1A2 gene encoding the astrocyte-located α2-isoform of the sodium-potassium pump (α2Na+/K+-ATPase). We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (α2+/G301R) phenocopy several FHM2-relevant disease traits e.g., by mimicking mood depression and OCD. In vitro studies showed impaired glutamate uptake in hippocampal mixed astrocyte-neuron cultures from α2G301R/G301R E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in α2+/G301R male mice. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific α2+/G301R behavioral phenotypes. Our findings demonstrate that studies of an in vivo relevant FHM2 disease knock-in mouse model provide a link between the female sex hormone cycle and the glutamate system and a link to co-morbid psychiatric manifestations of FHM2. PMID:26911348

Hot issues in female and male hormonal contraception.

PubMed

Gava, Giulia; Lantadilla, Claudia; Martelli, Valentina; Fattorini, Anna; Seracchioli, Renato; Meriggiola, Maria C

2016-02-01

In recent years a number of significant developments in the field of female hormonal contraception have been made which have produced new formulations and delivery systems providing high efficacy, safety and important non-contraceptive benefits. In particular long-acting reversible contraception (LARC) formulations have been demonstrated to ensure extremely high efficacy in typical use, minimal contraindications, optimal safety in all women thereby representing the best option for most women of all ages. Their effectiveness is not reliant upon user adherence and their ability to reduce unintended pregnancies and abortions has been proven. Unfortunately the same considerations cannot be made for male hormonal contraception. Although a large number of men are interested and would welcome the opportunity to use male contraceptive methods, no safe, effective and reversible methods are available on the market. Current methods available for men are limited to condoms and vasectomy. Highly effective prototype regimens have been developed but the pharmaceutical industry is unwilling to pursue further development and market these products. Of all new approaches to male contraception, hormonal methods are the closest to clinical application. These are based on the reversible suppression of luteinizing hormone and follicle stimulating hormone with subsequent reversible inhibition of spermatogenesis and consequent replacement to maintain androgen dependent physiological functions. Most approaches tested combination regimens such as testosterone and a progestin or testosterone and a GnRH analog.

Approach to the patient: contraception in women with polycystic ovary syndrome.

PubMed

Yildiz, Bulent O

2015-03-01

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder. Patients with PCOS present with clinical signs of androgen excess (ie, hirsutism and acne), menstrual irregularities, and infertility. Combined oral contraceptive (OC) pills are the first-line medical therapy for the long-term management of PCOS. Containing a combination of estrogen and progestin, OCs restore regular menses, improve androgen excess, and provide effective contraception and protection from endometrial cancer. The benefits of hormonal contraception outweigh the risks in the vast majority of women with PCOS. However, concerns have been raised about potential adverse cardiovascular and metabolic effects of OCs. Currently available evidence indicates an increased relative risk of venous thrombosis associated with OCs varying among different formulations. Arterial thrombosis risk attributable to OCs does not appear to be significantly increased in young nonsmoking women. OC use might be associated with increased risk of diabetes in morbidly obese women with PCOS with severe insulin resistance. A tailored clinical approach to oral contraception in women with PCOS requires individualized risk stratification and management by determination of each PCOS patient's personal cardiometabolic risk profile at baseline and during follow-up. Before prescribing an OC, clinicians should document individual risk factors including age, smoking, obesity, any degree of glucose intolerance including prediabetes and diabetes, hypertension, dyslipidemia, thrombophilia, and personal or family history of a venous thromboembolic event.

Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

PubMed

Thigpen, T; Brady, M F; Homesley, H D; Soper, J T; Bell, J

2001-01-15

In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.

Oral contraceptive therapy modulates hemispheric asymmetry in spatial attention.

PubMed

Cicinelli, Ettore; De Tommaso, Marina; Cianci, Antonio; Colacurci, Nicola; Rella, Leonarda; Loiudice, Luisa; Cicinelli, Maria Vittoria; Livrea, Paolo

2011-12-01

Functional cerebral asymmetries (FCAs) are known to fluctuate across the menstrual cycle. The visual line-bisection task administered to normally cycling women showed different patterns of the interhemispheric interactions during menses and the midluteal cycle phase. However, the contribution of estrogens and progestins hormones to this phenomenon is still unclear. The aim of our study was to show a variation of FCAs in women administered oral contraceptives (OCs) using the visual line-bisection task. Visual line-bisection task with three horizontal lines was administered to 36 healthy women taking a 21-day OC. Twenty-nine patients were right handed. The task was administered during OC intake (day 10) and at the end of the pill-free period. The right-handed women showed a significant leftward bias of veridical center on the first and third lines during OC intake compared with an opposite rightward bias during the pill-free period. The same phenomenon of contralateral deviation was observed in left-handed women on day 10 of OC intake. The results of this study confirm a hormonal modulation on interhemispheric interaction and suggest that OCs may improve the interhemispheric interaction reducing FCAs compared with the low hormone level period. This opens new insights in OC prescription and choice of administration schedule in order to improve cognitive performances. Copyright © 2011 Elsevier Inc. All rights reserved.

Progesterone and norgestrel alter transcriptional expression of genes along the hypothalamic-pituitary-thyroid axis in zebrafish embryos-larvae.

PubMed

Liang, Yan-Qiu; Huang, Guo-Yong; Ying, Guang-Guo; Liu, Shuang-Shuang; Jiang, Yu-Xia; Liu, Shan

2015-01-01

The aim of this study was to investigate the effects of progestins on the hypothalamic-pituitary-thyroid (HPT) axis in the early stage of zebrafish. Zebrafish embryos were exposed to progesterone (P4) or norgestrel (NGT) at 5, 50 and 100 ng L(-1) for 144 h post fertilization (hpf), and the transcriptional levels of target genes along the hypothalamic-pituitary-thyroid axis were determined daily. The results showed that P4 had only minor effects on the mRNA expression of thyroglobulin (Tg), iodothyronine deiodinase type Ι (Dio1) and thyroid hormone receptor β (Thrb) genes. Similarly, the effects of NGT on transcripts of thyrotropin-releasing hormone (Trh), Dio1, iodothyronine deiodinase type II (Dio2) and thyroid hormone receptor α (Thra) genes were generally low. In addition, NGT resulted in some alterations of Tg and Thrb transcripts at different time points. However, a strong induction of Nis mRNA by P4 and NGT was observed in zebrafish embryos-larvae. The overall results showed that besides Nis no effects on the hypothalamic-pituitary-thyroid (HPT) axis are observed following exposure to P4 and NGT, which imply that both P4 and NGT have potential effects on the thyroid endocrine system by inducing transcript of Nis gene during the early stage of zebrafish. Copyright © 2014 Elsevier Inc. All rights reserved.

Hormone induces binding of receptors and transcription factors to a rearranged nucleosome on the MMTV promoter in vivo.

PubMed Central

Truss, M; Bartsch, J; Schelbert, A; Haché, R J; Beato, M

1995-01-01

Hormonal induction of the mouse mammary tumour virus (MMTV) promoter is mediated by interactions between hormone receptors and other transcription factors bound to a complex array of sites. Previous results suggested that access to these sites is modulated by their precise organization into a positioned regulatory nucleosome. Using genomic footprinting, we show that MMTV promoter DNA is rotationally phased in intact cells containing either episomal or chromosomally integrated proviral fragments. Prior to induction there is no evidence for factors bound to the promoter. Following progesterone induction of cells with high levels of receptor, genomic footprinting detects simultaneous protection over the binding sites for hormone receptors, NF-I and the octamer binding proteins. Glucocorticoid or progestin induction leads to a characteristic chromatin remodelling that is independent of ongoing transcription. The centre of the regulatory nucleosome becomes more accessible to DNase I and restriction enzymes, but the limits of the nucleosome are unchanged and the 145 bp core region remains protected against micrococcal nuclease digestion. Thus, the nucleosome covering the MMTV promoter is neither removed nor shifted upon hormone induction, and all relevant transcription factors bind to the surface of the rearranged nucleosome. Since these factors cannot bind simultaneously to free DNA, maintainance of the nucleosome may be required for binding of factors to contiguous sites. Images PMID:7737125

Interaction of estradiol and high density lipoproteins on proliferation of the human breast cancer cell line MCF-7 adapted to grow in serum free conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jozan, S.; Faye, J.C.; Tournier, J.F.

1985-11-27

The responsiveness of the human mammary carcinoma cell line MCF-7 to estradiol and tamoxifen treatment has been studied in different culture conditions. Cells from exponentially growing cultures were compared with cells in their initial cycles after replating from confluent cultures (''confluent-log'' cells). It has been observed that estradiol stimulation of tritiated thymidine incorporation decreases with cell density and that ''confluent-log'' cells are estrogen unresponsive for a period of four cell cycles in serum-free medium conditions. On the other hand, growth of cells replated from exponentially growing, as well as from confluent cultures, can be inhibited by tamoxifen or a combinedmore » treatment with tamoxifen and the progestin levonorgestrel. This growth inhibitory effect can be rescued by estradiol when cells are replated from exponentially growing cultures. The growth inhibitory effect cannot be rescued by estradiol alone (10(-10) to 10(-8) M) when cells are replated from confluent cultures. In this condition, the addition of steroid depleted serum is necessary to reverse the state of estradiol unresponsiveness. Serum can be replaced by high density lipoproteins but not by low density lipoproteins or lipoprotein deficient serum. The present data show that estradiol and HDL interact in the control of MCF-7 cell proliferation.« less

Novel Roles for Hypoxia and Prostaglandin E2 in the Regulation of IL-8 During Endometrial Repair

PubMed Central

Maybin, Jacqueline A.; Hirani, Nikhil; Jabbour, Henry N.; Critchley, Hilary O.D.

2011-01-01

The endometrium has a remarkable capacity for efficient repair; however, factors involved remain undefined. Premenstrual progesterone withdrawal leads to increased prostaglandin (PG) production and local hypoxia. Here we determined human endometrial expression of interleukin-8 (IL-8) and the roles of PGE2 and hypoxia in its regulation. Endometrial biopsy specimens (n = 51) were collected. Endometrial cells and explants were exposed to 100 nmol/L of PGE2 or 0.5% O2. The endometrial IL-8 concentration peaked during menstruation (P < 0.001) and had a significant proangiogenic effect. IL-8 was increased by PGE2 and hypoxia in secretory but not proliferative explants, which suggests that exposure to progesterone is essential. In vitro progesterone withdrawal induced significant IL-8 up-regulation in proliferative explants primed with progestins, but only in the presence of hypoxia. Epithelial cells treated simultaneously with PGE2 and hypoxia demonstrated synergistic increases in IL-8. Inhibition of HIF-1 by short hairpin RNA abolished hypoxic IL-8 induction, and inhibition of NF-κB by an adenoviral dominant negative inhibitor decreased PGE2-induced IL-8 expression (P > 0.05). Increased menstrual IL-8 is consistent with a role in repair. Progesterone withdrawal, hypoxia, and PGE2 regulate endometrial IL-8 by acting via HIF-1 and NF-κB. Hence, progesterone withdrawal may activate two distinct pathways to initiate endometrial repair. PMID:21356375

Clinical utility of progesterone receptor modulators and their effect on the endometrium.

PubMed

Spitz, Irving M

2009-08-01

In view of the spate of recent publications related to mifepristone and some second generation progesterone receptor modulators (PRMs), this appears to be an opportune time to view the clinical status of these compounds. Randomized double-blind placebo-controlled trials have been conducted with mifepristone, CDB-4124 (Proellex), CDB-2914 (VA 2914, Ulipristal) and asoprisnil (J867). All these PRMs are effective in the treatment of uterine fibroids where they are associated with a reduction in pain, bleeding and improvement in quality of life and decrease in fibroid size. CDB-4124 is also efficacious in endometriosis. Long-term treatment with PRMs may be associated with endometrial thickening on ultrasound and there have been reports of endometrial hyperplasia. Several reassuring recent publications have done much to explain the mechanism underlying these endometrial changes. The most common histological finding is cystic glandular dilatation often associated with both admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histology has not been previously encountered in clinical practice and should not be confused with endometrial hyperplasia. The endometrial thickness is related to this cystic glandular dilatation. At this stage of development, PRMs cannot be administered for longer than 3 or 4 months. Even over this time, there is improvement of symptoms associated with fibroids and endometriosis. Clinicians and pathologists need to be aware that the endometrial thickening and histological appearance do not represent endometrial hyperplasia.

A primer on the hormone-free interval for combined oral contraceptives.

PubMed

Hauck, Brian A; Brown, Vivien

2015-01-01

The dosing, schedules, and other aspects of combined oral contraceptive (COC) design have evolved in recent years to address a variety of issues including short- and long-term safety, bleeding profiles, and contraceptive efficacy. In particular, several newer formulations have altered the length of the hormone-free interval (HFI), in order to minimize two key undesired effects that occur during this time: hormone-withdrawal-associated symptoms (HWaS) and follicular development. This primer reviews our current understanding of the key biological processes that occur during the HFI and how this understanding has led to changes in the dosing and schedule of newer COC formulations. In brief, HWaS are common, underappreciated, and a likely contributor to COC discontinuation; because of this, shortening the HFI and/or supplementing with estrogen during the progestin-free interval may provide relief from these symptoms and improve adherence. A short HFI (with or without estrogen supplementation) may also help maintain effective follicular suppression and contraceptive efficacy, even when the overall dose of estrogen throughout the cycle is low. Taken together, the available data about HWaS and follicular activity during the HFI support the rationale for recent COC designs that use a low estrogen dose and a short HFI. The availability of a variety of COC regimens gives physicians a range of choices when selecting the most appropriate COC for each woman's particular priorities and needs.

Estrogen Plus Progestin Therapy and Breast Cancer in Recently Postmenopausal Women

PubMed Central

Prentice, Ross L.; Chlebowski, Rowan T.; Stefanick, Marcia L.; Manson, JoAnn E.; Pettinger, Mary; Hendrix, Susan L.; Hubbell, F. Allan; Kooperberg, Charles; Kuller, Lewis H.; Lane, Dorothy S.; McTiernan, Anne; O’Sullivan, Mary Jo; Rossouw, Jacques E.; Anderson, Garnet L.

2009-01-01

The Women’s Health Initiative trial found a modestly increased risk of invasive breast cancer with daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate, with most evidence among women who had previously received postmenopausal hormone therapy. In comparison, observational studies mostly report a larger risk increase. To explain these patterns, the authors examined the effects of this regimen in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy (“gap time”) in the Women’s Health Initiative trial and in a corresponding subset of the Women’s Health Initiative observational study. Postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993–1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy initiation. Combined trial and observational study data support an adverse effect on breast cancer risk. Women who initiate use soon after menopause, and continue for many years, appear to be at particularly high risk. For example, for a woman who starts soon after menopause and adheres to this regimen, estimated hazard ratios are 1.64 (95% confidence interval: 1.00, 2.68) over a 5-year period of use and 2.19 (95% confidence interval: 1.56, 3.08) over a 10-year period of use. PMID:18372396

Gender and Sexual Health: Care of Transgender Patients.

PubMed

Hayon, Ronni

2016-10-01

Transgender and gender-nonconforming individuals experience significant health disparities. They are more likely to use drugs and alcohol, smoke, be diagnosed with HIV infection or other sexually transmitted infections, and experience depression or attempt suicide. Many also experience discrimination within the health care system. Office-level strategies to create a safe and affirming space for gender-expansive patients include posting of a nondiscrimination statement, use of intake forms that ask about current gender identity and birth-assigned sex, provision of gender-neutral restrooms, and staff training in use of appropriate language. Hormone or surgical therapy can be initiated for patients with persistent gender dysphoria who are of age and have the capacity to make informed decisions, and have reasonable control of coexisting medical and psychiatric conditions. Estrogens, antiandrogens, and progestins are used for feminization, and testosterone for masculinization. Hormone treatment should be followed by careful monitoring for potential adverse effects. Surgical options include male-to-female and female-to-male procedures. The family physician may need to provide a referral letter, preoperative and postoperative examinations and care, and advocacy with health insurance providers. Preventive care for transgender patients includes counseling for cardiovascular health, cancer screening, provision of appropriate contraception, and screening for sexually transmitted infections. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Ovarian hormones and obesity

PubMed Central

Leeners, Brigitte; Geary, Nori; Tobler, Philippe N.; Asarian, Lori

2017-01-01

Abstract BACKGROUND Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. OBJECTIVE AND RATIONALE We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. SEARCH METHODS Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. OUTCOMES We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone–melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. WIDER IMPLICATIONS The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health. PMID:28333235

Ovarian hormones and obesity.

PubMed

Leeners, Brigitte; Geary, Nori; Tobler, Philippe N; Asarian, Lori

2017-05-01

Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

[Historical survey of modern reversible contraceptive methods].

PubMed

Mbabajende, V

1986-04-01

Because of contraception, pregnancy need not be viewed by women as punishment for sexual activity but as a planned and desired event. Most of the contraceptive methods used in developing countries at present were introduced during the 1960s, but use of contraception has a long history and some methods date back to antiquity. Contraceptive pills were already used around 2000 BC in the form of mercury and arsenic tablets. Their effectiveness was questionable. The role of hormones in human reproduction began to be understood only in the early 1900s. The discovery of progesterone in a Mexican iguana in the 1940s permitted production of progesterone on a large scale. Estrogens had been identified around 1930. Human trials of a contraceptive pill beginning in 1956 in Puerto Rico demonstrated that progestins could prevent pregnancy by suppressing ovulation. Later on, estrogen was added to reduce menstrual irregularities. The 1st generation of combined oral contraceptives contained very high levels of hormones associated with high rates of side effects. Numerous formulations with lower hormonal contents became available beginning around 1970 and constitute the principal formulations in use today. A number of long acting hormonal methods based on progestins have been developed, including injectables, some IUDs and vaginal rings, and implants. The 1st commercially available injectable, norethisterone enanthate, did not acquire the wide distribution of medroxyprogesterone acetate, sold as Depo Provera and used to treat various pathological conditions as well as for contraception. The 1st true IUDs were small stones placed within the uteri of camels by nomads to prevent pregnancy during long caravans. An IUD was developed in 1909 by Richter, and the 2 most widely used models before 1960 were the Grafenberg and Ota silver rings. Use of the 2 rings became rare for medical reasons after 1935 despite their efficacy. Safe plastic IUDs which appeared beginning in the early 1960s were flexible and capable of returning to their original shape after insertion. The Lippes loop was the 1st highly successful IUD. Bioactive IUDs containing copper were developed in the 1970s. Research is underway to develop IUDs which will resist expulsion, reduce bleeding, be more appropriate for multiparas, and last longer. IUDs are used to treat intrauterine adhesions as well as for contraception. A gummy substance used to block the cervix was described in Egypt in 1850 BC. Japanese and Chinese prostitutes of antiquity placed oiled bamboo paper at the cervical opening for contraception. Diaphragms and cervical caps were developed in the 19th century in Germany. Large scale production became possible after 1880 with the development of better, more durable, and cheaper rubber. An Egyptian writing in 3500 BC began the study of spermicides. Numerous substances such as lemon juice and honey have been placed in the vagina to avoid pregnancy. Such substances are available to all women and some were reasonably effective. Current research is directed toward development of spermicides which will also prevent sexually transmitted diseases. The 1st condoms were made of animal skins by an English physician to prevent transmission of venereal diseases. Rubber condoms appeared in the early 20th century and are widely utilized in some family planning programs. Pregnancy vaccines and a reversible hormonal method for men are among methods under development.

The mammalian ovary from genesis to revelation.

PubMed

Edson, Mark A; Nagaraja, Ankur K; Matzuk, Martin M

2009-10-01

Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago.

The current status of oral contraceptive clinical development in Japan.

PubMed

Kuwabara, Y

1989-01-01

Since the oral contraceptive guideline was issued in April 1987, Japanese pharmaceutical firms have been asking physicians to perform clinical studies of the low-dose OCs. At present, eight products from six companies are under clinical development. Ethinyl estradiol (30-35 micrograms per tablet) as an estrogen component is common to all the test drugs. The progestin component in each OC is norethindrone, levonorgestrel, or desogestrel. Phase I clinical studies on small numbers of healthy volunteers showed that they could tolerate the test drugs without any serious complaints. The effects on endocrine systems, including the inhibition of ovulation, were also examined. Pharmacokinetic parameters of active ingredients were comparable to those of Western women, and no substantial difference seemed to exist between Japanese and Western women. As an example, the results of phase I studies of OJK-777 (Ortho-Novum 7/7/7) are mentioned. Phase III clinical studies, which are "open studies," are now under progress with more than 3,000 women. The major objectives are to examine (1) how well the drugs are tolerated, and the dropout rates; (2) the effects on cycle control, especially bleeding patterns; (3) effects on the cardiovascular system, including coagulation and lipid metabolism; (4) effects on hormone secretions. Although some women have been taking the test drugs for more than 12 cycles, overall statistics are not yet available, because the guideline requires long-term administration (for more than 24 cycles). However, some characteristic features observed thus far are discussed.

History of oral contraception.

PubMed

Dhont, Marc

2010-12-01

On the 50th birthday of the pill, it is appropriate to recall the milestones which have led to its development and evolution during the last five decades. The main contraceptive effect of the pill being inhibition of ovulation, it may be called a small miracle that this drug was developed long before the complex regulation of ovulation and the menstrual cycle was elucidated. Another stumbling block on its way was the hostile climate with regard to contraception that prevailed at the time. Animal experiments on the effect of sex steroids on ovulation, and the synthesis of sex steroids and orally active analogues were the necessary preliminaries. We owe the development of oral contraceptives to a handful of persons: two determined feminists, Margaret Sanger and Katherine McCormick; a biologist, Gregory Pincus; and a gynaecologist, John Rock. Soon after the introduction of the first pills, some nasty and life-threatening side effects emerged, which were due to the high doses of sex steroids. This led to the development of new preparations with reduced oestrogen content, progestins with more specific action, and alternative administration routes. Almost every decade we have witnessed a breakthrough in oral contraception. Social and moral objections to birth control have gradually disappeared and, notwithstanding some pill scares, oral contraceptives are now one of the most used methods of contraception. Finally, all's well that ends well: recent reports have substantiated the multiple noncontraceptive health benefits paving the way for a bright future for this 50-year-old product.

[Management of menometrorrhagia in women with and without pregnancy intention: hierarchy of therapies].

PubMed

Roman, H; Loisel, C; Puscasiu, L; Sentilhes, L; Marpeau, L

2008-12-01

The first line of treatment recommended for women with idiopathic menorrhagia is pharmaceutical agents, i.e. levonorgestrel intra-uterine device, tranexamic acid, estroprogestatif pills, oral progestin and non-sterodial anti-inflammatory drugs. The second line of treatment is surgical, using endometrial curettage for women who desire pregnancy in the future. On the other hand, in women who no longer intend to get pregnant either endometrial ablation or hysterectomy can be used. The menorrhagia associated with endometrial polyps is treated through the hysteroscopic polypectomy, which result can be improved by the use of the levonorgestrel intra-uterine device or the endometrial ablation. The menorrhagia related to submucosal myomas is managed by hysteroscopic myomectomy, either as a first line of treatment or following the failure of the pharmaceutical management. The first line of treatment of interstitial myomas is represented by the medical management, followed by laparoscopic or abdominal myomectomy for women who still want to be pregnant, and by myomectomy or uterine arteries embolization for women who no longer desire pregnancy. Hysterectomy is the most efficient treatment of menorrhagia due to interstitial myomas, and may be proposed either as a third line of treatment for the myomectomy and embolization failures or as a second line of treatment for women who do not wish to conserve their uterus. Finally, the treatment for women with clinically or radiologically suspected adenomyosis is medical, followed by hysterectomy for women who desire no pregnancy.

Comparison of bone density in amenorrheic women due to athletics, weight loss, and premature menopause.

PubMed

Jones, K P; Ravnikar, V A; Tulchinsky, D; Schiff, I

1985-07-01

Studied was the peripheral bone density of 39 women (ages 18 to 43) with the diagnosis of secondary amenorrhea in an effort to define the population of amenorrheic women at risk for osteoporosis. Eight women had exercise-induced amenorrhea (athletes), 20 women had amenorrhea associated with weight loss, and 11 women had premature menopause. These diagnoses were made on the basis of history, physical examination, and luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin levels, and failure to have withdrawal bleeding after the administration of progestin. Twenty-five nonathletic, normally menstruating women served as control subjects. The peripheral bone density of the amenorrheic athletes (0.738 g/cm2 +/- 0.047) was not significantly different from that of the controls (0.726 g/cm2 +/- 0.044). The average bone density of the group with weight loss-associated amenorrhea (0.672 g/cm2 +/- 0.066) was significantly less than controls (P less than .005) as was that of the women with premature menopause (0.616 g/cm2 +/- 0.048, P less than .001). There was a significant correlation between months of amenorrhea and decrease in bone density (r = 0.506, P less than .001). From this study it was concluded that women with exercise-associated amenorrhea are not at significant risk for cortical bone loss as measured by direct photon absorptiometry. Women with weight loss-associated amenorrhea and women with premature menopause are at significant risk for bone loss when compared with normal controls.

RNA sequencing and differential expression reveals the effects of serial oestrus synchronisation on ovarian genes in dairy goats.

PubMed

Sun, Shuang; Li, Cong; Liu, Shimin; Luo, Jun; Chen, Zhi; Zhang, Changhui; Zhang, Tianying; Huang, Jiangtao; Xi, Limeng

2018-06-07

A total of 24 female Xinong Saanen dairy goats were used to examine differentially expressed genes (DEGs) in the ovaries of goats treated once or three times for oestrus synchronisation (ES). The goats were randomly divided into two groups: one group received three ES treatments at fortnightly intervals (repeated or triple ES group), whereas the other was only treated once on the same day as the third ES treatment for the triple group (control group) during the breeding season. Ovaries of three goats in oestrus from each group were collected for morphological examination and transcriptome sequencing, while the rest of the goats were artificially inseminated twice. Litter size and fecundity rate tended (P=0.06) to be lower in the triple ES group. A total of 319 DEGs were identified, including carbohydrate sulphotransferase 8 (CHST8), corticosteroid-binding globulin (CBG), oestradiol 17-β-dehydrogenase 1 (DHB1), oestrogen receptor 1 (ESR1), progestin and adipoQ receptor family member 4 (PAQR4), PAQR9, prostacyclin synthase (PTGIS), contactin-associated protein (CNTNAP4), matrix metalloproteinase-2 (MMP-2), regulator of G-protein signalling 9-2 (RGS9-2) and sperm surface protein Sp17 (Sp17); these were the most promising novel candidate genes for reproductive performances in goats. Our study indicates that triple ES could cause DNA damage and alter gene expression in goat ovaries, potentially affecting ovary function, neural regulation and hormone secretion.

Perspectives on counseling patients about menopausal hormone therapy: strategies in a complex data environment.

PubMed

Parish, Sharon J; Nappi, Rossella E; Kingsberg, Sheryl

2018-03-05

This narrative review strives to give healthcare providers (HCPs) who care for menopausal women better tools and skills to initiate discussions with women about menopause and hormone therapy (HT), communicate complex concepts and data, and promote shared decision-making. We review relevant studies on HT, barriers to treatment of menopausal symptoms, and effective communication strategies. We also provide recommendations for communicating with patients about HT based on the medical literature and our own professional experience. Both patient and HCP-related barriers can prevent women from accessing treatment for bothersome symptoms of menopause. Many women and HCPs have a poor understanding of the complex, nuanced data regarding HT. The benefits and risks vary with patient age and time since menopause, duration of use, inclusion of a progestin, and patient medical history. Women may also have fears about potential side effects of HT and feel unable to make informed choices. Strategies for effective patient communication and shared decision-making include use of open-ended questions to elicit patient's concerns and preferences, reflecting back to the patient what the HCP heard, presenting evidence about benefits and risks in language the patient can understand, keeping risks in perspective (eg, provide absolute, and also relative risks) without minimizing them, and making conscious efforts to minimize potential bias. Necessary components for achieving high-quality, shared decisions about HT involve a combination of medical evidence, communication skills, and recognition of patient goals and concerns. Use of such strategies can enhance women's satisfaction with care.

Contraceptive Hormone Use and Cardiovascular Disease

PubMed Central

Shufelt, Chrisandra L.; Noel Bairey Merz, C.

2009-01-01

Contraceptive hormones, most commonly prescribed as oral contraceptives (OC), are a widely utilized method to prevent ovulation, implantation and therefore pregnancy. The Women’s Health Initiative demonstrated cardiovascular risk linked to menopausal hormone therapy among women without pre-existing cardiovascular disease, prompting review of the safety, efficacy and side effects of other forms of hormone therapy. A variety of basic science, animal and human data suggest that contraceptive hormones have anti-atheromatous effects, however relatively less is known regarding the impact on atherosclerosis, thrombosis, vasomotion and arrhythmogenesis. Newer generation OC formulations currently in use indicate no increased myocardial infarction (MI) risk for current users, but a persistent increased risk of venous thrombo-embolism (VTE). There are no cardiovascular data available for the newest generation contraceptive hormone formulations, including those that contain newer progestins that lower blood pressure, as well as the non-oral routes (topical and vaginal). Current guidelines indicate that, as with all medication, contraceptive hormones should be selected and initiated by weighing risks and benefits for the individual patient. Women 35 years and older should be assessed for cardiovascular risk factors including hypertension, smoking, diabetes, nephropathy and other vascular diseases including migraines, prior to use. Existing data are mixed with regard to possible protection from OC for atherosclerosis and cardiovascular events; longer-term cardiovascular follow-up of menopausal women with regard to prior OC use, including subgroup information regarding adequacy of ovulatory cycling, the presence of hyperandrogenic conditions, and the presence of prothrombotic genetic disorders is needed to address this important issue. PMID:19147038

Involvement of human decidual cell-expressed tissue factor in uterine hemostasis and abruption.

PubMed

Lockwood, C J; Paidas, M; Murk, W K; Kayisli, U A; Gopinath, A; Huang, S J; Krikun, G; Schatz, F

2009-11-01

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression.

The detection and assessment of the aneugenic potential of selected oestrogens, progestins and androgens using the in vitro cytokinesis blocked micronucleus assay.

PubMed

Kayani, M A; Parry, James M

2008-03-12

The use of 17-beta-oestradiol, testosterone, progesterone, zearanol, trenbolone acetate and melengesterol acetate in animal feed as growth promoters has been banned in the European Union since 1989. However, the data available on their genotoxicity is limited. To bridge this gap the present study was carried out with the aim of evaluating these hormones for their ability to induce aneuploidy. Aneuploidy has been recently considered sufficiently important to be included in the routine testing of chemicals and radiation. These types of numerical chromosomal aberrations may arise by at least two mechanisms, chromosome loss and non-disjunction. Over the past few years, the cytokinesis blocked micronucleus (CBMN) technique has evolved into a robust assay for the detection of aneuploidy induction. At the present time, it is the only assay which can reliably detect both chromosome loss and non-disjunction when the basic methodology is coupled with appropriate molecular probing techniques such as immunoflourescent labelling of kinetochores and Fluorescence in situ Hybridisation. In this present study, aneuploidy induction by three groups of hormones was studied using CBMN assay coupled with Fluorescence in situ Hybridisation. The results from the present study demonstrate that 17-beta-oestradiol, diethylstilboestrol, progesterone and testosterone are genotoxic and induce aneuploidy by non-disjunctional mechanism, whereas trenbolone is also genotoxic by a clastogenic mechanism. However, melengesterol acetate and zearanol proved to be non-genotoxic in vitro.

Polycystic ovary syndrome in adolescence.

PubMed

Driscoll, Deborah A

2003-11-01

Polycystic ovary syndrome (PCOS) is a common disorder among reproductive-age women, yet the diagnosis may be overlooked during adolescence. Although the clinical and metabolic features are similar to those found in adult women, it can be difficult to distinguish the young woman with PCOS from a normal adolescent. Irregular menses, anovulatory cycles, and acne are not uncommon in adolescent women. Adolescents with a history of premature pubarche, a family history of PCOS, Caribbean-Hispanic and African-American ancestry, and/or obesity are at risk for PCOS and deserve close surveillance. The laboratory evaluation of the adolescent with suspected PCOS or hyperandrogenism should be individualized based on the history, symptoms, and examination findings. The cornerstone of management of PCOS in adolescence includes either a combination oral contraceptive or progestin. Consideration of insulin-sensitizing agents, antiandrogens, topical treatments for acne, and various treatments for hair removal are dependent on the patient's symptoms and concerns. Healthy eating, regular exercise, and for the overweight adolescent, weight reduction, are encouraged to reduce the risk of cardiovascular disease and type II diabetes mellitus. Numerous studies have shown that weight loss and exercise decrease androgen levels, improve insulin sensitivity, and lead to the resumption of ovulation. Although initial studies suggest that Metformin may be particularly useful for treating the PCOS adolescent with insulin resistance and obesity, additional studies are needed to determine the efficacy and long-term outcome. Management of the adolescent with PCOS is challenging and requires a supportive, multidisciplinary team approach for optimal results.

Cardiovascular risk factors and events in women with androgen excess.

PubMed

Macut, D; Antić, I B; Bjekić-Macut, J

2015-03-01

Androgen excess (AE) was approximated to be present in 7% of the adult population of women. Polycystic ovary syndrome (PCOS) is the most prevalent among them, followed by idiopathic hirsutism (IH), congenital adrenal hyperplasia (CAH), hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome, and androgen-secreting neoplasms (ASNs). Increased cardiovascular risk was implicated in women with AE. Serum testosterone independently increases risk for cardiovascular disease (CVD), and correlates even with indices of subclinical atherosclerosis in various populations of postmenopausal women. Hyperandrogenism in PCOS is closely related to the aggravation of abdominal obesity, and together with insulin resistance forming the metabolic core for the development of CVD. However, phenotypic variability of PCOS generates significant influence on the cardiometabolic risks. Numerous risk factors in PCOS lead to 5-7 times higher risk for CVD and over 2-fold higher risk for coronary heart disease and stroke. However, issue on the cardiometabolic risk in postmenopausal women with hyperandrogenic history is still challenging. There is a significant overlapping in the CVD characteristics of women with PCOS and variants of CAH. Relevant clinical data on the prevalence and cardiometabolic risk and events in women with IH, HAIRAN syndrome or ASNs are scarce. The effects of various oral contraceptives (OCs) and antiandrogenic compounds on metabolic profile are varying, and could be related to the selected populations and different therapy regiments mainly conducted in women with PCOS. It is assumed relation of OCs containing antiandrogenic progestins to the increased risk of cardiovascular and thromboembolic events.

Stagnant contraceptive sales after the Zika epidemic in Brazil.

PubMed

Bahamondes, Luis; Ali, Moazzam; Monteiro, Ilza; Fernandes, Arlete

2017-10-01

Our aim was to assess national hormonal and non-hormonal contraceptive sales in Brazil after the Zika virus outbreak. Pharmaceutical companies based in Brazil provided data on monthly sales from September 2016 to June 2017. Data from both the public and private sectors were obtained about sales of registered, available modern contraceptive methods: combined oral contraceptive pill; progestin-only pill; vaginal and transdermal contraceptives; injectable contraceptives; long-acting reversible contraceptive (LARC) methods, including the copper-releasing intrauterine device, the levonorgestrel-releasing intrauterine system and the etonogestrel-releasing subdermal implant; and emergency contraceptive pills. Seventy-eight percent of sales comprised pills, patches and vaginal rings (11.1-13.8 million cycles/units per month), followed by emergency contraceptive pills (1.8-2.6 million pills), injectables (1.2-1.4 million ampoules) and LARC methods (6500-17,000 devices). The data showed much higher sales of short-acting methods compared with more effective LARC methods. The public sector needs to strengthen its focus on ensuring better access to LARC methods through a systematic approach ensuring regular supply, improved professional skills and better demand generation to couples wishing to avoid or delay pregnancy. In Zika virus-affected areas, many women of reproductive age may want to delay or postpone pregnancy by using an effective LARC method. The public sector should review its policies on LARC, as the need for these methods especially in Zika virus endemic areas may increase. A clear emphasis on quality in services, access and use is warranted.

Metabolic syndrome in Turner syndrome and relation between body composition and clinical, genetic, and ultrasonographic characteristics.

PubMed

Calcaterra, Valeria; Brambilla, Paola; Maffè, Gabriella Carnevale; Klersy, Catherine; Albertini, Riccardo; Introzzi, Francesca; Bozzola, Elena; Bozzola, Mauro; Larizza, Daniela

2014-04-01

An increased relative risk of diabetes, ischemic heart disease, atherosclerosis, and hypertension have been reported in Turner syndrome (TS) patients. No data are currently available on the prevalence of metabolic syndrome in TS subjects. We evaluated the frequency of metabolic syndrome in obese and nonobese patients with TS. We evaluated 85 TS patients (27.05 ± 11.17 years). Obesity was defined as standard deviation score body mass index (SDS-BMI) ≥ 2 or BMI ≥ 30 kg/m(2) in adult patients. We classified metabolic syndrome according to the International Diabetes Federation (IDF). Hepatic ultrasound was performed in all girls. The prevalence of metabolic syndrome was 4.7% (12.5% obese and 4.3% nonobese, P=0.16) and associated with visceral adiposity (P=0.008). Abnormalities in glucose metabolism and hypertension were not associated with genetic or therapeutic factors. The karyotype 45,X was associated with atherogenic profile. Pathological waist circumference was more frequent in girls treated with estro-progestin (P=0.03). Evidence of fatty liver was associated with metabolic syndrome (P=0.03) and insulin resistance (P=0.05). Elevated liver enzymes were found in 15 subjects and were not related to treatment or ultrasound abnormalities. Prevalence of each component of metabolic syndrome in TS patients is partially influenced by genetic makeup and treatment. Hepatosteatosis was associated with metabolic syndrome and insulin resistance, but not to elevated liver enzymes.

The effect of oral contraception on cardiometabolic risk factors in women with elevated androgen levels.

PubMed

Krysiak, Robert; Gilowska, Małgorzata; Okopień, Bogusław

2017-02-01

In unselected reproductive-aged women, use of combined estrogen-progestin oral contraceptive pills has been linked with an increased risk of vascular disease. The aim of this study was to investigate the effect of oral contraception on cardiometabolic risk factors in a population of women with hyperandrogenism. The study included 16 untreated women with elevated testosterone levels and 15 matched healthy women who were then treated with oral contraceptive pills containing ethinyl estradiol (30μg) and drospirenone (3mg). Plasma lipids, glucose homeostasis markers, circulating levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, as well as urinary albumin-to-creatinine ratio (UACR) were assessed at baseline and after 12 weeks of treatment. Compared to healthy women, women with elevated androgen levels showed increased plasma levels of hsCRP, fibrinogen and homocysteine, as well as a higher value of UACR. Oral contraception reduced androgen levels only in hyperandrogenic women. In healthy women, ethinyl estradiol plus drospirenone increased plasma levels of insulin, hsCRP, fibrinogen and homocysteine, while in women with elevated androgen levels their effect was limited only to a small increase in hsCRP. Our results suggest that a deteriorating effect of oral contraceptive pills containing ethinyl estradiol and drospirenone in hyperandrogenic women is weaker than in healthy young women and that ethinyl estradiol/drospirenone combination therapy may be safely used in the former group of patients. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Estrogens and Coronary Artery Disease: New Clinical Perspectives.

PubMed

Meyer, M R; Barton, M

2016-01-01

In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER), which like the "classical" receptors ERα and ERβ is highly abundant in the cardiovascular system. Here, we discuss the role of estrogen receptors in the pathogenesis of coronary artery disease and review natural and synthetic ligands of estrogen receptors as well as their effects in physiology, on cardiovascular risk factors, and atherosclerotic vascular disease. Data from preclinical and clinical studies using nonselective compounds activating GPER, which include selective estrogen receptor modulators such as tamoxifen or raloxifene, selective estrogen receptor downregulators such as Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol, strongly suggest that activation of GPER may afford therapeutic benefit for primary and secondary prevention in patients with or at risk for coronary artery disease. Evidence from preclinical studies suggest similar efficacy profiles for selective small molecule GPER agonists such as G-1 which are devoid of uterotrophic activity. Further clinical research in this area is warranted to provide opportunities for future cardiovascular drug development. © 2016 Elsevier Inc. All rights reserved.

History of oral contraceptive use and risk of spontaneous abortion

PubMed Central

Hahn, Kristen A.; Hatch, Elizabeth E.; Rothman, Kenneth J.; Mikkelsen, Ellen M.; Brogly, Susan B.; Sørensen, Henrik T.; Riis, Anders H.; Wise, Lauren A.

2015-01-01

Purpose To examine the association between pregravid oral contraceptive (OC) use and spontaneous abortion (SAB). Methods In an Internet-based preconception cohort study of 4,862 Danish pregnancy planners, we used Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between OC use and SAB. We controlled for maternal age, physical activity, parity, education, alcohol and caffeine consumption, body mass index, and smoking. Results Compared with women who discontinued OCs >1 year before conception, HRs were 0.95 (95% CI: 0.77, 1.17), 0.99 (95% CI: 0.82, 1.19), and 0.80 (95% CI: 0.60, 1.06) for women who discontinued OCs 7-12, 2-6, and 0-1 months before conception, respectively. Compared with <4 years of OC use, HRs for 4-7, 8-11, and ≥12 years of OC use were 1.05 (95% CI: 0.80, 1.37), 0.92 (95% CI: 0.71, 1.19), and 0.88 (95% CI: 0.65, 1.19), respectively. Dose of estrogen and generation of progestin were not materially associated with SAB risk. Conclusions We found no evidence that pregravid OC use is associated with an increase in SAB. Use within one month of conception was associated with a slightly lower risk of SAB, but this may be due to increased reproductive fitness in women who conceive quickly after discontinuation of OCs. PMID:26452607

The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa

PubMed Central

DiVasta, Amy D.; Feldman, Henry A.; Giancaterino, Courtney; Rosen, Clifford J.; LeBoff, Meryl S.; Gordon, Catherine M.

2012-01-01

Anorexia nervosa (AN) is characterized by subnormal estrogen and dehydroepiandrosterone (DHEA) levels. We sought to determine whether the combination of DHEA + estrogen/progestin is superior to placebo in preserving skeletal health over 18 months in AN. Females with AN, aged 13 to 27 years, were recruited for participation in this double-blind, placebo-controlled, randomized trial. Ninety-four subjects were randomized, of whom 80 completed baseline assessments and received either study drug (oral micronized DHEA 50 mg + 20 µg ethinyl estradiol/0.1 mg levonorgestrel combined oral contraceptive pill [COC] daily; n = 43) or placebo (n = 37). Serial measurements of areal bone mineral density (aBMD), bone turnover markers, and serum hormone concentrations were obtained. Sixty subjects completed the 18-month trial. Spinal and whole-body aBMD z scores were preserved in the DHEA + COC group, but decreased in the placebo group (comparing trends, P = .008 and P = .001, respectively). Bone turnover markers initially declined in subjects receiving DHEA + COC and then returned to baseline. No differences in body composition, adverse effects of therapy, or alterations in biochemical safety parameters were observed. Combined therapy with DHEA + COC appears to be safe and effective for preventing bone loss in young women with AN, whereas placebo led to decreases in aBMD. Dehydroepiandrosterone + COC may be safely used to preserve bone mass as efforts to reverse the nutritional, psychological, and other hormonal components of AN are implemented. PMID:22257645