Ma, Xiangling; Wang, Qing; Wang, Lili; Huang, Yanmei; Liao, Xiaoxiang; Li, Hui
The interaction of norgestrel with human serum albumin (HSA) was investigated by spectroscopy and molecular-docking methods. Results of spectroscopy methods suggested that the quenching mechanism of norgestrel on HSA was static quenching and that the quenching process was spontaneous. Negative values of thermodynamic parameters (ΔG, ΔH, and ΔS) indicated that hydrogen bonding and van der Waals forces dominated the binding between norgestrel and HSA. Three-dimensional fluorescence spectrum and circular dichroism spectrum showed that the HSA structure was slightly changed by norgestrel. Norgestrel mainly bound with Sudlow site I based on a probe study, as confirmed by molecular-docking results. Competition among similar structures indicated that ethisterone and norethisterone affected the binding of norgestrel with HSA. CH3 in R1 had little effect on norgestrel binding with HSA. The surface hydrophobicity properties of HSA, investigated using 8-anilino-1-naphthalenesulfonic acid, was changed with norgestrel addition. © 2016 Wiley Periodicals, Inc.
Zanchetta, Priscilla Garozi; Heringer, Otávio; Scherer, Rodrigo; Pacheco, Henrique Poltronieri; Gonçalves, Ricardo; Pena, Angelina
Pharmaceuticals are emerging contaminants and it must be noted that approximately 70 % of them are excreted via urine. Therefore, urine usage implies the risk of transfer of pharmaceutical residues to agricultural fields and environment contamination. Thus, this study aimed on the development and validation of a LC-MS/MS method for D-norgestrel (D-NOR) and progesterone (PRO) determination in human urine, as well as the evaluation of the removal efficiency of two methods (storage and evaporation), and the effects of acidification with sulfuric acid. The storage process was evaluated for 6 weeks, while the evaporation was assessed at three different temperatures (50, 75, and 100 °C). All experiments were done with normal urine (pH = 6.0) and acidified urine (pH = 2.0, with sulfuric acid). The results of validation showed good method efficiency. In the second week of storage, higher hormone degradation was observed. In the evaporation method, both D-NOR and PRO were almost completely degraded when the volume was reduced to the lowermost level. Results also indicate that acidification did not affect degradation. Overall, the results showed that combination of two methods can be employed for more efficient hormone removal in urine.
Liang, Yan-Qiu; Huang, Guo-Yong; Ying, Guang-Guo; Liu, Shuang-Shuang; Jiang, Yu-Xia; Liu, Shan
The aim of this study was to investigate the effects of progestins on the hypothalamic-pituitary-thyroid (HPT) axis in the early stage of zebrafish. Zebrafish embryos were exposed to progesterone (P4) or norgestrel (NGT) at 5, 50 and 100 ng L(-1) for 144 h post fertilization (hpf), and the transcriptional levels of target genes along the hypothalamic-pituitary-thyroid axis were determined daily. The results showed that P4 had only minor effects on the mRNA expression of thyroglobulin (Tg), iodothyronine deiodinase type Ι (Dio1) and thyroid hormone receptor β (Thrb) genes. Similarly, the effects of NGT on transcripts of thyrotropin-releasing hormone (Trh), Dio1, iodothyronine deiodinase type II (Dio2) and thyroid hormone receptor α (Thra) genes were generally low. In addition, NGT resulted in some alterations of Tg and Thrb transcripts at different time points. However, a strong induction of Nis mRNA by P4 and NGT was observed in zebrafish embryos-larvae. The overall results showed that besides Nis no effects on the hypothalamic-pituitary-thyroid (HPT) axis are observed following exposure to P4 and NGT, which imply that both P4 and NGT have potential effects on the thyroid endocrine system by inducing transcript of Nis gene during the early stage of zebrafish. Copyright © 2014 Elsevier Inc. All rights reserved.
Kesserü, E; Camacho-Ortega, P; Laudahn, G; Schopflin, G
The presence of progestogens in the cervical mucus suppresses and arrests sperm penetration. Using the Kremer technique, the effects of in vitro released progesterone, d-norgestrel, and cyproterone acetate were studied by inserting silicone rubber threads bearing the respective compounds into capillary tubes containing cervical mucus. Control tubes were fitted with nonmedicated silicone rubber threads. After 24 hours of incubation, the sperm migration test was carried out to evaluate penetration depth, qualitative motility, and proportion of motile forms. Progesterone produced the greatest alterations. Migration was arrested within 30 minutes, the distance reached was consistently less than 2 cm, and sperm were completely immobile at 24 hours. D-norgestrel also exhibited a distinct spermiostatic effect, but it was not as intense as that of progesterone. Cyproterone acetate was practically effective during the first 120 minutes and produced alterations only in the qualitative and proportional motility.
Lifchez, A S; Scommegna, A
Silastic rubber capsules in 2 thicknesses (.42 mm and .80 mm) and 3 lengths (9, 14, and 19 mm) were filled with progesterone, Provera, Norgestrel, or chlormadinone acetate and implanted under the skin of rats, and the amount of steroid released was measured after 1, 2, 4, and 8 weeks. The amount of steroid released was also measured from progesterone-filled capsules .42 mm thick and varying from 19-32 mm long inserted in the uterus of 16 women volunteers for 1-7 days. The rate of release of each steroid in the rats was found to be proportionate to the length of the capsule and related, but not proportional to the thickness of the capsule. The release rate of progesterone was 3-20 times greater than that of the other steroids, while Norgestrel diffused at the lowest rate. The influence of thickness of capsule was greater for the steroids with the highest diffusion rate, progesterone and chlormadinone acetate. The release rates of all except chlormadinone acetate were higher in the 1st week. The release rates of the synthetic progestins, unlike that of progesterone, were relatively constant after the 1st week. The release rate of progesterone tended to be related to the amount remaining in the capsule when the amount became small. The measured amount of progesterone released each day from each intrauterine capsule was also proportional to its length. It appears that Norgestrel, Provera, and chlormadinone acetate are all released slowly enough and have enough biologic activity at low concentrations to have a contraceptive effect for well over 1 year when administered in a 30 mm intrauterine capsule.
Olatunji, Lawrence Aderemi; Oyeyipo, Ibukun Peter; Usman, Taofeek Oluwamayowa
Oral contraceptive (OC) use and increased fructose feeding have been associated with altered cardiometabolic effects. The effect of increased dietary fructose during OC use on cardiometabolic parameters is unknown. We investigated the effects of a high-fructose diet on body weight gain, fasting blood glucose, glucose tolerance, plasma lipid and hemorheological parameters in female rats treated with a combination of OC steroids (norgestrel/ethinyl estradiol; NEE). Rats were given (p.o.) vehicle, high-dose NEE (10.0 μg norgestrel/1.0 μg ethinyl estradiol) or low-dose NEE (1.0 μg norgestrel/0.1 μg ethinyl estradiol) with or without high dietary fructose daily for 6 weeks. Results demonstrated that high-dose NEE but not low-dose NEE treatment led to significant increases in hematocrit, blood viscosity, and decreases in body weight gain, glucose tolerance, and plasma HDL-cholesterol level. Both NEE treatments resulted in significant increases in plasma viscosity and triglyceride. Increased dietary fructose without NEE treatment produced significant increases in fasting blood glucose, hematocrit, blood and plasma viscosities, while increased dietary fructose significantly potentiated the effects on blood and plasma viscosities observed during NEE treatment. Conversely, the effects of NEE treatment on body weight gain, glucose tolerance, plasma triglyceride and HDL-cholesterol were significantly attenuated. In conclusion, the results indicate that increase in dietary fructose may worsen abnormal blood rheology. The results also demonstrate that increased dietary fructose may not impact negatively on glucose and lipid metabolisms during OC use. The findings imply that fructose-enriched diet might be an important consideration during OC use regarding blood rheological properties.
Wood, P. J.; Gower, D. B.
This chapter covers the analysis of steroids with progesterone-like activity, classified as “progestagens”. Steroids in this group include the naturally occurring C21 steroids, progesterone (4-pregnene-3,20-dione) and its metabolites, together with synthetic steroids, such as norgestrel norethisterone (NE), and medroxyprogesterone acetate which also have progestational activity.
Canto, T E; Vera, L; Polanco, L E; Colven, C E
A non-comparative study of the progestogen-only oral contraceptive, norgestrel 0.075 mg, in breast-feeding women was conducted at the Centro de Investigaciones Regionales, Merida, Yucatan, Mexico. The study was designed to evaluate the overall acceptability and contraceptive efficacy of norgestrel in breast-feeding women. This report includes a survey of 200 women, all of whom were less than 26 weeks postpartum at admission; 113 were interval patients and 87 were postpartum. Follow-up visits were scheduled at 2, 6 and 12 months after admission. Overall, women experienced an increase in intermenstrual bleeding, amenorrhea, vaginal discharge and breast discomfort. The discontinuation rate at 12 months was 32.5 and the corresponding lost to follow-up rate was 22.5; this is a measure of acceptability. The 12-month life-table rate for pregnancy was 3.4 with a standard error of 2.0. Three women discontinued use of the mini-pill due to accidental pregnancy. One pregnancy was attributed to user failure and the woman conceived 9 months after entering into the study; the other two were attributed to method failure, one woman conceived 3 months after admission and the other conceived 6 months after admission.
Tahrim, Nurfaizah Abu; Abdullah, Md. Pauzi; Aziz, Yang Farina Abdul
In this present work, an analytical method based on solid phase extraction (SPE) followed by liquid chromatography-time-of-flight mass spectrometry (LC-TOF-MS) in positive electrospray ionisation mode was successfully applied to real samples for the determination of human pharmaceuticals in pre- and post-sewage treatment samples. The ten target compounds selected in this study include acetaminophen, theophylline, caffeine, metoprolol, sulfamethoxazole, carbamazepine, prednisolone, ketoprofen, norgestrel and simvastatin. Acetaminophen, theophylline and caffeine were present at all five raw sewage samples. In addition, this work provides the first report on the investigation and detection of theophylline in sewage treatment plant (STP) samples in Malaysia.
Rome, Ellen S; Issac, Veronica
Unplanned or unintended pregnancy remains a significant challenge for adolescents; many teens who plan ahead but opt not to choose long-acting reversible contraceptive methods have high failure rates with condom usage, oral contraceptives, and other less long-acting methods. Emergency contraception (EC) remains a necessity for those adolescents seeking a second chance to prevent the unintended consequences of unplanned sexual activity. At present, 5 postcoital methods remain available as EC globally: intrauterine devices, ulipristal acetate, a selective progesterone modulator, mifepristone; levonorgestrel, and ethinyl estradiol plus levonorgestrel or norgestrel (rarely used now that progestin only methods are more readily available). Copyright © 2017 Elsevier Inc. All rights reserved.
Simonson, Steven G; Martin, Paul D; Warwick, Mike J; Mitchell, Patrick D; Schneck, Dennis W
Aims To assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed. Methods This open-label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri-Cyclen®) on Days 1–21 and placebo OCS on Days 22–28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1–21 of Cycle B. Results Co-administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co-administration increased AUC[0–24] for ethinyl oestradiol (26%; 90% CI ratio 1.19–1.34), 17-desacetyl norgestimate (15%; 90% CI 1.10–1.20), and norgestrel (34%; 90% CI 1.25–1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17–1.33) and norgestrel (23%; 90% CI 1.14–1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle-stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6β-hydroxycortisol. Rosuvastatin significantly decreased low-density lipoprotein cholesterol [-55%], total cholesterol [-27%], and triglycerides [-12%], and significantly increased high-density lipoprotein cholesterol[11%]. Co-administration was well tolerated. Conclusions Rosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid-regulating effect was observed in this study, and there was no evidence of an altered lipid-regulating effect with OCS coadministration. PMID:14998424
Upreti, V V; Hsiang, C B; Li, L; Xu, X; LaCreta, F P; Boulton, D W
Saxagliptin (Onglyza™) is a dipeptidyl peptidase-4 (DPP4) inhibitor for treating type 2 diabetes mellitus. This open-label, randomized, two-way crossover study in 20 healthy female subjects investigated the effect of saxagliptin on the pharmacokinetics (PK) of the active components of a combined oral contraceptive (COC). Subjects received either COC (Ortho-Cyclen(®)) once daily (QD) for 21 days, then 5 mg saxagliptin QD + COC QD for 21 days, or vice versa. Coadministration of saxagliptin and COC did not alter the steady-state PK of the primary active oestrogen (ethinyl estradiol) or progestin (norelgestromin) COC components. The area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) of an active metabolite of norelgestromin (norgestrel) were increased by 13 and 17%, respectively, a magnitude that was not considered clinically meaningful. Coadministration of saxagliptin and COC in this study was generally well-tolerated. Saxagliptin can be co-prescribed with an oestrogen/progestin combination for women taking oral contraceptive. © 2012 Blackwell Publishing Ltd.
Olatunji, Lawrence A; Usman, Taofeek O; Seok, Young-Mi; Kim, In-Kyeom
Clinical studies have shown that combined oral contraceptive (COC) use is associated with cardiometabolic disturbances. Elevated renin-angiotensin system (RAS) and plasminogen activator inhibitor-1 (PAI-1) have also been implicated in the development of cardiometabolic events. To determine the effect of COC treatment on cardiac RAS and PAI-1 gene expressions, and whether the effect is circulating aldosterone or corticosterone dependent. Female rats were treated (p.o.) with olive oil (vehicle) or COC (1.0 µg ethinylestradiol and 10.0 µg norgestrel) daily for six weeks. COC treatment led to increases in blood pressure, HOMA-IR, Ace1 mRNA, Atr1 mRNA, Pai1 mRNA, cardiac PAI-1, plasma PAI-1, C-reactive protein, uric acid, insulin and corticosterone. COC treatment also led to dyslipidemia, decreased glucose tolerance and plasma 17β-estradiol. These results demonstrates that hypertension and insulin resistance induced by COC is associated with increased cardiac RAS and PAI-1 gene expression, which is likely to be through corticosterone-dependent but not aldosterone-dependent mechanism.
Some clinicians are not sure whether they need emergency contraceptive pills (ECPs) in their clinic. Deciding that one wants to use ECPs in any given clinic is, however, the first step toward making the contraceptive option available to women. Action must be taken both in the clinic and at the community level to make postcoital contraception a reality. Once the clinician or clinicians have decided to offer ECPs in the clinic, background information on ECPs should be assembled and a protocol established for the clinic. A pilot project offering ECPs to selected clients could instead be implemented to get things going in settings where strong resistance is expected to ECPs. Emergency contraception supplies must then be obtained. Wyeth-Ayerst Laboratories, based in Philadelphia, manufactures pills containing norgestrel, the only pills which have been studied for use as ECPs. The article describes the creation and distribution of emergency contraception kits. Such kits could include several condoms, a pack of Ovral to take in case of need after unprotected sexual intercourse, and information about taking ECPs. Women would probably take advantage of emergency contraception if clinics advertised more about its availability.
Olatunji, L A; Soladoye, A O
The present study sought to investigate the effects of prostaglandins synthesis inhibition with indomethacin on blood pressure, heart rate, cardiac weight, plasma electrolytes and cardiovascular responses to arterial baroreceptor stimulation in Oral contraceptive (OC) treated female Sprague-Dawley rats. Oral administration of synthetic oestrogen, ethinyl oestradiol in combination with progestogen, norgestrel for ten weeks significantly increased blood pressure and cardiac weight compared with those of the control rats. Concomitant treatment with indomethacin significantly abrogated increase in blood pressure but did not affect the increase in cardiac weight induced by OC. Heart rate, plasma sodium and potassium concentrations were not affected by OC and/or indomethacin treatment. OC treatment did not alter sympathetic-mediated pressor and tachycardiac responses caused by bilateral carotid baroreceptors unloading. However, these responses were significantly attenuated by indomethacin treatment. These results demonstrated that rat model of OC-induced high blood pressure developed cardiac hypertrophy that is not associated with altered sympathetic-mediated cardiovascular responses to arterial baroreceptor stimulation. The finding that indomethacin prevented OC-induced high blood pressure, but not associated cardiac hypertrophy implies that synthesis of prostaglandins may be an important determinant of OC-induced hypertension, while associated cardiac hypertrophy may not be pressure overload-dependent.
Duan, X; Ning, M
Preparation and in vitro/in vivo evaluation of mifepristone intravaginal ring formulations were investigated. In the present study, it is reported that a mifepristone intravaginal ring of reservoir design comprising of a mifepristone silicone elastomer core enclosed in a silicone layer. During the preparation of intravaginal ring solid dispersion method was employed which improved the release rate of drug from the intravaginal ring. In vitro release studies performed under sink conditions and the released drug amounts were estimated using UV spectrometry at 310 nm. In addition, the in vivo release profile of in-house devices was evaluated in female New Zealand white rabbits. The rabbit plasma samples were processed and analyzed using a validated HPLC-MS method. Norgestrel was used as internal standard, and plasma samples contained mifepristone and internal standard were deproteinized, and then subjected to HPLC-MS analysis under condition of electrospray ionization in the selected ion monitoring mode. The drug release from intravaginal ring made in house was constant for 21 days in rabbits, which suggested the mifepristone intravaginal ring release system would be useful in clinical practice in the future. The result indicated the in vitro/in vivo correlation is perfect, which explained in vitro release analysis method developed was feasible.
Tamura, Kazuhiro; Naraba, Hiroaki; Hara, Takahiko; Nakamura, Kota; Yoshie, Mikihiro; Kogo, Hiroshi; Tachikawa, Eiichi
Microsomal prostaglandin E synthase-1 (mPGES-1) is primarily expressed in granulosa cells (GCs) in the preovulatory follicle. Both prostaglandin E2 (PGE2) and progesterone (P4) are implicated in various reproductive functions. Here, we demonstrate that mPges-1 may be a direct downstream target gene of the P4 receptor and P4-stimulated PGE2 secretion can stimulate P4 production in a newly generated mouse GC line (GtsT). Treatment of GtsT cells with a P4 receptor agonist, norgestrel, markedly increased mPGES-1 expression detected by RT-PCR analysis. PGE2 secretion measured by an enzyme-linked immunosorbent assay was enhanced by P4 treatment. Luciferase assays revealed that the proximal promoter region of the mPges-1 gene was responsible for the effects of P4 treatment. Conversely, PGE2 treatment stimulated P4 secretion, which coordinated with mRNA expression of steroidogenic acute regulatory protein. Taken together, P4 may regulate mPGES-1 expression to increase PGE2 secretion and in turn P4 production. An autocrine loop between P4 and PGE2 might function to maintain the increased levels of both in GCs. Copyright © 2016 Elsevier Inc. All rights reserved.
Cirrincione, Lauren R; Penchala, Sujan Dilly; Scarsi, Kimberly K; Podany, Anthony T; Winchester, Lee C; Back, David J; Khoo, Saye H; Fletcher, Courtney V; Siccardi, Marco; Else, Laura J
Levonorgestrel (LNG) is a synthetic progestin that is available in oral contraceptive tablets, a subdermal implant, and an intrauterine system for contraception. LNG pharmacokinetics are a pivotal determinant of contraceptive efficacy and essential in assessing drug-drug interactions influencing LNG exposure following different routes of LNG administration. A highly sensitive LC-MS/MS method was developed and validated to quantify levonorgestrel in human plasma. Liquid-liquid extraction was utilized with a sample volume of 500 μL to extract levonorgestrel from plasma. Chromatographic separation of LNG was achieved with a Fortis™ C18 (3 μm: 100 mm × 2.1 mm) reverse phase analytical column. The mobile phases consisted of de-ionized water plus 0.1% NH 4 OH (100:0.1%, v/v) (A), and methanol plus 0.1% NH 4 OH (100:0.1%, v/v) (B) delivered as a gradient at a flow rate of 400 μL/min. Detection of LNG and internal standard (D-(-)-norgestrel-d7) was achieved using positive polarity mode monitoring at 313.2-245.2 amu and 320.1-251.2 amu, respectively. The assay was linear over the calibration range of 49.6 to 1500 pg/mL. This method was used to quantify plasma LNG released by subdermal implant in support of a drug interaction study among women with HIV receiving efavirenz- or nevirapine-based antiretroviral therapy. Copyright © 2018 Elsevier B.V. All rights reserved.
Liang, Yayun; Benakanakere, Indira; Besch-Williford, Cynthia; Hyder, Ryyan S; Ellersieck, Mark R; Hyder, Salman M
Previous studies have shown that sequential exposure to estrogen and progesterone or medroxyprogesterone acetate (MPA) stimulates vascularization and promotes the progression of BT-474 and T47-D human breast cancer cell xenografts in nude mice (Liang et al, Cancer Res 2007, 67:9929). In this follow-up study, the effects of progesterone, MPA, norgestrel (N-EL), and norethindrone (N-ONE) on BT-474 xenograft tumors were compared in the context of several different hormonal environments. N-EL and N-ONE were included in the study because synthetic progestins vary considerably in their biological effects and the effects of these two progestins on the growth of human tumor xenografts are not known. Estradiol-supplemented intact and ovariectomized immunodeficient mice were implanted with BT-474 cells. Progestin pellets were implanted simultaneously with estradiol pellets either 2 days before tumor cell injection (ie, combined) or 5 days after tumor cell injections (ie, sequentially). Progestins stimulated the growth of BT-474 xenograft tumors independent of exposure timing and protocol, MPA stimulated the growth of BT-474 xenograft tumors in ovariectomized mice, and progestins stimulated vascular endothelial growth factor elaboration and increased tumor vascularity. Progestins also increased lymph node metastasis of BT-474 cells. Therefore, progestins, including N-EL and N-ONE, induce the progression of breast cancer xenografts in nude mice and promote tumor metastasis. These observations suggest that women who ingest progestins for hormone therapy or oral contraception could be more at risk for developing breast cancer because of proliferation of existing latent tumor cells. Such risks should be considered in the clinical setting.
Liang, Yayun; Benakanakere, Indira; Besch-Williford, Cynthia; Hyder, Ryyan S; Ellersieck, Mark R.; Hyder, Salman M
Objective Previous studies showed that sequential exposure to estrogen and progesterone or medroxyprogesterone acetate (MPA) stimulates vascularization and promotes the progression of BT-474 and T47-D human breast cancer cell xenografts in nude mice (Liang et al, Cancer Res 2007, 67:9929). In this follow-up study, the effects of progesterone, MPA, norgestrel (N-EL) and norethindrone (N-ONE) on BT-474 xenograft tumors were compared in the context of several different hormonal environments. N-EL and N-ONE were included in the study since synthetic progestins vary considerably in their biological effects and the effects of these two progestins on the growth of human tumor xenografts are not known. Methods Estradiol-supplemented intact and ovariectomized Immunodeficient mice were implanted with BT-474 cells. Progestin pellets were implanted either simultaneously with estradiol pellets 2-days prior to tumor cell injection (i.e. combined), or 5-days following tumor cell injections (i.e. sequentially). Results Progestins stimulated the growth of BT-474 xenograft tumors independent of exposure timing and protocol, MPA stimulated the growth of BT-474 xenograft tumors in ovariectomized mice and progestins stimulated VEGF elaboration and increased tumor vascularity. Progestins also increased lymph node metastasis of BT-474 cells. Therefore, progestins, including N-EL and N-ONE, induce the progression of breast cancer xenografts in nude mice and promote tumor metastasis. Conclusions These observations suggests that women who ingest progestins for HT or oral contraception could be more at risk for developing breast cancer as a result of proliferation of existing latent tumor cells. Such risks should be considered in the clinical setting. PMID:20461021
Liu, Shan; Chen, Hui; Xu, Xiang-Rong; Liu, Shuang-Shuang; Sun, Kai-Feng; Zhao, Jian-Liang; Ying, Guang-Guo
The occurrence, bioconcentration, and human dietary exposure via seafood consumption of 24 steroids were investigated by rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) in six typical marine aquaculture farms surrounding Hailing Island, South China. Ten, 9, 10, 15 of 24 steroids were detected at concentrations ranging from <0.1 (testosterone) to 40 ng/L (prednisolone), from 0.1 (4-androstene-3,17-dione) to 2.4 ng/g (progesterone), from 0.3 ng/g (testosterone) to 21.4 ng/g (epi-androsterone), and from <0.1 (testosterone) to 560 ng/g (cortisol) (wet weight) in the water, sediment, feed and biota samples, respectively. Synthetic steroids (androsta-1,4-diene-3,17-dione, 17α-boldenone, 17β-boldenone, 17β-trenbolone, prednisolone, norgestrel) were detected in the feed samples, clearly demonstrating the illegal use of steroids in the feed. The field bioconcentration factors (BCFs) of steroids calculated in different aquatic organisms ranged from 93.8 to 4000. The estimated daily intakes (EDIs) of androgens, glucocorticoids, and progestagens via consumption of seafood (i.e., shrimps, crabs, mollusks, and fish) for different age groups were in the range of 33.4-134, 2061-8566, and 40.4-155 ng/d for children (2-5 years), youth (6-18 years), and adults (>18 years), respectively. Even though no significant risk from dietary exposure arises from individual steroid, elevated risk to humans can result from the occurrence of multiple steroids in the seafood raised in the aquaculture farms, especially for the sensitive populations, such as pregnant women and children. Copyright © 2014 Elsevier B.V. All rights reserved.
Liu, Shuang-Shuang; Ying, Guang-Guo; Liu, You-Sheng; Yang, Yuan-Yuan; He, Liang-Ying; Chen, Jun; Liu, Wang-Rong; Zhao, Jian-Liang
A total of 21 progestagens were screened in animal wastes and environmental samples from two representative swine farms and surrounding environments of South China using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) to assess the effectiveness of simple lagoon (and digester) treatment. The results showed that 11, 8 and 8 of 21 target progestagens were detected with the minimum concentration of 2.31 ng/L and maximum of 6150 ng/L in the water samples, with the minimum of 1.36 ng/L and maximum of 98.3 ng/L in the suspended particles, and with the minimum of 1.57 ng/g dry weight (dw) and maximum of 3310 ng/g dw in the solid samples, respectively. Trace levels (a few ng/L or ng/g levels) of dydrogesterone, 5α-dihydroprogesterone, norgestrel and progesterone were found in samples from nearby surface waters and vegetable fields impacted by animal wastes. The residual progestagens at the reported levels may still pose potential risks to aquatic organisms such as fish in the receiving aquatic environments. This finding suggests that swine wastewater and feces could lead to contamination of some detectable progestagens in the surrounding environments. Significant reduction in total progestagen concentrations were observed from the fresh swine wastewaters to the fish ponds, indicating effective removal of these compounds by the lagoon (and digester) treatment. In addition, the biogas digesters provided high removal of the progestagens in the waste streams. This low-cost and eco-friendly treatment system should be promoted in developing countries with concentrated animal operations. Copyright © 2015 Elsevier Ltd. All rights reserved.
Almeida, C; Nogueira, J M F
In this study, stir bar sorptive extraction and liquid desorption followed by high performance liquid chromatography with diode array detection (SBSE-LD-HPLC/DAD) were combined for the simultaneous determination of nine steroid sex hormones (estrone, 17alpha-estradiol, 17beta-estradiol, 17alpha-ethynylestradiol, diethylstilbestrol, mestranol, progesterone, 19-norethisterone and norgestrel) in water and urine matrices. During the method development, it has been demonstrated that equilibrium time, ionic strength and back extraction solvents are the most important parameters to control, for determining the nine-hormones in water matrices, in which stir bars coated with 126 microl of polydimethylsiloxane were used. Assays performed on 30 ml water samples spiked at 10 microg/l levels under optimised experimental conditions, yielded recoveries ranging from 11.1+/-4.9% (17beta-estradiol) to 100.2+/-10.4% (mestranol), showed that the methodology is well described by the octanol-water partition coefficients (K(PDMS/W) approximately K(O/W)) for the latter, while pronounced deviations to the theoretical efficiency (K(PDMS/W) not equal K(O/W)) were observed for the remaining hormones. From calibration studies, a good analytical performance for all hormones was attained, including a suitable precision (2.1-17.1%), low limits of detection (0.3-1.0 microg/l) and an excellent linear dynamic range (1.25-50.0 microg/l). Assays on environmental water and urine matrices showed recovery yields in worthy good agreement with the spiking level (10 microg/l), and suitability for profiling low microg/l levels of natural hormones in urine samples taken from pregnant women. The present methodology is easy, reliable and sensitive at the trace level, only requiring a low sample volume, showing to be a good analytical alternative to routine quality control for environmental and biomedical laboratories.
Herrera-Melián, José Alberto; Guedes-Alonso, Rayco; Borreguero-Fabelo, Alejandro; Santana-Rodríguez, José Juan; Sosa-Ferrera, Zoraida
Eight wastewater samples from a university campus were analysed between May and July of 2014 to determine the concentration of 14 natural and synthetic steroid hormones. An on-line solid-phase extraction combined with ultra-high performance liquid chromatography coupled with mass spectrometry (on-line SPE-UHPLC-MS/MS) was used as extraction, pre-concentration and detection method. In the samples studied, three oestrogens (17β-estradiol, estrone and estriol), two androgens (boldenone and testosterone), three progestogens (norgestrel, progesterone and norethisterone) and one glucocorticoid (prednisone) were detected. The removal of hormones was studied in primary and secondary constructed wetland mesocosms. The porous media of the primary constructed wetlands were palm tree mulch. These reactors were used to study the effect of water flow, i.e. horizontal (HF1) vs vertical (VF1). The latter was more efficient in the removal of 17β-estradiol (HF1: 30%, VF1: 50%), estrone (HF1: 63%, VF1: 85%), estriol (100% both), testosterone (HF1: 45%, VF1: 73%), boldenone (HF1:-77%, VF1: 100%) and progesterone (HF1: 84%, VF1: 99%). The effluent of HF1 was used as influent of three secondary constructed wetland mesocosms: two double-stage vertical flow constructed wetlands, one with gravel (VF2gravel) and one with palm mulch (VF2mulch), and a mineral-based, horizontal flow constructed wetland (HFmineral). VF2mulch was the most efficient of the secondary reactors, since it achieved the complete removal of the hormones studied with the exception of 17ß-estradiol. The significantly better removal of BOD and ammonia attained by VF2mulch suggests that the better aeration of mulch favoured the more efficient removal of hormones.
Etminan, Mahyar; Delaney, Joseph A.C.; Bressler, Brian; Brophy, James M.
Background Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives. Methods We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease. Results We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate). Interpretation In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically
Diak, James; Örmeci, Banu
This study examined the individual and combined effects of potassium ferrate(VI) additions and freeze-thaw conditioning for the treatment and dewatering of wastewater sludge in cold climates, with particular focus on the inactivation of fecal coliforms and oxidation of estrogens, androgens, and progestogens. The first phase of the study evaluated the effects of potassium ferrate(VI) pre-treatment followed by freeze-thaw at -20 °C using a low (0.5 g/L) and high (5.0 g/L) dose of potassium ferrate(VI). The results showed that pre-treatment of anaerobically digested sludge with 5 g/L of potassium ferrate(VI) reduced the concentration of fecal coliforms in the sludge cake to below 100 MPN/g DS. The second phase evaluated the ability of ferrate(VI) to oxidise selected hormones in sludge. Anaerobically digested sludge samples were spiked with 10 different hormones: estrone (E1), 17α-estradiol, 17β-estradiol (E2), estriol (E3), 17α-ethinylestradiol (EE2), equilin, mestranol, testosterone, norethindrone and norgestrel in two groups of low (3-75 ng/mL) and high (12-300 ng/L) concentration ranges of hormones. The samples were treated with either 0.5 or 1.0 g/L of potassium ferrate(VI), and hormone concentrations were measured again after treatment. Potassium ferrate(VI) additions as low as 1.0 g/L reduced the concentration of estrogens in sludge. Potassium ferrate(VI) additions of 0.5 and 1.0 g/L were less effective at reducing the concentrations of androgens and progestogens. Increasing ferrate(VI) dose would likely result in more substantial decreases in the concentrations of fecal coliforms and hormones. The results of this study indicate that the combined use of freeze-thaw and ferrate(VI) has the potential to provide a complete sludge treatment solution in cold regions.
Liu, Shan; Ying, Guang-Guo; Zhao, Jian-Liang; Chen, Feng; Yang, Bin; Zhou, Li-Jun; Lai, Hua-Jie
A sensitive rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) method, combined with solid-phase extraction, ultrasonic extraction and silica gel cartridge cleanup, was developed for 28 steroids including 4 estrogens (estrone (E1), 17β-estradiol (E2), 17α-ethynyl estradiol (EE2), diethylstilbestrol (DES)), 14 androgens (androsta-1,4-diene-3,17-dione (ADD), 17α-trenbolone, 17β-trenbolone, 4-androstene-3,17-dione, 19-nortestoserone, 17β-boldenone, 17α-boldenone, testosterone (T), epi-androsterone (EADR), methyltestosterone (MT), 4-hydroxy-androst-4-ene-17-dione (4-OHA), 5α-dihydrotestosterone (5α-DHT), androsterone (ADR), stanozolol (S)), 5 progestagens (progesterone (P), ethynyl testosterone (ET), 19-norethindrone, norgestrel, medroxyprogesterone (MP)), and 5 glucocorticoids (cortisol, cortisone, prednisone, prednisolone, dexamethasone) in surface water, wastewater and sludge samples. The recoveries of surface water, influents, effluents and sludge samples were 90.6-119.0% (except 5α-DHT was 143%), 44.0-200%, 60.7-123% and 62.6-138%, respectively. The method detection limits for the 28 analytes in surface water, influents, effluents and freeze-dried sludge samples were 0.01-0.24 ng/L, 0.02-1.44 ng/L, 0.01-0.49 ng/L and 0.08-2.06 ng/g, respectively. This method was applied in the determination of the residual steroidal hormones in two surface water of Danshui River, 12 wastewater and 8 sludge samples from two wastewater treatment plants (Meihu and Huiyang WWTPs) in Guangdong (China). Ten analytes were detected in surface water samples with concentrations ranging between 0.4 ng/L (17β-boldenone) and 55.3 ng/L (5α-DHT); twenty analytes in the wastewater samples with concentrations ranging between 0.3 ng/L (P) and 621 ng/L (5α-DHT); and 12 analytes in the sludge samples with concentrations ranging between 1.6 ng/g (E1) and 372 ng/g (EADR). Copyright © 2011 Elsevier B.V. All rights reserved.
Hasegawa, Shiori; Matsui, Toshinobu; Hane, Yuuki; Abe, Junko; Hatahira, Haruna; Motooka, Yumi; Sasaoka, Sayaka; Fukuda, Akiho; Naganuma, Misa; Hirade, Kouseki; Takahashi, Yukiko; Kinosada, Yasutomi
Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3–71.4), 29.1 (23.5–35.9), 42.9 (32.3–57.0), 44.7 (32.7–61.1), and 38.6 (26.3–56.7), respectively. The medians (25%–75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3–314.0), 128.0 (27.0–279.0), 204.0 (44.0–660.0), 142.0 (41.3–344.0), and 16.5 (8.8–32.0) days, respectively. The 95% CIs of the WSP-β for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning. PMID:28732067
Trippe, Zahra Anita; Brendani, Bruno; Meier, Christoph; Lewis, David
. This resulted in an output of 23 potential SSMs. The literature search identified two communications issued to health professionals concerning a substandard rivastigmine patch, which validated our initial findings. Furthermore, we identified excess reporting of product quality issues with an ethinyl estradiol/norgestrel combination and with salbutamol. These were categorized as confirmed clusters of substandard/spurious/falsely labelled/falsified/counterfeit (SSFFC) medical products by the UMC in 2014. This study illustrates the value of data mining of spontaneous adverse event reports and the applicability of disproportionality analysis to identify potential SSMs.
Benagiano, Giuseppe; Carrara, Sabina; Filippi, Valentina
The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two “enantiomers,” with only one form (designated as levonorgestrel) biologically active. When taken orally, it is rapidly absorbed, not subjected to a “first-pass” effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic) and peripheral (cervical mucus and endometrium) levels. Levonorgestrel (LNG), alone or in combination with ethinyl estradiol (EE), is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women’s attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and “usefulness” of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years empirically utilized various continuous administration regimens. The first extended-cycle oral contraceptive regimen introduced in clinical practice is an 84