Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus.

PubMed

Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C; Jang, Eunjung; Lydon, John P; Korach, Kenneth S; Chung, Sang-Hyuk

2016-04-05

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock-in mouse models expressing ERα mutants, we determined that the DNA-binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

Association Between Preovulatory Concentrations of Estradiol and Expression of Uterine Milk Protein Precursor, Inhibin Beta A, Period 1, Proenkephalin, and Receptors for Oxytocin, Progesterone, and Estradiol

USDA-ARS?s Scientific Manuscript database

Eliminating the preovulatory surge of estradiol decreased uterine weight, uterine protein, RNA to DNA ratio, rate of protein synthesis, and embryo survival following embryo transfer in sheep. Furthermore, cows that did not exhibit standing estrus (decreased preovulatory concentrations of estradiol) ...

Chronic exposure to bisphenol a impairs progesterone receptor-mediated signaling in the uterus during early pregnancy

PubMed Central

Li, Quanxi; Davila, Juanmahel; Bagchi, Milan K.; Bagchi, Indrani C.

2016-01-01

Environmental and occupational exposure to endocrine disrupting chemicals (EDCs) is a major threat to female reproductive health. Bisphenol A (BPA), an environmental toxicant that is commonly found in polycarbonate plastics and epoxy resins, has received much attention due to its estrogenic activity and high risk of chronic exposure in human. Whereas BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In a recent publication in Endocrinology, we demonstrated that prolonged exposure to an environmental relevant dose of BPA disrupts progesterone receptor-regulated uterine functions, thus affecting uterine receptivity for embryo implantation and decidua morphogenesis, two critical events for establishment and maintenance of early pregnancy. In particular we reported a marked impairment of progesterone receptor (PGR) expression and its downstream effector HAND2 in the uterine stromal cells in response to chronic BPA exposure. In an earlier study we have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor (FGF) expression and the MAP kinase signaling pathway, thus inhibiting epithelial proliferation. Interestingly we observed that downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with an enhanced activation of FGFR and MAPK signaling, aberrant proliferation, and lack of uterine receptivity in the epithelium. In addition, the proliferation and differentiation of endometrial stromal cells to decidual cells, an event critical for the maintenance of early pregnancy, was severely compromised in response to BPA. This research highlight will provide an overview of our findings and discuss the potential mechanisms by which chronic BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy. PMID:28239613

Progesterone is essential for maintenance and growth of uterine leiomyoma.

PubMed

Ishikawa, Hiroshi; Ishi, Kazutomo; Serna, Vanida Ann; Kakazu, Rafael; Bulun, Serdar E; Kurita, Takeshi

2010-06-01

Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17beta-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.

Saccharomyces cerevisiae Produces a Yeast Substance that Exhibits Estrogenic Activity in Mammalian Systems

NASA Astrophysics Data System (ADS)

Feldman, David; Stathis, Peter A.; Hirst, Margaret A.; Price Stover, E.; Do, Yung S.; Kurz, Walter

1984-06-01

Partially purified lipid extracts of Saccharomyces cerevisiae contain a substance that displaces tritiated estradiol from rat uterine cytosol estrogen receptors. The yeast product induces estrogenic bioresponses in mammalian systems as measured by induction of progesterone receptors in cultured MCF-7 human breast cancer cells and by a uterotrophic response and progesterone receptor induction after administration to ovariectomized mice. The findings raise the possibility that bakers' yeast may be a source of environmental estrogens.

Influence of Dexamethasone on Some Reproductive Hormones and Uterine Progesterone Receptor Localization in Pregnant Yankasa Sheep in Semiarid Zones of Nigeria.

PubMed

Yahi, Dauda; Ojo, Nicholas Adetayo; Mshelia, Gideon Dauda

2017-01-01

Dexamethasone is widely used in both veterinary and human medical practices. However, it seems to cause some deleterious effects on pregnancy probably by causing changes in the reproductive hormone levels and their corresponding receptor concentrations. This study investigated the effects of dexamethasone on these parameters. Twenty healthy adult Yankasa sheep comprising 18 ewes and 2 rams were used for this study. Pregnancies were achieved by natural mating after estrus synchronization. Dexamethasone was administered at 0.25 mg/kg body weight on days 1, 3, and 5 during first trimester; days 51, 53, and 55 during second trimester; and days 101, 103, and 105 during the third trimester. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested through caesarean section for immunohistochemical analysis. Results showed that dexamethasone significantly ( p < 0.05) decreased progesterone concentrations and caused abortion in Yankasa sheep but had no significant ( p > 0.05) effect on estrogen, while progesterone receptors (PR) were upregulated. The abortion could probably be due to decreased progesterone concentrations as a consequence of the adverse effects on placenta. The PR upregulation may be a compensatory mechanism to increase progesterone sensitivity. It was concluded that dexamethasone should not be used in advanced pregnancy in Yankasa sheep.

Influence of Dexamethasone on Some Reproductive Hormones and Uterine Progesterone Receptor Localization in Pregnant Yankasa Sheep in Semiarid Zones of Nigeria

PubMed Central

Ojo, Nicholas Adetayo; Mshelia, Gideon Dauda

2017-01-01

Dexamethasone is widely used in both veterinary and human medical practices. However, it seems to cause some deleterious effects on pregnancy probably by causing changes in the reproductive hormone levels and their corresponding receptor concentrations. This study investigated the effects of dexamethasone on these parameters. Twenty healthy adult Yankasa sheep comprising 18 ewes and 2 rams were used for this study. Pregnancies were achieved by natural mating after estrus synchronization. Dexamethasone was administered at 0.25 mg/kg body weight on days 1, 3, and 5 during first trimester; days 51, 53, and 55 during second trimester; and days 101, 103, and 105 during the third trimester. Blood samples were collected biweekly for hormonal assay. Uterine biopsies were harvested through caesarean section for immunohistochemical analysis. Results showed that dexamethasone significantly (p < 0.05) decreased progesterone concentrations and caused abortion in Yankasa sheep but had no significant (p > 0.05) effect on estrogen, while progesterone receptors (PR) were upregulated. The abortion could probably be due to decreased progesterone concentrations as a consequence of the adverse effects on placenta. The PR upregulation may be a compensatory mechanism to increase progesterone sensitivity. It was concluded that dexamethasone should not be used in advanced pregnancy in Yankasa sheep. PMID:29181440

Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus

PubMed Central

Lee, Jae Hee; Kim, Tae Hoon; Oh, Seo Jin; Yoo, Jung-Yoon; Akira, Shizuo; Ku, Bon Jeong; Lydon, John P.; Jeong, Jae-Wook

2013-01-01

Recent studies have shown that activation of the signal transducer and activator of transcription-3 (Stat3) is required for decidualization, interacting with progesterone receptor (PR) in uterus. Based on previous reports, we hypothesized that crosstalk between STAT3 and PR signaling is required for successful implantation. To identify the interaction between STAT3 and PR isoforms, we performed immunoprecipitation following transient cotransfection and found that STAT3 physically interacted with PR-A, which is known to be important for uterine development and function, but not with PR-B. To further investigate the role of Stat3 in uterine function, Stat3 was conditionally ablated only in the PR-positive cells (PRcre/+ Stat3f/f; Stat3d/d). Our studies revealed that ovarian function and uterine development of Stat3d/d mice were normal. However, Stat3d/d female mice were infertile due to defective embryo implantation. Unlike Stat3f/f mice, Stat3d/d mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3d/d mice were unable to undergo a well-characterized hormonally induced decidual reaction. The expression of stromal PR was decreased during decidualization and preimplantation period in Stat3d/d mice, and PR target genes were significantly down-regulated after progesterone induction. Our results suggest that STAT3 and PR crosstalk is required for successful implantation in the mouse uterus.—Lee, J. H., Kim, T. H., Oh, S. J., Yoo, J.-Y., Akira, S., Ku, B. J., Lydon, J. P., Jeong, J.-W. Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. PMID:23531596

Progesterone Receptor-Mediated Regulation of N-Acetylneuraminate Pyruvate Lyase (NPL) in Mouse Uterine Luminal Epithelium and Nonessential Role of NPL in Uterine Function

PubMed Central

Xiao, Shuo; Li, Rong; Diao, Honglu; Zhao, Fei; Ye, Xiaoqin

2013-01-01

N-acetylneuraminate pyruvate lyase (NPL) catalyzes N-acetylneuraminic acid, the predominant sialic acid. Microarray analysis of the periimplantation mouse uterine luminal epithelium (LE) revealed Npl being the most downregulated (35×) gene in the LE upon embryo implantation. In natural pregnant mouse uterus, Npl expression increased 56× from gestation day 0.5 (D0.5) to D2.5. In ovariectomized mouse uterus, Npl was significantly upregulated by progesterone (P4) but downregulated by 17β-estradiol (E2). Progesterone receptor (PR) antagonist RU486 blocked the upregulation of Npl in both preimplantation uterus and P4-treated ovariectomized uterus. Npl was specifically localized in the preimplantation D2.5 and D3.5 uterine LE. Since LE is essential for establishing uterine receptivity, it was hypothesized that NPL might play a critical role in uterine function, especially during embryo implantation. This hypothesis was tested in the Npl (−/−) mice. No significant differences were observed in the numbers of implantation sites on D4.5, gestation periods, litter sizes, and postnatal offspring growth between wild type (WT) and Npl (−/−) females from mating with WT males. Npl (−/−)xNpl (−/−) crosses produced comparable little sizes as that from WTxWT crosses. Comparable mRNA expression levels of several genes involved in sialic acid metabolism were observed in D3.5 uterus and uterine LE between WT and Npl (−/−), indicating no compensatory upregulation in the D3.5 Npl (−/−) uterus and LE. This study demonstrates PR-mediated dynamic expression of Npl in the periimplantation uterus and dispensable role of Npl in uterine function and embryo development. PMID:23741500

Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer

PubMed Central

Kim, J. Julie; Kurita, Takeshi

2013-01-01

Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases. PMID:23303565

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

Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus

PubMed Central

Mehta, Fabiola F.; Son, Jieun; Hewitt, Sylvia C.; Jang, Eunjung; Lydon, John P.; Korach, Kenneth S.; Chung, Sang-Hyuk

2016-01-01

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock−in mouse models expressing ERα mutants, we determined that the DNA−binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus. PMID:27007157

Estradiol, progesterone and genistein differentially regulate levels of aquaporin (AQP)-1, 2, 5 and 7 expression in the uteri of ovariectomized, sex-steroid deficient rats.

PubMed

Chinigarzadeh, Asma; Muniandy, Sekaran; Salleh, Naguib

2016-11-01

In this study, effects of estradiol, progesterone and genistein on uterine aquaporin (AQP)-1, 2, 5 and 7 expression were investigated in sex-steroid deficient state which could help to elucidate the mechanisms underlying uterine fluid volume changes that were reported under these hormone and hormone-like compound influences. Uteri from ovariectomized, female Sprague-Dawley rats receiving seven days estradiol, progesterone or genistein (25, 50 and 100mg/kg/day) were harvested and levels of AQP-1, 2, 5 and 7 proteins and mRNAs were determined by Western blotting and Real-time PCR (qPCR) respectively. Distribution of these proteins in uterus was observed by immunohistochemistry. Genistein caused a dose-dependent increase in uterine AQP-1, 2, 5 and 7 protein and mRNA expression, however at the levels lower than following estradiol or progesterone stimulations. Effects of genistein were antagonized by estradiol receptor blocker, ICI 182780. Estradiol caused the highest AQP-2 protein and mRNA expression while progesterone caused the highest AQP-1, 5 and 7 protein and mRNA expression in uterus. AQP-1, 2, 5 and 7 protein were found to be distributed in the myometrium as well as in uterine luminal and glandular epithelia and endometrial blood vessels. In conclusion, the observed effects of estradiol, progesterone and genistein on uterine AQP-1, 2, 5 and 7 expression could help to explain the differences in the amount of fluid accumulated in the uterus under these different conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Progesterone inhibits contraction and increases TREK-1 potassium channel expression in late pregnant rat uterus

PubMed Central

Yin, Zongzhi; Li, Yun; He, Wenzhu; Li, Dan; Li, Hongyan; Yang, Yuanyuan; Shen, Bing; Wang, Xi; Cao, Yunxia; Khalil, Raouf A.

2018-01-01

Objective The aim of this study was to investigate the effect and mechanism by which progesterone regulates uterine contraction in late pregnant rats Results Progesterone caused concentration-dependent relaxation of uterine strips that was enhanced compared with control nontreated uterine strips. Uterine strips incubated with progesterone showed a significant increase in TREK-1 mRNA expression and protein level. TREK-1 inhibitor L-methionine partly reversed uterine relaxation caused by the progesterone, while TREK-1 activator arachidonic acid did not cause significant change in progesterone-induced relaxation. Conclusions Progesterone inhibits uterine contraction and induces uterine relaxation in late pregnancy. The progesterone-induced inhibition of uterine contraction appears to partly involve increased potassium channel TREK-1 expression/activity. Materials and Methods Uterus from late-pregnant rats (gestational day 19) was isolated, and uterine strips were prepared for isometric contraction measurement. Oxytocin-induced contraction was compared in uterine strips pretreated with different concentration of progesterone. TREK-1 potassium channel inhibitor L-methionine and TREK-1 agonist arachidonic acid were used to determine whether the changes caused by progesterone involve changes in TREK-1 activity. The mRNA and protein expression of TREK-1 in uterine tissues were measured using qPCR and Western blot. PMID:29416642

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.

Uterine Natural Killer cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil

PubMed Central

Wilkens, Julia; Male, Victoria; Ghazal, Peter; Forster, Thorsten; Gibson, Douglas A.; Williams, Alistair RW; Brito-Mutunayagam, Savita L; Craigon, Marie; Lourenco, Paula; Cameron, Iain T; Chwalisz, Kristof; Moffett, Ashley; Critchley, Hilary OD

2013-01-01

Uterine NK cells (uNK) play a role in the regulation of placentation but their functions in non-pregnant endometrium are not understood. We have previously reported suppression of endometrial bleeding and alteration of spiral artery morphology in women exposed to asoprisnil, a progesterone receptor modulator. We now compare global endometrial gene expression in asoprisnil-treated versus control women, and we demonstrate a statistically significant reduction of genes in the IL-15 pathway, known to play a key role in uNK development and function. Suppression of IL-15 by asoprisnil was also observed at mRNA level (p<0.05), and immunostaining for NK cell marker CD56 revealed a striking reduction of uNK in asoprisnil-treated endometrium (p<0.001). IL-15 levels in normal endometrium are progesterone-responsive. Progesterone receptor (PR) positive stromal cells transcribe both IL-15 and IL-15RA. Thus, the response of stromal cells to progesterone will be to increase IL-15 trans-presentation to uNK, supporting their expansion and differentiation. In asoprisnil-treated endometrium, there is a marked down-regulation of stromal PR expression and virtual absence of uNK. These novel findings indicate that the IL-15 pathway provides a missing link in the complex interplay between endometrial stromal cells, uNK and spiral arteries affecting physiological and pathological endometrial bleeding. PMID:23913972

Effects of extending the length of pro-oestrus in an oestradiol- and progesterone-based oestrus synchronisation program on ovarian function, uterine environment and pregnancy establishment in beef heifers.

PubMed

de la Mata, J J; Núñez-Olivera, R; Cuadro, F; Bosolasco, D; de Brun, V; Meikle, A; Bó, G A; Menchaca, A

2018-05-21

The aim of the present study was to investigate the effects of a strategy for extending pro-oestrus (the interval between luteolysis and ovulation) in an oestrus synchronisation protocol (named J-Synch) in beef heifers on follicular growth, sexual steroid concentrations, the oestrogen receptor ERα and progesterone receptors (PR) in the uterus, insulin-like growth factor (IGF) 1 and pregnancy rates. In Experiment 1, heifers treated with the new J-Synch protocol had a longer pro-oestrus period than those treated with the conventional protocol (mean (±s.e.m.) 93.7±12.9 vs 65.0±13.7h respectively; P<0.05). The rate of dominant follicle growth from the time of progesterone device removal to ovulation was greater in heifers in the J-Synch than conventional group (P<0.05). Luteal area and serum progesterone concentrations were greater in the J-Synch Group (P<0.05) for the 12 days after ovulation. Progesterone receptor (PGR) staining on Day 6 after ovulation in the uterine stroma was lower in the J-Synch than conventional group (P<0.05), and the expression of PR gene (PGR) and IGF1 gene tended to be lower in J-Synch-treated heifers (P<0.1). In Experiment 2 (n=2349), the pregnancy rate 30-35 days after fixed-time AI (FTAI) was greater for heifers in the J-Synch than conventional group (56.1% vs 50.7% respectively). In conclusion, our strategy for extending pro-oestrus (i.e. the J-Synch protocol) significantly improves pregnancy establishment in beef heifers. This improvement was related to an increased rate of growth of the dominant ovulatory follicle, greater progesterone concentrations during the ensuing luteal phase and different uterine patterns of PGR and IGF1, which may have favoured embryo development and pregnancy establishment.

Mirvetuximab Soravtansine and Gemcitabine Hydrochloride in Treating Patients With FRa-Positive Recurrent Ovarian, Primary Peritoneal, Fallopian Tube, Endometrial, or Triple Negative Breast Cancer

ClinicalTrials.gov

2018-02-21

Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Triple-Negative Breast Carcinoma; Folate Receptor Alpha Positive

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.

Selective progesterone receptor modulators 1: use during pregnancy.

PubMed

Benagiano, Giuseppe; Bastianelli, Carlo; Farris, Manuela

2008-10-01

A large number of synthetic compounds known as selective progesterone receptor modulators can bind to progesterone receptors: the ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. Only a dozen or so selective progesterone receptor modulators have been tested to any significant extent: among them are mifepristone (RU 486), asoprisnil (J867), onapristone (ZK 98 299), ulipristal (CDB 2914), Proellex() (CDB 4124), ORG 33628 and ORG 31710. Their clinical applications during pregnancy are discussed. A careful evaluation of existing major review papers and recently published articles was carried out focusing on mifepristone, the most widely studied selective progesterone receptor modulator, which was first used for the voluntary interruption of an early gestation. Other selective progesterone receptor modulators, especially those with partial agonist action, have shown little activity during pregnancy in animal models. Besides early and late voluntary interruption of gestation, selective progesterone receptor modulators have been tested in a variety of obstetrical situations: to obtain a ripening of the cervix, for the medical management of early embryonic loss and foetal death, for the induction of labour at term and for the medical treatment of extra-uterine pregnancies. The only applications that seem worthy of large-scale utilisation during pregnancy are voluntary interruption of early and late gestation, medical management of early delayed miscarriage and late foetal demise.

Effect of biological characteristics of different types of uterine fibroids, as assessed with T2-weighted magnetic resonance imaging, on ultrasound-guided high-intensity focused ultrasound ablation.

PubMed

Zhao, Wen-Peng; Chen, Jin-Yun; Chen, Wen-Zhi

2015-02-01

The aims of this study were to assess the effects of the biological characteristics of different types of uterine fibroids, as assessed with T2-weighted magnetic resonance imaging (MRI), on ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation. Thirty-five patients with 39 symptomatic uterine fibroids who underwent myomectomy or hysterectomy were enrolled. Before surgery, the uterine fibroids were subdivided into hypo-intense, iso-intense, heterogeneous hyper-intense and homogeneous hyper-intense categories based on signal intensity on T2-weighted MRI. Tissue density and moisture content were determined in post-operative samples and normal uterine tissue, the isolated uterine fibroids were subjected to USgHIFU, and the extent of ablation was measured using triphenyltetrazolium chloride. Hematoxylin and eosin staining and sirius red staining were undertaken to investigate the organizational structure of the uterine fibroids. Estrogen and progesterone receptor expression was assayed via immunohistochemical staining. The mean diameter of uterine fibroids was 6.9 ± 2.8 cm. For all uterine fibroids, the average density and moisture content were 10.7 ± 0.7 mg/mL and 75.7 ± 2.4%, respectively; and for the homogeneous hyper-intense fibroids, 10.3 ± 0.5 mg/mL and 76.6 ± 2.3%. The latter subgroup had lower density and higher moisture content compared with the other subgroups. After USgHIFU treatment, the extent of ablation of the hyper-intense fibroids was 102.7 ± 42.1 mm(2), which was significantly less than those of the hypo-intense and heterogeneous hyper-intense fibroids. Hematoxylin and eosin staining and sirius red staining revealed that the homogeneous hyper-intense fibroids had sparse collagen fibers and abundant cells. Immunohistochemistry results revealed that estrogen and progesterone receptors were highly expressed in the homogeneous hyper-intense fibroids. This study revealed that lower density, higher moisture content, sparse collagen fibers, abundant cells and overexpression of estrogen and progesterone receptors are important biological characteristics that resulted in poor efficacy in the treatment of homogeneous hyper-intense fibroids. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma.

PubMed

Liang, Yun; Zhang, Xiaofei; Chen, Xiaoduan; Lü, Weiguo

2015-01-01

The differential diagnosis between atypical leiomyoma and leiomyosarcoma may be hard based on morphological criterion at times. It would be helpful to find out biomarkers that can be used to distinguish them. The aim of the study was to investigate the diagnostic value of progesterone receptor (PR), p16, p53 and pHH3 expression in a series of uterine smooth muscle tumors. Immunohistochemical expression of PR, p16, p53 and pHH3 was investigated on 32 atypical leiomyomas, 15 leiomyosarcomas and 15 usual leomyomas. The difference in expression was compared between atypical leiomyoma and other groups. The expression of PR, p16, and pHH3 was found significantly different between atypical leiomyomas and leiomyosarcomas, but lack of significant difference between atypical leiomyomas and usual leiomyomas. There was no significant difference with regard to p53 distribution among these uterine smooth muscle tumors. High p16, pHH3 expression and low PR expression preferred the diagnosis of leiomyosarcoma. The panel of antibodies used in this study is a useful complementary analysis in the assessment of problematic uterine smooth muscle tumors.

Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma

PubMed Central

Liang, Yun; Zhang, Xiaofei; Chen, Xiaoduan; Lü, Weiguo

2015-01-01

The differential diagnosis between atypical leiomyoma and leiomyosarcoma may be hard based on morphological criterion at times. It would be helpful to find out biomarkers that can be used to distinguish them. The aim of the study was to investigate the diagnostic value of progesterone receptor (PR), p16, p53 and pHH3 expression in a series of uterine smooth muscle tumors. Immunohistochemical expression of PR, p16, p53 and pHH3 was investigated on 32 atypical leiomyomas, 15 leiomyosarcomas and 15 usual leomyomas. The difference in expression was compared between atypical leiomyoma and other groups. The expression of PR, p16, and pHH3 was found significantly different between atypical leiomyomas and leiomyosarcomas, but lack of significant difference between atypical leiomyomas and usual leiomyomas. There was no significant difference with regard to p53 distribution among these uterine smooth muscle tumors. High p16, pHH3 expression and low PR expression preferred the diagnosis of leiomyosarcoma. The panel of antibodies used in this study is a useful complementary analysis in the assessment of problematic uterine smooth muscle tumors. PMID:26261614

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

Association between preovulatory concentrations of estradiol and expression of uterine milk protein precursor, inhibin beta A, Period 1, proenkephalin-A, and receptors for oxytocin, progesterone, and estradiol

USDA-ARS?s Scientific Manuscript database

Cows that did not exhibit standing estrus around the time of gonadotropin-releasing hormone (GnRH)-induced ovulation had decreased pregnancy success compared to cows that exhibited estrus. Therefore, the objective of the present experiment was to characterize changes in expression of uterine milk pr...

Functional Differentiation of Uterine Stromal Cells Involves Cross-regulation between Bone Morphogenetic Protein 2 and Kruppel-like Factor (KLF) Family Members KLF9 and KLF13

USDA-ARS?s Scientific Manuscript database

The inability of the uterine epithelium to enter a state of receptivity for the embryo to implant is a significant underlying cause of early pregnancy loss. We previously showed that mice null for the Progesterone Receptor (PGR)-interacting protein Kruppel-like Factor (KLF) 9 are subfertile and exhi...

Bone morphogenetic protein 2 (bmp2) and krüppel-like factor 9 (klf9) cross-regulation in uterine stromal cells promotes timing of uterine endometrial receptivity

USDA-ARS?s Scientific Manuscript database

Our laboratory has identified a novel progesterone receptor (PGR) co-activator protein, designated Krüppel-like Factor 9 (KLF9), whose absence in mice is associated with subfertility with decreased number of implanting embryos due to altered patterns of proliferation, apoptosis and aberrant P-respon...

Microarray analysis on gene regulation by estrogen, progesterone and tamoxifen in human endometrial stromal cells.

PubMed

Ren, Chun-E; Zhu, Xueqiong; Li, Jinping; Lyle, Christian; Dowdy, Sean; Podratz, Karl C; Byck, David; Chen, Hai-Bin; Jiang, Shi-Wen

2015-03-13

Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

Immunohistochemical analysis of an ectopic endometriosis in the uterine round ligament.

PubMed

Terada, Shinichi; Miyata, Yachiyo; Nakazawa, Hiroaki; Higashimori, Takamitsu; Arai, Takanari; Kikuchi, Yuji; Nozaki, Motohiro

2006-09-09

A rare case of the inguinal endometriosis was reported with immunohistochemical analysis. A 28-year-old woman had a thumb-sized tumor in the right groin for two years with a gradual increase in size and pain. An operation revealed an elastic hard tumor with an unclear margin and adhesion to the uterine round ligament. The histology showed irregular proliferation of the endometrial glands and stroma. The glandular epithelium stained weakly positive against CD125 antibody and the stromal matrix stained strongly positive against CD10 antibody. The nucleus in both the epithelial and stromal cells stained strongly positive against progesterone and estrogen receptor antibodies, and the cytoplasm in both types of cells stained moderately positive against COX-2 (cyclooxygenase-2) antibody. In conclusion, the combination of estrogen or progesterone receptor antibody for the nucleus and CD10 or COX-2 antibody for the cytoplasm could enhance the accuracy of diagnosis for ectopic endometriosis.

Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in T47D Breast Cancer Cells and Primary Leiomyoma Cells

PubMed Central

Huang, Lei; Owen, Jonas K.; Xie, Anna; Navarro, Antonia; Monsivais, Diana; Coon V, John S.; Kim, J. Julie; Dai, Yang; Bulun, Serdar E.

2012-01-01

Background Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells. Principal Findings ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and β were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types. Conclusions Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and breast cancer. PMID:22272226

Differential effects of centrally-administered oestrogen antagonist ICI-182,780 on oestrogen-sensitive functions in the hypothalamus.

PubMed

Steyn, F J; Anderson, G M; Grattan, D R

2007-01-01

Oestrogen actions within the hypothalamus are essential for a range of reproductive functions. In this study, we sought to develop a method for suppressing central oestrogen action without affecting peripheral oestrogenic effects. We administered the oestrogen receptor antagonist ICI-182,780 (ICI) via crystalline implants into the left lateral ventricle or the arcuate nucleus and measured the effectiveness of this drug on three endpoints known to be regulated by oestrogen: gonadotrophin-releasing hormone (GnRH) pulse frequency, progesterone receptor expression and the generation of a sustained prolactin surge during late pregnancy. To confirm that central ICI administration had no effect on peripheral actions of oestrogen, we monitored changes in uterine weight. Intracerebroventricular ICI treatment reversed the inhibitory effects of oestrogen on GnRH pulse frequency, as measured by plasma luteinising hormone pulse frequency. No effect on the oestrogenic induction of progesterone receptors within the arcuate nucleus or ventromedial hypothalamus was observed; however, a small yet significant reduction in progesterone receptor expression within dopaminergic neurones in the arcuate nucleus was observed. Intracerebroventricular or direct crystalline ICI administration to the arcuate nucleus did not change the serum prolactin level during late pregnancy. Central administration of ICI did not affect uterine weight, and thus did not have a peripheral effect. These data suggest that central administration of ICI can overcome some actions of oestrogen in the brain, such as GnRH pulse frequency, but does not affect other oestrogen mediated actions, including the induction of progesterone receptors or the antepartum prolactin surge. Thus, it appears that there is a differential sensitivity to the inhibition of central oestrogen actions by ICI.

The effect of prenatally administered vaginal progesterone on uterine artery Doppler in asymptomatic twin pregnancies.

PubMed

Agra, Isabela K R; Brizot, Maria L; Miyadahira, Mariana Y; Carvalho, Mário H B; Francisco, Rossana P V; Zugaib, Marcelo

2016-10-01

This study investigated the influence of vaginal progesterone on uterine circulation in asymptomatic twin gestations. This study was a secondary analysis of a randomized, double-blind, placebo-controlled trial of twin pregnancies exposed to vaginal progesterone or placebo. We included all trial participants who had undergone uterine artery pulsatility index evaluation at the time of randomization. During each ultrasound examination, the uterine artery pulsatility index was evaluated transabdominally. The mean uterine artery pulsatility index between the progesterone and placebo groups were compared for each gestational age, starting between 18 to 34 weeks and 6days and were analyzed at three (Time 1), six (Time 2) and nine (Time 3) weeks after randomization. The final analysis included 128 women in the progesterone group and 122 women in the placebo group. The baseline characteristics were similar in both groups. No difference in the mean uterine artery pulsatility index was observed between the progesterone and placebo groups at each week of gestation or throughout gestation. In twin pregnancies, the use of vaginal progesterone in the second half of pregnancy does not influence uterine circulation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

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.

Uterine activty and plasma progesterone levels in pregnant goats.

PubMed

Jones, D E; Kinfton, A

1977-01-01

Uterine activity was recorded during the last few weeks of pregnacy in goats, and related to changes in plasma progesterone concentration. In six of the 14 pregnancies, there was little activity until immediately pre-partum, but the remainder showed a progressive increase in uterine motility, particularly during the last seven days of pregnancy. There was a significant correlation between increased uterine activity and decline of peripheral plasma progesterone levels.

Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications

PubMed Central

Moravek, Molly B.; Yin, Ping; Ono, Masanori; Coon V, John S.; Dyson, Matthew T.; Navarro, Antonia; Marsh, Erica E.; Chakravarti, Debabrata; Kim, J. Julie; Wei, Jian-Jun; Bulun, Serdar E.

2015-01-01

BACKGROUND Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. METHODS A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. RESULTS Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and was found to be essential for ovarian steroid-dependent growth of leiomyomas. Interestingly, these stem-progenitor cells were deficient in ERα and PR and instead relied on the strikingly higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone action via paracrine signaling. CONCLUSIONS It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma, and the majority of medical treatments currently available for leiomyoma work by inhibiting steroid hormone production or action. A pitfall of these therapeutics is that they decrease leiomyoma size, but do not completely eradicate them, and tumors tend to regrow once treatment is stopped. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma has the potential to provide the missing link between developing therapeutics that temper leiomyoma growth and those that eradicate them. PMID:25205766

Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.

PubMed

Bouchard, Philippe; Chabbert-Buffet, Nathalie; Fauser, Bart C J M

2011-11-01

To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for gynecologic indications. Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant articles were identified from citations within these publications. None. None. None. None. Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins. Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids. Mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. 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.

A dynamical systems model of progesterone receptor interactions with inflammation in human parturition.

PubMed

Brubaker, Douglas; Barbaro, Alethea; R Chance, Mark; Mesiano, Sam

2016-08-19

Progesterone promotes uterine relaxation and is essential for the maintenance of pregnancy. Withdrawal of progesterone activity and increased inflammation within the uterine tissues are key triggers for parturition. Progesterone actions in myometrial cells are mediated by two progesterone receptor (PR) isoforms, PR-A and PR-B, that function as ligand-activated transcription factors. PR-B mediates relaxatory actions of progesterone, in part, by decreasing myometrial cell responsiveness to pro-inflammatory stimuli. These same pro-inflammatory stimuli promote the expression of PR-A which inhibits the anti-inflammatory activity of PR-B. Competitive interaction between the progesterone receptors then augments myometrial responsiveness to pro-inflammatory stimuli. The interaction between PR-B transcriptional activity and inflammation in the pregnancy myometrium is examined using a dynamical systems model in which quiescence and labor are represented as phase-space equilibrium points. Our model shows that PR-B transcriptional activity and the inflammatory load determine the stability of the quiescent and laboring phenotypes. The model is tested using published transcriptome datasets describing the mRNA abundances in the myometrium before and after the onset of labor at term. Surrogate transcripts were selected to reflect PR-B transcriptional activity and inflammation status. The model coupling PR-B activity and inflammation predicts contractile status (i.e., laboring or quiescent) with high precision and recall and outperforms uncoupled single and two-gene classifiers. Linear stability analysis shows that phase space bifurcations exist in our model that may reflect the phenotypic states of the pregnancy uterus. The model describes a possible tipping point for the transition of the quiescent to the contractile laboring phenotype. Our model describes the functional interaction between the PR-A:PR-B hypothesis and tissue level inflammation in the pregnancy uterus and is a first step in more sophisticated dynamical systems modeling of human partition. The model explains observed biochemical dynamics and as such will be useful for the development of a range of systems-based models using emerging data to predict preterm birth and identify strategies for its prevention.

Lipopolysaccharide-induced murine embryonic resorption involves changes in endocannabinoid profiling and alters progesterone secretion and inflammatory response by a CB1-mediated fashion.

PubMed

Wolfson, Manuel L; Correa, Fernando; Leishman, Emma; Vercelli, Claudia; Cymeryng, Cora; Blanco, Julieta; Bradshaw, Heather B; Franchi, Ana María

2015-08-15

Genital tract infections are a common complication of human pregnancy that can result in miscarriage. We have previously shown that a lipopolysaccharide (LPS) induces embryonic resorption in a murine model of inflammatory miscarriage. This is accompanied by a dramatic decrease in systemic progesterone levels associated with a robust pro-inflammatory response that results in embryo resorption. Here, we tested the hypothesis that the endogenous cannabinoid system (eCS), through cannabinoid receptor 1 (CB1), plays a role in regulating progesterone levels and, therefore, the pro-inflammatory response. We show that LPS treatment in pregnant mice causes significant changes in the eCS ligands, which are reversed by progesterone treatment. We further show the CB1-KO mice maintain higher plasma progesterone levels after LPS treatment, which is associated with a feebler uterine inflammatory response and a significant drop in embryo resorption. These data suggest that manipulation of CB1 receptors and/or ligands is a potential therapeutic avenue to decrease infection-induced miscarriage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator.

PubMed

Ioffe, Olga B; Zaino, Richard J; Mutter, George L

2009-03-01

Selective progesterone receptor modulators are a class of drugs with progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating sex hormones, is likely to be perturbed by progesterone receptor modulators through their progesterone antagonist properties. We examined endometrial histology in 58 premenopausal women treated with the progesterone receptor modulator CDB-4124 (also known as Proellex) for endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after 3 or 6 months with doses of 12.5, 25, or 50 mg daily oral CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174 biopsies) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124-treated patients was generally inactive or atrophic, and less frequently, proliferative or secretory, superimposed upon which were novel changes including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124-treated subjects correlated with increased endometrial thickness by ultrasound. None of the CDB-4124-treated patients developed endometrial carcinoma or hyperplasia while on therapy. CDB-4124 therapy for 3-6 months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, particularly as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other progesterone receptor modulators, including cystic architecture and mixed non-physiologic epithelial changes will prevent misdiagnosis.

Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications.

PubMed

Moravek, Molly B; Yin, Ping; Ono, Masanori; Coon, John S; Dyson, Matthew T; Navarro, Antonia; Marsh, Erica E; Chakravarti, Debabrata; Kim, J Julie; Wei, Jian-Jun; Bulun, Serdar E

2015-01-01

Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and was found to be essential for ovarian steroid-dependent growth of leiomyomas. Interestingly, these stem-progenitor cells were deficient in ERα and PR and instead relied on the strikingly higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone action via paracrine signaling. It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma, and the majority of medical treatments currently available for leiomyoma work by inhibiting steroid hormone production or action. A pitfall of these therapeutics is that they decrease leiomyoma size, but do not completely eradicate them, and tumors tend to regrow once treatment is stopped. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma has the potential to provide the missing link between developing therapeutics that temper leiomyoma growth and those that eradicate them. © The Author 2014. 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.

Changes in myometrial expression of progesterone receptor membrane components 1 and 2 are associated with human parturition at term.

PubMed

Wang, Ray; Sheehan, Penelope M; Brennecke, Shaun P

2016-04-01

While the exact mechanism of human parturition remains unknown, functional progesterone withdrawal is believed to play a key regulatory role. Progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) are putative progesterone receptors and the aim of this project was to investigate their expression in human myometrium. Human term myometrium was obtained from the lower uterine segment incision in women undergoing elective (not-in-labour, NIL; n=11) and emergency Caesarean sections (in-labour, IL; n=10), following written consent. PGRMC1 and 2 expression was quantified using real-time reverse transcription polymerase chain reaction and western blot. Subcellular localisation was performed by immunohistochemistry and immunofluorescence. There was a significant decrease in PGRMC1 mRNA (P=0.0317) and protein expression (P=0.0151) in IL myometrium, compared with NIL myometrium. PGRMC2 mRNA expression (P=0.0151) was also decreased in IL myometrium, compared with NIL myometrium. Immunostaining studies confirmed the presence of PGRMC1 and 2 in smooth-muscle cells. Expression was perinuclear in NIL myometrium and more generalised and cytoplasmic in IL myometrium. The decrease in PGRMC1 expression and the translocation away from a perinuclear location for both PGRMC1 and 2 could contribute to a functional progesterone withdrawal that may ultimately initiate parturition.

Progesterone-induced miR-133a inhibits the proliferation of endometrial epithelial cells.

PubMed

Pan, J-L; Yuan, D-Z; Zhao, Y-B; Nie, L; Lei, Y; Liu, M; Long, Y; Zhang, J-H; Blok, L J; Burger, C W; Yue, L-M

2017-03-01

This study aimed to understand the role of miR-133a in progesterone actions, explore the regulative mechanism of the progesterone receptor, and investigate the effects of miR-133a on the progesterone-inhibited proliferation of mouse endometrial epithelial cells. The expression of miR-133a induced by progesterone was detected by quantitative real-time PCR both in vivo and in vitro. Ishikawa subcell lines stably transfected with progesterone receptor subtypes were used to determine the receptor mechanism of progesterone inducing miR-133a. Specific miR-133a mimics or inhibitors were transfected into mouse uteri and primary cultured endometrial epithelial cells to overexpress or downregulate the miR-133a. The roles of miR-133a in the cell cycle and proliferation of endometrial epithelial cells were analysed by flow cytometry and Edu incorporation analysis. The protein levels of cyclinD2 in uterine tissue sections and primary cultured endometrial epithelial cells were determined by immunohistochemistry and Western blot analysis. Progesterone could induce miR-133a expression in a PRB-dependent manner in endometrial epithelial cells. miR-133a inhibited endometrial epithelial cell proliferation by arresting cell cycle at the G 1 -S transition. Moreover, miR-133a acted as an inhibitor in downregulating cyclinD2 in endometrial epithelial cells. We showed for the first time that progesterone-induced miR-133a inhibited the proliferation of endometrial epithelial cells by downregulating cyclinD2. Our research indicated an important mechanism for progesterone inhibiting the proliferation of endometrial epithelial cells by inducing special miRNAs to inhibit positive regulatory proteins in the cell cycle. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Uterine fibroids – what’s new?

PubMed Central

Williams, Alistair R.W.

2017-01-01

Uterine fibroids are the commonest benign tumours of women and affect all races with a cumulative lifetime risk of around 70%. Despite their high prevalence and the heavy economic burden of treatment, fibroids have received remarkably little attention compared to common female malignant tumours. This article reviews recent progress in understanding the biological nature of fibroids, their life cycle and their molecular genetic origins. Recent progress in surgical and interventional management is briefly reviewed, and medical management options, including treatment with selective progesterone receptor modulators, are also discussed. PMID:29259779

Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms.

PubMed

Tsigkou, Anastasia; Reis, Fernando M; Lee, Meng H; Jiang, Bingjie; Tosti, Claudia; Centini, Gabriele; Shen, Fang-Rong; Chen, You-Guo; Petraglia, Felice

2015-07-01

To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patient's age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. Cross-sectional study. Referral center. Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. None. Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (β = 0.363) and the number of myomas (β = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Uterine Development and Fertility Are Dependent on Gene Dosage of the Nuclear Receptor Coregulator REA

PubMed Central

Park, Sunghee; Yoon, Sangyeon; Zhao, Yuechao; Park, Seong-Eun; Liao, Lan; Xu, Jianming; Lydon, John P.; DeMayo, Francesco J.; O'Malley, Bert W.; Bagchi, Milan K.

2012-01-01

Although the effectiveness of nuclear hormone-receptor complexes is known to depend on coregulator partner proteins, relatively little is known about the roles of coregulators in uterine development and early stages of pregnancy and implantation. Because conventional genetic deletion of the coregulator, repressor of estrogen receptor activity (REA), was embryonic lethal, we here study REA conditional knockout mice generated by cre-loxP recombination, in which REA function was abrogated only in progesterone receptor-expressing tissues, to define the roles of REA in postembryonic stages and in a tissue-specific manner. We find that REA has gene dose-dependent activity impacting uterine development and fertility. Conditional homozygous mutant (REAd/d) mice developed to adulthood and showed normal ovarian function, but females were infertile with severely compromised uterine development and function characterized by cell cycle arrest, apoptosis, and altered adenogenesis (endometrial gland morphogenesis), resulting in failure of implantation and decidualization. By contrast, mice heterozygous for REA (REAf/d) had a very different phenotype, with estradiol treatment resulting in hyperstimulated, large uteri showing increased proliferation of luminal epithelial cells, and enhanced fluid imbibition associated with altered regulation of aquaporins. These REAf/d female mice showed a subfertility phenotype with reduced numbers and sizes of litters. These findings highlight that uterine development and regulation of estrogen receptor activities show a bimodal dependence on the gene dosage of REA. Optimal uterine development and functional activities require the normal gene dosage of REA, with partial or complete deletion resulting in hyperresponsiveness or underresponsiveness to hormone and subfertility or infertility, respectively. PMID:22585830

Progesterone Is Essential for Protecting against LPS-Induced Pregnancy Loss. LIF as a Potential Mediator of the Anti-inflammatory Effect of Progesterone

PubMed Central

Aisemberg, Julieta; Vercelli, Claudia A.; Bariani, María V.; Billi, Silvia C.; Wolfson, Manuel L.; Franchi, Ana M.

2013-01-01

Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders. PMID:23409146

Endometrial Expression of Steroidogenic Factor 1 Promotes Cystic Glandular Morphogenesis

PubMed Central

Vasquez, Yasmin M.; Wu, San-Pin; Anderson, Matthew L.; Hawkins, Shannon M.; Creighton, Chad J.; Ray, Madhumita; Tsai, Sophia Y.; Tsai, Ming-Jer; Lydon, John P.

2016-01-01

Epigenetic silencing of steroidogenic factor 1 (SF1) is lost in endometriosis, potentially contributing to de novo local steroidogenesis favoring inflammation and growth of ectopic endometrial tissue. In this study, we examine the impact of SF1 expression in the eutopic uterus by a novel mouse model that conditionally expresses SF1 in endometrium. In vivo SF1 expression promoted the development of enlarged endometrial glands and attenuated estrogen and progesterone responsiveness. Endometriosis induction by autotransplantation of uterine tissue to the mesenteric membrane resulted in the increase in size of ectopic lesions from SF1-expressing mice. By integrating the SF1-dependent transcriptome with the whole genome binding profile of SF1, we identified uterine-specific SF1-regulated genes involved in Wingless and Progesterone receptor-Hedgehog-Chicken ovalbumin upstream promoter transcription factor II signaling for gland development and epithelium-stroma interaction, respectively. The present results indicate that SF1 directly contributes to the abnormal uterine gland morphogenesis, an inhibition of steroid hormone signaling and activation of an immune response, in addition to previously postulated estrogen production. PMID:27018534

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

Uterine fibroid management: from the present to the future

PubMed Central

Donnez, Jacques; Dolmans, Marie-Madeleine

2016-01-01

Abstract Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications. Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid ‘radical’ surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids. There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention. There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies. The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids. PMID:27466209

Agonistic activity of ICI 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle.

PubMed

Baranda-Avila, Noemi; Mendoza-Rodríguez, C Adriana; Morimoto, Sumiko; Camacho-Arroyo, Ignacio; Guerra-Araiza, Christian; Langley, Elizabeth; Cerbón, Marco

2013-07-01

We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00 h on the day of proestrus or at 00:00 h on the day of estrus and sacrificed at 13:00 h of metaestrus. Estradiol (E₂) and progesterone (P₄) plasma levels were measured by radioimmunoassay. Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of ICI at 08:00 h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00 h on estrus day had no effect on these parameters. The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized + E₂ animal model. Copyright © 2013 Elsevier Ltd. All rights reserved.

Ptn functions downstream of C/EBPβ to mediate the effects of cAMP on uterine stromal cell differentiation through targeting Hand2 in response to progesterone.

PubMed

Yu, Hai-Fan; Tao, Ran; Yang, Zhan-Qing; Wang, Kai; Yue, Zhan-Peng; Guo, Bin

2018-02-01

Ptn is a pleiotropic growth factor involving in the regulation of cellular proliferation and differentiation, but its biological function in uterine decidualization remains unknown. Here, we showed that Ptn was highly expressed in the decidual cells, and could induce the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1 which were two well-established differentiation markers for decidualization, suggesting an important role of Ptn in decidualization. In the uterine stromal cells, progesterone stimulated the expression of Ptn accompanied with an accumulation of intracellular cAMP level. Silencing of Ptn impeded the induction of progesterone and cAMP on the differentiation of uterine stromal cells. Administration of PKA inhibitor H89 resulted in a blockage of progesterone on Ptn expression. Further analysis evidenced that regulation of progesterone and cAMP on Ptn was mediated by C/EBPβ. During in vitro decidualization, knockdown of Ptn could weaken the up-regulation of Prl8a2 and Prl3c1 elicited by C/EBPβ overexpression, while constitutive activation of Ptn reversed the repressive effects of C/EBPβ siRNA on the expression of Prl8a2 and Prl3c1. Meanwhile, Ptn might mediate the regulation of C/EBPβ on Hand2 which was a downstream target of Ptn in the differentiation of uterine stromal cells. Attenuation of Ptn or C/EBPβ by specific siRNA blocked the stimulation of Hand2 by progesterone and cAMP. Collectively, Ptn may play a vital role in the progesterone-induced decidualization pathway. © 2017 Wiley Periodicals, Inc.

Molecular Regulation of Parturition: A Myometrial Perspective

PubMed Central

Renthal, Nora E.; Williams, Koriand’r C.; Montalbano, Alina P.; Chen, Chien-Cheng; Gao, Lu; Mendelson, Carole R.

2015-01-01

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called “contractile” genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered. PMID:26337112

WINGLESS (WNT) signaling is a progesterone target for rat uterine stromal cell proliferation

PubMed Central

Talbott, Alex; Bhusri, Anuradha; Krumsick, Zach; Foster, Sierra; Wormington, Joshua; Kimler, Bruce F

2016-01-01

Preparation of mammalian uterus for embryo implantation requires a precise sequence of cell proliferation. In rodent uterus, estradiol stimulates proliferation of epithelial cells. Progesterone operates as a molecular switch and redirects proliferation to the stroma by down-regulating glycogen synthase kinase-3β (GSK-3β) and stimulating β-catenin accumulation in the periluminal stromal cells. In this study, the WNT signal involved in the progesterone-dependent proliferative switch was investigated. Transcripts of four candidate Wnt genes were measured in the uteri from ovariectomized (OVX) rats, progesterone-pretreated (3 days of progesterone, 2mg/daily) rats, and progesterone-pretreated rats given a single dose (0.2µg) of estradiol. The spatial distribution of the WNT proteins was determined in the uteri after the same treatments. Wnt5a increased in response to progesterone and the protein emerged in the periluminal stromal cells of progesterone-pretreated rat uteri. To investigate whether WNT5A was required for proliferation, uterine stromal cell lines were stimulated with progesterone (1µM) and fibroblast growth factor (FGF, 50ng/mL). Proliferating stromal cells expressed a two-fold increase in WNT5A protein at 12h post stimulation. Stimulated stromal cells were cultured with actinomycin D (25µg/mL) to inhibit new RNA synthesis. Relative Wnt5a expression increased at 4 and 6 h of culture, suggesting that progesterone plus FGF preferentially increased Wnt5a mRNA stability. Knockdown of Wnt5a in uterine stromal cell lines inhibited stromal cell proliferation and decreased Wnt5a mRNA. The results indicate that progesterone initiates and synchronizes uterine stromal cell proliferation by increasing WNT5A expression and signaling. PMID:26975616

Uterine ALK3 is essential during the window of implantation

PubMed Central

Monsivais, Diana; Clementi, Caterina; Peng, Jia; Titus, Mary M.; Barrish, James P.; Creighton, Chad J.; Lydon, John P.; DeMayo, Francesco J.; Matzuk, Martin M.

2016-01-01

The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3flox/flox-Pgr-cre–positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity. PMID:26721398

Effect of exogenous progesterone on embryo size and ewe uterine gene expression in an ovine 'dam size' model of maternal constraint.

PubMed

Fermin, Lisanne M; Pain, Sarah J; Morel, Patrick C H; Gedye, Kristene R; Kenyon, Paul R; Blair, Hugh T

2017-11-21

Progesterone (P4), acting via its receptor, regulates uterine function and histotroph production, which are crucial to embryo growth. This study aimed to examine exogenous P4 effects on embryo size and differential endometrial gene expression at Day 19 of gestation using a 'dam size' sheep model of maternal constraint. Purebred Suffolk (S, genotypically large) embryos were transferred into recipient groups of Cheviot (C, genotypically small) or Suffolk ewes that had, or had not, been pre-treated with P4 from Days 0 to 6 of pregnancy. At Day 19S embryos were collected from four experimental groups: P4 pretreated S ewes (SP4; n=5), untreated S ewes (SnP4; n=15), P4 pretreated C ewes (CP4; n=7) and untreated C ewes (CnP4; n=21). Day-19 embryos from CP4 ewes were larger (P<0.05) than those from CnP4 ewes and similar in size (P>0.05) to embryos from SnP4 and SP4 ewes. Expression of mucin 1 (MUC1) and prostaglandin-endoperoxide synthase 2 (PTGS2) was upregulated in uterine horns ipsilateral to the corpus luteum from CP4 ewes. Prostaglandin receptor (PGR), MUC1 and PTGS2 expression was upregulated, whilst cathepsin L (CTSL) and radical S-adenosyl methionine domain-containing 2 (RSAD2) expression was downregulated in the ipsilateral horn of SP4 ewes. This suggests that pretreating ewes with exogenous P4 may alleviate early pregnancy maternal constraint via mechanisms that alter uterine function. However, further research is required to investigate the timing of P4 administration and its impact on conception rates.

Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids†

PubMed Central

Ali, Mohamed

2017-01-01

Abstract Uterine fibroids (UFs, AKA leiomyoma) are the most important benign neoplastic threat to women's health, with costs up to hundreds of billions of health care dollars worldwide. Uterine fibroids caused morbidities exert a tremendous health toll, impacting the quality of life of women of all ethnicities, especially women of color. Clinical presentations include heavy vaginal bleeding, pelvic pain, bulk symptoms, subfertility, and obstetric complications. Current management strategies heavily lean toward surgical procedures; nonetheless, the choice of treatment is generally subject to patient's age and her desire to preserve future fertility. Women with UF who desire to maintain future fertility potential face a dilemma because of the limited treatment choices that are currently available to help them achieve that goal. Recently, ulipristal acetate the first of the promising family of oral selective progesterone receptor modulators has been approved for UF treatment in Europe, Canada, and several other countries and is under review for possible approval in the USA. In this review article, we discuss recent advances in the management options against UF with a bend toward oral effective long-term treatment alternatives who are particularly suited for those seeking to preserve their future fertility potential. We also explore the transformative concept of primary and secondary UF prevention using these new anti-UF agents. We envision a remarkable shift in the management of UF in future years from surgical/invasive treatment to orally administrated options; clearly, this potential shift will require additional intense clinical research. PMID:29025038

Predictive value of uterine contractility and the serum levels of progesterone and oestrogens with regard to preterm labour.

PubMed

Smit, D A; Essed, G G; de Haan, J

1984-01-01

A longitudinal investigation regarding the serum concentrations of oestradiol, oestriol and progesterone in relation to uterine activity has been performed in 80 healthy primigravid women during the course of pregnancy up to the 37th week of pregnancy. The frequency of uterine contractions was quantitatively objectivated by means of external toco-dynamometry; simultaneously the uterine activity has been recorded by the pregnant women qualitatively. It appears that there is a gradual increase of all the three mentioned hormones during the course of pregnancy. However, there is a large interindividual spread. There exists no relation between the hormonal serum levels and uterine activity (quantitatively as well as qualitatively recorded). Between these two latter there is a poor relation. It is impossible to predict the occurrence of preterm birth based on hormonal serum changes. This holds for the progesterone-oestradiol ratio.

Uterine Fibroids: Diagnosis and Treatment.

PubMed

De La Cruz, Maria Syl D; Buchanan, Edward M

2017-01-15

Uterine fibroids are common benign neoplasms, with a higher prevalence in older women and in those of African descent. Many are discovered incidentally on clinical examination or imaging in asymptomatic women. Fibroids can cause abnormal uterine bleeding, pelvic pressure, bowel dysfunction, urinary frequency and urgency, urinary retention, low back pain, constipation, and dyspareunia. Ultrasonography is the preferred initial imaging modality. Expectant management is recommended for asymptomatic patients because most fibroids decrease in size during menopause. Management should be tailored to the size and location of fibroids; the patient's age, symptoms, desire to maintain fertility, and access to treatment; and the experience of the physician. Medical therapy to reduce heavy menstrual bleeding includes hormonal contraceptives, tranexamic acid, and nonsteroidal anti-inflammatory drugs. Gonadotropin-releasing hormone agonists or selective progesterone receptor modulators are an option for patients who need symptom relief preoperatively or who are approaching menopause. Surgical treatment includes hysterectomy, myomectomy, uterine artery embolization, and magnetic resonance-guided focused ultrasound surgery.

In vivo intra-luteal implants of prostaglandin (PG) E(1) or E(2) (PGE(1), PGE(2)) prevent luteolysis in cows. I. Luteal weight, circulating progesterone, mRNA for luteal luteinizing hormone (LH) receptor, and occupied and unoccupied luteal receptors for LH.

PubMed

Weems, Yoshie S; Arreguin-Arevalo, J Alejandro; Nett, Torrance M; Vann, Rhonda C; Ford, Stephen P; Bridges, Phillip J; Welsh, Thomas H; Lewis, Andrew W; Neuendorff, Don A; Randel, Ronald D; Weems, Charles W

2011-08-01

Previously, it was reported that chronic intra-uterine infusion of PGE(1) or PGE(2) every four hours inhibited luteolysis in ewes. However, estradiol-17β or PGE(2) given intra-uterine every 8h did not inhibit luteolysis in heifers, but infusion of estradiol+PGE(2) inhibited luteolysis in heifers. The objective of this experiment was to determine whether and how intra-luteal implants containing PGE(1) or PGE(2) prevent luteolysis in Angus or Brahman cows. On day-13 post-estrus, Angus cows received no intra-luteal implant and corpora lutea were retrieved or Angus and Brahman cows received intra-luteal silastic implants containing Vehicle, PGE(1), or PGE(2) and corpora lutea were retrieved on day-19. Coccygeal blood was collected daily for analysis for progesterone. Breed did not influence the effect of PGE(1) or PGE(2) on luteal mRNA for LH receptors or unoccupied or occupied luteal LH receptors did not differ (P>0.05) so the data were pooled. Luteal weights of Vehicle-treated Angus or Brahman cows from days-13-19 were lower (P<0.05) than those treated with intra-luteal implants containing PGE(1) or PGE(2). Day-13 Angus luteal weights were heavier (P<0.05) than Vehicle-treated Angus cows on day-19 and luteal weights of day-13 corpora lutea were similar (P>0.05) to Angus cows on day-19 treated with intra-luteal implants containing PGE(1) or PGE(2). Profiles of circulating progesterone in Angus or Brahman cows treated with intra-luteal implants containing PGE(1) or PGE(2) differed (P<0.05) from controls, but profiles of progesterone did not differ (P>0.05) between breeds or between cows treated with intra-luteal implants containing PGE(1) or PGE(2). Intra-luteal implants containing PGE(1) or PGE(2) prevented (P<0.05) loss of luteal mRNA for LH receptors and unoccupied or occupied receptors for LH compared to controls. It is concluded that PGE(1) or PGE(2) alone delays luteolysis regardless of breed. We also conclude that either PGE(1) or PGE(2) prevented luteolysis in cows by up-regulating expression of mRNA for LH receptors and by preventing loss of unoccupied and occupied LH receptors in luteal tissue. Copyright © 2011 Elsevier Inc. All rights reserved.

A gata2-dependent transcription network regulates uterine progesterone responsiveness and endometrial function

USDA-ARS?s Scientific Manuscript database

Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2) are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen si...

Uterine fibroid management: from the present to the future.

PubMed

Donnez, Jacques; Dolmans, Marie-Madeleine

2016-11-01

Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications.Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids.There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention.There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies.The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids. © 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 molecular mechanisms and morphological manifestations of leiomyoma reduction induced by selective progesterone receptor modulators].

PubMed

Demura, T A; Revazova, Z V; Kogan, E A; Adamyan, L V

to investigate the molecular mechanisms and morphological substrate of reduced uterine leiomyoma in patients receiving the selective progesterone receptor modulator (SPRM) ulipristal acetate for 3 months, by estimating the immunohistochemical expression of the markers steroid receptor coactivator 1 (SRC-1), nuclear receptor corepressor 1 (NCoR-1), ER, PgR, Ki-67, p16, TGF-β, and VEGF in tumor tissue. The investigation enrolled 75 women with uterine leiomyoma, menorrhagias, and anemia. Group 1 included 40 patients who were treated with ulipristal for 3 months, followed by laparoscopic myomectomy. Group 2 consisted of 35 patients who underwent surgery without previous preparation. The intra- and postoperative parameters and molecular and morphological changes in the myomatous nodules were comparatively analyzed in both groups. After 3 months of therapy initiation, menorrhagia completely ceased, myomatous nodules decreased in size (p<0.05), hemoglobin levels were elevated (p<0.01), and total intraoperative blood loss and operative time decreased in all the patients in Group 1. The morphological substrate of partial leiomyoma reduction was leiomyocyte apoptosis and dystrophy, tumor stroma sclerosis and hyalinosis with diminished Ki-67 expression and elevated p16 in the smooth muscle cells, trophic nodular tissue disorders exhibited by vascular wall sclerosis and lower VEGF and TGF-β expression, and leiomyocyte hormonal reception dysregulation that made itself evident through the reduced expression of SRC-1 with the unchanged expression of PR and ER and the maintained level of NCoR-1. The molecular mechanisms of tumor reduction involved the reduced Ki-67 expression and elevated p16, lower VEGF and TGF-β, diminished SRC-1 expression with the maintained level of PR, ER, and NCoR-1. Overall, this is suggestive of enhanced apoptosis and reduced leiomyoma proliferation and angiogenesis induced by SPRM and indicative of the expediency of using ulipristal acetate as a preoperative agent for organ-sparing surgery in reproductive-aged patients with uterine myoma, menorrhagias, and anemia.

Gastrin-Releasing Peptide (GRP) in the Ovine Uterus: Regulation by Interferon Tau and Progesterone1

PubMed Central

Song, Gwonhwa; Satterfield, M. Carey; Kim, Jinyoung; Bazer, Fuller W.; Spencer, Thomas E.

2008-01-01

Gastrin-releasing peptide (GRP) is abundantly expressed by endometrial glands of the ovine uterus and processed into different bioactive peptides, including GRP1-27, GRP18-27, and a C-terminus, that affect cell proliferation and migration. However, little information is available concerning the hormonal regulation of endometrial GRP and expression of GRP receptors in the ovine endometrium and conceptus. These studies determined the effects of pregnancy, progesterone (P4), interferon tau (IFNT), placental lactogen (CSH1), and growth hormone (GH) on expression of GRP in the endometrium and GRP receptors (GRPR, NMBR, BRS3) in the endometrium, conceptus, and placenta. In pregnant ewes, GRP mRNA and protein were first detected predominantly in endometrial glands after Day 10 and were abundant from Days 18 through 120 of gestation. Treatment with IFNT and progesterone but not CSH1 or GH stimulated GRP expression in the endometrial glands. Western blot analyses identified proGRP in uterine luminal fluid and allantoic fluid from Day 80 unilateral pregnant ewes but not in uterine luminal fluid of either cyclic or early pregnant ewes. GRPR mRNA was very low in the Day 18 conceptus and undetectable in the endometrium and placenta; NMBR and BRS3 mRNAs were undetectable in ovine uteroplacental tissues. Collectively, the present studies validate GRP as a novel IFNT-stimulated gene in the glands of the ovine uterus, revealed that IFNT induction of GRP is dependent on P4, and found that exposure of the ovine uterus to P4 for 20 days induces GRP expression in endometrial glands. PMID:18448839

Uterine Deletion of Gp130 or Stat3 Shows Implantation Failure with Increased Estrogenic Responses

PubMed Central

Sun, Xiaofei; Bartos, Amanda; Whitsett, Jeffrey A.

2013-01-01

Leukemia inhibitory factor (LIF), a downstream target of estrogen, is essential for implantation in mice. LIF function is thought to be mediated by its binding to LIF receptor (LIFR) and recruitment of coreceptor GP130 (glycoprotein 130), and this receptor complex then activates signal transducer and activator of transcription (STAT)1/3. However, the importance of LIFR and GP130 acting via STAT3 in implantation remains uncertain, because constitutive inactivation of Lifr, Gp130, or Stat3 shows embryonic lethality in mice. To address this issue, we generated mice with conditional deletion of uterine Gp130 or Stat3 and show that both GP130 and STAT3 are critical for uterine receptivity and implantation. Implantation failure in these deleted mice is associated with higher uterine estrogenic responses prior to the time of implantation. These heightened estrogenic responses are not due to changes in ovarian hormone levels or expression of their nuclear receptors. In the deleted mice, estrogen-responsive gene, Lactoferrin (Ltf), and Mucin 1 protein, were up-regulated in the uterus. In addition, progesterone-responsive genes, Hoxa10 and Indian hedgehog (Ihh), were markedly down-regulated in STAT3-inactivated uteri. These changes in uteri of deleted mice were reflected by the failure of differentiation of the luminal epithelium, which is essential for blastocyst attachment. PMID:23885093

Synthesis and Biological Evaluation of Water-soluble Progesterone-Conjugated Probes for Magnetic Resonance Imaging of Hormone Related Cancers

PubMed Central

Sukerkar, Preeti A.; MacRenaris, Keith W.; Townsend, Taryn R.; Ahmed, Roshan A.; Burdette, Joanna E.; Meade, Thomas J.

2011-01-01

Progesterone receptor (PR) is strongly associated with disease prognosis and therapeutic efficacy in hormone related diseases such as endometriosis and breast, ovarian, and uterine cancers. Receptor status is currently determined by immunohistochemistry assays. However, noninvasive PR imaging agents could improve disease detection and help elucidate pathological molecular pathways, leading to new therapies and animal disease models. A series of water-soluble PR-targeted magnetic resonance imaging (MRI) probes were synthesized using Cu(I)-catalyzed click chemistry and evaluated in vitro and in vivo. These agents demonstrated activation of PR in vitro and preferential accumulation in PR(+) compared to PR(−) human breast cancer cells with low toxicity. In xenograft tumor models, the agents demonstrated enhanced signal intensity in PR(+) tumors compared to PR(−) tumors. The results suggest that these agents may be promising MRI probes for PR(+) diseases. PMID:21972997

Steroid Hormones and Uterine Vascular Adaptation to Pregnancy

PubMed Central

Chang, Katherine; Zhang, Lubo

2008-01-01

Pregnancy is a physiological state that involves a significant decrease in uterine vascular tone and an increase in uterine blood flow, which is mediated in part by steroid hormones, including estrogen, progesterone, and cortisol. Previous studies have demonstrated the involvement of these hormones in the regulation of uterine artery contractility through signaling pathways specific to the endothelium and the vascular smooth muscle. Alterations in endothelial nitric oxide synthase expression and activity, nitric oxide production, and expression of enzymes involved in PGI2 production contribute to the uterine artery endothelium-specific responses. Steroid hormones also have an effect on calcium-activated potassium channel activity, PKC signaling pathway and myogenic tone, and alterations in pharmacomechanical coupling in the uterine artery smooth muscle. This review addresses current understanding of the molecular mechanisms by which steroid hormones including estrogen, progesterone, and cortisol modulate uterine artery contractility to alter uterine blood flow during pregnancy with an emphasis on the pregnant ewe model. PMID:18497342

Direct Chronic Effect of Steroid Hormones in Attenuating Uterine Arterial Myogenic Tone: Role of PKC/ERK1/2

PubMed Central

Xiao, Daliao; Huang, Xiaohui; Yang, Shumei; Zhang, Lubo

2009-01-01

Pregnancy is associated with a significant decrease in uterine vascular tone and an increase in uterine blood flow. The present study tested the hypothesis that estrogen and progesterone differentially regulate the ERK1/2 and PKC signaling pathways in vascular smooth muscle resulting in a decrease in uterine vascular myogenic tone in pregnancy. Uterine arteries were isolated from nonpregnant (NPUA) and near-term pregnant (PUA) sheep. Chronic treatment (48 h) of NPUA with 17β-estradiol and progesterone caused a significant decrease in PKC-mediated contractions and pressure-induced myogenic tone. In accordance, treatment of PUA for 48 h with ICI 182,780 and RU 486 significantly increased PKC-induced contractions and myogenic tone. In contrast, acute treatment for 30 min had no effects on uterine artery contractility. An ERK1/2 inhibitor PD098059 restored the chronic effect of steroids on PKC-mediated contractions in NPUA. ERK1/2 protein and mRNA levels were greater in PUA as compared with NPUA. 17β-Estradiol and progesterone increased ERK1/2 protein in NPUA. In agreement, ICI 182,780 and RU 486 caused a significant decrease in ERK1/2 protein in PUA. Western blot showed six PKC isozymes, α, βI, βII, δ, ε and ζ in the uterine arteries. 17β-Estradiol and progesterone decreased the particulate-to-cytosolic ratio of PKCα, ε, and ζ, respectively, in NPUA. ICI 182,780 and RU 486 increased them in PUA. The results indicate a direct chronic effect of the steroid hormones in the up-regulation of ERK1/2 expression and down-regulation of PKC signaling pathway, resulting in attenuated myogenic tone of uterine artery in pregnancy. PMID:19528364

Defining Postpartum Uterine Disease and the Mechanisms of Infection and Immunity in the Female Reproductive Tract in Cattle 1

PubMed Central

Sheldon, I Martin; Cronin, James; Goetze, Leopold; Donofrio, Gaetano; Schuberth, Hans-Joachim

2009-01-01

Uterine microbial disease affects half of all dairy cattle after parturition, causing infertility by disrupting uterine and ovarian function. Infection with Escherichia coli, Arcanobacterium pyogenes and bovine herpesvirus 4 causes endometrial tissue damage. Toll-like receptors (TLRs) on endometrial cells detect pathogen-associated molecules such as bacterial DNA, lipids and lipopolysaccharide (LPS), leading to secretion of cytokines, chemokines and anti-microbial peptides. Chemokines attract neutrophils and macrophages to eliminate the bacteria, although persistence of neutrophils is associated with subclinical endometritis and infertility. Cows with uterine infections are less likely to ovulate because they have slower growth of the postpartum dominant follicle in the ovary, lower peripheral plasma estradiol concentrations, and perturbation of hypothalamic and pituitary function. The follicular fluid of animals with endometritis contains LPS, which is detected by the TLR4/CD14/LY96 (MD2) receptor complex on granulosa cells leading to lower aromatase expression and reduced estradiol secretion. If cows with uterine disease ovulate, the peripheral plasma concentrations of progesterone are lower than in normal animals. However luteal phases are often extended in animals with uterine disease, probably because infection switches the endometrial epithelial secretion of prostaglandins from the F to the E series, by a phospholipase A2 mediated mechanism, which would disrupt luteolysis. The regulation of endometrial immunity depends on steroid hormones, somatotrophins and local regulatory proteins. Advances in knowledge about infection and immunity in the female genital tract should be exploited to develop new therapeutics for uterine disease. PMID:19439727

Contributions of an animal scientist to understanding the biology of the uterus and pregnancy.

PubMed

Bazer, Fuller W

2012-01-01

I developed a passion for reproductive biology when taking a course in Physiology of Reproduction at Louisiana State University while preparing to apply for Veterinary School at Texas A&M University. My career path changed. I entered graduate school, obtained a Ph.D. and have enjoyed an academic career conducting research in uterine biology and pregnancy in animal science departments at the University of Florida and at Texas A&M University. My contributions to science include: (1) identification of molecules secreted by or transported by uterine epithelia into the uterine lumen that are critical to successful establishment and maintenance of pregnancy, (2) discovery of steroids and proteins required for pregnancy-recognition signalling and their mechanisms of action in pigs and ruminants, (3) patterns of fetal-placental development and placental transport of nutrients, (4) identification of links between nutrients and components of histotroph that affect fetal-placental development, (5) characterising aspects of the endocrinology of pregnancy and (6) contributing to efforts to exploit the therapeutic value of interferon tau, particularly for treatment of autoimmune and inflammatory diseases. Current research focuses on select nutrients in the uterine lumen, specifically amino acids, glucose and fructose, that affect conceptus development, the therapeutic potential for interferon tau, stromal-epithelial cell signalling whereby progesterone and oestrogen act via steroid receptors in uterine stromal cells to stimulate secretion of growth factors (e.g. fibroblast growth factors and hepatocyte growth factor) that regulate uterine epithelial cells and conceptus trophectoderm, and roles of toll-like receptors expressed by uterine epithelia and conceptus trophectoderm in pregnancy.

Progesterone Receptor-A and -B Have Opposite Effects on Proinflammatory Gene Expression in Human Myometrial Cells: Implications for Progesterone Actions in Human Pregnancy and Parturition

PubMed Central

Tan, Huiqing; Yi, Lijuan; Rote, Neal S.; Hurd, William W.

2012-01-01

Context: Progesterone promotes uterine relaxation during pregnancy and its withdrawal induces labor. Progesterone withdrawal in human parturition is mediated in part by changes in the relative levels of the nuclear progesterone receptor isoforms, PR-A and PR-B, in myometrial cells. Parturition also involves myometrial inflammation; however, the functional link between nuclear PR-mediated progesterone actions and inflammation in human myometrial cells is unclear. Objective: Our objective was to determine how PR-A and PR-B regulate progesterone action in human myometrial cells and specifically the expression of genes encoding contraction-associated proteins and proinflammatory mediators. Design: Effects of PR-A and PR-B on the capacity for progesterone to modulate gene expression was determined using an immortalized human myometrial cell line stably transfected with inducible PR-A and PR-B expression transgenes and conditioned to express various PR-A and PR-B levels. Gene expression was assessed by genome wide transcriptome analysis, quantitative RT-PCR and immunoblotting. Results: PR-A and PR-B were each transcriptionally active in response to progesterone and affected the expression of distinct gene cohorts. The capacity for progesterone to affect gene expression was dependent on the PR-A to PR-B ratio. This was especially apparent for the expression of proinflammatory genes. Progesterone decreased proinflammatory gene expression when the PR-A to PR-B ratio favored PR-B and increased proinflammatory gene expression when the ratio favored PR-A. Progesterone via PR-B increased expression of inhibitor-κBα, a repressor of the nuclear factor-κB transcription factor, and inhibited basal and lipopolysaccharide-induced proinflammatory gene expression. Both of those PR-B-mediated effects were inhibited by PR-A. Conclusions: Our data suggest that during most of human pregnancy, when myometrial cells are PR-B dominant, progesterone promotes myometrial quiescence through PR-B-mediated antiinflammatory actions. At parturition, the rise in PR-A expression promotes labor by inhibiting the antiinflammatory actions of PR-B and stimulating proinflammatory gene expression in response to progesterone. PMID:22419721

Interleukin (IL)-1 in rat parturition: IL-1 receptors 1 and 2 and accessory proteins abundance in pregnant rat uterus at term - regulation by progesterone.

PubMed

Ishiguro, Tomohito; Takeda, Jun; Fang, Xin; Bronson, Heather; Olson, David M

2016-07-01

The role of interleukin-1 (IL-1), a pro-inflammatory cytokine, in parturition is typically noted by changes in its concentrations. Studying the expression of its receptor family, IL-1 receptor (IL-1R) 1, IL-1R2, IL-1R accessory protein (IL-1RAcP), and its predominantly brain isoform, IL-1RAcPb, during late gestation in the uterus in the Long-Evans rat is another. We assessed changes in their mRNA and protein relative abundance in the uterus and compared IL-1RAcP and IL-1RAcPb mRNA abundance in uterus, cervix, ovaries, placenta, and whole blood of Long-Evans rats during late gestation or in RU486 and progesterone-treated dams using quantitative real-time PCR and western immunoblotting. IL-1R1, IL-1RAcP, and IL-1RAcPb mRNA abundance significantly increased in the uterus at delivery whereas IL-1R2 mRNA abundance significantly decreased. IL-1R1 protein increased at term and IL-1R2 protein decreased at term compared to nonpregnant uteri. IL1-RAcPb mRNA abundance was less than IL-1RAcP, but in the lower uterine segment it was the highest of all tissues examined. RU486 stimulated preterm delivery and an increase in IL-1R1 mRNA abundance whereas progesterone administration extended pregnancy and suppressed the increase in IL-1R1. These data suggest that changes in uterine sensitivity to IL-1 occur during late gestation and suggest another level of regulation for the control of delivery. The roles for IL-1RAcP and IL-1RAcPb need to be determined, but may relate to different intracellular signaling pathways. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

[Benign metastasizing leiomyoma: An unusual cause of aggressive femoral bone tumor].

PubMed

Alexandre, L; Taillieu, F; Arlet, J-B; Passeron, A; Michon, A; Bats, A-S; Pouchot, J; Ranque, B

2018-06-01

Benign metastasizing leiomyoma (BML) is a rare condition characterized by histologically benign "metastatic" smooth muscle tumors, which can affect women with history of uterine surgery. We report the case of a patient with bone metastases of BML. A 78-year-old woman who had undergone uterine surgery six years before hospital admission, was diagnosed with large pulmonary and pleural metastases that necessitated surgical removal. Pathological examination allowed the diagnosis of BML with positive staining for estrogen and progesterone receptors. Three years later, a BML metastasis in the right femoral diaphysis was unexpectedly discovered and treated by osteosynthesis because of a high risk of fracture. Despite an aromatase-inhibitor treatment, new lungs lesions appeared in the next few months. BML is a potential cause of aggressive, although histologically benign, bone tumor in women with a history of uterine surgery. Copyright © 2018. Published by Elsevier SAS.

The expression of genes involved in myometrial contractility changes during ex situ culture of pregnant human uterine smooth muscle tissue.

PubMed

Ilicic, Marina; Butler, Trent; Zakar, Tamas; Paul, Jonathan W

2017-01-01

Ex situ analyses of human myometrial tissue has been used to investigate the regulation of uterine quiescence and transition to a contractile phenotype. Following concerns about the validity of cultured primary cells, we examined whether myometrial tissue undergoes culture-induced changes ex situ that may affect the validity of in vitro models. To determine whether human myometrial tissue undergoes culture-induced changes ex situ in Estrogen receptor 1 (ESR1), Prostaglandin-endoperoxide synthase 2 (PTGS2) and Oxytocin receptor (OXTR) expression. Additionally, to determine whether culture conditions approaching the in vivo environment influence the expression of these key genes. Term non-laboring human myometrial tissues were cultured in the presence of specific treatments, including; serum supplementation, progesterone and estrogen, cAMP, PMA, stretch or NF-κB inhibitors. ESR1, PTGS2 and OXTR mRNA abundance after 48 h culture was determined using quantitative RT-PCR. Myometrial tissue in culture exhibited culture-induced up-regulation of ESR1 and PTGS2 and down-regulation of OXTR mRNA expression. Progesterone prevented culture-induced increase in ESR1 expression. Estrogen further up-regulated PTGS2 expression. Stretch had no direct effect, but blocked the effects of progesterone and estrogen on ESR1 and PTGS2 expression. cAMP had no effect whereas PMA further up-regulated PTGS2 expression and prevented decline of OXTR expression. Human myometrial tissue in culture undergoes culture-induced gene expression changes consistent with transition toward a laboring phenotype. Changes in ESR1, PTGS2 and OXTR expression could not be controlled simultaneously. Until optimal culture conditions are determined, results of in vitro experiments with myometrial tissues should be interpreted with caution.

Uterine activin receptor-like kinase 5 is crucial for blastocyst implantation and placental development

PubMed Central

Peng, Jia; Monsivais, Diana; You, Ran; Zhong, Hua; Pangas, Stephanie A.; Matzuk, Martin M.

2015-01-01

Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin receptor-like kinase 5 (ALK5) is the major type 1 receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine–cytokine receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction. PMID:26305969

Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes

PubMed Central

Lee, Yun; Sooranna, Suren R; Terzidou, Vasso; Christian, Mark; Brosens, Jan; Huhtinen, Kaisa; Poutanen, Matti; Barton, Geraint; Johnson, Mark R; Bennett, Phillip R

2012-01-01

The absence of a fall in circulating progesterone levels has led to the concept that human labour is associated with ‘functional progesterone withdrawal’ caused through changes in the expression or function of progesterone receptor (PR). At the time of labour, the human uterus is heavily infiltrated with inflammatory cells, which release cytokines to create a ‘myometrial inflammation’ via NF-κB activation. The negative interaction between NF-κB and PR, may represent a mechanism to account for ‘functional progesterone withdrawal’ at term. Conversely, PR may act to inhibit NF-κB function and so play a role in inhibition of myometrial inflammation during pregnancy. To model this inter-relationship, we have used small interfering (si) RNA-mediated knock-down of PR in human pregnant myocytes and whole genome microarray analysis to identify genes regulated through PR. We then activated myometrial inflammation using IL-1β stimulation to determine the role of PR in myometrial inflammation regulation. Through PR-knock-down, we found that PR regulates gene networks involved in myometrial quiescence and extracellular matrix integrity. Activation of myometrial inflammation was found to antagonize PR-induced gene expression, of genes normally upregulated via PR. We found that PR does not play a role in repression of pro-inflammatory gene networks induced by IL-1β and that only MMP10 was significantly regulated in opposite directions by IL-1β and PR. We conclude that progesterone acting through PR does not generally inhibit myometrial inflammation. Activation of myometrial inflammation does cause ‘functional progesterone withdrawal’ but only in the context of genes normally upregulated via PR. PMID:22435466

Peptidoglycan inhibits progesterone and androstenedione production in bovine ovarian theca cells.

PubMed

Magata, F; Horiuchi, M; Miyamoto, A; Shimizu, T

2014-08-01

Uterine bacterial infection perturbs uterine and ovarian functions in postpartum dairy cows. Peptidoglycan (PGN) produced by gram-positive bacteria has been shown to disrupt the ovarian function in ewes. The aim of this study was to determine the effect of PGN on steroid production in bovine theca cells at different stages of follicular development. Bovine theca cells isolated from pre- and post-selection ovarian follicles (<8.5mm and >8.5mm in diameter, respectively) were cultured in vitro and challenged with PGN. Steroid production was evaluated by measuring progesterone (P4) and androstenedione (A4) concentration in culture media after 48 h or 96 h of culture. Bovine theca cells expressed PGN receptors including Toll-like receptor 2 and nucleotide-binding oligomerization domain 1 and 2. Treatment with PGN (1, 10, or 50 μg/ml) led to a decrease in P4 and A4 production by theca cells in both pre- and post-selection follicles. The mRNA expression of steroidogenic enzymes were decreased by PGN treatment. Moreover, A4 production was further suppressed when theca cells of post-selection follicles were simultaneously treated by PGN and lipopolysaccharide (0.1, 1, or 10 μg/ml). These findings indicate that bacterial toxins may act locally on ovarian steroidogenic cells and compromise follicular development in postpartum dairy cows. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Selective Progesterone Receptor Modulator CDB4124 Inhibits Proliferation and Induces Apoptosis in Uterine Leiomyoma Cells

PubMed Central

Luo, Xia; Yin, Ping; Coon V., John S.; Cheng, You-Hong; Wiehle, Ronald D.; Bulun, Serdar E.

2009-01-01

Objective To evaluate the effects of selective progesterone receptor modulator CDB4124 on cell proliferation and apoptosis in cultured human uterine leiomyoma smooth muscle (LSM) cells and control myometrial smooth muscle (MSM) cells in matched uteri. Design Laboratory research. Setting Academic medical center. Patient(s) Premenopausal women (n=12) undergoing hysterectomy for leiomyoma-related symptoms. Intervention(s) Treatment of primary LSM and MSM cells with CDB4124 (10-8-10-6M) or vehicle for 24, 48 or 72 hours. Main Outcome Measure(s) Western blot for protein expression of proliferating cell nuclear antigen (PCNA), cleaved poly-adenosine 5’-diphosphate-ribose polymerase (PARP), Bcl-2 and Krüppel-like transcription factor 11 (KLF11); MTT assay to evaluate viable cell numbers; and real-time polymerase chain reaction to quantify mRNA levels. Result(s) Treatment with CDB4124 significantly decreased levels of the proliferation marker PCNA, the number of viable LSM cells, and the anti-apoptotic protein Bcl-2. On the other hand, treatment with CDB4124 increased levels of the apoptosis marker cleaved PARP and the tumor suppressor KLF11 in a dose- and time-dependent manner in LSM cells. In matched MSM cells, however, CDB4124 did not affect cell proliferation or apoptosis. Conclusion(s) CDB4124 selectively inhibits proliferation and induces apoptosis in LSM but not in MSM cells. PMID:20056218

Novel orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium

PubMed Central

Catherino, William H.; Malik, Minnie; Driggers, Paul; Chappel, Scott; Segars, James; Davis, Joseph

2012-01-01

Context Uterine leiomyomas are highly prevalent and often symptomatic. Current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. Objective and Methods To determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947 in human immortalized leiomyoma and patient-matched myometrial cells. Receptor binding in vitro was assessed using LNCaP, Ishikawa, T-47D, and HeLa cell extracts for AR, ER-α, PR, and GR, respectively. Progestational activity assessed by alkaline phosphatase assay in T47D cells and ER-α expression in human leiomyoma and myometrial cells. In vivo progestational activity assayed by the McPhail assay. Proliferation and gene expression studies (q RT-PCR and western blot) were performed in immortalized leiomyoma and myometrial cells. Results Both CP8863 and CP8947 is highly selective for PR but not for ER-α, AR, and GR. Both induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-α in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium. Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. The decreased proliferation correlated with increased TRAIL and caspase -7, suggesting induction of apoptosis in leiomyoma cells. ECM components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. Conclusions CP8947 was a potent novel non-steroidal SPRM that was selective for PR, showed progestational activity in endometrium, inhibited leiomyoma cell proliferation (potentially via induction of apoptosis), and decreased ECM component production, without disrupting myometrial cell proliferation. PMID:20493256

Sex steroid receptor expression in the oviduct and uterus of sheep with estrus synchronized with progestagen or prostaglandin analogues.

PubMed

García-Palencia, P; Sánchez, M A; Nieto, A; Vilar, M P; González, M; Veiga-Lopez, A; González-Bulnes, A; Flores, J M

2007-01-01

The objective of this study was to investigate differences in the expression of estrogen receptor-alpha (ERalpha), progesterone receptor (PR) and the proliferative indexes (Ki-67), in the uterus and oviduct of sheep with estrus synchronized either by prostaglandin analogues (Group PA, n=27) or by treatment with progestagens (Group P, n=29) on days 4 and 7 (day 0=estrus), when the embryos were collected. Immunohistochemical methods were used to quantify ERalpha, PR and Ki-67 in six superficial and deep compartments in the uterus and oviduct. The expression of ERalpha was significantly (P<0.01) lower in progestagen treated ewes than in prostaglandin analogues treated group in the luminal epithelium, superficial glands and superficial stroma in the uterus on day 4. The expression of PR was significantly lower in progesterone treated ewes than in the PA Group in the superficial gland (P<0.05) in both days studied. The lowest expression of PR was observed in the luminal caruncular epithelium and superficial glands in both treatments, obtaining the lowest levels on day 4 (P<0.05). There were significant differences between days 4 and 7 in the Ki-67 immunostaining in the luminal epithelium (P<0.01) and superficial glands (P<0.05). A higher cell proliferation was observed in the uterine epithelium (P<0.05) on day 4 in the animals treated with progestagens. Results indicate that sheep with synchronization of estrus with progestagens showed a reduction of ERalpha and PR protein expression in most of oviductal and uterine cells.

Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.

PubMed

Czajkowski, Krzysztof; Sienko, Jacek; Mogilinski, Mariusz; Bros, Magdalena; Szczecina, Roman; Czajkowska, Anna

2007-03-01

To compare the influence of vaginal micronized progesterone and oral dydrogesterone supplementation on uteroplacental circulation in early pregnancy that is complicated by threatened abortion. Randomized, parallel group, double-blind, double dummy-controlled study. Tertiary care university hospital. Fifty-three patients with threatened abortion and a living embryo. Three hundred milligrams of micronized vaginal progesterone or 30 mg of oral dydrogesterone daily supplementation for 6 weeks, serial transvaginal Doppler ultrasound measurement of pulsatility index, resistance index, and systolic/diastolic ratio of the spiral arteries, the uterine arteries, and the intrachorionic area. Uteroplacental blood flow. The study demonstrated that vaginal progesterone administration, but not oral dydrogesterone treatment, results in the decrease in the spiral artery pulsatility and resistance index and systolic/diastolic ratio. Insignificant decrease in pulsatility index and resistance index of the uterine artery was observed at >9 weeks and was not associated with treatment regimen. Dydrogesterone treatment was only accompanied by the decrease in the uterine artery systolic/diastolic ratio. Vaginal progesterone and oral dydrogesterone supplementation have a different influence on the uteroplacental circulation in early pregnancy that is complicated by threatened abortion.

A longitudinal study of the control of renal and uterine hemodynamic changes of pregnancy.

PubMed

Ogueh, Onome; Clough, Angela; Hancock, Maggie; Johnson, Mark R

2011-01-01

We have determined the sequence and extent of maternal renal and uterine adaptation to pregnancy and examined the role of hormonal factors in their regulation. Renal bipolar diameter (RBD), renal artery resistance index (RARI), uterine artery pulsatility index (UAPI), and plasma relaxin, human chorionic gonadotropin (hCG), progesterone, estradiol, urea, and creatinine were measured longitudinally in women with normal spontaneous singleton pregnancies, in vitro fertilization (IVF) singleton pregnancies, ovum donation (OD) singleton pregnancies, and multiple pregnancies from prepregnancy to postpartum. There was a progressive increase in the RBD and the RARI and a decrease in the UAPI during pregnancy. These changes reversed toward prepregnancy levels by 6 weeks post delivery. There was no difference in the rate of change of RBD, RARI, and UAPI between spontaneous singleton, IVF singleton, OD singleton, and multiple pregnancies (p < 0.05), but relaxin was directly correlated to the RARI (r = 0.654, p = 0.015), and progesterone was inversely correlated to uterine artery PI (r = 0.554, p = 0.049). These data show that renal size and resistance to blood flow increase with advancing gestation, whereas the uterine artery resistance declined with gestation. These changes may be influenced by relaxin and progesterone.

Uterine fibroids: current perspectives

PubMed Central

Khan, Aamir T; Shehmar, Manjeet; Gupta, Janesh K

2014-01-01

Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman’s menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge. PMID:24511243

The management of uterine leiomyomas.

PubMed

Vilos, George A; Allaire, Catherine; Laberge, Philippe-Yves; Leyland, Nicholas

2015-02-01

The aim of this guideline is to provide clinicians with an understanding of the pathophysiology, prevalence, and clinical significance of myomata and the best evidence available on treatment modalities. The areas of clinical practice considered in formulating this guideline were assessment, medical treatments, conservative treatments of myolysis, selective uterine artery occlusion, and surgical alternatives including myomectomy and hysterectomy. The risk-to-benefit ratio must be examined individually by the woman and her health care provider. Implementation of this guideline should optimize the decision-making process of women and their health care providers in proceeding with further investigation or therapy for uterine leiomyomas, having considered the disease process and available treatment options, and reviewed the risks and anticipated benefits. Published literature was retrieved through searches of PubMed, CINAHL, and Cochrane Systematic Reviews in February 2013, using appropriate controlled vocabulary (uterine fibroids, myoma, leiomyoma, myomectomy, myolysis, heavy menstrual bleeding, and menorrhagia) and key words (myoma, leiomyoma, fibroid, myomectomy, uterine artery embolization, hysterectomy, heavy menstrual bleeding, menorrhagia). The reference lists of articles identified were also searched for other relevant publications. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to January 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, and national and international medical specialty societies. The majority of fibroids are asymptomatic and require no intervention or further investigations. For symptomatic fibroids such as those causing menstrual abnormalities (e.g. heavy, irregular, and prolonged uterine bleeding), iron defficiency anemia, or bulk symptoms (e.g., pelvic pressure/pain, obstructive symptoms), hysterectomy is a definitive solution. However, it is not the preferred solution for women who wish to preserve fertility and/or their uterus. The selected treatment should be directed towards an improvement in symptomatology and quality of life. The cost of the therapy to the health care system and to women with fibroids must be interpreted in the context of the cost of untreated disease conditions and the cost of ongoing or repeat investigative or treatment modalities. The quality of evidence in this document was rated using the criteria described in the Report of the Caadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. Uterine fibroids are common, appearing in 70% of women by age 50; the 20% to 50% that are symptomatic have considerable social and economic impact in Canada. (II-3) 2. The presence of uterine fibroids can lead to a variety of clinical challenges. (III) 3. Concern about possible complications related to fibroids in pregnancy is not an indication for myomectomy except in women who have had a previous pregnancy with complications related to these fibroids. (III) 4. Women who have fibroids detected in pregnancy may require additional maternal and fetal surveillance. (II-2) 5. Effective medical treatments for women with abnormal uterine bleeding associated with uterine fibroids include the levonorgestrel intrauterine system, (I) gonadotropin-releasing hormone analogues, (I) selective progesterone receptor modulators, (I) oral contraceptives, (II-2) progestins, (II-2) and danazol. (II-2) 6. Effective medical treatments for women with bulk symptoms associated with fibroids include selective progesterone receptor modulators and gonadotropin-releasing hormone analogues. (I) 7. Hysterectomy is the most effective treatment for symptomatic uterine fibroids. (III) 8. Myomectomy is an option for women who wish to preserve their uterus or enhance fertility, but carries the potential for further intervention. (II-2) 9. Of the conservative interventional treatments currently available, uterine artery embolization has the longest track record and has been shown to be effective in properly selected patients. (II-3) 10. Newer focused energy delivery methods are promising but lack long-term data. (III) Recommendations 1. Women with asymptomatic fibroids should be reassured that there is no evidence to substantiate major concern about malignancy and that hysterectomy is not indicated. (III-D) 2. Treatment of women with uterine leiomyomas must be individualized based on symptomatology, size and location of fibroids, age, need and desire of the patient to preserve fertility or the uterus, the availability of therapy, and the experience of the therapist. (III-B) 3. In women who do not wish to preserve fertility and/or their uterus and who have been counselled regarding the alternatives and risks, hysterectomy by the least invasive approach possible may be offered as the definitive treatment for symptomatic uterine fibroids and is associated with a high level of satisfaction. (II-2A) 4. Hysteroscopic myomectomy should be considered first-line conservative surgical therapy for the management of symptomatic intracavitary fibroids. (II-3A) 5. Surgical planning for myomectomy should be based on mapping the location, size, and number of fibroids with the help of appropriate imaging. (III-A) 6. When morcellation is necessary to remove the specimen, the patient should be informed about possible risks and complications, including the fact that in rare cases fibroid(s) may contain unexpected malignancy and that laparoscopic power morcellation may spread the cancer, potentially worsening their prognosis. (III-B) 7. Anemia should be corrected prior to proceeding with elective surgery. (II-2A) Selective progesterone receptor modulators and gonadotropin-releasing hormone analogues are effective at correcting anemia and should be considered preoperatively in anemic patients. (I-A) 8. Use of vasopressin, bupivacaine and epinephrine, misoprostol, peri-cervical tourniquet, or gelatin-thrombin matrix reduce blood loss at myomectomy and should be considered. (I-A) 9. Uterine artery occlusion by embolization or surgical methods may be offered to selected women with symptomatic uterine fibroids who wish to preserve their uterus. Women choosing uterine artery occlusion for the treatment of fibroids should be counselled regarding possible risks, including the likelihood that fecundity and pregnancy may be impacted. (II-3A) 10. In women who present with acute uterine bleeding associated with uterine fibroids, conservative management with estrogens, selective progesterone receptor modulators, antifibrinolytics, Foley catheter tamponade, and/or operative hysteroscopic intervention may be considered, but hysterectomy may become necessary in some cases. In centres where available, intervention by uterine artery embolization may be considered. (III-B).

Racial and Ethnic Differences in the Pathogenesis and Clinical Manifestations of Uterine Leiomyoma

PubMed Central

Catherino, William H.; Eltoukhi, Heba M.; Al-Hendy, Ayman

2014-01-01

Uterine leiomyomas are the most common benign gynecologic condition. The prevalence is three times more common among women of African ethnicity. Disparity in this disease is evidenced by earlier age of onset, greater severity of symptoms, and different response to treatment. Although the pathogenesis of disease development is not completely known, growing evidence focuses on investigating the molecular mechanisms in disease development and the influence of ethnicity. Variation in the expression levels or function of estrogen and progesterone receptors, polymorphism of genes involved in estrogen synthesis and/or metabolism (COMT, CYP17), retinoic acid nuclear receptors (retinoid acid receptor-α, retinoid X receptor-α), and aberrant expression of micro-RNAs (miRNAs) are some of the molecular mechanisms that may be involved. Nutritional factors, such as vitamin D deficiency, might also contribute to the higher incidence in dark skinned populations who are also commonly suffer from hypovitaminosis D. Culture and environmental difference might have a role in disease development. Further analysis and better understanding of these mechanisms will provide insight into the molecular basis of racial disparities in leiomyoma formation and will help to develop new innovations in leiomyoma treatment. PMID:23934698

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

PubMed

Migale, Roberta; MacIntyre, David A; Cacciatore, Stefano; Lee, Yun S; Hagberg, Henrik; Herbert, Bronwen R; Johnson, Mark R; Peebles, Donald; Waddington, Simon N; Bennett, Phillip R

2016-06-13

Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.

Sox9 overexpression in uterine epithelia induces endometrial gland hyperplasia

PubMed Central

Gonzalez, Gabriel; Mehra, Shyamin; Wang, Ying; Akiyama, Haruhiko

2016-01-01

SOX9 is a high mobility group transcription factor that is required in many biological processes, including cartilage differentiation, endoderm progenitor maintenance, hair differentiation, and testis determination. SOX9 has also been linked to colorectal, prostate, and lung cancer. We found that SOX9 is expressed in the epithelium of the adult mouse and human uterus, predominantly marking the uterine glands. To determine if SOX9 plays a role in the development of endometrial cancer we overexpressed Sox9 in the uterine epithelium using a progesterone receptor-Cre mouse model. Sox9 overexpression in the uterine epithelium led to the formation of simple and complex cystic glandular structures in the endometrium of aged-females. Histological analysis revealed that these structures appeared morphologically similar to structures present in patients with endometrial hyperplastic lesions and endometrial polyps that are thought to be precursors of endometrial cancer. The molecular mechanisms that cause the glandular epithelium to become hyperplastic, leading to endometrial cancer are still poorly understood. These findings indicate that chronic overexpression of Sox9 in the uterine epithelium can induce the development of endometrial hyperplastic lesions. Thus, SOX9 expression may be a factor in the formation of endometrial cancer. PMID:27262401

Reproductive Management for Optimal Uterine Preparedness for Pregnancy

USDA-ARS?s Scientific Manuscript database

It is clear that decreased serum concentrations of preovulatory estradiol create uterine deficiencies that prevent the maintenance of pregnancy and losses are related to reduced ability of the developing embryo to implant. The uterine deficiencies in response to reduced post-ovulatory progesterone ...

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma.

PubMed

Wu, Xin; Serna, Vanida A; Thomas, Justin; Qiang, Wenan; Blumenfeld, Michael L; Kurita, Takeshi

2017-12-15

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here, we report the elucidation of the biological characteristics of the two most prevalent uterine leiomyoma subtypes, MED12-mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) uterine leiomyomas. Because each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-uterine leiomyoma were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of extracellular matrix in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both uterine leiomyoma subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these uterine leiomyoma subtypes emphasize the importance of subtypes and genotypes in designing nonsurgical therapeutic strategies for uterine leiomyoma. Cancer Res; 77(24); 6891-901. ©2017 AACR . ©2017 American Association for Cancer Research.

Endometrial proteins: a reappraisal.

PubMed

Seppälä, M; Julkunen, M; Riittinen, L; Koistinen, R

1992-06-01

Uterine factors influence reproduction at the macro-anatomy level, and the effects of hormonal steroids on endometrial morphology are well recognized in the histopathological diagnosis of dysfunctional bleeding and infertility. During the past decade, attention has been paid to endometrial protein synthesis and secretion with respect to endocrine stimuli and implantation, and to the paracrine/autocrine effects of endometrial peptide growth factors, their binding proteins and other factors. The emphasis of this presentation is on protein secretion of the secretory endometrium, in which progesterone plays a pivotal role. Insulin-like growth factors have receptors on the endometrium, and IGF-binding proteins, stimulated by progesterone, modulate the effects of IGFs locally. Also other protein products of the secretory endometrium have been reviewed in this communication, with special emphasis on studies of a progesterone-associated endometrial protein which has many names in the literature, such as PEP, PP14, alpha 2-PEG and AUP. Extensive studies are ongoing in many laboratories to elucidate the regulation, function, interplay at tissue and cellular levels, and clinical significance of these proteins.

Isoflavone genistein inhibits estrogen-induced chloride and bicarbonate secretory mechanisms in the uterus in rats.

PubMed

Chinigarzadeh, Asma; Karim, Kamarulzaman; Muniandy, Sekaran; Salleh, Naguib

2017-04-01

We hypothesized that genistein could affect the chloride (Cl - ) and bicarbonate (HCO 3 - ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl - and HCO 3 - concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl - /HCO 3 - exchanger (SLC26a6), Na + /HCO 3 - cotransporter (SLC4a4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl - and HCO 3 - concentrations and expression of CFTR, SLC26a6, SLC4a4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility. © 2016 Wiley Periodicals, Inc.

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

Influence of controlled ovarian hyperstimulation on uterine peristalsis in infertile women.

PubMed

Zhu, Lin; Li, Yanping; Xu, Aizhuang

2012-09-01

Is there a difference in the characteristics of uterine peristalsis in natural and controlled ovarian hyperstimulation (COH) cycles? COH significantly changed the uterine peristaltic pattern. In natural menstrual cycles, the periodic changes of uterine peristalsis are closely related to the reproductive process. This is a prospective cohort study with a total of 64 subjects involved. The study was performed between May 2011 and August 2011. Sixty-four infertile women with regular, ovulatory menstrual cycles underwent follicular tracking in one natural cycle and after ovarian stimulation (GnRH-agonist down-regulation) in the subsequent cycle (COH). Three time points were studied in both cycles: at LH surge/HCG plus 1 day, ovulation/oocyte retrieval and 2 days after ovulation/retrieval. The study was performed in an IVF center of the university-affiliated Xiangya hospital. Uterine peristaltic wave frequency was 1.31 times higher in the COH than in the natural cycle (P< 0.01). At all three time points in the COH cycle, waves moving from the cervix to fundus dominated, comprising 80-90% of the wave types observed, while 'no activity' was more frequently observed in the natural cycle. The wave frequency was positively correlated with the level of serum estradiol (E(2)) (r= 0.30; P< 0.01) and negatively correlated with the progesterone level (r= -0.48; P< 0.01) for the physiological range of steroid levels. No correlation was found between the wave frequency and supraphysiological concentrations of E(2) or progesterone. The two observers were not independent and this was a limitation of the study. Quantitative measurements of wave amplitude in the different cycles should be compared in future research. Uterine peristalsis was much higher in the COH cycle than in the natural cycle. The endometrial movements did not weaken to the natural level before embryo transfer, even with high levels of progesterone. The wave frequency was positively correlated with serum E(2) level and negatively correlated with that of progesterone within the physiological range. No correlation was found between the wave frequency and supraphysiological concentrations of E(2) and progesterone.

Altered Gene Expression Patterns During the Initiation and Promotion Stages of Neonatally Diethylstilbestrol-Induced Hyperplasia/Dysplasia/Neoplasia in the Hamster Uterus

PubMed Central

Hendry, William J.; Hariri, Hussam Y.; Alwis, Imala D.; Gunewardena, Sumedha S.; Hendry, Isabel R.

2014-01-01

Neonatal treatment of hamsters with diethylstilbestrol (DES) induces uterine hyperplasia/dysplasia/neoplasia (endometrial adenocarcinoma) in adult animals. We subsequently determined that the neonatal DES exposure event directly and permanently disrupts the developing hamster uterus (initiation stage) so that it responds abnormally when it is stimulated with estrogen in adulthood (promotion stage). To identify candidate molecular elements involved in progression of the disruption/neoplastic process, we performed: 1) immunoblot analyses and 2) microarray profiling (Affymetrix Gene Chip System) on sets of uterine protein and RNA extracts, respectively, and 3) immunohistochemical analysis on uterine sections; all from both initiation stage and promotion stage groups of animals. Here we report that: 1) progression of the neonatal DES-induced hyperplasia/dysplasia/neoplasia phenomenon in the hamster uterus involves a wide spectrum of specific gene expression alterations and 2) the gene products involved and their manner of altered expression differ dramatically during the initiation vs. promotion stages of the phenomenon. Particularly interesting changes included members in the functional categories of nuclear receptors (progesterone receptor), cell-cell interactions (E-cadherin, connexins), cytokine action (IRF-1, Stat5A), growth factor action (IRS-1), extracellular matrix component (tenascin-C), transcription factors (Nrf2, Sp1), and multi-functional nuclear protein (SAFB1). PMID:25242112

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

Bae, Sijeong; Kwon, Hwang; Yoon, Hyemin

The sine oculis homeobox 1 (SIX1) is a member of the Six gene family. SIX1 is involved in tissue development by regulating proliferation, apoptosis, and differentiation. However, function of SIX1 in the uterus remains unknown. Here, we found that Six1 expression is regulated along the estrous cycle in mouse uterus. Six1 expression was significantly increased at estrus stage and decreased at the rest of stages. SIX1 is detected in the luminal and glandular epithelium of uterine endometrium at the estrus stage. Estrogen injection increased Six1 expression in the ovariectomized mouse uterus, whereas progesterone had no effect on its expression. Estrogenmore » receptor antagonist inhibited estrogen-induced Six1 expression. Our findings imply that SIX1 may play a role as an important regulator to orchestrate the dynamic of uterine endometrium in response to estrogen level during the estrous cycle. These results will give us a better understanding of uterine biology. - Highlights: • Six1 expression is regulated during the estrous cycle in mouse uterus. • Six1 is highly expressed at the estrus stage of estrous cycle. • SIX1 is detected in luminal/glandular epithelium of the uterus at the estrus stage. • Estrogen stimulates Six1 expression in an estrogen receptor-dependent manner.« less

Ultrasound assessment of endometrial cavity in perimenopausal women on oral progesterone for abnormal uterine bleeding: comparison of diagnostic accuracy of imaging with hysteroscopy-guided biopsy.

PubMed

Dasgupta, Subhankar; Dasgupta, Shyamal; Sharma, Partha Pratim; Mukherjee, Amitabha; Ghosh, Tarun Kumar

2011-11-01

To investigate the effect of oral progesterone on the accuracy of imaging studies performed to detect endometrial pathology in comparison to hysteroscopy-guided biopsy in perimenopausal women on progesterone treatment for abnormal uterine bleeding. The study population comprised of women aged 40-55 years with complaints of abnormal uterine bleeding who were also undergoing oral progesterone therapy. Women with a uterus ≥ 12 weeks' gestation size, previous abnormal endometrial biopsy, cervical lesion on speculum examination, abnormal Pap smear, active pelvic infection, adnexal mass on clinical examination or during ultrasound scan and a positive pregnancy test were excluded. A transvaginal ultrasound followed by saline infusion sonography were done. On the following day, a hysteroscopy followed by a guided biopsy of the endometrium or any endometrial lesion was performed. Comparison between the results of the imaging study with the hysteroscopy and guided biopsy was done. The final analysis included 83 patients. For detection of overall pathology, polyp and fibroid transvaginal ultrasound had a positive likelihood ratio of 1.65, 5.45 and 5.4, respectively, and a negative likelihood ratio of 0.47, 0.6 and 0.43, respectively. For detection of overall pathology, polyp and fibroid saline infusion sonography had a positive likelihood ratio of 4.4, 5.35 and 11.8, respectively, and a negative likelihood ratio of 0.3, 0.2 and 0.15, respectively. In perimenopausal women on oral progesterone therapy for abnormal uterine bleeding, imaging studies cannot be considered as an accurate method for diagnosing endometrial pathology when compared to hysteroscopy and guided biopsy. © 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.

Effects of ovarian steroids upon responses mediated by adrenoceptors in separated layers of the myometrium and in the costo-uterine muscle of the guinea-pig

PubMed Central

Hartley, Margaret L.; Pennefather, Jocelyn N.; Story, Margot E.

1983-01-01

1 This study describes the effects of ovarian steroid hormones upon the responses to adrenoceptor agonists of isolated myometrium, separated into its longitudinal and circular layers, and of costo-uterine muscle from guinea-pigs. The preparations were field-stimulated at 100 s intervals, and the adrenoceptor agonists phenylephrine and isoprenaline produced enhancement or inhibition of the evoked contractions. 2 Isoprenaline produced propranolol-sensitive inhibitory effects in longitudinal and circular myometrium and costo-uterine muscle preparations from animals from all experimental groups: i.e. from nonsteroid-treated animals (ovariectomized and intact); intact animals treated with either oestrogen or progesterone alone; ovariectomized animals treated with oestrogen; ovariectomized and intact animals treated with progesterone following oestrogen priming; and from animals 1-4 days post-partum. Longitudinal myometrial preparations from progesterone-treated oestrogen-primed and from post-partum animals were most sensitive to this agonist. 3 Phenylephrine produced phentolamine-sensitive excitatory effects in circular myometrial and costo-uterine muscle preparations from animals from all the experimental groups. In contrast, propranolol-sensitive inhibitory responses to phenylephrine occurred in longitudinal myometrial preparations taken from animals treated with progesterone following oestrogen priming, and from post-partum animals. Longitudinal myometrium from animals from the remaining experimental groups exhibited phentolamine-sensitive excitatory responses to phenylephrine. 4 The basis for the selective effect upon the longitudinal myometrium of exposure to progesterone following a period of oestrogen priming, is discussed. The results described are consistent with the possibility that in the longitudinal layer of guinea-pig uterus exposed to progesterone following oestrogen priming there is an increase in the proportion of β-adrenoceptors in this layer. This increase may reduce the likelihood of contractions arising via direct stimulation of α-adrenoceptors in this layer in response to sympathetic activation during pregnancy. PMID:6871558

Select nutrients, progesterone, and interferon tau affect conceptus metabolism and development

PubMed Central

Bazer, Fuller W; Kim, Jingyoung; Song, Gwonhwa; Ka, Hakhyun; Tekwe, Carmen D; Wu, Guoyao

2012-01-01

Interferon tau (IFNT), a novel multifunctional type I interferon secreted by trophectoderm, is the pregnancy recognition signal in ruminants that also has antiviral, antiproliferative, and immunomodulatory bioactivities. IFNT, with progesterone, affects availability of the metabolic substrate in the uterine lumen by inducing expression of genes for transport of select nutrients into the uterine lumen that activate mammalian target of rapamycin (mTOR) cell signaling responsible for proliferation, migration, and protein synthesis by conceptus trophectoderm. As an immunomodulatory protein, IFNT induces an anti-inflammatory state affecting metabolic events that decrease adiposity and glutamine:fructose-6-phosphate amidotransferase 1 activity, while increasing insulin sensitivity, nitric oxide production by endothelial cells, and brown adipose tissue in rats. This short review focuses on effects of IFNT and progesterone affecting transport of select nutrients into the uterine lumen to stimulate mTOR cell signaling required for conceptus development, as well as effects of IFNT on the immune system and adiposity in rats with respect to its potential therapeutic value in reducing obesity. PMID:23050969

Successful pregnancy after treatment with ulipristal acetate for uterine fibroids.

PubMed

Monleón, Javier; Martínez-Varea, Alicia; Galliano, Daniela; Pellicer, Antonio

2014-01-01

This case report presents a clinical pregnancy after ulipristal acetate (UA) to decrease uterine fibroid size. A 37-year-old patient, gravida 1, abortus 1, with uterine fibroids was treated with 5 mg of UA daily for 13 weeks starting eight months after a multiple laparotomic myomectomy. Fibroid shrinkage and restoration of the morphology of endometrial cavity were evaluated in order to allow a subsequent pregnancy. A decrease of the uterine fibroids and a normal morphology of the endometrial cavity were noted by transvaginal ultrasound after treatment. An endometrial biopsy excluded histologic endometrial changes. Three months after the end of UA the patient reported amenorrhea for 5 weeks and a clinical pregnancy was confirmed with transvaginal ultrasound. She underwent a subsequent uneventful pregnancy. Thus, the spontaneous pregnancy after UA to reduce fibroid size may support the potential clinical utility of this selective progesterone receptor modulator in the management of women with pregnancy desire and uterine fibroids after a prior myomectomy. Patients who refuse a new surgical procedure and/or those who are going to undergo assisted reproductive techniques would benefit from UA. It effectively shrinks fibroids, avoids risks of a new surgical procedure, and allows an immediate attempt at conception after the end of treatment.

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice.

PubMed

Kim, Yeon Sun; Kim, Hye-Ryun; Kim, Hyongbum; Yang, Seung Chel; Park, Mira; Yoon, Jung Ah; Lim, Hyunjung J; Hong, Seok-Ho; DeMayo, Francesco J; Lydon, John P; Choi, Youngsok; Lee, Dong Ryul; Song, Haengseok

2016-02-02

DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8(d/d)) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8(d/d) females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8(d/d) mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice.

Differences in uterine immunoexpression of PR, ERα and OTR when comparing prostaglandin- to progestagen-based protocols for ovine estrus synchronization.

PubMed

Ruiz-González, I; Sánchez, M A; García-Palencia, P; Sánchez, B; García-Fernández, R A; González-Bulnes, A; Flores, J M

2012-07-01

The aim of this work was to compare PR, ERα and OTR uterine expression between days 9 and 21 of pregnancy in ewes whose estrus had been synchronized with two different protocols. Sixty-four adult Manchega ewes were synchronized with either conventional progestagens (P) or prostaglandin analogues (PG), and mated. Uterine samples were obtained from pregnant animals (group P, n=24; group PG, n=25) on days 9 post coitus (pc), 13pc, 15pc, 17pc and 21pc. Immunohistochemical detection of progesterone receptor (PR), estrogen receptor-α (ERα) and oxytocin receptor (OTR) was assessed in different uterine cell compartments including luminal and glandular epithelium, stroma and myometrium. Interaction day × treatment was obtained when assessing PR expression in the caruncular stroma (P=0.027) and myometrium (P=0.000), as well as for ERα in the superficial stroma (P=0.05). Significant "day post coitus" effect was found regarding to PR (P<0.01, with the exception of the superficial stroma, deep stroma and myometrium), ERα (P<0.01), and OTR (P<0.05, except in the deep compartments). No significant "treatment" effect was found for PR, ERα or OTR protein immunoexpression. This study supports the implication of PR, ERα and OTR within days 9-21 of the ovine pregnancy. Moreover, different expression pattern of PR and ERα proteins has been found between treatments in various compartments studied. Collectively, these results indicate that PR, ERα and OTR expression during early pregnancy is similar between ewes treated with either progestagens or prostaglandin analogues-based protocols for estrus synchronization. Copyright © 2012 Elsevier B.V. All rights reserved.

Primary uterine inertia in four labrador bitches.

PubMed

Davidson, Autumn P

2011-01-01

Uterine inertia is a common cause of dystocia in the bitch and is designated as primary (i.e., uterine contractions fail to ever be initiated) or secondary (i.e., uterine contractions cease after a period of time but before labor is completed). The etiology of primary uterine inertia is not well understood. The accurate diagnosis of primary uterine inertia requires the use of tocodynamometry (uterine monitoring). Primary uterine inertia has been postulated to result from a failure of luteolysis resulting in persistently elevated progesterone concentrations. In this study, primary uterine inertia was diagnosed in a series of four bitches in which luteolysis was documented suggesting some other etiopathogenesis for primary uterine inertia.

Uterine angioleiomyoma: a rare variant of uterine leiomyoma.

PubMed

Garg, Garima; Mohanty, Sambit K

2014-08-01

Uterine angioleiomyoma is an extremely rare and unique variant of leiomyoma. It usually occurs in middle-aged women, who commonly present with menorrhagia, abdominal pain, or abdominal mass. The lesions are either single or multiple and manifest as submucosal, intramural, or subserosal whorled nodules. Microscopy of the individual nodule shows interlacing fascicles of spindle cells swirling around thick-walled blood vessels. Angioleiomyoma usually lacks mitotic figures, pleomorphism, or necrosis, although cases with marked nuclear atypia and multinucleated giant cells have been reported. The tumor cells are immunoreactive for smooth muscle actin, desmin, h-caldesmon, and progesterone receptor, with a low Ki-67 labeling index. Because these lesions are vascular, they may undergo spontaneous rupture and pose a life-threatening emergency, especially in pregnancy. There are no specific imaging findings; therefore, a preoperative diagnosis is extremely difficult. It is important to recognize this entity and differentiate it from a malignancy, particularly when angioleiomyoma shows significant cytologic atypia or raised cancer antigen 125 levels by thorough sampling. When required, a proper immunohistochemical panel should be used to arrive at a correct diagnosis. In this review, we discuss the current knowledge on uterine angioleiomyoma and its clinical relevance.

Expression Profiling of Nuclear Receptors Identifies Key Roles of NR4A Subfamily in Uterine Fibroids

PubMed Central

Yin, Hanwei; Lo, Jay H.; Kim, Ji-Young; Marsh, Erica E.; Kim, J. Julie; Ghosh, Asish K.; Bulun, Serdar

2013-01-01

Uterine fibroids (UFs), also known as uterine leiomyomas, are benign, fibrotic smooth muscle tumors. Although the GnRH analog leuprolide acetate that suppresses gonadal steroid hormones is used as a treatment, it has significant side effects, thereby limiting its use. Availability of more effective therapy is limited because of a lack of understanding of molecular underpinnings of the disease. Although ovarian steroid hormones estrogen and progesterone and their receptors are clearly involved, the role of other nuclear receptors (NRs) in UFs is not well defined. We used quantitative real-time PCR to systematically profile the expression of 48 NRs and identified several NRs that were aberrantly expressed in UFs. Among others, expression of NR4A subfamily members including NGFIB (NR4A1), NURR1 (NR4A2), and NOR1 (NR4A3) were dramatically suppressed in leiomyoma compared with the matched myometrium. Restoration of expression of each of these NR4A members in the primary leiomyoma smooth muscle cells decreased cell proliferation. Importantly, NR4As regulate expressions of the profibrotic factors including TGFβ3 and SMAD3, and several collagens that are key components of the extracellular matrix. Finally, we identify NR4A members as targets of leuprolide acetate treatment. Together, our results implicate several NRs including the NR4A subfamily in leiomyoma etiology and identify NR4As as potential therapeutic targets for treating fibrotic diseases. PMID:23550059

Spontaneous endometriosis in a mandrill (Mandrillus sphinx).

PubMed

Nakamura, S; Ochiai, K; Ochi, A; Ito, M; Kamiya, T; Yamamoto, H

2012-01-01

A 25-year-old female mandrill (Mandrillus sphinx) died after exhibiting weakness and recumbency with serosanguineous ascites. Gross findings included haemoperitoneum and multifocal to diffuse serosal thickening with petechiae and ecchymoses throughout the peritoneum. The uterus was covered entirely with large blood clots and was adherent to the ovaries and pelvic wall. Microscopical and immunohistochemical examination revealed extra- and intra-uterine growth of ectopic endometrial tissue with marked fibrosis. The ectopic endometrial tissues predominantly consisted of stromal cells expressing CD10 and progesterone receptor and variably-sized glands lined by the epithelium with occasional slight expression of oestrogen receptor α. A diagnosis of endometriosis was made. This is the first report of naturally occurring endometriosis in a mandrill. Copyright © 2012 Elsevier Ltd. All rights reserved.

Interleukin-6 is an essential determinant of on-time parturition in the mouse.

PubMed

Robertson, Sarah A; Christiaens, Inge; Dorian, Camilla L; Zaragoza, Dean B; Care, Alison S; Banks, Anke M; Olson, David M

2010-08-01

IL-6 abundance in amniotic fluid and uterine tissues increases in late gestation or with infection-associated preterm labor. A role in regulation of labor onset is suggested by observations that IL-6 increases expression of genes controlling prostaglandin synthesis and signaling in isolated uterine cells, but whether IL-6 is essential for normal parturition is unknown. To evaluate the physiological role of IL-6 in parturition in mice, we investigated the effect of Il6 null mutation on the timing of parturition and expression of genes associated with uterine activation. Il6 null mutant mice delivered 24 h later than wild-type mice, although circulating progesterone fell similarly in both genotypes during the prepartal period. Il6 null mutant mice were also refractory to low doses of lipopolysaccharide sufficient to induce preterm delivery in wild-type mice. The characteristic late-gestation elevation in uterine expression of Oxtr mRNA encoding oxytocin receptor, and peripartal increases in Ptgfr and Ptgs2 mRNAs regulating prostaglandin synthesis and signaling were delayed by 24 h in Il6 null mutant mice. Conversely, Ptger4 mRNA encoding the prostaglandin E receptor-4 was abnormally elevated in late-gestation in Il6 null mutant mice. Administration of recombinant IL-6 from d 11.5 postcoitum until term restored the normal timing of delivery and normalized Ptger4 mRNA expression in late gestation. We conclude that IL-6 has a key role in controlling the progression of events culminating in parturition and that it acts downstream of luteolysis in the uterus to regulate genes involved in the prostaglandin-mediated uterine activation cascade.

Uterine flushing proteome of the tammar wallaby after reactivation from diapause.

PubMed

Martin, Florine C; Ang, Ching-Seng; Gardner, David K; Renfree, Marilyn B; Shaw, Geoff

2016-11-01

The marsupial tammar wallaby has the longest period of embryonic diapause of any mammal, up to 11 months, during which there is no cell division or blastocyst growth. Since the blastocyst in diapause is surrounded by acellular coats, the signals that maintain or terminate diapause involve factors that reside in uterine secretions. The nature of such factors remains to be resolved. In this study, uterine flushings (UFs) were used to assess changes in uterine secretions of tammars using liquid chromatography-mass spectrometry (LC-MS/MS) during diapause (day 0 and 3) and reactivation days (d) 4, 5, 6, 8, 9, 11 and 24 after removal of pouch young (RPY), which initiates embryonic development. This study supports earlier suggestions that the presence of specific factors stimulate reactivation, early embryonic growth and cell proliferation. A mitogen, hepatoma-derived growth factor and soluble epidermal growth factor receptors were observed from d3 until at least d11 RPY when these secreted proteins constituted 21% of the UF proteome. Binding of these factors to specific cellular receptors or growth factors may directly stimulate DNA synthesis and division in endometrial gland cells. Proteins involved in the p53/CDKN1A (p21) cell cycle inhibition pathway were also observed in the diapause samples. Progesterone and most of the oestrogen-regulated proteins were present in the UF after d3, which is concomitant with the start of blastocyst mitoses at d4. We propose that once the p21 inhibition of the cell cycle is lost, growth factors including HDGF and EGFR are responsible for reactivation of the diapausing blastocyst via the uterine secretions. © 2016 Society for Reproduction and Fertility.

Effects of vaginal progesterone on pain and uterine contractility in patients with threatened abortion before twelve weeks of pregnancy.

PubMed

Palagiano, A; Bulletti, C; Pace, M C; DE Ziegler, D; Cicinelli, E; Izzo, A

2004-12-01

Fifty women with previous diagnosis of inadequate luteal phase and threatened abortion underwent a prospective, randomized, double-blind study in one medical center carried out with a parallel trial. The primary objective was to establish the effects of vaginal progesterone (Crinone 8%) in reducing both pain and uterine contractions (UCs). The gel with or without (placebo) vaginal progesterone was administered once a day since the diagnosis of threatened abortion and for 5 days. The efficacy on pain symptom amelioration was evaluated by a 5-score intensity gradation, while the UCs were evaluated by ultrasound. The secondary objective of the study was to evaluate the outcome of the pregnancies. The use of progesterone was effective both on pain relief and on the frequency of the UCs that decreased after 5 days of vaginal progesterone administration (P < 0.005). The evaluation of the ongoing pregnancy and spontaneous abortion in both study groups after 60 days showed that 4 patients of group A and 8 patients of group B miscarried (P < 0.05). In conclusion, patients with threatened abortion benefit from vaginal progesterone by a reduction of UCs and pain. The use of vaginal progesterone improved the outcome of pregnancies complicated by threatened abortion and previous diagnosis of inadequate luteal phase.

Biological relevance of decamethylcyclopentasiloxane (D5) induced rat uterine endometrial adenocarcinoma tumorigenesis: Mode of action and relevance to humans.

PubMed

Klaunig, James E; Dekant, Wolfgang; Plotzke, Kathy; Scialli, Anthony R

2016-02-01

Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the production and formulation of consumer products with potential exposure to manufacturing workers, consumer, and the general public. Following a combined 2-year inhalation chronic bioassay performed in Fischer 344 (F344) rats, an increase in uterine endometrial adenocarcinomas was noted at the highest concentration to which animals were exposed. No other neoplasms were detected. In this study, a dose of 160 ppm produced an incidence of 8% endometrial adenocarcinomas. Based on a number of experimental studies with D5, the current manuscript examines the biological relevance and possible modes of action for the uterine endometrial adenocarcinomas observed in the rat following chronic exposure to D5. Variable rates of spontaneous uterine endometrial adenocarcinomas have been reported for untreated F344 CrlBr rats. As such, we concluded that the slight increase in uterine endometrial adenocarcinomas observed in the D5 chronic bioassay might not be the result of D5 exposure but may be related to variability of the spontaneous tumor incidence in this strain of rat. However, if the uterine endometrial adenocarcinomas are related to D5-exposure, alteration in the estrous cycle in the aging F344 rat is the most likely mode of action. D5 is not genotoxic or estrogenic. The alteration in the estrous cycle is caused by a decrease in progesterone with an increase in the estrogen:progesterone ratio most likely induced by a decrease in prolactin concentration. Available data support that exposure to D5 influences prolactin concentration. Although the effects on prolactin concentrations in a number of experiments were not always consistent, the available data support the conclusion that D5 is acting via a dopamine receptor agonist-like mechanism to alter the pituitary control of the estrous cycle. In further support of this mode of action, studies in F344 aged animals showed that the effects of D5 on estrous cyclicity produced a response consistent with a dopamine-like effect and further suggest that D5 is accelerating the aging of the reproductive endocrine system in the F344 rat utilized in this study. This mode of action for uterine endometrial adenocarcinoma tumorigenesis is not relevant for humans. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics.

PubMed

Islam, Md Soriful; Ciavattini, Andrea; Petraglia, Felice; Castellucci, Mario; Ciarmela, Pasquapina

2018-01-01

Uterine leiomyoma (also known as fibroid or myoma) is the most common benign tumor of the uterus found in women of reproductive age. It is not usually fatal but can produce serious clinical symptoms, including excessive uterine bleeding, pelvic pain or pressure, infertility and pregnancy complications. Due to lack of effective medical treatments surgery has been a definitive choice for the management of this tumor. Extracellular matrix (ECM) accumulation and remodeling are thought to be crucial for fibrotic diseases such as uterine leiomyoma. Indeed, ECM plays important role in forming the bulk structure of leiomyoma, and the ECM-rich rigid structure within these tumors is thought to be a cause of abnormal bleeding and pelvic pain. Therefore, a better understanding of ECM accumulation and remodeling is critical for developing new therapeutics for uterine leiomyoma. PubMed and Google Scholar were searched for all original and review articles/book chapters related to ECM and medical treatments of uterine leiomyoma published in English until May 2017. This review discusses the involvement of ECM in leiomyoma pathogenesis as well as current and future medical treatments that target ECM directly or indirectly. Uterine leiomyoma is characterized by elevated levels of collagens, fibronectin, laminins and proteoglycans. They can induce the mechanotransduction process, such as activation of the integrin-Rho/p38 MAPK/ERK pathway, resulting in cellular responses that are involved in pathogenesis and altered bidirectional signaling between leiomyoma cells and the ECM. ECM accumulation is affected by growth factors (TGF-β, activin-A and PDGF), cytokines (TNF-α), steroid hormones (estrogen and progesterone) and microRNAs (miR-29 family, miR-200c and miR-93/106b). Among these, TGF-βs (1 and 3) and activin-A have been suggested as key players in the accumulation of excessive ECM (fibrosis) in leiomyoma. The presence of elevated levels of ECM and myofibroblasts in leiomyoma supports the fibrotic character of these tumors. Interestingly, ECM may serve as a reservoir of profibrotic growth factors and enhance their activity by increasing their stability and extending their duration of signaling. At present, several classes of compounds, including gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate), GnRH antagonist (cetrorelix acetate), selective progesterone receptor modulators (ulipristate acetate and asoprisnil), antiprogestin (mifepristone) and natural compounds like vitamin D and resveratrol have been studied as medical treatments that target ECM in uterine leiomyoma. Although several types of drugs (mostly antiproliferative agents) are available for leiomyoma treatment, none of them were introduced specifically as antifibrotic agents. In light of its critical role in the process of fibrosis in leiomyoma, we propose that ECM should be considered as a crucial target for future therapeutics. Thus, the introduction of drugs that are specifically antifibrotic could be a good solution to control abnormal leiomyoma growth and associated clinical symptoms. The antifibrotic compounds can be introduced based on their ability to regulate ECM components and their receptors, as well as growth factors, cytokines, steroid hormones and their corresponding receptors and intracellular signaling pathways, as well as microRNAs, involved in ECM production in leiomyoma. © 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

Endocrine Activity of Extraembryonic Membranes Extends beyond Placental Amniotes

PubMed Central

Albergotti, Lori C.; Hamlin, Heather J.; McCoy, Michael W.; Guillette,, Louis J.

2009-01-01

Background During development, all amniotes (mammals, reptiles, and birds) form extraembryonic membranes, which regulate gas and water exchange, remove metabolic wastes, provide shock absorption, and transfer maternally derived nutrients. In viviparous (live-bearing) amniotes, both extraembryonic membranes and maternal uterine tissues contribute to the placenta, an endocrine organ that synthesizes, transports, and metabolizes hormones essential for development. Historically, endocrine properties of the placenta have been viewed as an innovation of placental amniotes. However, an endocrine role of extraembryonic membranes has not been investigated in oviparous (egg-laying) amniotes despite similarities in their basic structure, function, and shared evolutionary ancestry. In this study, we ask whether the oviparous chorioallantoic membrane (CAM) of chicken (Gallus gallus) has the capability to synthesize and receive signaling of progesterone, a major placental steroid hormone. Methodology/Principal Findings We quantified mRNA expression of key steroidogenic enzymes involved in progesterone synthesis and found that 3β-hydroxysteroid dehydrogenase, which converts pregnenolone to progesterone exhibited a 464 fold increase in the CAM from day 8 to day 18 of embryonic development (F5, 68 = 89.282, p<0.0001). To further investigate progesterone synthesis, we performed explant culture and found that the CAM synthesizes progesterone in vitro in the presence of a steroid precursor. Finally, we quantified mRNA expression and performed protein immunolocalization of the progesterone receptor in the CAM. Conclusions/Significance Collectively, our data indicate that the chick CAM is steroidogenic and has the capability to both synthesize progesterone and receive progesterone signaling. These findings represent a paradigm shift in evolutionary reproductive biology by suggesting that endocrine activity of extraembryonic membranes is not a novel characteristic of placental amniotes. Rather, we hypothesize that these membranes may share an additional unifying characteristic, steroidogenesis, across amniotes at large. PMID:19424488

Metastasizing leiomyoma to heart.

PubMed

Consamus, Erin N; Reardon, Michael J; Ayala, Alberto G; Schwartz, Mary R; Ro, Jae Y

2014-01-01

Cardiac smooth muscle tumors are rare. Three different clinical settings for these tumors have been reported, including benign metastasizing leiomyoma from the uterus, primary cardiac leiomyoma and leiomyosarcoma, and intravenous cardiac extension of pelvic leiomyoma, which is the most common. We present a case of a 55-year-old woman with a benign metastasizing leiomyoma to the heart 17 years after hysterectomy and 16 years after metastasis to the lung. Immunohistochemical stains for smooth muscle actin, desmin, and estrogen and progesterone receptors were positive, indicating a smooth muscle tumor of uterine origin. To our knowledge, this is only the fourth reported case of benign metastasizing leiomyoma to the heart and the first case of long-delayed cardiac metastasis after successful treatment of pulmonary metastasis. It illustrates that benign metastasizing leiomyoma should be included in the differential diagnosis of cardiac tumors in patients with a history of uterine leiomyoma, especially when associated with pulmonary metastasis.

Benign metastasizing leiomyomas in the lungs: a case study

PubMed Central

Bruliński, Krzysztof

2016-01-01

Benign metastasizing leiomyoma (BML) is a rare disease that occurs in middle-aged women with a history of uterine myomas. The most common location of BML is the lungs. We report the case of a 44-year-old obese woman (BMI 45.5) who underwent surgery to remove uterine leiomyomata and then continued to take a drug containing the hormone estradiol for a period of 15 years. Computed tomography chest examinations revealed multiple size nodules of varying size in both lungs. Videothoracoscopy and right thoracotomy was performed, and a few nodules were enucleated from each lobe of the right lung. Postoperative histopathological examination revealed benign metastasizing leiomyoma staining positive for estrogen and progesterone receptors (ER+, PR+). Because of the hormonally dependent cell proliferation, the previously used hormonal drug was discontinued. Treatment with a gonadotropin-releasing hormone analog was included, yielding radiological stabilization of the lung lesions. PMID:27212984

Paf receptor expression in the marsupial embryo and endometrium during embryonic diapause.

PubMed

Fenelon, Jane C; Shaw, Geoff; O'Neill, Chris; Frankenberg, Stephen; Renfree, Marilyn B

2014-01-01

The control of reactivation from embryonic diapause in the tammar wallaby (Macropus eugenii) involves sequential activation of the corpus luteum, secretion of progesterone that stimulates endometrial secretion and subsequent changes in the uterine environment that activate the embryo. However, the precise signals between the endometrium and the blastocyst are currently unknown. In eutherians, both the phospholipid Paf and its receptor, platelet-activating factor receptor (PTAFR), are present in the embryo and the endometrium. In the tammar, endometrial Paf release in vitro increases around the time of the early progesterone pulse that occurs around the time of reactivation, but whether Paf can reactivate the blastocyst is unknown. We cloned and characterised the expression of PTAFR in the tammar embryo and endometrium at entry into embryonic diapause, during its maintenance and after reactivation. Tammar PTAFR sequence and protein were highly conserved with mammalian orthologues. In the endometrium, PTAFR was expressed at a constant level in the glandular epithelium across all stages and in the luminal epithelium during both diapause and reactivation. Thus, the presence of the receptor appears not to be a limiting factor for Paf actions in the endometrium. However, the low levels of PTAFR in the embryo during diapause, together with its up-regulation and subsequent internalisation at reactivation, supports earlier results suggesting that endometrial Paf could be involved in reactivation of the tammar blastocyst from embryonic diapause.

Decidual tissue growth and regression in the guinea pig: regulation by uterine blood flow and relation to circulating progesterone concentrations.

PubMed

Garris, D R

1984-05-01

The role of uterine blood flow (UBF) in the modulation of experimentally induced decidua formation was assessed in mature guinea pigs. The response to endometrial trauma, as indexed by uterine weight changes, was dependent upon the type of stimulus used, with deciduogenic effectiveness as follows: saline = oil = knife scratch less than scissor cut. Both the knife scratch and scissor cut techniques induced elevations in UBF compared with control values. Neither uterine weight nor UBF increased when trauma was applied to unresponsive uteri, indicating that inflammation was not the cause of uterine hyperemia. Uterine weight increased from basal levels on the day of trauma (i.e. day 5 of the estrous cycle) to a maximal weight between days 10 and 12 posttrauma. Maximal growth of the induced decidua occurred under conditions of elevated UBF. Subsequently, UBF declined between days 10 and 15 posttrauma, preceding the associate resorption of the induced decidua. During the period of decidua growth, serum progesterone levels were elevated compared with those in control animals. These data indicate that experimentally induced decidua formation in the guinea pig is associated with uterine hyperemia and increased corpus luteum activity, both of which are necessary for proper endometrial differentiation. It is hypothesized that these events mimic the uterine hyperemia associated with blastocyst implanplantation and early placentation in this species.

Expression of progesterone receptor protein in the ovine uterus during the estrous cycle: Effects of nutrition, arginine and FSH.

PubMed

Grazul-Bilska, Anna T; Thammasiri, Jiratti; Kraisoon, Aree; Reyaz, Arshi; Bass, Casie S; Kaminski, Samantha L; Navanukraw, Chainarong; Redmer, Dale A

2018-03-01

To evaluate expression of progesterone receptor (PGR) AB in follicle stimulating hormone (FSH)-treated or non-treated sheep administered with arginine (Arg) or saline (Sal) fed a control (C), excess (O) or restricted (U) diet, uterine tissues were collected at the early, mid and/or late luteal phases. In exp. 1, ewes from each diet were randomly assigned to one of two treatments, Arg or Sal administration three times daily from day 0 of the first estrous cycle until uterine tissue collection. In exp. 2, ewes were injected twice daily with FSH on days 13-15 of the first estrous cycle. Uterine tissues were immunostained to detect PGR followed by image analysis. PGR were detected in luminal epithelium (LE), endometrial glands (EG), endometrial stroma (ES), myometrium (Myo), and endometrial and myometrial blood vessels. The percentage of PR-positive cells and/or intensity of staining were affected by phase of the estrous cycle, plane of nutrition, and/or FSH but not by Arg. In exp. 1, percentage of PGR-positive cells in LE and EG but not in ES and Myo was greater at the early and mid than late luteal phase, was not affected by plane of nutrition, and was similar in LE and EG. Intensity of staining was affected by phase of the estrous cycle and plane of nutrition in LE, EG and Myo, and was the greatest in LE, less in EG, and least in ES and Myo. In exp. 2, percentage of PGR-positive cells in LE, EG, ES and Myo was affected by phase of the estrous cycle, but not by plane of nutrition; was greater at the early than mid luteal phase; and was greatest in LE and EG, less in luminal (superficial) ES and Myo and least in deep ES. Intensity of staining was affected by phase of the estrous cycle and plane of nutrition in all compartments but ES, and was the greatest in LE and luminal EG, less in deep EG, and least in ES and Myo. Comparison of data for FSH (superovulated) and Sal-treated (non-superovulated) ewes demonstrated that FSH affected PR expression in all evaluated uterine compartments depending on plane of nutrition and phase of the estrous cycle. Thus, PGR are differentially distributed in uterine compartments, and PGR expression is affected by nutritional plane and FSH, but not Arg depending on phase of the estrous cycle. Such changes in dynamics of PGR expression indicate that diet plays a regulatory role and that FSH-treatment may alter uterine functions. Copyright © 2017 Elsevier Inc. All rights reserved.

WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse

PubMed Central

Franco, Heather L.; Dai, Daisy; Lee, Kevin Y.; Rubel, Cory A.; Roop, Dennis; Boerboom, Derek; Jeong, Jae-Wook; Lydon, John P.; Bagchi, Indrani C.; Bagchi, Milan K.; DeMayo, Francesco J.

2011-01-01

WNT4, a member of the Wnt family of ligands, is critical for the development of the female reproductive tract. Analysis of Wnt4 expression in the adult uterus during pregnancy indicates that it may play a role in the regulation of endometrial stromal cell proliferation, survival, and differentiation, which is required to support the developing embryo. To investigate the role of Wnt4 in adult uterine physiology, conditional ablation of Wnt4 using the PRcre mouse model was accomplished. Ablation of Wnt4 rendered female mice subfertile due to a defect in embryo implantation and subsequent defects in endometrial stromal cell survival, differentiation, and responsiveness to progesterone signaling. In addition to altered stromal cell function, the uteri of PRcre/+Wnt4f/f (Wnt4d/d) mice displayed altered epithelial differentiation characterized by a reduction in the number of uterine glands and the emergence of a p63-positive basal cell layer beneath the columnar luminal epithelial cells. The altered epithelial cell phenotype was further escalated by chronic estrogen treatment, which caused squamous cell metaplasia of the uterine epithelium in the Wnt4d/d mice. Thus, WNT4 is a critical regulator not only of proper postnatal uterine development, but also embryo implantation and decidualization.—Franco, H. L., Dai, D., Lee, K. Y., Rubel, C. S., Roop, D., Boerboom, D., Jeong, J.-W., Lydon, J.-P., Bagchi, I. C., Bagchi, M. K., DeMayo, F. J. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. PMID:21163860

Fibroblast growth factor receptor two (FGFR2) regulates uterine epithelial integrity and fertility in mice.

PubMed

Filant, Justyna; DeMayo, Franco J; Pru, James K; Lydon, John P; Spencer, Thomas E

2014-01-01

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate luminal epithelial (LE) cell proliferation in the adult mouse uterus. This study tested the hypothesis that FGFR2 has a biological role in postnatal development and function of the uterus by conditionally deleting Fgfr2 after birth using progesterone receptor (Pgr)-Cre mice. Adult Fgfr2 mutant female mice were initially subfertile and became infertile with increasing parity. No defects in uterine gland development were observed in conditional Fgfr2 mutant mice. In the adult, Fgfr2 mutant mice possessed a histologically normal reproductive tract with the exception of the uterus. The LE of the Fgfr2 mutant uterus was stratified, but no obvious histological differences were observed in the glandular epithelium, stroma, or myometrium. Within the stratified LE, cuboidal basal cells were present and positive for basal cell markers (KRT14 and TRP63). Nulliparous bred Fgfr2 mutants contained normal numbers of blastocysts on Day 3.5 postmating, but the number of embryo implantation sites was substantially reduced on Day 5.5 postmating. These results support the idea that loss of FGFR2 in the uterus after birth alters its development, resulting in LE stratification and peri-implantation pregnancy loss.

Cellular progesterone receptor phosphorylation in response to ligands activating protein kinases

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

Rao, K.V.; Peralta, W.D.; Greene, G.L.

1987-08-14

Progesterone receptors were immunoprecipitated with monoclonal antibodies KD68 from lysates of human breast carcinoma T47D cells labelled to steady state specific activity with /sup 32/Pi. The 120 kDa /sup 32/P-labelled progesterone receptor band was resolved by polyacrylamide gel electrophoresis and identified by autoradiography. Phosphoamino acid analysis revealed serine phosphorylation, but no threonine or tyrosine phosphorylation. Treatment of the /sup 32/Pi-labelled cells with EGF, TPA or dibutyryl cAMP had no significant quantitative effect on progesterone receptor phosphorylation, though the EGF receptor and the cAMP-dependent protein kinases have been reported to catalyze phosphorylation of purified avian progesterone receptor preparations in cell freemore » systems. Progesterone receptor phosphorylation on serine residues was increased by 2-fold in cells treated with 10 nM progesterone; EGF had no effect on progesterone-mediated progesterone receptor phosphorylation.« less

Supplementation of corn dried distillers' grains plus solubles to gestating beef cows fed low-quality forage:II. Impacts on uterine blood flow, circulating estradiol-17beta and progesterone, and hepatic steriod metabolizing

USDA-ARS?s Scientific Manuscript database

Improving uterine blood flow in nutrient restricted cows is vital to prevent under development of the fetus leading to decreased production characteristics of the offspring. This study examined uterine blood flow, steroid concentrations, and the activity of steroid metabolizing enzymes in pregnant b...

Abnormal uterine bleeding in perimenopause.

PubMed

Goldstein, S R; Lumsden, M A

2017-10-01

Abnormal uterine bleeding is one of the commonest presenting complaints encountered in a gynecologist's office or primary-care setting. The wider availability of diagnostic tools has allowed prompt diagnosis and treatment of an increasing number of menstrual disorders in an office setting. This White Paper reviews the advantages and disadvantages of transvaginal ultrasound, blind endometrial sampling and diagnostic hysteroscopy. Once a proper diagnosis has been established, appropriate therapy may be embarked upon. Fortunately, only a minority of such patients will have premalignant or malignant disease. When bleeding is sufficient to cause severe anemia or even hypovolemia, prompt intervention is called for. In most of the cases, however, the abnormal uterine bleeding will be disquieting to the patient and significantly affect her 'quality of life'. Sometimes, reassurance and expectant management will be sufficient in such patients. Overall, however, in cases of benign disease, some intervention will be required. The use of oral contraceptive pills especially those with a short hormone-free interval, the insertion of the levonorgestrel intrauterine system, the incorporation of newer medical therapies including antifibrinolytic drugs and selective progesterone receptor modulators and minimally invasive treatments have made outpatient therapy increasingly effective. For others, operative hysteroscopy and endometrial ablation are proven therapeutic tools to provide both long- and short-term relief of abnormal uterine bleeding, thus avoiding, or deferring, hysterectomy.

Ability of induced corpora lutea to maintain pregnancy from the third month of gestation to term in cattle.

PubMed

Starbuck, M J; Poole, D H; Inskeep, E K

2006-07-15

The local relationship between the pregnant uterine horn and the CL during maternal recognition of pregnancy is well-documented. It continues beyond that time; pregnancies were maintained in lutectomized cows when CL were induced on the ovary ipsilateral, but not contralateral, to the uterine horn of pregnancy during Days 28-53. This study evaluated factors affecting maintenance of pregnancy by CL induced after Day 53, in lutectomized cows that had received exogenous progesterone from Day 29 to 15 days after induction of a CL. Twenty-four suckled beef cows were lutectomized on Day 29 of gestation; pregnancy was maintained with progesterone from two controlled internal drug releasing (CIDR) inserts, exchanged every 5 days. Beginning on Day 53, ovaries and viability of pregnancy were evaluated by ultrasonography every 5 days. When a follicle >or=10 mm in diameter was present ipsilateral to the fetus, each cow received 1,000 IU of hCG. Following induction of a CL (20 of 24), progesterone was reduced to a single CIDR for 5 days, then removed. Retention of pregnancy was confirmed by rectal palpation and calving. Cows with induced CL maintained pregnancy to term, including four with the CL contralateral to the fetus. Three cows failed to form normal CL by Day 98 and lost pregnancy after removal of exogenous progesterone. One cow that did not respond to hCG lost pregnancy during exogenous progesterone. In conclusion, CL induced after Day 53 maintained pregnancy to term, even when induced contralateral to the pregnant uterine horn.

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice*

PubMed Central

Lei, Wei; Feng, Xu-Hui; Deng, Wen-Bo; Ni, Hua; Zhang, Zhi-Rong; Jia, Bo; Yang, Xin-Ling; Wang, Tong-Song; Liu, Ji-Long; Su, Ren-Wei; Liang, Xiao-Huan; Qi, Qian-Rong; Yang, Zeng-Ming

2012-01-01

Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus. PMID:22403396

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

MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells

PubMed Central

Yoo, Jung-Yoon; Yang, Woo Sub; Lee, Jae Hee; Kim, Byung Gak; Broaddus, Russell R.; Lim, Jeong M.; Kim, Tae Hoon; Jeong, Jae-Wook

2017-01-01

Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4 resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2fcre+Mig-6f/f). Female mutant mice develop endometrial hyperplasia due to aberrant phosphorylation of STAT3 and proliferation of the endometrial epithelial cells. The results from our immunoprecipitation and cell culture experiments showed that MIG-6 inhibited phosphorylation of STAT3 via protein interactions. Our previous study showed P4 resistance in mice with Mig-6 ablation in Pgr positive cells (Pgrcre/+Mig-6f/f). However, Sprr2fcre+Mig-6f/f mice were P4 responsive. P4 treatment significantly decreased STAT3 phosphorylation and epithelial proliferation in the uterus of mutant mice. We showed that Mig-6 has an important function of tumor suppressor via inhibition of STAT3 phosphorylation in uterine epithelial cells and the anti-tumor effects of P4 are mediated by the endometrial stroma. This data helps to develop a new signaling pathway in the regulation of steroid hormones in the uterus, and to overcome P4 resistance in human reproductive diseases, such as endometrial cancer. PMID:28925396

The regulation of progesterone receptor by 17 beta estradiol and tamoxifen in the Zr-75-1 human breast cancer cell line in defined medium.

PubMed

Allegra, J C; Korat, O; Do, H M; Lippman, M

1981-01-01

The regulation of progesterone receptor by 17 beta estradiol and tamoxifen in the ZR-75-1 human breast cancer cell line in defined medium is described. ZR-75-1 cells maintained in serum free hormone supplemented medium minus estradiol lack progesterone receptor activity. Readdition of estradiol to these cells leads to a marked stimulation of progesterone receptor activity (0 to greater than 100 fmols of specifically bound progesterone per million cells). Tamoxifen (10(-6)M-10(-8)M) does not stimulate progesterone receptor activity in this cell line. The presence of progesterone receptor activity is not directly related to growth. Withdrawal of insulin in the continued presence of estradiol has no effect on progesterone receptor concentration although net cell growth ceases. Conversely, withdrawal of estradiol in the continued presence of insulin induces a cessation of net cell growth accompanied by a loss of all progesterone receptor activity within 3-5 days.

Modelling maternal obesity: the effects of a chronic high-fat, high-cholesterol diet on uterine expression of contractile-associated proteins and ex vivo contractile activity during labour in the rat.

PubMed

Muir, Ronan; Ballan, Jean; Clifford, Bethan; McMullen, Sarah; Khan, Raheela; Shmygol, Anatoly; Quenby, Siobhan; Elmes, Matthew

2016-02-01

Maternal obesity is associated with prolonged and dysfunctional labour and emergency caesarean section, but the mechanisms are unknown. The present study investigated the effects of an adiposity-inducing high-fat, high-cholesterol (HFHC) diet on uterine contractile-associated protein (CAP) expression and ex vivo uterine contractility in term non-labouring (TNL) and term labouring (TL) rats. Female rats were fed either control chow (CON n=20) or HFHC (n=20) diet 6 weeks before conception and during pregnancy. On gestational day 21 (TNL) or day 22 (TL) CON and HFHC (n=10) rats were killed to determine plasma cholesterol, triacylglycerol and progesterone concentrations and collection of myometrium for contractility studies and expression of CAPs caveolin-1 (Cav-1), connexin-43 (CX-43) and it's phosphorylated form (pCX-43), oxytocin receptor (OXTR) and cyclooxygenase-2 (COX-2). HFHC feeding increased visceral fat (P≤0.001), plasma cholesterol (P≤0.001) and triacylglycerol (P=0.039) concentrations. Stage of labour effected uterine expression of CAV-1 (P<0.02), pCX43 and COX-2 (both P<0.03). CAV-1 and pCX43 decreased but COX-2 increased with parturition. Significant diet- and labour-stage interactions were evident for CX-43 and pCX43 (P<0.03 and P<0.004 respectively). CX-43 decreased with TL in HFHC animals but was unaltered in CON. pCX-43 fell with labour in CON but remained high in HFHC. OXTR expression was significantly higher in HFHC compared with CON animals (P<0.03). Progesterone was higher in HFHC rats at term (P<0.014) but fell significantly with labour to similar concentrations as CON. Contractility studies identified synchronous contractions of stable amplitude in lean animals, but unstable asynchronous contractions with obesity. Uterine dose response to oxytocin was blunted during labour in HFHC rats with a log EC50 of -8.84 compared with -10.25 M in CON for integral activity (P<0.05). In conclusion, our adiposity model exhibits adverse effects on contractile activity during labour that can be investigated further to unravel the mechanisms causing uterine dystocia in obese women. © 2016 The Author(s).

CDB-4124, a progesterone receptor modulator, inhibits mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis.

PubMed

Wiehle, Ronald; Lantvit, Daniel; Yamada, Tohru; Christov, Konstantin

2011-03-01

CDB-4124 (Proellex or telapristone acetate) is a modulator of progesterone receptor (PR) signaling, which is currently employed in preclinical studies for prevention and treatment of breast cancer and has been used in clinical studies for treatment of uterine fibroids and endometriosis. Here we provide evidence for its action on steroid hormone-signaling, cell cycle-regulated genes and in vivo on mammary carcinogenesis. When CDB-4124 is given to rats at 200 mg/kg for 24 months, it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. Also, CDB-4124 given as subcutaneous pellets at two different doses suppressed, dose dependently, N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis. The high dose (30 mg, over 84 days) increased tumor latency from 66 ± 24 days to 87 ± 20 days (P < 0.02), decreased incidence from 85% to 35% (P < 0.001), and reduced multiplicity from 3.0 to 1.1 tumors/animal (P < 0.001). Tumor burden decreased from 2.6 g/animal to 0.26 g/animal (P < 0.01). CDB-4124 inhibited cell proliferation and induced apoptosis in MNU-induced mammary tumors, which correlated with a decreased proportion of PR(+) tumor cells and with decreased serum progesterone. CDB-4124 did not affect serum estradiol. In a mechanistic study employing T47D cells we found that CDB-4124 suppressed G(1)/G(0)-S transition by inhibiting CDK2 and CDK4 expressions, which correlated with inhibition of estrogen receptor (ER) expression. Taken together, these data indicate that CDB-4124 can suppress the development of precancerous lesions and carcinogen-induced ER(+) mammary tumors in rats, and may have implications for prevention and treatment of human breast cancer.

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

Regulation of immune cells in the uterus during pregnancy in ruminants.

PubMed

Hansen, P J

2007-03-01

Pregnancy results in a change in number and function of immune cells in utero that potentially affects fetal survival and uterine defense mechanisms postpartum. These changes are driven by local signals from the conceptus as well as from hormonal changes mediated by the placenta or maternal system. In sheep, for example, macrophages accumulate in the uterine endometrium during pregnancy (Tekin and Hansen, 2004). Use of a unilaterally pregnant model, in which pregnancy is surgically confined to 1 uterine horn, has revealed that accumulation of macrophages is due to systemic signals (numbers of cells in the nonpregnant uterine horn of the unilaterally pregnant ewe higher than amounts in uteri of nonpregnant ewes) and locally produced signals (number of cells in the uterus of unilaterally ligated ewes higher in the pregnant horn than in the nonpregnant horn; Tekin and Hansen, 2004). Gamma-delta T cells also accumulate in uterine epithelium during pregnancy as a result of unidentified systemic signals (Lee et al., 1992; Majewski et al., 2001). These cells may participate in growth of the conceptus, immunosuppression, or placental detachment at parturition. One of the key regulators of uterine immune function is progesterone. In sheep, progesterone can block tissue graft rejection in utero when injected to achieve concentrations too low to directly inhibit lymphocyte proliferation (Majewski and Hansen, 2002; Padua et al., 2005). Progesterone probably inhibits uterine immune responses in sheep indirectly by inducing secretion of a member of the serine proteinase inhibitor family called uterine serpin from the endometrial epithelium. Uterine serpin can block lymphocyte proliferation in vitro in sheep (Peltier et al., 2000) and natural killer cell-mediated abortion in vivo in mice (Liu and Hansen, 1993). Uterine serpin is also present in cattle, goats, and pigs, but its role in immune function in these species has not been documented. The relevance of changes in uterine immune function to the reproductive and immune status of ruminants has not been fully established. There is evidence for immunological causes of pregnancy loss associated with cloned fetuses (Hill et al., 2002) and with mastitis (Hansen et al., 2004), but it is not known whether inappropriate recognition of alloantigens on the conceptus is an important cause of pregnancy loss. It is also possible that downregulation of uterine immune function during pregnancy can lead to a postpartum uterus with a compromised capacity for preventing establishment of infectious disease. Thus, optimal immune function in utero requires a balance between the need to maintain effective immune surveillance and effector mechanisms with the requirement that immunological responses leading to conceptus demise are minimized.

Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability

PubMed Central

Beckley, Ethan H.; Scibelli, Angela C.; Finn, Deborah A.

2010-01-01

Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone’s GABAA receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. PMID:21163582

Integrins β1 and β3 are biomarkers of uterine condition for embryo transfer.

PubMed

Chen, Guowu; Xin, Aijie; Liu, Yulin; Shi, Changgen; Chen, Junling; Tang, Xiaofeng; Chen, Ying; Yu, Min; Peng, Xiandong; Li, Lu; Sun, Xiaoxi

2016-10-26

Clinical ovulation induction induces blood estrogen (E 2 ) in excess of physiological levels, which can hinder uterine receptivity. In contrast, progesterone produces the opposite clinical effect, suggesting that it might be capable of recovering the lost receptivity resulting from exposure to high estrogen levels. Integrins are the most widely used biological markers for monitoring uterine conditions. We studied progesterone-induced changes in integrin β expression patterns as biomarkers for changes in uterine receptivity in response to increased estrogen levels. Endometrial biopsy samples from patients were screened for their estrogen (E 2 ) and progesterone (P4) content and expressing levels of integrin β1 and β3. Uterine receptivity was evaluated using human endometrial adenocarcinoma cells in an embryo attachment model. The respective and concatenated effects of embryo attachment and changes in the integrin β1 and β3 expression patterns on the adenocarcinoma cell plasma membranes in response to 100 nM concentrations of E 2 and P4 were evaluated. Increased blood E 2 concentrations were associated with significantly decreased the levels of integrin β3 expression in uterine biopsy samples. In vitro experiments revealed that a 100 nM E 2 concentration inhibited the distribution of integrin β3 on the plasma membranes of human endometrial adenocarcinoma cells used in the embryo attachment model, and resulted in decreased rates of embryo attachment. In contrast, P4 enhanced the expression of integrin β1 and promoted its distribution on the plasma membranes. Furthermore, P4 recovered the embryo attachment efficiency that was lost by exposure to 100 nM E 2 . Blood E2 and P4 levels and integrin β3 and β1 expression levels in uterine biopsy samples should be considered as biomarkers for evaluating uterine receptivity and determining the optimal time for embryo transfer. Trial registration Trial number: ChiCTR-TRC-13003777; Name of registry: Chinese Clinical Trial Registry; Date of registration: 4 September 2013; Date of enrollment of the first study participant: 15 October 2013.

Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability.

PubMed

Beckley, Ethan H; Scibelli, Angela C; Finn, Deborah A

2011-07-01

Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. Copyright © 2010 Elsevier Ltd. All rights reserved.

Differences in the binding mechanism of RU486 and progesterone to the progesterone receptor

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

Skafar, D.F.

1991-11-12

The binding mechanism of the antagonist RU486 to the progesterone receptor was compared with that of the agonists progesterone and R5020. Both progesterone and RU486 bound to the receptor with a Hill coefficient of 1.2, indicating the binding of each ligand is positive cooperative. However, when each ligand was used to compete with ({sup 3}H)progesterone for binding to the receptor at receptor concentrations near 8 nM, at which the receptor is likely a dimer, the competition curve for RU486 was significantly steeper than the curves for progesterone and R5020. This indicated that a difference in the binding mechanism of RU486more » and progesterone can be detected when both ligands are present. In contrast, at receptor concentrations near 1 nM, at which the receptor is likely a monomer, the competition curves for all three ligands were indistinguishable. These results indicate that RU486 and agonists have different binding mechanisms for the receptor and further suggest that this difference may be related to site-site interactions within the receptor.« less

Novel DNA Motif Binding Activity Observed In Vivo With an Estrogen Receptor α Mutant Mouse

PubMed Central

Li, Leping; Grimm, Sara A.; Winuthayanon, Wipawee; Hamilton, Katherine J.; Pockette, Brianna; Rubel, Cory A.; Pedersen, Lars C.; Fargo, David; Lanz, Rainer B.; DeMayo, Francesco J.; Schütz, Günther; Korach, Kenneth S.

2014-01-01

Estrogen receptor α (ERα) interacts with DNA directly or indirectly via other transcription factors, referred to as “tethering.” Evidence for tethering is based on in vitro studies and a widely used “KIKO” mouse model containing mutations that prevent direct estrogen response element DNA- binding. KIKO mice are infertile, due in part to the inability of estradiol (E2) to induce uterine epithelial proliferation. To elucidate the molecular events that prevent KIKO uterine growth, regulation of the pro-proliferative E2 target gene Klf4 and of Klf15, a progesterone (P4) target gene that opposes the pro-proliferative activity of KLF4, was evaluated. Klf4 induction was impaired in KIKO uteri; however, Klf15 was induced by E2 rather than by P4. Whole uterine chromatin immunoprecipitation-sequencing revealed enrichment of KIKO ERα binding to hormone response elements (HREs) motifs. KIKO binding to HRE motifs was verified using reporter gene and DNA-binding assays. Because the KIKO ERα has HRE DNA-binding activity, we evaluated the “EAAE” ERα, which has more severe DNA-binding domain mutations, and demonstrated a lack of estrogen response element or HRE reporter gene induction or DNA-binding. The EAAE mouse has an ERα null–like phenotype, with impaired uterine growth and transcriptional activity. Our findings demonstrate that the KIKO mouse model, which has been used by numerous investigators, cannot be used to establish biological functions for ERα tethering, because KIKO ERα effectively stimulates transcription using HRE motifs. The EAAE-ERα DNA-binding domain mutant mouse demonstrates that ERα DNA-binding is crucial for biological and transcriptional processes in reproductive tissues and that ERα tethering may not contribute to estrogen responsiveness in vivo. PMID:24713037

Prevention of preterm birth by progestational agents: what are the molecular mechanisms?

PubMed Central

Nold, Christopher; Maubert, Monique; Anton, Lauren; Yellon, Steven; Elovitz, Michal A.

2013-01-01

OBJECTIVE Clinically, vaginal progesterone (VP) and 17 alpha-hydroxyprogestreone caproate (17P) have been shown to prevent preterm birth (PTB) in high risk populations. We hypothesize treatment with these agents may prevent PTB by altering molecular pathways involved in uterine contractility or cervical remodeling. STUDY DESIGN Using a mouse model, on days E14-E17 CD-1 pregnant mice were treated with either 1) 0.1cc of 25 mg/ml of 17P subcutaneously, 2) 0.1cc of castor oil subcutaneously, 3) 0.1 cc of 10 mg/ml of progesterone in Replens vaginally, or 4) 0.1cc of Replens vaginally, with four dams per treatment group. Mice were sacrificed six hours after treatment on E17.5. Cervices and uteri were collected for molecular analysis. RESULTS Exposure to VP significantly increased the expression of Defensin 1 compared to Replens (p<0.01) on E17.5. Neither VP nor 17P altered the expression of uterine contraction-associated proteins, progesterone mediated regulators of uterine quiescence, microRNAs involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune cell trafficking or collagen content in the cervix. CONCLUSION Neither VP nor 17P had any effect on the studied pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP was noted to increase the expression of the antimicrobial protein Defensin 1. Whether this molecular change from VP results in a functional effect and is a key mechanism by which VP prevents PTB requires further study. PMID:23433326

Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the 'MALOVA' ovarian cancer study.

PubMed

Høgdall, Estrid V S; Christensen, Lise; Høgdall, Claus K; Blaakaer, Jan; Gayther, Simon; Jacobs, Ian J; Christensen, Ib Jarle; Kjaer, Susanne K

2007-11-01

Estrogen and progesterone are important hormones secreted by the ovary acting through specific receptors. Tumor tissue expression profiles of these have demonstrated prognostic value in malignancies such as breast, uterine and prostate cancer. In this study, including tissue samples from 773 Danish patients with an ovarian tumor, we evaluated whether estrogen receptor (ER) and progesterone receptor (PR) expression correlated with clinico-pathological parameters, and a possible prognostic impact on ovarian cancer (OC) patients was investigated. Using tissue array and immunohistochemistry, we analyzed the ER and PR expression levels in tissues from 582 women with OC and 191 women with low malignancy potential (LMP) ovarian tumors. Our results demonstrated that ER was expressed in 30 of the 191 LMP tumors (16%) and in 207 of the 582 OC (36%). PR was expressed in 38 LMP tumors (20%) and in 115 OC (20%). For both tumor types an excess of positive tumors was found in the serous compared to the mucinous subtype (p< or =0.00001). The frequency of ER expression-positive OC increased with increasing FIGO stage (p=0.0003), and the frequency of PR-positive tumors increased with increasing histological grade (p=0.0006). In a Cox survival analysis, a tissue ER and PR expression 10% or higher was found to imply an independent significant advantageous course of patient disease-specific survival (ER: hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.63-0.99; PR: HR, 0.69; 95% CI, 0.51-0.94) together with FIGO stage, residual tumor after primary surgery, age at diagnosis and other histological types vs. serous adenocarcinoma. The histological grade of tumor was found to have no independent prognostic value. The prognostic value of ER and PR was found additive with a HR for patients with high ER and PR expression of 0.48 (95% CI, 0.31-0.74) compared to patients with <10% expression for both receptors. In conclusion, our results predict that an elevated expression of ER and PR, alone and in combination, point to a favorable outcome for patients with OC.

Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

PubMed Central

Johannessen, Molly; Fontanilla, Dominique; Mavlyutov, Timur; Ruoho, Arnold E.

2011-01-01

σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ1- and σ2-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na+ channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na+ channel Nav1.5. Patch-clamp recording in this cell line tested Na+ current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ1-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ2-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ1-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions. PMID:21084640

Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels.

PubMed

Johannessen, Molly; Fontanilla, Dominique; Mavlyutov, Timur; Ruoho, Arnold E; Jackson, Meyer B

2011-02-01

σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ(1)- and σ(2)-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na(+) channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na(+) channel Na(v)1.5. Patch-clamp recording in this cell line tested Na(+) current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ(1)-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.

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

Microvascular development and growth of uterine tissue during the estrous cycle in mares.

PubMed

Ferreira-Dias, G M; Serrão, P M; Durão, J F; Silva, J R

2001-04-01

To document uterine growth and microvascular development in the endometrium of uteri with differing degrees of fibrosis as well as uterine growth throughout the estrous cycle of mares. 30 mares. Uterine tissue was obtained during the breeding season from a slaughter facility. Stage of estrous cycle of the mares was assessed on the basis of ovarian structures and plasma progesterone concentrations. Endometrium was characterized by use of light microscopy, and blood vessel walls were marked by histochemical techniques. Microvascular development was evaluated by a computerized image analysis system. Growth of uterine tissue was based on cellular content of DNA and RNA, RNA:DNA, and protein:DNA. Significant differences in vascular density were not observed in the endometrium of uteri obtained from mares euthanatized during the follicular or luteal phase of the estrous cycle, regardless of whether endometrial classification of degree of fibrosis was considered. There was a 3-fold increase in amount of DNA and RNA of endometrial cells in the follicular phase when compared to myometrium. Hypertrophy of endometrial tissue during the luteal phase was reflected by a significant increase in cell protein content and protein:DNA. Endometrial growth of vascular tissues during the estrous cycle may be coordinated with development of nonvascular tissue. Estrogen and progesterone may play a role in regulation of uterine growth and angiogenesis.

Endothelial vasodilator production by ovine uterine and systemic arteries: ovarian steroid and pregnancy control of ERα and ERβ levels

PubMed Central

Byers, Michael J; Zangl, Amy; Phernetton, Terrance M; Lopez, Gladys; Chen, Dong-bao; Magness, Ronald R

2005-01-01

Pregnancy and the follicular phase are physiological states of elevated oestrogen levels and rises in uterine blood flow (UBF). The dramatic increase in utero-placental blood flow during gestation is required for normal fetal growth and development. Oestrogen exerts its vasodilatory effect by binding to its specific oestrogen receptors (ER) in target cells, resulting in increased expression and activity of endothelial nitric oxide synthase (eNOS) to relax vascular smooth muscle (VSM). However, the regulation of endothelial versus VSM ERα and ERβ expression in uterine arteries (UAs) during the ovarian cycle, pregnancy and with exogenous hormone replacement therapy (HRT) are currently unknown. ER mRNA and protein localization was determined by in situ hybridization (ISH) using 35S-labelled riboprobes and immunohistochemistry (IHC), respectively. UA endothelial (UAendo), UA VSM, omental artery endothelium (OA endo), and OA VSM proteins were isolated and ERα and ERβ protein expression was determined by Western analysis. We observed by ISH and IHC that ERα and ERβ mRNA and protein were localized in both UAendo and UA VSM. Immunoblot data demonstrated ovarian hormone specific regulation of ERα and ERβ protein in UAendo and UA VSM. Compared to luteal phase sheep, both ERα and ERβ levels in UAendo were elevated in follicular phase sheep. Whereas ERβ was elevated by pregnancy in UAendo and UA VSM, ERα was not appreciably altered. eNOS was increased in UAendo from follicular and pregnant sheep. Ovariectomized ewes (OVEX) had substantially reduced UAendo ERβ, but not UAendo ERα or OAendo ERα and ERβ. In contrast, OVEX increased UA VSM ERα and ERβ and decreased OA VSM ERα and ERβ. Treatment with oestradiol-17β (E2β), but not progesterone or their combination, increased UAendo ERα levels. The reduced ERβ in UAendo from OVEX ewes was reversed by E2β and progesterone treatment. While ERα and eNOS were not elevated in any other reproductive or non-reproductive endothelia tested, ERβ was augmented by pregnancy in uterine, mammary, placenta, and coronary artery endothelia. ERα and ERβ mRNA and protein are expressed in UA endothelium with expression levels depending on the endocrine status of the animal, indicating UA endothelium is a target for oestrogen action in vivo, and that the two receptors appear to be differentially regulated in a spatial and temporal fashion with regard to the reproductive status or HRT. PMID:15774511

Pregnancy interceptive efficacy and biological profile of 3-amino-6,7-dimethoxy-1H-pyrazolo [3,4-b] quinoline (compound 85/83) in rodents.

PubMed

Mehrotra, P K; Shukla, R; Dwivedi, A; Srivastava, R P; Bhat, N; Seth, M; Bhaduri, A P; Kamboj, V P

1991-05-01

Administration of compound 85/83 during the peri- and post-implantation period intercepted pregnancy in hamster and guinea pig by parenteral route and in hamster by oral route also. The m.e.d. for hamster and guinea pig was 10 and 20 mg/kg, respectively; lower doses were less effective. Restricting the administration to early post-implantation schedule interrupted pregnancy partially in both species. The compound was, however, ineffective in rat and in the pre-implantation schedule (days 1-4 post-coitum) in hamster. When tested in vitro on growing trophoblasts at 13.8 x 10(-5) M concentration, it prevented growth and caused degeneration of the cells within 24 h; lower concentration (9.2 x 10(-5) M) was less effective. The compound was found to be devoid of estrogenic, antiestrogenic, progestational and antiprogestational properties in conventional bioassays. In hormone competition assays, its relative binding affinity (RBA) to estrogen receptor was negligible (0.002% of estradiol-17 beta), while for uterine cytosol progesterone receptors in rabbit and hamster was 0.06 and 0.08% of progesterone, respectively. The compound 85/83 appears to intercept pregnancy by interfering with development of trophoblast cells.

Bone growth and turnover in progesterone receptor knockout mice.

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

Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda

2008-05-01

The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bonesmore » of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.« less

Elements of functional genital asymmetry in the cow.

PubMed

Trigal, B; Díez, C; Muñoz, M; Caamaño, J N; Goyache, F; Correia-Alvarez, E; Corrales, F J; Mora, M I; Carrocera, S; Martin, D; Gómez, E

2014-01-01

Asymmetry in the cow affects ovarian function and pregnancy. In this work we studied ovarian and uterine asymmetry. Synchronised animals, in which in vitro-produced embryos (n=30-60) had been transferred on Day 5 to the uterine horn ipsilateral to the corpus luteum (CL), were flushed on Day 8. Ovulatory follicle diameter, oestrus response and total protein flushed did not differ between sides. However, a corpus luteum in the right ovary led to plasma progesterone concentrations that were higher than when it was present in the left ovary. Fewer embryos were recovered from the left than the right horn. Among 60 uterine proteins identified by difference gel electrophoresis, relative abundance of nine (acyl-CoA dehydrogenase, very long chain; twinfilin, actin-binding protein, homologue 1; enolase 1; pyruvate kinase isozymes M1/M2 (rabbit); complement factor B Bb fragment ; albumin; fibrinogen gamma-B chain; and ezrin differed (P<0.05) between horns. Glucose concentration was higher, and fructose concentration lower, in the left horn. In a subsequent field trial, pregnancy rates after embryo transfer did not differ between horns (51.0±3.6, right vs 53.2±4.7, left). However, Day 7 blood progesterone concentrations differed (P=0.018) between pregnant and open animals in the left (15.9±1.7 vs 8.3±1.2) but not in the right horn (12.4±1.3 vs 12.4±1.2). Progesterone effects were independent of CL quality (P=0.55). Bilateral genital tract asymmetry in the cow affects progesterone, proteins and hexoses without altering pregnancy rates.

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

PubMed Central

Chen, Juanjuan; Khalil, Raouf A.

2017-01-01

Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy. MMP expression/activity may be altered during complications of pregnancy. Decreased vascular MMP-2 and MMP-9 may lead to decreased vasodilation, increased vasoconstriction, hypertensive pregnancy and preeclampsia. Abnormal expression of uteroplacental integrins, cytokines and MMPs may lead to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate remodeling of spiral arteries, and reduced uterine perfusion pressure (RUPP). RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, or stimulate the release of inflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could target MMPs in the extracellular matrix as well as endothelial and vascular smooth muscle cells, causing generalized vascular dysfunction, increased vasoconstriction and hypertension in pregnancy. MMP activity can also be altered by endogenous tissue inhibitors of metalloproteinases (TIMPs) and changes in the MMP/TIMP ratio. In addition to their vascular effects, decreases in expression/activity of MMP-2 and MMP-9 in the uterus could impede uterine growth and expansion and lead to premature labor. Understanding the role of MMPs in uteroplacental and vascular remodeling and function could help design new approaches for prediction and management of preeclampsia and premature labor. PMID:28662830

1,25-Dihydroxyvitamin D3 Treatment Shrinks Uterine Leiomyoma Tumors in the Eker Rat Model1

PubMed Central

Halder, Sunil K.; Sharan, Chakradhari; Al-Hendy, Ayman

2012-01-01

ABSTRACT Uterine leiomyomas (fibroids) are the most common benign tumors in women of reproductive age. These tumors are three to four times more prevalent in African American women, who also have a 10 times higher incidence of hypovitaminosis D than white women. Recent studies have demonstrated the antitumor effects of 1,25-dihydroxyvitamin D3 on several cancers, but its effects on uterine leiomyomas are still unknown. To determine the antitumor and therapeutic effects of 1,25-dihydroxyvitamin D3 on uterine leiomyomas, female Eker rats (14–16 mo old) harboring uterine leiomyomas were randomized into control and experimental groups and were given vehicle versus 1,25-dihydroxyvitamin D3 (0.5 μg/kg per day) subcutaneously for 3 wk, respectively. At the end of the experiment, the rats were euthanized, and the leiomyoma tumors were analyzed. Treatment with 1,25-dihydroxyvitamin D3 significantly reduced leiomyoma tumor size in Eker rats. It also reduced leiomyoma size by suppressing cell growth and proliferation-related genes (Pcna, cyclin D1 [Ccnd1], Myc, Cdk1, Cdk2, and Cdk4), antiapoptotic genes (Bcl2 and Bcl2l1 [Bcl-x]), and estrogen and progesterone receptors. Additionally, immunohistochemistry revealed decreased expression of PCNA and MKI67 (a marker of proliferation) and increased expression of caspase 3 in 1,25-dihydroxyvitamin D3-treated Eker rat leiomyomas. Toxicity analyses using serum samples showed similar levels of SGOT, SGPT, calcium, and total bilirubin in 1,25-dihydroxyvitamin D3-treated and vehicle-treated control Eker rats. These results support that 1,25-dihydroxyvitamin D3 is an antitumor agent that may be a potential safe, nonsurgical therapeutic option for the treatment of uterine leiomyomas. PMID:22302692

Effects of neonatal exposure to a glyphosate-based herbicide on female rat reproduction.

PubMed

Ingaramo, Paola I; Varayoud, Jorgelina; Milesi, María M; Schimpf, Marlise Guerrero; Muñoz-de-Toro, Mónica; Luque, Enrique H

2016-11-01

In this study, we investigated whether neonatal exposure to a glyphosate-based herbicide (GBH) alters the reproductive performance and the molecular mechanisms involved in the decidualization process in adult rats. Newborn female rats received vehicle or 2 mg/kg/day of a GBH on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate (i) the reproductive performance on gestational day (GD) 19 and (ii) the ovarian steroid levels, uterine morphology, endometrial cell proliferation, apoptosis and cell cycle regulators, and endocrine pathways that regulate uterine decidualization (steroid receptors/COUP-TFII/Bmp2/Hoxa10) at the implantation sites (IS) on GD9. The GBH-exposed group showed a significant increase in the number of resorption sites on GD19, associated with an altered decidualization response. In fact, on GD9, the GBH-treated rats showed morphological changes at the IS, associated with a decreased expression of estrogen and progesterone receptors, a downregulation of COUP-TFII (Nr2f2) and Bmp2 mRNA and an increased expression of HOXA10 and the proliferation marker Ki67(Mki67) at the IS. We concluded that alterations in endometrial decidualization might be the mechanism of GBH-induced post-implantation embryo loss. © 2016 Society for Reproduction and Fertility.

Expression of estrogen and progesterone receptors in astrocytomas: a literature review

PubMed Central

Tavares, Cléciton Braga; Gomes-Braga, Francisca das Chagas Sheyla Almeida; Costa-Silva, Danylo Rafhael; Escórcio-Dourado, Carla Solange; Borges, Umbelina Soares; Conde, Airton Mendes; da Conceição Barros-Oliveira, Maria; Sousa, Emerson Brandão; da Rocha Barros, Lorena; Martins, Luana Mota; Facina, Gil; da-Silva, Benedito Borges

2016-01-01

Gliomas are the most common type of primary central nervous system neoplasm. Astrocytomas are the most prevalent type of glioma and these tumors may be influenced by sex steroid hormones. A literature review for the presence of estrogen and progesterone receptors in astrocytomas was conducted in the PubMed database using the following MeSH terms: “estrogen receptor beta” OR “estrogen receptor alpha” OR “estrogen receptor antagonists” OR “progesterone receptors” OR “astrocytoma” OR “glioma” OR “glioblastoma”. Among the 111 articles identified, 13 studies met our inclusion criteria. The majority of reports showed the presence of estrogen and progesterone receptors in astrocytomas. Overall, higher tumor grades were associated with decreased estrogen receptor expression and increased progesterone receptor expression. PMID:27626480

Chronic Exposure to Bisphenol A Affects Uterine Function During Early Pregnancy in Mice

PubMed Central

Davila, Juanmahel; Kannan, Athilakshmi; Flaws, Jodi A.; Bagchi, Milan K.

2016-01-01

Environmental and occupational exposure to bisphenol A (BPA), a chemical widely used in polycarbonate plastics and epoxy resins, has received much attention in female reproductive health due to its widespread toxic effects. Although BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In this study, we addressed the effect of prolonged exposure to an environmental relevant dose of BPA on embryo implantation and establishment of pregnancy. Our studies revealed that treatment of mice with BPA led to improper endometrial epithelial and stromal functions thus affecting embryo implantation and establishment of pregnancy. Upon further analyses, we found that the expression of progesterone receptor (PGR) and its downstream target gene, HAND2 (heart and neural crest derivatives expressed 2), was markedly suppressed in BPA-exposed uterine tissues. Previous studies have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor and the MAPK signaling pathways and inhibiting epithelial proliferation. Interestingly, we observed that down-regulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of fibroblast growth factor and MAPK signaling in the epithelium, thus contributing to aberrant proliferation and lack of uterine receptivity. Further, the differentiation of endometrial stromal cells to decidual cells, an event critical for the establishment and maintenance of pregnancy, was severely compromised in response to BPA. In summary, our studies revealed that chronic exposure to BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy. PMID:27022677

Wnt antagonist DKK1 is a target of Kruppel-like factor 9 (KLF9) in endometrial stromal cells: Implications for uterine receptivity

USDA-ARS?s Scientific Manuscript database

A significant underlying cause of pregnancy loss in mammals is the inability of the uterine epithelium to enter a "state of receptivity" for embryo implantation, due partly to the dysfunctional response of endometrial cells to progesterone (P). We previously showed that mice null for the Sp1-related...

Ovarian and placental production of progesterone and oestradiol during pregnancy in reindeer.

PubMed

Flood, P F; Tyler, N J C; Read, E K; Rodway, M J; Chedrese, P J

2005-01-01

We obtained uterine and peripheral venous plasma, and samples of luteal and placental tissues from 2- to 7-year-old, Eurasian mountain reindeer (Rangifer tarandus tarandus) from a free-living, semi-domesticated herd in northern Norway in November 1995, and February and March 1996. In November, ovarian venous blood was also collected from four animals. Plasma samples were assayed for progesterone and oestradiol. The tissue samples were examined by light and electron microscopy, steroid dehydrogenase histochemistry, and northern blot analysis for RNAs for 3beta-hydroxy-steroid dehydrogenase (3beta-HSD) and P450 (side chain cleavage (scc)). Peripheral blood was taken from non-pregnant females in the same herd on the same dates. Peripheral progesterone concentrations in pregnant reindeer (3.4 +/- 0.5 ng/ml, n = 8) clearly exceeded those in non-pregnant animals (0.40 +/- 0.14 ng/ml; P < 0.0004 , n = 10) but oestradiol levels were only marginally higher in pregnant (6.0 +/- 0.7 pg/ml) than in non-pregnant (4.8 +/- 0.5 pg/ml; P = 0.35) reindeer at the stages examined. In pregnant animals, peripheral progesterone and oestradiol concentrations rose slightly between November and March but the differences did not reach significance (progesterone, P = 0.083; oestradiol, P = 0.061). In November, progesterone concentrations in the ovarian vein (79 +/- 15 ng/ml) greatly exceeded (P < 0.03) those in the uterine vein ( 10 +/- 4 ng/ml) which in turn exceeded the levels in the peripheral blood (2.8 +/- 0.4 ng/ml; P < 0.29). Oestradiol concentrations were slightly but significantly (P < 0.05) higher in the ovarian (20 +/- 3 pg/ml) than the uterine vein (13 +/- 1 pg/ml) and, in turn, greater (P < 0.03) than in peripheral blood (4.6 +/- 0.4 pg/ml). All samples of luteal tissue consisted exclusively of normal fully-differentiated cells and stained intensely for 3beta-HSD. Isolated groups of placental cells also stained strongly for 3beta-HSD. RNA for P450 (scc) and 3beta-HSD was abundant in all corpora lutea and lower concentrations of P450 (scc) were present in the placenta. 3beta-HSD RNA in the placenta was below the limit of detection. We conclude that the corpus luteum remains an important source of progesterone throughout pregnancy in reindeer but that the placenta is also steroidogenic.

Attachment reaction of rat uterine luminal epithelium. II. The effect of progesterone on the morphology of the uterine glands and the luminal epithelium of the spayed, virgin rat.

PubMed

Ljungkvist, I

1971-01-01

Ovariosalpingectomized rat uterine glands and luminal epithelium were examined by electron microscopy and in serial cross sections under light microscopy after up to 8 days of treatment with 5 mg progesterone daily. Under light microscopy, the gland lumen was narrow or absent in many epon sections, but wide in many paraffin sections, filled with toluidine blue stained secretion, and serial sections showed that the openings were closed, allowing no connection between the gland lumen and the uterus. In electron micrographs, only those glands without an opening appeared altered by progesterone. The most notable differences in the glandular epithelium were microvilli, condensed ribosome-free cytoplasm next to the lumen, numerous vesicles, sacs and dilated Golgi cisternae in the apical cytoplasm, and more giant mitrochondria in the basal cytoplasm than usually seen in controls. In the luminal epithelium, there were 3 distinct regions: the apical region had condensed cytoplasm often extruded into the lumen, with close-packed, smooth, empty vesicles; the middle region had granular endoplasmic reticulum, mitrochondria, dense bodies, multivesicular bodies, and lipid granules; the basal region contained the nucleus, granular endoplasmic reticulum, mitrochondria and dense abodies. These observations were interpreted as indicative of a transitional state from secretion to absorption, especially since without an opening, secretion would be of little significance.

Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.

PubMed

Whitaker, L H R; Murray, A A; Matthews, R; Shaw, G; Williams, A R W; Saunders, P T K; Critchley, H O D

2017-03-01

What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives. Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. N/A. A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium

PubMed Central

Whitaker, L.H.R.; Murray, A.A.; Matthews, R.; Shaw, G.; Williams, A.R.W.; Saunders, P.T.K.

2017-01-01

Abstract STUDY QUESTION What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. STUDY DESIGN SIZE, DURATION Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9–12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38–52 with fibroids were derived from institutional tissue archives. PARTICIPANTS/MATERIALS, SETTING, METHODS Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. MAIN RESULTS AND THE ROLE OF CHANCE UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. LARGE SCALE DATA N/A. LIMITATIONS REASONS FOR CAUTION A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. STUDY FUNDING/COMPETING INTEREST(S) H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland. PMID:28130434

Convergent Pathways for Steroid Hormone-and Neurotransmitter-Induced Rat Sexual Behavior

NASA Astrophysics Data System (ADS)

Mani, S. K.; Allen, J. M. C.; Clark, J. H.; Blaustein, J. D.; O'Malley, B. W.

1994-08-01

Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D_1 receptor agonist, but not a D_2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitatory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D_1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

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 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).

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

PubMed Central

Yang, Qiwei; Mas, Aymara; Diamond, Michael P.; Al-Hendy, Ayman

2015-01-01

Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and ten-eleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17β-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options. PMID:25922306

Effect of progesterone-carbachol derivative on perfusion pressure and coronary resistance in isolated rat heart: via activation of the M2 muscarinic receptor.

PubMed

Figueroa-Valverde, Lauro; Diaz-Cedillo, Francisco; Garcia-Cervera, Elodia; Gomez, Eduardo Pool; Lopez-Ramos, Maria

2014-01-01

The present study was designed to investigate the effects of progesterone-carbachol derivative on perfusion pressure and coronary resistance in rats. An additional aim was to identify the molecular mechanisms involved. The Langendorff model was used to measure perfusion pressure and coronary resistance changes in isolated rat heart after progesterone-carbachol derivative alone and after the following compounds; mifepristone (progesterone receptor blocker), yohimbine (α2 adreno-receptor antagonist), ICI 118,551 (selective β2 receptor blocker), atropine (non-selective muscarinic receptor antagonist), methoctramine (antagonist of M2 receptor) and L-NAME (inhibitor of nitric oxide synthase). The results show that progesterone-carbachol derivative [10(-9) mM] significantly decreased perfusion pressure (P=0.005) and coronary resistance (P=0.006) in isolated rat heart. Additionally, the effect of progesterone-carbachol on perfusion pressure [10(-9) to 10(-4) mM] was only blocked in the presence of methoctramine and L-NAME. These data suggest that progesterone derivative exert its effect on perfusion pressure via activation of the M2 muscarinic. In addition, this phenomenon involves stimulation of nitric oxide synthase (NOS).

Changes in cervical compliance at parturition independent of uterine activity.

PubMed

Stys, S J; Clewell, W H; Meschia, G

1978-02-15

A new animal model has been developed to measure intrinsic changes of cerivcal compliance during spontaneous parturition or exposure to hormonal manipulation. Intermittent measurements of cervical compliance and continous measurements of uterine and cervical pressure were made during the last month of gestation of nine pregnant ewes. Cervical compliance increased abruptly and dramatically during spontanous and dexamethasone-induced parturition. Maternal progesterone supplementation at parturition inhibited uterine contractions but not the increase in cervical compliance, demonstrating the independence of the two events. The cervix was found to contract rhythmically and vigorously with a gradual decrease in activity as parturition approached.

Effects of liver depression and psychological stress on human uterine leiomyoma cells by an AR-cAMP-PKA signal transduction pathway.

PubMed

Xia, Tian; Li, Shuang; Ma, Ruihong; Guan, Sufen; Li, Jiacui; Li, Hongqin; Zhang, Hexin; Lin, Qiu; Zhao, Zhimei; Wang, Baojuan

2017-06-01

Based on the emotional theory of Traditional Chinese Medicine, and combined with the modern medicine theory of psychological stress, a research model of human uterine leiomyoma cells (ULM) was cultured in vitro to determine the effectiveness of adrenergic receptor (AR) agonists in human ULM cell growth. In addition, we studied the functional influence of "liver depression and psychological stress theory" on fibroid formation by intervening in the AR-cAMP-PKA signaling pathway. The intention was to establish a new method to prevent and cure fibroids through "liver depression and psychological stress theory" and provide an experimental basis for the Traditional Chinese Medicine emotional theory. Primary human ULM cells were enriched by collagenase digestion. Immunohistochemistry and hematoxylin and eosin (HE) staining were used for cytological identification. Using this model, we studied intervention using specific AR agonists on ULM cells to observe the influence of "liver depression and psychological stress theory" on estrogen receptor (ER), progesterone receptor (PR), vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGF). Norepinephrine (NE) and epinephrine (E) are adrenergic receptor agonists. They promoted ULM cell proliferation and increased the levels of ER, PR, VEGF and FGF. In contrast, isoproterenol (ISO) inhibited ULM cell proliferation and decreased the levels of ER, PR, VEGF and FGF. The protein expression of cAMP and PKA in ULM cells was reduced and the levels of ER, PR, VEGF and FGF were increased when co-treatment with the α-AR blocker (phentolamine). The β-AR blocker (metoprolol) displayed an opposite effect. AR agonists modulated ER, PR, VEGF and FGF levels in ULM cells in an AR-cAMP-PKA-dependent signaling pathways to influence fibroid occurrence and development. Copyright © 2017. Published by Elsevier B.V.

The clinicopathologic significance of the loss of BAF250a (ARID1A) expression in endometrial carcinoma.

PubMed

Zhang, Zheng-mao; Xiao, Shuang; Sun, Guang-yu; Liu, Yue-ping; Zhang, Feng-hua; Yang, Hong-fang; Li, Jia; Qiu, Hong-bing; Liu, Yang; Zhang, Chao; Kang, Shan; Shan, Bao-en

2014-03-01

AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that encodes the BAF250a protein. Recent studies have shown the loss of ARID1A expression in several types of tumors. We aimed to investigate the clinical and pathologic role of BAF250a in endometrial carcinoma. We examined the expression of BAF250a and its correlation with the expression of p53, estrogen receptor, progesterone receptor, glucocorticoid receptor, hypoxiainduciblefactor-1α, and vascular endothelial growth factor in normal and various malignant endometrial tissues. The expression of BAF250 was significantly down-regulated in endometrial carcinoma when compared with normal endometrial tissues. The loss of BAF250a expression was found in 25% of endometrial carcinoma samples but not in normal endometrial tissues, complex endometrial hyperplasia, and atypical endometrial hyperplasia samples. Subtypes of endometrial carcinoma, especially uterine endometrioid carcinoma and uterine clear cell carcinoma, had higher frequency of loss of BAF250a expression. In addition, the expression of BAF250a was positively correlated with estrogen receptor and negatively correlated with p53 in poorly differentiated endometrial adenocarcinoma. Moreover, the expression of BAF250a was significantly associated with the differentiation status of endometrial carcinoma but not associated with clinical stage, the depth of myometrial invasion, lymph node metastasis, and overall survival of patients with endometrial carcinoma. Our data showed that loss of BAF250a is frequently found in high-grade endometrioid and clear cell carcinomas but not in other types of endometrial carcinoma. The loss of BAF250a expression does not have prognostic value for endometrial carcinoma.

Progesterone receptors in the female lower urinary tract

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

Batra, S.C.; Iosif, C.S.

1987-11-01

When female estrogenized rabbits were injected i.v. with /sup 3/H-progesterone, the tritium concentration determined after one hour was about two to three times higher in urethra, urinary bladder and vagina than in the heart. High affinity progesterone receptors (KD = 1-2 nM) could be demonstrated in both cytoplasmic and nuclear fractions prepared from estrogenized rabbit urethra, bladder and vagina. The cytosolic receptor concentration in both urethra and bladder was about half of that in the vagina. The concentration of nuclear receptors in urethra was not significantly different from that in the vagina, but in the bladder the concentration was onlymore » about one fourth of that in the vagina or urethra. The mean KD of cytosolic receptors from bladder was significantly higher than the corresponding values in urethra and vagina. Progesterone binding sites in the bladder had a broader hormonal specificity than those in the urethra or vagina. The present demonstration of specific progesterone receptors in the female urethra might provide a possible link between estrogen progesterone interaction and the appearance of urinary incontinence during pregnancy in women.« less

[Interest of selective progesterone receptor modulators in endometriosis].

PubMed

Merviel, P; Lourdel, E; Sanguin, S; Gagneur, O; Cabry, R; Nasreddine, A

2013-09-01

The SPRM (selective progesterone receptor modulators) are agonists and/or antagonists of progesterone receptor. They are responsible for anovulation, amenorrhea and a lower prostaglandin levels, which leads to an improvement in pain and regression of lesions in endometriosis. On the endometrium, a particular aspect, the progesterone receptor modulator-associated endometrial changes (PAEC), raises additional studies to verify its harmlessness. However, due to the lack of hypoestrogenism and metabolic effects with these drugs, it is very likely that the SPRM will in the near future an important place in the treatment of endometriosis. Copyright © 2013. Published by Elsevier SAS.

Control of Endothelin-A Receptor Expression by Progesterone Is Enhanced by Synergy With Gata2

PubMed Central

Zhang, Yanping; Knutsen, Gregory R.; Brown, Matthew D.

2013-01-01

The endothelin-A receptor (Ednra) is involved in several physiological, pathological, and developmental pathways. Known for its function in vasoconstriction after being activated by endothelin-1, Ednra also controls cephalic neural crest cell development and appears to play a role in several pathologies, including cancer and periodontitis. However, the mechanisms regulating Ednra expression have not been identified despite its important functions. In this study, we investigated the role progesterone plays in Ednra gene expression in vivo and in vitro. In mice, pregnancy promotes Ednra expression in the heart, kidney, lung, uterus, and placenta, and the up-regulation is mediated by progesterone. We determined that the conserved region between −5.7 and −4.2 kb upstream of the mouse Ednra gene is necessary for the progesterone response. We also found that progesterone mediates Ednra activation through progesterone receptor B activation by its recruitment to PRE6, one of the 6 progesterone response elements found in that locus. However, gene activation by means of a GATA2 site was also necessary for the progesterone response. The Gata2 transcription factor enhances the progesterone response mediated by the progesterone receptor B. Together these results indicate that progesterone regulates Ednra expression by synergizing with Gata2 activity, a previously unknown mechanism. This mechanism may have an impact on pathologies involving the endothelin signaling. PMID:23592430

Ulipristal acetate prior to in vitro fertilization in a female patient affected by uterine fibroids: a case report.

PubMed

Lo Monte, G; Piva, I; Graziano, A; Engl, B; Marci, R

2016-01-01

Uterine leiomyomatosis and especially submucosal myomas hamper the outcomes of Assisted Reproductive Techniques (ART). Even though surgical treatment eliminates gross anatomical anomalies, medical treatment should be encouraged to improve the overall structure of the uterus, thereby enabling ART. We report the case of an infertile female patient suffering from symptomatic uterine fibromatosis, who received 5 mg/day ulipristal acetate (UPA), a selective progesterone receptor modulator (SPRMs), for three months before and after hysteroscopic myomectomy. Uterine bleeding reduced on the eight days of treatment, with a subsequent improvement of pelvic pain. Under transvaginal ultrasound the uterus appeared globally enlarged with a diffuse leiomyomatosis of the myometrial layer. Saline infusion showed a markedly distorted cavity due two submucosal myomas (sized 31 × 24 mm and 21 × 19 mm, respectively) and one intramural myoma (37 × 34 mm). After three months the size of the myomas was reduced by 30-40%, allowing the hysteroscopic removal of the submucosal fibroids and the bigger intramural one. The smaller fibroids involving the myometrial layer were instead too diffused to be removed. At the conclusion of the subsequent cycle of UPA, the overall appearance of the cavity had improved, and the endometrial layer was regular, allowing the patient to undergo in vitro fertilization (IVF). There was no adverse effect related to treatment, and the endometrial biopsy did not reveal any histologic change. UPA seems to have a triple effect: it ensures prompt symptom relief, it reduces the size of the myomas enabling surgery and it improves the morphology of the uterus.

Alkaline phosphatases contribute to uterine receptivity, implantation, decidualization and defense against bacterial endotoxin in hamsters

PubMed Central

Lei, Wei; Nguyen, Heidi; Brown, Naoko; Ni, Hua; Kiffer-Moreira, Tina; Reese, Jeff; Millán, José Luis; Paria, Bibhash C.

2013-01-01

Alkaline phosphatase (AP) activity has been demonstrated in the uterus of several species, but its importance in the uterus, in general and during pregnancy, is yet to be revealed. In this study, we focused on identifying AP isozyme types, and their hormonal regulation, cell-type and event-specific expression and possible functions in the hamster uterus during the cycle and early pregnancy. Our RT-PCR and in situ hybridization studies demonstrated that among the known Akp2, Akp3, Akp5 and Akp6 murine AP isozyme genes, hamster uteri express only Akp2 and Akp6; and both genes are co-expressed in luminal epithelial cells. Studies in cyclic and ovariectomized hamsters established that while progesterone is the major uterine Akp2 inducer, both progesterone and estrogen are strong Akp6 regulators. Studies in preimplantation uteri showed induction of both genes and the activity of their encoded isozymes in luminal epithelial cells during uterine receptivity. However, at the beginning of implantation, Akp2 showed reduced expression in luminal epithelial cells surrounding the implanted embryo. In contrast, expression of Akp6 and its isozyme was maintained in luminal epithelial cells adjacent to, but not away from, the implanted embryo. Following implantation, stromal transformation to decidua was associated with induced expressions of only Akp2 and its isozyme. We next demonstrated that uterine APs dephosphorylate and detoxify endotoxin lipopolysaccharide at their sites of production and activity. Taken together, our findings suggest that uterine APs contribute to uterine receptivity, implantation, and decidualization in addition to their role in protection of the uterus and pregnancy against bacterial infection. PMID:23929901

Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives

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

Kloosterboer, H.J.; Vonk-Noordegraaf, C.A.; Turpijn, E.W.

1988-09-01

The relative binding affinities (RBAs) of four progestational compounds (norethisterone, levonorgestrel, 3-keto-desogestrel and gestodene) for the human progesterone and androgen receptors were measured in MCF-7 cytosol and intact MCF-7 cells. For the binding to the progesterone receptor, both Org 2058 and Org 3236 (or 3-keto-desogestrel) were used as labelled ligands. The following ranking (low to high) for the RBA of the nuclear (intact cells) progesterone receptor irrespective of the ligand used is found: norethisterone much less than levonorgestrel less than 3-keto-destogestrel less than gestodene. The difference between the various progestagens is significant with the exception of that between 3-keto-desogestrel andmore » gestodene, when Org 2058 is used as ligand. For the cytosolic progesterone receptor, the same order is found with the exception that similar RBAs are found for gestodene and 3-keto-desogestrel. The four progestagens clearly differ with respect to binding to the androgen receptor using dihydrotestosterone as labelled ligand in intact cells; the ranking (low to high) is: norethisterone less than 3 keto-desogestrel less than levonorgestrel and gestodene. The difference between 3-keto-desogestrel and levonorgestrel or gestodene is significant. The selectivity indices (ratio of the mean RBA for the progesterone receptor to that of androgen receptor) in intact cells are significantly higher for 3-keto-desogestrel and gestodene than for levonorgestrel and norethisterone. From these results we conclude that the introduction of the 18-methyl in norethisterone (levonorgestel) increases both the binding to the progesterone and androgen receptors.« less

Progesterone Modulates a Neuronal Nicotinic Acetylcholine Receptor

NASA Astrophysics Data System (ADS)

Valera, S.; Ballivet, M.; Bertrand, D.

1992-10-01

The major brain nicotinic acetylcholine receptor is assembled from two subunits termed α 4 and nα 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor.

Role of Epidermal Growth Factor Receptors and Their Ligands in Normal Mammary Epithelial and Breast Cancer Cells

DTIC Science & Technology

1997-07-01

have an estrogen receptor and progesterone receptor negative phenotype, high proliferation rates, poor response to endocrine therapy, and reduced...mitogenic effects of estrogen, progesterone and prolactin in breast cancer cell lines (3), and part of the growth promoting effects of an activated ras...of the cases (51,52), and an inverse relationship with estrogen and progesterone receptors; in such tumors, a poor response to endocrine therapy

Hormone Receptor Status in Breast Cancer and its Relation to Age and Other Prognostic Factors

PubMed Central

Pourzand, Ali; Fakhree, M. Bassir A.; Hashemzadeh, Shahryar; Halimi, Monireh; Daryani, Amir

2011-01-01

Background: Increasing evidence shows the importance of young age, estrogen receptor (ER), progesterone receptor (PR) status, and HER-2 expression in patients with breast cancers. Patients and methods: We organized an analytic cross-sectional study of 105 women diagnosed with breast cancer who have been operated on between 2008 to 2010. We evaluated age, size, hormone receptor status, HER-2 and P53 expression as possible indicator of lymph node involvement. Results: There is a direct correlation between positive progesterone receptor status and being younger than 40 (P < 0.05). Also, compared with older women, young women had tumors that were more likely to be large in size and have higher stages (P < 0.05). Furthermore patients with negative progesterone receptor status were more likely to have HER-2 overexpression (P < 0.05). The differences in propensity to lymph node metastasis between hormone receptor statuses were not statically significant. Conclusions: Although negative progesterone receptor tumors were more likely to have HER-2 overexpression, it is possible that higher stage and larger size breast cancer in younger women is related to positive progesterone receptor status. PMID:21695095

Recent pharmacological advances in the treatment of preterm membrane rupture, labour and delivery.

PubMed

Doggrell, Sheila A

2004-09-01

Preterm delivery (before 37 completed weeks of gestation) is the major determinant of infant mortality. In women with a previous preterm birth associated with bacterial vaginosis, prophylactic antibiotics (e.g., metronidazole) reduce the risk of preterm birth and low birth weight. Trichomonas vaginalis increases the risk of preterm delivery, but metronidazole is not beneficial for this and may even be detrimental. Antibiotic use (e.g., erythromycin) prolongs pregnancy in late premature rupture and has health benefits for the neonate. However, antibiotics are probably not useful in preterm labour. Intramuscular 17alpha-progesterone and vaginal progesterone reduce the rate of preterm labour in high-risk pregnancies, including previous spontaneous preterm delivery. Magnesium sulfate, beta2-adrenoceptor agonists and the oxytocin-receptor antagonist, atosiban, are effective in reducing uterine contractions short-term, but there is little evidence that this leads to improved outcomes for the neonate. However, tocolysis with calcium-channel blockers does seem to lead to better outcomes for the neonate. Fetal side effects, such as ductus arteriosus constriction and impaired renal function, are associated with the inhibition of prostaglandin synthesis with indomethacin. New approaches and more effective drugs are required in the treatment of preterm delivery.

Long-term exposure to electromagnetic radiation from mobile phones and Wi-Fi devices decreases plasma prolactin, progesterone, and estrogen levels but increases uterine oxidative stress in pregnant rats and their offspring.

PubMed

Yüksel, Murat; Nazıroğlu, Mustafa; Özkaya, Mehmet Okan

2016-05-01

We investigated the effects of mobile phone (900 and 1800 MHz)- and Wi-Fi (2450 MHz)-induced electromagnetic radiation (EMR) exposure on uterine oxidative stress and plasma hormone levels in pregnant rats and their offspring. Thirty-two rats and their forty newborn offspring were divided into the following four groups according to the type of EMR exposure they were subjected to: the control, 900, 1800, and 2450 MHz groups. Each experimental group was exposed to EMR for 60 min/day during the pregnancy and growth periods. The pregnant rats were allowed to stand for four generations (total 52 weeks) before, plasma and uterine samples were obtained. During the 4th, 5th, and 6th weeks of the experiment, plasma and uterine samples were also obtained from the developing rats. Although uterine lipid peroxidation increased in the EMR groups, uterine glutathione peroxidase activity (4th and 5th weeks) and plasma prolactin levels (6th week) in developing rats decreased in these groups. In the maternal rats, the plasma prolactin, estrogen, and progesterone levels decreased in the EMR groups, while the plasma total oxidant status, and body temperatures increased. There were no changes in the levels of reduced glutathione, total antioxidants, or vitamins A, C, and E in the uterine and plasma samples of maternal rats. In conclusion, although EMR exposure decreased the prolactin, estrogen, and progesterone levels in the plasma of maternal rats and their offspring, EMR-induced oxidative stress in the uteri of maternal rats increased during the development of offspring. Mobile phone- and Wi-Fi-induced EMR may be one cause of increased oxidative uterine injury in growing rats and decreased hormone levels in maternal rats. TRPV1 cation channels are the possible molecular pathways responsible for changes in the hormone, oxidative stress, and body temperature levels in the uterus of maternal rats following a year-long exposure to electromagnetic radiation exposure from mobile phones and Wi-Fi devices. It is likely that TRPV1-mediated Ca(2+) entry in the uterus of pregnant rats involves accumulation of oxidative stress and opening of mitochondrial membrane pores that consequently leads to mitochondrial dysfunction, substantial swelling of the mitochondria with rupture of the outer membrane and release of oxidants such as superoxide (O2 (-)) and hydrogen peroxide (H2O2). The superoxide radical is converted to H2O2 by superoxide dismutase (SOD) enzyme. Glutathione peroxidase (GSH-Px) is an important antioxidant enzyme for removing lipid hydroperoxides and hydrogen peroxide and it catalyzes the reduction of H2O2 to water.

Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

PubMed

Wolfson, Manuel Luis; Schander, Julieta Aylen; Bariani, María Victoria; Correa, Fernando; Franchi, Ana María

2015-12-15

Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS. Here we sought to investigate whether the in vivo administration of progesterone modulated the LPS-induced nitric oxide production from peripheral blood mononuclear cells from pregnant and non-pregnant mice. We found that progesterone downregulated LPS-induced nitric oxide production by a progesterone receptor-independent mechanism. Moreover, our results suggest a possible participation of glucocorticoid receptors in at least some of the anti-inflammatory effects of progesterone. Copyright © 2015 Elsevier B.V. All rights reserved.

Membrane progesterone receptors in reproduction and cancer.

PubMed

Valadez-Cosmes, Paulina; Vázquez-Martínez, Edgar Ricardo; Cerbón, Marco; Camacho-Arroyo, Ignacio

2016-10-15

Progesterone is a sexual steroid hormone that has a critical role in reproductive processes in males and females of several species, including humans. Furthermore, progesterone has been associated with pathological diseases such as breast, gynecological and brain cancer, regulating cell proliferation, apoptosis, and metastasis. In the past, progesterone actions were thought to be only mediated by its intracellular receptor (PR). However, recent evidence has demonstrated that membrane progesterone receptors (mPRs) mediate most of the non-classical progesterone actions. The role of the different mPRs subtypes in progesterone effects in reproduction and cancer is an emerging and exciting research area. Here we review studies to date regarding mPRs role in reproduction and cancer and discuss their functions and clinical relevance, suggesting mPRs as putative pharmacological targets and disease markers in cancer and diseases associated with reproduction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Progesterone bioavailability with a progesterone-releasing silicone vaginal ring in IVF candidates.

PubMed

Dragonas, C; Maltaris, T; Binder, H; Kat, M; Mueller, A; Cupisti, S; Hoffmann, I; Beckmann, M W; Dittrich, Ralf

2007-06-27

A vaginal ring made of silicone polymers and barium sulfate, and containing 1 g of pure micronized progesterone, was developed for luteal supplementation in women undergoing cycles of in vitro fertilization (IVF). The ring, modeled on the Estring, was designed as a means of providing continuous intravaginal delivery of progesterone. Bioavailability of progesterone in the blood was demonstrated for 24 hours in IVF candidates who had an endogenous progesterone deficiency after treatment with gonadotropin-releasing hormone (GnRH) analogues. After the first 4 h of increasing release of progesterone from the ring (with mean serum levels of 1.39 +/- 0.8 ng/ml after 4 h), only a slight increase in serum progesterone levels (with a mean peak of 1.5 +/- 0.45 ng/ml after 24 h) was observed during the rest of the test period. Gonadotropin levels were not affected after insertion of the ring. The ring was well tolerated by the patients. The maximum serum progesterone level was lower in comparison with other forms of progesterone application, but it should be sufficiently high, due to the uterine first-pass effect. This study demonstrated that progesterone administration through a silicone ring for luteal support is feasible in IVF treatment. As the vaginal ring is very well tolerated by the patients, these findings may encourage the pharmaceutical industry to design an appropriate progesterone ring for luteal support.

Fructose Synthesis and Transport at the Uterine-Placental Interface of Pigs: Cell-Specific Localization of SLC2A5, SLC2A8, and Components of the Polyol Pathway.

PubMed

Steinhauser, Chelsie B; Landers, McKinsey; Myatt, Louise; Burghardt, Robert C; Vallet, Jeffrey L; Bazer, Fuller W; Johnson, Greg A

2016-11-01

The fetal fluids and uterine flushings of pigs contain higher concentrations of fructose than glucose, but fructose is not detected in maternal blood. Fructose can be synthesized from glucose via enzymes of the polyol pathway, aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD), transported across cell membranes by solute carriers SLC2A5 and SLC2A8, and converted to fructose-1-phosphate by ketohexokinase (KHK). SLC2A8, SLC2A5, AKR1B1, SORD, and KHK mRNAs and proteins were analyzed using quantitative PCR and immunohistochemistry or in situ hybridization in endometria and placentae of cyclic and pregnant gilts, cyclic gilts injected with estrogen, and ovariectomized gilts injected with progesterone. Progesterone up-regulated SLC2A8 protein in uterine luminal (LE) and glandular epithelia during the peri-implantation period, and expression became exclusively placental, chorion and blood vessels, after Day 30. P4 up-regulated SLC2A5 mRNA in uterine LE and glandular epithelia after implantation, and the chorion expressed SLC2A5 between Days 30 and 85. AKR1B1 and SORD proteins localized to uterine LE during the peri-implantation period, but expression switched to chorion by Day 20 and was maintained through Day 85. Uterine expression of AKR1B1 mRNA was down-regulated by estrogen. KHK protein localized to trophectoderm/chorion throughout gestation. These results provide evidence that components for the conversion of glucose to fructose and for fructose transport are present at the uterine-placental interface of pigs. The shift in expression from LE to chorion during pregnancy suggests free-floating conceptuses are supported by fructose synthesized by the uterus, but after implantation, the chorion becomes self-sufficient for fructose synthesis and transport. © 2016 by the Society for the Study of Reproduction, Inc.

Defining the extent of cables loss in endometrial cancer subtypes and its effectiveness as an inhibitor of cell proliferation in malignant endometrial cells in vitro and in vivo.

PubMed

DeBernardo, Robert L; Littell, Ramey D; Luo, Hongwei; Duska, Linda R; Oliva, Esther; Kirley, Sandra D; Lynch, Maureen P; Zukerberg, Lawrence R; Rueda, Bo R

2005-01-01

Loss of Cables expression is associated with a high incidence of endometrial hyperplasia and endometrial adenocarcinoma in humans. The Cables mutant mouse develops endometrial hyperplasia and following exposure to chronic estrogen develops early endometrial adenocarcinoma. The objectives of the current study were to determine if: (1) loss of Cables expression occurred in high grade endometrioid adenocarcinoma, uterine serous and clear cell carcinoma as observed in endometrial hyperplasia and low grade endometrial adenocarcinoma; (2) overexpression of Cables inhibited cell proliferation in endometrial cancer (EC) cells in vitro and in vivo; and (3) progesterone could regulate the expression of Cables mRNA. Hyperplastic endometrium and low and high grade endometrioid adenocarcinoma showed loss of Cables expression when compared to benign control secretory endometrium. Loss of Cables expression in serous and clear cell tumors was similar to that observed in endometrioid adenocarcinomas with greater than 80% showing loss of protein expression. Treatment of EC lines with progesterone increased cables expression in low-grade EC whereas it had no effect on cables expression in cells derived from high-grade EC. The progesterone-induced increase in cables was abrogated in the presence of a progesterone receptor (PR) antagonist, suggesting the PR mediates the increase. Cables overexpression inhibited cell proliferation of well differentiated EC cells and had no effect on the poorly differentiated EC cells. The capacity to form tumors was dramatically reduced in the Cables overexpressing cell lines compared to those cells containing the control vector. Collectively these results suggest that Cables is an important regulator of cell proliferation and loss of Cables expression contributes to the development of all types of EC.

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α.

PubMed

Pang, Yefei; Dong, Jing; Thomas, Peter

2015-05-15

Progesterone exerts beneficial effects on the human cardiovascular system by inducing rapid increases in nitric oxide (NO) production in vascular endothelial cells, but the receptors mediating these nongenomic progesterone actions remain unclear. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that progesterone binds to plasma membranes of HUVECs with the characteristics of membrane progesterone receptors (mPRs). The selective mPR agonist Org OD 02-0 had high binding affinity for the progesterone receptor on HUVEC membranes, whereas nuclear PR (nPR) agonists R5020 and medroxyprogesterone acetate displayed low binding affinities. Immunocytochemical and Western blot analyses confirmed that mPRs are expressed in HUVECs and are localized on their plasma membranes. NO levels increased rapidly after treatment with 20 nM progesterone, Org OD 02-0, and a progesterone-BSA conjugate but not with R5020, suggesting that this progesterone action is at the cell surface and initiated through mPRs. Progesterone and Org OD 02-0 (20 nM) also significantly increased endothelial nitric oxide synthase (eNOS) activity and eNOS phosphorylation. Knockdown of mPRα expression by treatment with small-interfering RNA (siRNA) blocked the stimulatory effects of 20 nM progesterone on NO production and eNOS phosphorylation, whereas knockdown of nPR was ineffective. Treatment with PI3K/Akt and MAP kinase inhibitors blocked the stimulatory effects of progesterone, Org OD 02-0, and progesterone-BSA on NO production and eNOS phosphorylation and also prevented progesterone- and Org OD 02-0-induced increases in Akt and ERK phosphorylation. The results suggest that progesterone stimulation of NO production in HUVECs is mediated by mPRα and involves signaling through PI3K/Akt and MAP kinase pathways. Copyright © 2015 the American Physiological Society.

Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling

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

Yoo, Jung-Yoon; Kim, Tae Hoon; Lee, Jae Hee

2015-07-10

Mitogen inducible gene 6 (Mig-6) is an important mediator of progesterone (P4) signaling to inhibit estrogen (E2) signaling in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced endometrial cancer. To identify the molecular pathways regulated by Mig-6, we performed microarray analysis on the uterus of ovariectomized Mig-6{sup f/f} and PGR{sup cre/+}Mig-6{sup f/f} (Mig-6{sup d/d}) mice treated with vehicle or P4 for 6 h. The results revealed that 772 transcripts were significantly regulated in the Mig-6{sup d/d} uterus treated with vehicle as compared with Mig-6{sup f/f} mice. The pathway analysis showed thatmore » Mig-6 suppressed the expression of gene-related cell cycle regulation in the absence of ovarian steroid hormone. The epithelium of Mig-6{sup d/d} mice showed a significant increase in the number of proliferative cells compared to Mig-6{sup f/f} mice. This microarray analysis also revealed that 324 genes are regulated by P4 as well as Mig-6. Cited2, the developmentally important transcription factor, was identified as being regulated by the P4-Mig-6 axis. To determine the role of Cited2 in the uterus, we used the mice with Cited2 that were conditionally ablated in progesterone receptor-positive cells (PGR{sup cre/+}Cited2{sup f/f}; Cited2{sup d/d}). Ablation of Cited2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Identification and analysis of these responsive genes will help define the role of P4 as well as Mig-6 in regulating uterine biology. - Highlights: • We identify Mig-6- and P4-regulated uterine genes by microarray analysis. • Mig-6 suppresses cell cycle progression and epithelial cell proliferation in uterus. • We identify the Mig-6 dependent induced genes by P4. • Cited2 plays an important role for decidualization as a P4 and Mig-6 target gene.« less

EMMPRIN-Mediated Induction of Uterine and Vascular Matrix Metalloproteinases during Pregnancy and in Response to Estrogen and Progesterone

PubMed Central

Dang, Yiping; Li, Wei; Tran, Victoria; Khalil, Raouf A.

2013-01-01

Pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during pregnancy are unclear. MMPs expression, activity and tissue distribution were measured in uterus, placenta and aorta of virgin, mid-pregnant (mid-Preg) and late pregnant (late-Preg) rats. Western blots and gelatin zymography revealed increases in MMP-2 and -9 in uterus and aorta of late-Preg compared with virgin and mid-Preg rats. In contrast, MMP-2 and -9 were decreased in placenta of late-Preg versus mid-Preg rats. Extracellular MMP inducer (EMMPRIN) was increased in uterus and aorta of pregnant rats, but was less in placenta of late-Preg than mid-Preg rats. Prolonged treatment of uterus or aorta of virgin rats with 17β-estradiol and progesterone increased the amount of EMMPRIN, MMP-2 and -9, and the sex hormone-induced increases in MMPs were prevented by EMMPRIN neutralizing antibody. Immunohistochemistry revealed that MMP-2 and -9 and EMMPRIN increased in uterus and aorta of pregnant rats, but decreased in placenta of late-Preg versus mid-Preg rats. Thus pregnancy-associated upregulation of uterine MMPs is paralleled by increased vascular MMPs, and both are mediated by EMMPRIN and induced by estrogen and progesterone, suggesting similar role of MMPs in uterine and vascular tissue remodeling and function during pregnancy. The decreased MMPs and EMMPRIN in placenta of late-Preg rats suggests reduced role of MMPs in feto-placental circulation during late pregnancy. PMID:23856290

EMMPRIN-mediated induction of uterine and vascular matrix metalloproteinases during pregnancy and in response to estrogen and progesterone.

PubMed

Dang, Yiping; Li, Wei; Tran, Victoria; Khalil, Raouf A

2013-09-15

Pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during pregnancy are unclear. MMPs expression, activity and tissue distribution were measured in uterus, placenta and aorta of virgin, mid-pregnant (mid-Preg) and late pregnant (late-Preg) rats. Western blots and gelatin zymography revealed increases in MMP-2 and -9 in uterus and aorta of late-Preg compared with virgin and mid-Preg rats. In contrast, MMP-2 and -9 were decreased in placenta of late-Preg versus mid-Preg rats. Extracellular MMP inducer (EMMPRIN) was increased in uterus and aorta of pregnant rats, but was less in placenta of late-Preg than mid-Preg rats. Prolonged treatment of uterus or aorta of virgin rats with 17β-estradiol and progesterone increased the amount of EMMPRIN, MMP-2 and -9, and the sex hormone-induced increases in MMPs were prevented by EMMPRIN neutralizing antibody. Immunohistochemistry revealed that MMP-2 and -9 and EMMPRIN increased in uterus and aorta of pregnant rats, but decreased in placenta of late-Preg versus mid-Preg rats. Thus pregnancy-associated upregulation of uterine MMPs is paralleled by increased vascular MMPs, and both are mediated by EMMPRIN and induced by estrogen and progesterone, suggesting similar role of MMPs in uterine and vascular tissue remodeling and function during pregnancy. The decreased MMPs and EMMPRIN in placenta of late-Preg rats suggests reduced role of MMPs in feto-placental circulation during late pregnancy. Copyright © 2013 Elsevier Inc. All rights reserved.

A Phase II Study Evaluating the Role of Androgen Receptors as Targets for Therapy of Pre-treated Post-menopausal Patients With ER/PgR-negative/AR-positive or ER and/or PgRpositive/ AR-positive Metastatic Breast Cancer (ARTT)

ClinicalTrials.gov

2016-09-28

Metastatic Breastcancer; Estrogen Receptor Positive Breast Cancer; Estrogen Receptor Negative Neoplasm; Progesterone Receptor Positive Tumor; Progesterone Receptor Negative Neoplasm; Androgen Receptor Gene Overexpression

PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Alterations in uteroplacental hemodynamics during melatonin supplementation in sheep and cattle.

PubMed

Lemley, C O; Vonnahme, K A

2017-05-01

Compromised placental function can result in fetal growth restriction which is associated with greater risk of neonatal morbidity and mortality. Large increases in transplacental nutrient and waste exchange, which support the exponential increase in fetal growth during the last half of gestation, are dependent primarily on the rapid growth and vascularization of the uteroplacenta. The amplitude of melatonin secretion has been associated with improved oxidative status and altered cardiovascular function in several mammalian species; however, melatonin mediated alterations of uteroplacental capacity in sheep and cattle are lacking. Therefore, our laboratories are examining uteroplacental blood flow and fetal development during maternal melatonin supplementation. Using a mid- to late-gestation ovine model of intrauterine growth restriction, we examined uteroplacental blood flow and fetal growth during supplementation with 5 mg/d of dietary melatonin. Maternal nutrient restriction decreased uterine arterial blood flow, while melatonin supplementation increased umbilical arterial blood flow compared with non-supplemented controls. Although melatonin treatment did not rescue fetal weight in nutrient restricted ewes; we observed disproportionate fetal size and fetal organ development. Elevated fetal concentrations of melatonin may result in altered blood flow distribution during important time points of development. These melatonin specific responses on umbilical arterial hemodynamics and fetal development may be partially mediated through vascular melatonin receptors. Recently, we examined the effects of supplementing Holstein heifers with 20 mg/d of dietary melatonin during the last third of gestation. Uterine arterial blood flow was increased by 25% and total serum antioxidant capacity was increased by 43% in melatonin supplemented heifers vs. non-supplemented controls. In addition, peripheral concentrations of progesterone were decreased in melatonin supplemented heifers vs. non-supplemented controls. Using an in vitro model, melatonin treatment increased the activity of cytochrome P450 2C, a progesterone inactivating enzyme, which was blocked by treatment with the melatonin receptor antagonist, luzindole. Elucidating the consequences of specific hormonal supplements on the continual plasticity of placental function will allow us to determine important endogenous mediators of offspring growth and development.

Steroid hormone receptors ERalpha and PR characterised by immunohistochemistry in the mare adrenal gland.

PubMed

Alm, Ylva Hedberg; Sukjumlong, Sayamon; Kindahl, Hans; Dalin, Anne-Marie

2009-07-22

Sex steroid hormone receptors have been identified in the adrenal gland of rat, sheep and rhesus monkey, indicating a direct effect of sex steroids on adrenal gland function. In the present study, immunohistochemistry using two different mouse monoclonal antibodies was employed to determine the presence of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) in the mare adrenal gland. Adrenal glands from intact (n = 5) and ovariectomised (OVX) (n = 5) mares, as well as uterine tissue (n = 9), were collected after euthanasia. Three of the OVX mares were treated with a single intramuscular injection of oestradiol benzoate (2.5 mg) 18-22 hours prior to euthanasia and tissue collection (OVX+Oe). Uterine tissue was used as a positive control and showed positive staining for both ERalpha and PR. ERalpha staining was detected in the adrenal zona glomerulosa, fasciculata and reticularis of all mare groups. Ovariectomy increased cortical ERalpha staining intensity. In OVX mares and one intact mare, positive ERalpha staining was also detected in adrenal medullary cells. PR staining of weak intensity was present in a low proportion of cells in the zona fasciculata and reticularis of all mare groups. Weak PR staining was also found in a high proportion of adrenal medullary cells. In contrast to staining in the adrenal cortex, which was always located within the cell nuclei, medullary staining for both ERalpha and PR was observed only in the cell cytoplasm. The present results show the presence of ERalpha in the adrenal cortex, indicating oestradiol may have a direct effect on mare adrenal function. However, further studies are needed to confirm the presence of PR as staining in the present study was only weak and/or minor. Also, any possible effect of oestradiol treatment on the levels of steroid receptors cannot be determined by the present study, as treatment time was of a too short duration.

Endocrine Disrupting Effects of Triclosan on the Placenta in Pregnant Rats

PubMed Central

Zhang, Zhaobin; Shi, Jiachen; Jiao, Zhihao; Shao, Bing

2016-01-01

Triclosan (TCS) is a broad-spectrum antimicrobial agent that is frequently used in pharmaceuticals and personal care products. Reports have shown that TCS is a potential endocrine disruptor; however, the potential effects of TCS on placental endocrine function are unclear. The aim of this study was to investigate the endocrine disrupting effects of TCS on the placenta in pregnant rats. Pregnant rats from gestational day (GD) 6 to GD 20 were treated with 0, 30, 100, 300 and 600 mg/kg/d TCS followed by analysis of various biochemical parameters. Of the seven tissues examined, the greatest bioaccumulation of TCS was observed in the placenta. Reduction of gravid uterine weight and the occurrence of abortion were observed in the 600 mg/kg/d TCS-exposed group. Moreover, hormone detection demonstrated that the serum levels of progesterone (P), estradiol (E2), testosterone (T), human chorionic gonadotropin (hCG) and prolactin (PRL) were decreased in groups exposed to higher doses of TCS. Real-time quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR) analysis revealed a significant increase in mRNA levels for placental steroid metabolism enzymes, including UDP-glucuronosyltransferase 1A1 (UGT1A1), estrogen sulfotransferase 1E1 (SULT1E1), steroid 5α-reductase 1 (SRD5A1) and steroid 5α-reductase 2 (SRD5A2). Furthermore, the transcriptional expression levels of progesterone receptor (PR), estrogen receptor (ERα) and androgen receptor (AR) were up-regulated. Taken together, these data demonstrated that the placenta was a target tissue of TCS and that TCS induced inhibition of circulating steroid hormone production might be related to the altered expression of hormone metabolism enzyme genes in the placenta. This hormone disruption might subsequently affect fetal development and growth. PMID:27149376

Progesterone suppresses triple-negative breast cancer growth and metastasis to the brain via membrane progesterone receptor α.

PubMed

Zhou, Li; Zhou, Wei; Zhang, Hongwei; Hu, Yan; Yu, Lei; Zhang, Yufei; Zhang, Yanli; Wang, Shuang; Wang, Peng; Xia, Wei

2017-09-01

Progesterone plays an important role in mammary epithelial cell proliferation and differentiation. Evidence from experimental and clinical studies indicates that progesterone is a risk factor for breast cancer under certain conditions through binding nuclear progesterone receptor (PR). These mechanisms, however, are not applicable to triple-negative breast cancer (TNBC) due to the lack of PR in these cancers. In this study, we demonstrate that membrane progesterone receptor α (mPRα) is expressed in TNBC tissues and the expression level of mPRα is negatively associated with the TNM stage. We found that progesterone suppressed the growth, migration and invasion of mPRα+ human TNBC cells in vitro, which was neither mediated by PR nor by PR membrane component 1 (PGRMCl). Notably, these effects exerted by progesterone were significantly blocked by shRNA specific to mPRα. Moreover, the knockdown of mPRα expression impaired the inhibitory effects of progesterone on mPRα+ tumor growth and metastasis in vivo. These data collectively indicate that progesterone suppresses TNCB growth and metastasis via mPRα, which provides evidence of the anti-neoplastic effects of progesterone-mPRα pathway in the treatment of human TNBC.

Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression

PubMed Central

Yang, Xiaoxiao; Zhang, Wenwen; Chen, Yuanli; Li, Yan; Sun, Lei; Liu, Ying; Liu, Mengyang; Yu, Miao; Li, Xiaoju; Han, Jihong; Duan, Yajun

2016-01-01

Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor γ (PPARγ). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPARγ expression and PPARγ promoter activity in a PR-dependent manner and the binding of PR with the progesterone response element in the PPARγ promoter. Specific deletion of macrophage PPARγ (MφPPARγ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPARγ expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPARγ expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPARγ-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy. PMID:27226602

Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression: THE DUAL PATHOPHYSIOLOGICAL ROLES OF PROGESTERONE.

PubMed

Yang, Xiaoxiao; Zhang, Wenwen; Chen, Yuanli; Li, Yan; Sun, Lei; Liu, Ying; Liu, Mengyang; Yu, Miao; Li, Xiaoju; Han, Jihong; Duan, Yajun

2016-07-15

Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor γ (PPARγ). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPARγ expression and PPARγ promoter activity in a PR-dependent manner and the binding of PR with the progesterone response element in the PPARγ promoter. Specific deletion of macrophage PPARγ (MφPPARγ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPARγ expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPARγ expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPARγ-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Atypical Uterine Smooth Muscle Tumors: A Retrospective Evaluation of Clinical and Pathologic Features.

PubMed

Maltese, Giuseppa; Fontanella, Caterina; Lepori, Stefano; Scaffa, Cono; Fucà, Giovanni; Bogani, Giorgio; Provenzano, Salvatore; Carcangiu, Maria Luisa; Raspagliesi, Francesco; Lorusso, Domenica

2018-01-01

Clinical characteristics combined with new biomarkers help discriminate between atypical uterine smooth muscle tumors (AUSMT) and leiomyosarcomas (LMS). We retrospectively collected a series of leiomyomas (LM), AUSMT, and LMS. Estrogen receptors (ER), progesterone receptors (PR), p16, Ki-67, and p53 expression were assessed by immunohistochemistry. For AUSMT patients, immunohistochemistry evaluations were performed at the time of diagnosis and at recurrences. A total of 27 cases of AUSMT, 22 LM, and 31 LMS were identified. The expression of ER and PR decreased from LM to LMS (ER+: LM 95.5%, AUSMT 88.9%, LMS 41.9%, p < 0.001; PR+: LM 100%, AUSMT 88.9%, LMS 38.2%, p = 0.002). By contrast, p16 and p53 expression increased (p16+: LM 4.5%, AUSMT 40.7%, LMS 45.2%, p = 0.004; p53: LM 9.1%, AUSMT 33.3%, LMS 58.1%, p = 0.001). At a median follow-up of 33.47 months, 40.7% of patients with AUSMT experienced recurrent disease, 6 patients relapsed as AUSMT and 5 as LMS. In univariate analysis was observed that ER status (p = 0.027) and p53 expression (p = 0.015) predicted risk of relapse. Treatment of AUSMT should be centralized in dedicated centers. International collaborations are needed to optimize research strategy, which may lead to the identification of new useful biomarkers and to improvement in the clinical management of this rare disease. © 2017 S. Karger AG, Basel.

The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells.

PubMed

Luo, Xia; Yin, Ping; Coon V, John S; Cheng, You-Hong; Wiehle, Ronald D; Bulun, Serdar E

2010-05-15

To evaluate the effects of selective P receptor (PR) modulator CDB4124 on cell proliferation and apoptosis in cultured human uterine leiomyoma smooth muscle (LSM) cells and control myometrial smooth muscle (MSM) cells in matched uteri. Laboratory research. Academic medical center. Premenopausal women (n = 12) undergoing hysterectomy for leiomyoma-related symptoms. Treatment of primary LSM and MSM cells with CDB4124 (10(-8)-10(-6) M) or vehicle for 24, 48, or 72 hours. Western blot for protein expression of proliferating cell nuclear antigen, cleaved polyadenosine 5'-diphosphate-ribose polymerase, Bcl-2, and Krüppel-like transcription factor 11; 93-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate viable cell numbers; and real-time polymerase chain reaction (PCR) to quantify messenger RNA (mRNA) levels. Treatment with CDB4124 significantly decreased levels of the proliferation marker proliferating cell nuclear antigen, the number of viable LSM cells, and the antiapoptotic protein Bcl-2. On the other hand, treatment with CDB4124 increased levels of the apoptosis marker cleaved polyadenosine 5'-diphosphate-ribose polymerase and the tumor suppressor Krüppel-like transcription factor 11 in a dose- and time-dependent manner in LSM cells. In matched MSM cells, however, CDB4124 did not affect cell proliferation or apoptosis. CDB4124 selectively inhibits proliferation and induces apoptosis in LSM but not in MSM cells. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Uterine Gene Expression in the Live-Bearing Lizard, Chalcides ocellatus, Reveals Convergence of Squamate Reptile and Mammalian Pregnancy Mechanisms

PubMed Central

Brandley, Matthew C.; Young, Rebecca L.; Warren, Dan L.; Thompson, Michael B.; Wagner, Günter P.

2012-01-01

Although the morphological and physiological changes involved in pregnancy in live-bearing reptiles are well studied, the genetic mechanisms that underlie these changes are not known. We used the viviparous African Ocellated Skink, Chalcides ocellatus, as a model to identify a near complete gene expression profile associated with pregnancy using RNA-Seq analyses of uterine transcriptomes. Pregnancy in C. ocellatus is associated with upregulation of uterine genes involved with metabolism, cell proliferation and death, and cellular transport. Moreover, there are clear parallels between the genetic processes associated with pregnancy in mammals and Chalcides in expression of genes related to tissue remodeling, angiogenesis, immune system regulation, and nutrient provisioning to the embryo. In particular, the pregnant uterine transcriptome is dominated by expression of proteolytic enzymes that we speculate are involved both with remodeling the chorioallantoic placenta and histotrophy in the omphaloplacenta. Elements of the maternal innate immune system are downregulated in the pregnant uterus, indicating a potential mechanism to avoid rejection of the embryo. We found a downregulation of major histocompatability complex loci and estrogen and progesterone receptors in the pregnant uterus. This pattern is similar to mammals but cannot be explained by the mammalian model. The latter finding provides evidence that pregnancy is controlled by different endocrinological mechanisms in mammals and reptiles. Finally, 88% of the identified genes are expressed in both the pregnant and the nonpregnant uterus, and thus, morphological and physiological changes associated with C. ocellatus pregnancy are likely a result of regulation of genes continually expressed in the uterus rather than the initiation of expression of unique genes. PMID:22333490

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.

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.

Estrogen and progesterone receptor testing in breast carcinoma: concordance of results between local and reference laboratories in Brazil.

PubMed

Wludarski, Sheila Cristina Lordelo; Lopes, Lisandro Ferreira; Duarte, Ivison Xavier; Carvalho, Filomena Marino; Weiss, Lawrence; Bacchi, Carlos Eduardo

2011-01-01

Breast cancer accounts for approximately one quarter of all cancers in females. Estrogen and progesterone receptor testing has become an essential part of the clinical evaluation of breast carcinoma patients, and accurate results are critical in identifying patients who may benefit from hormone therapy. The present study had the aim of investigating the concordance of the results from hormone receptor tests between a reference laboratory and local (or community) laboratories in Brazil. Retrospective study at a reference pathology laboratory. The concordance in the results from hormone receptor tests between a reference laboratory and 146 local laboratories in Brazil was compared in relation to 500 invasive breast carcinoma cases, using immunohistochemistry. There was concordance in 89.4% (447/500 cases) and 85.0% (425/500 cases) of the results from estrogen (κ = 0.744, P < 0.001) and progesterone (κ = 0.688, P < 0.001) receptor tests, respectively, between local and reference laboratories. This was similar to findings in other countries. The false negative rates from estrogen and progesterone receptor tests in local laboratories were 8.7% and 14.4%, respectively. The false positive rates from estrogen and progesterone receptor tests in local laboratories were 15.5% and 16.0%, respectively. Technical and result interpretation issues may explain most of the discordances in hormone receptor testing in local laboratories. Validation of estrogen and progesterone receptor tests at local laboratories, with rigorous quality control measures, is strongly recommended in order to avoid erroneous treatment of breast cancer patients.

Low-power interstitial photocoagulation of uterine leiomyomas by KTP/YAG laser: a review of 50 consecutive cases

NASA Astrophysics Data System (ADS)

Chapman, Roxana

1994-12-01

Interstitial laser photocoagulation (ILP), which is a new method of low power laser destruction of tumors, has been used to treat laparoscopically 50 consecutive patients with symptomatic uterine leiomyomas which were difficult or impossible to remove via laparoscopy. The KTP/YAG laser, with wavelengths of 532 and 1064 nm respectively, was employed. Holes 2 cm apart were drilled with a 600 micrometers quartz laser fiber employing the KTP component at 8 W and subsequent coagulation of the surrounding myoma tissue was accomplished during the withdrawal of the fiber over the course of 10 - 30 s but using the YAG component at 8 W until the whole myoma had been treated. Thirty seven became symptom free and have remained so. Six were lost to follow up. Of 10 complaining of subfertility 4, in whom uterine myomas were the only etiological factor, have become pregnant. Seven patients required further treatment: Two were retreated because their myomas were excessively large and did not completely disappear with the initial ILP, 2 received further ILP because of the development of new myomas and 3 were subjected to laparoscopically assisted vaginal hysterectomy at patients' request (2 because of the development of new myomas and 1 because of the development of further endometriosis). Finally, in 7 cases, residual tumor or scar tissue was biopsied and examined for the presence of oestrogen and progesterone receptors. None was discovered and in 2 subsequent pregnancy did not cause further growth of residual myoma tissue.

Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice

PubMed Central

Buckley, Jill; Willingham, Emily; Agras, Koray; Baskin, Laurence S

2006-01-01

Background Vinclozolin is a fungicide that has been reported to have anti-androgenic effects in rats. We have found that in utero exposure to natural or synthetic progesterones can induce hypospadias in mice, and that the synthetic progesterone medroxyprogesterone acetate (MPA) feminizes male and virilizes female genital tubercles. In the current work, we selected a relatively low dose of vinclozolin to examine its in utero effects on the development of the genital tubercle, both at the morphological and molecular levels. Methods We gave pregnant dams vinclozolin by oral gavage from gestational days 13 through 17. We assessed the fetal genital tubercles from exposed fetuses at E19 to determine location of the urethral opening. After determination of gonadal sex, either genital tubercles were harvested for mRNA quantitation, or urethras were injected with a plastic resin for casting. We analyzed quantified mRNA levels between treated and untreated animals for mRNA levels of estrogen receptors α and β, progesterone receptor, and androgen receptor using nonparametric tests or ANOVA. To determine effects on urethral length (males have long urethras compared to females), we measured the lengths of the casts and performed ANOVA analysis on these data. Results Our morphological results indicated that vinclozolin has morphological effects similar to those of MPA, feminizing males (hypospadias) and masculinizing females (longer urethras). Because these results reflected our MPA results, we investigated the effects of in utero vinclozolin exposure on the mRNA expression levels of androgen, estrogen α and β, and progesterone receptors. At the molecular level, vinclozolin down-regulated estrogen receptor α mRNA in females and up-regulated progesterone receptor mRNA. Vinclozolin-exposed males exhibited up-regulated estrogen receptor α and progesterone receptor mRNA, effects we have also seen with exposure to the synthetic estrogen, ethinyl estradiol. Conclusion The results suggest that vinclozolin virilizes females and directly or indirectly affects progesterone receptor expression. It also affects estrogen receptor expression in a sex-based manner. We found no in vivo effect of vinclozolin on androgen receptor expression. We propose that vinclozolin, which has been designated an anti-androgen, may also exert its effects by involving additional steroid-signaling pathways. PMID:16504050

Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice.

PubMed

Buckley, Jill; Willingham, Emily; Agras, Koray; Baskin, Laurence S

2006-02-21

Vinclozolin is a fungicide that has been reported to have anti-androgenic effects in rats. We have found that in utero exposure to natural or synthetic progesterones can induce hypospadias in mice, and that the synthetic progesterone medroxyprogesterone acetate (MPA) feminizes male and virilizes female genital tubercles. In the current work, we selected a relatively low dose of vinclozolin to examine its in utero effects on the development of the genital tubercle, both at the morphological and molecular levels. We gave pregnant dams vinclozolin by oral gavage from gestational days 13 through 17. We assessed the fetal genital tubercles from exposed fetuses at E19 to determine location of the urethral opening. After determination of gonadal sex, either genital tubercles were harvested for mRNA quantitation, or urethras were injected with a plastic resin for casting. We analyzed quantified mRNA levels between treated and untreated animals for mRNA levels of estrogen receptors alpha and beta, progesterone receptor, and androgen receptor using nonparametric tests or ANOVA. To determine effects on urethral length (males have long urethras compared to females), we measured the lengths of the casts and performed ANOVA analysis on these data. Our morphological results indicated that vinclozolin has morphological effects similar to those of MPA, feminizing males (hypospadias) and masculinizing females (longer urethras). Because these results reflected our MPA results, we investigated the effects of in utero vinclozolin exposure on the mRNA expression levels of androgen, estrogen alpha and beta, and progesterone receptors. At the molecular level, vinclozolin down-regulated estrogen receptor alpha mRNA in females and up-regulated progesterone receptor mRNA. Vinclozolin-exposed males exhibited up-regulated estrogen receptor alpha and progesterone receptor mRNA, effects we have also seen with exposure to the synthetic estrogen, ethinyl estradiol. The results suggest that vinclozolin virilizes females and directly or indirectly affects progesterone receptor expression. It also affects estrogen receptor expression in a sex-based manner. We found no in vivo effect of vinclozolin on androgen receptor expression. We propose that vinclozolin, which has been designated an anti-androgen, may also exert its effects by involving additional steroid-signaling pathways.

Paclitaxel, Nab-paclitaxel, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer

ClinicalTrials.gov

2016-11-14

Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; HER2/Neu Positive; Male Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIC Breast Cancer AJCC v6; Stage IV Breast Cancer

A mathematical model of in vivo bovine blastocyst developmental to gestational Day 15.

PubMed

Shorten, P R; Donnison, M; McDonald, R M; Meier, S; Ledgard, A M; Berg, D

2018-06-20

Bovine embryo growth involves a complex interaction between the developing embryo and the growth-promoting potential of the uterine environment. We have previously established links between embryonic factors (embryo stage, embryo gene expression), maternal factors (progesterone, body condition score), and embryonic growth to 8 d after bulk transfer of Day 7 in vitro-produced blastocysts. In this study we recovered blastocysts on Days 7 and 15 after artificial insemination to test the hypothesis that in vivo and in vitro embryos follow a similar growth program. We conducted our study using 4 commercial farms and repeated our study over 2 yr (2014, 2015), with data available from 2 of the 4 farms in the second year. Morphological and gene expression measurements (196 candidate genes) of the Day 7 embryos were measured and the progesterone concentration of the cows were measured throughout the reproductive cycle as a reflection of the state of the uterine environment. These data were also used to assess the interaction between the uterine environment and the developing embryo and to examine how well Day 7 embryo stage can be predicted from the Day 7 gene expression profile. Progesterone was not a strong predictor of in vivo embryo growth to Day 15. This contrasts with a range of Day 7 embryo transfer studies which demonstrated that progesterone is a very good predictor of embryo growth to Day 15. Our analysis demonstrates that in vivo embryos are 3 times less sensitive to progesterone than in vitro-transferred embryos (up to Day 15). This highlights that caution must be applied when extrapolating the results of in vitro embryo transfer studies to the in vivo situation. The similar variance in measured and predicted (based on Day 15 length) Day 7 embryo stage indicate low stochastic perturbations for in vivo embryo growth (large stochastic growth effects would generate a significantly larger standard deviation in measured embryo length on Day 15). We also identified that Day 7 embryo stage could be predicted based on the Day 7 gene expression profile (58% overall success rate for classification of 5 embryo stages). Our analysis also associated genes with each developmental stage and demonstrates the high level of temporal regulation of genes that occurs during early embryonic development. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Disrupted cell cycle control in cultured endometrial cells from patients with endometriosis harboring the progesterone receptor polymorphism PROGINS.

PubMed

D'Amora, Paulo; Maciel, Thiago Trovati; Tambellini, Rodrigo; Mori, Marcelo A; Pesquero, João Bosco; Sato, Helio; Girão, Manoel João Batista Castello; Guerreiro da Silva, Ismael Dale Cotrim; Schor, Eduardo

2009-07-01

Presently, little is understood about how endometriosis is established or maintained, or how genetic factors can predispose women to the disease. Because of the crucial role that the progesterone receptor polymorphism PROGINS plays in predisposing women to the development of endometriosis, we hypothesized that this variant may influence critical steps during endometrial cell metabolism that are involved in the pathogenesis of endometriosis. Eutopic endometria were collected from three sources: women with endometriosis who had a single PROGINS allele (from the progesterone receptor gene); women with endometriosis who had the wild-type progesterone receptor allele; and women without endometriosis who had the wild-type allele. Cells prepared from the eutopic endometria of these women were stimulated with both estradiol and progesterone, and then examined for cell proliferation, viability, and apoptosis. The cells from women with endometriosis that carried the PROGINS allele demonstrated increased proliferation, greater viability, and decreased apoptosis following progesterone treatment. In general, these parameters were very different as compared with those of women with endometriosis but without the PROGINS allele and women in the control group. This result indicates there is a reduced level of progesterone responsiveness in women who carry the PROGINS polymorphism. Because progesterone responsiveness is known to be an important characteristic of women with endometriosis, these data support the contention that the PROGINS polymorphism enhances the endometriosis phenotype.

Disrupted Cell Cycle Control in Cultured Endometrial Cells from Patients with Endometriosis Harboring the Progesterone Receptor Polymorphism PROGINS

PubMed Central

D'Amora, Paulo; Maciel, Thiago Trovati; Tambellini, Rodrigo; Mori, Marcelo A.; Pesquero, João Bosco; Sato, Helio; Girão, Manoel João Batista Castello; Guerreiro da Silva, Ismael Dale Cotrim; Schor, Eduardo

2009-01-01

Presently, little is understood about how endometriosis is established or maintained, or how genetic factors can predispose women to the disease. Because of the crucial role that the progesterone receptor polymorphism PROGINS plays in predisposing women to the development of endometriosis, we hypothesized that this variant may influence critical steps during endometrial cell metabolism that are involved in the pathogenesis of endometriosis. Eutopic endometria were collected from three sources: women with endometriosis who had a single PROGINS allele (from the progesterone receptor gene); women with endometriosis who had the wild-type progesterone receptor allele; and women without endometriosis who had the wild-type allele. Cells prepared from the eutopic endometria of these women were stimulated with both estradiol and progesterone, and then examined for cell proliferation, viability, and apoptosis. The cells from women with endometriosis that carried the PROGINS allele demonstrated increased proliferation, greater viability, and decreased apoptosis following progesterone treatment. In general, these parameters were very different as compared with those of women with endometriosis but without the PROGINS allele and women in the control group. This result indicates there is a reduced level of progesterone responsiveness in women who carry the PROGINS polymorphism. Because progesterone responsiveness is known to be an important characteristic of women with endometriosis, these data support the contention that the PROGINS polymorphism enhances the endometriosis phenotype. PMID:19497994

The effect of luteal-phase support with vaginal progesterone on pregnancy rates in gonadotropin and clomiphene citrate/intra-uterine insemination cycles in unexplained infertility: A prospective randomised study.

PubMed

Karadag, Burak; Dilbaz, Berna; Karcaaltincaba, Deniz; Sahin, Elif Gulsah; Ercan, Fedi; Karasu, Yetkin; Tonyalı, Nazan Vanlı

2016-08-01

The purpose of this study is to analyse the effect of luteal-phase support on pregnancy rates in gonadotropin + intra-uterine insemination (Gn/IUI) and clomiphene citrate (CC) +IUI (CC/IUI) cycles in patients with unexplained infertility. Equal numbers of patients were recruited in two treatment arms (CC/IUI and Gn/IUI) (n = 100, n = 100, respectively). In each group, 50 patients received vaginal progesterone for 14 days (Crinone 8% vaginal gel, 90 mg per day) for luteal-phase support from the day after IUI and continued until menstruation or the 10th week of gestation if pregnant. There were 29 clinical pregnancies among 200 patients. Pregnancy rates were 12% in CC/IUI cycles, 10% in luteal-phase-supported CC/IUI cycles 16% in Gn/IUI cycles and 20% in luteal-phase-supported Gn/IUI cycles. Although pregnancy rates were higher in Gn/IUI cycles compared to CC/IUI cycles, luteal-phase support did not significantly affect the pregnancy rates in both groups. This study implies that luteal-phase support with progesterone has no pronounced beneficial effect on pregnancy rates in either CC/IUI or Gn/IUI cycles in patients with unexplained infertility.

Nuclear binding of progesterone in hen oviduct. Binding to multiple sites in vitro.

PubMed Central

Pikler, G M; Webster, R A; Spelsberg, T C

1976-01-01

Steroid hormones, including progesterone, are known to bind with high affinity (Kd approximately 1x10(-10)M) to receptor proteins once they enter target cells. This complex (the progesterone-receptor) then undergoes a temperature-and/or salt-dependent activation which allows it to migrate to the cell nucleus and to bind to the deoxyribonucleoproteins. The present studies demonstrate that binding the hormone-receptor complex in vitro to isolated nuclei from the oviducts of laying hens required the same conditions as do other studies of bbinding in vitro reported previously, e.g. the hormone must be complexed to intact and activated receptor. The assay of the nuclear binding by using multiple concentrations of progesterone receptor reveals the presence of more than one class of binding site in the oviduct nuclei. The affinity of each of these classes of binding sites range from Kd approximately 1x10(-9)-1x10(-8)M. Assays using free steroid (not complexed with receptor) show no binding to these sites. The binding to each of the classes of sites, displays a differential stability to increasing ionic concentrations, suggesting primarily an ionic-type interaction for all classes. Only the highest-affinity class of binding site is capable of binding progesterone receptor under physioligical-saline conditions. This class represent 6000-10000 sites per cell nucleus and resembles the sites detected in vivo (Spelsberg, 1976, Biochem. J. 156, 391-398) which cause maximal transcriptional response when saturated with the progesterone receptor. The multiple binding sites for the progesterone receptor either are not present or are found in limited numbers in the nuclei of non-target organs. Differences in extent of binding to the nuclear material between a target tissue (oviduct) and other tissues (spleen or erythrocyte) are markedly dependent on the ionic conditions, and are probably due to binding to different classes of sites in the nuclei. PMID:182147

Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

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

Thompson, Scott K.; Washburn, David G.; Frazee, James S.

2010-09-03

Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

Versican Proteolysis by ADAMTS Proteases and Its Influence on Sex Steroid Receptor Expression in Uterine Leiomyoma

PubMed Central

Mead, Timothy J.; Koch, Christopher D.; Biscotti, Charles V.; Falcone, Tommaso; Apte, Suneel S.

2017-01-01

Context: Leiomyomas have abundant extracellular matrix (ECM), with upregulation of versican, a large proteoglycan. Objective: We investigated ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs) protease-mediated versican cleavage in myometrium and leiomyoma and the effect of versican knockdown in leiomyoma cells. Design: We used quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and RNA in situ hybridization for analysis of myometrium, leiomyoma and immortalized myometrium and leiomyoma cells. Short interfering RNA (siRNA) was used to knockdown versican in leiomyoma cells. Setting: This study was performed in an academic laboratory. Patients: Study subjects were women with symptomatic or asymptomatic leiomyoma. Main Outcome Measures: We quantified messenger RNAs (mRNAs) for versican splice variants. We identified ADAMTS-cleaved versican in myometrium and leiomyoma and ADAMTS messenger RNAs and examined the effect of VCAN siRNA on smooth muscle differentiation and expression of estrogen and progesterone receptors. Results: The women in the symptomatic group (n = 7) had larger leiomyoma (P = 0.01), heavy menstrual bleeding (P < 0.01), and lower hemoglobin levels (P = 0.02) compared with the asymptomatic group (n = 7), but were similar in age and menopausal status. Versican V0 and V1 isoforms were upregulated in the leiomyomas of symptomatic versus asymptomatic women (P = 0.03 and P = 0.04, respectively). Abundant cleaved versican was detected in leiomyoma and myometrium, as well as in myometrial and leiomyoma cell lines. ADAMTS4 (P = 0.03) and ADAMTS15 (P = 0.04) were upregulated in symptomatic leiomyomas. VCAN siRNA did not effect cell proliferation, apoptosis, or smooth muscle markers, but reduced ESR1 and PR-A expression (P = 0.001 and P = 0.002, respectively). Conclusions: Versican in myometrium, leiomyomas and in the corresponding immortalized cells is cleaved by ADAMTS proteases. VCAN siRNA suppresses production of estrogen receptor 1 and progesterone receptor-A. These findings have implications for leiomyoma growth. PMID:28323982

Versican Proteolysis by ADAMTS Proteases and Its Influence on Sex Steroid Receptor Expression in Uterine Leiomyoma.

PubMed

Gueye, Ndeye-Aicha; Mead, Timothy J; Koch, Christopher D; Biscotti, Charles V; Falcone, Tommaso; Apte, Suneel S

2017-05-01

Leiomyomas have abundant extracellular matrix (ECM), with upregulation of versican, a large proteoglycan. We investigated ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs) protease-mediated versican cleavage in myometrium and leiomyoma and the effect of versican knockdown in leiomyoma cells. We used quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and RNA in situ hybridization for analysis of myometrium, leiomyoma and immortalized myometrium and leiomyoma cells. Short interfering RNA (siRNA) was used to knockdown versican in leiomyoma cells. This study was performed in an academic laboratory. Study subjects were women with symptomatic or asymptomatic leiomyoma. We quantified messenger RNAs (mRNAs) for versican splice variants. We identified ADAMTS-cleaved versican in myometrium and leiomyoma and ADAMTS messenger RNAs and examined the effect of VCAN siRNA on smooth muscle differentiation and expression of estrogen and progesterone receptors. The women in the symptomatic group (n = 7) had larger leiomyoma (P = 0.01), heavy menstrual bleeding (P < 0.01), and lower hemoglobin levels (P = 0.02) compared with the asymptomatic group (n = 7), but were similar in age and menopausal status. Versican V0 and V1 isoforms were upregulated in the leiomyomas of symptomatic versus asymptomatic women (P = 0.03 and P = 0.04, respectively). Abundant cleaved versican was detected in leiomyoma and myometrium, as well as in myometrial and leiomyoma cell lines. ADAMTS4 (P = 0.03) and ADAMTS15 (P = 0.04) were upregulated in symptomatic leiomyomas. VCAN siRNA did not effect cell proliferation, apoptosis, or smooth muscle markers, but reduced ESR1 and PR-A expression (P = 0.001 and P = 0.002, respectively). Versican in myometrium, leiomyomas and in the corresponding immortalized cells is cleaved by ADAMTS proteases. VCAN siRNA suppresses production of estrogen receptor 1 and progesterone receptor-A. These findings have implications for leiomyoma growth. Copyright © 2017 by the Endocrine Society

Combination Chemotherapy and Filgrastim Before Surgery in Treating Patients With HER2-Positive Breast Cancer That Can Be Removed By Surgery

ClinicalTrials.gov

2018-02-12

Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer

Progesterone treatment shows greater protection in brain vs. retina in a rat model of middle cerebral artery occlusion: Progesterone receptor levels may play an important role

PubMed Central

Allen, Rachael S.; Sayeed, Iqbal; Oumarbaeva, Yuliya; Morrison, Katherine C.; Choi, Paul H.; Pardue, Machelle T.; Stein, Donald G.

2018-01-01

Background/Objective To determine whether inflammation increases in retina as it does in brain following middle cerebral artery occlusion (MCAO), and whether the neurosteroid progesterone, shown to have protective effects in both retina and brain after MCAO, reduces inflammation in retina as well as brain. Methods MCAO rats treated systemically with progesterone or vehicle were compared with shams. Protein levels of cytosolic NF-κB, nuclear NF-κB, phosphorylated NF-κB, IL-6, TNF-α, CD11b, progesterone receptor A and B, and pregnane × receptor were assessed in retinas and brains at 24 and 48 h using western blots. Results Following MCAO, significant increases were observed in the following inflammatory markers: pNF-κB and CD11b at 24 h in both brain and retina, nuclear NF-κB at 24 h in brain and 48 h in retina, and TNF-α at 24 h in brain. Progesterone treatment in MCAO animals significantly attenuated levels of the following markers in brain: pNF-κB, nuclear NF-κB, IL-6, TNF-α, and CD11b, with significantly increased levels of cytosolic NF-κB. Retinas from progesterone-treated animals showed significantly reduced levels of nuclear NF-κB and IL-6 and increased levels of cytosolic NF-κB, with a trend for reduction in other markers. Post-MCAO, progesterone receptors A and B were upregulated in brain and downregulated in retina. Conclusion Inflammatory markers increased in both brain and retina after MCAO, with greater increases observed in brain. Progesterone treatment reduced inflammation, with more dramatic reductions observed in brain than retina. This differential effect may be due to differences in the response of progesterone receptors in brain and retina after injury. PMID:27802245

Progesterone treatment shows greater protection in brain vs. retina in a rat model of middle cerebral artery occlusion: Progesterone receptor levels may play an important role.

PubMed

Allen, Rachael S; Sayeed, Iqbal; Oumarbaeva, Yuliya; Morrison, Katherine C; Choi, Paul H; Pardue, Machelle T; Stein, Donald G

2016-11-22

To determine whether inflammation increases in retina as it does in brain following middle cerebral artery occlusion (MCAO), and whether the neurosteroid progesterone, shown to have protective effects in both retina and brain after MCAO, reduces inflammation in retina as well as brain. MCAO rats treated systemically with progesterone or vehicle were compared with shams. Protein levels of cytosolic NF-κB, nuclear NF-κB, phosphorylated NF-κB, IL-6, TNF-α, CD11b, progesterone receptor A and B, and pregnane X receptor were assessed in retinas and brains at 24 and 48 h using western blots. Following MCAO, significant increases were observed in the following inflammatory markers: pNF-κB and CD11b at 24 h in both brain and retina, nuclear NF-κB at 24 h in brain and 48 h in retina, and TNF-α at 24 h in brain.Progesterone treatment in MCAO animals significantly attenuated levels of the following markers in brain: pNF-κB, nuclear NF-κB, IL-6, TNF-α, and CD11b, with significantly increased levels of cytosolic NF-κB. Retinas from progesterone-treated animals showed significantly reduced levels of nuclear NF-κB and IL-6 and increased levels of cytosolic NF-κB, with a trend for reduction in other markers. Post-MCAO, progesterone receptors A and B were upregulated in brain and downregulated in retina. Inflammatory markers increased in both brain and retina after MCAO, with greater increases observed in brain. Progesterone treatment reduced inflammation, with more dramatic reductions observed in brain than retina. This differential effect may be due to differences in the response of progesterone receptors in brain and retina after injury.

Contractile effect of rifaximin on bovine uterus in the presence of steroid hormone antagonists.

PubMed

Sciorsci, R L; Piccinno, M; Rizzo, A

2018-04-01

This in vitro study investigated the modulatory effect of rifaximin on bovine uterus contractility, in both phases of the oestrous cycle, with and without the steroid hormones that are predominant in the respective phases: oestrogen in the follicular phase and progesterone in the luteal phase. The procedures were conducted in an isolated organ bath by using rifaximin alone (10 -4  M) and in association with the steroid hormone antagonists (10 -5  M) tamoxifen (oestrogen antagonist) in the follicular phase and mifepristone (progesterone antagonist) in the luteal phase. The results indicated that rifaximin can stimulate uterine contractility. Indeed, the administration of rifaximin in the presence of tamoxifen or mifepristone increased the tonic activity of the uterus in both phases of the cycle. This result is clinically significant because rifaximin might also enable, in vivo, a simultaneous increase in uterine cleaning and the antimicrobial action against bacteria during the first 14 days postpartum, during the development of acute metritis. Copyright © 2018 Elsevier Inc. All rights reserved.

Human Uterine Leiomyoma Stem/Progenitor Cells Expressing CD34 and CD49b Initiate Tumors In Vivo

PubMed Central

Ono, Masanori; Moravek, Molly B.; Coon, John S.; Navarro, Antonia; Monsivais, Diana; Dyson, Matthew T.; Druschitz, Stacy A.; Malpani, Saurabh S.; Serna, Vanida A.; Qiang, Wenan; Chakravarti, Debabrata; Kim, J. Julie; Bulun, Serdar E.

2015-01-01

Context: Uterine leiomyoma is the most common benign tumor in reproductive-age women. Using a dye-exclusion technique, we previously identified a side population of leiomyoma cells exhibiting stem cell characteristics. However, unless mixed with mature myometrial cells, these leiomyoma side population cells did not survive or grow well in vitro or in vivo. Objective: The objective of this study was to identify cell surface markers to isolate leiomyoma stem/progenitor cells. Design: Real-time PCR screening was used to identify cell surface markers preferentially expressed in leiomyoma side population cells. In vitro colony-formation assay and in vivo tumor-regeneration assay were used to demonstrate functions of leiomyoma stem/progenitor cells. Results: We found significantly elevated CD49b and CD34 gene expression in side population cells compared with main population cells. Leiomyoma cells were sorted into three populations based on the expression of CD34 and CD49b: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b− cells, with the majority of the side population cells residing in the CD34+/CD49b+ fraction. Of these populations, CD34+/CD49b+ cells expressed the lowest levels of estrogen receptor-α, progesterone receptor, and α-smooth muscle actin, but the highest levels of KLF4, NANOG, SOX2, and OCT4, confirming their more undifferentiated status. The stemness of CD34+/CD49b+ cells was also demonstrated by their strongest in vitro colony-formation capacity and in vivo tumor-regeneration ability. Conclusions: CD34 and CD49b are cell surface markers that can be used to enrich a subpopulation of leiomyoma cells possessing stem/progenitor cell properties; this technique will accelerate efforts to develop new therapies for uterine leiomyoma. PMID:25658015

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.

An antiprogestin, CDB4124, blocks progesterone's attenuation of the negative effects of a mild stress on sexual behavior.

PubMed

Uphouse, Lynda; Hiegel, Cindy

2013-03-01

These experiments were designed to test the hypothesis that a progesterone receptor antagonist would block progesterone's ability to reduce the negative effects of a 5 min restraint on female rat sexual behavior. Ovariectomized Fischer rats were injected with 10 μg estradiol benzoate. Two days later, rats were injected subcutaneously (sc) with the progesterone receptor antagonist, CDB4124 (17α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione) (60 mg/kg), or vehicle (20% DMSO+propylene glycol). One hour later, rats were injected sc with 500 μg progesterone or vehicle (sesame seed oil). Rats were assigned to one of three different treatment conditions: (1) (ECV) estradiol benzoate, CDB4124, sesame seed oil vehicle, (2) (ECP) estradiol benzoate, CDB4124, progesterone, and (3) (EVP) estradiol benzoate, DMSO/propylene glycol vehicle, progesterone. That afternoon sexual behavior was examined before and after a 5 min restraint experience. Before restraint, lordosis behavior was comparable across treatment conditions but only progesterone-treated rats exhibited proceptive behavior. CDB4124 did not block progesterone's induction of proceptivity. However, after restraint, CDB4124 attenuated the positive effects of progesterone on all sexual behaviors examined. The restraint experience inhibited sexual behavior in rats treated with estradiol benzoate and CDB4124 and in rats treated with estradiol benzoate, CDB4124, and progesterone but not in rats given estradiol benzoate and progesterone without CDB4124. These findings are consistent with the hypothesis that progesterone receptors mediate progesterone's ability to reduce the negative sexual behavioral effects of a mild stressor. Copyright © 2012 Elsevier B.V. All rights reserved.

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.

Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas: A Randomized Controlled Trial.

PubMed

Simon, James A; Catherino, William; Segars, James H; Blakesley, Rick E; Chan, Anna; Sniukiene, Vilma; Al-Hendy, Ayman

2018-03-01

To assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. This phase 3, double-blind, placebo-controlled study enrolled premenopausal women (aged 18-50 years) with abnormal uterine bleeding, one or more discrete leiomyomas, and uterine size 20 weeks of gestation or less. Patients were randomized 1:1:1 to 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks followed by 12-week drug-free follow-up. Coprimary endpoints were rate of and time to amenorrhea, defined as no bleeding for the last 35 consecutive days of treatment. Secondary endpoints included rates of amenorrhea from day 11 and change from baseline to endpoint in the Revised Activities subscale of the Uterine Fibroid Symptom and Quality of Life questionnaire, which includes questions pertaining to physical and social activities. Safety assessments included adverse event monitoring and endometrial biopsies. A sample size of 150 was planned to compare separately each dose of ulipristal with placebo. From March 2014 to March 2016, 157 patients were randomized. Demographics were similar across treatment groups. Amenorrhea was achieved by 25 of 53 (47.2% [97.5% CI 31.6-63.2]) and 28 of 48 (58.3% [97.5% CI 41.2-74.1]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 1 of 56 (1.8% [97.5% CI 0.0-10.9]) placebo-treated patients (both P<.001). Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001). Common adverse events (5% or greater in either ulipristal group during treatment) were hypertension, elevated blood creatinine phosphokinase, and hot flushes. Serious adverse events occurred in four patients, but none was considered related to treatment. Endometrial biopsies were benign. Ulipristal at 5 mg and 10 mg were well tolerated and superior to placebo in rate of and time to amenorrhea in women with symptomatic uterine leiomyomas. Clinicaltrials.gov number, NCT02147197.

MK2206 in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer

ClinicalTrials.gov

2017-08-01

Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; HER2/Neu Positive; Progesterone Receptor Negative; Progesterone Receptor Positive; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma

Viral Therapy In Treating Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Cancer or Metastatic Breast Cancer

ClinicalTrials.gov

2018-02-16

Estrogen Receptor Negative; Estrogen Receptor Positive; Head and Neck Squamous Cell Carcinoma; HER2/Neu Negative; HER2/Neu Positive; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Head and Neck Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca

ClinicalTrials.gov

2018-04-17

Breast Adenocarcinoma; Estrogen Receptor- Negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive Tumor; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Triple-negative Breast Carcinoma

Relationship between ploidy and steroid hormone receptors in primary invasive breast cancer.

PubMed Central

Horsfall, D. J.; Tilley, W. D.; Orell, S. R.; Marshall, V. R.; Cant, E. L.

1986-01-01

The relationship between ploidy, as measured by flow cytometry, and the presence of oestrogen and progesterone receptors was investigated in 145 primary invasive breast cancers. The tumours were considered as an integral group, and as subgroups of lobular and ductal carcinomas. An association was found between the presence of aneuploid stemlines and an absence of oestrogen receptors (ER), for the total tumour population (P less than 0.02), and for the ductal carcinoma group (P less than 0.05). An association between aneuploidy and an absence of progesterone receptors (PR) was observed for the total tumour group (P less than 0.05). Evaluation of a combined oestrogen and progesterone receptor status indicated that the association between aneuploidy and an absence of both receptors was highly significant. The probability of such an association was P less than 0.001 for the total tumour population, and P less than 0.01 for the ductal tumour group. Assessment of progesterone receptor expression by breast cancers containing oestrogen receptors indicated that aneuploid tumours were as likely to express PR as were diploid tumours. Hence, the biological activity of oestrogen receptors appears unmodified by the presence of aneuploid nuclei. PMID:3004547

Melatonin regulates delayed embryonic development in the short-nosed fruit bat, Cynopterus sphinx.

PubMed

Banerjee, Arnab; Meenakumari, K J; Udin, S; Krishna, A

2009-12-01

The aim of the present study was to evaluate the seasonal variation in serum melatonin levels and their relationship to the changes in the serum progesterone level, ovarian steroidogenesis, and embryonic development during two successive pregnancies of Cynopterus sphinx. Circulating melatonin concentrations showed two peaks; one coincided with the period of low progesterone synthesis and delayed embryonic development, whereas the second peak coincided with regressing corpus luteum. This finding suggests that increased serum melatonin level during November-December may be responsible for delayed embryonic development by suppressing progesterone synthesis. The study showed increased melatonin receptors (MTNR1A and MTNR1B) in the corpus luteum and in the utero-embryonic unit during the period of delayed embryonic development. The in vitro study showed that a high dose of melatonin suppressed progesterone synthesis, whereas a lower dose of melatonin increased progesterone synthesis by the ovary. The effects of melatonin on ovarian steroidogenesis are mediated through changes in the expression of peripheral-type benzodiazepine receptor, P450 side chain cleavage enzyme, and LH receptor proteins. This study further showed a suppressive impact of melatonin on the progesterone receptor (PGR) in the utero-embryonic unit; this effect might contribute to delayed embryonic development in C. sphinx. The results of the present study thus suggest that a high circulating melatonin level has a dual contribution in retarding embryonic development in C. sphinx by impairing progesterone synthesis as well as by inhibiting progesterone action by reducing expression of PGR in the utero-embryonic unit.

Uterine diseases in cattle after parturition

PubMed Central

Sheldon, I. Martin; Williams, Erin J.; Miller, Aleisha N.A.; Nash, Deborah M.; Herath, Shan

2008-01-01

Bacterial contamination of the uterine lumen is common in cattle after parturition, often leading to infection and uterine disease. Clinical disease can be diagnosed and scored by examination of the vaginal mucus, which reflects the presence of pathogenic bacteria such as Escherichia coli and Arcanobacterium pyogenes. Viruses may also cause uterine disease and bovine herpesvirus 4 (BoHV-4) is tropic for endometrial cells, causing a rapid cytopathic effect. The elimination of pathogens by the innate immune system is dependent on pattern recognition receptors binding pathogen-associated molecules. Uterine epithelial and stromal cells express receptors such as Toll-like Receptor 4 that binds E. coli lipopolysaccharide. The infertility associated with uterine disease is caused by damage to the endometrium and disruption of ovarian cyclic activity. Bacteria modulate endometrial prostaglandin secretion, and perturb ovarian follicle growth and function. Understanding the molecular basis of uterine disease will lead to novel approaches to treating infertility. PMID:18329302

Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry.

PubMed

Benagiano, Giuseppe; Bastianelli, Carlo; Farris, Manuela

2008-10-01

A number of synthetic steroids are capable of modulating progesterone receptors with a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. The best known of these are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex() (CDB 4124), ORG 33628 and ORG 31710. Outside reproduction selective modulators of progesterone receptors have been under investigation for a large variety of indications, for example in oncology as adjuvants in breast, cervical, endometrial, ovarian and prostate cancer, as well as inoperable meningioma and leiomyosarcoma. In addition, they have been used as antiglucocorticoids. It is therefore useful to review the results obtained in these conditions. 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 modulators of progesterone receptors for which data are available. In preliminary studies selective modulators of progesterone receptors had some activity on a number of neoplasias. Their antiglucocorticoid activity has been tested with some success in Cushing's syndrome, several psychiatric conditions (e.g., mood disorders and Alzheimer's disease) and acute renal failure. Finally they are being used in a gene regulator system.

A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization

PubMed Central

Mestre-Citrinovitz, Ana C.; Kleff, Veronika; Vallejo, Griselda

2015-01-01

Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone) and estrogen receptor (ICI182780) antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets. PMID:25897495

Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer

ClinicalTrials.gov

2018-04-20

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma

Estrogen Receptor-α Correlates with Higher Fungal Cell Number in Oral Paracoccidioidomycosis in Women.

PubMed

Caixeta, Clenivaldo Alves; de Carli, Marina Lara; Ribeiro Júnior, Noé Vital; Sperandio, Felipe Fornias; Nonogaki, Suely; Nogueira, Denismar Alves; Pereira, Alessandro Antônio Costa; Hanemann, João Adolfo Costa

2018-05-23

Paracoccidioidomycosis is a neglected tropical fungal infection with great predilection for adult men, indicating the participation of female hormone estrogen in preventing paracoccidioidomycosis development in women. Estrogen has an immunologic effect leading to polarization toward the Th2 immune response, which favors the disease evolution. To evaluate estrogen and progesterone receptors in oral paracoccidioidomycosis lesions and to verify any association with tissue fungi counting in women and men. Thirty-two cases of chronic oral paracoccidioidomycosis were included. Immunohistochemical analyses for anti-estrogen receptor-α, anti-progesterone receptor and anti-Paracoccidioides brasiliensis antibodies were performed. The differences between women and men and the relations among the immunomarkers for each gender were also evaluated. A significant positive correlation was observed between estrogen receptor-α and the amount of fungi in women. In addition, estrogen receptor-α was mildly expressed in the inflammatory cells of female patients, while progesterone receptor was expressed in both genders, with similar expression between women and men. Moreover, fungi counting revealed no differences between genders. Estrogen receptor-α was expressed only in women and showed a positive correlation with the amount of fungi in oral paracoccidioidomycosis, while progesterone receptor was observed in both genders and exhibited no correlation with estrogen receptor-α or fungi counting.

The concentration-dependent effect of progesterone on follicle growth in the mouse ovary.

PubMed

Komatsu, Kouji; Masubuchi, Satoru

2017-06-21

Follicle growth in the mammalian ovary is coordinately controlled by multiple factors to sustain periodic ovulation. In this study, we investigated the role of progesterone on follicle growth in the mouse ovary. As the concentration of progesterone changes during the estrus cycle, we cultured the sliced mouse ovary in a medium containing 10 ng/ml, 100 ng/ml, and 1 μg/ml progesterone. Progesterone promoted the growth of primordial to primary follicles at 100 ng/ml, while it suppressed the growth of secondary follicles at 1 μg/ml. Follicles at other developmental stages in the cultured ovary were unaffected with different concentrations of progesterone. The number of ovulated oocytes increased in the medium containing 100 ng/ml progesterone but decreased in the presence of 1 μg/ml progesterone. Follicles expressed two types of progesterone receptors, progesterone receptor (PGR) and PGR membrane component 1 (PGRMC1). While PGR shows transient expression on granulosa cells of Graafian follicles, PGRMC1 expresses in granulosa cells of developing follicles. These results suggest that progesterone controls the growth of developing follicles through PGRMC1. Our study shows that the effect of progesterone on ovulation and follicle growth in mouse ovary is dependent on the concentration of progesterone and the follicle stage.

Progesterone as a bone-trophic hormone.

PubMed

Prior, J C

1990-05-01

Experimental, epidemiological, and clinical data indicate that progesterone is active in bone metabolism. Progesterone appears to act directly on bone by engaging an osteoblast receptor or indirectly through competition for a glucocorticoid osteoblast receptor. Progesterone seems to promote bone formation and/or increase bone turnover. It is possible, through estrogen-stimulated increased progesterone binding to the osteoblast receptor, that progesterone plays a role in the coupling of bone resorption with bone formation. A model of the interdependent actions of progesterone and estrogen on appropriately-"ready" cells in each bone multicellular unit can be tied into the integrated secretions of these hormones within the ovulatory cycle. Figure 5 is an illustration of this concept. It shows the phases of the bone remodeling cycle in parallel with temporal changes in gonadal steroids across a stylized ovulatory cycle. Increasing estrogen production before ovulation may reverse the resorption occurring in a "sensitive" bone multicellular unit while gonadal steroid levels are low at the time of menstrual flow. The bone remodeling unit would then be ready to begin a phase of formation as progesterone levels peaked in the midluteal phase. From this perspective, the normal ovulatory cycle looks like a natural bone-activating, coherence cycle. Critical analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This review provides the preliminary basis for further molecular, genetic, experimental, and clinical investigation of the role(s) of progesterone in bone remodeling. Much further data are needed about the interrelationships between gonadal steroids and the "life cycle" of bone. Feldman et al., however, may have been prophetic when he commented; "If this anti-glucocorticoid effect of progesterone also holds true in bone, then postmenopausal osteoporosis may be, in part, a progesterone deficiency disease."

A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors.

PubMed

Zhu, Xiaoyan; Fréchou, Magalie; Liere, Philippe; Zhang, Shaodong; Pianos, Antoine; Fernandez, Neïké; Denier, Christian; Mattern, Claudia; Schumacher, Michael; Guennoun, Rachida

2017-11-08

Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes. SIGNIFICANCE STATEMENT The brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5α-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the female brain. An important role of endogenous progesterone in cerebroprotection was demonstrated by the conditional inactivation of its receptor in neural cells. These results show the importance of endogenous progesterone, its metabolites, and neural progesterone receptors in acute cerebroprotection after stroke. This new concept could be exploited therapeutically by taking into account the progesterone status of patients and by supplementing and reinforcing endogenous progesterone signaling for attaining its full cerebroprotective potential. Copyright © 2017 the authors 0270-6474/17/3710998-23$15.00/0.

Expression of matrix metalloproteinase enzymes in endometrium of women with abnormal uterine bleeding.

PubMed

Grzechocinska, Barbara; Dabrowski, Filip A; Chlebus, Marcin; Gondek, Agata; Czarzasta, Katarzyna; Michalowski, Lukasz; Cudnoch-Jedrzejewska, Agnieszka; Wielgos, Miroslaw

2018-02-01

Abnormal uterine bleeding (AUB) is caused by derangement of physiological processes of tissue growth, shedding and regeneration. It is known that interplay between metalloproteinases (MMP's) and tissue inhibitors of metalloproteinases (TIMP's) may play a crucial role in its occurrence. To define if expression of proMMP-2, MMP-2 and TIMP-1 in endometrium of women with AUB is dependent on steroid sex hormone concentration and histopathological picture. Endometrial scraps were taken from 21 women with AUB and 19 controls. Samples were evaluated in light microscopy by a certified pathologist. Activity of proMMP-2 and MMP-2 proteins levels were evaluated by gelatin zymography and TIMP-1 by reversed zymography. The results has been correlated with serum estradiol and progesterone concentrations in linear regression model. Expression: of proMMP-2 in endometrium of women with AUB is correlated with estradiol concentration and inversely correlated with progesterone levels. It was significantly higher in women with dysfunctional endometrium (p<0.001). Expression of MMP-2 was highest in women with endometrial polyps and longer bleeding (p<0.01), while expression of TIMP-1 was independent from hormone concentration. Lack of correlation between proMMP-2 and MMP-2 levels suggest different pathway of their activation in AUB. ProMMP-2 is up regulated by estradiol and down regulated by progesterone while MMP-2 levels increase with the length of bleeding.

The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep.

PubMed

Cheng, Guanliang; Coolen, Lique M; Padmanabhan, Vasantha; Goodman, Robert L; Lehman, Michael N

2010-01-01

Recent work in sheep has identified a neuronal subpopulation in the arcuate nucleus that coexpresses kisspeptin, neurokinin B, and dynorphin (referred to here as KNDy cells) and that mediate the negative feedback influence of progesterone on GnRH secretion. We hypothesized that sex differences in progesterone negative feedback are due to sexual dimorphism of KNDy cells and compared neuropeptide and progesterone receptor immunoreactivity in this subpopulation between male and female sheep. In addition, because sex differences in progesterone negative feedback and neurokinin B are due to the influence of testosterone (T) during fetal life, we determined whether prenatal T exposure would mimic sex differences in KNDy cells. Adult rams had nearly half the number of kisspeptin, neurokinin B, dynorphin, and progesterone receptor-positive cells in the arcuate nucleus as did females, but the percentage of KNDy cells colocalizing progesterone receptors remained high in both sexes. Prenatal T treatment also reduced the number of dynorphin, neurokinin B, and progesterone receptor-positive cells in the female arcuate nucleus; however, the number of kisspeptin cells remained high and at levels comparable to control females. Thus, sex differences in kisspeptin in the arcuate nucleus, unlike that of dynorphin and neurokinin B, are not due solely to exposure to prenatal T, suggesting the existence of different critical periods for multiple peptides coexpressed within the same neuron. In addition, the imbalance between inhibitory (dynorphin) and stimulatory (kisspeptin) neuropeptides in this subpopulation provides a potential explanation for the decreased ability of progesterone to inhibit GnRH neurons in prenatal T-treated ewes.

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

PubMed

Chen, RuiQi; Yu, Yue; Dong, Xuesen

2017-02-01

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Response of potassium channels to estrogen and progesterone in the uterine smooth muscle cells of adenomyosis in vitro].

PubMed

Shi, Jinghua; Jin, Li; Leng, Jinhua; Lang, Jinghe

2015-11-01

To investigate the expression of potassium channels and the influence of estrogen and progesterone on the cultured uterine smooth muscle cells (USMC) of adenomyosis in vitro. There were 22 cases of adenomyosis hysterectomy in the adenomyosis group and 12 patients with cervical intraepithelial neoplasia III removal of the uterus in the control group. USMC were separated and cultured in vitro, incubated with different concentrations of estrogen and progesterone. We used reverse transcription-PCR to dectect the expression of large-conductance calcium- and voltage-sensitive potassium channel α subunit (BKCa α) and voltage-gated potassium channel 4.3 (Kv4.3). The mRNA expression of BKCa α and Kv4.3 in the adenomyosis group (4.43±2.05 and 4.52±1.97) were significantly higher than those in the control group (0.83±0.25 and 0.86±0.19, P<0.05). In the control group, Kv4.3 mRNA decreased after treated with 0.1 nmol/L (0.17±0.10) and 1.0 nmol/L (0.13±0.08) estrogen than before (0.55±0.29, P<0.05). In the adenomyosis group, BKCa α mRNA decreased significantly after treated with 10.0 nmol/L estrogen (0.56±0.27 versus 1.01±0.35, P<0.05). 0.1 µmol/L progesterone elevated both BKCa α mRNA (0.44±0.24 versus 0.16±0.09) and Kv4.3 mRNA (1.29±0.51 versus 0.55±0.29) in the control group (all P<0.05); however, there were no significant difference in adenomyosis group of different concentration of progestrone (P>0.05). There is an abnormal expression of potassium channels in the adenomyosis USMC, which is regulated by high concentration of estrogen and might be resistant to progesterone.

Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization

PubMed Central

Mao, Lan; Pierce, Stephanie L.; Swamy, Geeta K.; Heine, R. Phillips; Murtha, Amy P.

2016-01-01

Oxytocin is a potent uterotonic agent and is used clinically for induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein-coupled receptor family, which is prone to molecular desensitization. After oxytocin binding, the OXTR is phosphorylated by a member of the G protein-coupled receptor kinase (GRK) family, which allows for recruitment of β-arrestin, receptor internalization, and desensitization. According to previous in vitro analyses, desensitization of calcium signaling by the OXTR is mediated by GRK6. The objective of this study was to determine the role of GRK6 in mediating uterine contractility. Here, we demonstrate that uterine GRK6 levels increase in pregnancy and using a telemetry device to measure changes in uterine contractility in live mice during labor, show that mice lacking GRK6 produce a phenotype of enhanced uterine contractility during both spontaneous and oxytocin-induced labor compared with wild-type or GRK5 knockout mice. In addition, the observed enhanced contractility was associated with high rates of term stillbirth. Lastly, using a heterologous in vitro model, we show that β-arrestin recruitment to the OXTR, which is necessary for homologous OXTR desensitization, is dependent on GRK6. Our findings suggest that GRK6-mediated OXTR desensitization in labor is necessary for normal uterine contractile patterns and optimal fetal outcome. PMID:26886170

Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Older Patients With Locally Advanced or Metastatic Breast Cancer

ClinicalTrials.gov

2018-03-05

Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

The effects of the early uterine environment on the subsequent development of embryo and fetus.

PubMed

Barnes, F L

2000-01-15

Synchrony between the embryo and the uterine endometrium is essential for the establishment of pregnancy and birth in people and livestock. When asynchronous conditions occur a variety of complication result that include failure of the embryo to implant, early embryonic mortality, retarded development and growth, and accelerated development and growth. These complications all appear to be induced within the first week of embryo development and not withstanding the immediate endpoint of large or small size at birth, may alter the course of development throughout the life of the animal. Progesterone appears to play a causative role in establishing the abnormal growth of the fetus by decelerating or accelerating embryonic development. This may act through increasing the transport of blood born growth factors into the uterine lumen or by stimulating the release of growth factors from the endometrium directly. It can not be ruled out that progesterone mediated abundance of, or absence of, appropriate nutrition may bring about the same lifelong outcome. In vitro culture situations that include serum and/or co-culture can also bring about these abnormalities of growth. It is hypothesized that exposure to growth factors "out of phase" may result in an irreversible induction of abnormal development. The described abnormalities that occur in sheep and cattle have not yet been described for children resulting from IVF.

Serial hCG and progesterone levels to predict early pregnancy outcomes in pregnancies of uncertain viability: A prospective study.

PubMed

Puget, Claire; Joueidi, Yolaine; Bauville, Estelle; Laviolle, Bruno; Bendavid, Claude; Lavoué, Vincent; Le Lous, Maela

2018-01-01

To assess the value of serial hCG and progesterone serum level in the diagnosis of early pregnancy viability. It was a prospective cohort study. Women with a pregnancy of uncertain viability (PUV), defined as the presence of an intra-uterine embryo with a crown-rump length <7mm with no cardiac activity or an intra-uterine gestational sac size <25mm with no visible embryonic structure in a transvaginal ultrasound scan (TVS) were eligible. The diagnosis value of serial plasmatic hCG levels on the first day and 48h after as well as the initial progesterone level were evaluated to diagnose pregnancy viability. Pregnancy viability was assessed by TVS 7 to 14days after inclusion. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of an hCG H48/H0 ratio increase <11% to diagnose an early pregnancy loss were 70.6%, 100%, 100% and 85.3%, respectively. The sensitivity, specificity, PPV and NPV of a 6.2ng/ml progesterone level to diagnose an early pregnancy loss were 20%, 100%, 100% and 65.2%, respectively. The sensitivity, specificity, PPV and NPV of an hCG H48/H0 ratio increase >75% to diagnose a viable pregnancy were 100%, 31%, 45.9% and 100%, respectively. hCG H48/H0 ratio increase <11% was associated with early pregnancy loss in 100% of the cases. hCG H48/H0 ratio increase >75% was associated with 100% of viable pregnancies in 100% of the cases. Serial hCG levels alone permitted an early viability diagnosis within 48h for 41.1% of patients with PUV instead of 7 to 14days with TVS. Copyright © 2017 Elsevier B.V. All rights reserved.

Kruppel-like Factor 9 is a Negative Regulator of Ligand-dependent Estrogen Receptor Alpha Signaling in Ishikawa Endometrial Adenocarcinoma Cells

USDA-ARS?s Scientific Manuscript database

Estrogen (E) and progesterone (P), acting through their respective receptors and other nuclear proteins, exhibit opposing activities in target cells. We previously reported that Krüppel-like factor 9 (KLF9) cooperates with progesterone receptor (PR) to facilitate P-dependent gene transcription in ut...

Physiology, production and action of progesterone.

PubMed

Taraborrelli, Stefania

2015-11-01

The aim of this article is to review the physiology of progesterone and focus on its physiological actions on tissues such as endometrium, uterus, mammary gland, cardiovascular system, central nervous system and bones. In the last decades, the interest of researchers has focused on the role of progesterone in genomic and non-genomic receptor mechanisms. We searched PubMed up to December 2014 for publications on progesterone/steroidogenesis. A better understanding of the biological genomic and non-genomic receptor mechanisms could enable us in the near future to obtain a more comprehensive knowledge of the safety and efficacy of this agent during hormone replacement therapy (natural progesterone), in vitro fertilization (water-soluble subcutaneous progesterone), in traumatic brain injury, Alzheimer's disease and diabetic neuropathy, even though further clinical studies are needed to prove its usefulness. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

Medical Treatment of Uterine Leiomyoma

PubMed Central

Sabry, Mohamed; Al-Hendy, Ayman

2012-01-01

Uterine leiomyomas (also called myomata or fibroids) are the most common gynecologic tumors in the United States. The prevalence of leiomyomas is at least 3 to 4 times higher among African American women than in white women. Pathologically, uterine leiomyomas are benign tumors that arise in any part of the uterus under the influence of local growth factors and sex hormones, such as estrogen and progesterone. These common tumors cause significant morbidity for women and they are considered to be the most common indication for hysterectomy in the world; they are also associated with a substantial economic impact on health care systems that amounts to approximately $2.2 billion/year in the United States alone. Uterine myomas cause several reproductive problems such as heavy or abnormal uterine bleeding, pelvic pressure, infertility, and several obstetrical complications including miscarriage and preterm labor. Surgery has traditionally been the gold standard for the treatment of uterine leiomyomas and has typically consisted of either hysterectomy or myomectomy. In recent years, a few clinical trials have evaluated the efficacy of orally administered medications for the management of leiomyoma-related symptoms. In the present review, we will discuss these promising medical treatments in further detail. PMID:22378865

Progesterone Receptors: Form and Function in Brain

PubMed Central

Brinton, Roberta Diaz; Thompson, Richard F.; Foy, Michael R.; Baudry, Michel; Wang, JunMing; Finch, Caleb E; Morgan, Todd E.; Stanczyk, Frank Z.; Pike, Christian J.; Nilsen, Jon

2008-01-01

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRβ and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and / or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging. PMID:18374402

Regulation of Facilitative Glucose Transporters and AKT/MAPK/PRKAA Signaling via Estradiol and Progesterone in the Mouse Uterine Epithelium1

PubMed Central

Kim, Sung Tae; Moley, Kelle H.

2009-01-01

Adequate uterine glucose metabolism is an essential part of embryo implantation and the development of an adequate utero-fetal environment. However, expression of facilitative glucose transporters (GLUTs [solute transporter family SLC2A]) and AKT/MAPK/PRKAA (PRKAA) signaling has not been described in the mouse uterine cells, to our knowledge. The objective of this study was to determine the hormonal regulation of SLC2A protein expression and AKT/MAPK/PRKAA signaling in the mouse uterine epithelial cells during estrous cycles and peri-implantation periods. SLC2As 1, 4, 8, and 9B were highly expressed in the luminal and glandular epithelia of estrous stage. In metestrous and diestrous stages, expression of SLC2As 1, 4, 8, and 9B was lower than that in proestrous stage. Levels of activated phospho-AKT (p-AKT), p-MAPK3, and p-MAPK1 also varied during the estrous cycle. Estrogen and progesterone injection in an ovariectomized mouse (delayed implantation model) resulted in a decrease and an increase, respectively, in expression of GLUTs in the luminal epithelial cells of the uterus. The expression of SLC2A1, SLC2A8, SLC2A9B, p-AKT, p-MAPK3/1, and p-PRKAA was increased in the decidual region of the implantation sites and was significantly increased in the uterus of activated implantation. Using an artificial decidualization mouse model, it was also demonstrated that expression of the same GLUTs, p-MAPK3/1, and p-PRKAA was dramatically higher in the decidualized uteri than that in the control uteri. These results suggest that steroid hormones regulate expression of uterine epithelial GLUTs possibly through AKT/MAPK/PRKAA signaling pathways and that glucose utilization may have an important role in decidualization and possibly in the maintenance of pregnancy. PMID:19208550

Estradiol stimulates glycogen synthesis whereas progesterone promotes glycogen catabolism in the uterus of the American mink (Neovison vison).

PubMed

Bowman, Kole; Rose, Jack

2017-01-01

Glycogen synthesis by mink uterine glandular and luminal epithelia (GE and LE) is stimulated by estradiol (E 2 ) during estrus. Subsequently, the glycogen deposits are mobilized to near completion to meet the energy requirements of pre-embryonic development and implantation by as yet undetermined mechanisms. We hypothesized that progesterone (P 4 ) was responsible for catabolism of uterine glycogen reserves as one of its actions to ensure reproductive success. Mink were treated with E 2 , P 4 or vehicle (controls) for 3 days and uteri collected 24 h (E 2 , P 4 and vehicle) and 96 h (E 2 ) later. To evaluate E 2 priming, mink were treated with E 2 for 3 days, then P 4 for an additional 3 days (E 2 →P 4 ) and uteri collected 24 h later. Percent glycogen content of uterine epithelia was greater at E 2 + 96 h (GE = 5.71 ± 0.55; LE = 11.54 ± 2.32) than E 2 +24 h (GE = 3.63 ± 0.71; LE = 2.82 ± 1.03), and both were higher than controls (GE = 0.27 ± 0.15; LE = 0.54 ± 0.30; P < 0.05). Treatment as E 2 →P 4 reduced glycogen content (GE = 0.61 ± 0.16; LE = 0.51 ± 0.13), to levels not different from controls, while concomitantly increasing catabolic enzyme (glycogen phosphorylase m and glucose-6-phosphatase) gene expression and amount of phospho-glycogen synthase protein (inactive) in uterine homogenates. Interestingly, E 2 →P 4 increased glycogen synthase 1 messenger RNA (mRNA) and hexokinase 1mRNA and protein. Our findings suggest to us that while E 2 promotes glycogen accumulation by the mink uterus during estrus and pregnancy, it is P 4 that induces uterine glycogen catabolism, releasing the glucose that is essential to support pre-embryonic survival and implantation. © 2016 Japanese Society of Animal Science.

Progesterone receptor knockout mice have an improved glucose homeostasis secondary to -cell proliferation

NASA Astrophysics Data System (ADS)

Picard, Frédéric; Wanatabe, Mitsuhiro; Schoonjans, Kristina; Lydon, John; O'Malley, Bert W.; Auwerx, Johan

2002-11-01

Gestational diabetes coincides with elevated circulating progesterone levels. We show that progesterone accelerates the progression of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor (PR), reduces blood glucose levels in both female WT and db/db mice. Furthermore, female, but not male, PR-/- mice had lower fasting glycemia than PR+/+ mice and showed higher insulin levels on glucose injection. Pancreatic islets from female PR-/- mice were larger and secreted more insulin consequent to an increase in -cell mass due to an increase in -cell proliferation. These findings demonstrate an important role of progesterone signaling in insulin release and pancreatic function and suggest that it affects the susceptibility to diabetes.

Progesterone and estradiol synergistically promote the lung metastasis of tuberin-deficient cells in a preclinical model of lymphangioleiomyomatosis

PubMed Central

Sun, Yang; Zhang, Erik; Lao, Taotao; Pereira, Ana M.; Li, Chenggang; Xiong, Li; Morrison, Tasha; Haley, Kathleen J.; Zhou, Xiaobo; Yu, Jane J.

2014-01-01

Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 hyperactivation. The gender specificity of LAM suggests that female hormones contribute to disease progression. Clinical findings indicate that estradiol exacerbates LAM behaviors and symptoms. Although hormonal therapy with progesterone has been employed, the benefit in LAM improvement has not been achieved. We have previously found that estradiol promotes the survival and lung metastasis of cells lacking tuberin in a preclinical model of LAM. In this study, we hypothesize that progesterone alone or in combination with estradiol promote metastatic behaviors of TSC2-deficient cells. In cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we found that progesterone treatment or progesterone plus estradiol resulted in increased phosphorylation of Akt and ERK1/2, induced the proliferation, and enhanced the migration and invasiveness. In addition, treatment of progesterone plus estradiol synergistically decreased the levels of reactive oxygen species, and enhanced cell survival under oxidative stress. In a murine model of LAM, treatment of progesterone plus estradiol promoted the growth of xenograft tumors; however, progesterone treatment did not affect the development of xenograft tumors of Tsc2-deficient cells. Importantly, treatment of progesterone plus estradiol resulted in alteration of lung morphology, and significantly increased the number of lung micrometastases of Tsc2-deficient cells compared with estradiol treatment alone. Collectively, these data indicate that progesterone increases the metastatic potential of TSC2-deficient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting progesterone-mediated signaling events may have therapeutic benefit for LAM and possibly other hormonally dependent cancers. PMID:25069840

Endometrial estrogen and progesterone receptors within 2-14 days of missed menses in the human.

PubMed

Garg, K; Sujata, P; Kumari, G L; Pandey, P K; Padubidri, V; Anand, C

1993-04-01

Serial changes in the endometrial levels of estrogen and progesterone receptors (ER and PR) were measured in 50 women from days 2 to 14 of missed menses and correlated with the plasma concentrations of hCG, progesterone and 17 beta-estradiol. Both ER and PR of nuclei were higher than cytosolic proteins, with a shift in the ratio of nER/nPR to nPR from 4th day after missed menses. On Scatchard analysis of the cytosolic and nuclear binding proteins, two classes of proteins, corresponding to Type I and II, were found. While the increasing levels of hCG maintained luteal secretion of progesterone and 17 beta-estradiol at normal mid-luteal phase levels, a gradual increase in 17 beta estradiol from 9th day of missed menses was noted. This delicate balance between circulating levels of progesterone and 17 beta-estradiol and their nuclear receptors at early stages of pregnancy may be of significance.

The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial

PubMed Central

2012-01-01

Background To assess the impact of luteal phase support on the expression of estrogen receptor (ER) alpha and progesterone receptors B (PR-B) on the endometrium of oocyte donors undergoing controlled ovarian hyperstimulation (COH). Methods A prospective, randomized study was conducted in women undergoing controlled ovarian hyperstimulation for oocyte donation. Participants were randomized to receive no luteal support, vaginal progesterone alone, or vaginal progesterone plus orally administered 17 Beta estradiol. Endometrial biopsies were obtained at 4 time points in the luteal phase and evaluated by tissue microarray for expression of ER alpha and PR-B. Results One-hundred and eight endometrial tissue samples were obtained from 12 patients. No differences were found in expression of ER alpha and PR-B among all the specimens with the exception of one sample value. Conclusions The administration of progesterone during the luteal phase of COH for oocyte donor cycles, either with or without estrogen, does not significantly affect the endometrial expression of ER alpha and PR. PMID:22360924

Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17beta-treated, intact follicular and pregnant sheep.

PubMed

Magness, Ronald R; Phernetton, Terrance M; Gibson, Tiffini C; Chen, Dong-Bao

2005-05-15

Oestrogen dramatically increases uterine blood flow (UBF) in ovariectomized (Ovx) ewes. Both the follicular phase and pregnancy are normal physiological states with elevated levels of circulating oestrogen. ICI 182 780 is a pure steroidal oestrogen receptor (ER) antagonist that blocks oestrogenic actions in oestrogen-responsive tissue. We hypothesized that an ER-mediated mechanism is responsible for in vivo rises in UBF in physiological states of high oestrogen. The purpose of the study was to examine the effect of an ER antagonist on exogenous and endogenous oestradiol-17beta (E2beta)-mediated elevations in UBF. Sheep were surgically instrumented with bilateral uterine artery blood flow transducers, and uterine and femoral artery catheters. Ovx animals (n = 8) were infused with vehicle (35% ethanol) or ICI 182 780 (0.1-3.0 microg min(-1)) into one uterine artery for 10 min before and 50 min after E2beta was given (1 microg kg(-1) I.V. bolus) and UBF was recorded for an additional hour. Intact, cycling sheep were synchronized to the follicular phase using progesterone, prostaglandin F2alpha(PGF2alpha) and pregnant mare serum gonadotrophin (PMSG). When peri-ovulatory rises in UBF reached near peak levels, ICI 182 780 (1 or 2 microg (ml uterine blood flow)-1) was infused unilaterally (n = 4 sheep). Ewes in the last stages of pregnancy (late pregnant ewes) were also given ICI 182 780 (0.23-2.0 microg (ml uterine blood flow)-1; 60 min infusion) into one uterine artery (n = 8 sheep). In Ovx sheep, local infusion of ICI 182 780 did not alter systemic cardiovascular parameters, such as mean arterial blood pressure or heart rate; however, it maximally decreased ipsilateral, but not contralateral, UBF vasodilatory responses to exogenous E2beta by approximately 55-60% (P < 0.01). In two models of elevated endogenous E2beta, local ICI 182 780 infusion inhibited the elevated UBF seen in follicular phase and late pregnant ewes in a time-dependent manner by approximately 60% and 37%, respectively; ipsilateral > contralateral effects (P < 0.01). In late pregnant sheep ICI 182 780 also mildly and acutely (for 5-30 min) elevated mean arterial pressure and heart rate (P < 0.05). We conclude that exogenous E2beta-induced increases in UBF in the Ovx animal and endogenous E2beta-mediated elevations of UBF during the follicular phase and late pregnancy are partially mediated by ER-dependent mechanisms.

Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17β-treated, intact follicular and pregnant sheep

PubMed Central

Magness, Ronald R; Phernetton, Terrance M; Gibson, Tiffini C; Chen, Dong-bao

2005-01-01

Oestrogen dramatically increases uterine blood flow (UBF) in ovariectomized (Ovx) ewes. Both the follicular phase and pregnancy are normal physiological states with elevated levels of circulating oestrogen. ICI 182 780 is a pure steroidal oestrogen receptor (ER) antagonist that blocks oestrogenic actions in oestrogen-responsive tissue. We hypothesized that an ER-mediated mechanism is responsible for in vivo rises in UBF in physiological states of high oestrogen. The purpose of the study was to examine the effect of an ER antagonist on exogenous and endogenous oestradiol-17β (E2β)-mediated elevations in UBF. Sheep were surgically instrumented with bilateral uterine artery blood flow transducers, and uterine and femoral artery catheters. Ovx animals (n = 8) were infused with vehicle (35% ethanol) or ICI 182 780 (0.1–3.0 μg min−1) into one uterine artery for 10 min before and 50 min after E2β was given (1 μg kg−1i.v. bolus) and UBF was recorded for an additional hour. Intact, cycling sheep were synchronized to the follicular phase using progesterone, prostaglandin F2α(PGF2α) and pregnant mare serum gonadotrophin (PMSG). When peri-ovulatory rises in UBF reached near peak levels, ICI 182 780 (1 or 2 μg (ml uterine blood flow)−1) was infused unilaterally (n = 4 sheep). Ewes in the last stages of pregnancy (late pregnant ewes) were also given ICI 182 780 (0.23–2.0 μg (ml uterine blood flow)−1; 60 min infusion) into one uterine artery (n = 8 sheep). In Ovx sheep, local infusion of ICI 182 780 did not alter systemic cardiovascular parameters, such as mean arterial blood pressure or heart rate; however, it maximally decreased ipsilateral, but not contralateral, UBF vasodilatory responses to exogenous E2β by ∼55–60% (P < 0.01). In two models of elevated endogenous E2β, local ICI 182 780 infusion inhibited the elevated UBF seen in follicular phase and late pregnant ewes in a time-dependent manner by ∼60% and 37%, respectively; ipsilateral ≫ contralateral effects (P < 0.01). In late pregnant sheep ICI 182 780 also mildly and acutely (for 5–30 min) elevated mean arterial pressure and heart rate (P < 0.05). We conclude that exogenous E2β-induced increases in UBF in the Ovx animal and endogenous E2β-mediated elevations of UBF during the follicular phase and late pregnancy are partially mediated by ER-dependent mechanisms. PMID:15774510

The Research of Feasibility and Efficacy of Radiofrequency Ablation in Treating Uterine Fibroids

PubMed Central

Luo, Xin; Shu, Shan-rong; Ma, Xue-feng; Shuai, Han-lin

2015-01-01

Abstract To explore the feasibility and efficacy of radiofrequency ablation in treating uterine fibroids. Ninety patients with multiple uterine fibroids, who had undergone hysterectomy were included in the study. After the uterus was resected, the temperature of 60, 80, 100°C were adopted to ablate the in vitro fibroid with each temperature dealing with 30 patients. Simultaneously, 5 patients were included, whose in vivo fibroid were ablated with the temperature of 100°C before the fibroids were removed after laparotomy. After the fibroids were ablated, the smooth muscle in the ablated center (group A), the ablated edge (group B) and 1 cm away from the ablated edge (group C) were taken. Then, the samples were stained with hematoxylin and eosin (HE) to examine the histopathological changes, and immunohistochemistry was performed to detect the expression of estrogen receptor (ER) and progesterone receptor (PR). After radiofrequency ablation, the ablated lesions were round, toast tan, and dry on gross appearance. There were no obvious tissue carbonization and there were distinct boundary from periphery tissue. In vitro: On automated analysis, the average optical density of ER and PR in group A, B, and C was lower than the control group (P < 0.05), and which were gradually raised with the increased distance to electrode. In the same treatment group, ER optical density was gradually decreased with the increased temperature among 3 different groups. The PR optical density was decreased with the increased temperature under different temperatures in group A and group B, there was significant difference among groups (P < 0.05). But in group C, there was no difference in PR expression among the temperature of 60, 80, and 100°C (P > 0.05). In vivo: Compared with the control group, the average optical density of ER and PR were significantly different among group A, B, and C (P < 0.05), what's more, it was gradually raised with the increased distance to electrode. After radiofrequency ablation, the tissues displayed coagulative necrosis, and decreased ER and PR expression. Radiofrequency ablation may be considered a minimally invasive alternative for those women who wish to retain their reproductive potential. Eighty degree Celsius was expected to be the optimum temperature in radiofrequency ablation treatment of uterine fibroid. PMID:26632689

In vitro decidualisation of canine uterine stromal cells.

PubMed

Kautz, Ewa; de Carvalho Papa, Paula; Reichler, Iris M; Gram, Aykut; Boos, Alois; Kowalewski, Mariusz P

2015-08-05

The uterine response to the presence of embryos is poorly understood in the domestic dog (Canis familiaris). The intimate embryo-maternal cross-talk, which begins following the hatching of blastocysts and embryo attachment leads to strong structural and functional remodelling of the uterus. A part of this process is decidualisation, comprising morphological and biochemical changes that result in formation of maternal stroma-derived decidual cells. These are an integral part of the canine placenta materna, which together with the maternal vascular endothelium are the only cells of the canine endotheliochorial placenta able to resist trophoblast invasion. These cells are also the only ones within the canine placenta expressing the progesterone receptor (PGR). Understanding the decidualisation process thus appears essential for understanding canine reproductive physiology. Here, we investigated the capability of canine uterine stromal cells to decidualise in vitro, thereby serving as a canine model of decidualisation. A dbcAMP-mediated approach was chosen during a time course of 24 - 72 h. Tissue material from six (n = 6) healthy, dioestric bitches was used (approximately 2 weeks after ovulation). Cells were characterized by differential staining, nearly 100 % of which were vimentin-positive. Scanning and transmission electron microscope analyses were applied, and morphological changes were recorded with a live cell imaging microscope. Expression of several decidualisation markers was investigated. The in vitro cultured stromal cells acquired characteristics of decidual cells when incubated with 0.5 mM dbcAMP for 72 h. Their shape changed from elongated to rounded, while ultrastructural analysis revealed higher numbers of mitochondria and secretory follicles, and an increased proliferation rate. Elevated expression levels of IGF1, IGF2, PRLR and ERα were observed in decidualised cells; PRL and ERβ remained mostly below the detection limit, while PGR remained unaffected. The expression of smooth muscle α actin (αSMA), another decidualisation marker, was strongly induced. Among prostaglandin system members, levels of COX2 (PTGS2) and of PGE2-synthase (PTGES) were upregulated. Expression of the PGE2 receptors, PTGER2 and PTGER4, was clearly detectable. An in vitro decidualisation model with canine uterine stromal cells was successfully established, allowing future, more detailed studies to be undertaken on the underlying molecular and endocrine mechanisms of canine decidualisation.

Progesterone, estradiol, arachidonic acid, oxytocin, forskolin and cAMP influence on aquaporin 1 and 5 expression in porcine uterine explants during the mid-luteal phase of the estrous cycle and luteolysis: an in vitro study.

PubMed

Skowronska, Agnieszka; Młotkowska, Patrycja; Wojciechowicz, Bartosz; Okrasa, Stanisław; Nielsen, Soren; Skowronski, Mariusz T

2015-02-18

The cell membrane water channel protein, aquaporins (AQPs), regulate cellular water transport and cell volume and play a key role in water homeostasis. Recently, AQPs are considered as important players in the field of reproduction. In previous studies, we have established the presence of AQP1 and 5 in porcine uterus. Their expression at protein level altered in distinct tissues of the female reproductive system depending on the phase of the estrous cycle. However, the regulation of aquaporin genes and proteins expression has not been examined in porcine uterine tissue. Therefore, we have designed an in vitro experiment to explain whether steroid hormones, progesterone (P4) and estradiol (E2), and other factors: oxytocine (OT), arachidonic acid (AA; substrate for prostaglandins synthesis) as well as forskolin (FSK; adenylate cyclase activator) and cAMP (second messenger, cyclic adenosine monophosphate) may impact AQPs expression. Uterine tissues were collected on Days 10-12 and 14-16 of the estrous cycle representing the mid-luteal phase and luteolysis. Real-time PCR and Western blot analysis were performed to examine the expression of porcine AQP1 and AQP5. Their expression in the uterine explants was also evaluated by immunohistochemistry. The results indicated that uterine expression of AQP1 and AQP5 potentially remains under control of steroid hormones and AA-derived compounds (e.g. prostaglandins). P4, E2, AA, FSK and cAMP cause translocation of AQP5 from apical to the basolateral plasma membrane of the epithelial cells, which might affect the transcellular water movement (through epithelial cells) between uterine lumen and blood vessels. The AC/cAMP pathway is involved in the intracellular signals transduction connected with the regulation of AQPs expression in the pig uterus. This study documented specific patterns of AQP1 and AQP5 expression in response to P4, E2, AA, FSK and cAMP, thereby providing new indirect evidence of their role in maintaining the local fluid balance within the uterus during the mid-luteal phase of the estrous cycle and luteolysis in pigs.

Cellular Mechanics of Primary Human Cervical Fibroblasts: Influence of Progesterone and a Pro-inflammatory Cytokine.

PubMed

Shukla, Vasudha; Barnhouse, Victoria; Ackerman, William E; Summerfield, Taryn L; Powell, Heather M; Leight, Jennifer L; Kniss, Douglas A; Ghadiali, Samir N

2018-01-01

The leading cause of neonatal mortality, pre-term birth, is often caused by pre-mature ripening/opening of the uterine cervix. Although cervical fibroblasts play an important role in modulating the cervix's extracellular matrix (ECM) and mechanical properties, it is not known how hormones, i.e., progesterone, and pro-inflammatory insults alter fibroblast mechanics, fibroblast-ECM interactions and the resulting changes in tissue mechanics. Here we investigate how progesterone and a pro-inflammatory cytokine, IL-1β, alter the biomechanical properties of human cervical fibroblasts and the fibroblast-ECM interactions that govern tissue-scale mechanics. Primary human fibroblasts were isolated from non-pregnant cervix and treated with estrogen/progesterone, IL-1β or both. The resulting changes in ECM gene expression, matrix remodeling, traction force generation, cell-ECM adhesion and tissue contractility were monitored. Results indicate that IL-1β induces a significant reduction in traction force and ECM adhesion independent of pre-treatment with progesterone. These cell level effects altered tissue-scale mechanics where IL-1β inhibited the contraction of a collagen gel over 6 days. Interestingly, progesterone treatment alone did not modulate traction forces or gel contraction but did result in a dramatic increase in cell-ECM adhesion. Therefore, the protective effect of progesterone may be due to altered adhesion dynamics as opposed to altered ECM remodeling.

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.

Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

PubMed

Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

2017-01-01

Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System

PubMed Central

Lei, K.; Georgiou, E. X.; Chen, L.; Yulia, A.; Sooranna, S. R.; Brosens, J. J.; Bennett, P. R.

2015-01-01

Progesterone (P4) maintains uterine quiescence during pregnancy and its functional withdrawal is associated with increased prostaglandin synthesis and the onset of labor. In primary human myometrial cells, the glucocorticoid receptor (GR) rather than the P4 receptor mediates P4 antagonism of IL-1β-induced cyclooxygenase-2 (COX-2) expression, the rate-limiting enzyme in prostaglandin synthesis. We now report that P4 also acts via GR to induce MAPK phosphatase (MKP)-1 and knockdown of MKP-1 impairs the ability of P4 to repress IL-1β-dependent COX-2 induction. Microarray analysis revealed that P4 repressed preferentially activator protein-1-responsive genes in response to IL-1β. Consistent with these observations, we found that the ability of P4 to reduce c-Jun activation was lost upon GR as well as MKP-1 knockdown. Interestingly, c-Jun levels in human myometrial cells declined upon GR and MKP-1 knockdown, which suggests the presence of an activator protein-1 feedback loop. This is supported by our observation that c-Jun levels declined after an initial rise in primary myometrial cells treated with phorbol 12-myrisatate 13-acetate, a potent activator of c-Jun N-terminal kinase. Finally, we show that MKP-1 is an intermediate in P4-mediated repression of some but not all IL-1β-responsive genes. For example, P4 repression of IL11 and IRAK3 was maintained upon MKP-1 knockdown. Taken together, the data show that P4 acts via GR to drive MKP-1 expression, which in turn inhibits IL-1β-dependent c-Jun activation and COX-2 expression. PMID:26280733

Progesterone and gravidity differentially regulate expression of extracellular matrix components in the pregnant rat myometrium.

PubMed

Shynlova, Oksana; Mitchell, Jennifer A; Tsampalieros, Anne; Langille, B Lowell; Lye, Stephen J

2004-04-01

Myometrial growth and remodeling during pregnancy depends on increased synthesis of interstitial matrix proteins. We hypothesize that the presence of mechanical tension in a specific hormonal environment regulates the expression of extracellular matrix (ECM) components in the uterus. Myometrial tissue was collected from pregnant rats on Gestational Days 0, 12, 15, 17, 19, 21, 22, 23 (labor), and 1 day postpartum and ECM expression was analyzed by Northern blotting. Expression of fibronectin, laminin beta2, and collagen IV mRNA was low during early gestation but increased dramatically on Day 23 during labor. Expression of fibrillar collagens (type I and III) peaked Day 19 and decreased near term. In contrast, elastin mRNA remained elevated from midgestation onward. Injection of progesterone (P4) on Days 20-23 (to maintain elevated plasma P4 levels) delayed the onset of labor, caused dramatic reductions in the levels of fibronectin and laminin mRNA, and prevented the fall of collagen III mRNA levels on Day 23. Treatment of pregnant rats with the progesterone receptor antagonist RU486 on Day 19 induced preterm labor on Day 20 and a premature increase in mRNA levels of collagen IV, fibronectin, and laminin. Analysis of the uterine tissue from unilaterally pregnant rats revealed that most of the changes in ECM gene expression occurred specifically in the gravid horn. Our results show a decrease in expression of fibrillar collagens and a coordinated temporal increase in expression of components of the basement membrane near term associated with decreased P4 and increased mechanical tension. These ECM changes contribute to myometrial growth and remodeling during late pregnancy and the preparation for the synchronized contractions of labor.

Progesterone receptor antagonism inhibits progestogen-related carcinogenesis and suppresses tumor cell proliferation.

PubMed

Lee, Oukseub; Choi, Mi-Ran; Christov, Konstantin; Ivancic, David; Khan, Seema A

2016-07-01

Blockade of the progestogen-progesterone receptor (PR) axis is a novel but untested strategy for breast cancer prevention. We report preclinical data evaluating telapristone acetate (TPA), ulipristal acetate (UPA), and mifepristone. Tumors were induced with medroxyprogesterone acetate (MPA) plus 7,12-dimethylbenz[a]anthracene (DMBA) in mice, and MPA or progesterone plus N-methyl-N-nitrosourea (MNU) in rats. Mammary gland histology, tumor incidence, latency, multiplicity, burden and histology were evaluated, along with immunohistochemical labeling of pHH3 (proliferation), CD34 (angiogenesis), and estrogen and progesterone receptors (ER and PR). A concentration gradient of TPA, UPA, and mifepristone was tested for growth inhibition of T47D spheroids. In mouse mammary glands, no tumors formed, but TPA opposed the pro-hyperplastic effects of MPA (p = 0.002). In rats, TPA decreased tumor incidence (p = 0.037 for MPA + TPA vs. MPA, and p = 0.032 for progesterone + TPA vs. progesterone) and tumor burden (p = 0.042 for progesterone + TPA vs. progesterone), with significant decreases in pHH3 and CD34 positive cells. TPA and UPA were superior to mifepristone in growth inhibition of T47D spheroids. TPA has consistent anti-tumorigenic effects in several models, which are accompanied by decreases in cell proliferation, angiogenesis, and hormone receptor expression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

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.

Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer

ClinicalTrials.gov

2018-06-26

Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Positive; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7

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.

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 ...

Adrenocortical nuclear progesterone-binding protein: Identification by photoaffinity labeling and evidence for deoxyribonucleic acid binding and stimulation by adrenocorticotropin

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

Demura, T.; Driscoll, W.J.; Lee, Y.C.

1991-01-01

Nuclei of the guinea pig adrenal cortex contain a protein that specifically binds progesterone and that, biochemically, is clearly distinct from the classical progesterone receptor. The adrenocortical nuclear progesterone-binding protein has now been purified more than 2000-fold by steroid-affinity chromatography with a 75% yield. The purified protein preparation demonstrated three major bands on sodium dodecyl sulfate-polyacrylamide gel of 79K, 74K, and 50K. To determine which of the three might represent the progesterone-binding protein, steroid photoaffinity labeling was performed which resulted in the specific and exclusive labeling of a 50K band. Thus, the adrenocortical nuclear progesterone-binding protein appears to be distinctmore » from the classical progesterone receptor not only biochemically, but also on the basis of molecular size. To test whether the adrenocortical nuclear progesterone-binding protein can be hormonally stimulated, guinea pigs were treated with ACTH. The chronic administration of ACTH caused a 4- to 6-fold increase in the specific progesterone binding capacity without a change in the binding affinity. There appeared to be no significant difference in nuclear progesterone binding between the zona fasciculata and zona reticularis. This finding suggests a mediating role for the progesterone-binding protein in ACTH action. In addition, the nuclear progesterone-binding protein bound to nonspecific DNA sequences, further suggesting a possible transcriptional regulatory role.« less

The effect of 7 days of letrozole pretreatment combined with misoprostol on the expression of progesterone receptor and apoptotic factors of placental and decidual tissues from first-trimester abortion: a randomized controlled trial.

PubMed

Yung, Sofie Shuk Fei; Lee, Vivian Chi Yan; Chiu, Philip Chi Ngong; Li, Hang Wun Raymond; Ng, Ernest Hung Yu; Yeung, William Shu Biu; Ho, Pak Chung

2016-04-01

To evaluate if letrozole-induced suppression of estradiol reduces progesterone receptor expression and apoptosis in the first-trimester placenta. We performed a double-blinded, randomized, placebo-controlled trial. We randomized 20 women requesting first-trimester abortion with gestation up to 63 days to receive either letrozole 10 mg daily or placebo pretreatment for 7 days before administrating 400 mcg of vaginal misoprostol followed by suction abortion. We collected the placental and decidual tissues on which we performed immunohistochemical staining for progesterone receptor and apoptotic markers (active caspase 3, caspase 3, Bcl2, CD95, fas ligand) and determined H-scores of each based on the intensities of staining. We performed terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay for apoptosis in the samples of four women to confirm the findings from apoptotic markers. We excluded one woman in the letrozole group from the analysis because she had passage of abortus after taking letrozole, leaving 19 women (9 in the letrozole group, 10 in the placebo group) for analysis. There was no significant difference in the H-scorings of progesterone receptor and apoptotic markers, as well as proportion of apoptotic cells on TUNEL assay between the two groups. The H-scores for the progesterone receptor were 8.17 ± 2.67 (mean ± SD) in the letrozole group and 9.01 ± 2.82 in the placebo group (p=0.36). We did not detect a difference in the expression of progesterone receptor and apoptotic markers in placental and decidual tissues after letrozole pretreatment for 7 days in first-trimester abortion. We did not confirm the hypothesis that letrozole reduces progesterone receptor expression and induces apoptosis in the first-trimester placenta. Further studies are required to allow better understanding of the mechanism by which estrogen suppression following the use of letrozole can lead to improved abortion rate in the first trimester. Copyright © 2016 Elsevier Inc. All rights reserved.

An Antiprogestin, CDB4124, Blocks Progesterone’s Attenuation of the Negative Effects of a Mild Stress on Sexual Behavior

PubMed Central

Uphouse, Lynda; Hiegel, Cindy

2012-01-01

These experiments were designed to test the hypothesis that a progesterone receptor antagonist would block progesterone’s ability to reduce the negative effects of a 5 min restraint on female rat sexual behavior. Ovariectomized Fisher rats were injected with 10 μg estradiol benzoate. Two days later, rats were injected subcutaneously (sc) with the progesterone receptor antagonist, CDB4124 (17 α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione) (60 mg/kg), or vehicle (20% DMSO + propylene glycol). One hr later, rats were injected sc with 500 μg progesterone or vehicle (sesame seed oil). Rats were assigned to one of three different treatment conditions: (1) (ECV) estradiol benzoate, CDB4124, sesame seed oil vehicle, (2) (ECP) estradiol benzoate, CDB4124, progesterone, and (3) (EVP) estradiol benzoate, DMSO/propylene glycol vehicle, progesterone. That afternoon sexual behavior was examined before and after a 5 min restraint experience. Before restraint, lordosis behavior was comparable across treatment conditions but only progesterone-treated rats exhibited proceptive behavior. CDB4124 did not block progesterone’s induction of proceptivity. However, after restraint, CDB4124 attenuated the positive effects of progesterone on all sexual behaviors examined. The restraint experience inhibited sexual behavior in rats treated with estradiol benzoate and CDB4124 and in rats treated with estradiol benzoate, CDB4124, and progesterone but not in rats given estradiol benzoate and progesterone without CDB4124. These findings are consistent with the hypothesis that progesterone receptors mediate progesterone’s ability to reduce the negative sexual behavioral effects of a mild stressor. PMID:23153933

Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization

PubMed Central

Whirledge, Shannon D.; Oakley, Robert H.; Myers, Page H.; Lydon, John P.; DeMayo, Francesco; Cidlowski, John A.

2015-01-01

In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic–pituitary–adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PRcre mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions. PMID:26598666

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.

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...

Unraveling the Molecular Mechanism(s) Underlying ER+/PR- Breast Tumorigenesis Using a Novel Genetically Engineered Mouse Model

DTIC Science & Technology

2010-09-01

Gria4 Glutamate receptor ionotropic , AMPA 4 NM_019691 transport ion transport 3.00 Slc2a1 solute carrier family 2,member 1 NM_011400...unlimited 13. SUPPLEMENTARY NOTES 14. A BSTRACT Estrogen-rece ptor alpha (E Rα)-positive Progesterone receptor ne gative (ER+ /PR-) breast ductal...fo r t reating ER+/PR- breast cancers that are resistant to tamoxifen or trastuzumab. 15. SUBJECT TERMS Estrogen receptor , Progesterone receptor

Early pregnancy diagnosis on days 18 to 21 postinsemination using high-resolution imaging in lactating dairy cows.

PubMed

Scully, S; Butler, S T; Kelly, A K; Evans, A C O; Lonergan, P; Crowe, M A

2014-01-01

The aim was to assess the ability of corpus luteum (CL) and uterine ultrasound characteristics on d 18 to 21 to predict pregnancy status in lactating dairy cows. Ultrasound examinations were carried out on cows (n = 164) on d 18 to 21 following artificial insemination (AI). Images of the uterus and CL were captured using a Voluson i ultrasound device (General Electric Healthcare Systems, Vienna, Austria) equipped with a 12-MHz, multi frequency, linear array probe. Serum concentrations of progesterone were determined from blood samples collected at each ultrasound examination. Images of the CL were captured and stored for calculation of CL tissue area and echotexture. Images of the CL and associated blood flow area were captured and stored for analysis of luteal blood flow ratio. Longitudinal B-mode images of the uterine horns were stored for analysis of echotexture. Diagnosis of pregnancy was made at each ultrasound examination based on CL blood flow, CL size, and uterine echotexture. Pregnancy was confirmed by ultrasonography on d 30 after AI. The relationship between ultrasound measures and pregnancy outcome, as well as the accuracy of the pregnancy diagnosis made at each ultrasound examination was assessed. Progesterone concentrations and CL tissue area were greater in pregnant compared with nonpregnant cows on all days. The CL blood flow ratio was higher in pregnant compared with nonpregnant cows on d 20 and 21 after AI. Echotexture measures of the CL and uterus were not different between pregnant and nonpregnant cows on any day of examination. The best logistic regression model to predict pregnancy included scores for CL blood flow, CL size, and uterine echotexture on d 21 following AI. Accuracy of pregnancy diagnosis was highest on d 21, with sensitivity and specificity being 97.6 and 97.5%, respectively. Uterine echotexture scores were similar for pregnant and nonpregnant cows from d 18 to 20. On d 21, pregnant cows had higher uterine echotexture scores compared with nonpregnant cows. The logistic regression equation most likely to provide a correct pregnancy diagnosis in lactating dairy cows included the visual score for CL blood flow, CL size, and uterine echotexture on d 21 after AI. In support of this finding, the diagnostic accuracy for visual scores of CL blood flow, CL size, and uterine echotexture were also highest on d 21. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Life after Roe v. Wade.

PubMed

Bauerlein, M

1992-01-01

With the possibility that the US Supreme Court will overturn or "substantially erode" Roe v. Wade, interest has focused on two alternative abortion techniques: RU-486, the French "abortion pill," and "menstrual extraction," a self-taught procedure performed up to the 8th week of pregnancy. RU-486 is legally available in only a few countries. In France, a woman signs a lengthy consent form and waits a week under French abortion law before receiving 3 200-milligram tablets of RU-486. RU-486 causes an extended, heavy, and somewhat painful menstruation by blocking receptors for progesterone, which prevents the uterine lining from growing; the lining sloughs off, carrying the embryo with it. 2 days later she returns to the clinic and receives an injection or vaginal suppository of prostaglandin to stimulate uterine contractions and increase the effectiveness of RU-486 from 85% to 95%. A week later, she returns for a checkup. RU-486 is a popular choice; complications compare favorable with standard vacuum-aspiration abortions. Proponents argue for RU-486 in the US for research in areas from AIDS to breast cancer. However, the US Food and Drug Administration has an import alert on the drug, prohibiting its entry into the US. Despite the simplicity of this drug, it still fails to guarantee access for private, easily accessible, inexpensive alternatives to traditional abortion services. Although home-performed abortions are illegal in most places, menstrual extraction allows a woman complete control of her body at home via a sterilized cannula attached to as plastic tube that feeds through a hole in a rubber stopper into a jar; 2nd hole holds a tube with a syringe. The cannula is inserted into the uterus, as helper creates suction with the syringes, and observes the uterine contents flush through the clear tubing and into the jar.

Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.

PubMed

Seitz, Christian; Bumbuliene, Žana; Costa, Ana Rosa; Heikinheimo, Oskari; Heweker, Andrea; Hudeček, Robert; Jacquemyn, Yves; Melis, Gian Benedetto; Parashar, Pooja; Rechberger, Tomasz; Sánchez, Antonio Cano; van Aken, Bart; Zatik, János; Gemzell-Danielsson, Kristina

2017-04-01

Uterine fibroids (UFs) may be treated with progesterone receptor modulators (PRMs), which have been shown to reduce heavy menstrual bleeding and the size of UFs. To date, one PRM (ulipristal acetate) has received regulatory approval for the treatment of UFs; therapy comprises intermittent treatment courses of up to 3months each, followed by a break to allow two menstruations to occur. We report the design of ASTEROID (Assess Safety and efficacy of vilaprisan in patients with uTERine fibrOIDs) 2, a phase 2 study examining the efficacy and safety of a novel PRM, vilaprisan, in women with UFs. In this randomized multi-arm study, vilaprisan (2mg daily) will be administered in different regimens: continuous treatment for 12 or 24weeks, or two 12-week treatment periods separated by a break to allow one menstruation to occur. Efficacy and safety will be compared with that of ulipristal acetate (5mg daily) and placebo. Patients randomized to receive placebo for 12weeks will also be given active treatment for 12weeks. The primary measure of efficacy will be amenorrhoea rate; secondary measures include time to normalized menstrual bleeding and percentage change in UF volume. Endometrial changes will be monitored throughout the study. The placebo- and active comparator-controlled trial ASTEROID 2 is the first study to evaluate systematically the efficacy and safety of different treatment regimens of PRMs in women with UFs. The findings of this study will direct the planning of future clinical trials of vilaprisan. Copyright © 2017 Bayer AG. Published by Elsevier Inc. All rights reserved.

Prevention of breast cancer.

PubMed

Olver, Ian N

2016-11-21

Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.

Alternative Oral Agents in Prophylaxis and Therapy of Uterine Fibroids-An Up-to-Date Review.

PubMed

Ciebiera, Michał; Łukaszuk, Krzysztof; Męczekalski, Błażej; Ciebiera, Magdalena; Wojtyła, Cezary; Słabuszewska-Jóźwiak, Aneta; Jakiel, Grzegorz

2017-12-01

Uterine fibroids (UFs) are the most common tumors of the female genital tract. The effect of UFs on the quality of life and the overall cost of treatment are significant issues worldwide. Tumor size and location are the two specific factors which influence the occurrence of symptoms, the need for, and method of, treatment (some tumors require surgery while some can be treated with selected drugs). Primary prevention and treatment of early UF disease are worthy goals that might have a great impact on health care systems. Several treatments and prophylactic methods can be used in this endeavor. This publication presents current data about lesser-known substances which may have a beneficial effect on the treatment or prophylaxis of UFs and can be administered orally, serving as an alternative to (or complement of) surgery or selective progesterone receptor modulators (SPRMs). Early prevention and treatment of UFs in women from high-risk groups should be our priority. Innovative forms of UF management are under intensive investigation and may be promising options in the near future. Many of them evaluated vitamin D, paricalcitol, epigallocatechin gallate (EGCG), elagolix, aromatase inhibitors (AIs), and cabergoline and deemed them to be safe and effective. The next step in such projects should be properly constructed randomized control trials (RCTs), carried out by successive phases.

Alternative Oral Agents in Prophylaxis and Therapy of Uterine Fibroids—An Up-to-Date Review

PubMed Central

Łukaszuk, Krzysztof; Męczekalski, Błażej; Ciebiera, Magdalena; Wojtyła, Cezary; Słabuszewska-Jóźwiak, Aneta; Jakiel, Grzegorz

2017-01-01

Uterine fibroids (UFs) are the most common tumors of the female genital tract. The effect of UFs on the quality of life and the overall cost of treatment are significant issues worldwide. Tumor size and location are the two specific factors which influence the occurrence of symptoms, the need for, and method of, treatment (some tumors require surgery while some can be treated with selected drugs). Primary prevention and treatment of early UF disease are worthy goals that might have a great impact on health care systems. Several treatments and prophylactic methods can be used in this endeavor. This publication presents current data about lesser-known substances which may have a beneficial effect on the treatment or prophylaxis of UFs and can be administered orally, serving as an alternative to (or complement of) surgery or selective progesterone receptor modulators (SPRMs). Early prevention and treatment of UFs in women from high-risk groups should be our priority. Innovative forms of UF management are under intensive investigation and may be promising options in the near future. Many of them evaluated vitamin D, paricalcitol, epigallocatechin gallate (EGCG), elagolix, aromatase inhibitors (AIs), and cabergoline and deemed them to be safe and effective. The next step in such projects should be properly constructed randomized control trials (RCTs), carried out by successive phases. PMID:29194370

The conservative and interventional treatment of fibroids.

PubMed

Boosz, Alexander Stephan; Reimer, Peter; Matzko, Matthias; Römer, Thomas; Müller, Andreas

2014-12-22

Fibroids are the most common benign tumors in women. One-third of all women of reproductive age undergo treatment for symptomatic fibroids. In recent years, the spectrum of available treatments has been widened by the introduction of new drugs and interventional procedures. Selective literature review on the treatment of uterine fibroids, including consideration of several Cochrane Reviews. Fibroids can be treated with drugs, interventional procedures (uterine artery embolization [UAE] and focused ultrasound treatment [FUS]), and surgery. The evidence regarding the various available treatments is mixed. All methods improve symptoms, but only a few comparative studies have been performed. A meta-analysis revealed that recovery within 15 days is more common after laparoscopic enucleation than after open surgery (odds ratio [OR], 3.2). A minimally invasive hysterectomy, or one performed by the vaginal route, is associated with a shorter hospital stay and a more rapid recovery than open transabdominal hysterectomy. UAE is an alternative to hysterectomy for selected patients. The re-intervention rates after fibroid enucleation, hysterectomy, and UAE are 8.9-9%, 1.8-10.7%, and 7-34.6%, respectively. The main drugs used to treat fibroids are gonadotropin-releasing hormone analogs and selective progesterone receptor modulators. Multiple treatment options are available and enable individualized therapy for symptomatic fibroids. The most important considerations in the choice of treatment are the question of family planning and, in some cases, the technical limitations of the treatments themselves.

Ultrasonographic and laparoscopic evaluation of the reproductive tract of the captive female African lion (Panthera leo).

PubMed

Kirberger, Robert M; Schulman, Martin L; Hartman, Marthinus J

2011-09-15

The use of transabdominal ultrasonography to assess the oestrous cycle has not been previously described in the African lion (Panthera leo). Twelve sexually mature lionesses and five female cubs had their reproductive organs assessed by transabdominal ultrasound. Ovarian findings were compared to laparoscopic findings while performing laparoscopic ovariectomy or salpingectomy. Vaginal cytology was performed and serum progesterone levels were determined. By combining all data the oestrous cycle stage of each lion was determined. One lion was far pregnant and was not operated on. In adults a uterine body could be seen ultrasonographically in 67% of lions while mural structures could be distinguished in 44% of lions. Five uterine horns could be seen in 3 lions. In 12 adults 10 ovaries were found of which eight had discernable follicles or luteal structures. During laparoscopy 12 active ovaries were seen with luteal structures seen in 11 ovaries and follicles in 2 ovaries. Using laparoscopy as the gold standard, ultrasonography had a sensitivity of 66% and specificity of 83% to detect ovarian reproductive activity. Two uterine cysts and a cluster of periovarian cysts were seen in three different lions. Three lions were pregnant, two were in oestrus, three in a luteal phase (dioestrus), and four were in anoestrus. Transabdominal ultrasound in combination with serum progesterone levels and vaginal cytology can be used to assess ovarian cyclical activity with reasonable accuracy in captive bred lions. Copyright © 2011 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

Treatment of fibroadenomatous hyperplasia in cats with aglépristone.

PubMed

Görlinger, S; Kooistra, H S; van den Broek, A; Okkens, A C

2002-01-01

Fibroadenomatous hyperplasia (FAH) is characterized by a rapid proliferation of mammary stroma and duct epithelium of 1 or more glands and predominantly affects younger female cats. Endogenous progesterone and exogenous progestogens play an important role in the genesis of FAH. The presence of progesterone receptors in fibroadenomatous tissue allows for targeted endocrine therapy with progesterone receptor blockers. We report on 22 young cats with FAH, none of which had responded to the withdrawal of progestogens or ovariectomy. The common signs were tachycardia (11 cats); skin ulceration, painful mammary glands, or both (16 cats); lethargy (8 cats); and anorexia (4 cats). The cats were treated with subcutaneous injections of the progesterone receptor blocker aglépristone on 1 (7 cats, 20 mg/kg) or 2 consecutive days (15 cats, 10 mg/kg/d) once weekly. All but 1 cat responded with a complete and lasting remission of signs after 1-4 weeks of treatment. Two cats had a short-term skin irritation at the site of the aglépristone injection. Two pregnant cats with FAH aborted after treatment with aglépristone and subsequently developed endometritis. In conclusion, the results of this study demonstrate that FAH in cats can be treated successfully with the progesterone receptor blocker aglépristone.

Breast-Conserving Surgery Followed by Radiation Therapy With MRI-Detected Stage I or Stage II Breast Cancer

ClinicalTrials.gov

2011-12-07

Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Male Breast Cancer; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Tubular Ductal Breast Carcinoma

Levonorgestrel-releasing intrauterine system placement for severe uterine cervical stenosis after conization: two case reports.

PubMed

Motegi, Emi; Hasegawa, Kiyoshi; Kawai, Satoshi; Kiuchi, Kaori; Kosaka, Nobuaki; Mochizuki, Yoshiko; Fukasawa, Ichio

2016-03-09

Several approaches for treating severe uterine cervical stenosis after conization for cervical intraepithelial neoplasia have been reported; yet, the condition can still be difficult to treat successfully. We performed uterine cervical dilation surgery in two patients with severe stenosis, followed by insertion of the levonorgestrel-releasing intrauterine system, which is used for dysmenorrhea or endometriosis-related pain because of its strong progesterone activity. Patient 1 was a 34-year-old Japanese woman who was diagnosed with dysmenorrhea caused by recurrent uterine cervical stenosis and hematometra after laser conization. Patient 2 was a 44-year-old Japanese woman who developed dysmenorrhea and prolonged menstruation caused by uterine cervical stenosis without hematometra. After providing informed consent, they underwent cervical dilation surgery followed by insertion of the levonorgestrel-releasing intrauterine system. After treatment, their symptoms immediately improved, and after removal of their devices, they remained asymptomatic. To the best of our knowledge, this is the first report to confirm the usefulness and easy applicability of the levonorgestrel-releasing intrauterine system for uterine cervical stenosis. Although we had success with the method, this study of two patients is preliminary. Further study with larger numbers of patients is necessary to confirm the usefulness of our technique.

Progesterone-driven local regulatory T cell induction does not prevent fetal loss in the CBA/J×DBA/2J abortion-prone model.

PubMed

Schumacher, Anne; Dauven, Dominique; Zenclussen, Ana C

2017-03-01

Best known for its endocrine and immunologic properties, progesterone (P4) is a pivotal player for pregnancy success. However, the immunologic actions underlying P4 protection are not completely understood. Here, we investigated whether P4 application in a murine abortion-prone combination regulates regulatory T cells (Treg) and dendritic cells (DCs) and thereby affects pregnancy outcome. Progesterone or vehicle was applied to DBA/2J-mated CBA/J abortion-prone animals in early pregnancy. On gestation day 10, peripheral and local DC and Treg numbers were analyzed and pregnancy outcome was determined. Progesterone application provoked a significant increase in the uterine Treg pool but did not alter the abortion rate. Moreover, no significant changes could be observed in peripheral Treg levels and DC numbers after P4 application. Our findings suggest that P4-induced local Treg elevation is not sufficient to overcome fetal rejection in this specific model of disturbed fetal tolerance. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sex hormone-binding globulin and corticosteroid-binding globulin mRNA levels in infertile women with luteal phase deficiency.

PubMed

Misao, R; Nakanishi, Y; Fujimoto, J; Tamaya, T

1995-09-01

This study was designed to investigate the biological significance in intracellular expression of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNA in uterine endometrium with luteal phase deficiency (designated as out-of-phase endometrium or low serum progesterone level). The levels of such mRNAs were measured by the quantitative reverse transcription-polymerase chain reaction. Under the normal serum 17 beta-estradiol and progesterone levels in the mid-luteal phase, the levels of SHBG and CBG mRNAs in the out-of-phase endometria were not significantly different from those in the normal endometria. On the other hand, SHBG and CBG mRNA levels in the endometria of low serum midluteal progesterone level were significantly (p < 0.05) reduced and raised, respectively, compared with normal levels. These findings suggest that the synthesis of endometrial steroid-binding proteins in the out-of-phase endometrium is conserved, as that in the in-phase endometrium, whereas the decreased progesterone level might up-regulate CBG expression with down-regulation of SHBG expression.

Effect of progesterone receptor status on maspin synthesis via nitric oxide production in neutrophils in human breast cancer.

PubMed

Ganguly Bhattacharjee, Karabi; Bhattacharyya, Mau; Halder, Umesh Chandra; Jana, Pradipta; Sinha, Asru K

2014-09-01

Although progesterone receptor (PR) status, similarly to estrogen receptor status, is of prognostic importance in breast cancer, the involvement of the PR in breast cancer remains obscure. Studies were conducted to determine the function of the PR in neutrophils in the nitric oxide-induced synthesis of maspin, an anti-breast-cancer protein produced in nonmalignant mammary cells and in neutrophils in the circulation. PR status was determined by immunohistochemistry. Maspin synthesis was determined by in-vitro translation of messenger RNA and quantified by enzyme-linked immunosorbent assay. Nitric oxide was determined by the methemoglobin method. It was found that PR status in neutrophils was identical with that in malignant breast tissues. A Scatchard plot for progesterone binding to normal and PR-positive (PR+) neutrophils revealed that whereas normal neutrophils had 11.5 × 10(10) PR sites/cell with K d = 47.619 nM, PR+ neutrophils had 6.6 × 10(10) PR sites/cell with K d = 47.619 nM. The progesterone negative (PR-) neutrophils failed to bind to progesterone. Incubation of normal and PR+ neutrophils with 25 nM progesterone produced 1.317 μM NO and 2.329 nM maspin; the PR+ neutrophils produced 0.72 μM NO and 1.138 nM maspin. The PR- neutrophils failed to produce any NO or maspin in the presence of progesterone. Inhibition of progesterone-induced NO synthesis led to complete inhibition of maspin synthesis in all neutrophils. These results suggest that estrogen and progesterone complement each other in NO-induced maspin synthesis, and do not necessarily antagonize in the synthesis of the anti-breast-cancer protein.

Progesterone regulation of primordial follicle assembly in bovine fetal ovaries.

PubMed

Nilsson, Eric E; Skinner, Michael K

2009-12-10

Fertility in mammals is dependant on females having an adequate primordial follicle pool to supply oocytes for fertilization. The formation of primordial follicles is called ovarian follicular assembly. In rats and mice progesterone and estradiol have been shown to inhibit follicle assembly with assembly occurring after birth when the pups are removed from the high-steroid maternal environment. In contrast, primordial follicle assembly in other species, such as cattle and humans, occurs during fetal development before birth. The objective of the current study is to determine if progesterone levels regulate primordial follicle assembly in fetal bovine ovaries. Ovaries and blood were collected from bovine fetuses. Interestingly, ovarian progesterone and estradiol concentrations were found to decrease with increasing fetal age and correlated to increased primordial follicle assembly. Microarray analysis of fetal ovary RNA suggests that progesterone membrane receptor and estrogen nuclear receptor are expressed. Treatment of fetal bovine ovary cultures with a higher progesterone concentration significantly decreased primordial follicle assembly. Observations indicate that progesterone affects ovarian primordial follicle assembly in cattle, as it does in rats and mice.

Progesterone Regulation of Primordial Follicle Assembly In Bovine Fetal Ovaries

PubMed Central

Nilsson, Eric E.; Skinner, Michael K.

2009-01-01

Fertility in mammals is dependant on females having an adequate primordial follicle pool to supply oocytes for fertilization. The formation of primordial follicles is called ovarian follicular assembly. In rats and mice progesterone and estradiol have been shown to inhibit follicle assembly with assembly occurring after birth when the pups are removed from the high-steroid maternal environment. In contrast, primordial follicle assembly in other species, such as cattle and humans, occurs during fetal development before birth. The objective of the current study is to determine if progesterone levels regulate primordial follicle assembly in fetal bovine ovaries. Ovaries and blood were collected from bovine fetuses. Interestingly, ovarian progesterone and estradiol concentrations were found to decrease with increasing fetal age and correlated to increased primordial follicle assembly. Microarray analysis of fetal ovary RNA suggests that progesterone membrane receptor and estrogen nuclear receptor are expressed. Treatment of fetal bovine ovary cultures with a higher progesterone concentration significantly decreased primordial follicle assembly. Observations indicate that progesterone affects ovarian primordial follicle assembly in cattle, as it does in rats and mice. PMID:19747959

Sexual Dimorphism in the Regulation of Estrogen, Progesterone, and Androgen Receptors by Sex Steroids in the Rat Airway Smooth Muscle Cells

PubMed Central

Zarazúa, Abraham; González-Arenas, Aliesha; Ramírez-Vélez, Gabriela; Bazán-Perkins, Blanca; Guerra-Araiza, Christian; Campos-Lara, María G.

2016-01-01

The role of sex hormones in lung is known. The three main sex steroid receptors, estrogen, progesterone, and androgen, have not been sufficiently studied in airway smooth muscle cells (ASMC), and the sex hormone regulation on these receptors is unknown. We examined the presence and regulation of sex hormone receptors in female and male rat ASMC by Western blotting and flow cytometry. Gonadectomized rats were treated with 17β-estradiol, progesterone, 17β-estradiol + progesterone, or testosterone. ASMC were enzymatically isolated from tracheas and bronchi. The experiments were performed with double staining flow cytometry (anti-α-actin smooth muscle and antibodies to each hormone receptor). ERα, ERβ, tPR, and AR were detected in females or males. ERα was upregulated by E2 and T and downregulated by P4 in females; in males, ERα was downregulated by P4, E + P, and T. ERβ was downregulated by each treatment in females, and only by E + P and T in males. tPR was downregulated by P4, E + P, and T in females. No hormonal regulation was observed in male receptors. AR was downregulated in males treated with E + P and T. We have shown the occurrence of sex hormone receptors in ASMC and their regulation by the sex hormones in female and male rats. PMID:27110242

A role for the endocannabinoid system in premature luteal regression and progesterone withdrawal in lipopolysaccharide-induced early pregnancy loss model.

PubMed

Schander, Julieta Aylen; Correa, Fernando; Bariani, María Victoria; Blanco, Julieta; Cymeryng, Cora; Jensen, Federico; Wolfson, Manuel Luis; Franchi, Ana María

2016-11-01

What is the role of the endocannabinoid system (eCS) in the alterations of the endocrine system in a murine model of lipopolysaccharide (LPS)-induced miscarriage? In 7-days pregnant wild type, but not cannabinoid receptor type 1 knockout (CB1-KO) mice, LPS increased COX-2 expression and prostaglandin F 2α (PGF 2α ) production in the uterus leading to lower expression of prolactin receptor in the ovary and a marked regression of corpora lutea (CL), suggesting that the eCS mediates the deleterious effects of LPS on reproductive events. Appropriate systemic progesterone levels are critical for a successful pregnancy outcome. Precocious loss of luteal progesterone (P4) secretion leads to miscarriage in rodents. We have previously shown that LPS administration to pregnant mice induces embryonic resorption accompanied by a dramatic decrease in systemic progesterone levels in a murine model of inflammatory miscarriage, with the eCS mediating these LPS-induced deleterious effects. CD1 wild-type (WT) and CB1-KO mice were randomly allocated to Vehicle (saline; i.p.) or LPS (0.5 μg/g body weight; i.p.) treated groups: (WT-Vehicle; WT-LPS; CB1-KO-Vehicle and CB1-KO-LPS). A single injection was given on day 7 of pregnancy and tissues (blood, ovary, uterus) were collected 6, 12, 24 and 48 h later. P4 and PGF2α plasma levels were determined by radioimmunoassay. Cyclooxygenase-2 (COX-2) mRNA (RT-PCR) and protein (Western blot) content in uterus was assayed. COX-2 and prolactin receptor (PrlR) mRNA levels in the ovary were assayed by RT-PCR. Tissue morphology of the CL was assessed by haematoxylin-eosin staining. Treatment of 7-day pregnant WT mice with LPS induced a P4 withdrawal (p < 0.05), increased in uterine COX-2 mRNA and protein expression (p < 0.05) as well as an increase in uterine PGF 2α production (p < 0.05). These changes were absent in LPS-treated 7-day pregnant CB1-KO mice. In ovarian tissues, LPS treatment to 7-day pregnant WT mice induced a downregulation of PrlR mRNA expression (p < 0.05) together with an increase in COX-2 mRNA expression (p < 0.05) and PGF 2α content (p < 0.05). These effects were absent in the CB1-KO mice. Collectively, our results suggest a role for the eCS mediating LPS-induced deleterious effects on reproductive tissues. An important caveat of this study is the endocrine differences between mice and humans during pregnancy (e.g. P4 is produced by the CL throughout pregnancy in mice, whereas this is not the case in humans), which limits the extrapolation of the results presented here. Our findings provide new insights in the role of the endocannabinoid system in the physiopathology of reproduction as well as the role of this endogenous system as a mediator of LPS deleterious effects on reproductive tissues. None. Dr Ana María Franchi was funded by Agencia Nacional para la Promoción Científica y Tecnológica (PICT 2010/0813 and PICT 2013/0097) and by Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 2012/0061). The authors have no competing interests. © 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.

Delayed Parturition and Altered Myometrial Progesterone Receptor Isoform A Expression in Mice Null for Kruppel-like Factor 9

USDA-ARS?s Scientific Manuscript database

Pre-term and delayed labor conditions are devastating health problems, with currently unknown etiologies. We previously showed that the transcription factor Krüppel-like factor 9 (KLF9) influences the expression and/or transcriptional activity of receptors for estrogen and progesterone in endometria...

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

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.

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns ▿

PubMed Central

Giannoni, Eric; Guignard, Laurence; Knaup Reymond, Marlies; Perreau, Matthieu; Roth-Kleiner, Matthias; Calandra, Thierry; Roger, Thierry

2011-01-01

Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-κB pathway but not the mitogen-activated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period. PMID:21518785

Effect of antiprogestin ZK 98. 734 on the ovarian cycle, early pregnancy, and on its binding to progesterone receptors in the myometrium of marmoset Callithrix jacchus

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

Puri, C.P.; Kholkute, S.D.; Pongubala, J.M.

1988-04-01

The antiprogestin ZK 98.734 (11 beta-(4-dimethylaminophenyl-17 beta-hydroxy-17 alpha-(3-hydroxy-prop-1(Z)-enyl-4,9(10)-estradien-3-one) was administered i.m. (5 mg/day) for three consecutive days to two groups of common marmosets. In one group (nonpregnant, n = 6), it was injected during the luteal phase, and to the second group (pregnant, n = 7), it was injected during early pregnancy, on Days 24-26 of the mid-cycle estradiol peak. Administration of ZK 98.734 during the luteal phase caused a sharp drop in plasma progesterone levels. The luteal phase was shortened whether the drug was administered during the early or the late luteal phase. Similarly, administration of ZK 98.734 duringmore » early pregnancy caused a significant drop in progesterone levels, and pregnancy was terminated in all of the animals. The post-treatment cycles in both groups of animals were ovulatory and of normal duration. /sup 3/H-ZK 98.734 showed specific binding to myometrial cytosol fraction. ZK 98.734 also displaced the binding of /sup 3/H-progesterone to progesterone receptors. However, progesterone had higher binding affinity than did ZK 98.734. The antifertility action of ZK 98.734 could be a result either of its luteolytic action or of its blocking the progesterone receptors in the target tissue. This study, therefore, indicates that in the common marmoset ZK 98.734 is a progesterone antagonist with a potential to terminate early pregnancy.« less

Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status - a short report.

PubMed

Godbole, Mukul; Tiwary, Kanishka; Badwe, Rajendra; Gupta, Sudeep; Dutt, Amit

2017-08-01

Pre-operative progesterone treatment of breast cancer has been shown to confer survival benefits to patients independent of their progesterone receptor (PR) status. The underlying mechanism and the question whether such an effect can also be observed in PR negative breast cancer cells remain to be resolved. We performed proteome profiling of PR-positive and PR-negative breast cancer cells in response to progesterone using a phospho-kinase array platform. Western blotting was used to validate the results. Cell-based phenotypic assays were conducted using PR-positive and PR-negative breast cancer cells to assess the effect of progesterone. We found that progesterone induces de-phosphorylation of 12 out of 43 kinases tested, which are mostly involved in cellular invasion and migration regulation. Consistent with this observation, we found through cell-based phenotypic assays that progesterone inhibits the invasion and migration of breast cancer cells independent of their PR status. Our results indicate that progesterone can inhibit breast cancer cell invasion and migration mediated by the de-phosphorylation of kinases. This inhibition appears to be independent of the PR status of the breast cancer cells. In a broader context, our study may provide a basis for an association between progesterone treatment and recurrence reduction in breast cancer patients, thereby providing a lead for modelling a randomized in vitro study.

Salivary progesterone and cervical length measurement as predictors of spontaneous preterm birth.

PubMed

Maged, Ahmed M; Mohesen, Mohamed; Elhalwagy, Ahmed; Abdelhafiz, Ali

2015-07-01

To evaluate the efficacy of salivary progesterone, cervical length measurement in predicting preterm birth (PTB). Prospective observational study included 240 pregnant women with gestational age (GA) 26-34 weeks classified into two equal groups; group one are high risk for PTB (those with symptoms of uterine contractions or history of one or more spontaneous preterm delivery or second trimester abortion) and group 2 are controls. There was a highly significant difference between the two study groups regarding GA at delivery (31.3 ± 3.75 in high risk versus 38.5 ± 1.3 in control), cervical length measured by transvaginal ultrasound (24.7 ± 8.6 in high risk versus 40.1 ± 4.67 in control) and salivary progesterone level (728.9 ± 222.3 in high risk versus 1099.9 ± 189.4 in control; p < 0.001). There was a statistically significant difference between levels of salivary progesterone at different GA among the high risk group (p value 0.035) but not in low risk group (p value 0.492). CL measurement showed a sensitivity of 71.5% with 100% specificity, 100% PPV, 69.97% NPV and accuracy of 83%, while salivary progesterone showed a sensitivity of 84% with 90% specificity, 89.8% PPV, 85.9% NPV and accuracy of 92.2%. The measurement of both salivary progesterone and cervical length are good predictors for development of PTB.

Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium.

PubMed Central

Bruner, K L; Rodgers, W H; Gold, L I; Korc, M; Hargrove, J T; Matrisian, L M; Osteen, K G

1995-01-01

Unlike most normal adult tissues, cyclic growth and tissue remodeling occur within the uterine endometrium throughout the reproductive years. The matrix metalloproteinases (MMPs), a family of structurally related enzymes that degrade specific components of the extracellular matrix are thought to be the physiologically relevant mediators of extracellular matrix composition and turnover. Our laboratory has identified MMPs of the stromelysin family in the cycling human endometrium, implicating these enzymes in mediating the extensive remodeling that occurs in this tissue. While the stromelysins are expressed in vivo during proliferation-associated remodeling and menstruation-associated endometrial breakdown, none of the stromelysins are expressed during the progesterone-dominated secretory phase of the cycle. Our in vitro studies of isolated cell types have confirmed progesterone suppression of stromal MMPs, but a stromal-derived paracrine factor was found necessary for suppression of the epithelial-specific MMP matrilysin. In this report, we demonstrate that transforming growth factor beta (TGF-beta) is produced by endometrial stroma in response to progesterone and can suppress expression of epithelial matrilysin independent of progesterone. Additionally, we find that an antibody directed against the mammalian isoforms of TGF-beta abolishes progesterone suppression of matrilysin in stromal-epithelial cocultures, implicating TGF-beta as the principal mediator of matrilysin suppression in the human endometrium. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7638197

Breast Cancer Risk Factors Defined by Estrogen and Progesterone Receptor Status

PubMed Central

Monroe, Kristine R.; Wilkens, Lynne R.; Kolonel, Laurence N.; Pike, Malcolm C.; Henderson, Brian E.

2009-01-01

Prospective data on ethnic differences in hormone receptor-defined subtypes of breast cancer and their risk factor profiles are scarce. The authors examined the joint distributions of estrogen receptor (ER) and progesterone receptor (PR) status across 5 ethnic groups and the associations of established risk factors with ER/PR status in the Multiethnic Cohort Study (Hawaii and Los Angeles, California). During an average of 10.4 years of follow-up of 84,427 women between 1993–1996 and 2004/2005, 2,543 breast cancer cases with data on ER/PR status were identified: 1,672 estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+); 303 ER+/progesterone receptor-negative (PR−); 77 estrogen receptor-negative (ER−)/PR+; and 491 ER−/PR−. ER/PR status varied significantly across racial/ethnic groups even within the same tumor stage (for localized tumors, P < 0.0001; for advanced tumors, P = 0.01). The highest fraction of ER−/PR− tumors was observed in African Americans (31%), followed by Latinas (25%), Whites (18%), Japanese (14%), and Native Hawaiians (14%). Associations differed between ER+/PR+ and ER−/PR− cases for postmenopausal obesity (P = 0.02), age at menarche (P = 0.05), age at first birth (P = 0.04), and postmenopausal hormone use (P < 0.0001). African Americans are more likely to be diagnosed with ER−/PR− tumors independently of stage at diagnosis, and there are disparate risk factor profiles across the ER/PR subtypes of breast cancer. PMID:19318616

[IUD-related anatomical, cytological and pathological modifications in the uterine tract (author's transl)].

PubMed

Levrier, M

1982-05-01

This paper presents a study of the anatomical, cytological, and pathological reactions of the vaginal, cervical, and endometrial mucosa in 445 women wearing inert IUDs, copper IUDs, and progesterone-releasing IUDs. Vaginal cytology does not seem to be affected by any type of IUD. Cervical cytology shows with time increased levels of leuko-histiocytosis and at 18 months cellular alterations are evident; in the series presented here after 24 months there were 2% of cases of light or moderate dysplasia. Endometrial cytology shows cellular inflammation, which worsens with time. Endometrial histology shows: 1) for inert IUDs and after 3-4 years of use, a histio-leukocytic action is evident; 2) for copper IUDs there is no particular alteration for the 1st months; after 18-24 months papillary metaplasia is evident; and 3) for progesterone-releasing IUDs a lympho-plasmocytic infiltration is visible in the 1st month of use, with typical hormonal reactions. This study shows that the uterine mucosa is not affected by an IUD for the 1st 2 years of use, after which the signs of inflammatory reaction are minor and common to any IUD type. The regeneration of the mucosa is very quick after IUD removal.

Electrical properties of the costo-uterine muscle of the guinea-pig.

PubMed Central

Parkington, H C

1983-01-01

The spontaneous electrical and mechanical activity of the costo-uterine muscle of the guinea-pig are described. The spontaneous electrical activity, recorded intracellularly, is similar to that observed previously in longitudinal myometrium of rat (Marshall, 1959) and ionic substitution suggests that, though calcium may be the predominant ion carrying the current during the upstroke of the action potential, some influence of sodium cannot be ruled out. During dioestrus, when circulating progesterone levels are high, there is an increase in the resting membrane potential and a decrease in the frequency of electrical and mechanical activity. There is a two-fold decrease in the space constant (lambda) during dioestrus. At this time the membrane time constant (tau m) is also decreased. The diameter and length of the smooth muscle cells are smaller during dioestrus. However, the differences in cell diameter do not explain all of the differences observed in lambda at this time and it is suggested that there may be an increase in the resistance to current flow between cells. It is concluded that high circulating progesterone may bring about quiescence of target smooth muscle in two ways: by stabilizing the cell membrane and by restricting the spread of activity. PMID:6683758

Environmental gestagens activate fathead minnow (Pimephales promelas) nuclear progesterone and androgen receptors in vitro

EPA Science Inventory

Gestagen is a collective term for endogenous and synthetic progesterone receptor (PR) ligands. In teleost fishes, 17á,20â-dihydroxy-4-pregnen-3-one (DHP) and17á,20â,21- trihydroxy-4-pregnen-3-one (20â-S) are the predominant progestogens, whereas in other vertebrates the major pro...

[Endocrine differences between patients with luteal phase deficiency and inadequate endometrial response].

PubMed

Xu, M; Zhang, Z; Jiang, S

1997-03-01

To study the difference of endocrine characteristics between patients with luteal phase deficiency (LPD) and inadequate endometrial response (IER). Serum estradiol (E2), progesterone (P), follicle-stimulating hormone, luteinizing hormone and prolactin levels were determined by radioimmunoassay in cycles of LPD, IER and normal controls. Contents of endometrial cytoplasmic estradiol receptors (ERc), nuclear estradiol receptors (ERn), cytoplasmic progesterone receptors (PRc) and nuclear progesterone receptors (PRn) were determined by dextran coated charcoal assay in the same cycle. Serum E2 and P levels in the luteal phase of patients with LPD were significantly lower than those of normal group (P < 0.001), no significant difference of endometrial estrogen receptor and progesterone receptor contents was found between the two groups (P > 0.1). Serum E2 levels in both follicular and luteal phase of IER patients were significantly lower than those of normal groups (P < 0.001), but serum P levels in luteal phase of the two groups showed no difference (P > 0.1). The contents of ERc and PRn in proliferative phase and PRc contents throughout the menstrual cycle were also lower than those of the normal group (P < 0.001, < 0.001 and < 0.05 respectively). These results indicate that LPD and IER are two distinct entities in terms of endocrine characteristics. To distinguish underdeveloped endometrium caused by either LPD or IER is the key to choose appropriate treatment.

Progesterone Decreases in vitro Indoleamine 2, 3-dioxygenase Expression in Dendritic and CD4+ Cells from Maternal-Fetal Interface of Rats.

PubMed

Bianchi, Pedro Kastein Faria da Cunha; Leandro, Rafael Magdanelo; Poscai, Aline Nayara; Yoshinaga, Tulio; Gonçalez, Patrícia Orlandini; Kfoury Junior, José Roberto

2017-07-01

Several mechanisms contribute to the tolerogenic state observed during pregnancy, such as the activity of the enzyme indoleamine 2, 3-dioxygenase (IDO). This initializes the catabolism of tryptophan, inducing T cells to apoptosis due to its deprivation and by the action of its catabolites in the placental microenvironment. Progesterone plays an important part on immunological tolerance mechanisms during pregnancy; however, there is no evidence it is related to IDO activity. Thus, this study aimed to investigate progesterone influence on the maternal-fetal interface of pregnant Wistar rats, by identifying IDO positive cells by immunophenotyping and flow cytometry under exogenous progesterone supplementation. Placenta and embryo cells were cultured and separated into groups that received interferon γ or progesterone, supplemented or not with mifepristone. After 2 and 24 h, these were labeled with an anti-IDO and a series of antibodies specific to leucocytes and progesterone receptor and processed through flow cytometry analysis. Progesterone induced a significant decrease in the expression of IDO in dendritic cells and CD4 + lymphocytes. The blocking of progesterone receptor on these cells by mifepristone restored IDO expression levels and may constitute evidence of the participation of this hormone through a direct route in these cells.

Estrogen receptor, progesterone receptor and CD8+ expression in endometrium of women of unexplained infertility.

PubMed

Dixit, Shilpi Gupta; Ghatak, Surajit; Singh, Pratibha; Bhattacharya, Shilajit

2018-05-18

The present study aimed to investigate the changes of endometrial progesterone and estrogen receptors in luteal phase biopsy specimens of infertile women and find a correlation, if any, between these and CD8+ receptors in the same. The study was conducted on luteal phase endometrial biopsy specimens of 30 women of unexplained infertility and 15 age matched controls. Paraffin sections were first H & E stained. A standardized immunohistochemical protocol was then used to localize the estrogen, progesterone and CD8+ receptors in these samples that were expressed as percentage positivity. Unpaired T test was applied between the controls and cases both for epithelial and stromal cells. The data was also analyzed for correlation in cases for the positivity of CD8+ Cells with that of ER and PR. The positivity of estrogen receptors (ER) in stromal cells was significantly lower (p<0.001) in the infertile women when compared to controls and in both the epithelial and stromal cells for progesterone receptors (p<0.001). The results were non significant for CD8+ cells (p=0.19) and also showed no significant correlation in the positivity of CD8+ cells with that of ER and PR. The development of molecular probe like ER and PR positivity in endometrial epithelial and stromal cells allows a new approach to be made to the characterization of normal and defective endometrial function. Copyright © 2018. Published by Elsevier Masson SAS.

Negative Effects of SRD5A1 on Nuclear Activity of Progesterone Receptor Isoform B in JEG3 Cells.

PubMed

Miao, Zhuo; Sun, Min; Jiang, Feng; Yao, Yuanqing; Li, Yi

2016-02-01

Progesterone withdrawal signals labor in mammals. Elevated intracellular metabolism contributes to progesterone functional withdrawal through unknown mechanism, which is thought to act via progesterone receptor (PR). This study aims to investigate molecular mechanisms underlying progesterone withdrawal during pregnancy and labor. We investigated the role of 5α-reductase type I (SRD5A1) in enzymatic catalysis of progesterone and loss of PR function in a human trophoblast choriocarcinoma cell line JEG3. The PR isoform B (PR-B) was robustly expressed in JEG3 cells. The SRD5A1 small-interfering RNA knockdown led to significant increase in PR-B nuclear import, ectopic, whereas SRD5A1 overexpression resulted in remarkable inhibition of nuclear PR-B in P4-treated cells. Repression of SRD5A1 activated PR-B responsive gene, whereas overexpression of SRD5A1 possessed an inhibitory effect. JEG3 cell line is a valuable tool to study mechanisms responsible for loss of PR function and screening of drugs for preterm birth treatment. Our study aims to investigate the molecular mechanisms underlying progesterone withdrawal during pregnancy and labor. © The Author(s) 2015.

Uterine responses to feeding soy protein isolate and treatment with 17β-estradiol differ in ovariectomized female rats

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

Ronis, Martin J., E-mail: mronis@lsuhsc.edu; Gomez-Acevedo, Horacio; Blackburn, Michael L.

There are concerns regarding reproductive toxicity from consumption of soy foods, including an increased risk of endometriosis and endometrial cancer, as a result of phytoestrogen consumption. In this study, female rats were fed AIN-93G diets made with casein (CAS) or soy protein isolate (SPI) from postnatal day (PND) 30, ovariectomized on PND 50 and infused with 5 μg/kg/d 17β-estradiol (E2) or vehicle. E2 increased uterine wet weight (P < 0.05). RNAseq analysis revealed that E2 significantly altered expression of 1991 uterine genes (P < 0.05). SPI feeding had no effect on uterine weight and altered expression of far fewer genesmore » than E2 at 152 genes (P < 0.05). Overlap between E2 and SPI genes was limited to 67 genes. Functional annotation analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of estrogen receptor (ER)α to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were carcinogenesis and extracellular matrix organization, whereas SPI feeding up-regulated uterine peroxisome proliferator activated receptor (PPAR) signaling and fatty acid metabolism. The combination of E2 and SPI resulted in significant regulation of 504 fewer genes relative to E2 alone. The ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA) as measured by expression of PCNA and Ki67 mRNA was suppressed by feeding SPI (P < 0.05). These data suggest that SPI is a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and is anti-estrogenic in the presence of endogenous estrogens. - Highlights: • Concerns exist regarding risk of uterine cancer from consumption of soy products. • These concerns are related to potential estrogenicity. • Estradiol and soy protein isolate effects on uterine gene expression were compared. • Soy acts as a selective estrogen receptor modulator not a weak estrogen. • Soy feeding blocked uterine proliferation after treatment with estradiol and DMBA.« less

Plasma progesterone levels and corpus luteum morphology in the female prairie dog (Cynomys ludovicianus).

PubMed

Foreman, D; Garris, D

1984-08-01

Plasma progesterone levels in female prairie dogs were determined by a radioimmunoassay specific for progesterone. Plasma progesterone levels were determined in samples taken before estrus, at estrus, during the luteal phase, and during anestrus from females maintained all year in the laboratory. Progesterone levels were also determined in plasma samples taken in the laboratory from two pregnant and three postparturient females captured in the field. Progesterone levels were low before estrus and continued low during estrus. They rose on the first week after estrus to 0.8 ng/ml or above and continued at or above this level for 9-14 weeks following estrus. Gestation in prairie dogs is 35 days in this species. Progesterone levels of three postparturient females were above 1.0 ng/ml for 7 weeks after their arrival in the laboratory. These females all had uterine scars showing that they had delivered their litters before they were captured. Two females were determined to be pregnant at the time of their capture. These females later reabsorbed their fetuses (determined by laparotomy). Progesterone values of samples from these females were all above 1.0 ng/ml except for one low value in one female which occurred 3 weeks after her capture and after reabsorption of her fetuses was in progress. The cells of the corpus lutea (CL) of nonpregnant, pregnant, and postparturient females had well-developed rings of cytoplasmic basophilia but as the CL regressed this pattern became disorganized and disappeared. The function of this basophilia is not known. The long luteal phase found in female prairie dogs is compared to those found in other species of mammals. This is the first annually breeding rodent reported to have a longer luteal phase that the period of gestation.

Involvement of GABAA receptor in Bufo arenarum oocyte maturation.

PubMed

Toranzo, G Sánchez; Zelarayán, L; Bonilla, F; Oterino, J; Bühler, M I

2008-05-01

Amphibian oocytes meiotic arrest is released under the stimulus of progesterone; this hormone interacts with the oocyte surface and starts a cascade of events leading to the activation of a cytoplasmic maturation promoting factor (MPF) that induces germinal vesicle breakdown (GVBD), chromosome condensation and extrusion of the first polar body. The aim of this work was to determine whether the activation of a GABAA receptor is able to induce GVBD in fully grown denuded oocytes of Bufo arenarum and to analyse its possible participation in progesterone-induced maturation. We also evaluated the role of purines and phospholipids in the maturation process induced by a GABAA receptor agonist such as muscimol. Our results indicated that the activation of the GABAA receptor by muscimol induces maturation in a dose- and time-dependent manner and that this activation is a genuine maturation that enables oocytes to form pronuclei. Assays with a receptor antagonist, picrotoxine, showed that the maturation induced by muscimol was inhibited. Treatment with picrotoxine, however, shows that the participation of GABAA receptor in progesterone-induced maturation is not significant. In addition, our results indicate that high intracellular levels of purines obtained by the use of db-AMPc and theophylline or the inhibition of the phosphatidylinositol 4,5-bisphosphate (PIP2 hydrolysis by neomycin and PIP2 turn over by LiCl, respectively, inhibited the maturation induced by muscimol. Treatment with H-7 indicated, however, that PKC activation is not necessary for GVBD induced by the GABAA receptor agonist. Results suggest that the transduction pathway used by the GABAA receptor to induce maturation is different from those used by progesterone.

Haploinsufficiency for Adrenomedullin Reduces Pinopodes and Diminishes Uterine Receptivity in Mice1

PubMed Central

Li, Manyu; Wu, Yongqin; Caron, Kathleen M.

2008-01-01

Adrenomedullin (AM) is a multifunctional peptide vasodilator that signals through a G-protein-coupled receptor when the receptor, called calcitonin receptor-like receptor (CL), is associated with a receptor activity-modifying protein 2 (RAMP2). We demonstrated previously that haploinsufficieny for each of these genes led to reduced maternal fertility, and that even a modest genetic reduction of AM peptide caused maternal defects in implantation, placentation, and fetal growth. Here, we further demonstrate that Adm+/− female mice displayed reduced pregnancy success rates that were not caused by defects in folliculogenesis, ovulation, or fertilization. The poor fertility of Adm+/− female mice could not be rescued by transfer of wild-type blastocysts, which suggested an underlying defect in uterine receptivity. In fact, we found that Adm, Calcrl, and Ramp2 gene expressions are tightly and spatiotemporally regulated in the luminal epithelial cells of the uterus during the estrus cycle and the peri-implantation period. RAMP3, which also generates an AM receptor when associated with CL, had a diametrically opposite expression pattern than that of Adm, Calcrl, and Ramp2 and was most robustly induced in the stroma of the uterus. Finally, we discovered that Adm+/− female mice have a substantially reduced number of pinopodes on the uterine luminal epithelial surface, which is indicative and possibly causative of the poor uterine receptivity. Taken together, our studies identify a new class of pharmacologically tractable proteins that are involved in establishing uterine receptivity through the regulation of pinopode formation. PMID:18716289

Selective suppression of endothelial cytokine production by progesterone receptor.

PubMed

Goddard, Lauren M; Ton, Amy N; Org, Tõnis; Mikkola, Hanna K A; Iruela-Arispe, M Luisa

2013-01-01

Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL-8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibition of Delta-like 4 mediated signaling induces abortion in mice due to deregulation of decidual angiogenesis.

PubMed

García-Pascual, C M; Ferrero, H; Zimmermann, R C; Simón, C; Pellicer, A; Gómez, R

2014-07-01

To explore whether the Dll4/Notch1 pathway plays a key role in regulating the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) driven decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. Progesterone-replaced ovariectomized pregnant mice received a single injection of YW152F (Dll4 blocking antibody, BAb) or placebo at embryonic day (E) 4.5. Animals were sacrificed at different time points; blood and uterus were collected for further analysis. Number of embryos and implantation site, uteri weight, and serum progesterone levels were assessed. Alterations in the tip/stalk phenotype were determined by quantitative immunofluorescent analysis of vascularization, Dll4 expression, cellular proliferation and apoptosis in uterine sections. Abrogation of Dll4 signaling leads to a promiscuous expression of Dll4, increased cell proliferation, apoptosis and vascularization at E 6.5. Such an abrogation was associated with a dramatic disruption of embryo growth and development starting at E 9.5. The observed promiscuous expression of Dll4 and the increase in cell proliferation, apoptosis and vascularization are events compatible with loss of the tip/stalk phenotype. Excessive (although very likely defective) decidual angiogenesis due to such vascular alterations is the most likely cause of subsequent interruption of embryo development and related pregnancy in Dll4 treated mice. Dll4 plays a key role in regulating decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. Copyright © 2014 Elsevier Ltd. All rights reserved.

Muscarinic receptor subtypes involved in carbachol-induced contraction of mouse uterine smooth muscle.

PubMed

Kitazawa, Takio; Hirama, Ryuichi; Masunaga, Kozue; Nakamura, Tatsuro; Asakawa, Koichi; Cao, Jinshan; Teraoka, Hiroki; Unno, Toshihiro; Komori, Sei-ichi; Yamada, Masahisa; Wess, Jürgen; Taneike, Tetsuro

2008-06-01

Functional muscarinic acetylcholine receptors present in the mouse uterus were characterized by pharmacological and molecular biological studies using control (DDY and wild-type) mice, muscarinic M2 or M3 single receptor knockout (M2KO, M3KO), and M2 and M3 receptor double knockout mice (M2/M3KO). Carbachol (10 nM-100 microM) increased muscle tonus and phasic contractile activity of uterine strips of control mice in a concentration-dependent manner. The maximum carbachol-induced contractions (Emax) differed between cervical and ovarian regions of the uterus. The stage of the estrous cycle had no significant effect on carbachol concentration-response relationships. Tetrodotoxin did not decrease carbachol-induced contractions, but the muscarinic receptor antagonists (11-[[2-[(diethylaminomethyl)-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b[2,3-b][1,4]benzodiazepin6-one (AF-DX116), N-[2-[2-[(dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4] benzodiazepine-11-carboxamide (AF-DX384), 4-diphenylacetoxy-N-methyl-piperidine(4-DAMP), para-fluoro-hexa hydro-sila-diphenidol (p-F-HHSiD), himbacine, methoctramine, pirenzepine, and tropicamide) inhibited carbachol-induced contractions in a competitive fashion. The pKb values for these muscarinic receptor antagonists correlated well with the known pKi values of these antagonists for the M3 muscarinic receptor. In uterine strips isolated from mice treated with pertussis toxin (100 microg/kg, i.p. for 96 h), Emax values for carbachol were significantly decreased, but effective concentration that caused 50% of Emax values (EC50) remained unchanged. In uterine strips treated with 4-DAMP mustard (30 nM) and AF-DX116 (1 microM), followed by subsequent washout of AF-DX116, neither carbachol nor N,N,N,-trimethyl-4-(2-oxo-1-pyrolidinyl)-2-butyn-1-ammonium iodide (oxotremorine-M) caused any contractile responses. Both M2 and M3 muscarinic receptor messenger RNAs were detected in the mouse uterus via reverse transcription polymerase chain reaction. Carbachol also caused contraction of uterine strips isolated from M2KO mice, but the concentration-response curve was shifted to the right and downward compared with that for the corresponding wild-type mice. On the other hand, uterine strips isolated from M3KO and M2/M3 double KO mice were virtually insensitive to carbachol. In conclusion, although both M2 and M3 muscarinic receptors were expressed in the mouse uterus, carbachol-induced contractile responses were predominantly mediated by the M3 receptor. Activation of M2 receptors alone did not cause uterine contractions; however, M2 receptor activation enhanced M3 receptor-mediated contractions in the mouse uterus.

Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway.

PubMed

Tropea, Teresa; De Francesco, Ernestina Marianna; Rigiracciolo, Damiano; Maggiolini, Marcello; Wareing, Mark; Osol, George; Mandalà, Maurizio

2015-01-01

The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature. The aim of this study was to determine the function of GPER in uterine arteries mainly during pregnancy. Uterine arteries were isolated from nonpregnant and pregnant rats. Vessels were contracted with phenylephrine and then incubated with incremental doses (10-12-10-5 M) of the selective GPER agonist G1. G1 induced a dose-dependent vasodilation which was: 1) significantly increased in pregnancy, 2) endothelium-dependent, 3) primarily mediated by NO/cGMP pathway and 4) unaffected by BKca channel inhibition. This is the first study to show the potential importance of GPER signaling in reducing uterine vascular tone during pregnancy. GPER may therefore play a previously unrecognized role in the regulation of uteroplacental blood flow and normal fetus growth.

Effects of phytoestrogens genistein and daidzein on progesterone and estrogen (estradiol) production of human term trophoblast cells in vitro.

PubMed

Richter, Dagmar Ulrike; Mylonas, Ioannis; Toth, Bettina; Scholz, Christoph; Briese, Volker; Friese, Klaus; Jeschke, Udo

2009-01-01

Phytoestrogens are a diverse group of nonsteroidal plant compounds that occur naturally in many plants. Because they possess a ring system similar to estrogens they are able to bind on estrogen receptors alpha and beta in humans. The effects of the phytoestrogens genistein and daidzein on the production of progesterone and estrogen in isolated human term trophoblast cells in vitro were tested in this study. Cytotrophoblast cells were isolated from human term placentas. Phytoestrogens genistein and daidzein were incubated in different concentrations with trophoblast cells. Untreated cells were used as controls. After 24 h aliquots were removed and tested for progesterone and estrogen production. The production of the steroid hormones progesterone and estrogen are influenced by phytoestrogens genistein and daidzein in human term trophoblast cells. A strong inhibition effect of both phytoestrogens tested in the production of progesterone was demonstrated. In addition, a significant stimulating effect on estrogen production by genistein and daidzein was observed. Results obtained with this study show that phytoestrogens (genistein and daidzein) sufficiently reduce progesterone production in human term trophoblast cells. Because blockade of progesterone is a possible mechanism involved in initiation of labor, we may speculate that high doses of phytoestrogens at the feto-maternal interphase could play a negative role in maintenance of pregnancy. Stimulation of estrogen production by genistein and daidzein in trophoblast cells is probably due to estrogen receptor blocking effects of both phytoestrogens. Trophoblast cells seem to compensate blocking of its estrogen receptors by higher estrogen production.

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.

Pregnancy Recognition and Implantation of the Conceptus in the Mare.

PubMed

Klein, Claudia

2015-01-01

Few, if any, biological processes are as diverse among domestic species as establishment of early pregnancy, in particular maternal recognition of pregnancy. Following fertilization and initial development in the mare oviduct, selective transport of the embryo through the uterotubal junction driven by embryo-derived PGE2 occurs. Upon arrival in the uterus, an acellular glycoprotein capsule is formed that covers the embryo, blastocyst, and conceptus (embryo and associated extraembryonic membranes) between the second and third weeks of pregnancy. Between Days 9 and 15/16 of pregnancy, the conceptus undergoes an extended phase of mobility. Conceptus mobility is driven by conceptus-derived PGF2α and PGE2 that stimulate uterine contractions which in turn propel migration of the conceptus within the uterine lumen. Cessation of conceptus mobility is referred to as fixation and appears to be attributable to increasing size of the conceptus, preferential thickening of the endometrium near the mesometrial attachment referred to as encroachment, and a reduction in sialic acid content of the capsule. During maternal recognition of pregnancy, endometrial PGF2α release is attenuated, a consequence of reduced expression of key enzymes involved in prostaglandin production. Oxytocin responsiveness is altered during early pregnancy, and reduced expression of the oxytocin receptor appears to be regulated at the posttranscriptional level rather than the transcriptional level. Prostaglandin release is attenuated temporarily only during early pregnancy; during the third week of pregnancy, the endometrium resumes the ability to secrete PGF2α. The equine conceptus initiates steroidogenesis as early as Day 6 and synthesizes estrogens, androgens, and progesterone. Estrogens are metabolized locally, presumably regulating their bioavailability and actions. Results of experiments attempting to prove that conceptus-derived estrogens are responsible for extension of corpus luteum function have been inconclusive. By the fourth week of pregnancy, the chorionic girdle becomes visible on the trophoblast. Subsequent invasion of chorionic girdle cells leads to formation of endometrial cups which secrete equine chorionic gonadotropin. Equine chorionic gonadotropin has luteinizing hormone functions in the mare, causing luteinization of follicles resulting in the formation of secondary corpora lutea essential to production of progesterone and maintenance of pregnancy.

The role of oestrogen and progesterone receptors in breast cancer – immunohistochemical evaluation of oestrogen and progesterone receptor expression in invasive breast cancer in women

PubMed Central

Patera, Janusz; Sobol, Maria; Przybylski, Jacek

2015-01-01

Aim of the study Expression of oestrogen and progesterone receptors is a very powerful and useful predictor. Because the response rate to hormonal treatment in breast cancer is associated with the presence of oestrogen and progesterone receptors, assessment of the receptor expression profile allows for prediction of breast cancer response to hormonal treatment. The aim of this study was to assess whether the expression of receptors for oestrogen (ER) and progesterone (PR) in the tumour tissue of patients with invasive breast cancer correlated with tumour histological type, histological grade of malignancy, tumour size, and lymph node status. Material and methods Materials consisted of histological preparations derived from patients treated for invasive breast cancer. Evaluations were conducted with histopathological and immunohistochemical methods using suitable antibodies. Results Among 231 cases of breast cancer 18 invasive lobular carcinomas (ILC) and 213 invasive ductal carcinomas (IDC) were diagnosed. Taking the histological type of tumour into account, oestrogen receptor-positive reaction was observed in 74.2% of IDC and 77.8% of ILC, and the positive response to PR was observed in 67.1% of IDC and 61.1% of ILC. Considering the histological grade, ER- in the largest percentage (72%) was observed in second-grade (G2) invasive carcinomas. Similarly, PR expression (75%) was found in the largest percentage in second-grade (G2) carcinomas. Based on our own studies and data from literature, it appears that the ER (+) status is an indicator of good prognosis, because it points to a less aggressive cancer, in which overall survival and disease-free time is longer in comparison with ER (–) tumours. Conclusions Determination of ER status may, therefore, have significant clinical value and is widely used in routine pathological diagnostics. PMID:26557763

Novel 5-aryl-1,3-dihydro-indole-2-thiones. potent, orally active progesterone receptor agonists.

PubMed

Fensome, Andrew; Koko, Marci; Wrobel, Jay; Zhang, Puwen; Zhang, Zhiming; Cohen, Jeffrey; Lundeen, Scott; Rudnick, Kelly; Zhu, Yuan; Winneker, Richard

2003-04-07

During the course of our studies on 3,3-disubstituted-5-aryloxindoles derived progesterone receptor (PR) antagonists we discovered that changing the amide funtionality to a thio-amide resulted in compounds displaying potent PR agonist activity. In this communication, the synthesis, structure activity relationships (SAR) and in vivo activity of various 5-arylthio-oxindoles will be discussed.

Human Chorionic Gonadotrophin as a Possible Mediator of Leiomyoma Growth during Pregnancy: Molecular Mechanisms.

PubMed

Sarais, Veronica; Cermisoni, Greta Chiara; Schimberni, Matteo; Alteri, Alessandra; Papaleo, Enrico; Somigliana, Edgardo; Vigano', Paola

2017-09-20

Uterine fibroids are the most common gynecologic benign tumors. Studies supporting a strong pregnancy-related growth of leiomyomas generally claimed a crucial role of sex steroid hormones. However, sex steroids are unlikely the unique actors involved as estrogen and progesterone achieve a pick serum concentration in the last trimester while leiomyomas show a typical increase during the first trimester. Given the rapid exponential raise in serum human Chorionic Gonadotrophin (hCG) at the beginning of gestation, we conducted a review to assess the potential role of hCG in the striking growth of leiomyomas during initial pregnancy. Fibroid growth during initial pregnancy seems to correlate to the similar increase of serum hCG levels until 12 weeks of gestation. The presence of functional Luteinizing Hormone/human Chorionic Gonadotropin (LH/hCG) receptors was demonstrated on leiomyomas. In vitro treatment of leiomyoma cells with hCG determines an up to 500% increase in cell number after three days. Expression of cyclin E and cyclin-dependent kinase 1 was significantly increased in leiomyoma cells by hCG treatment. Moreover, upon binding to the receptor, hCG stimulates prolactin secretion in leiomyoma cells, promoting cell proliferation via the mitogen-activated protein kinase cascade. Fibroid enlargement during initial pregnancy may be regulated by serum hCG.

Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

PubMed

Johnson, Michael D; Kenney, Nicholas; Stoica, Adriana; Hilakivi-Clarke, Leena; Singh, Baljit; Chepko, Gloria; Clarke, Robert; Sholler, Peter F; Lirio, Apolonio A; Foss, Colby; Reiter, Ronald; Trock, Bruce; Paik, Soonmyoung; Martin, Mary Beth

2003-08-01

It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

Human Chorionic Gonadotrophin as a Possible Mediator of Leiomyoma Growth during Pregnancy: Molecular Mechanisms

PubMed Central

Sarais, Veronica; Cermisoni, Greta Chiara; Schimberni, Matteo; Alteri, Alessandra; Papaleo, Enrico; Somigliana, Edgardo; Vigano’, Paola

2017-01-01

Uterine fibroids are the most common gynecologic benign tumors. Studies supporting a strong pregnancy-related growth of leiomyomas generally claimed a crucial role of sex steroid hormones. However, sex steroids are unlikely the unique actors involved as estrogen and progesterone achieve a pick serum concentration in the last trimester while leiomyomas show a typical increase during the first trimester. Given the rapid exponential raise in serum human Chorionic Gonadotrophin (hCG) at the beginning of gestation, we conducted a review to assess the potential role of hCG in the striking growth of leiomyomas during initial pregnancy. Fibroid growth during initial pregnancy seems to correlate to the similar increase of serum hCG levels until 12 weeks of gestation. The presence of functional Luteinizing Hormone/human Chorionic Gonadotropin (LH/hCG) receptors was demonstrated on leiomyomas. In vitro treatment of leiomyoma cells with hCG determines an up to 500% increase in cell number after three days. Expression of cyclin E and cyclin-dependent kinase 1 was significantly increased in leiomyoma cells by hCG treatment. Moreover, upon binding to the receptor, hCG stimulates prolactin secretion in leiomyoma cells, promoting cell proliferation via the mitogen-activated protein kinase cascade. Fibroid enlargement during initial pregnancy may be regulated by serum hCG. PMID:28930160

Progesterone-Mediated Non-Classical Signaling.

PubMed

Garg, Deepika; Ng, Sinnie Sin Man; Baig, K Maravet; Driggers, Paul; Segars, James

2017-09-01

Progesterone is essential for pregnancy maintenance and menstrual cycle regulation. Hormone action has been primarily ascribed to the well-characterized classical signaling pathway involving ligand binding, activation of nuclear progesterone receptors (PRs), and subsequent activation of genes containing progesterone response elements (PREs). Recent studies have revealed progesterone actions via non-classical signaling pathways, often mediated by non-genomic signaling. Progesterone signaling, in conjunction with growth factor signaling, impacts on the function of growth factors and regulates important physiological actions such as cell growth and remodeling, as well as apoptosis. This review focuses on non-classical progesterone signaling pathways, both including and excluding PR, and highlights how research in this area will provide a better understanding of progesterone actions and may inform novel therapeutic strategies. Copyright © 2017. Published by Elsevier Ltd.

Progesterone promotes maternal–fetal tolerance by reducing human maternal T‐cell polyfunctionality and inducing a specific cytokine profile

PubMed Central

Eldershaw, Suzy A.; Inman, Charlotte F.; Coomarasamy, Aravinthan; Moss, Paul A. H.; Kilby, Mark D.

2015-01-01

Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4+ and CD8+ T cells, with reductions not only in potentially deleterious IFN‐γ and TNF‐α production but also in IL‐10 and IL‐5. Conversely, production of IL‐4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL‐4. This was accompanied by reduced T‐cell proliferation. Using fetal and viral antigen‐specific CD8+ T‐cell clones, we confirmed that this as a direct, nonantigen‐specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4+ and CD8+ T cells responded to progesterone in a dose‐dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal–fetal interface. This characterization of how progesterone modulates T‐cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss. PMID:26249148

[Effects of ursodeoxycholic acid on the liver plasma membrane fluidity, hepatic glutathione concentration, hepatic estrogen receptors and progesterone receptors in pregnant rats with ethinylestradiol and progesterone induced intrahepatic cholestasis].

PubMed

Shi, Qing-yun; Kong, Bei-hua; Ma, Kai-dong; Zhang, Xiang-li; Jiang, Sen

2003-11-01

To explore the effects of ursodeoxycholic acid (UDCA) on the fluidity of hepatic plasma membrane, glutathione concentration in liver, hepatic estrogen receptors and progesterone receptors in pregnant rats with ethinylestradiol and progesterone induced intrahepatic cholestasis. sixty clean SD pregnant rats were selected and divided into three groups at random. Since the 13th day of pregnancy after taking blood, normal group was injected subcutaneously with refined vegetable oil 2.5 ml x kg(-1) x d(-1). Control group and treatment group were injected subcutaneously with the solution of progesterone 75 mg x kg(-1) x d(-1) and 17-alpha-ethynylestradio 1.25 mg x kg(-1) x d(-1) till the 17th day. Since the 17th day control group, normal group were fedwish 0.9% natriichloridi solution 5 ml x kg(-1) x d(-1); Treatment group was fedwish UDCA 50 mg x kg(-1) x d(-1) every day. On the 21th day, all rats were killed. Then the livers were collected for study. Membrane fluidity was measured by fluorescence polarization using 1,6-diphenyl-1,3,5-hexatriene (DPH) as a probe. Glutathione concentration was measured by 5,5'-dithionbis (2-nitrobenzoic acid) (DTNB). Estrogen receptors and progesterone receptors were measured by flow cytometry. (1) Hepatic plasma membrane fluidity and glutathione (GSH) concentration: significantly lower level of GSH concentration and higher fluorescence polarization (P) were detected in control group (GSH: 1.13 +/- 0.03, P: 0.149 +/- 0.008) in comparison with normal group (GSH: 2.11 +/- 0.07, P: 0.132 +/- 0.004, P < 0.05). However, Significantly higher level of GSH concentration and lower fluorescence polarization were detected in treatment group (GSH: 1.82 +/- 0.04, P: 0.141 +/- 0.006) in comparison with control group (P < 0.05). The level of GSH concentration and fluorescence polarization were no difference between treatment group and normal group. Hepatic estrogen receptors (ER) and progesterone receptors (PR): The expression of ER and PR in control group (ER: 89.4 +/- 8.4, PR: 112.3 +/- 11.6) were higher than that of other two groups (P < 0.05). The expression of ER and PR in treatment group (ER: 56.4 +/- 7.5, PR: 70.1 +/- 9.3) were lower than that of control group (P < 0.05). But there was no difference between treatment group and normal group (ER: 39.5 +/- 7.3, PR: 59.6 +/- 7.4; P > 0.05). Ursodeoxycholic acid may be effective drug in treatment intrahepatic cholestasis of pregnancy.

TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain.

PubMed

Ortíz-Rentería, Miguel; Juárez-Contreras, Rebeca; González-Ramírez, Ricardo; Islas, León D; Sierra-Ramírez, Félix; Llorente, Itzel; Simon, Sidney A; Hiriart, Marcia; Rosenbaum, Tamara; Morales-Lázaro, Sara L

2018-02-13

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.

Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators.

PubMed

Donnez, Jacques; Arriagada, Pablo; Donnez, Olivier; Dolmans, Marie-Madeleine

2015-12-01

To review the current management of myomas with the advent of selective progesterone receptor modulators. Selective progesterone receptor modulators have proved effective and recent publications on the use of ulipristal acetate (UPA) have analyzed the performance of long-term intermittent utilization of 10 mg UPA given in repeated courses of 3 months. This long-term intermittent therapy maximizes the efficacy of UPA. Indeed, control of bleeding is achieved sooner after each course. With each subsequent course, a statistically greater number of patients show a fibroid volume reduction of more than 50%. The choice of therapy is influenced by different factors, such as the severity of symptoms, tumor characteristics, age, and wish to preserve the uterus (and fertility). Use of UPA will undoubtedly modify the surgical approach.

Accelerated Episodic LH Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca mulatta) Exposed to Testosterone During Early-to-Mid Gestation.

PubMed

Abbott, David H; Vepraskas, Sarah H; Horton, Teresa H; Terasawa, Ei; Levine, Jon E

2018-06-15

Ovarian theca cell hyperandrogenism in women with PCOS is compounded by androgen receptor-mediated impairment of estradiol and progesterone negative feedback regulation of episodic LH release. The resultant LH hypersecretion, likely the product of accelerated episodic release of GnRH from the median eminence of the hypothalamus, hyperstimulates ovarian theca cell steroidogenesis, enabling testosterone (T) and androstenedione excess. Prenatally androgenized female monkeys (PA) exposed to fetal male levels of T during early-to-mid gestation, when adult, demonstrate PCOS-like traits, including high T and LH levels. This study tests the hypothesis that progesterone resistance-associated acceleration in episodic LH release contributes to PA monkey LH excess. 4 PA and 3 regularly cycling, healthy control adult female rhesus monkeys of comparable age and body mass index underwent (1) a 10 h, frequent intravenous sampling assessment for LH episodic release, immediately followed by (2) IV infusion of exogenous GnRH to quantify continuing pituitary LH responsiveness, and subsequently (3) an SC injection of a progesterone receptor antagonist, mifepristone, to examine LH responses to blockade of progesterone-mediated action. Compared to controls, the relatively hyperandrogenic PA females exhibited ~100% increase (p = 0.037) in LH pulse frequency, positive correlation of LH pulse amplitude (p = 0.017) with androstenedione, ~100% greater increase (p = 0.034) in acute (0--10 min) LH responses to exogenous GnRH, and an absence (p = 0.008) of modest LH elevation following acute progesterone receptor blockade suggestive of diminished progesterone negative feedback. Such dysregulation of LH release in PCOS-like monkeys implicates impaired feedback control of episodic release of hypothalamic GnRH reminiscent of PCOS neuroendocrinopathy. 2018 S. Karger AG, Basel.

A comprehensive approach to the treatment of uterine leiomyomata.

PubMed

Stein, Karen; Ascher-Walsh, Charles

2009-12-01

Leiomyomas (fibroids) are the most common tumors in women, with a prevalence between 30% and 50%. They affect women primarily during their reproductive years, spontaneously regressing after menopause in most women. They may cause significant symptoms of pain, dysmenorrhea, abnormal uterine bleeding, and infertility. Because leiomyomas are so common, treatment should be reserved for those patients with symptoms. Treatment options have recently expanded beyond hysterectomy. Medical therapies, including gonadotropin-releasing hormone agonists and progesterone modulators, have become more widely used. Less invasive options such as uterine fibroid embolization, magnetic resonance imaging-guided focused ultrasound, and radiofrequency ablation are being used to avoid more invasive surgery. Because of limited and negative information regarding these alternatives to surgery, they are not recommended for women desiring future fertility. If surgery is desired or required, often less invasive approaches via hysteroscopy for intracavitary lesions or robot-assisted laparoscopy for patients with a small number of myomas have become preferred options. Treatment should be tailored to the patient. Copyright 2009 Mount Sinai School of Medicine.

The effect of intra-uterine devices on the reproductive physiology and behaviour of pony mares.

PubMed

Argo, C M; Turnbull, E B

2010-10-01

Spherical (35 mm diameter) glass intra-uterine devices (IUDs) are commonly understood to modify sexual behaviour in performance mares. The effect of IUDs on the endocrinology (luteinising hormone, oestradiol, progesterone, testosterone), ovarian and uterine function, sexual and social behaviours associated with the ovarian cycle were evaluated during the natural breeding season in nine, nuliparous pony mares (4.6±0.5 years old, 230±12 kg bodyweight). Age and weight-matched groups were allocated to sham-treatment (n=5) or IUD-implantation (n=4) groups. Fifty complete ovarian cycles were evaluated, with 26 ovarian cycles monitored for the nine mares prior to treatment and a further 12 cycles were evaluated for mares in each of the groups post-treatment. Detailed characterisation of cyclic reproductive changes in the pony may be of value for controlled breeding programmes. The presence of an IUD was well-tolerated, but failed to modify any recorded aspect of reproductive physiology or behaviour. Crown Copyright © 2009. Published by Elsevier Ltd. All rights reserved.

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.

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.

Progesterone receptor modulates estrogen receptor-α action in breast cancer

PubMed Central

Mohammed, Hisham; Russell, I. Alasdair; Stark, Rory; Rueda, Oscar M.; Hickey, Theresa E.; Tarulli, Gerard A.; Serandour, Aurelien A. A.; Birrell, Stephen N.; Bruna, Alejandra; Saadi, Amel; Menon, Suraj; Hadfield, James; Pugh, Michelle; Raj, Ganesh V.; Brown, Gordon D.; D’Santos, Clive; Robinson, Jessica L. L.; Silva, Grace; Launchbury, Rosalind; Perou, Charles M.; Stingl, John; Caldas, Carlos; Tilley, Wayne D.; Carroll, Jason S.

2015-01-01

Summary Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions. PMID:26153859

Transforming Growth Factor β1 (TGFβ1) and Progesterone Regulate Matrix Metalloproteinases (MMP) in Human Endometrial Stromal Cells

PubMed Central

Itoh, Hiroko; Kishore, Annavarapu Hari; Lindqvist, Annika; Rogers, David E.

2012-01-01

Context: Menstruation is preceded by progesterone withdrawal and endometrial matrix remodeling predominantly through induction of matrix metalloproteinases (MMP) and recruitment of invading neutrophils. Design: Using endometrial tissues from women during various phases of the menstrual cycle, we found that MMP2, MMP9, and MMP11 were up-regulated in the late secretory phase/premenstrual phase. Because TGFβ-responsive genes were also up-regulated in endometrium during this time, we tested the hypothesis that TGFβ1 and progesterone regulate expression of MMP in human endometrial stromal cells (HESC). Results: Treatment of HESC with TGFβ1 resulted in marked increases in MMP2 and MMP11 mRNA and pro- and active MMP2 activity. Progesterone inhibited TGFβ1-induced stimulation of MMP2 and MMP11 through its nuclear hormone receptors. Interestingly, TGFβ1 also decreased progesterone receptor (PR)-A and PR-B in HESC with a more pronounced effect on PR-A. Conclusions: These data support the hypothesis that TGFβ1 has endogenous anti-progestational effects in HESC and that the opposing effects of progesterone and TGFβ1 are important in regulation of matrix integrity in human endometrium. PMID:22466340

Developmental profiles of progesterone receptor transcripts and molecular responses to gestagen exposure during Silurana tropicalis early development.

PubMed

Thomson, Paisley; Langlois, Valerie S

2018-05-18

Environmental gestagens are an emerging class of contaminants that have been recently measured in surface water and can interfere with reproduction in aquatic vertebrates. Gestagens include endogenous progestogens, such as progesterone (P4), which bind P4-receptors and have critically important roles in vertebrate physiology and reproduction. Gestagens also include synthetic progestins, which are components of human and veterinary drugs, such as melengestrol acetate (MGA). Endogenous progestogens are essential in the regulation of reproduction in mammalian species, but the role of P4 in amphibian larval development remains unclear. This project aims to understand the roles and the regulatory mechanisms of P4 in amphibians and to assess the consequences of exposures to environmental gestagens on the P4-receptor signaling pathways in frogs. Here, we established the developmental profiles of the P4 receptors: the intracellular progesterone receptor (ipgr), the membrane progesterone receptor β (mpgrβ), and the progesterone receptor membrane component 1 (pgrmc1) in Western clawed frog (Silurana tropicalis) embryos using real-time qPCR. P4-receptor mRNAs were detected throughout embryogenesis. Transcripts for ipgr and pgrmc1 were detected in embryos at Nieuwkoop and Faber (NF) stage 2 and 7, indicative of maternal transfer of mRNA. We also assessed the effects of P4 and MGA exposure in embryonic and early larval development. Endocrine responses were evaluated through transcript analysis of a suite of gene targets of interest, including: ipgr, mpgrβ, pgrmc1, androgen receptor (ar), estrogen receptor α (erα), follicle stimulating hormone β (fshβ), prolactin (prl), and the steroid 5-alpha reductase family (srd5α1, 2, and 3). Acute exposure (NF 12-46) to P4 caused a 2- to 5-fold change increase of ipgr, mpgrβ, pgrmc1, and ar mRNA levels at the environmentally relevant concentration of 195 ng/L P4. Acute exposure to MGA induced a 56% decrease of srd5α3 at 1140 ng/L MGA. We conclude that environmental exposure to P4 induced multiple endocrine-related transcript responses in amphibians; however, the differential responses of MGA suggest that the effects of MGA are not mediated through the classical P4 signaling pathway in S. tropicalis. Copyright © 2018 Elsevier Inc. All rights reserved.

GPR30 Activation Opposes Estrogen-Dependent Uterine Growth via Inhibition of Stromal ERK1/2 and Estrogen Receptor Alpha (ERα) Phosphorylation Signals

PubMed Central

Gao, Fei; Ma, Xinghong; Ostmann, Alicia B.

2011-01-01

Although estradiol-17β (E2)-regulated early and late phase uterine responses have been well defined, the molecular mechanisms linking the phases remain poorly understood. We have previously shown that E2-regulated early signals mediate cross talk with estrogen receptor (ER)-α to elicit uterine late growth responses. G protein-coupled receptor (GPR30) has been implicated in early nongenomic signaling mediated by E2, although its role in E2-dependent uterine biology is unclear. Using selective activation of GPR30 by G-1, we show here a new function of GPR30 in regulating early signaling events, including the inhibition of ERK1/2 and ERα (Ser118) phosphorylation signals and perturbation of growth regulation under the direction of E2 in the mouse uterus. We observed that GPR30 primarily localizes in the uterine epithelial cells, and its activation alters gene expression and mediates inhibition of ERK1/2 and ERα (Ser118) phosphorylation signals in the stromal compartment, suggesting a paracrine signaling is involved. Importantly, viral-driven manipulation of GPR30 or pharmacological inhibition of ERK1/2 activation effectively alters E2-dependent uterine growth responses. Overall, GPR30 is a negative regulator of ERα-dependent uterine growth in response to E2. Our work has uncovered a novel GPR30-regulated inhibitory event, which may be physiologically relevant in both normal and pathological situations to negatively balance ERα-dependent uterine growth regulatory functions induced by E2. PMID:21303939

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.

Induction of the Estrogenic Marker Calbindn-D9k by Octamethylcyclotetrasiloxane

PubMed Central

Lee, Dongoh; Ahn, Changhwan; An, Beum-Soo; Jeung, Eui-Bae

2015-01-01

Interrupting the hormonal balance of an organism by interfering with hormones and their target receptors gives rise to various problems such as developmental disorders. Collectively, these reagents are known as endocrine disruptors (EDs). Cyclic volatile methyl siloxanes (cVMSs) are a group of silicone polymers that including octamethylcyclotetrasiloxane (D4). In the present study, we examined the estrogenicity of D4 through in vitro and in vivo assays that employed calcium-binding protein 9K (calbindin-D9k; CaBP-9K) as a biomarker. For in vitro investigation, GH3 rat pituitary cells were exposed to vehicle, 17β-estradiol (E2), or D4 with/without ICI 182 780 (ICI). CaBP-9K and progesterone receptor (PR) both were up-regulated by E2 and D4 which were completely blocked by ICI. Transcription of estrogen receptor α (ER α) was decreased by E2 and D4 but increased by ICI. D4 was also administered to immature female rats for an uterotrophic (UT) assay and detection of CaBP-9K. Ethinyl estradiol (EE) or D4 was administered subcutaneously with or without ICI. Although uterine weight was not significant altered by D4, an effect thought to be due to cytochrome P450 (CYP), it induced CaBP-9K and PR gene expression. Based on these results we reveal that D4 has estrogenic potential proven under in vitro and in vivo experimental conditions. PMID:26593928

Ethanolic extract of dandelion (Taraxacum mongolicum) induces estrogenic activity in MCF-7 cells and immature rats.

PubMed

Oh, Seung Min; Kim, Ha Ryong; Park, Yong Joo; Lee, Yong Hwa; Chung, Kyu Hyuck

2015-11-01

Plants of the genus Taraxacum, commonly known as dandelions, are used to treat breast cancer in traditional folk medicine. However, their use has mainly been based on empirical findings without sufficient scientific evidence. Therefore, we hypothesized that dandelions would behave as a Selective estrogen receptor modulator (SERM) and be effective as hormone replacement therapy (HRT) in the postmenopausal women. In the present study, in vitro assay systems, including cell proliferation assay, reporter gene assay, and RT-PCR to evaluate the mRNA expression of estrogen-related genes (pS2 and progesterone receptor, PR), were performed in human breast cancer cells. Dandelion ethanol extract (DEE) significantly increased cell proliferation and estrogen response element (ERE)-driven luciferase activity. DEE significantly induced the expression of estrogen related genes such as pS2 and PR, which was inhibited by tamoxifen at 1 μmol·L(-1). These results indicated that DEE could induce estrogenic activities mediated by a classical estrogen receptor pathway. In addition, immature rat uterotrophic assay was carried out to identify estrogenic activity of DEE in vivo. The lowest concentration of DEE slightly increased the uterine wet weight, but there was no significant effect with the highest concentration of DEE. The results demonstrate the potential estrogenic activities of DEE, providing scientific evidence supporting their use in traditional medicine. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Influence of cornual insemination on conception in dairy cattle.

PubMed

Senger, P L; Becker, W C; Davidge, S T; Hillers, J K; Reeves, J J

1988-11-01

The objective of this study was to compare conception to artificial insemination (AI) services in dairy cattle when semen was deposited into the uterine body or into both uterine horns (cornual insemination). Nine herdsman inseminators (HI) in four commercial dairy herds in Washington constituted the experimental units. Herds ranged in size from 393 cows to 964 cows. The duration of the experiment was 12 mo in three herds and 18 mo in the fourth herd. At the beginning of the experiment all inseminators were trained to deposit semen in the body of the uterus. Inseminators were instructed to use this method for 6 mo. Following employment of body deposition, the same inseminators were retrained to deposit one-half of the semen into the right uterine horn and one-half into the left uterine horn. Cornual inseminations were performed for 6 mo. A total of 4,178 services constituted the data set. Milk samples were collected from cows on the day of insemination and later were assayed for progesterone (P4). There was variation (P less than .01) in conception associated with month of insemination and insemination method (P less than .001). The monthly variation was not associated with season of the year. Least squares means for conception when semen was deposited in the uterine body was 44.7%, compared with 64.6% when cornual insemination was employed. The insemination treatment X inseminator interaction was not significant. Results suggest that cornual insemination provides an alternative to deposition of semen in the uterine body.

Uterine NDRG2 expression is increased at implantation sites during early pregnancy in mice, and its down-regulation inhibits decidualization of mouse endometrial stromal cells.

PubMed

Gu, Yan; Zhang, Xuan; Yang, Qian; Wang, Jian-mei; He, Ya-ping; Sun, Zhao-gui; Zhang, Hui-qin; Wang, Jian

2015-05-27

N-myc down-regulated gene 2 (NDRG2) is a tumor suppressor involved in cell proliferation and differentiation. The aim of this study was to determine the uterine expression pattern of this gene during early pregnancy in mice. Uterine NDRG2 mRNA and protein expression levels were determined by RT-PCR and Western blot analyses, respectively, during the peri-implantation period in mice. Immunohistochemical (IHC) analysis was performed to examine the spatial localization of NDRG2 expression in mouse uterine tissues. The in vitro decidualization model of mouse endometrial stromal cells (ESCs) was used to evaluate decidualization of ESCs following NDRG2 knock down by small interfering RNA (siRNA). Statistical significance was analyzed by one-way ANOVA using SPSS 19.0 software. Uterine NDRG2 gene expression was significantly up-regulated and was predominantly localized to the secondary decidual zone on days 5 and 8 of pregnancy in mice. Its increased expression was associated with artificial decidualization as well as the activation of delayed implantation. Furthermore, uterine NDRG2 expression was induced by estrogen and progesterone treatments. The in vitro decidualization of mouse ESCs was accompanied by up-regulation of NDRG2 expression, and knock down of its expression in these cells by siRNA inhibited the decidualization process. These results suggest that NDRG2 might play an important role in the process of decidualization during early pregnancy.

Uterine biology in pigs and sheep

PubMed Central

2012-01-01

There is a dialogue between the developing conceptus (embryo-fetus and associated placental membranes) and maternal uterus which must be established during the peri-implantation period for pregnancy recognition signaling, implantation, regulation of gene expression by uterine epithelial and stromal cells, placentation and exchange of nutrients and gases. The uterus provide a microenvironment in which molecules secreted by uterine epithelia or transported into the uterine lumen represent histotroph required for growth and development of the conceptus and receptivity of the uterus to implantation. Pregnancy recognition signaling mechanisms sustain the functional lifespan of the corpora lutea (CL) which produce progesterone, the hormone of pregnancy essential for uterine functions that support implantation and placentation required for a successful outcome of pregnancy. It is within the peri-implantation period that most embryonic deaths occur due to deficiencies attributed to uterine functions or failure of the conceptus to develop appropriately, signal pregnancy recognition and/or undergo implantation and placentation. With proper placentation, the fetal fluids and fetal membranes each have unique functions to ensure hematotrophic and histotrophic nutrition in support of growth and development of the fetus. The endocrine status of the pregnant female and her nutritional status are critical for successful establishment and maintenance of pregnancy. This review addresses the complexity of key mechanisms that are characteristic of successful reproduction in sheep and pigs and gaps in knowledge that must be the subject of research in order to enhance fertility and reproductive health of livestock species. PMID:22958877

Inhalation of progesterone inhibits chronic airway inflammation of mice exposed to ozone.

PubMed

Fei, Xia; Bao, Wuping; Zhang, Pengyu; Zhang, Xue; Zhang, Guoqing; Zhang, Yingying; Zhou, Xin; Zhang, Min

2017-05-01

Chronic ozone exposure leads to a model of mice with lung inflammation, emphysema and oxidative stress. Progesterone plays an important role in attenuating the neuroinflammation. We assume that progesterone will reduce the chronic airway inflammation exposed to ozone and evaluate whether combination of progesterone with glucocorticoids results in synergistic effects. C57/BL6 mice were exposed to ozone (2.5ppm, 3h) 12 times over 6 weeks, and were administered with progesterone (0.03 or 0.3mg/L; inhaled) alone or combined with budesonide (BUD) (0.2g/L) after each exposure until the tenth week. Mice were studied 24h after final exposure, cells and inflammatory mediators were assessed in bronchoalveolar lavage fluid (BALF) and lungs used for evaluation of glucocorticoids receptors (GR), p38 mitogen-activated protein kinase (MAPK) phosphorylation and nuclear transcription factor κB (NF-κB) activation. Exposure to ozone resulted in a marked lung neutrophilia. Moreover, in ozone-exposed group, the levels of oxidative stress-related interleukin (IL)-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, airway inflammatory cells infiltration density, mean linear intercept (Lm) were greatly increased, FEV 25 and glucocorticoids receptors (GR) were markedly decreased. Comparable to BUD, progesterone treatment dose-dependently led to a significant reduction of IL-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, and an increase of FEV 25 and GR. Progesterone combined with BUD resulted in dramatic changes, compared to monotherapy of BUD or progesterone. Therefore, these results demonstrate that chronic ozone exposure has profound airway inflammatory effects counteracted by progesterone and progesterone acts synergistically with glucocorticoids in attenuating the airway inflammation dose-dependently. Copyright © 2017 Elsevier Ltd. All rights reserved.

TGF-β1 downregulates StAR expression and decreases progesterone production through Smad3 and ERK1/2 signaling pathways in human granulosa cells.

PubMed

Fang, Lanlan; Chang, Hsun-Ming; Cheng, Jung-Chien; Leung, Peter C K; Sun, Ying-Pu

2014-11-01

Regulation of progesterone production in granulosa cells is important for normal reproductive functions. Steroidogenic acute regulatory protein (StAR) is recognized as the key regulatory protein involved in the rate-limiting step of steroidogenesis. TGF-β1 protein is detected in human follicular fluid, and TGF-β1 and its receptors are expressed in human granulosa cells. However, the functional role of TGF-β1 in the regulation of StAR expression and progesterone production in human granulosa cells remains unknown. Our objective was to investigate the effects of TGF-β1 on StAR expression and progesterone production in human granulosa cells. SVOG cells are human granulosa cells that were obtained from women undergoing in vitro fertilization and immortalized with SV40 large T antigen. SVOG cells were used to investigate the effects of TGF-β1 on StAR expression and progesterone production at an academic research center. Levels of mRNA and protein were examined by RT-qPCR and western blotting, respectively. The accumulation levels of progesterone were measured by enzyme-linked immunosorbent assay (ELISA). TGF-β1 treatment downregulated StAR expression and decreased progesterone production. The suppressive effects of TGF-β1 on StAR expression and progesterone production were abolished by the inhibition of TGF-β type I receptor. In addition, treatment with TGF-β1 activated the Smad2/3 and ERK1/2 signaling pathways. The inhibition of the Smad3 and ERK1/2 signaling pathways attenuated the TGF-β1-induced downregulation of StAR expression and progesterone production. TGF-β1 downregulated StAR expression and decreased progesterone production by activating the Smad3 and ERK1/2 signaling pathways in human granulosa cells.

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

Endocrinology of human parturition.

PubMed

Vannuccini, Silvia; Bocchi, Caterina; Severi, Filiberto M; Challis, John R; Petraglia, Felice

2016-06-01

The mechanisms involved in human pregnancy maintenance and parturition are highly complex and involve mother, fetus and placenta. The "final common pathway" to delivery is composed by inflammatory and endocrine interactive paths that tip the balance in favor of coordinated uterine contractility and cervical dilation. These mechanisms involve a shift from progesterone to estrogen dominance, CRH action, increased sensitivity to oxytocin, gap junction formation, and increased prostaglandins activity. Complementary changes in the cervix involve a decrease in progesterone dominance and the actions of prostaglandins and relaxin, via connective tissue alterations, leading to cervical softening and dilation. Neuronal, hormonal, inflammatory and immune pathways participate in initiation of labor and the utero-placental unit plays a major role in the synthesis and release of parturition mediators. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Termination of pseudopregnancy in the rat alters the response to progesterone, chlordiazepoxide, and MK-801 in the elevated plus-maze.

PubMed

Bitran, Daniel; Solano, Steven M

2005-07-01

Allopregnanolone, a neurosteroid-reduced metabolite of progesterone, is a well-documented positive modulator of the gamma-aminobutyric type A (GABA(A)) receptor. As has been reported for other positive modulators of the GABA(A) receptor, chronic exposure to neurosteroids is hypothesized to decrease GABA(A) receptor function. Drawing from the literature on chronic exposure to benzodiazepines or alcohol, putative changes in N-methyl-D-aspartate (NMDA) receptor function are also expected after chronic neurosteroid exposure. To assess the sensitivity of the GABA(A) and NMDA receptors after chronic elevation of neurosteroid produced by termination of pseudopregnancy in behavioral tests of anxiety and sensorimotor coordination. Female rats ovariectomized on day 10 of pseudopregnancy were tested in the elevated plus-maze and on the rotor rod after an acute injection of progesterone (4 mg/0.2 ml, s.c.), chlordiazepoxide (5 or 15 mg/kg, i.p.), or MK-801 (0.025, 0.05, or 0.1 mg/kg, i.p.). Pseudopregnancy termination produced an anxiogenic-like response in the plus-maze; an acute injection of progesterone restored baseline levels of behavior in this test. Pseudopregnancy termination eliminated the anxiolytic-like, sedative, and ataxic effects of chlordiazepoxide. In contrast, pseudopregnancy termination produced an increased sensitivity to the anxiolytic-like and ataxic effects of MK-801. The effects of pseudopregnancy termination on the behavioral response to positive modulators of the GABA(A) receptor are consistent with results from studies in which chronic exposure to neurosteroids decreases the response to acute neurosteroid and benzodiazepine administration. However, unlike the enhanced glutamatergic tone resulting from discontinuation of chronic benzodiazepine or alcohol exposure, the termination of pseudopregnancy apparently decreases NMDA receptor function.

Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile.

PubMed

Lissauer, David; Eldershaw, Suzy A; Inman, Charlotte F; Coomarasamy, Aravinthan; Moss, Paul A H; Kilby, Mark D

2015-10-01

Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4(+) and CD8(+) T cells, with reductions not only in potentially deleterious IFN-γ and TNF-α production but also in IL-10 and IL-5. Conversely, production of IL-4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL-4. This was accompanied by reduced T-cell proliferation. Using fetal and viral antigen-specific CD8(+) T-cell clones, we confirmed that this as a direct, nonantigen-specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4(+) and CD8(+) T cells responded to progesterone in a dose-dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal-fetal interface. This characterization of how progesterone modulates T-cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss. © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Progestogen treatments for cycle management in a sheep model of assisted conception affect the growth patterns, the expression of luteinizing hormone receptors, and the progesterone secretion of induced corpora lutea.

PubMed

Letelier, Claudia; García-Fernández, Rosa Ana; Contreras-Solis, Ignacio; Sanchez, María Angeles; Garcia-Palencia, Pilar; Sanchez, Belen; Gonzalez-Bulnes, Antonio; Flores, Juana María

2010-03-01

To determine, in a sheep model, the effect of a short-term progestative treatment on growth dynamics and functionality of induced corpora lutea. Observational, model study. Public university. Sixty adult female sheep. Synchronization and induction of ovulation with progestogens and prostaglandin analogues; ovarian ultrasonography, blood sampling, and ovariectomy. Determination of pituitary function and morphologic characteristics, expression of luteinizing hormone (LH) receptors, and progesterone secretion of corpora lutea. The use of progestative pretreatments for assisted conception affect the growth patterns, the expression of LH receptors, and the progesterone secretion of induced corpora lutea. The current study indicates, in a sheep model, the existence of deleterious effects from progestogens on functionality of induced corpora lutea. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Inhibition of oxytocin-induced but not angiotensin-induced rat uterine contractions following exposure to sodium sulfide

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

Hayden, L.J.; Franklin, K.J.; Roth, S.H.

1989-01-01

Low concentrations of sodium sulfide reversibly attenuate the contractile response of the isolate rat uterus to oxytocin without affecting angiotensin II responsiveness. These findings suggest that functionally important disulfide bonds in the rat uterine oxytocin receptor, but not the angiotensin receptor, are sensitive to hydrosulfide ion. Reduction of oxytocin receptors by hydrosulfide ion may be a mechanism by which low level of H{sub 2}S delay parturition in rats.

Effects of thyroid hormones on the antioxidative status in the uterus of young adult rats

PubMed Central

KONG, Lingfa; WEI, Quanwei; FEDAIL, Jaafar Sulieman; SHI, Fangxiong; NAGAOKA, Kentaro; WATANABE, Gen

2015-01-01

Thyroid hormones and oxidative stress play significant roles in the normal functioning of the female reproductive system. Nitric oxide (NO), a free radical synthesized by nitric oxide synthases (NOS), participates in the regulation of thyroid function and is also a good biomarker for assessment of the oxidative stress status. Therefore, the purpose of this study was to investigate effects of thyroid hormones on uterine antioxidative status in young adult rats. Thirty immature female Sprague-Dawley rats were randomly divided into three groups: control, hypothyroid (hypo-T) and hyperthyroid (hyper-T). The results showed the body weights decreased significantly in both the hypo-T and hyper-T groups and that uterine weights were decreased significantly in the hypo-T group. The serum concentrations of total triiodothyronine (T3) and thyroxine (T4), as well as estradiol (E2), were significantly decreased in the hypo-T group, but increased in the hyper-T group. The progesterone (P4) concentrations in the hypo- and hyperthyroid rats markedly decreased. Immunohistochemistry results provided evidence that thyroid hormone nuclear receptor α/β (TRα/β) and three NOS isoforms were located in different cell types of rat uteri. The NO content and total NOS and inducible NOS (iNOS) activities were markedly diminished in the hypo-T group but increased in the hyper-T group. Moreover, the activities of both glutathione peroxidase (GSH-Px) and catalase (CAT) exhibited significant decreases and increases in the hypo-T and hyper-T groups, respectively. The malondialdehyde (MDA) contents in both the hypo-T and hyper-T groups showed a significant increase. Total superoxide dismutase (T-SOD) activity in the hypo- and hyper-T rats markedly decreased. In conclusion, these results indicated that thyroid hormones have an important influence on the modulation of uterine antioxidative status. PMID:25797533

Steroidogenesis in plants--Biosynthesis and conversions of progesterone and other pregnane derivatives.

PubMed

Lindemann, Peter

2015-11-01

In plants androstanes, estranes, pregnanes and corticoids have been described. Sometimes 17β-estradiol, androsterone, testosterone or progesterone were summarized as sex hormones. These steroids influence plant development: cell divisions, root and shoot growth, embryo growth, flowering, pollen tube growth and callus proliferation. First reports on the effect of applicated substances and of their endogenous occurrence date from the early twenties of the last century. This caused later on doubts on the identity of the compounds. Best investigated is the effect of progesterone. Main steps of the progesterone biosynthetic pathway have been analyzed in Digitalis. Cholesterol-side-chain-cleavage, pregnenolone and progesterone formation as well as the stereospecific reduction of progesterone are described and the corresponding enzymes are presented. Biosynthesis of androstanes, estranes and corticoids is discussed. Possible progesterone receptors and physiological reactions on progesterone application are reviewed. Copyright © 2015 Elsevier Inc. All rights reserved.

Mirvetuximab Soravtansine and Rucaparib Camsylate in Treating Participants With Recurrent Endometrial, Ovarian, Fallopian Tube or Primary Peritoneal Cancer

ClinicalTrials.gov

2018-06-09

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Folate Receptor Alpha Positive; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Recurrent Uterine Serous Carcinoma; Recurrent Uterine Carcinosarcoma; Platinum Resistant Ovarian Cancer

Stimulation of GPR30 increases release of EMMPRIN-containing microvesicles in human uterine epithelial cells.

PubMed

Burnett, Lindsey A; Light, Mallory M; Mehrotra, Pavni; Nowak, Romana A

2012-12-01

Uterine remodeling is highly dependent on the glycosylated transmembrane protein extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN). Previous studies indicate estradiol can increase EMMPRIN expression in uterine cells and promote subsequent induction of MMP production. The aim of this study was to investigate the role of G protein-coupled receptor 30 (GPR30) stimulation on EMMPRIN microvesicle release in the human uterine epithelial cell line hTERT-EEC (EECs). We examined EMMPRIN release by human EECs in response to GPR30 stimulation by microvesicle isolation, Western blot, and immunocytochemistry. We employed a pharmacological approach using the GPR30-selective agonist G1 and the antagonist G15 to determine the receptor specificity of this response. We demonstrated GPR30 expression in EECs and release of EMMPRIN in microvesicles in response to stimulation of GPR30. G1, estradiol, and cholera toxin stimulated EMMPRIN release in microvesicles as detected by Western blot and immunocytochemistry, indicating that stimulation of GPR30 can induce EMMPRIN microvesicle release. These data indicate that EMMPRIN release in microvesicles can be mediated by stimulation of GPR30 in human EECs, suggesting that inappropriate stimulation or expression of this receptor may be significant in uterine pathology.

Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

ClinicalTrials.gov

2018-01-24

Hormone Receptor Positive Malignant Neoplasm of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Metastatic Breast Cancer

Expression of oxytocin receptors is greatly reduced in the placenta of heavy mares with retained fetal membranes due to secondary uterine atony.

PubMed

Rapacz-Leonard, A; Raś, A; Całka, J; Janowski, T E

2015-09-01

Fetal membrane retention can be a life-threatening condition and its incidence exceeds 50% in heavy draught mares. Although fetal membrane retention is commonly treated with repeated injections of oxytocin, based on the suggestion that it is caused mainly by secondary atony of the uterus, this treatment sometimes fails. This led us to ask if expression of oxytocin receptors differs in mares that retain fetal membranes due to secondary uterine atony. To determine whether expression of oxytocin receptors in equine placental tissues differs when heavy draught mares expel fetal membranes or retain them because of secondary uterine atony. Controlled study using archived tissues. Placental biopsies (containing the endometrium and allantochorion) were taken from 8 heavy draught mares during parturition. Four mares expelled fetal membranes shortly after foaling (control mares) and 4 mares retained them (expulsion time was >3 h from delivery). The 4 mares that retained fetal membranes had secondary atony of the uterus. The amount of oxytocin receptors was estimated by measuring the intensity of western blot bands. The presence and location of oxytocin receptors were determined by immunocytochemistry. Oxytocin receptor expression was nearly 50 times less intense in mares with placenta retention due to secondary atony of the uterus and immunocytochemical staining was barely visible. In the control mares, oxytocin receptors were found in both epithelial and endothelial cells of the placenta and staining was most intense where the endometrium contacts the allantochorion. Inadequate expression of oxytocin receptors may be a cause of uterine atony leading to fetal membrane retention. © 2015 EVJ Ltd.

Evaluation of the effects of fulvestrant and micronized progesterone on the post-operative adhesion formation and ovarian reserve in rat model with immunohistochemical and biochemical analysis.

PubMed

Oner, Gokalp; Ulug, Pasa; Demirci, Elif; Kumtepe, Yakup; Gündogdu, Cemal

2015-01-01

To evaluate the effects of fulvestrant and micronized progesterone on post-operative adhesion formation and ovarian reserve in a rat uterine horn adhesion. In this prospective randomized controlled trial, 32 female Wistar albino rats were randomly divided into four groups including control group (Group 1), the control adhesion group (Group 2), 1 mg/kg daily intramuscular fulvestrant received group (Group 3) and 1 mg/kg daily oral micronized progesterone received group (Group 4). The extent and severity of adhesions were scored and samples were taken from adhesion areas to investigate the grades of adhesions according to the immunohistochemical scoring system. Ovarian reserves were measured with anti-Müllerian hormone (AMH) and histological ovarian follicles count. The extent, severity and total adhesion scores were reduced in all treatment groups compared to control adhesion group (Group 2). Similarly, immunohistochemical adhesion scores were lower in the treatment groups. AMH and follicle count were significantly found lower in adhesion groups compared with control group. However, treatment groups were found to have higher ovarian reserve compared to control adhesion group (Group 2). Fulvestrant and micronized progesterone were found to reduce post-operative adhesion formations and have decreased detrimental effects of adhesion formation on ovarian reserve.

Neonatal uterine and vaginal cell proliferation and adenogenesis are independent of estrogen receptor 1 (ESR1) in the mouse.

PubMed

Nanjappa, Manjunatha K; Medrano, Theresa I; March, Amelia G; Cooke, Paul S

2015-03-01

Neonatal uterus and vagina express estrogen receptor 1 (ESR1) and respond mitogenically to exogenous estrogens. However, neonatal ovariectomy does not inhibit preweaning uterine cell proliferation, indicating that this process is estrogen independent. Extensive literature suggests that ESR1 can be activated by growth factors in a ligand-independent manner and drive uterine cell proliferation. Alternatively, neonatal uterine cell proliferation could be ESR1 independent despite its obligatory role in adult luminal epithelial proliferation. To determine ESR1's role in uterine and vaginal development, we analyzed cell proliferation, apoptosis, and uterine gland development (adenogenesis) in wild-type (WT) and Esr1 knockout (Esr1KO) mice from Postnatal Day 2 to Postnatal Day 60. Uterine and vaginal cell proliferation, apoptosis, and uterine adenogenesis were comparable in WT and Esr1KO mice before weaning. By Days 29-60, glands had regressed, and uterine cell proliferation was reduced in Esr1KO mice in contrast to continued adenogenesis and proliferation in WT. Apoptosis in Esr1KO uterine epithelium was not increased compared to WT at any age, indicating that differences in cell proliferation, rather than apoptosis, cause divergence of uterine size in these two groups at puberty. Similarly, vaginal epithelial proliferation was reduced, and the epithelium became atrophic in Esr1KO mice by 29 days of age and later in Esr1KO mice. These results indicate that preweaning uterine and vaginal development is ESR1 independent but becomes dependent on ESR1 by Day 29 on. It is not yet clear what mechanisms drive preweaning vaginal and uterine development, but ligand-independent activation of ESR1 is not involved. © 2015 by the Society for the Study of Reproduction, Inc.

The effect of metritis on luteal function in dairy cows

PubMed Central

2013-01-01

Background Disturbed uterine involution impairs ovarian function in the first weeks after calving. This study analyzed the long-term effect of metritis on luteal function of 47 lactating Holstein-Friesian cows during the first four postpartum estrous cycles. Cows with abnormal uterine enlargement and malodorous lochia were classified as having metritis (group M, n = 18), and all others were considered healthy (group H, n = 29). Luteal size was measured once between days 9 and 13 of the first (group H, n = 11; group M, n = 12), second (group H, n = 23; group M, n = 18) and fourth (group H, n = 11; group M, n = 7) postpartum luteal phases. Serum progesterone concentration was measured at the same time. Sixteen cows (group H, n = 9; group M, n = 7) underwent transvaginal luteal biopsy for gene expression analysis of steroidogenic regulatory proteins during the second and fourth cycles. Cows with persistence of the corpus luteum (CL) underwent determination of luteal size, luteal biopsy and serum progesterone measurement once between days 29 and 33, followed by prostaglandin treatment to induce luteolysis. The same procedures were repeated once between days 9 and 13 of the induced cycle. Results The cows in group M had smaller first-cycle CLs than the cows in group H (p = 0.04), but progesterone concentrations did not differ between groups. Luteal size, progesterone concentration and gene expression did not differ between the two groups during the second and fourth cycles. Compared with healthy cows (10%), there was a trend (p = 0.07) toward a higher prevalence of persistent CLs in cows with metritis (33%). Persistent CLs were limited to the first cycle. Persistent CLs and the induced cyclic CLs did not differ with regard to the variables investigated. Conclusions An effect of metritis on luteal activity was apparent in the first postpartum estrous cycle. However, after the first postpartum cycle, no differences occurred in analyzed parameters between metritis and control cows. Therefore, a metritis is able to impair luteal activity transiently, but does not seem to have a long-term effect on luteal function. PMID:24304943

[Semiquantitative measurement of progesterone receptors in luteal-phase-defect endometrial cells during secretory phase].

PubMed

Ma, Q; Han, Z; Huang, W

1998-03-01

To investigate the changes of endometrial progesterone receptor (PR) of luteal-phase-defect (LPD) patients during the secretory phase, thirteen patients with complaints of infertility or habitual abortion were studied. During the early-mid secretory phase, endometrial tissue was obtained by dilatation and curettage (D & C) for histological and receptor study: meanwhile serum E2, P, FSH, LH and PRL were measured. Based on histologic diagnosis, the patients were divided into two groups: the LPD group (n = 7) and the normal control group(n = 6). PR content was determined by immunohisto-chemical (IHC) assay. The results showed that during the early-mid luteal phase a significantly low PR content on endometrial glandular nucleus was observed in LPD group, compared with normal control(6.75 +/- 2.57 vs 9.50 +/- 1.64 P < 0.05), but no difference in serum progesterone was noted between the two groups. These findings suggest that during early-mid secretory phase, PR content on endometrial glandular nucleus decreases in LPD cases, which results in deficient response of endometrium to proper stimulus of progesterone. This change may cause endometrial secretory deficiency and blockade of embreyo implantation. That is why infertility or habitual abortion happened.

Improving the developability profile of pyrrolidine progesterone receptor partial agonists

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

Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.

2010-09-17

The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.

PubMed

Paul, Jonathan W; Hua, Susan; Ilicic, Marina; Tolosa, Jorge M; Butler, Trent; Robertson, Sarah; Smith, Roger

2017-03-01

The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus. Copyright © 2016. Published by Elsevier Inc.

Dienogest inhibits C-C motif chemokine ligand 20 expression in human endometriotic epithelial cells.

PubMed

Mita, Shizuka; Nakakuki, Masanori; Ichioka, Masayuki; Shimizu, Yutaka; Hashiba, Masamichi; Miyazaki, Hiroyasu; Kyo, Satoru

2017-07-01

C-C motif chemokine ligand 20 is thought to contribute to the development of endometriosis by recruiting Th17 lymphocytes into endometriotic foci. The present study investigated the effects of dienogest, a progesterone receptor agonist used to treat endometriosis, on C-C motif chemokine ligand 20 expression by endometriotic cells. Effects of dienogest on mRNA expression and protein secretion of C-C motif chemokine ligand 20 induced by interleukin 1β were assessed in three immortalized endometriotic epithelial cell lines, parental cells (EMosis-CC/TERT1), and stably expressing human progesterone receptor isoform A (EMosis-CC/TERT1/PRA+) or isoform B (EMosis-CC/TERT1/PRA-/PRB+). Dienogest markedly inhibited interleukin 1β-stimulated C-C motif chemokine ligand 20 mRNA expression and protein secretion in EMosis-CC/TERT1/PRA-/PRB+, which was abrogated by the progesterone receptor antagonist RU486. In EMosis-CC/TERT1/PRA+, dienogest slightly inhibited C-C motif chemokine ligand 20 mRNA and protein. In EMosis-CC/TERT1, dienogest slightly inhibited C-C motif chemokine ligand 20 mRNA, but had no effect on C-C motif chemokine ligand 20 protein. Dienogest inhibited interleukin 1β-induced up-regulation of C-C motif chemokine ligand 20 in endometriotic epithelial cells, mainly mediated by progesterone receptor B. Copyright © 2017 Elsevier B.V. All rights reserved.

Training Grant in Epidemiology and Prevention of Breast Cancer

DTIC Science & Technology

2005-07-01

progesterone receptor gene expression in human breast cancer. J Mammary Gland Biol progesterone , medroxyprogesterone acetate and noretpisterone on the...an R01- equivalent research proposal to the American Cancer Society in October 2003 (resubmitted in April 2004). The goal of the proposal is to develop... progesterone concentrations and breast cancer risk among postmenopausal womenŕ". "* Ms. Sonia (Matthews) Maruti had an abstract accepted to "Breast Cancer

Immunologic analysis of human breast cancer progesterone receptors. 1. Immunonaffinity purification of transformed receptors and production of monoclonal antibodies

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

Estes, P.A.; Suba, E.J.; Lawler-Heavner, J.

1987-09-22

A monoclonal antibody (MAb), designated PR-6, produced against chick oviduct progesterone receptors cross-reacts with the M/sub r/ 120,000 human B receptors. An immunomatrix prepared with PR-6 was used to purify progesterone receptors (PR) from T47D human breast cancer cells. Single-step immunoaffinity chromatography results in enrichment of B receptors (identified by immunoblot with PR-6 and by photoaffinity labeling with (/sup 3/H)promegestone) to a specific activity of 1915 pmol/mg of protein (or 23% purity) and with 27% yield. Purity and yields as judged by gel electrophoresis and densitometric scanning of the B protein were approximately 1.7-fold higher due to partial loss inmore » hormone binding activity at the elution step. B receptors purified under these conditions are transformed and biologically active. They were maintained as undergraded 120-kDa doublets and retained both hormone and DNA binding activities. These purified B receptors were used as immunogen for production of four monoclonal antibodies against human PR. Three of the MAbs, designated as B-30 (IgG/sub 1/), B-64 (IgG/sub 1/), and B-11 (IgM), are specific for B receptors. The fourth MAb, A/B-52 (IgG/sub 1/), reacts with both A and B receptors. The IgG MAbs are monospecific for human PR since they recognize and absorb native receptor-hormone complexes, displace the sedimentation of 4S receptors on salt containing sucrose gradients, and, by immunoblot assay of crude T47D cytosol, react only with receptor polypeptides. Although mice were injected with B receptors only, production of A/B-52 which recognized both A and B receptors provides evidence that these two proteins share regions of structural homology.« less

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells.

PubMed

Amini, Peyvand; Michniuk, Daniel; Kuo, Kelly; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Peters, Gregory A; Tan, Huiqing; Wang, Junye; Malemud, Charles J; Mesiano, Sam

2016-11-01

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HM A/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC 50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition.

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells

PubMed Central

Amini, Peyvand; Michniuk, Daniel; Kuo, Kelly; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Peters, Gregory A.; Tan, Huiqing; Wang, Junye; Malemud, Charles J.

2016-01-01

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HMA/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition. PMID:27653036

Differential roles of MAPK-Erk1/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells.

PubMed

Seto-Young, D; Avtanski, D; Varadinova, M; Park, A; Suwandhi, P; Leiser, A; Parikh, G; Poretsky, L

2011-06-01

Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis. © Georg Thieme Verlag KG Stuttgart · New York.

Beta-Estradiol Regulates Voltage-Gated Calcium Channels and Estrogen Receptors in Telocytes from Human Myometrium.

PubMed

Banciu, Adela; Banciu, Daniel Dumitru; Mustaciosu, Cosmin Catalin; Radu, Mihai; Cretoiu, Dragos; Xiao, Junjie; Cretoiu, Sanda Maria; Suciu, Nicolae; Radu, Beatrice Mihaela

2018-05-09

Voltage-gated calcium channels and estrogen receptors are essential players in uterine physiology, and their association with different calcium signaling pathways contributes to healthy and pathological conditions of the uterine myometrium. Among the properties of the various cell subtypes present in human uterine myometrium, there is increasing evidence that calcium oscillations in telocytes (TCs) contribute to contractile activity and pregnancy. Our study aimed to evaluate the effects of beta-estradiol on voltage-gated calcium channels and estrogen receptors in TCs from human uterine myometrium and to understand their role in pregnancy. For this purpose, we employed patch-clamp recordings, ratiometric Fura-2-based calcium imaging analysis, and qRT-PCR techniques for the analysis of cultured human myometrial TCs derived from pregnant and non-pregnant uterine samples. In human myometrial TCs from both non-pregnant and pregnant uterus, we evidenced by qRT-PCR the presence of genes encoding for voltage-gated calcium channels (Cav3.1, Ca3.2, Cav3.3, Cav2.1), estrogen receptors (ESR1, ESR2, GPR30), and nuclear receptor coactivator 3 (NCOA3). Pregnancy significantly upregulated Cav3.1 and downregulated Cav3.2, Cav3.3, ESR1, ESR2, and NCOA3, compared to the non-pregnant condition. Beta-estradiol treatment (24 h, 10, 100, 1000 nM) downregulated Cav3.2, Cav3.3, Cav1.2, ESR1, ESR2, GRP30, and NCOA3 in TCs from human pregnant uterine myometrium. We also confirmed the functional expression of voltage-gated calcium channels by patch-clamp recordings and calcium imaging analysis of TCs from pregnant human myometrium by perfusing with BAY K8644, which induced calcium influx through these channels. Additionally, we demonstrated that beta-estradiol (1000 nM) antagonized the effect of BAY K8644 (2.5 or 5 µM) in the same preparations. In conclusion, we evidenced the presence of voltage-gated calcium channels and estrogen receptors in TCs from non-pregnant and pregnant human uterine myometrium and their gene expression regulation by beta-estradiol in pregnant conditions. Further exploration of the calcium signaling in TCs and its modulation by estrogen hormones will contribute to the understanding of labor and pregnancy mechanisms and to the development of effective strategies to reduce the risk of premature birth.

Clinical validation of nuclear factor kappa B expression in invasive breast cancer.

PubMed

Agrawal, Anil Kumar; Pielka, Ewa; Lipinski, Artur; Jelen, Michal; Kielan, Wojciech; Agrawal, Siddarth

2018-01-01

Breast cancer is the most commonly diagnosed cancer in Polish women. The expression of transcription nuclear factor kappa B, a key inducer of inflammatory response promoting carcinogenesis and cancer progression in breast cancer, is not well-established. We assessed the nuclear factor kappa B expression in a total of 119 invasive breast carcinomas and 25 healthy control samples and correlated this expression pattern with several clinical and pathologic parameters including histologic type and grade, tumor size, lymph node status, estrogen receptor status, and progesterone receptor status. The data used for the analysis were derived from medical records. An immunohistochemical analysis of nuclear factor kappa B, estrogen receptor, and progesterone receptor was carried out and evaluation of stainings was performed. The expression of nuclear factor kappa B was significantly higher than that in the corresponding healthy control samples. No statistical difference was demonstrated in nuclear factor kappa B expression in relation to age, menopausal status, lymph node status, tumor size and location, grade and histologic type of tumor, and hormonal status (estrogen receptor and progesterone receptor). Nuclear factor kappa B is significantly overexpressed in invasive breast cancer tissues. Although nuclear factor kappa B status does not correlate with clinicopathological findings, it might provide important additional information on prognosis and become a promising object for targeted therapy.

Uterine bacterial flora in postpartum Danish Holstein dairy cows determined using DNA-based fingerprinting: correlation to uterine condition and calving management.

PubMed

Elkjær, K; Ancker, M-L; Gustafsson, H; Friggens, N C; Waldmann, A; Mølbak, L; Callesen, H

2013-04-01

The overall aim of this study was to describe uterine bacterial flora during the postpartum period in Danish Holstein cows using the Terminal Restriction Fragment Length Polymorphism (T-RFLP) method. This method produces a pattern of nucleic acid fragments from the microorganisms present, reflecting the "fingerprint" of the actual microbial flora. As well as characterizing changes in flora with time from calving and between herds, data were examined for strong relations between uterine bacterial flora, calving management and uterine condition. In total 125 Holstein cows from five herds were included, and for each cow calving management was recorded. Cows were clinically examined on average 8 (range 0-19) and 28 (range 22-38) days after calving, and a uterine sample was taken for bacterial identification using T-RFLP. Milk samples were taken weekly for progesterone analysis. Bacteria were found in all cows at both examinations, and the flora was composed of many species, including species not traditionally reported to be present in the bovine uterus. The bacterial composition differed according to days from calving and herd. In all five herds Fusobacterium necrophorum, Pseudomonas/Acinetobacter and Bacteroides/Sphingobacterium/Prevotellaceae were among the most common at both examinations. In four herds there was a percentage decrease of F. necrophorum from first to second examination, and in all herds there was a percentage increase of Pseudomonas/Acinetobacter from first to second examination. No differences in bacterial flora were found between cows with different uterine scores, which were influenced by herd, calving difficulty and retained placenta. Copyright © 2013 Elsevier B.V. All rights reserved.

Uterine-Specific Loss of Tsc2 Leads to Myometrial Tumors in Both the Uterus and Lungs

PubMed Central

Prizant, Hen; Sen, Aritro; Light, Allison; Cho, Sung-Nam; DeMayo, Francesco J.; Lydon, John P.

2013-01-01

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases. PMID:23820898

The Balance of HCO3- Secretion vs. Reabsorption in the Endometrial Epithelium Regulates Uterine Fluid pH

PubMed Central

Xie, Zhang-Dong; Guo, Yi-Min; Ren, Mei-Juan; Yang, Jichun; Wang, Shao-Fang; Xu, Tong-Hui; Chen, Li-Ming; Liu, Ying

2018-01-01

Uterine fluid contains a high concentration of HCO3- which plays an essential role in sperm capacitation and fertilization. In addition, the HCO3- concentration in uterine fluid changes periodically during the estrous cycle. It is well-known that the endometrial epithelium contains machineries involving the apical SLC26 family anion exchangers for secreting HCO3- into the uterine fluid. In the present study, we find for the first time that the electroneutral Na+/HCO3- cotransporter NBCn1 is expressed at the apical membrane of the endometrial epithelium. The protein abundance of the apical NBCn1 and that of the apical SLC26A4 and SLC26A6 are reciprocally regulated during the estrous cycle in the uterus. NBCn1 is most abundant at diestrus, whereas SLC26A4/A6 are most abundant at proestrus/estrus. In the ovariectomized mice, the expression of uterine NBCn1 is inhibited by β-estradiol, but stimulated by progesterone, whereas that of uterine SLC26A4/A6 is stimulated by β-estradiol. In vivo perfusion studies show that the endometrial epithelium is capable of both secreting and reabsorbing HCO3-. Moreover, the activity for HCO3- secretion by the endometrial epithelium is significantly higher at estrus than it is at diestrus. The opposite is true for HCO3- reabsorption. We conclude that the endometrial epithelium simultaneously contains the activity for HCO3- secretion involving the apical SLC26A4/A6 and the activity for HCO3- reabsorption involving the apical NBCn1, and that the acid-base homeostasis in the uterine fluid is regulated by the finely-tuned balance of the two activities. PMID:29422866

Transcriptional regulation of genes related to progesterone production.

PubMed

Mizutani, Tetsuya; Ishikane, Shin; Kawabe, Shinya; Umezawa, Akihiro; Miyamoto, Kaoru

2015-01-01

Steroid hormones are synthesized from cholesterol in various tissues, mainly in the adrenal glands and gonads. Because these lipid-soluble steroid hormones immediately diffuse through the cells in which they are produced, their secretion directly reflects the activity of the genes related to their production. Progesterone is important not only for luteinization and maintenance of pregnancy, but also as a substrate for most other steroids. Steroidogenic acute regulatory protein (STAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4) isomerase (3β-HSD) are well-known proteins essential for progesterone production. In addition to them, glutathione S-transferase A1-1 and A3-3 are shown to exert Δ(5)-Δ(4) isomerization activity to produce progesterone in a cooperative fashion with 3β-HSD. 5-Aminolevulinic acid synthase 1, ferredoxin 1, and ferredoxin reductase also play a role in steroidogenesis as accessory factors. Members of the nuclear receptor 5A (NR5A) family (steroidogenic factor 1 and liver receptor homolog 1) play a crucial role in the transcriptional regulation of these genes. The NR5A family activates these genes by binding to NR5A responsive elements present within their promoter regions, as well as to the elements far from their promoters. In addition, various NR5A-interacting proteins including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear receptor subfamily 0, group B, member 1 (DAX-1), and CCAAT/enhancer-binding proteins (C/EBP) are involved in the transcription of NR5A target genes and regulate the transcription either positively or negatively under both basal and tropic hormone-stimulated conditions. In this review, we describe the transcriptional regulation of genes related to progesterone production.

Expression of membrane progesterone receptors (mPRs) in rat peripheral glial cell membranes and their potential role in the modulation of cell migration and protein expression.

PubMed

Castelnovo, Luca F; Magnaghi, Valerio; Thomas, Peter

2017-09-28

The role played by progestogens in modulating Schwann cell pathophysiology is well established. Progestogens exert their effects in these cells through both classical genomic and non-genomic mechanisms, the latter mediated by the GABA-A receptor. However, there is evidence that other receptors may be involved. Membrane progesterone receptors (mPRs) are novel 7-transmembrane receptors coupled to G proteins that have been characterized in different tissues and cells, including the central nervous system (CNS). The mPRs were shown to mediate some of progestogens' neuroprotective effects in the CNS, and to be upregulated in glial cells after traumatic brain injury. Based on this evidence, this paper investigated the possible involvement of mPRs in mediating progestogen actions in S42 Schwann cells. All five mPR isoforms and progesterone receptor membrane component 1 (PGRMC1) were detected in Schwann cells, and were present on the cell membrane. Progesterone and the mPR-specific agonist, Org-OD-02-0 (02) bound to these membranes, indicating the presence of functional mPRs. The mPR agonist 02 rapidly increased cell migration in an in vitro assay, suggesting a putative role of mPRs in the nerve regeneration process. Treatment with pertussis toxin and 8-Br-cAMP blocked 02-induced cell migration, suggesting this progestogen action is mediated by activation of an inhibitory G protein, leading to a decrease in intracellular cAMP levels. In contrast, long-term mPR activation led to increased expression levels of myelin associated glycoprotein (MAG). Taken together, these findings show that mPRs are present and active in Schwann cells and have a role in modulating their physiological processes. Copyright © 2017 Elsevier Inc. All rights reserved.

Diffusion Profiling via a Histogram Approach Distinguishes Low-grade from High-grade Meningiomas, Can Reflect the Respective Proliferative Potential and Progesterone Receptor Status.

PubMed

Gihr, Georg Alexander; Horvath-Rizea, Diana; Garnov, Nikita; Kohlhof-Meinecke, Patricia; Ganslandt, Oliver; Henkes, Hans; Meyer, Hans Jonas; Hoffmann, Karl-Titus; Surov, Alexey; Schob, Stefan

2018-02-01

Presurgical grading, estimation of growth kinetics, and other prognostic factors are becoming increasingly important for selecting the best therapeutic approach for meningioma patients. Diffusion-weighted imaging (DWI) provides microstructural information and reflects tumor biology. A novel DWI approach, histogram profiling of apparent diffusion coefficient (ADC) volumes, provides more distinct information than conventional DWI. Therefore, our study investigated whether ADC histogram profiling distinguishes low-grade from high-grade lesions and reflects Ki-67 expression and progesterone receptor status. Pretreatment ADC volumes of 37 meningioma patients (28 low-grade, 9 high-grade) were used for histogram profiling. WHO grade, Ki-67 expression, and progesterone receptor status were evaluated. Comparative and correlative statistics investigating the association between histogram profiling and neuropathology were performed. The entire ADC profile (p10, p25, p75, p90, mean, median) was significantly lower in high-grade versus low-grade meningiomas. The lower percentiles, mean, and modus showed significant correlations with Ki-67 expression. Skewness and entropy of the ADC volumes were significantly associated with progesterone receptor status and Ki-67 expression. ROC analysis revealed entropy to be the most accurate parameter distinguishing low-grade from high-grade meningiomas. ADC histogram profiling provides a distinct set of parameters, which help differentiate low-grade versus high-grade meningiomas. Also, histogram metrics correlate significantly with histological surrogates of the respective proliferative potential. More specifically, entropy revealed to be the most promising imaging biomarker for presurgical grading. Both, entropy and skewness were significantly associated with progesterone receptor status and Ki-67 expression and therefore should be investigated further as predictors for prognostically relevant tumor biological features. Since absolute ADC values vary between MRI scanners of different vendors and field strengths, their use is more limited in the presurgical setting.

Embryo-endometrial interactions during early development after embryonic diapause in the marsupial tammar wallaby.

PubMed

Renfree, Marilyn B; Shaw, Geoff

2014-01-01

The marsupial tammar wallaby has the longest period of embryonic diapause of any mammal. Reproduction in the tammar is seasonal, regulated by photoperiod and also lactation. Reactivation is triggered by falling daylength after the austral summer solstice in December. Young are born late January and commence a 9-10-month lactation. Females mate immediately after birth. The resulting conceptus develops over 6- 7 days to form a unilaminar blastocyst of 80-100 cells and enters lactationally, and later seasonally, controlled diapause. The proximate endocrine signal for reactivation is an increase in progesterone which alters uterine secretions. Since the diapausing blastocyst is surrounded by the zona and 2 other acellular coats, the mucoid layer and shell coat, the uterine signals that maintain or terminate diapause must involve soluble factors in the secretions rather than any direct cellular interaction between uterus and embryo. Our studies suggest involvement of a number of cytokines in the regulation of diapause in tammars. The endometrium secretes platelet activating factor (PAF) and leukaemia inhibitory factor, which increase after reactivation. Receptors for PAF are low on the blastocyst during diapause but are upregulated at reactivation. Conversely, there is endometrial expression of the muscle segment homeobox gene MSX2 throughout diapause, but it is rapidly downregulated at reactivation. These patterns are consistent with those observed in diapausing mice and mink after reactivation, despite the very different patterns of endocrine control of diapause in these 3 divergent species. These common patterns suggest a similar underlying mechanism for diapause, perhaps common to all mammals, but which is activated in only a few.

Abundance and Localization of Progesterone Receptor Isoforms in Endometrium in Women With and Without Endometriosis and in Peritoneal and Ovarian Endometriotic Implants

PubMed Central

Bedaiwy, Mohamed A.; Dahoud, Wissam; Skomorovska-Prokvolit, Yelena; Yi, Lijuan; Liu, James H.; Falcone, Tommaso; Hurd, William W.; Mesiano, Sam

2015-01-01

Background: Several studies suggest that resistance to progesterone may contribute to the pathophysiology of endometriosis. Progesterone mediates its biological activity via the 2 progesterone receptor (PR) isoforms (PR-A and PR-B). Effects of progesterone are determined by the PR-A:PR-B ratio such that a PR-B-dominant state promotes progesterone signaling, whereas a PR-A-dominant state decreases progesterone responsiveness. Our objective was to compare the abundance and cellular localization of the PR isoforms in endometrium and endometriotic lesions from women with and without peritoneal and ovarian endometriosis. Methods: This in vitro study was conducted in a tertiary care facility. Reproductive-age women with surgically diagnosed endometriosis (n = 18) and asymptomatic control individuals (n = 20) were prospectively recruited at the late proliferative and the early secretory phases. At laparoscopy, samples of eutopic endometrium, peritoneal and ovarian endometriosis, and disease-free peritoneum were obtained for subsequent immunohistochemical and immunoblot analysis of PR-B and total PR localization and PR-A and PR-B abundance, respectively. Results: The PR-A and PR-B were detected in eutopic endometrium and in peritoneal and ovarian endometriosis but not in disease-free peritoneum from patients with and without endometriosis. In peritoneal endometriosis, PR-A was the predominant isoform detected, whereas both receptors were detected in ovarian endometriosis and eutopic endometrium. In eutopic endometrium, levels of PR-A were significantly elevated in women with endometriosis compared with women without disease, regardless of menstrual phase. The PR-A levels were significantly elevated in ovarian endometriosis compared with peritoneal endometriosis. Conclusions: Endometriotic lesions and eutopic endometrium from women with endometriosis are uniform in a PR-A-dominant state. The data suggest that menstrual efflux of a PR-A-dominant endometrial tissue into the peritoneal cavity may play a role in the pathophysiology of endometriosis. PMID:26037298

Cripto-1 ablation disrupts alveolar development in the mouse mammary gland through a progesterone receptor-mediated pathway.

PubMed

Klauzinska, Malgorzata; McCurdy, David; Rangel, Maria Cristina; Vaidyanath, Arun; Castro, Nadia P; Shen, Michael M; Gonzales, Monica; Bertolette, Daniel; Bianco, Caterina; Callahan, Robert; Salomon, David S; Raafat, Ahmed

2015-11-01

Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Microsomal receptor for steroid hormones: functional implications for nuclear activity.

PubMed

Muldoon, T G; Watson, G H; Evans, A C; Steinsapir, J

1988-01-01

Target tissues for steroid hormones are responsive by virtue of and to the extent of their content of functional intracellular receptors. Recent years have seen a shift in considerations of the cellular dynamics and distribution of these receptors, with current views favoring predominant intranuclear localization in the intact cell. This paper summarizes our analyses of the microsomal estrogen and androgen binding capability of rat uterine and ventral prostate tissue, respectively; these studies have revealed a set of high affinity sites that may act as a conduit for estrogen traversing the cell en route to the nucleus. These sites have many properties in common with cytosolic receptors, with the salient difference of a failure to activate to a more avid DNA-binding form under conditions which permit such activation of cytosolic receptors. The microsomal estrogen-binding proteins also have appreciable affinity for progesterone, another distinction from other known cellular estrogen receptor species. Various experimental approaches were employed to demonstrate that the microsomal receptors were not simply cytosol contaminants; the most convincing evidence is the recent successful separation of the cytosolic and microsomal forms by differential ammonium sulfate precipitation. Discrete subfractionation of subcellular components on successive sucrose gradients, with simultaneous assessments of binding capability and marker enzyme concentrations, indicates that the major portion of the binding is localized within the vesicles of the endoplasmic reticulum free of significant plasma membrane contamination. The microsomal receptors are readily solubilized by extraction with high- or low-salt-containing buffers or with steroid. The residual microsomes following such extraction have the characteristics of saturable acceptor sites for cytosolic estrogen-receptor complexes. The extent to which these sites will accept the cytosolic complexes is equal to the concentration of microsomal binding sites extracted. These observations suggest three possible roles for the microsomal receptor-like proteins: (a) modulation of estrogen access to nuclear binding sites; (b) formation of functional complexes which diffuse to other extranuclear sites to alter non-genomic cellular processes; (c) regulation of nuclear concentration of estrogen-receptor complexes by virtue of producing microsomal acceptor sites for uptake of free or loosely associated nuclear complexes, previously thought to exist in the cytoplasm.

Characterization and distribution of natriuretic peptide receptors in the rat uterus.

PubMed

Dos Reis, A M; Fujio, N; Dam, T V; Mukaddam-Daher, S; Jankowski, M; Tremblay, J; Gutkowska, J

1995-10-01

Atrial natriuretic peptide (ANP) receptors were characterized in rat uterus. The binding of [125I]ANP to uterine membranes was completely competed for by increasing concentrations of unlabeled ANP (Kd = 0.39 nM) and brain natriuretic peptide (Kd = 1.24 nM) and partially by C-type natriuretic peptide (CNP; Kd = 80.4 nM), but not by C-ANF. Also, [125I]Tyr-CNP bound to uterine membranes was completely competed by unlabeled CNP (Kd = 1.12 nM). Cross-linking of [125I]ANP to uterine membranes revealed the presence of one band of 130 kilodaltons, corresponding to the guanylyl cyclase (GC-A and/or GC-B) subtypes of natriuretic peptide receptors. The presence of messenger RNA coding for genes of both GC-A and GC-B receptors was shown by quantitative reverse transcriptase polymerase chain reaction. Furthermore, ANP and, to a lesser degree, CNP stimulated the production of cGMP in rat uterus. Autoradiographic studies localized the highest binding of [125I]ANP in the endometrium, whereas [125I]Tyr-CNP binding was distributed in the endometrium as well as in the myometrium. These results demonstrate that rat uterine ANP receptors are of the guanylyl cyclase-coupled subtypes. The uterus is a target of natriuretic peptides where ANP induces its biological effects through the production of cGMP.

Enhanced response to ozone exposure during the follicular phase of the menstrual cycle

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

Fox, S.D.; Adams, W.C.; Brookes, K.A.

Exposure to ozone (O[sub 3]), a toxic component of photochemical smog, results in significant airway inflammation, respiratory discomfort, and pulmonary function impairment. These effects can be reduced via pretreatment with anti-inflammatory agents. Progesterone, a gonadal steroid, is known to reduce general inflammation in the uterine endometrium. However, it is not known whether fluctuation in blood levels of progesterone, which are experienced during the normal female menstrual cycle, could alter O[sub 3] inflammatory-induced pulmonary responses. In this study, we tested the hypothesis that young, adult females are more responsive to O[sub 3] inhalation with respect to pulmonary function impairment during theirmore » follicular (F) menstrual phase when progesterone levels are lowest that during their mid-luteal (ML) phase when progesterone levels are highest. Nine subjects with normal ovarian function were exposed in random order for 1 hour each to filtered air and to 0.30 ppm O[sub 3] in their F and ML menstrual phases. Ozone responsiveness was measured by percent change in pulmonary function from pre- to postexposure. Significant gas concentration effects (filtered air versus O[sub 3]) were observed for forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV[sub 1]), and forced expiratory flow between 25 and 75% of FVC (FEF[sub 25-75]), showed a significant menstrual phase and gas concentration interaction effect, with larger decrements observed in the F menstrual phase when progesterone concentrations were significantly lower. We conclude that young, adult females appear to be more responsive to acute O[sub 3] exposure during the F phase than during the ML phase of their menstrual cycles. This difference in pulmonary function response could be related to the anti-inflammatory effects of increased progesterone concentrations during the luteal phase.« less

Conditional deletion of Tsc1 in the female reproductive tract impedes normal oviductal and uterine function by enhancing mTORC1 signaling in mice

PubMed Central

Daikoku, Takiko; Yoshie, Mikihiro; Xie, Huirong; Sun, Xiaofei; Cha, Jeeyeon; Ellenson, Lora Hedrick; Dey, Sudhansu K.

2013-01-01

Heightened mammalian target of rapamycin complex 1 (mTORC1) activity by genetic deletion of its direct inhibitor, Tsc1, is associated with aberrant development and dysfunction of the female reproductive tract in mice. Here, we compared the phenotypes of mice with conditional deletion of Tsc1 in the female reproductive tract by either progesterone receptor (PR)-Cre (Tsc1PR(d/d)), which inactivates Tsc1 in all major cell types in the uterus (epithelium, stroma and myometrium), or anti-Mullerian hormone type 2 receptor (Amhr2)-Cre (Tsc1Amhr2(d/d)), which inactivates stromal and myometrial Tsc1. Tsc1PR(d/d) and Tsc1Amhr2(d/d) females are infertile resulting from oviductal hyperplasia, retention of embryos in the oviduct and implantation failure. In contrast to the appropriate embryonic development after fertilization seen in Tsc1Amhr2(d/d) females, embryo development was disrupted in Tsc1PR(d/d) females. In addition, uteri in Tsc1PR(d/d) and Tsc1Amhr2(d/d) females showed epithelial hyperplasia but not endometrial cancer. In conclusion, Tsc1PR(d/d) and Tsc1Amhr2(d/d) have overlapping yet distinct phenotypes in the context of compartment-specific deletion of Tsc1. PMID:23475984

Asperosaponin VI promotes progesterone receptor expression in decidual cells via the notch signaling pathway.

PubMed

Gao, Jie; Zhou, Chun; Li, Yadi; Gao, Feixia; Wu, Haiwang; Yang, Lilin; Qiu, Weiyu; Zhu, Lin; Du, Xin; Lin, Weixian; Huang, Dandan; Liu, Haibin; Liang, Chun; Luo, Songping

2016-09-01

Recurrent spontaneous abortion (RSA) is a common clinical condition, but its reasons remain unknown in 37-79% of the affected women. The steroid hormone progesterone (P4) is an integral mediator of early pregnancy events, exerting its effects via the progesterone receptor (PR). Dipsaci Radix (DR) has long been used for treating gynecological diseases in Chinese medicine, while its molecular mechanisms and active ingredients are still unclear. We report here the progesterone-like effects of the alcohol extraction and Asperosaponin VI from DR in primary decidual cells and HeLa cell line. We first determined the safe concentration of Asperosaponin VI in the cells with MTT assay and then found by using dual luciferase reporter and Western blotting that Asperosaponin VI significantly increased PR expression. Moreover, we explored the mechanisms of action of the DR extracts and Asperosaponin VI, and the results showed that they could activate Notch signaling, suggesting that they may function by promoting decidualization. Copyright © 2016 Elsevier B.V. All rights reserved.

Bitter taste receptors as targets for tocolytics in preterm labor therapy.

PubMed

Zheng, Kaizhi; Lu, Ping; Delpapa, Ellen; Bellve, Karl; Deng, Ruitang; Condon, Jennifer C; Fogarty, Kevin; Lifshitz, Lawrence M; Simas, Tiffany A Moore; Shi, Fangxiong; ZhuGe, Ronghua

2017-09-01

Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity, with few prevention and treatment options. Uterine contraction is a central feature of PTB, so gaining new insights into the mechanisms of this contraction and consequently identifying novel targets for tocolytics are essential for more successful management of PTB. Here we report that myometrial cells from human and mouse express bitter taste receptors (TAS2Rs) and their canonical signaling components ( i.e., G-protein gustducin and phospholipase C β2). Bitter tastants can completely relax myometrium precontracted by different uterotonics. In isolated single mouse myometrial cells, a phenotypical bitter tastant (chloroquine, ChQ) reverses the rise in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and cell shortening induced by uterotonics, and this reversal effect is inhibited by pertussis toxin and by genetic deletion of α-gustducin. In human myometrial cells, knockdown of TAS2R14 but not TAS2R10 inhibits ChQ's reversal effect on an oxytocin-induced rise in [Ca 2+ ] i Finally, ChQ prevents mouse PTBs induced by bacterial endotoxin LPS or progesterone receptor antagonist mifepristone more often than current commonly used tocolytics, and this prevention is largely lost in α-gustducin-knockout mice. Collectively, our results reveal that activation of the canonical TAS2R signaling system in myometrial cells produces profound relaxation of myometrium precontracted by a broad spectrum of contractile agonists, and that targeting TAS2Rs is an attractive approach to developing effective tocolytics for PTB management.-Zheng, K., Lu, P., Delpapa, E., Bellve, K., Deng, R., Condon, J. C., Fogarty, K., Lifshitz, L. M., Simas, T. A. M., Shi, F., ZhuGe, R. Bitter taste receptors as targets for tocolytics in preterm labor therapy. © FASEB.

Stimulation of GPR30 Increases Release of EMMPRIN-Containing Microvesicles in Human Uterine Epithelial Cells

PubMed Central

Light, Mallory M.; Mehrotra, Pavni; Nowak, Romana A.

2012-01-01

Context: Uterine remodeling is highly dependent on the glycosylated transmembrane protein extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN). Previous studies indicate estradiol can increase EMMPRIN expression in uterine cells and promote subsequent induction of MMP production. Objective: The aim of this study was to investigate the role of G protein-coupled receptor 30 (GPR30) stimulation on EMMPRIN microvesicle release in the human uterine epithelial cell line hTERT-EEC (EECs). Design: We examined EMMPRIN release by human EECs in response to GPR30 stimulation by microvesicle isolation, Western blot, and immunocytochemistry. We employed a pharmacological approach using the GPR30-selective agonist G1 and the antagonist G15 to determine the receptor specificity of this response. Results: We demonstrated GPR30 expression in EECs and release of EMMPRIN in microvesicles in response to stimulation of GPR30. G1, estradiol, and cholera toxin stimulated EMMPRIN release in microvesicles as detected by Western blot and immunocytochemistry, indicating that stimulation of GPR30 can induce EMMPRIN microvesicle release. Conclusions: These data indicate that EMMPRIN release in microvesicles can be mediated by stimulation of GPR30 in human EECs, suggesting that inappropriate stimulation or expression of this receptor may be significant in uterine pathology. PMID:23012390

Chronic hyperandrogenemia in the presence and absence of a western-style diet impairs ovarian and uterine structure/function in young adult rhesus monkeys.

PubMed

Bishop, Cecily V; Mishler, Emily C; Takahashi, Diana L; Reiter, Taylor E; Bond, Kise R; True, Cadence A; Slayden, Ov D; Stouffer, Richard L

2018-01-01

Does chronic hyperandrogenemia beginning at menarche, in the absence and presence of a western-style diet (WSD), alter ovarian and uterine structure-function in young adult rhesus monkeys? Phenotypic alterations in ovarian and uterine structure/function were induced by exogenous testosterone (T), and compounded in the presence of a WSD (T+WSD). Hyperandrogenemia is a well-established component of PCOS and is observed in adolescent girls, indicating a potential pubertal onset of disease symptoms. Obesity is often associated with hyperandrogenemia and it is hypothesized that metabolic dysfunction exacerbates PCOS symptoms. Macaque females (n = 40) near the onset of menarche (~2.5 years of age) were assigned to a 2 by 2 factorial cohort design. Effects on reproductive characteristics were evaluated after 3 years of treatment. Rhesus macaques (Macaca mulatta) were fed either a normal balanced diet (n = 20) or a WSD (n = 20). Additionally, implants containing cholesterol (n = 20) or T (n = 20) were implanted subcutaneously to elevate serum T approximately 5-fold. This resulted in treatment groups of controls (C), T, WSD and T+WSD (n = 10/group). Vaginal swabbing was performed daily to detect menses. After 3 years of treatment, daily serum samples from one menstrual cycle were assayed for hormone levels. Ovarian structure was evaluated in the early follicular phase by 3D/4D ultrasound. Uterine endometrial size and ovarian/luteal vascular function was also evaluated in subgroups (n = 6/group) in the late follicular and mid-luteal phases by 3D/4D ultrasound and contrast-enhanced ultrasound, respectively. Expression of steroid hormone receptors and markers of decidualization and endometrial receptivity were assessed in endometrial biopsies at mid-luteal phase. Approximately 90% of menstrual cycles appeared ovulatory with no differences in frequency or duration between groups. Serum estradiol (E2) levels during the early follicular phase were greatest in the T alone group, but reduced in T+WSD (P < 0.02). Serum LH was elevated in the T group (P < 0.04); however, there were no differences among groups in FSH levels (P > 0.13). Ovarian size at menses tended to be greater in the WSD groups (P < 0.07) and antral follicles ≥1 mm were more numerous in the T+WSD group (P < 0.05). Also, females in T and T+WSD groups displayed polycystic ovarian morphology (PCOM) at greater frequency than C or WSD groups (P < 0.01). Progesterone (P4) levels during the luteal phase were reduced in the T+WSD group compared to C and T groups (P < 0.05). Blood volume (BV) and vascular flow (VF) within the corpus luteum was reduced in all treatment groups compared to C (P < 0.01, P = 0.03), with the WSD alone group displaying the slowest BV and VF (P < 0.05). C and WSD groups displayed endometrial glands at mid-luteal phase with low estrogen receptor 1 (ESR1) and progesterone receptor (PGR) mRNA and immunohistochemical staining in the functionalis zone, but appreciable PGR in the stroma. In contrast, T and T+WSD treatment resulted in glands with less secretory morphology, high ESR1 expression in the glandular epithelium and low PGR in the stroma. Endometrial levels of TIMP3 and MMP26 mRNA and immunostaining were also decreased in the T and T+WSD groups, whereas AR expression was unchanged. None. Females are young adults, so effects could change as they reach prime reproductive age. The T level generated for hyperandrogenemia may be somewhat greater than the 3-4-fold increase observed in adolescent girls, but markedly less than those observed in male monkeys or adolescent boys. Alterations to ovarian and uterine structure-function observed in T and, in particular, T+WSD-treated female macaques are consistent with some of the features observed in women diagnosed with polycystic ovary syndrome (PCOS), and suggest impaired fertility. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under Award Number P50HD071836 (to RLS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding was provided by Office of the Director, NIH under Award Number P51OD011092 (Support for National Primate Research Center). Authors declare no competing interests. © 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 e-mail: journals.permissions@oup.com

Progesterone Inhibition of Neuronal Calcium Signaling Underlies Aspects of Progesterone-Mediated Neuroprotection

PubMed Central

Luoma, Jessie I; Stern, Christopher M; Mermelstein, Paul G.

2011-01-01

Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors. PMID:22101209

Delayed effects of neonatal exposure to 17alpha-ethynylestradiol on the estrous cycle and uterine carcinogenesis in Wistar Hannover GALAS rats.

PubMed

Takahashi, Miwa; Inoue, Kaoru; Morikawa, Tomomi; Matsuo, Saori; Hayashi, Seigo; Tamura, Kei; Watanabe, Gen; Taya, Kazuyoshi; Yoshida, Midori

2013-09-01

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

[Early recurrent miscarriage: Evaluation and management].

PubMed

Gallot, V; Nedellec, S; Capmas, P; Legendre, G; Lejeune-Saada, V; Subtil, D; Nizard, J; Levêque, J; Deffieux, X; Hervé, B; Vialard, F

2014-12-01

To establish recommendations for early recurrent miscarriages (≥3 miscarriages before 14weeks of amenorrhea). Literature review, establishing levels of evidence and recommendations for grades of clinical practice. Women evaluation includes the search for a diabetes (grade A), an antiphospholipid syndrome (APS) (grade A), a thyroid dysfunction (grade A), a hyperprolactinemia (grade B), a vitamin deficiency and a hyperhomocysteinemia (grade C), a uterine abnormality (grade C), an altered ovarian reserve (grade C), and a couple chromosome analysis (grade A). For unexplained early recurrent miscarriages, treatment includes folic acid and progesterone supplementation, and a reinsurance policy in the first quarter (grade C). It is recommended to prescribe the combination of aspirin and low-molecular-weight heparin when APS (grade A), glycemic control in diabetes (grade A), L-Thyroxine in case of hypothyroidism (grade A) or the presence of thyroid antibodies (grade B), bromocriptine if hyperprolactinemia (grade B), a substitution for vitamin deficiency or hyperhomocysteinemia (grade C), sectionning a uterine septum (grade C) and treating an uterine acquired abnormality (grade C). These recommendations should improve the management of couples faced with early recurrent miscarriages. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Altered Stem Cell Receptor Activity in the Ovarian Surface Epithelium by Exogenous Zinc and/or Progesterone.

PubMed

Oktem, G; Sahin, C; Dilsiz, O Y; Demiray, S B; Goker, E N T; Tavmergen, E

2015-05-01

Ovarian surface epithelium (OSE) has the characteristics of a stem cell and the potential for differentiation. Previous studies on this subject have succeeded in deriving oocytes from OSE stem cells, leading to the belief that OSE could be used for infertility treatment. Each rat (n = 10) was subjected to zinc and/or progesterone injection for 5 days after conception. After a 6-day implantation period, ovarian tissues were removed and comprehensive immunohistochemical analysis of stem cell markers was conducted: Sox2, Klf4, Oct3/4, c-Myc, CD117, CD90, SSEA-1 and Notch pathway analysis; Notch1, Jagged1, and Delta1 in the OSE and ovarian stromal cells were evaluated after treatment with zinc, progesterone, or both. Progesterone moderately affected Sox2 expression (p < 0.001), while zinc application strongly affected Klf4 and Oct3/4 and immunoreactivity (p < 0.001). CD90 immunoreactivity was decreased in the OSE and stroma of the progesterone group (p = 0.006) compared with the zinc (p = 0.244) and zinc/progesterone groups (p = 0.910). On the other hand, SSEA-1 showed moderate staining in the OSE and weak staining in stromal cells in animals treated with zinc (p = 0.727), progesterone (p = 0.626), and zinc/progesterone (p = 0.371), with no differences compared with control. Zinc application affected Notch pathway immunoreactivity, with a significant increase in Notch1 (p = 0.0015) and Jagged1 (p < 0.001). The expression of putative stem cell markers in the OSE was verified and stem cell receptor activity was raised in the OSE and ovarian stromal cells by zinc and progesterone. Thus, this increased expression allows the therapeutic use of zinc and progesterone in ovary-related infertility and brings a different perspective to reproductive medicine. © Georg Thieme Verlag KG Stuttgart · New York.

Vaccine Therapy With or Without Sirolimus in Treating Patients With NY-ESO-1 Expressing Solid Tumors

ClinicalTrials.gov

2016-10-03

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Anaplastic Oligodendroglioma; Estrogen Receptor Negative; Estrogen Receptor Positive; Glioblastoma; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma; Metastatic Renal Cell Cancer; Recurrent Adult Brain Neoplasm; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Colorectal Carcinoma; Recurrent Esophageal Carcinoma; Recurrent Gastric Carcinoma; Recurrent Hepatocellular Carcinoma; Recurrent Lung Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Uterine Corpus Carcinoma; Resectable Hepatocellular Carcinoma; Sarcoma; Stage IA Breast Cancer; Stage IA Ovarian Cancer; Stage IA Uterine Corpus Cancer; Stage IB Breast Cancer; Stage IB Ovarian Cancer; Stage IB Uterine Corpus Cancer; Stage IC Ovarian Cancer; Stage II Uterine Corpus Cancer; Stage IIA Breast Cancer; Stage IIA Lung Carcinoma; Stage IIA Ovarian Cancer; Stage IIB Breast Cancer; Stage IIB Esophageal Cancer; Stage IIB Lung Carcinoma; Stage IIB Ovarian Cancer; Stage IIB Skin Melanoma; Stage IIC Ovarian Cancer; Stage IIC Skin Melanoma; Stage IIIA Breast Cancer; Stage IIIA Esophageal Cancer; Stage IIIA Lung Carcinoma; Stage IIIA Ovarian Cancer; Stage IIIA Skin Melanoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Breast Cancer; Stage IIIB Esophageal Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Skin Melanoma; Stage IIIB Uterine Corpus Cancer; Stage IIIC Breast Cancer; Stage IIIC Esophageal Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Skin Melanoma; Stage IIIC Uterine Corpus Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Esophageal Cancer; Stage IV Ovarian Cancer; Stage IV Prostate Cancer; Stage IV Skin Melanoma; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

Triptorelin and cetrorelix induce immune responses and affect uterine development and expressions of genes and proteins of ESR1, LHR, and FSHR of mice.

PubMed

Wei, Suocheng; Guo, Huiling; Gong, Zhuandi; Zhang, Fengwei; Ma, Zhongren

2016-06-01

GnRH immunity can reduce the expression of pituitary GnRH levels, and cause the changes in reproductive behaviors. It is unclear whether triptorelin (TRI) and cetrorelix (CET) immunity influences uterine development and expression of follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), and estradiol receptor 1 (ERS1) in the uterus. The study investigated the effects of active immunity of GnRH agonist and antagonist on uterine development, microstructures, expression of hormone receptors mRNAs, and proteins in uteri. One hundred and five mice were assigned into CET, TRI, and control groups (CG). Mice in CET-1, CET-2, and CET-3 (n = 15) were subcutaneously injected with 10, 20, and 40 μg CET antigens for seven days, respectively. Mice in TRI-1, TRI-2, and TRI-3 were injected with 10, 20, and 40 μg TRI antigens for seven days, respectively. The qPCR and Western blot were implemented to determine expressions of ESR1, LHR and FSHR mRNAs, and proteins. Compared with CG, the uterine weights of CET-1, CET-2, and CET-3 increased by 42.86, 62.86, and 10.00% on day 35 (p < 0.05), respectively. Uterine weights of TRI-2, TRI-3 reduced by 28.57% and 11.43% (p < 0.05), respectively. The uterine cavity in CET-1, CET-2, and CET-3 increased; the uterine wall became thick. The cytoplasm of endometrial epithelial cells (EEC) increased slightly. In TRI group, the uterine wall thinned. Uterine cavity became narrow slightly in TRI-1. Numbers of uterine glands reduced. The endometrium epithelial thickness (EET) in CET-1 and CET-2 increased by 68.21% and 79.46% (p < 0.05), respectively. EET in TRI-1 was decreased by 13.69%. Uterine wall thicknesses (UWT) in CET-1 and CET-2 were higher than CG, with the increment of 28.59% and 30.72%. UWT of TRI-1, TRI-2, and TRI-3 reduced by 29.35, 15.36, and 14.41%, respectively. Expressions of ESR1, FSHR, and LHR mRNAs in CET and TRI mice increased. ESR1 and FSHR protein levels increased in all experimental mice (p < 0.05), with a maximum of TRI-3. LHR protein levels of the CET decreased. LHR protein levels of TRI group increased, with a maximum of TRI-3 (p < 0.05). ESR1 protein level had significant negative correlations to mRNA expressions of ESR1, LHR, and FSHR. CET immunity promoted the uterine development, improved EET and UWT, and also promoted the expressions of ESR1 and FSHR protein levels. It lessened the LHR protein levels. TRI immunity blocked EET and UWT, inhibited uterine growth and development. The efficacy of CET immunity was more obvious than TRI.

(/sup 3/H)-(Thr4,Gly7)OT: a highly selective ligand for central and peripheral OT receptors

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

Elands, J.; Barberis, C.; Jard, S.

1988-01-01

Oxytocin receptors in rat hippocampal synaptic plasma membranes were compared with mammary gland and uterine oxytocin receptors. For this purpose, a highly specific oxytocic agonist (Thr4,Gly7)oxytocin was tritiated. We demonstrated that this ligand labels oxytocin receptors selectively. Scatchard analyses revealed a high affinity for all the oxytocin receptors investigated, with equilibrium dissociation constants between 1.0 and 2.0 nM. Binding appeared to take place at a single population of receptor sites. Competition experiments confirmed the high affinity of arginine vasopressin for hippocampal oxytocin receptors but also revealed that mammary gland and uterine oxytocin receptors do not discriminate more efficiently between oxytocinmore » and arginine vasopressin. This lack in specificity is not affected by applying different concentrations of Mg ions.« less

Oxytocin for labour and caesarean delivery: implications for the anaesthesiologist.

PubMed

Dyer, Robert A; Butwick, Alexander J; Carvalho, Brendan

2011-06-01

The implications of the obstetric use of oxytocin for obstetric anaesthesia practice are summarised. The review focuses on recent research on the uterotonic effects of oxytocin for prophylaxis and management of uterine atony during caesarean delivery. Oxytocin remains the first-line agent in the prevention and management of uterine atony. In-vitro and in-vivo studies show that prior exposure to oxytocin induces uterine muscle oxytocin receptor desensitization. This may influence oxytocin dosing for adequate uterine tone following delivery. Oxytocin has important cardiovascular side-effects (hypotension, tachycardia and myocardial ischaemia). Recent studies suggest that the effective dose of oxytocin for prophylaxis against uterine atony during caesarean delivery is significantly lower than the 5-10 IU historically used by anaesthesiologists. Slow administration of small bolus doses of oxytocin minimises maternal haemodynamic disturbance. Continuous oxytocin infusions are recommended for maintaining uterine tone after bolus administration, although ideal infusion rates are still to be established. The efficacy of the long-acting oxytocin analogue carbetocin requires further investigation. Recommendations are presented for oxytocin dosing during caesarean delivery. Oxytocin remains the first-line uterotonic after vaginal and caesarean delivery. Recent research elucidates the therapeutic range of oxytocin during caesarean delivery, as well as receptor desensitization. Evidenced-based protocols for the prevention and treatment of uterine atony during caesarean delivery are recommended.

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

Cripto-1 Ablation Disrupts Alveolar Development in the Mouse Mammary Gland through a Progesterone Receptor–Mediated Pathway

PubMed Central

Klauzinska, Malgorzata; McCurdy, David; Rangel, Maria Cristina; Vaidyanath, Arun; Castro, Nadia P.; Shen, Michael M.; Gonzales, Monica; Bertolette, Daniel; Bianco, Caterina; Callahan, Robert; Salomon, David S.; Raafat, Ahmed

2016-01-01

Cripto-1, a member of the epidermal growth factor–Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways. PMID:26429739

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.

The state-of-the-art of emergency contraception with the cutting edge drug.

PubMed

Sarkar, Narendra Nath

2011-01-01

The objective of this study is to evaluate and elucidated the potential of selective progesterone receptor modulators (SPRMs) to be an effective emergency contraception (EC). The data are extracted from the literature through the MEDLINE database service from 2000-2010. The SPRMs are in fact progesterone receptor ligands that could bind to progesterone receptor (PR) and exert antagonistic, agonistic or mixed agonist-antagonistic effects. These SPRMs are mifepristone, onapristone, asoprisnil, ulipristal, proellex among other compounds. Currently developed SPRMs may exert contraceptive effects by inhibiting ovulation and retarding endometrial synchronization. Low-doses of progesterone antagonists retard endometrial maturation without affecting ovulation. Mifepristone being a SPRM is effective for prevention of pregnancy but with prostaglandin acts as an excellent abortifacient; yet could not compete with levonorgestrel as EC. However, a single dose of 30 mg ulipristal acetate, another SPRM with similar effectiveness and side effect profiles as 1.5 mg levonorgestrel EC, has shown wider 'window of effect' by inhibition of the LH peak even if administered at the advanced pre-ovulatory phase, a time when use of levonorgestrel EC is no longer effective. Thus, ulipristal acetate goes one-step ahead of levonorgestrel in the field of emergency contraception treatment. Further studies are needed to explore the potential of other SPRMs to be cutting edge emergency contraceptive drugs.

Effect of uterine size on fertility of lactating dairy cows.

PubMed

Baez, Giovanni M; Barletta, Rafael V; Guenther, Jerry N; Gaska, Jerry M; Wiltbank, Milo C

2016-05-01

There are multiple reasons for reduced fertility in lactating dairy cows. We hypothesized that one cause of reduced fertility could be the overall size of the reproductive tract, particularly the uterus, given well-established uterine functions in many aspects of the reproductive process. Thus, the objectives of this study were to evaluate the variability in uterine size in primiparous and multiparous dairy cows and to analyze whether there was an association between uterine size and fertility, particularly within a given parity. Lactating Holstein dairy cows (n = 704) were synchronized to receive timed artificial insemination (TAI) on Day 81 ± 3 of lactation by using the Double-Ovsynch protocol (GnRH-7d-PGF-3d-GnRH-7d-GnRH-7d-PGF-56h-GnRH-16h-TAI). At the time of the last injection of PGF, uterine diameter was determined at the greater curvature using ultrasound, uterine length was determined by rectal palpation, and uterine volume was calculated from these two measurements. Blood samples were also taken to measure progesterone to assure synchronization of all cows used in the final analysis (n = 616; primiparous, n = 289; multiparous, n = 327). Primiparous cows had greater percentage pregnant/AI (P/AI) compared to multiparous cows (49.8% vs. 39.1% at 67 days of pregnancy diagnosis, P = 0.009). Diameter, length, and volume of the uterus were larger in multiparous than in primiparous cows (P < 0.001). For multiparous cows, uterine diameter and volume were smaller in cows that became pregnant compared to cows that were not pregnant to the TAI with a similar tendency observed in primiparous cows. Logistic regression and quartile analysis also showed that as uterine volume increased, there was decreased P/AI in either primiparous or multiparous cows. Thus, there is a negative association between uterine size and fertility in lactating dairy cows with a larger uterus associated with reduced fertility, particularly for multiparous cows. Copyright © 2016 Elsevier Inc. All rights reserved.

The effects of the ovarian cycle and pregnancy on uterine vascular impedance and uterine artery mechanics

PubMed Central

Sprague, Benjamin J.; Phernetton, Terrance M.; Magness, Ronald R.; Chesler, Naomi C.

2009-01-01

Objectives Uterine vascular resistance (UVR) is the ratio of systemic mean arterial pressure to mean uterine blood flow and is sensitive to changes in small arteries and arterioles. However, it provides little or no insight into changes in large, conduit arteries. Fluctuations in estrogen (E2) and progesterone (P4) levels during the ovarian cycle are thought to cause uterine resistance artery vasodilation; the effects on large arteries are unknown. Herein, our objective was to use the uterine vascular impedance, which is sensitive to changes in small and large arteries, to determine the effects of the ovarian cycle and pregnancy on the entire uterine vasculature. Study Design Uterine vascular perfusion pressure and flow rate were recorded simultaneously on anesthetized sheep in the nonpregnant (NP) luteal (NP-L, n=6) and follicular (NP-F, n=7) phases and in late gestation pregnant (CP, n=10) sheep. Impedance and metrics of impedance (input impedance Z0, index of wave reflection RW, characteristic impedance ZC) were calculated. E2 and P4 levels were measured from jugular vein blood samples. Finally, from pressure-diameter tests post-mortem, large uterine artery circumferential elastic modulus (ECirc) was measured. Significant differences were evaluated by two-way ANOVA or Student’s t-test. Results As expected, E2:P4 was higher in the NP-F group compared to the NP-L group (p<0.05). Also as expected, UVR and Z0 decreased in the follicular phase compared to the luteal (p<0.05), but RW, ZC, and ECirc were unaltered. Pregnancy not only substantially decreased UVR (and Z0) (p<0.00001) but also decreased ZC (p<0.001), RW (p<0.0001), ECirc (p<0.01), and pulse wave velocity (p<0.0001). Conclusions The E2:P4 ratio mediates resistance artery vasodilatation in nonpregnant states, but has no effect on conduit artery size or stiffness. In contrast, pregnancy causes dramatic vasodilation and remodeling, including substantial reductions in conduit artery stiffness and increases in conduit artery size, which affect pulsatile uterine hemodynamics. PMID:19297074

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

PubMed

Taketa, Yoshikazu; Inoue, Kaoru; Takahashi, Miwa; Sakamoto, Yohei; Watanabe, Gen; Taya, Kazuyoshi; Yoshida, Midori

2016-06-01

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Granulocytes and Vascularization Regulate Uterine Bleeding and Tissue Remodeling in a Mouse Menstruation Model

PubMed Central

Menning, Astrid; Walter, Alexander; Rudolph, Marion; Gashaw, Isabella; Fritzemeier, Karl-Heinrich; Roese, Lars

2012-01-01

Menstruation-associated disorders negatively interfere with the quality of life of many women. However, mechanisms underlying pathogenesis of menstrual disorders remain poorly investigated up to date. Among others, this is based on a lack of appropriate pre-clinical animal models. We here employ a mouse menstruation model induced by priming mice with gonadal hormones and application of a physical stimulus into the uterus followed by progesterone removal. As in women, these events are accompanied by menstrual-like bleeding and tissue remodeling processes, i.e. disintegration of decidualized endometrium, as well as subsequent repair. We demonstrate that the onset of bleeding coincides with strong upregulation of inflammatory mediators and massive granulocyte influx into the uterus. Uterine granulocytes play a central role in regulating local tissue remodeling since depletion of these cells results in dysregulated expression of matrix modifying enzymes. As described here for the first time, uterine blood loss can be quantified by help of tampon-like cotton pads. Using this novel technique, we reveal that blood loss is strongly reduced upon inhibition of endometrial vascularization and thus, is a key regulator of menstrual bleeding. Taken together, we here identify angiogenesis and infiltrating granulocytes as critical determinants of uterine bleeding and tissue remodeling in a mouse menstruation model. Importantly, our study provides a technical and scientific basis allowing quantification of uterine blood loss in mice and thus, assessment of therapeutic intervention, proving great potential for future use in basic research and drug discovery. PMID:22879894

Detection of potential (anti)progestagenic endocrine disruptors using a recombinant human progesterone receptor binding and transactivation assay.

PubMed

Viswanath, Gunda; Halder, Sujata; Divya, Gunda; Majumder, Chandrajeet B; Roy, Partha

2008-11-25

The present work describes the identification of (anti)progestin endocrine disrupting chemicals (EDC) using a two step screening system. In the first step a competitive binding assay was developed using recombinant human progesterone receptor (hPR). The tested chemicals were of various classes like insecticides, their metabolites, industrial chemicals and waste water treatment plant (WWTP) effluents. All the tested chemicals demonstrated a high affinity binding for hPR. The average IC50 values of the test chemicals were within the range of 1-25microM. In the second step of screening, a mammalian cell-based hPR transactivation assay was developed where HEK 293 cells were co-transfected with hPR and luciferase reporter gene under the control of progesterone-response element. Stimulation of the cells with progesterone resulted in about 25-fold up regulation of luciferase activity, with EC50 value of 4nM. Potent anti-progesterone, RU486, significantly inhibited progesterone-induced transactivation and non-progestagenic steroids failed to transactivate hPR till 1microM concentrations. The chemicals showing high binding affinities in competitive binding assays were then tested in transactivation assay and all of them were found to be anti-progestative except WWTP effluents. Transactivation assays using extracted water samples from five different WWTP effluents showed that it was rich in progestative compounds. The levels of induction caused by these effluents were in the range of 15-25% of induction by progesterone and they represented about 6ng/l equivalent progesterone activities. In conclusion, we demonstrated that this two step assay provides an efficient screening tool for the detection of (anti)progestative EDC in various samples.

Actions of Steroids: New Neurotransmitters

PubMed Central

Cornil, Charlotte A.; Mittelman-Smith, Melinda A.; Rainville, Jennifer R.; Remage-Healey, Luke; Sinchak, Kevin; Micevych, Paul E.

2016-01-01

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. PMID:27911748

Pembrolizumab and Enobosarm in Treating Patients With Androgen Receptor Positive Metastatic Triple Negative Breast Cancer

ClinicalTrials.gov

2018-04-05

Androgen Receptor Positive; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Procedure for successful interspecific embryo transfer from mouflon (Ovis gmelini musimon) to Spanish Merino sheep (Ovis aries).

PubMed

Santiago-Moreno, J; González-Bulnes, A; Gómez-Brunet, A; Cocero, M J; del Campo, A; García-García, R; López-Sebastián, A

2001-09-01

Embryos from five anesthetized mouflons (Ovis gmelini musimon), superovulated with FSH-o (Ovagen) were transferred into preselected Spanish Merino sheep (Ovis aries). Myorelaxation was complete in four of five donor mouflons. The status of the uterus of potential recipients was evaluated by transrectal ultrasonography, and those ewes with fluid in the uterine horn were rejected. The corpus luteum in each ewe was assessed ultrasonographically the day before surgery. Plasma progesterone levels and the quality of the corpora lutea were the criteria for selection of recipients. Ten embryos were transferred to the five selected Spanish Merino recipients, resulting in four pregnancies and seven live-born lambs, including three sets of twins. This study shows that determination of plasma progesterone levels combined with ultrasonographic assessment of the corpus luteum provides information useful for screening of potential recipients.

Regulation of Steroid Hormone Receptor Function By the 52-kDa FK506-Binding Protein (FKBP52)

PubMed Central

Sivils, Jeffrey C.; Storer, Cheryl L.; Galigniana, Mario D.; Cox, Marc B.

2011-01-01

The large FK506-binding protein FKBP52 has been characterized as an important positive regulator of androgen, glucocorticoid and progesterone receptor signaling pathways. FKBP52 associates with receptor-Hsp90 complexes and is proposed to have roles in both receptor hormone binding and receptor subcellular localization. Data from biochemical and cellular studies has been corroborated in whole animal models as fkbp52-deficient male and female mice display characteristics of androgen, glucocorticoid and/or progesterone insensitivity. FKBP52 receptor specificity and the specific phenotypes displayed by the fkbp52-deficient mice have firmly established FKBP52 as a promising target for the treatment of a variety of hormone-dependent diseases. Recent studies demonstrated that the FKBP52 FK1 domain and the proline-rich loop within this domain are functionally important for FKBP52 regulation of receptor function. Based on these data, efforts are currently underway to target the FKBP52 FK1 domain and the proline-rich loop with small molecule inhibitors. PMID:21511531

Time course of the estradiol-dependent induction of oxytocin receptor binding in the ventromedial hypothalamic nucleus of the rat

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

Johnson, A.E.; Ball, G.F.; Coirini, H.

1989-09-01

Oxytocin (OT) transmission is involved in the steroid-dependent display of sexual receptivity in rats. One of the biochemical processes stimulated by the ovarian steroid 17 beta-estradiol (E2) that is relevant to reproduction is the induction of OT receptor binding in the ventromedial hypothalamic nucleus (VMN). The purpose of these experiments was to determine if E2-induced changes in OT receptor binding in the VMN occur within a time frame relevant to cyclic changes in ovarian steroid secretion. OT receptor binding was measured in the VMN of ovariectomized rats implanted for 0-96 h with E2-containing Silastic capsules. The rate of decay ofmore » OT receptor binding was measured in another group of animals 6-48 h after capsule removal. Receptors were labeled with the specific OT receptor antagonist ({sup 125}I)d(CH2)5(Tyr(Me)2,Thr4,Tyr-NH2(9))OVT, and binding was measured with quantitative autoradiographic methods. In addition, plasma E2 levels and uterine weights were assessed in animals from each treatment condition. Significant increases in E2-dependent OT receptor binding and uterine weight occurred within 24 h of steroid treatment. After E2 withdrawal, OT receptor binding and uterine weight decreased significantly within 24 h. These results are consistent with the hypothesis that steroid modulation of OT receptor binding is necessary for the induction of sexual receptivity.« less

Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3-5 weeks post partum, a randomized, double-blind clinical trial.

PubMed

Hirsbrunner, Gaby; Burkhardt, Heinz W; Steiner, Adrian

2006-12-21

Delayed uterine involution has negative effects on the fertility of cows; use of prostaglandin F2alpha alone as a single treatment has not been shown to consistently improve fertility. Combined administration of PGF2alpha and PGE2 increased uterine pressure in healthy cows. We hypothesized, that the combination of both prostaglandins would accelerate uterine involution and have, therefore, a positive effect on fertility variables. In commercial dairy farming, the benefit of a single post partum combined prostaglandin treatment should be demonstrated. 383 cows from commercial dairy farms were included in this study. Uterine size and secretion were evaluated at treatment 21-35 days post partum and 14 days later. Cows were randomly allocated to one of three treatment groups: PGF2alpha and PGE2, PGF2alpha or placebo. For every animal participating in the study, the following reproduction variables were recorded: Interval from calving to first insemination, days open, number of artificial inseminations (AI) to conception; subsequent treatment of uterus, subsequent treatment of ovaries. Plasma progesterone level at time of treatment was used as a covariable. For continuous measurements, analysis of variance was performed. Fisher's exact test for categorical non-ordered data and exact Kruskal-Wallis test for ordered data were used; pairwise group comparisons with Bonferroni adjustment of significance level were performed. There was no significant difference among treatment groups in uterine size. Furthermore, there was no significant difference among treatments concerning days open, number of AI, and subsequent treatment of uterus and ovaries. Days from calving to first insemination tended to be shorter for cows with low progesterone level given PGF2alpha and PGE2 in combination than for the placebo-group (P = 0.024). The results of this study indicate that the administration of PGF2alpha or a combination of PGF2alpha and PGE2 21 to 35 days post partum had no beneficial effect upon measured fertility variables. The exception was a tendency for a shorter interval from calving to first insemination after administration of the combination of PGF2alpha and PGE2, as compared to the placebo group. Further research should be done in herds with reduced fertility and/or an increased incidence of postpartum vaginal discharge.

Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3–5 weeks post partum, a randomized, double-blind clinical trial

PubMed Central

Hirsbrunner, Gaby; Burkhardt, Heinz W; Steiner, Adrian

2006-01-01

Background Delayed uterine involution has negative effects on the fertility of cows; use of prostaglandin F2alpha alone as a single treatment has not been shown to consistently improve fertility. Combined administration of PGF2alpha and PGE2 increased uterine pressure in healthy cows. We hypothesized, that the combination of both prostaglandins would accelerate uterine involution and have, therefore, a positive effect on fertility variables. In commercial dairy farming, the benefit of a single post partum combined prostaglandin treatment should be demonstrated. Methods 383 cows from commercial dairy farms were included in this study. Uterine size and secretion were evaluated at treatment 21–35 days post partum and 14 days later. Cows were randomly allocated to one of three treatment groups: PGF2alpha and PGE2, PGF2alpha or placebo. For every animal participating in the study, the following reproduction variables were recorded: Interval from calving to first insemination, days open, number of artificial inseminations (AI) to conception; subsequent treatment of uterus, subsequent treatment of ovaries. Plasma progesterone level at time of treatment was used as a covariable. For continuous measurements, analysis of variance was performed. Fisher's exact test for categorical non-ordered data and exact Kruskal-Wallis test for ordered data were used; pairwise group comparisons with Bonferroni adjustment of significance level were performed. Results There was no significant difference among treatment groups in uterine size. Furthermore, there was no significant difference among treatments concerning days open, number of AI, and subsequent treatment of uterus and ovaries. Days from calving to first insemination tended to be shorter for cows with low progesterone level given PGF2alpha and PGE2 in combination than for the placebo-group (P = 0.024). Conclusion The results of this study indicate that the administration of PGF2alpha or a combination of PGF2alpha and PGE2 21 to 35 days post partum had no beneficial effect upon measured fertility variables. The exception was a tendency for a shorter interval from calving to first insemination after administration of the combination of PGF2alpha and PGE2, as compared to the placebo group. Further research should be done in herds with reduced fertility and/or an increased incidence of postpartum vaginal discharge. PMID:17184541

Development of an evidence-based approach to external quality assurance for breast cancer hormone receptor immunohistochemistry: comparison of reference values.

PubMed

Makretsov, Nikita; Gilks, C Blake; Alaghehbandan, Reza; Garratt, John; Quenneville, Louise; Mercer, Joel; Palavdzic, Dragana; Torlakovic, Emina E

2011-07-01

External quality assurance and proficiency testing programs for breast cancer predictive biomarkers are based largely on traditional ad hoc design; at present there is no universal consensus on definition of a standard reference value for samples used in external quality assurance programs. To explore reference values for estrogen receptor and progesterone receptor immunohistochemistry in order to develop an evidence-based analytic platform for external quality assurance. There were 31 participating laboratories, 4 of which were previously designated as "expert" laboratories. Each participant tested a tissue microarray slide with 44 breast carcinomas for estrogen receptor and progesterone receptor and submitted it to the Canadian Immunohistochemistry Quality Control Program for analysis. Nuclear staining in 1% or more of the tumor cells was a positive score. Five methods for determining reference values were compared. All reference values showed 100% agreement for estrogen receptor and progesterone receptor scores, when indeterminate results were excluded. Individual laboratory performance (agreement rates, test sensitivity, test specificity, positive predictive value, negative predictive value, and κ value) was very similar for all reference values. Identification of suboptimal performance by all methods was identical for 30 of 31 laboratories. Estrogen receptor assessment of 1 laboratory was discordant: agreement was less than 90% for 3 of 5 reference values and greater than 90% with the use of 2 other reference values. Various reference values provide equivalent laboratory rating. In addition to descriptive feedback, our approach allows calculation of technical test sensitivity and specificity, positive and negative predictive values, agreement rates, and κ values to guide corrective actions.

Immunophenotype of nipple adenoma in a male patient.

PubMed

Fernandez-Flores, Angel; Suarez-Peñaranda, Jose-Manuel

2011-03-01

Adenoma of the nipple is rare in men. It must be distinguished from a breast carcinoma and from Paget disease. In this sense, immunohistochemistry can be of some help. In women, for instance, immunoexpression of c-erbB-2 favors a diagnosis of Paget disease, according to some studies. Nevertheless, we have not found any studies on HER2/neu status, estrogen receptors, or progesterone receptors in nipple adenoma of male patients. We present a case of an adenoma of the nipple in a 21-year-old man in which we carried out a wide immunohistochemical study. The lesion did not express estrogen receptors, progesterone receptors, or androgen receptors. The HercepTest was negative. Smooth muscle Actin and p63 were remarked in the basal layer of the tumoral tubules, supporting the benignancy of the lesion. This case of adenoma of the nipple in a male shows an immunophenotype that is similar to the ones reported in female patients.

The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride reduces uterine bleeding in RU486-induced abortion mice.

PubMed

Li, Xia; Wang, Bin; Li, Yuzhu; Wang, Li; Zhao, Xiangzhong; Zhou, Xianbin; Guo, Yuqi; Jiang, Guosheng; Yao, Chengfang

2013-01-09

The Th1/Th2/Th17/Treg paradigm plays an important role in achieving maternal-fetal immunotolerance and participates in RU486-induced abortion. Excessive uterine bleeding is the most common side effect of RU486-induced abortion; however, its etiopathogenesis has not been fully understood. Therefore, elucidating the correlation between the Th1/Th2/Th17/Treg paradigm and the volume of uterine bleeding may offer novel therapeutic target for reducing uterine bleeding in RU486-induced abortion. Leonurus sibiricus has been used in clinics to reduce postpartum hemorrhage with low toxicity and high efficiency; however, the effective constituents and therapeutic mechanism have not been described. Stachydrine hydrochloride is the main constituent of L. sibiricus, therefore L. sibiricus is regarded as a candidate for reducing uterine bleeding in RU486-induced abortion mice by regulating the Th1/Th2/Th17/Treg paradigm. The purpose of this study was to determine the Th1/Th2/Th17/Treg paradigm in uterine bleeding of RU486-induced abortion mice and to elucidate the immunopharmacologic effects of stachydrine hydrochloride on inducing the Th1/Th2/Th17/Treg paradigm in reducing the uterine bleeding volume in RU486-induced abortion mice. To investigate the Th1/Th2/Th17/Treg paradigm in uterine bleeding during RU486-induced abortion mice, pregnant BALB/c mice were treated with high- and low-dose RU486 (1.5mg/kg and 0.9 mg/kg, respectively), and the serum progesterone (P(4)) protein level, uterine bleeding volume, and proportions of Th1/Th2/Th17/Treg cells in mice at the maternal-fetal interface were detected by ELISA assay, alkaline hematin photometric assay, and flow cytometry, respectively. To determine the regulatory effect of stachydrine hydrochloride on the Th1/Th2/Th17/Treg paradigm in vitro, splenocytes of non-pregnant mice were separated and treated with P(4,) RU486, and/or stachydrine hydrochloride (10(-5)M, 10(-4)M, and 10(-3)M, respectively). The proportions of Th1/Th2/Th17/Treg cells were analyzed using flow cytometry. To evaluate the effect of stachydrine hydrochloride in reducing uterine bleeding via regulation of the Th1/Th2/Th17/Treg paradigm, pregnant mice were treated with RU486 (1.5mg/kg) and/or stachydrine hydrochloride (2.5mg/kg, 5mg/kg, and 10mg/kg). The serum P(4) level, uterine bleeding volume, and proportions of Th1/Th2/Th17/Treg cells at the mice maternal-fetal interface were detected. Moreover, the protein levels of cytokines (IL-12 and IL-6) and the cytokine soluble receptors were analyzed by ELISA assay, and the mRNA expression of transcription factors (T-bet, GATA-3, RORγt, and Foxp3) were detected by RT-PCR assay. Th1- and Th17-biased immunity was observed in RU486-induced abortion mice. The volume of uterine bleeding during RU486-induced abortion was negatively related to the proportions of Th1 and Th17 cells, as well as the ratios of Th1:Th2 cells and Th17:Treg cells, and positively related to the proportions of Th2 and Treg cells. Stachydrine hydrochloride promoted the protein expression of IL-12 and IL-6, as well as the mRNA expression of T-bet and RORγt, while inhibiting the mRNA expression of GATA-3 and Foxp3. Therefore, the Th1/Th2/Th17/Treg paradigm in RU486-induced abortion mice shifted to Th1 and Th17 after stachydrine hydrochloride administration. The volume of uterine bleeding during RU486-induced abortion was reduced significantly after stachydrine hydrochloride administration. The Th1/Th2/Th17/Treg paradigm is closely related to the volume of uterine bleeding in RU486-induced abortion mice. The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride contributed to the reduction in uterine bleeding in RU486-induced abortion mice. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Ultrasonographic and laparoscopic evaluation of the reproductive tract in older captive female cheetahs (Acinonyx jubatus).

PubMed

Schulman, M L; Kirberger, R M; Tordiffe, A S W; Marker, L L; Schmidt-Küntzel, A; Hartman, M J

2015-12-01

The study uniquely described the clinical value of transabdominal ultrasonography for monitoring features characterizing the estrous cycle in female cheetahs (Acinonyx jubatus). The reproductive tracts of 21 female, nulliparous, and relatively aged (median: 11 and interquartile range: 9.25-14 years) captive cheetahs resident on two sites in Namibia were assessed by transabdominal ultrasound. Subsequently, the ovarian findings on ultrasound were compared with direct visualization while performing laparoscopic sterilization. A combination of these observations supported by concurrent sampling for vaginal cytology and serum progesterone concentrations defined the estrous status of individual animals. At one site, six cheetahs had been implanted with the GnRH agonist, deslorelin as a contraceptive at least once within the preceding 11 years. On ultrasound, 31 uterine horns and 35 ovaries with discernible structures on 28 (86%) were visualized in the 21 cheetahs. The uterine body was difficult to visualize because of its intrapelvic location. Eleven of 19 uteri (58%) visualized showed endometrial edema suggestive of estrogenization. The uteri of four cheetahs (19%) showed evidence of mild cystic endometrial hyperplasia. Paraovarian cysts were seen on ultrasound (n = 21) and laparoscopy (n = 26) in 16 (76.2%) and 18 (85.7%) cheetahs, respectively. Ovarian volumes obtained from ultrasonographically determined dimensions predicted cyclic activity. Laparoscopy showed that 19 ovaries had discernible follicular structures. In the study population, 10 (47.6%) cheetahs were in proestrus or estrus; none in the luteal phase; and 11 (52.4%) in anestrus. Transabdominal ultrasound, in combination with serum progesterone concentrations and vaginal cytology, was used with acceptable accuracy to assess cyclic ovarian activity in captive cheetahs. A considerable proportion of this aged population showed ovarian activity and the prevalence of paraovarian cysts was notable. A history of prior deslorelin treatment was not associated with either reproductive activity or uterine pathology. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of reproductive ageing on pregnant mouse uterus and cervix

PubMed Central

Patel, Rima; Moffatt, James D.; Mourmoura, Evangelia; Demaison, Luc; Seed, Paul T.; Poston, Lucilla

2017-01-01

Key points Older pregnant women have a greater risk of operative delivery, still birth and post‐term induction.This suggests that maternal age can influence the timing of birth and processes of parturition.We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour.Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function.Uterine ageing and labour dysfunction should be investigated further in older primigravid women. Abstract Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth and post‐term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3‐month‐old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin‐43 mRNA expression were reduced in the myometrium from 8‐month‐old vs. 3‐month‐old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age‐induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8‐month‐old mice provide a useful model of reproductive ageing. The present study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women. PMID:28083928

Confirmation of the progesterone receptor as an efficient marker of treatment with 17β-estradiol in veal calves.

PubMed

Pezzolato, Marzia; Botta, Mario; Baioni, Elisa; Richelmi, Guia Benedetta; Pitardi, Danilo; Varello, Katia; Caramelli, Maria; Bozzetta, Elena

2016-01-01

Under current European Union legislation the use of anabolic steroids in food-producing livestock is banned because of their long-term adverse effects on human health. We examined the expression profile of the immunohistochemical marker progesterone receptor in veal calves' sex accessory glands following experimental administration of anabolic compounds. The aim was to confirm the accuracy of the immunohistochemical approach in the detection of the over-expression of the progesterone receptor induced by the administration of sexual steroids at low levels (17β-estradiol and nandrolone alone or in combination). A total of 217 male veal calves were randomly divided into four groups: group A (104 calves) treated with 17β-estradiol (5 mg/head; 4 weekly injections); group B (20 calves) treated with nandrolone (50 mg/head; 4 weekly injections); group C (20 calves) treated with the association of the two steroids (5 mg estradiol + 50 mg nandrolone; 4 weekly injections); and group K (73 calves) kept as a control. All the sexual accessory glands were collected at the slaughterhouse (15 days after the last administration) and subjected to immunohistochemical staining with anti-progesterone receptor antibody. All the calves treated with 17β-estradiol alone or in association with nandrolone (groups A and C) showed strong positivity, while nandrolone-treated calves and controls (groups B and K) gave negative results to the immunohistochemical investigation. The statistical analysis showed that the progesterone receptor is a significant predictor of 17β-estradiol treatment alone or in association with nandrolone (p < 0.001): the immunohistochemical study resulted in 100% sensitivity (CI = 95%: 97.1-100%) and specificity (CI = 95%: 95.1-100%) for prostate and 99% sensitivity (CI = 95%: 95.6-100%) and 100% specificity (CI = 95%: 95.1-100%) for bulbo-urethral glands. The data confirm that this innovative biological approach offers a reliable tool to enhance the efficacy of the histological test to detect illegal treatments with estrogens alone or in association with androgens.

Effects of tachykinins on uterine smooth muscle.

PubMed

Patak, E N; Pennefather, J N; Story, M E

2000-11-01

1. Sensory nerves supplying the mammalian uterus have been shown to contain substance P (SP) and neurokinin (NK)A. This review presents some of the advances that have led to a greater understanding of the effects of tachykinins on uterine smooth muscle. 2. The cell-surface peptidase neprilysin (EC.3 24.11, endopeptidase 24.11, enkephalinase, CALLA, CD10) has been shown to play a major role in regulating the actions of tachykinins on both rat and human myometrium. Because this peptidase is known to be regulated by steroids and pregnancy, its effects may be of physiological relevance. 3. Tachykinins produce contractions of isolated myometrial preparations from non-pregnant rats and mice. The NK2 receptor mediates these effects in rat uterus, while the NK1 receptor may mediate these effects in the mouse uterus. 4. The effects of tachykinins have been examined on myometrial preparations obtained at Caesarean section from near-term pregnant women. In the presence of the peptidase inhibitors (thiorphan, captopril and bestatin), the mammalian tachykinins SP, NKA and NKB produced concentration-dependent uterine contractions. 5. The order of agonist potency NKA > SP = NKB suggested that NK2 receptors mediate uterine contractions in the human. This was confirmed using the stable analogues [Sar9,Met(O2)11]SP, [Lys5MeLeu9Nle10]NKA(4-10) and [N-MePhe7]NKB, which are NK1, NK2 and NK3 receptor selective, respectively. Only [Lys5MeLeu9Nle10]NKA(4-10) produced concentration-related contractions of human uterine smooth muscle. 6. The experimental findings described in the present review, taken together with results published previously in the literature, indicate that tachykinin peptides may play a physiological or pathophysiological role in regulating uterine smooth muscle activity. However, more extensive research will be required to confirm such a role for these peptides.

Does Breast or Ovarian Cancer Run in Your Family?

MedlinePlus

... receptors, progesterone receptors and human epidermal growth factor receptor 2.) Cancer in both breasts Breast cancer in a male relative Ovarian, fallopian tube, or primary peritoneal cancer Pancreatic cancer or high grade prostate cancer Breast, ovarian, pancreatic, or high grade prostate ...

Combinatorial effects of quercetin and sex-steroids on fluid and electrolytes’ (Na+, Cl-, HCO3-) secretory mechanisms in the uterus of ovariectomised female Sprague-Dawley rats

PubMed Central

Shahzad, Huma; Giribabu, Nelli; Karim, Kamarulzaman; Kassim, Normadiah M.; Muniandy, Sekaran

2017-01-01

Dysregulation of uterine fluid environment could impair successful reproduction and this could be due to the effect of environmental estrogens. Therefore, in this study, effect of quercetin, an environmental estrogen on uterine fluid and electrolytes concentrations were investigated under sex-steroid influence. Ovariectomised adult female Sprague-Dawley rats were given 10, 50 or 100mg/kg/day quercetin subcutaneously with 17-β estradiol (E) for seven days or three days E, then three days E plus progesterone (P) (E+P) treatment. Uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations were determined by in-vivo perfusion. Following sacrifice, uteri were harvested and levels of the proteins of interest were identified by Western blotting and Realtime PCR. Distribution of these proteins in the uterus was observed by immunofluorescence. Levels of uterine cAMP were measured by enzyme-linked immunoassay (EIA). Administration of quercetin at increasing doses increased uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations, but to the levels lesser than that of E. In concordant, levels of CFTR, SLC4A4, ENaC (α, β and γ), Na+/K+-ATPase, GPα/β, AC and cAMP in the uterus increased following increased in the doses of quercetin. Co-administration of quercetin with E caused uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations to decrease. In concordant, uterine CFTR, SLC26A6, SLC4A4, ENaC (α, β and γ), Na+/K+-ATPase, GPα/β, AC and cAMP decreased. Greatest effects were observed following co-administration of 10mg/kg/day quercetin with E. Co-administration of quercetin with E+P caused uterine fluid Na+ and HCO3- concentrations to increase but no changes in fluid secretion rate and Cl- concentration were observed. Co-administration of high dose quercetin (100 mg/kg/day) with E+P caused uterine CFTR, SLC26A6, AC, GPα/β and ENaC (α, β and γ) to increase. Quercetin-induced changes in the uterine fluid secretion rate and electrolytes concentrations could potentially affect the uterine reproductive functions under female sex-steroid influence. PMID:28253299

Gynecological efficacy and chemical investigation of Vitex agnus-castus L. fruits growing in Egypt.

PubMed

Ibrahim, N A; Shalaby, A S; Farag, R S; Elbaroty, G S; Nofal, S M; Hassan, E M

2008-04-15

Flavonoid glycosides, orientin and apigenin 3, 8-di-C-glycosides in addition to, iridoid compound, aucubin were isolated from the ethanolic extract of Vitex agnus-castus fruits. Their structures were identified on the basis of the spectroscopic data. The estrogenic activity of the ethanolic extract in two dose levels 0.6 and 1.2 g kg(-1) per body weight (b.w.) was studied by the vaginal smear, and uterine weight methods for normal and ovariectomized female rats. The extract induced significant increase in the uterine weight of ovariectomized rats at two dose levels comparable to that of control group. The percentages of the total average number of scores were increased significantly too. Significant increases in plasma progesterone and total estrogens levels were shown at the two dose levels when compared to that of control group. On the other side, the extract induced significant reduction in luteinizing and plasma prolactin hormones.

Feeding prepubescent gilts a high-fat diet induces molecular changes in the hypothalamus-pituitary-gonadal axis and predicts early timing of puberty.

PubMed

Zhuo, Yong; Zhou, Dongsheng; Che, Lianqiang; Fang, Zhengfeng; Lin, Yan; Wu, De

2014-01-01

The onset of puberty in females has been occurring earlier over the past decades, presumably as a result of improved nutrition in developed countries. However, the underlying molecular mechanisms responsible for the early attainment of puberty as a result of nutrition fortification remain largely unknown. The aim of this study was to evaluate the hormone and gene expression changes in prepubescent gilts fed a high-fat diet to investigate whether these changes could predict the early timing of puberty. Forty gilts were fed a daily basal diet (LE) or a basal diet with an additional 270 g/d or 340 g/d of fat (HE) during the prepubescent phase. Blood samples were collected during the prepubescent phase to detect hormone secretion changes in insulin-like growth factor-1, kisspeptin, estradiol, progesterone, and leptin. The gene expressions at the hypothalamus-pituitary-gonadal axis were examined on day 73 of the experiment (average age on day 177) during the prepubescent phase. An HE diet resulted in accelerated body weight gain and back-fat thickness at the P2 point compared with LE gilts during the prepubescent phase. Gilts that were fed HE diets attained puberty 12 d earlier than LE gilts, and a larger proportion of HE gilts reached puberty at day 180 or 190 of age. A postmortem analysis revealed a promoted development of the uterus and ovary tissue that was characterized by a 53.7% and 29.5% increase in the uterine and ovary weight, respectively, and an increased length of the uterine horn and oviduct tissue in HE gilts. Real-time quantitative polymerase chain reaction revealed that HE gilts had higher Kiss-1, G protein-coupled receptor 54, gonadotropin-releasing hormone and estrogen receptor α mRNA expression levels in the hypothalamic anteroventral periventricular nucleus; the leptin receptor mRNA expression level was higher in the hypothalamic arcuate nucleus and ovary tissue; the insulin-like growth factor-1 receptor expression was higher in the pituitary and ovary tissues, and the follicle-stimulating hormone and luteinizing hormone mRNA expression levels were higher in the pituitary gland. These data showed that the consumption of additional fat can facilitate early attainment of puberty, which can be predicted by the changes in secreted hormones and gene expression in the hypothalamus-pituitary-gonadal axis. Copyright © 2014 Elsevier Inc. All rights reserved.

Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective.

PubMed

Mahesh, Virendra B

2012-01-01

This career retrospective describes how the initial work on the mechanism of hormone action provided the tools for the study of hirsutism, virilism, and polycystic ovarian disease. After excessive ovarian and or adrenal androgen secretion in polycystic ovarian disease had been established, the question whether the disease was genetic or acquired, methods to manage hirsutism and methods for the induction of ovulation were addressed. Recognizing that steroid gonadotropin feedback was an important regulatory factor, initial studies were done on the secretion of LH and FSH in the ovulatory cycle. This was followed by the study of basic mechanisms of steroid-gonadotropin feedback system, using castration and steroid replacement and the events surrounding the natural onset of puberty. Studies in ovariectomized rats showed that progesterone was a pivotal enhancer of estrogen-induced gonadotropin release, thus accounting for the preovulatory gonadotropin surge. The effects of progesterone were manifested by depletion of the occupied estrogen receptors of the anterior pituitary, release of hypothalamic LHRH, and inhibition of enzymes that degrade LHRH. Progesterone also promoted the synthesis of FSH in the pituitary. The 3α,5α-reduced metabolite of progesterone brought about selective LH release and acted using the GABA(A) receptor system. The 5α-reduced metabolite of progesterone brought about selective FSH release; the ability of progesterone to bring about FSH release was dependent on its 5α-reduction. The GnRH neuron does not have steroid receptors; the steroid effect was shown to be mediated through the excitatory amino acid glutamate, which in turn stimulated nitric oxide. These observations led to the replacement of the long-accepted belief that ovarian steroids acted directly on the GnRH neuron by the novel concept that the steroid feedback effect was exerted at the glutamatergic neuron, which in turn regulated the GnRH neuron. The neuroprotective effects of estrogens on brain neurons are of considerable interest.

Regulation of the ovarian inflammatory response at ovulation by nuclear progesterone receptor.

PubMed

Akison, Lisa K; Robertson, Sarah A; Gonzalez, Macarena B; Richards, JoAnne S; Smith, C Wayne; Russell, Darryl L; Robker, Rebecca L

2018-06-01

The nuclear progesterone receptor (PGR) transcription factor is essential for ovulation; however, the exact mechanisms by which PGR controls ovulation are not known. The aim of this study was to determine whether PGR regulates inflammatory mediators in the ovary. Ovaries from mice lacking PGR (PRKO) and heterozygous PR+/- littermates were subjected to microarray analysis of a large panel of inflammatory genes. Immune cell subsets were detected by gene expression; and neutrophils by immunohistochemistry and chemotaxis assay. PRKO ovaries exhibited dysregulated expression of vasodilator (Edn1), cytokine (Il-6, Tgfb1), adhesion receptor (Cd34), apoptotic factor (Bax) and transcription factors (Nfkb2, Socs1, Stat3). Ptgs2 was also reduced in PRKO ovaries, but mRNA and protein were not different in granulosa cells. There were reduced neutrophils in ovaries of PRKO mice at ovulation; however, chemotaxis assays showed PRKO neutrophils migrate normally and that PRKO ovarian extracts exhibit chemotactic properties in vitro. Specific inflammatory mediators are altered in the ovaries of PRKO mice indicating that progesterone regulates features of inflammation at ovulation. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sufficient progesterone-priming prior to estradiol stimulation is required for optimal induction of the cervical prostaglandin system in pregnant sheep at 0.7 gestations.

PubMed

Wu, Wen Xuan; Coksaygan, Turhan; Chakrabarty, Kaushik; Collins, Valta; Rose, James C; Nathanielsz, Peter W

2005-08-01

The purposes of this study were to determine the separate and interactive functions of progesterone and estradiol in regulating the cervical prostaglandin (PG) system in pregnant sheep at 0.7 gestations. At 106-108 days of gestational age (dGA), ewes were treated with vehicle for 14 days (n = 5) or vehicle for 12 days followed by estradiol 5 mg twice a day, intramuscularly for 2 days (n = 5) or progesterone 100 mg, twice a day, intramuscularly for 14 days (n = 5) or progesterone 100 mg twice a day, intramuscularly for 10 days and then 2 days vehicle followed by estradiol 5 mg twice a day intramuscularly for 2 days (n = 5). At 121-123 dGA, cervical tissues were obtained under halothane anesthesia. Cervical RNA and protein were extracted and analyzed for prostaglandin-endoperoxide synthase 2 (COX2), two PGE(2) receptors, PTGER2 and PTGER4, and estrogen receptor alpha (ESR1) by Northern and Western blot analysis. Immunocytochemistry and in situ hybridization were applied to localize cellular distribution of COX2, PTGER2, and PTGER4 in the cervix. Data were analyzed by ANOVA. COX2 and PTGER4 mRNAs and proteins were increased (P < 0.05) in ewes treated with combined estradiol and progesterone but not in ewes treated with estradiol or progesterone alone compared with controls. ESR1 mRNA was increased in ewes treated with progesterone and estradiol plus progesterone. In contrast, PTGER2 mRNA and protein remained the same after all treatments. COX2 mRNA and protein were localized only in cervical glandular epithelial cells, whereas PTGER2 and PTGER4 were localized in both cervical glandular epithelial and smooth muscle cells. In conclusion, these data suggest that additional progesterone priming at 0.7 gestations synergizes with estradiol to induce cervical COX2, PTGER4, and ESR1 and support our hypothesis that stimulation of the cervical PG system by estradiol is optimized by sufficient progesterone priming in the pregnant sheep cervix.

Dysfunctional uterine bleeding as an early sign of polycystic ovary syndrome during adolescence.

PubMed

Deligeoroglou, E K; Creatsas, G K

2015-08-01

Excessive uterine bleeding during the early years after menarche can be worrisome to the girl and her parents. The most prevalent diagnosis set is Dysfunctional uterine bleeding (DUB), after thorough examination and exclusion of other causes of abnormal uterine bleeding. The aim of this article was to review our knowledge and share our experience as tertiary reference center of pediatric-adolescent gynecology in Greece. We conducted a review of current literature using Pubmed and MedLine as our primary databases, as well as providing commentary considering work up, treatment and follow-up of our DUB patients. Insufficient progesterone production and subsequent abnormal shedding of the endometrium appears to orchestrate the pathophysiology of DUB in adolescence. Hypothalamic-pituitary-ovarian (HPO) axis immaturity right after menarche, is usually the most plausible cause. Nevertheless, it is necessary to exclude other, possibly even life-threatening causes. Complete work up including physical examination, laboratory and imaging studies (complete blood count, b-HCG, hormonal levels and ultrasonography) is needed, and appropriate treatment with combined oral contraceptives is administered accordingly. Although menstrual disorders are very common in early adolescence, a severe episode of DUB should always be thoroughly attended by any physician. Follow-up should be offered in all young patients due to high incidence of recurrence or subsequent development of endocrine disorders such as Polycystic Ovary Syndrome (PCOS).

Biological functions of hCG and hCG-related molecules

PubMed Central

2010-01-01

Background hCG is a term referring to 4 independent molecules, each produced by separate cells and each having completely separate functions. These are hCG produced by villous syncytiotrophoblast cells, hyperglycosylated hCG produced by cytotrophoblast cells, free beta-subunit made by multiple primary non-trophoblastic malignancies, and pituitary hCG made by the gonadotrope cells of the anterior pituitary. Results and discussion hCG has numerous functions. hCG promotes progesterone production by corpus luteal cells; promotes angiogenesis in uterine vasculature; promoted the fusion of cytotrophoblast cell and differentiation to make syncytiotrophoblast cells; causes the blockage of any immune or macrophage action by mother on foreign invading placental cells; causes uterine growth parallel to fetal growth; suppresses any myometrial contractions during the course of pregnancy; causes growth and differentiation of the umbilical cord; signals the endometrium about forthcoming implantation; acts on receptor in mother's brain causing hyperemesis gravidarum, and seemingly promotes growth of fetal organs during pregnancy. Hyperglycosylated hCG functions to promote growth of cytotrophoblast cells and invasion by these cells, as occurs in implantation of pregnancy, and growth and invasion by choriocarcinoma cells. hCG free beta-subunit is produced by numerous non-trophoblastic malignancies of different primaries. The detection of free beta-subunit in these malignancies is generally considered a sign of poor prognosis. The free beta-subunit blocks apoptosis in cancer cells and promotes the growth and malignancy of the cancer. Pituitary hCG is a sulfated variant of hCG produced at low levels during the menstrual cycle. Pituitary hCG seems to mimic luteinizing hormone actions during the menstrual cycle. PMID:20735820

Acute and Chronic Effects of Oral Genistein Administration in Neonatal Mice1

PubMed Central

Cimafranca, Melissa A.; Davila, Juanmahel; Ekman, Gail C.; Andrews, Rachel N.; Neese, Steven L.; Peretz, Jackye; Woodling, Kellie A.; Helferich, William G.; Sarkar, Jhimly; Flaws, Jodi A.; Schantz, Susan L.; Doerge, Daniel R.; Cooke, Paul S.

2010-01-01

Soy-based infant formulas are widely used in the United States and some other countries. These formulas contain high levels of the estrogenic isoflavone genistein, leading to concern that neonatal genistein exposure could cause acute and/or long-term adverse effects on reproductive and other organs. However, previous work to assess genistein effects in rodent models has not typically replicated the route of delivery and/or serum genistein concentrations reported for soy formula-fed human infants. Our objective was to develop a mouse model that more closely mimics the oral genistein exposure and total serum genistein concentrations observed in soy formula-fed infants. Mouse pups were dosed orally with genistein in a soy formula-corn oil emulsion from Postnatal Day (PND) 1 to PND 5, then effects on reproductive and nonreproductive organs were assessed after dosing and during subsequent development. Neonatal treatment resulted in changes both at the completion of dosing (PND 5) and in adult animals. At PND 5, neonatal genistein treatment caused increased relative uterine weight and down-regulation of progesterone receptor in uterine epithelia. Estrogenic effects of genistein were also seen in the neonatal ovary and thymus, which had an increase in the incidence of multioocyte follicles (MOFs) and a decrease in thymic weight relative to body weight, respectively. The increased incidence of MOFs persisted into adulthood for neonatally treated genistein females, and estrous cycle abnormalities were seen at 6 mo of age despite normal fertility in these mice. The immediate and long-term effects in this neonatal animal model raise concerns that high serum concentrations of genistein are estrogenic and could potentially impact the development of human infants fed soy formula. PMID:20357267

Phase II Study of Everolimus Beyond Progression

ClinicalTrials.gov

2017-09-29

Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

Interaction of the conceptus and endometrium to establish pregnancy in mammals: role of interleukin 1β

PubMed Central

Fazleabas, Asgerally; Lucy, Mathew; Mathew, Daniel

2016-01-01

Implantation and the establishment of pregnancy in mammals involves an intricate interplay of hormones, cytokines, growth factors, proteins, lipids, ions and the extracellular matrix between the uterine epithelium, stroma, immune cells and the conceptus trophectoderm. The divergent nature of implantation in the mouse, human and pig provides not only an interesting contrast in the establishment of pregnancy and early embryonic development but also intriguing similarities with regard to early endometrial-conceptus signaling. An interesting pro-inflammatory cytokine expressed in a number of mammalian species during the period of implantation is interleukin-1β (IL1B). The presence of IL1B might be involved with immunotolerance at the maternal-placental interface and has been proposed as one of the mediators in placental viviparity. The production of IL1B and other proinflammatory cytokines might play a role in establishing pregnancy through modulation of the nuclear factor kappa-B (NFKB) system in a number of species. A model for the regulation of cellular progesterone receptor expression and NFKB activation for endometrial receptivity and conceptus attachment is continuing to evolve and is discussed in the present review. PMID:24286196

Interaction of the conceptus and endometrium to establish pregnancy in mammals: role of interleukin 1β

PubMed Central

Fazleabas, Asgerally; Lucy, Mathew; Mathew, Daniel

2016-01-01

Implantation and the establishment of pregnancy in mammals involves an intricate interplay of hormones, cytokines, growth factors, proteins, lipids, ions and the extracellular matrix between the uterine epithelium, stroma, immune cells and the conceptus trophectoderm. The divergent nature of implantation in the mouse, human and pig provides not only an interesting contrast in the establishment of pregnancy and early embryonic development but also intriguing similarities with regard to early endometrial-conceptus signaling. An interesting pro-inflammatory cytokine expressed in a number of mammalian species during the period of implantation is interleukin-1β (IL1B). The presence of IL1B might be involved with immunotolerance at the maternal-placental interface and has been proposed as one of the mediators in placental viviparity. The production of IL1B and other proinflammatory cytokines might play a role in establishing pregnancy through modulation of the nuclear factor kappa-B (NFKB) system in a number of species. A model for the regulation of cellular progesterone receptor expression and NFKB activation for endometrial receptivity and conceptus attachment is continuing to evolve and is discussed in the present review. PMID:22382391

Identification of CRASH, a gene deregulated in gynecological tumors.

PubMed

Evtimova, Vesna; Zeillinger, Robert; Kaul, Sepp; Weidle, Ulrich H

2004-01-01

We have identified CRASH, a human asparaginase-like protein which is composed of 308 amino acids and exhibits 32% homology to human aspartylglucosaminadase at the amino acid level. Database analysis revealed that the gene corresponding to CRASH is composed of 7 exons and 6 introns. Steady-state level of CRASH mRNA was found to be increased in 5 cell lines derived from metastatic lesions compared with 2 cell lines derived from primary mammary carcinoma and HMEC (human mammary epithelial cells). We found that the mRNA level of CRASH correlates with the metastatic propensity of several isogenic human colon cancer and pancreatic carcinoma cell lines. CRASH corresponds to a recently identified sperm autoantigen and furthermore we have demonstrated inducibility of CRASH mRNA by androgen and progesterone. Investigation of several types of human cancers and their corresponding normal tissues revealed high levels of CRASH mRNA in uterine, mammary and ovarian tumors compared with the corresponding normal tissues. CRASH mRNA expression was analysed in breast cancer samples with disclosed clinico-pathological features and corresponding normal tissues. The levels of CRASH mRNA were significantly up-regulated in tumors compared with normal breast tissues and correlate with lack of estrogen receptor expression of the tumors.

Induction of calcium-dependent nitric oxide synthases by sex hormones.

PubMed

Weiner, C P; Lizasoain, I; Baylis, S A; Knowles, R G; Charles, I G; Moncada, S

1994-05-24

We have examined the effects of pregnancy and sex hormones on calcium-dependent and calcium-independent nitric oxide synthases (NOSs) in the guinea pig. Pregnancy (near term) caused a > 4-fold increase in the activity of calcium-dependent NOS in the uterine artery and at least a doubling in the heart, kidney, skeletal muscle, esophagus, and cerebellum. The increase in NOS activity in the cerebellum during pregnancy was inhibited by the estrogen-receptor antagonist tamoxifen. Treatment with estradiol (but not progesterone) also increased calcium-dependent NOS activity in the tissues examined from both females and males. Testosterone increased calcium-dependent NOS only in the cerebellum. No significant change in calcium-independent NOS activity was observed either during pregnancy or after the administration of any sex hormone. Both pregnancy and estradiol treatment increased the amount of mRNAs for NOS isozymes eNOS and nNOS in skeletal muscle, suggesting that the increases in NOS activity result from enzyme induction. Thus both eNOS and nNOS are subject to regulation by estrogen, an action that could explain some of the changes that occur during pregnancy and some gender differences in physiology and pathophysiology.

Toward an understanding of the pathophysiology of clear cell carcinoma of the ovary (Review)

PubMed Central

UEKURI, CHIHARU; SHIGETOMI, HIROSHI; ONO, SUMIRE; SASAKI, YOSHIKAZU; MATSUURA, MIYUKI; KOBAYASHI, HIROSHI

2013-01-01

Endometriosis-associated ovarian cancers demonstrate substantial morphological and genetic diversity. The transcription factor, hepatocyte nuclear factor (HNF)-1β, may be one of several key genes involved in the identity of ovarian clear cell carcinoma (CCC). The present study reviews a considerably expanded set of HNF-1β-associated genes and proteins that determine the pathophysiology of CCC. The current literature was reviewed by searching MEDLINE/PubMed. Functional interpretations of gene expression profiling in CCC are provided. Several important CCC-related genes overlap with those known to be regulated by the upregulation of HNF-1β expression, along with a lack of estrogen receptor (ER) expression. Furthermore, the genetic expression pattern in CCC resembles that of the Arias-Stella reaction, decidualization and placentation. HNF-1β regulates a subset of progesterone target genes. HNF-1β may also act as a modulator of female reproduction, playing a role in endometrial regeneration, differentiation, decidualization, glycogen synthesis, detoxification, cell cycle regulation, implantation, uterine receptivity and a successful pregnancy. In conclusion, the present study focused on reviewing the aberrant expression of CCC-specific genes and provided an update on the pathological implications and molecular functions of well-characterized CCC-specific genes. PMID:24179489

Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types

PubMed Central

Ossovskaya, Valeria; Koo, Ingrid Chou; Kaldjian, Eric P.; Alvares, Christopher; Sherman, Barry M.

2010-01-01

Poly (ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair and is implicated in pathways of tumorigenesis. PARP inhibitors have gained recent attention as rationally designed therapeutics for the treatment of several malignancies, particularly those associated with dysfunctional DNA repair pathways, including triple-negative breast cancer (TNBC). We investigated the PARP1 gene expression profile in surgical samples from more than 8,000 primary malignant and normal human tissues. PARP1 expression was found to be significantly increased in several malignant tissues, including those isolated from patients with breast, uterine, lung, ovarian, and skin cancers, and non-Hodgkin’s lymphoma. Within breast infiltrating ductal carcinoma (IDC) samples tested, mean PARP1 expression was significantly higher relative to normal breast tissue, with over 30% of IDC samples demonstrating upregulation of PARP1, compared with 2.9% of normal tissues. Because of known DNA repair defects, including BRCA1 dysfunction, associated with TNBC, exploration of PARP1 expression in breast cancers related to expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) led to the observation that negative expression of any of the 3 receptors was associated with upregulation of PARP1 expression, compared with receptor-positive tissues. To validate these observations, an independent set of breast adenocarcinomas was evaluated and demonstrated >2-fold upregulation of PARP1 in approximately 70% of primary breast adenocarcinomas, including TNBC, compared with syngeneic nonmalignant breast tissues. Immunohistochemistry (IHC) showed that upregulation of the PARP1 gene was consistent with increased protein expression in TNBC. These analyses suggest a potential biological role for PARP1 in several distinct malignancies, including TNBC. Further investigation of PARP1 as a biomarker for the therapeutic activity of PARP inhibitor-based therapy is warranted. PMID:21779467

Effect of progesterone on the expression of GABA(A) receptor subunits in the prefrontal cortex of rats: implications of sex differences and brain hemisphere.

PubMed

Andrade, Susie; Arbo, Bruno D; Batista, Bruna A M; Neves, Alice M; Branchini, Gisele; Brum, Ilma S; Barros, Helena M T; Gomez, Rosane; Ribeiro, Maria Flavia M

2012-12-01

Progesterone is a neuroactive hormone with non-genomic effects on GABA(A) receptors (GABA(A)R). Changes in the expression of GABA(A)R subunits are related to depressive-like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABA(A)R α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg⁻¹) or vehicle, during two complete female estrous cycles (8-10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive-like behaviors and GABA(A)R α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABA(A)R γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABA(A) system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABA(A) R α1 subunit expression in the right prefrontal cortex of female rats. Copyright © 2012 John Wiley & Sons, Ltd.

Deletion of RhoA in Progesterone Receptor-Expressing Cells Leads to Luteal Insufficiency and Infertility in Female Mice.

PubMed

El Zowalaty, Ahmed E; Li, Rong; Zheng, Yi; Lydon, John P; DeMayo, Francesco J; Ye, Xiaoqin

2017-07-01

Ras homolog gene family, member A (RhoA) is widely expressed throughout the female reproductive system. To assess its role in progesterone receptor-expressing cells, we generated RhoA conditional knockout mice RhoAd/d (RhoAf/f-Pgr-Cre+/-). RhoAd/d female mice had comparable mating activity, serum luteinizing hormone, prolactin, and estradiol levels and ovulation with control but were infertile with progesterone insufficiency, indicating impaired steroidogenesis in RhoAd/d corpus luteum (CL). RhoA was highly expressed in wild-type luteal cells and conditionally deleted in RhoAd/d CL. Gestation day 3.5 (D3.5) RhoAd/d ovaries had reduced numbers of CL, less defined corpus luteal cord formation, and disorganized CL collagen IV staining. RhoAd/d CL had lipid droplet and free cholesterol accumulation, indicating the availability of cholesterol for steroidogenesis, but disorganized β-actin and vimentin staining, indicating disrupted cytoskeleton integrity. Cytoskeleton is important for cytoplasmic cholesterol movement to mitochondria and for regulating mitochondria. Dramatically reduced expression of mitochondrial markers heat shock protein 60 (HSP60), voltage-dependent anion channel, and StAR was detected in RhoAd/d CL. StAR carries out the rate-limiting step of steroidogenesis. StAR messenger RNA expression was reduced in RU486-treated D3.5 wild-type CL and tended to be induced in progesterone-treated D3.5 RhoAd/d CL, with parallel changes of HSP60 expression. These data demonstrated the in vivo function of RhoA in CL luteal cell cytoskeleton integrity, cholesterol transport, StAR expression, and progesterone synthesis, and a positive feedback on StAR expression in CL by progesterone signaling. These findings provide insights into mechanisms of progesterone insufficiency.

Testosterone stimulates progesterone production and STAR, P450 cholesterol side-chain cleavage and LH receptor mRNAs expression in hen (Gallus domesticus) granulosa cells.

PubMed

Rangel, P L; Rodríguez, A; Rojas, S; Sharp, P J; Gutierrez, C G

2009-12-01

The chicken ovary is organized into a hierarchy of yellow yolky follicles that ovulate on successive days. Active or passive immunization of laying hens against testosterone blocks ovulation without affecting follicle development. Testosterone may play a role in pre-ovulatory follicle maturation by stimulating granulosa progesterone production. We assessed whether this stimulus is dose-related and depends on the maturity of the donor follicle, and if it does so by stimulating granulosa cell STAR, P450 cholesterol side-chain cleavage (P450scc), and LH receptor (LHCGR) mRNAs expression. Progesterone production by granulosa cells from F1, F3, and F4 follicles, cultured for 3 h without testosterone was greater in cells collected 11-14 h than 1-4 h after ovulation. These differences in progesterone production were less pronounced after granulosa cells had been cultured for 24 h. Culture of granulosa cells for 3 or 24 h with testosterone (1-100 ng/ml) stimulated progesterone production in cells collected from F4, F3, or F1 follicles 1-4, or 11-14 h after ovulation. Testosterone (0-4000 ng/ml) alone or in combination with LH (0-100 ng/ml) increased progesterone production by F1 granulosa cells, collected 1-4 and 11-14 h after ovulation and cultured for 3 h. Finally, testosterone (10 or 100 ng/ml) increased STAR, P450scc, and LHCGR mRNAs, when added to 3 h cultures of F1 granulosa cells. In conclusion, testosterone stimulates granulosa cell progesterone production in hen pre-ovulatory hierarchical follicles irrespective of maturational state, acting alone or additively with LH. We propose that testosterone promotes granulosa cell maturation to facilitate the pre-ovulatory release of LH.

Organotin compounds cause structure-dependent induction of progesterone in human choriocarcinoma Jar cells.

PubMed

Hiromori, Youhei; Yui, Hiroki; Nishikawa, Jun-ichi; Nagase, Hisamitsu; Nakanishi, Tsuyoshi

2016-01-01

Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), are typical environmental contaminants and suspected endocrine-disrupting chemicals because they cause masculinization in female mollusks. In addition, previous studies have suggested that the endocrine disruption by organotin compounds leads to activation of peroxisome proliferator-activated receptor (PPAR)γ and retinoid X receptor (RXR). However, whether organotin compounds cause crucial toxicities in human development and reproduction is unclear. We here investigated the structure-dependent effect of 12 tin compounds on mRNA transcription of 3β-hydroxysteroid dehydrogenase type I (3β-HSD I) and progesterone production in human choriocarcinoma Jar cells. TBT, TPT, dibutyltin, monophenyltin, tripropyltin, and tricyclohexyltin enhanced progesterone production in a dose-dependent fashion. Although tetraalkyltin compounds such as tetrabutyltin increased progesterone production, the concentrations necessary for activation were 30-100 times greater than those for trialkyltins. All tested active organotins increased 3β-HSD I mRNA transcription. We further investigated the correlation between the agonistic activity of organotin compounds on PPARγ and their ability to promote progesterone production. Except for DBTCl2, the active organotins significantly induced the transactivation function of PPARγ. In addition, PPARγ knockdown significantly suppressed the induction of mRNA transcription of 3β-HSD I by all active organotins except DBTCl2. These results suggest that some organotin compounds promote progesterone biosynthesis in vitro by inducing 3β-HSD I mRNA transcription via the PPARγ signaling pathway. The placenta represents a potential target organ for these compounds, whose endocrine-disrupting effects might cause local changes in progesterone concentration in pregnant women. Copyright © 2014 Elsevier Ltd. All rights reserved.

Progesterone receptor blockade in human breast cancer cells decreases cell cycle progression through G2/M by repressing G2/M genes.

PubMed

Clare, Susan E; Gupta, Akash; Choi, MiRan; Ranjan, Manish; Lee, Oukseub; Wang, Jun; Ivancic, David Z; Kim, J Julie; Khan, Seema A

2016-05-23

The synthesis of specific, potent progesterone antagonists adds potential agents to the breast cancer prevention and treatment armamentarium. The identification of individuals who will benefit from these agents will be a critical factor for their clinical success. We utilized telapristone acetate (TPA; CDB-4124) to understand the effects of progesterone receptor (PR) blockade on proliferation, apoptosis, promoter binding, cell cycle progression, and gene expression. We then identified a set of genes that overlap with human breast luteal-phase expressed genes and signify progesterone activity in both normal breast cells and breast cancer cell lines. TPA administration to T47D cells results in a 30 % decrease in cell number at 24 h, which is maintained over 72 h only in the presence of estradiol. Blockade of progesterone signaling by TPA for 24 h results in fewer cells in G2/M, attributable to decreased expression of genes that facilitate the G2/M transition. Gene expression data suggest that TPA affects several mechanisms that progesterone utilizes to control gene expression, including specific post-translational modifications, and nucleosomal organization and higher order chromatin structure, which regulate access of PR to its DNA binding sites. By comparing genes induced by the progestin R5020 in T47D cells with those increased in the luteal-phase normal breast, we have identified a set of genes that predict functional progesterone signaling in tissue. These data will facilitate an understanding of the ways in which drugs such as TPA may be utilized for the prevention, and possibly the therapy, of human breast cancer.

The presence of a membrane-bound progesterone receptor induces growth of breast cancer with norethisterone but not with progesterone: A xenograft model.

PubMed

Zhao, Yue; Ruan, Xiangyan; Wang, Husheng; Li, Xue; Gu, Muqing; Wang, Lijuan; Li, Yanglu; Seeger, Harald; Mueck, Alfred O

2017-08-01

During menopausal hormone therapy (MHT) a possible increase in breast cancer risk is thought to depend mainly on the progestogen component. In vitro studies have shown that the progesterone receptor membrane component 1 (PGRMC1) is important for tumor proliferation induced by progestogens. The primary aim of this study was to compare for the first time the natural progestogen, progesterone (P), with a synthetic progestogen, norethisterone (NET), using a xenograft model. MCF7 cells, transfected with PGRMC1 plasmid or empty vector, were injected into nude mice and estradiol (E2) pellets were implanted. After 12days, NET or P or placebo pellets were implanted. Tumor volumes in all groups (6 mice/group) were monitored for 6-7 weeks. Immunohistochemical expression of PGRMC1 and KI-67 was assessed. These experiments were repeated using T47D cells. Compared with the control condition, E2 and sequential E2/NET combination increased xenograft tumor growth with MCF7 and T47D cells that transgenically expressed PGRMC1 (p<0.01); progesterone did not increase growth. Breast cancer cells transfected with empty vectors did not respond to either progestogen. Comparing KI-67 and PGRMC1 expression, the Pearson correlation was r=0.848, p=0.002. E2 plus NET increases tumor growth in human breast cancer cells overexpressing PGRMC1, but there is no change with progesterone. To our knowledge, this is the first comparison of both progestogens in vivo using nude mice, which are frequently used in xenograft models. Clinical trials are needed to determine whether women with overexpression of PGRMC1 are at increased risk of breast cancer if NET instead of progesterone is used in MHT. Copyright © 2017 Elsevier B.V. All rights reserved.

Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival.

PubMed

Laws, Mary J; Taylor, Robert N; Sidell, Neil; DeMayo, Francesco J; Lydon, John P; Gutstein, David E; Bagchi, Milan K; Bagchi, Indrani C

2008-08-01

In the uterus, the formation of new maternal blood vessels in the stromal compartment at the time of embryonic implantation is critical for the establishment and maintenance of pregnancy. Although uterine angiogenesis is known to be influenced by the steroid hormones estrogen (E) and progesterone (P), the underlying molecular pathways remain poorly understood. Here, we report that the expression of connexin 43 (Cx43), a major gap junction protein, is markedly enhanced in response to E in uterine stromal cells surrounding the implanted embryo during the early phases of pregnancy. Conditional deletion of the Cx43 gene in these stromal cells and the consequent disruption of their gap junctions led to a striking impairment in the development of new blood vessels within the stromal compartment, resulting in the arrest of embryo growth and early pregnancy loss. Further analysis of this phenotypical defect revealed that loss of Cx43 expression resulted in aberrant differentiation of uterine stromal cells and impaired production of several key angiogenic factors, including the vascular endothelial growth factor (Vegf). Ablation of CX43 expression in human endometrial stromal cells in vitro led to similar findings. Collectively, these results uncovered a unique link between steroid hormone-regulated cell-cell communication within the pregnant uterus and the development of an elaborate vascular network that supports embryonic growth. Our study presents the first evidence that Cx43-type gap junctions play a critical and conserved role in modulating stromal differentiation, and regulate the consequent production of crucial paracrine signals that control uterine neovascularization during implantation.

Fertility after uterine artery embolization: investigation using a sheep model.

PubMed

Yamagami, Takuji; Yoshimatsu, Rika; Matsumoto, Tomohiro; Anzai, Hiroshi; Yoshizawa, Masahiro; Fukui, Yutaka; Nishimura, Tsunehiko

2010-04-01

To investigate the influence of uterine artery embolization (UAE) on fertility after bilateral UAE with either tris-acryl gelatin microspheres (TAGM) or gelatin particles (GP). Six ewes that underwent UAE with TAGM, 6 ewes that underwent UAE with GP, and 6 control ewes were compared. After hormonal synchronization of the menstrual cycle, artificial insemination (AI) was performed. When pregnancy did not result, ewes were naturally inseminated. After AI, progesterone concentrations in blood increased and were maintained at >1.0 ng/mL in 9 ewes (3 per group). Three ewes became pregnant after AI. The abortion rate was higher in the UAE group. The remaining 15 sheep were naturally inseminated, with 14 delivering 15 lambs. Mean period of term gestation in UAE group ewes was 155.7 versus 158.6 days in control group ewes. Lambs' body weight, body length, and withers height after birth did not differ between those from UAE group and control group. Lambs from ewes embolized with GP tended to be smaller and had lower body weight than those from other groups. Uterine artery embolization influenced reproductive ability in sheep and UAE with GP could lead to intrauterine growth retardation.

Economic evaluation of pregnancy diagnosis in dairy cattle: a decision analysis approach.

PubMed

Oltenacu, P A; Ferguson, J D; Lednor, A J

1990-10-01

Cost-benefit evaluations of several pregnancy diagnosis schemes were performed. The strategy using on-farm milk progesterone test on d 19 after service, followed by treatment of nonpregnant cows with prostaglandin, was the most profitable returning $10.50 per cow above the cost of the intervention. An increase in efficiency of detection of estrus of greater than 20% among cows diagnosed nonpregnant and an error rate in pregnancy diagnosis of less than or equal to 3% were needed to ensure profitability. Pregnancy diagnosis by uterine palpation per rectum on d 35 after service, combined with the use of pressure-sensitive mounting devices on nonpregnant cows was the second most profitable strategy and returned $5.10 per cow. An increase in efficiency of detection of estrus of greater than or equal to 20% was required to ensure profitability. Embryonic mortality was also critical and an increase from a baseline value of 10% to 12%, as a result of early uterine palpation, made this scheme unprofitable ($-4.80 per cow). Pregnancy diagnosis by uterine palpation per rectum at 50 or 65 d was less profitable, with a return of $2.50 and $.10 per cow, respectively.

STAT3 Regulates Uterine Epithelial Remodeling and Epithelial-Stromal Crosstalk During Implantation

PubMed Central

Pawar, Sandeep; Starosvetsky, Elina; Orvis, Grant D.; Behringer, Richard R.; Bagchi, Indrani C.

2013-01-01

Embryo implantation is regulated by a variety of endometrial factors, including cytokines, growth factors, and transcription factors. Earlier studies identified the leukemia inhibitory factor (LIF), a cytokine produced by uterine glands, as an essential regulator of implantation. LIF, acting via its cell surface receptor, activates the signal transducer and activator of transcription 3 (STAT3) in the uterine epithelial cells. However, the precise mechanism via which activated STAT3 promotes uterine function during implantation remains unknown. To identify the molecular pathways regulated by STAT3, we created SWd/d mice in which Stat3 gene is conditionally inactivated in uterine epithelium. The SWd/d mice are infertile due to a lack of embryo attachment to the uterine luminal epithelium and consequent implantation failure. Gene expression profiling of uterine epithelial cells of SWd/d mice revealed dysregulated expression of specific components of junctional complexes, including E-cadherin, α- and β-catenin, and several claudins, which critically regulate epithelial junctional integrity and embryo attachment. In addition, uteri of SWd/d mice exhibited markedly reduced stromal proliferation and differentiation, indicating that epithelial STAT3 controls stromal function via a paracrine mechanism. The stromal defect arose from a drastic reduction in the production of several members of the epidermal growth factor family in luminal epithelium of SWd/d uteri and the resulting lack of activation of epidermal growth factor receptor signaling and mitotic activity in the stromal cells. Collectively, our results uncovered an intricate molecular network operating downstream of STAT3 that regulates uterine epithelial junctional reorganization, and stromal proliferation, and differentiation, which are critical determinants of successful implantation. PMID:24100212

Uterine artery leptin receptors during the ovarian cycle and pregnancy regulate angiogenesis in ovine uterine artery endothelial cells†

PubMed Central

Vargas, Vladimir E.; Landeros, Rosalina Villalon; Lopez, Gladys E.; Zheng, Jing; Magness, Ronald R.

2017-01-01

Abstract Leptin regulates body weight, reproductive functions, blood pressure, endothelial function, and fetoplacental angiogenesis. Compared to the luteal phase, the follicular phase and pregnancy are physiological states of elevated estrogen, angiogenesis, and uterine blood flow (UBF). Little is known concerning regulation of uterine artery (UA) angiogenesis by leptin and its receptors. We hypothesized that (1) ex vivo expression of leptin receptors (LEPR) in UA endothelium (UAendo) and UA vascular smooth muscle (UAvsm) is elevated in pregnant versus nonpregnant (Luteal and Follicular) sheep; (2) in vitro leptin treatments differentially modulate mitogenesis in uterine artery endothelial cells from pregnant (P-UAECs) more than in nonpregnant (NP-UAECs) ewes; and (3) LEPR are upregulated in P-UAECs versus NP-UAECs in association with leptin activation of phospho-STAT3 signaling. Local UA adaptations were evaluated using a unilateral pregnant sheep model where prebreeding uterine horn isolation (nongravid) restricted gravidity to one horn. Immunolocalization revealed LEPR in UAendo and UAvsm from pregnant and nonpregnant sheep. Contrary to our hypothesis, western analysis revealed that follicular UAendo and UAvsm LEPR were greater than luteal, nongravid, gravid, and control pregnant. Compared to pregnant groups, LEPR were elevated in renal artery endothelium of follicular and luteal sheep. Leptin treatment significantly increased mitogenesis in follicular phase NP-UAECs and P-UAECs, but not luteal phase NP-UAECs. Although UAEC expression of LEPR was similar between groups, leptin treatment only activated phospho-STAT3 in follicular NP-UAECs and P-UAECs. Thus, leptin may play an angiogenic role particularly in preparation for the increased UBF during the periovulatory period and subsequently to meet the demands of the growing fetus. PMID:28339937

Veliparib in Combination With Carboplatin and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors

ClinicalTrials.gov

2015-05-22

Adult Solid Neoplasm; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Male Breast Carcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Zoledronic Acid in Aromatase Inhibitor Induced Musculoskeletal Symptoms

ClinicalTrials.gov

2017-10-05

Ductal Carcinoma in Situ; Estrogen Receptor-positive Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

ClinicalTrials.gov

2018-03-05

Breast Carcinoma Metastatic in the Bone; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy

PubMed Central

Estiú, Maria C; Monte, Maria J; Rivas, Laura; Moirón, Maria; Gomez-Rodriguez, Laura; Rodriguez-Bravo, Tomas; Marin, Jose JG; Macias, Rocio IR

2015-01-01

Aim Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio. Method Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence. Results In ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2. Conclusion UDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP. PMID:25099365

Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy.

PubMed

Estiú, Maria C; Monte, Maria J; Rivas, Laura; Moirón, Maria; Gomez-Rodriguez, Laura; Rodriguez-Bravo, Tomas; Marin, Jose J G; Macias, Rocio I R

2015-02-01

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio. Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence. In ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates > unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2. UDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP. © 2014 The British Pharmacological Society.

Human Chorionic Gonadotropin: Unknown about Known.

PubMed

Borisova, M A; Moiseenko, D Yu; Smirnova, O V

2017-01-01

The last two decade discoveries shift the accent from consideration of human chorionic gonadotripin (hCG) as a hormone, that controls progesterone production by corpus luteum cells, to a powerful paracrine regulator which'in the tandem with its hyperglycozilated analog (hCG-H) induces successful implantation and coordinated dialog between blastocyst and uterus tissues. Ability of hCG to interact with TSH receptor and hCG-H with TGF-beta-RII extend significantly the spectrum of processes controlled by these molecules. Differences between intracellular pathways of signal transduction between hCG and LH mediated by the same receptor (LH/hCG-R) impugn unity of their effector mechanisms previously considered as obvious. Paracine properties-of hCG comprise control of fusing of trophoblasts into syncytiotrophoblasts, angiogenesis, immunity regulation and endometrium predisposition to implantation. Angiogenesis is associated with LH/hCG-R expressed on mural cells of uterine spiral arteries as well as induced secretion of soluble VEGF type by endometrial cells. hCG.regulates ratio between different forms of T-helper cells in maternal organism on the initial gestation stage determining high level of Th2 cells. hCG supports local immunotolerance acting as chemoattractant for T-suppressors (T-Treg) and apoptotic factor for T-lymphocytes. Endometrial susceptibility arises from activation of osteopantin secretion and decline of mucin secretion by epithelial cells. hCG-H acts on the same tissues as hCG as a paracrine agent regulating multiple cascades of cytokines. hCG-H plays the key role in trophoblast invasion into,uterine decidua as a result of gelatinase secretion by these cells.The degree of angiogenic effect of hCG-H is compatiblewith hCG but its signal transduction is mediated by TGF-beta signal transduction pathway that stimulates mural cell proliferation. hCG-H acts as mitogen on NK-cells and is able to activate them and direct to angiogenesis maintenance. In this article the attempt was made to elucidate the most important discoveries about the role of hCG and its hyperglycosylated analog yet accomplished and still upcoming.

Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice.

PubMed

Kassotis, Christopher D; Bromfield, John J; Klemp, Kara C; Meng, Chun-Xia; Wolfe, Andrew; Zoeller, R Thomas; Balise, Victoria D; Isiguzo, Chiamaka J; Tillitt, Donald E; Nagel, Susan C

2016-09-01

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies.

Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice

PubMed Central

Kassotis, Christopher D.; Bromfield, John J.; Klemp, Kara C.; Meng, Chun-Xia; Wolfe, Andrew; Zoeller, R. Thomas; Balise, Victoria D.; Isiguzo, Chiamaka J.; Tillitt, Donald E.

2016-01-01

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies. PMID:27560547

Progesterone inhibits the in vitro L3/L4 molting process in Haemonchus contortus.

PubMed

Gutiérrez-Amézquita, R A; Morales-Montor, J; Muñoz-Guzmán, M A; Nava-Castro, K E; Ramírez-Álvarez, H; Cuenca-Verde, C; Moreno-Mendoza, N A; Cuéllar-Ordaz, J A; Alba-Hurtado, F

2017-12-15

We evaluated the direct effects of progesterone on the morphology, maturation and behavior of Haemonchus contortus larvae in vitro. The presence and location of possible progesterone receptors in these larvae were also determined. The addition of 8ng/mL of progesterone to larval cultures over 10days reduced larval enlargement, while the addition of 160ng/mL of the hormone increased the enlargement. Up to 62% and 65% of the H. contortus larvae molted from third-stage larvae (L3) to fourth-stage larvae (L4) when cultured in RPMI-1640 media without hormone for 5 and 10days, respectively. The addition of different progesterone concentrations (1, 8, 16, 80 and 160ng/mL) to the larval cultures significantly inhibited the molting process within the same periods. The addition of 8ng/mL or higher progesterone concentrations to the cultures significantly increased larval motility (p<0.05) compared with unstimulated larvae. Flow cytometry showed the expression of progesterone receptors (P4-R) in 15% of the cells from newly isolated H. contortus larvae. When the larvae were cultured for 5days in the presence of the hormone, the percentage of P 4 -R+ cells remained the same. In contrast, unstimulated larvae showed a significant reduction in the number of P 4 -R+ cells. Using confocal microscopy, a greater concentration of P 4 -Rs was immunolocated in the anterior portion of the alimentary tract of the larvae, suggesting that the cells in this region are targeted by the hormone. The results of the present study show that H. contortus larvae have possible P 4 -Rs and respond to this hormone by inhibiting their molting process, thereby suggesting the participation of progesterone in the larval arrest phenomenon. Copyright © 2017 Elsevier B.V. All rights reserved.

Regulation of GnRH I receptor gene expression by the GnRH agonist triptorelin, estradiol, and progesterone in the gonadotroph-derived cell line alphaT3-1.

PubMed

Weiss, J M; Polack, S; Treeck, O; Diedrich, K; Ortmann, O

2006-08-01

The secretion of luteinizing hormone (LH) and the GnRH receptor (GnRH-R) concentration are modulated by ovarian steroids and GnRH. To elucidate whether this regulation is due to alterations at the transcriptional level, we examined the GnRH I-R mRNA expression in the gonadotroph-derived cell line alphaT3-1 treated with different estradiol and progesterone paradigms and the GnRH I agonist triptorelin. alphaT3-1 cells were treated with different steroid paradigms: 1 nM estradiol or 100 nM progesterone for 48 h alone or in combination. Cells were exposed to 10 nM or 100 pM triptorelin for 30 min, 3 h, 9 h, or, in pulsatile way, with a 5-min pulse per hour. The GnRH I-R mRNA was determined by Northern blot analysis. GnRH I-R mRNA from cells treated with continuous triptorelin decreased in a time- and concentration-dependent manner. Pulsatile triptorelin increased GnRH I-R gene expression. Progesterone alone further enhanced this effect, whereas estradiol and its combination with progesterone diminished it. Continuous combined treatment with estradiol and progesterone lead to a significant decrease of GnRH I-R mRNA by 30% and by 35% for estradiol alone. The addition of 10 nM triptorelin for 30 min or 3 h could not influence that steroid effect. In conclusion, estradiol and progesterone exclusively decreased GnRH I-R mRNA in alphaT3-1 cells no matter whether they are treated additionally with the GnRH I agonist triptorelin. The enhanced sensitivity of gonadotrophs and GnRH I-R upregulation by estradiol is not due to increased GnRH I gene expression because GnRH I-R mRNA is downregulated by estradiol and progesterone. Other pathways of the GnRH I-R signal transduction might be involved.

The methoxychlor metabolite, HPTE, inhibits rat luteal cell progesterone production.

PubMed

Akgul, Yucel; Derk, Raymond C; Meighan, Terence; Rao, K Murali Krishna; Murono, Eisuke P

2011-07-01

The methoxychlor metabolite, HPTE, was shown to inhibit P450-cholesterol side-chain cleavage (P450scc) activity resulting in decreased progesterone production by cultured ovarian follicular cells in previous studies. It is not known whether HPTE has any effect on progesterone formation by the corpus luteum. Exposure to 100 nM HPTE reduced progesterone production by luteal cells with progressive declines to <22% of control at 500 nM HPTE. Similarly, HPTE progressively inhibited progesterone formation and P450scc catalytic activity of hCG- or 8 Br-cAMP-stimulated luteal cells. However, HPTE did not alter mRNA and protein levels of P450scc. Compounds acting as estrogen (17 β-estradiol, bisphenol-A or octylphenol), antiestrogen (ICI) or antiandrogen (monobutyl phthalate, flutamide or M-2) added alone to luteal cells did not mimic the action of HPTE on progesterone and P450scc activity. These results suggest that HPTE directly inhibits P450scc catalytic activity resulting in reduced progesterone formation, and this action was not mediated through estrogen or androgen receptors. Published by Elsevier Inc.

Estradiol and progesterone influence on influenza infection and immune response in a mouse model.

PubMed

Davis, Sarah M; Sweet, Leigh M; Oppenheimer, Karen H; Suratt, Benjamin T; Phillippe, Mark

2017-10-01

Influenza infection severity may be mediated by estradiol and/or progesterone. An exploratory study was designed to evaluate 17-β-estradiol and progesterone on influenza infection and examine immune-mediated response in a mouse model. Inoculation with placebo or mouse-adapted H1N1 influenza virus occurred. Treatment groups included 17-β-estradiol, progesterone, ovariectomy, and pregnancy. Mice were assessed for morbidity and mortality. Toll-like receptor gene studies and airspace cell differentials were performed. Onset of morbidity was earlier and morbidity duration greater for progesterone. Absence of morbidity/mortality and overall survival was greater for 17-β-estradiol. Airspace cell differentials suggest improved immune cell recruitment for 17-β-estradiol. Pregnant mouse data demonstrate significant mortality during the period of increased progesterone. Select immune cell markers demonstrate patterns of regulation that may promote proper immune response to influenza infection for 17-β-estradiol. Estradiol may play a protective and progesterone a detrimental role in the pathophysiology of influenza infection. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Uterine epithelial cell proliferation and endometrial hyperplasia: evidence from a mouse model

PubMed Central

Gao, Yang; Li, Shu; Li, Qinglei

2014-01-01

In the uterus, epithelial cell proliferation changes during the estrous cycle and pregnancy. Uncontrolled epithelial cell proliferation results in implantation failure and/or cancer development. Transforming growth factor-β (TGF-β) signaling is a fundamental regulator of diverse biological processes and is indispensable for multiple reproductive functions. However, the in vivo role of TGF-β signaling in uterine epithelial cells remains poorly defined. We have shown that in the uterus, conditional deletion of the Type 1 receptor for TGF-β (Tgfbr1) using anti-Müllerian hormone receptor type 2 (Amhr2) Cre leads to myometrial defects. Here, we describe enhanced epithelial cell proliferation by immunostaining of Ki67 in the uteri of these mice. The aberration culminated in endometrial hyperplasia in aged females. To exclude the potential influence of ovarian steroid hormones, the proliferative status of uterine epithelial cells was assessed following ovariectomy. Increased uterine epithelial cell proliferation was also revealed in ovariectomized Tgfbr1 Amhr2-Cre conditional knockout mice. We further demonstrated that transcript levels for fibroblast growth factor 10 (Fgf10) were markedly up-regulated in Tgfbr1 Amhr2-Cre conditional knockout uteri. Consistently, treatment of primary uterine stromal cells with TGF-β1 significantly reduced Fgf10 mRNA expression. Thus, our findings suggest a potential involvement of TGFBR1-mediated signaling in the regulation of uterine epithelial cell proliferation, and provide genetic evidence supporting the role of uterine epithelial cell proliferation in the pathogenesis of endometrial hyperplasia. PMID:24770950

Steroid receptors analysis in human mammary tumors by isoelectric focusing in agarose.

PubMed

Bailleul, S; Gauduchon, P; Malas, J P; Lechevrel, C; Roussel, G; Goussard, J

1988-08-01

A high resolution and quantitative method for isoelectric focusing has been developed to separate the isoforms of estrogen and progesterone receptors in human mammary tumor cytosols stabilized by sodium molybdate. Agarose gels (0.5%) were used. Six samples can be analyzed on one gel in about 2 h, and 35-microliters samples are sufficient to determine the estrogen receptor isoform pattern. The constant yields and the reproducibility of data allow a quantitative analysis of these receptors. Four estrogen receptor isoforms have been observed (pI 4.7, 5.5, 6, and 6.5), isoforms with pI 4.7 and 6.5 being present in all tumors. After incubation at 28 degrees C in high ionic strength, the comparison of isoelectric focusing and high-performance size exclusion chromatography patterns of estrogen receptor confirms the oligomeric structure of the pI 4.7 isoform and suggests a monomeric structure for the pI 6.5 isoform. Under the same conditions of analysis, only one progesterone receptor isoform has been detected with pI 4.7.

The impact of using different doses of progesterone on memory performance.

PubMed

Roozbehi, A; Sharafi, M T; Karimi, F; Kamali, A M

2017-01-01

Progesterone is a sex hormone and its receptors are expressed throughout the hippocampus. This study was aimed at evaluating the effects of different doses of progesterone on memory. Male rats were arbitrarily assigned to nine groups, namely Group I: control, Group II: control-cannula, Group III received 0.5 μl of saline by cannula, Groups IV , V, VI, VII and VIII received progesterone in doses of 0.5, 1, 1.5, 2, and 3 μg/ 0.5 μl by cannula, respectively. Group IX received 0.5 μl almond oil by cannula. Memory performance was tested in form of passive avoidance task. Our results indicated that progesterone at doses of 1.5 and 2 µg (p < 0.05) significantly increased the memory performance while at a dose of 3 µg (p < 0.05), it significantly decreased memory as compared to the control group. The current study revealed that the influence of progesterone on memory is related to its dose (Fig. 1, Ref. 25).

The Role of Progesterone and a Novel Progesterone Receptor, Progesterone Receptor Membrane Component 1, in the Inflammatory Response of Fetal Membranes to Ureaplasma parvum Infection.

PubMed

Feng, Liping; Ransom, Carla E; Nazzal, Matthew K; Allen, Terrence K; Li, Yi-Ju; Truong, Tracy; Potts, Lauren C; Seed, Patrick C; Murtha, Amy P

2016-01-01

Ureaplasma parvum (U. parvum) is gaining recognition as an important pathogen for chorioamnionitis and preterm premature rupture of membranes. We aimed to investigate the roles of progesterone (P4) and a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), in the response of fetal membranes to U. parvum. Fetal membrane cells (amnion, chorion and decidua) were isolated and confirmed to be free of Mycoplasmataceae. Cells were treated with U. parvum (5x106 CFU), and adherence was quantified by qPCR. Amnion and chorion cells were transfected with scrambled siRNA or validated PGRMC1 siRNA for 72h. Cells were then treated with U. parvum for 4h with or without pretreatment with P4 (10-7 M) or ethanol for 1h. Interleukin-8 (IL-8), matrix metalloproteinase 9 (MMP9) and cyclooxygenase (COX-2) mRNA expression were quantified by qRT-PCR. Culture medium was harvested and analyzed for IL-8 and prostaglandin (PGE2) secretion by ELISA and MMP9 activity by zymography. U. parvum had a mean adherence of 15.0±0.6%, 16.9± 3.7% and 4.7±0.3% in cultured amnion, chorion and decidua cells, respectively. Exposure to U. parvum elicited significant inflammatory responses including induction of IL-8, COX-2, PGE2 and MMP9. A possible role of PGRMC1 was identified in the inhibition of U. parvum-stimulated COX-2 and MMP9 mRNA expression in chorion cells and MMP9 activity in amnion cells. On the other hand, it might enhance the U. parvum-stimulated IL-8 protein secretion in amnion cells. P4, mediated through PGRMC1, significantly inhibited U. Parvum-induced MMP9 mRNA and COX-2 mRNA expression in chorion cells. P4 appeared to attenuate U. parvum induced IL-8 mRNA expression in chorion cells, but this P4 effect might not mediated through PGRMC1. In summary, U. parvum preferentially adheres to and induces inflammatory responses in chorion and amnion cells. P4 and PGRMC1 appear to differentially modulate the inflammatory responses induced by U. parvum among amnion and chorion cells.

Sex differences in oestrogen receptor levels in adrenal glands of sheep during the breeding season.

PubMed

van Lier, E; Meikle, A; Bielli, A; Akerberg, S; Forsberg, M; Sahlin, L

2003-11-01

The concentrations of the oestrogen receptor (ER), and the mRNA levels of ERalpha, progesterone receptor (PR) and insulin-like growth factor I (IGF-I) were characterised in adrenal glands and uterine tissue of adult Corriedale sheep during the breeding season. The sheep were of different sex and gonadal status. Ewes had higher levels of cytosolic ER in the adrenals than the rams (mean+/-S.E.M.: 7.3+/-2.0 fmol/mg protein and 2.5+/-1.0 fmol/mg protein, respectively; P=0.0091) and gonadectomy increased ER (mean+/-S.E.M.: 2.9+/-1.2 fmol/mg protein and 8.6+/-2.3 fmol/mg protein, intact and gonadectomised sheep, respectively; P=0.0071). No differences could be observed in mRNA levels for ERalpha and IGF-I in the adrenal glands of all of the sheep. PR mRNA levels were reduced in ovariectomised ewes and enhanced in castrated rams (sex x gonadal status: P=0.009). PR mRNA levels tended to be higher in ewes in the follicular phase than in ovariectomised ewes and intact rams (P<0.1). All of the animals had positive nuclear staining for ERalpha in the adrenal cortex, but no differences were observed between the groups. In this study, we demonstrated the existence of ER in the adrenal gland of sheep and found varying sensitivity to oestrogens as the ER levels differed among sex and gonadal status. These findings indicate that oestrogens most likely affect steroidogenesis directly at the adrenal cortex and suggest that oestrogens are partly responsible for the sex differences in cortisol secretion in sheep.

Mechanism of Action of Bolandiol (19-Nortestosterone-3β,17β-Diol), a Unique Anabolic Steroid with Androgenic, Estrogenic, and Progestational Activities*

PubMed Central

Attardi, Barbara J.; Page, Stephanie T.; Hild, Sheri A.; Coss, Christopher C.; Matsumoto, Alvin M.

2009-01-01

Bolandiol is a synthetic anabolic steroid that increases lean body mass and bone mineral density without significant stimulation of sex accessory glands in castrate adult male rats. Since bolandiol suppresses gonadotropins and endogenous testosterone (T) production, we investigated its mechanism of action. We compared the potency of bolandiol in vitro and in vivo with T, 5α-dihydrotestosterone (DHT), 19-nortestosterone (19-NT) and estradiol (E2). Bolandiol bound with lower affinity to the recombinant rat androgen receptor (AR) than the other androgens and had low, but measurable, affinity for recombinant human progestin receptors (PR-A, PR-B), and estrogen receptors (ERα and β-1). Functional agonist activity was assessed in transcription assays mediated by AR, PR, or ER. Bolandiol was stimulatory in all these assays, but only 4–9% as potent as T, DHT, and 19-NT via AR, 1% as potent as progesterone via PR, and 3% and 1% as potent as E2 acting through ERα or ERβ, respectively. In immature castrate rats, bolandiol was equipotent to T in stimulating growth of the levator ani muscle but less potent than T in stimulating growth of the sex accessory glands. Bolandiol also stimulated uterine weight increases in immature female rats, which were partly blocked by ICI 182,780, but it was not aromatized in vitro by recombinant human aromatase. In contrast to T, stimulation of sex accessory gland weights by bolandiol was not inhibited by concomitant treatment with the dual 5α-reductase inhibitor dutasteride. As bolandiol exhibits tissue selectivity in vivo, it may act via AR, PR, and/or ER, utilize alternative signaling pathway(s) or transcriptional coregulators, and/or be metabolized to a more potent selective steroid. PMID:19941958

Prolactin modulates luteal activity in the short-nosed fruit bat, Cynopterus sphinx during delayed embryonic development.

PubMed

Anuradha; Krishna, Amitabh

2017-07-01

The aim of this study was to evaluate the role of prolactin as a modulator of luteal steroidogenesis during the period of delayed embryonic development in Cynopterus sphinx. A marked decline in circulating prolactin levels was noted during the months of November through December coinciding with the period of decreased serum progesterone and delayed embryonic development. The seasonal changes in serum prolactin levels correlated positively with circulating progesterone (P) level, but inversely with circulating melatonin level during first pregnancy showing delayed development in Cynopterus sphinx. The results also showed decreased expression of prolactin receptor-short form (PRL-RS) both in the corpus luteum and in the utero-embryonic unit during the period of delayed embryonic development. Bats treated in vivo with prolactin during the period of delayed development showed significant increase in serum progesterone and estradiol levels together with significant increase in the expression of PRL-RS, luteinizing hormone receptor (LH-R), steroidogenic acute receptor protein (STAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) in the ovary. Prolactin stimulated ovarian angiogenesis (vascular endothelial growth factor) and cell survival (B-cell lymphoma 2) in vivo. Significant increases in ovarian progesterone production and the expression of prolactin-receptor, LH-R, STAR and 3β-HSD proteins were noted following the exposure of LH or prolactin in vitro during the delayed period. In conclusion, short-day associated increased melatonin level may be responsible for decreased prolactin release during November-December. The decline in prolactin level might play a role in suppressing P and estradiol-17β (E2) estradiol levels thereby causing delayed embryonic development in C. sphinx. Copyright © 2017 Elsevier Inc. All rights reserved.

Biomarkers in Tissue Samples From Patients With Newly Diagnosed Breast Cancer Treated With Zoledronic Acid

ClinicalTrials.gov

2018-06-01

Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

Saracatinib in Treating Patients With Metastatic or Locally Advanced Breast Cancer That Cannot Be Removed By Surgery

ClinicalTrials.gov

2014-04-02

Estrogen Receptor-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

Unopposed Estrogen Supplementation/Progesterone Deficiency in Post-Reproductive Age Affects the Secretory Profile of Resident Macrophages in a Tissue-Specific Manner in the Rat.

PubMed

Stanojević, Stanislava; Kovačević-Jovanović, Vesna; Dimitrijević, Mirjana; Vujić, Vesna; Ćuruvija, Ivana; Blagojević, Veljko; Leposavić, Gordana

2015-11-01

The influence of unopposed estrogen replacement/isolated progesterone deficiency on macrophage production of pro-inflammatory/anti-inflammatory mediators in the post-reproductive age was studied. Considering that in the rats post-ovariectomy the circulating estradiol, but not progesterone level rises to the values in sham-operated controls, 20-month-old rats ovariectomized at the age of 10 months served as an experimental model. Estrogen and progesterone receptor expression, secretion of pro- and anti-inflammatory cytokines, and arginine metabolism end-products were examined in splenic and peritoneal macrophages under basal conditions and following lipopolysaccharide (LPS) stimulation in vitro. Almost all peritoneal and a subset of splenic macrophages expressed the intracellular progesterone receptor. Ovariectomy diminished cytokine production by splenic (IL-1β) and peritoneal (TNF-α, IL-1β, IL-10) macrophages and increased the production of IL-10 by splenic and TGF-β by peritoneal cells under basal conditions. Following LPS stimulation, splenic macrophages from ovariectomized rats produced less TNF-α and more IL-10, whereas peritoneal macrophages produced less IL-1β and TGF-β than the corresponding cells from sham-operated rats. Ovariectomy diminished urea production in both subpopulations of LPS-stimulated macrophages. Although long-lasting isolated progesterone deficiency in the post-reproductive age differentially affects cytokine production in the macrophages from distinct tissue compartments, in both subpopulations, it impairs the pro-inflammatory/anti-inflammatory cytokine secretory balance. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Krall, J.F.; Morin, A.

Cells growing in culture with previously described properties of rat uterine smooth muscle accumulated /sup 45/Ca/sup 2 +/ from the medium. Ca/sup 2 +/ uptake by these cells was stimulated by the addition to the medium of 8-bromo-cGMP but not by 8-bromo-cAMP. Ca/sup 2 +/ uptake was also stimulated by carbachol and by the nitro-vasodilator nitroprusside. Although cholinergic agonists have been shown previously to stimulate contraction but not cGMP synthesis in the rat myometrium, both carbachol and nitroprusside stimulated cGMP production by the cultured cells. These results suggested the cells had cholinergic receptor-medicated functions that reflected some neurotransmitter-sensitive properties ofmore » uterine smooth muscle in situ. When determined by a specific radioligand binding assay, subcellular fractions of the cultured cells bound muscarinic cholinergic agonists and antagonists with affinities expected of the muscarinic receptor. The cells were also sensitive to the ..beta..-adrenergic catecholamine agonist isoproterenol, which stimulated cAMP production but not Ca/sup 2 +/ uptake. Carbachol failed to inhibit isoproterenol-dependent cAMP production, which is an important property of the cholinergic receptor in uterine smooth muscle in situ. These results suggest some but not all acetylcholine-sensitive properties of uterine smooth muscle may be retained in cell culture.« less

Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer.

PubMed

Sinreih, Maša; Hevir, Neli; Rižner, Tea Lanišnik

2013-02-25

Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. It is associated with prolonged exposure to estrogens that is unopposed by the protective effects of progesterone, which suggests that altered progesterone biosynthesis, metabolism and actions might be implicated in the development of EC. Our aim was to evaluate these processes through quantitative real-time PCR expression analysis in up to 47 pairs of EC tissue and adjacent control endometrium. First, we examined the expression of genes encoding proteins associated with progesterone biosynthesis: steroidogenic acute regulatory protein (STAR); a side chain cleavage enzyme (CYP11A1); and 3β-hydroxysteroid dehydrogenase/ketosteroid isomerase (HSD3B). There were 1.9- and 10.0-fold decreased expression of STAR and CYP11A1, respectively, in EC versus adjacent control endometrium, with no significant differences in the expression of HSD3B1 and HSD3B2. Next, we examined expression of genes encoding five progesterone metabolizing enzymes: the 3-keto and 20-ketosteroid reductases (AKR1C1-AKR1C3) and 5α-reductases (SRD5A1 and SRD5A2); and the opposing 20α-hydroxysteroid dehydrogenase (HSD17B2). These genes are expressed in EC and adjacent control endometrium. No statistically significant differences were seen in mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1. Expression of HSD17B2 was 3.0-fold increased, and expression of SRD5A2 was 3.7-fold decreased, in EC versus adjacent control endometrium. We also examined mRNA levels of progesterone receptors A and B (PGR), and separately the expression of progesterone receptor B (PR-B). Here we saw 1.8- and 2.0-fold lower mRNA levels of PGR and PR-B, respectively, in EC versus adjacent control endometrium. This down-regulation of STAR, CYP11A1 and PGR in endometrial cancer may lead to decreased progesterone biosynthesis and actions although the effects on progesterone levels should be further studied. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Increased progesterone production in cumulus-oocyte complexes of female mice sired by males with the Y-chromosome long arm deletion and its potential influence on fertilization efficiency.

PubMed

Kotarska, Katarzyna; Galas, Jerzy; Przybyło, Małgorzata; Bilińska, Barbara; Styrna, Józefa

2015-02-01

It was revealed previously that B10.BR(Y(del)) females sired by males with the Y-chromosome long arm deletion differ from genetically identical B10.BR females sired by males with the intact Y chromosome. This is interpreted as a result of different epigenetic information which females of both groups inherit from their fathers. In the following study, we show that cumulus-oocyte complexes ovulated by B10.BR(Y(del)) females synthesize increased amounts of progesterone, which is important sperm stimulator. Because their extracellular matrix is excessively firm, the increased progesterone secretion belongs presumably to factors that compensate this feature enabling unchanged fertilization ratios. Described compensatory mechanism can act only on sperm of high quality, presenting proper receptors. Indeed, low proportion of sperm of Y(del) males that poorly fertilize B10.BR(Y(del)) oocytes demonstrates positive staining of membrane progesterone receptors. This proportion is significantly higher for sperm of control males that fertilize B10.BR(Y(del)) and B10.BR oocytes with the same efficiency. © The Author(s) 2014.

Potassium Channels and Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia

PubMed Central

Zhu, Ronghui; Xiao, DaLiao; Zhang, Lubo

2014-01-01

During a normal course of pregnancy, uterine vascular tone is significantly decreased resulting in a striking increase in uterine blood flow, which is essential for fetal development and fetal growth. Chronic hypoxia during gestation may adversely affect the normal adaptation of uterine vascular tone and increase the risk of preeclampsia and fetal intrauterine growth restriction. In this review, we present evidence that the regulation of K+ channels is an important mechanism in the adaptation of uterine vascular tone to pregnancy and hypoxia. There are four types of K+ channels identified in arterial smooth muscle cells: 1) voltage-dependent K+ (Kv) channels, 2) Ca2+-activated K+ (KCa) channels, 3) inward rectifier K+ (KIR) channels, and 4) ATP-sensitive K+ (KATP) channels. Pregnancy differentially augments the expression and activity of K+ channels via downregulation of protein kinase C signaling in uterine and other vascular beds, leading to decreased uterine vascular tone and increased uterine blood flow. Sex steroid hormones play an important role in the pregnancy-mediated alteration of K+ channels in the uterine vasculature. In addition, chronic hypoxia alters uterine vascular K+ channels expression and activities via modulation of steroid hormones/receptors-mediated signaling, resulting in increased uterine vascular tone during pregnancy. PMID:24063385

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

Role of sex steroids and their receptors in human preterm infants: Impacts on future treatment strategies for cerebral development.

PubMed

Hübner, Stephanie; Reich, Bettina; Heckmann, Matthias

2015-12-15

Preterm birth is a major risk factor for cerebral complications, such as hemorrhage or periventricular leukomalacia, which lead to lifelong neurodevelopmental deficits. Hypoxia/ischemia, inflammation, hyperoxia, and prematurity itself contribute to the extent of impaired neurodevelopment. Preterm birth leads to disruption of the placental supply of estrogens and progesterone. Postnatally, the plasma levels of estrogens and progesterone drop 100-fold. Preterm infants are deprived of the placental supply of these hormones for up to sixteen weeks. Thus, supplementation of estradiol and progesterone to mimic intrauterine conditions may potentially improve a premature infant́s extrauterine development and help protect the brain against neurological complications. However, preliminary clinical studies did not find improved outcomes except for a trend towards less cerebral palsy. The decrease in estrogen and progesterone concentrations is accompanied by persistent, high postnatal production of fetal zone steroids, mainly dehydroepiandrosterone, which serve as precursors for maternal estrogen synthesis during pregnancy. This commentary will combine knowledge from endocrinology, pharmacology, and neonatology to explain the discrepancies between promising animal models and clinical findings. Most important targets will be classical and non-classical estrogen receptors, which interact differently-not only with estrogens but also with fetal zone steroids. The fetal zone is unique among humans and higher primates. Therefore, a clearly defined model is required to study the role of sex steroids and their receptors before further clinical studies begin. Copyright © 2015 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

Mutation of Hip’s Carboxy-Terminal Region Inhibits a Transitional Stage of Progesterone Receptor Assembly

PubMed Central

Prapapanich, Viravan; Chen, Shiying; Smith, David F.

1998-01-01

Steroid receptor complexes are assembled through an ordered, multistep pathway involving multiple components of the cytoplasmic chaperone machinery. Two of these components are Hsp70-binding proteins, Hip and Hop, that have some limited homology in their C-terminal regions, outside the sequences mapped for Hsp70 binding. Within this region of Hip is a DPEV sequence that occurs twice; in Hop, one DPEV sequence plus a partial second sequence occurs. In an effort to better understand Hip function as it relates to assembly of progesterone receptor complexes, the DPEV region of Hip was targeted for mutations. Each DPEV sequence was mutated to an APAV sequence, singly or in combination. The combined mutation, APAV2, was further combined with a deletion of Hip’s tetratricopeptide repeat region that is required for Hsp70 binding or with a deletion of Hip’s GGMP repeat. An additional mutant was prepared by truncation of Hip’s DPEV-containing C terminus. By comparing interactions of various Hip forms with Hsp70, it was determined that mutation of the DPEV sequences created a dominant inhibitory form of Hip. The mutant Hip-Hsp70 complex was not prevented from interacting with progesterone receptor, but the mutant caused a dose-dependent inhibition of receptor assembly with Hsp90. The behavior of the Hip mutant is consistent with a model in which Hip and Hop are required to facilitate the transition from an early receptor complex with Hsp70 into later complexes containing Hsp90. PMID:9447991

Influence of tumor cell proliferation and sex-hormone receptors on effectiveness of radiation therapy for dogs with incompletely resected meningiomas.

PubMed

Théon, A P; Lecouteur, R A; Carr, E A; Griffey, S M

2000-03-01

To assess the influence of tumor cell proliferation and sex-hormone receptors on the efficacy of megavoltage irradiation for dogs with incompletely resected meningiomas. Longitudinal clinical trial. 20 dogs with incompletely resected intracranial meningiomas. Dogs were treated with 48 Gy of radiation administered 3 times per week on an alternate-day schedule of 4 Gy/fraction for 4 weeks, using bilateral parallel-opposed fields. Tumor proliferative fraction measured by immunohistochemical detection of proliferating cell nuclear antigen (PFPCNA index) ranged from 10 to 42% (median, 24%). Progesterone receptor immunoreactivity was detected in 70% of tumors. Estrogen receptor immunoreactivity was not detected. An inverse correlation was found between detection of progesterone receptors and the PFPCNA index. The overall 2-year progression-free survival (PFS) rate was 68%. The only prognostic factor that significantly affected PFS rate was the PFPCNA index. The 2-year PFS was 42% for tumors with a high PFPCNA index (value > or = 24%) and 91% for tumors with a low PFPCNA index (value < 24%). Tumors with a high PFPCNA index were 9.1 times as likely to recur as were tumors with a low PFPCNA index. This study confirms the value of irradiation for dogs with incompletely resected meningiomas. Prognostic value of the PFPCNA index suggests-that duration of treatment and interval from surgery to start of irradiation may affect outcome. Loss of progesterone receptors in some tumors may be responsible for an increase in PFPCNA index and may indirectly affect prognosis after radiation therapy.