Component Of Oral Contraceptives Research Articles

Drug-Drug Interaction Potential of Mavacamten with Oral Contraceptives: Results from a Clinical Pharmacokinetic Study and a Physiologically Based Pharmacokinetic Model.

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and, as such, could reduce the exposure of the active components of oral contraceptives, ethinyl estradiol (EE) and norethindrone (NOR), where CYP3A4 is involved in metabolism. This study assessed if repeat doses of mavacamten led to a drug-drug interaction with EE and/or NOR. This was an open-label study in healthy women. In Period 1, participants received 35mcg of EE and 1 mg of NOR. In Period 2, participants received oral loading doses of mavacamten 25 mg on Days 1-2, 15 mg/day on Days 3-17, and 35 mcg of EE and 1 mg of NOR on Day 15. Plasma concentrations of mavacamten, EE, and NOR were obtained before dosing and up to 72 hours after dosing. For EE only, a physiologically based pharmacokinetic model was used to simulate mavacamten-mediated CYP3A4 induction with EE for various CYP2C19 phenotypes. In total, 13 women were enrolled (mean age, 38.9 [standard deviation, 9.65] years). After mavacamten administration, modest increases in area under the concentration-time curves were observed for both EE and NOR. The maximum concentrations and half-lives for EE and NOR were not affected by coadministration with mavacamten. Criteria for bioequivalence were met or nearly met for EE and NOR exposure with geometric mean ratios between 0.8 and 1.25. All adverse events were mild. The physiologically based pharmacokinetic model predicted a less than 15% decrease in EE exposure across CYP2C19 phenotypes. Coadministration of mavacamten at a therapeutically relevant dose with EE and NOR did not decrease the exposure to either EE or NOR to a level that may lead to reduced effectiveness.

17α-ethinylestradiol modulates endothelial function in ovariectomized rat carotid arteries

17α-ethinylestradiol (EE2), a derivative of 17β-estradiol (E2), is a potent estrogenic substance that is used as the estrogenic component of oral contraceptives (OCPs). However, women who take OCPs have an increased risk of cardiovascular events. Since few studies have examined EE2 endothelial effects, we explored the effects of EE2 on endothelial function in ovariectomized and isoflavone-free rats. After ovariectomy, 12-week-old female Sprague-Dawley rats were assigned to EE2, E2 or control groups. After 16 weeks, the EE2 and E2 groups were orally administered EE2 (8.3 μg/day) and E2 (12.6 μg/day) for 4 weeks, respectively. At 18 weeks, endothelial denudation of the left common carotid arteries was performed, and they were harvested at 20 weeks. The rats in the EE2 and E2 groups exhibited significantly decreased body weights and significantly increased uterine weights, respectively, but no differences were observed between the EE2 and E2 groups. The EE2 and E2 groups showed significantly enhanced acetylcholine-induced endothelium-dependent relaxation, with apamin plus charybdotoxin inhibiting only the EE2 group. Endothelial nitric oxide (NO) synthase expression was significantly higher in the EE2 group than in the control, but lower than in the E2 group. The intima-to-media ratio of denuded arteries was significantly lower in the E2 group than in the other groups, suggesting that NO decreased in the EE2 group compared to the E2 group. We conclude that EE2 has a weaker ability than E2 to produce NO and, for the first time, we demonstrate the ability of EE2 to enhance the activity of endothelial-derived hyperpolarizing factor.

Activation of natural killer T cells contributes to Th1 bias in the murine liver after 14 d of ethinylestradiol exposure

BACKGROUNDAs the main component of oral contraceptives (OCs), ethinylestradiol (EE) has been widely applied as a model drug to induce murine intrahepatic cholestasis. The clinical counterpart of EE-induced cholestasis includes women who are taking OCs, sex hormone replacement therapy, and susceptible pregnant women. Taking intrahepatic cholestasis of pregnancy (ICP) as an example, ICP consumes the medical system due to its high-risk fetal burden and the impotency of ursodeoxycholic acid in reducing adverse perinatal outcomes.AIMTo explore the mechanisms and therapeutic strategies of EE-induced cholestasis based on the liver immune microenvironment. METHODSMale C57BL/6J mice or invariant natural killer T (iNKT) cell deficiency (Jα18-/- mice) were administered with EE (10 mg/kg, subcutaneous) for 14 d.RESULTSBoth Th1 and Th2 cytokines produced by NKT cells increased in the liver skewing toward a Th1 bias. The expression of the chemokine/chemokine receptor Cxcr6/Cxcl16, toll-like receptors, Ras/Rad, and PI3K/Bad signaling was upregulated after EE administration. EE also influenced bile acid synthase Cyp7a1, Cyp8b1, and tight junctions ZO-1 and Occludin, which might be associated with EE-induced cholestasis. iNKT cell deficiency (Jα18-/- mice) robustly alleviated cholestatic liver damage and lowered the expression of the abovementioned signaling pathways.CONCLUSIONHepatic NKT cells play a pathogenic role in EE-induced intrahepatic cholestasis. Our research improves the understanding of intrahepatic cholestasis by revealing the hepatic immune microenvironment and also provides a potential clinical treatment by regulating iNKT cells.

Pharmacokinetic and Pharmacodynamic Profiles of Ethinylestradiol/Norgestimate Combination or Norethindrone upon Coadministration with Elagolix 150 mg Once Daily in Healthy Premenopausal Women.

BackgroundTwo pharmacokinetic/pharmacodynamic studies were conducted to evaluate the potential drug–drug interaction between elagolix, an oral gonadotropin-releasing hormone receptor antagonist, and an oral contraceptive (ethinylestradiol [EE] 0.035 mg and norgestimate 0.18/0.215/0.25 mg) or progestin-only contraceptive (norethindrone 0.35 mg) in healthy premenopausal women.MethodsThese phase I studies used a two-period, sequential design, where period 1 included treatment with oral contraceptives, followed by period 2 with contraceptives coadministered with elagolix 150 mg once daily.ResultsIn study 1, pharmacokinetic exposures for EE in period 2 increased by 30% and the norgestimate metabolites decreased by approximately 15% when coadministered with elagolix. Mean hormone exposure appeared lower for follicle-stimulating hormone (FSH; 31%), luteinizing hormone (LH; 38%), and estradiol (E2; 16%). The percentage of women with consecutive progesterone (P) concentrations above 5 nmol/L was similar in both periods. Norethindrone pharmacokinetic exposures were comparable in both periods. The hormone exposure for LH and FSH was similar, and mean E2 exposure was 32% lower in period 2. The percentage of subjects with consecutive ovulatory P concentrations was also similar in both periods (study 2). Safety and tolerability profiles were unremarkable in both studies.ConclusionsCoadministration of elagolix 150 mg once daily with oral contraceptives containing EE and norgestimate, or norethindrone, resulted in small pharmacokinetic changes in the oral contraceptive components. Similar or lower FSH, LH, and E2 exposures were observed during coadministration, with ovulatory P concentrations also comparable in both periods. The pharmacodynamic profiles of the oral contraceptives were maintained when coadministered with elagolix.

Papillary Thyroid Cancer-Promoting Activities of Combined Oral Contraceptive Components

Background: Thyroid cancer is more common in women at reproductive age, suggesting the relationship between its high-incidence and therapeutic use of hormonal medications, such as oral contraceptives (OCPs). The aim of this study was to identify the effect of low-dose combined OCP (LD-COC) on proliferation, apoptosis, and migration of human papillary thyroid cancer (PTC) BCPAP cell line. Materials and Methods: BCPAP cells were cultured and treated with the combination of 90nM levonorgestrel (LNG) and 20nM ethinylestradiol (EE) for 48 hours. Afterward, using 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay, the proliferation of the cells was measured. Apoptosis was determined by using a Caspase-3 ELISA kit. Migratory properties of combined LNG and EE were studied through wound scratch assay. The expression levels of pro-apoptotic factor BAX, anti-apoptotic factor Bcl2, and proliferation marker Ki67 were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting. Results: Upon treatment with the combination of LNG and EE, proliferation and migration of BCPAP cells were significantly enhanced. However, LNG and EE remarkably inhibited apoptosis of these cells. Furthermore, treating PTC cells with combined LNG and EE caused a marked increase in the expression of Bcl2 and Ki67 and a considerable decrease in BAX levels (P˂ 0.05). Conclusion: Our data linked the use of COCs and the progression and aggressiveness of PTC, suggesting the role of these hormonal compounds as promoting factors for PTC tumors. Despite these observations, further investigations will be required to fully establish the pathogenic impact of these medications on PTC. [GMJ.2020;9:e1648]

Papillary Thyroid Cancer-Promoting Activities of Combined Oral Contraceptive Components.

Background: Thyroid cancer is more common in women at reproductive age, suggesting the relationship between its high-incidence and therapeutic use of hormonal medications, such as oral contraceptives (OCPs). The aim of this study was to identify the effect of low-dose combined OCP (LD-COC) on proliferation, apoptosis, and migration of human papillary thyroid cancer (PTC) BCPAP cell line. Materials and Methods: BCPAP cells were cultured and treated with the combination of 90nM levonorgestrel (LNG) and 20nM ethinylestradiol (EE) for 48 hours. Afterward, using 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay, the proliferation of the cells was measured. Apoptosis was determined by using a Caspase-3 ELISA kit. Migratory properties of combined LNG and EE were studied through wound scratch assay. The expression levels of pro-apoptotic factor BAX, anti-apoptotic factor Bcl2, and proliferation marker Ki67 were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting. Results: Upon treatment with the combination of LNG and EE, proliferation and migration of BCPAP cells were significantly enhanced. However, LNG and EE remarkably inhibited apoptosis of these cells. Furthermore, treating PTC cells with combined LNG and EE caused a marked increase in the expression of Bcl2 and Ki67 and a considerable decrease in BAX levels (P˂0.05). Conclusion: Our data linked the use of COCs and the progression and aggressiveness of PTC, suggesting the role of these hormonal compounds as promoting factors for PTC tumors. Despite these observations, further investigations will be required to fully establish the pathogenic impact of these medications on PTC.

DNA Interaction with 17α‐Ethinylestradiol Studied Using Electrochemical Biosensors and Biosensing in Solution

AbstractThe synthetic estrogen 17α‐ethinylestradiol (EE2) is an active component of oral contraceptives. It is considered as an endocrine disrupting compound that, once incorporated into an organism, affects the hormonal balance of animals and humans. In this study we characterized the DNA‐EE2 interaction using an electrochemical biosensor and biosensing in solution phase with the double stranded DNA from salmon sperm and deoxyguanosine monophosphate (dGMP). Differential pulse voltammetry method has been applied based on voltammetric anodic responses of the deoxyguanine (dGuo) and deoxyadenine (dAdo) as well as EE2 in the medium of phosphate buffer solution pH 7.0. Binding of EE2 to the nucleobases leads to a decrease of their anodic signals. Association constant for DNA‐EE2 interaction has been estimated to be about 1.1 ⋅ 103 L mol−1 and 1.4 ⋅ 103 L mol−1 for dGuo and dAdo responses, respectively. The association is reversible as indicated by decrease of the EE2 response in pure buffer solution due to leaching of EE2 from the surface attached DNA. The DNA‐EE2 association has been confirmed also by UV‐vis spectrometric experiments.

Effects of combined oral contraceptives on the sexuality and quality of life of women

Aim. Examine the impact of combined oral contraceptive on sexuality and the quality of women’s life. Materials and methods. The article presents a review of Electronic literature databases MEDLINE, PubMed, EMBASE, Cochrane Library and Elibrary. Results. Since its first introduction in the 1960s, hormonal contraception has been widely used as a highly effective birth control method. However, the hormonal components of oral contraceptives affect the neuroendocrine system of women, exerting various effects on mood, libido, on sexuality and quality of life in general. Based on literature data the effect of contraception on sexuality, the physiological and emotional state of women are various. It is known that the hormonal supplementation of sexual desire is associated with ovarian hormones. At the same time, a high concentration of estrogen and testosterone receptors has been determined in the hypothalamus, which controls sexual function and mood. The mechanisms to implement the effects of androgen and progesterone on sexual desire are ambiguous. It was found a positive relationship between a sexual interest, sexual response, sexual fantasy, frequency of sexual intercourse and a testosterone level. At the same time, it is known that estradiol can increase the ability of women to orgasmic response and sexual satisfaction by acting on specific brain structures. Conclusion. The effect of contraception on women’s sexual life is an important factor when choosing a method of contraception and an integral part in the obstetrician-gynecologist’s practice, which requires further research in this direction.

No additive genetic variance for tolerance to ethynylestradiol exposure in natural populations of brown trout (Salmo trutta).

One of the most common and potent pollutants of freshwater habitats is 17‐alpha‐ethynylestradiol (EE2), a synthetic component of oral contraceptives that is not completely eliminated during sewage treatment and that threatens natural populations of fish. Previous studies found additive genetic variance for the tolerance against EE2 in different salmonid fishes and concluded that rapid evolution to this type of pollution seems possible. However, these previous studies were done with fishes that are lake‐dwelling and hence typically less exposed to EE2 than river‐dwelling species. Here, we test whether there is additive genetic variance for the tolerance against EE2 also in river‐dwelling salmonid populations that have been exposed to various concentrations of EE2 over the last decades. We sampled 287 adult brown trout (Salmo trutta) from seven populations that show much genetic diversity within populations, are genetically differentiated, and that vary in their exposure to sewage‐treated effluent. In order to estimate their potential to evolve tolerance to EE2, we collected their gametes to produce 730 experimental families in blockwise full‐factorial in vitro fertilizations. We then raised 7,302 embryos singly in 2‐ml containers each and either exposed them to 1 ng/L EE2 (an ecologically relevant concentration, i.e., 2 pg per embryo added in a single spike to the water) or sham‐treated them. Exposure to EE2 increased embryo mortality, delayed hatching time, and decreased hatchling length. We found no population differences and no additive genetic variance for tolerance to EE2. We conclude that EE2 has detrimental effects that may adversely affect population even at a very low concentration, but that our study populations lack the potential for rapid genetic adaptation to this type of pollution. One possible explanation for the latter is that continuous selection over the last decades has depleted genetic variance for tolerance to this synthetic stressor.

17α-Ethinylestradiol and 17β-estradiol removal from a secondary urban wastewater using an RBC treatment system.

The presence of micropollutants that include endocrine-disrupting compounds (EDC) in aquatic environments is currently one of the most relevant aspects of water quality due to their adverse effects on aquatic organisms and human health. From the several categories of EDC, 17β-estradiol (E2) is a natural hormone, which is prevalent in vertebrates, associated with the female reproductive system and maintenance of the sexual characters. 17α-Ethinylestradiol (EE2) is a synthetic hormone produced from the natural hormone E2 and is an essential component of oral contraceptives. These compounds are susceptible to bioconcentration and have high potential to bioaccumulation. Wastewater treatment plants are the main point source of E2 and EE2 into aquatic environments, but conventional wastewater treatment systems are not specifically designed for steroid removal. To overcome this problem, biological tertiary treatment may be a solution for the removal of emergent pollutants such as E2 and EE2. The main purpose of the present study is to provide a solution based on the optimization of a rotating biological contactor system to remove estrogens, specifically E2 and EE2, and to quantify their removal efficiency on different matrices, namely real wastewater and different synthetic wastewaters. All assays presented viable removal efficiencies for compound E2 with values always above 50%; real wastewater yielded the highest removal efficiencies. EE2 removal had better removal efficiencies with synthetic wastewater as feed solution, with removals above 15%, whereas the removal efficiency with real wastewater was inexistent.

Do oral contraceptives increase epileptic seizures?

ABSTRACTIntroduction: Hormonal contraceptives are used by over 100 million people worldwide. Recently, there has been an emerging interest in studying the potential impact of oral contraceptives (OCs) on certain neurological conditions. It has been suspected for some time that hormonal birth control increases seizure activity in women with epilepsy, but there is little supportive data.Areas covered: Literature from PubMed and online sources was analyzed with respect to hormonal contraception and epilepsy or seizures. New evidence indicates that OCs can cause an increase in seizures in women with epilepsy. The epilepsy birth control registry, which surveyed women with epilepsy, found that those using hormonal contraceptives self-reported 4.5 times more seizures than those that did not use such contraceptives. A preclinical study confirmed these outcomes wherein epileptic animals given ethinyl estradiol, the primary component of OCs, had more frequent seizures that are more likely to be resistant.Expert commentary: OC pills may increase seizures in women with epilepsy and such refractory seizures are more likely to cause neuronal damage in the brain. Thus, women of child bearing age with epilepsy should consider using non-hormonal forms of birth control to avoid risks from OC pills. Additional research into the mechanisms and prospective clinical investigation are needed.

Transgender women, hormonal therapy and HIV treatment: a comprehensive review of the literature and recommendations for best practices

IntroductionStudies have shown that transgender women (TGW) are disproportionately affected by HIV, with an estimated HIV prevalence of 19.1% among TGW worldwide. After receiving a diagnosis, HIV-positive TGW have challenges accessing effective HIV treatment, as demonstrated by lower rates of virologic suppression and higher HIV-related mortality. These adverse HIV outcomes have been attributed to the multiple sociocultural and structural barriers that negatively affect their engagement within the HIV care continuum. Guidelines for feminizing hormonal therapy among TGW recommend combinations of oestrogens and androgen blockers. Pharmacokinetic studies have shown that certain antiretroviral therapy (ART) agents, such as protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and cobicistat, interact with ethinyl estradiol, the key oestrogen component of oral contraceptives (OCPs). The goal of this article is to provide an overview of hormonal regimens used by TGW, to summarize the known drug-drug interactions (DDIs) between feminizing hormonal regimens and ART, and to provide clinical care recommendations.MethodsThe authors identified English language articles examining DDIs between oestrogen therapy, androgen blockers and ART published between 1995 and 2015 using PubMed, Cumulative Index to Nursing and Allied Health Literature and EBSCOhost.Results and DiscussionPublished articles predominantly addressed interactions between ethinyl estradiol and NNRTIs and PIs. No studies examined interactions between ART and the types and doses of oestrogens found in feminizing regimens. DDIs that may have the potential to result in loss of virologic suppression included ethinyl estradiol and amprenavir, unboosted fosamprenavir and stavudine. No clinically significant DDIs were noted with other anti-retroviral agents or androgen blockersConclusionsThere are insufficient data to address DDIs between ART and feminizing hormone regimens used by TGW. There is an urgent need for further research in this area, specifically pharmacokinetic studies to study the direction and degree of interactions between oral, injectable and transdermal estradiol and ART. Clinicians need to be vigilant about possible interactions and monitor hormone levels if concerns arise. More research is also needed on the provision of hormone therapy and gender-affirming care on the long-term health outcomes of HIV-positive TGW.

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

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

Metabolic Profiles in Phase 2 Study of Two 21/7 Oral Contraceptive Regimens (±7 Hormone-Free Days)

INTRODUCTION: Metabolic changes observed in women taking combined oral contraceptives may vary depending on the dose and regimen of the combined oral contraceptive components. METHODS: We compared metabolic profiles (secondary endpoints) in women enrolled in a multinational randomized parallel-group open-label study comparing a 21-day combined oral contraceptive regimen containing 150 micrograms desogestrel and 20 micrograms ethinyl estradiol followed by 7 days of 10 micrograms of ethinyl estradiol (Lecette; Treatment 1) compared with a traditional combined oral contraceptive with 7 no treatment (hormone-free) days (Treatment 2). Healthy women aged 18-40 years with regular menstrual cycles and no contraindications to estrogens progestins or both received one of the two combined oral contraceptive regimens for six consecutive 28-day cycles. Serum total cortisol cortisol-binding globulin thyroid-stimulating hormone and sex hormone-binding globulin were measured at baseline and weeks 11 and 23. RESULTS: Of 293 women randomized 246 comprised the per-protocol population (Treatment 1: n=125; Treatment 2: n=121). Mean baseline metabolic parameters were similar for both groups. Increases in mean total cortisol cortisol-binding globulin and sex hormone-binding globulin evident by week 11 were similar with both combined oral contraceptives through week 23. Overall least square mean changes+/-standard errors for Treatments 1 and 2 were 239.0+/-15.7 and 230.8+/-16.0 nmol/L respectively for total cortisol (P=.71) and 40.8+/-1.6 and 37.2+/-1.6 mg/L for cortisol-binding globulin (P=.11); overall sex hormone-binding globulin rose by 163.4+/-7.3 and 149.1+/-7.5 nmol/L (P=.17). Neither group had clinically relevant changes in thyroid-stimulating hormone. CONCLUSIONS: Observed total cortisol cortisol-binding globulin and sex hormone-binding globulin increases in women taking a 21/7 combined oral contraceptive regimen followed by either 7 days of 10 micrograms ethinyl estradiol or 7 hormone-free days were similar.

Review: Combined oral contraceptives are associated with venous thrombosis

Source Citation Stegeman BH, de Bastos M, Rosendaal FR, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347:f5298. 24030561

The Effect of Hormonal Oral Contraception on Acquisition of Peak Bone Mineral Density of Adolescents and Young Women

Maximizing bone mass in youth is touted as the best strategy to offset the natural losses of aging and the menopausal transition. Not achieving maximum peak bone mineral density (BMD) is an independent risk factor for osteoporosis and thus a public health concern. Adolescence is a critical time of bone mineralization mediated by endogenous estradiol. Research has shown that the highest velocity of bone mass accrual occurs 1 year before menarche and after the first 3 years. Low-peak attainment of BMD in young women is associated with contributing factors such as diets low in calcium, eating disorders, lack of exercise, smoking, and low estrogen states. Oral contraceptives (OCs) suppress endogenous estradiol production by suppressing the hypothalamic–pituitary–ovarian axis. Thus, OCs, by replacing endogenous estradiol with ethinyl estradiol (EE), establish and maintain new hormone levels. The early initiation and the use of very low dose of EE raises the possibility that bone mass accrual at a critical time of bone mineralization in young women or adolescents may be jeopardized. This review examines the studies of BMD in adolescents and young women that use combination hormonal contraception. Some studies had inherent limitations, such as small trial, poor control of confounders, failure to exclude women with prior use of hormonal contraceptives, or prior pregnancy from control groups. The vast majority of reviewed studies showed OCs containing 20 to 30 µg of EE interfere with acquisition of peak BMD. Limited numbers of studies examine the effects of OCs containing 35 µg on adolescents and young adults. Additionally, studies are needed evaluating the progestin component of OCs as their differing androgenic properties may affect bone mineralization as well.

Proliferative Effects of Estradiol- or Ethinylestradiol-Progestogen Combinations on Human Breast Cancer Cells in an Intermitted and a Long-term Regimen

Currently the use of natural estradiol as estrogenic component in oral contraceptives is more and more extended. It is unknown whether the application of this estrogen is associated with a different breast cancer risk as compared to the common use of the synthetic ethinylestradiol. In addition with the intention to reduce menstruation associated symptoms and bleeding periods an extended-cycle regimen is currently considered. In the present in vitro work, we have compared the effect of these different estrogenic compounds and the different treatment regimens on breast cancer risk. Human breast cancer cells (ZR75-1 and HCC1500) were incubated with equimolar concentrations of estradiol or ethinylestradiol combined with various progestogens, dienogest, drospirenone, keto-desogestrel, levonorgestrel, and nomegestrel. Usual and extended cycle was mimicked by incubation periods of 3 days with 1 day hormones off and 4 days, respectively. Molecular markers for proliferation and apoptosis were investigated by Western blot. In both cell lines estradiol and ethinylestradiol elicited a significant increase in the proliferation rate without difference between the 2 estrogens. The effect in the long-term cycle tended to be more pronounced than in the intermitted cycle. Progestogen addition most significantly reduced the estrogen-induced proliferation rate. The molecular markers were influenced by the progestogens mostly in the same manner, reducing the proliferation/apoptosis rate. Our results indicate that both estrogenic based combinations with progestogens may not increase breast cancer risk independent from the regimen, intermitted or long-term cycle. However clinical studies are necessary to prove these in vitro results.

Electrochemical detection of a powerful estrogenic endocrine disruptor: Ethinylestradiol in water samples through bioseparation procedure

The synthetic estrogen ethinylestradiol (EE2) is an active component of oral contraceptives (OCs), considered as an endocrine disrupting compound (EDC). It is excreted from humans and released via sewage treatment plant effluents into aquatic environments. EDCs are any environmental pollutant chemical that, once incorporated into an organism, affects the hormonal balance of various species including humans. Its presence in the environment is becoming of great importance in water quality. This paper describes the development of an accurate, sensitive and selective method for capture, preconcentration and determination of EE2 present in water samples using: magnetic particles (MPs) as bioaffinity support for the capture and preconcentration of EE2 and a glassy carbon electrode modified with multi-walled carbon nanotubes (MWCNTs/GCE) as detection system. The capture procedure was based on the principle of immunoaffinity, the EE2 being extracted from the sample using the anti-EE2 antibodies (anti-EE2 Ab) which were previously immobilized on MPs. Subsequently the analyte desorption was done employing a sulfuric acid solution and the determination of the EE2 in the pre-concentrated solution was carried out by square wave voltammetry (SWV).This method can be used to determine EE2 in the range of 0.035–70ngL−1 with a detection limit (LOD) of 0.01ngL−1 and R.S.D.<4.20%. The proposed method has been successfully applied to the determination of EE2 in water samples and it has promising analytical applications for the direct determination of EE2 at trace levels.

Transporter Studies with the 3-O-Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Liver Drug Transporters

17alpha-Ethinylestradiol (EE2), a component of oral contraceptives, is known to undergo considerable first-pass 3-O-sulfation in the intestine and liver. Once formed, the 3-O-sulfate conjugate (EE2-Sul) is detected in circulation at appreciable levels (versus parent EE2) and is present in bile. Therefore, hepatic uptake of EE2-Sul was assessed with suspensions of cryopreserved human primary hepatocytes. In this instance, there was evidence for active (temperature-dependent) uptake, which was described by a two-K(m) (Michaelis constant) model (K(m1) = 220 nM; K(m2) = 15.5 microM). Uptake was inhibited (approximately 90%) by bromosulfophthalein but not by tetraethylammonium or p-aminohippurate. In agreement, EE2-Sul was shown to be a substrate of recombinant organic anion transporter peptides (OATP1B1 and OATP2B1), and Na(+)/taurocholate-cotransporting polypeptide (NTCP), expressed individually in human embryonic kidney (HEK) 293 cells. Transport by OATP1B1 was described by two K(m) values (87 nM and 141 microM), whereas OATP2B1- and NTCP-mediated uptake into HEK-293 cells conformed to single K(m) kinetics (10.7 and 2.6 microM, respectively). EE2-Sul was also assessed as an efflux transporter substrate using membrane vesicles expressing bile salt export pump, breast cancer resistance protein (BCRP), and individual forms of multidrug resistance-associated protein (MRP1, MRP2, and MRP3). Transport studies were also conducted with a cell line expression P-glycoprotein. Only vesicles that contained BCRP exhibited ATP-dependent uptake of EE2-Sul (K(m1) = 2.9 and K(m2) = 307 microM). Collectively, the data show that hepatic uptake of EE2-Sul can be mediated by three transporters (OATP1B1, OATP2B1, and NTCP), whereas biliary excretion of EE2-Sul into bile likely involves BCRP.

Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives

Contraceptive management in women with epilepsy is critical owing to the potential maternal and fetal risks if contraception or seizure management fails. This article briefly describes the pharmacokinetic interactions between antiepileptic drugs (AEDs) and hormonal contraceptives and the rational strategies that may overcome these risks. Hormonal contraception, including the use of oral contraceptives (OCs), is widely used in many women with epilepsy – there is no strong evidence of seizures worsening with their use. AEDs are the mainstay for seizure control in women with epilepsy. However, there are many factors to consider in the choice of AED therapy and hormonal contraception, since some AEDs can reduce the efficacy of OCs owing to pharmacokinetic interactions. Estrogens and progestogens are metabolized by cytochrome P450 3A4. AEDs, such as phenytoin, phenobarbital, carbamazepine, felbamate, topiramate, oxcarbazepine and primidone, induce cytochrome P450 3A4, leading to enhanced metabolism of either or both the estrogenic and progestogenic component of OCs, thereby reducing their efficacy in preventing pregnancy. OCs can also decrease the concentrations of AEDs such as lamotrigine and, thereby, increase the risk of seizures. Increased awareness of AED interactions may help optimize seizure therapy in women with epilepsy.