Μg Ethinyl Estradiol Research Articles

Hormonal Contraceptives and Migraine With Aura-Is There Still a Risk?

Unnecessary confusion still surrounds the use of combined hormonal contraceptives (CHCs) in the setting of migraine with aura (MwA). Clearing this confusion is a key issue for headache specialists, since most women with migraine have menstrual-related migraine (MRM), and some CHCs can prevent this particularly severe migraine. Their use, however, is still restricted by current guidelines due to concerns of increased stroke risk - concerns that originated over half a century ago in the era of high dose contraceptives. Yet studies consistently show that stroke risk is not increased with today's very low dose CHCs containing 20-25 µg ethinyl estradiol (EE), and continuous ultra low-dose formulations (10-15 µg EE) may even reduce aura frequency, thereby potentially decreasing stroke risk. This article clarifies the stroke risk of CHCs and examines their impact on migraine. It also examines how stroke risk is altered by the estrogen content of the CHC, by contributing factors such as smoking, age and hypertension, and by aura frequency. And finally, it puts these risks into a meaningful context with a risk/benefit assessment.

Discontinuation of modern hormonal contraceptives: an Italian survey

Objectives: The aim of the study was to examine, in a sample of Italian women, the rate of discontinuation of use of hormonal contraception.Methods: In a retrospective cross-sectional study, data were collected from a chart review of 1809 women using or stopping the hormonal contraceptive prescribed by their physician. The name of the contraceptive and the reason for discontinuation were taken from the charts. The differences between the methods regarding reasons for discontinuation were analysed.Results: Of the 1809 women examined, 34.9% had discontinued their hormonal contraception: 6.9% did so for non-method-related reasons, 20.5% due to minor side effects, 4.4% due to major side effects and 3.8% due to difficulties with compliance. Irregular bleeding, weight gain and headache were the main reasons reported for discontinuation. Pills containing 30 μg or 20 μg ethinylestradiol (EE) and the vaginal ring were the most used contraceptive methods. Women using the vaginal ring discontinued less frequently compared with pill users (p < .005). Pills containing 20 μg and 30 μg EE had the same discontinuation rate. Venous thrombosis was the most frequently reported major side effect leading to discontinuation.Conclusion: About one-third of women who used modern hormonal contraceptives discontinued the method. Although the percentage of women who gave up as a result of minor side effects was lower than it used to be, and the use of low doses of EE by the vaginal route has decreased the rate of discontinuation, physicians should counsel women about the possibility of side effects and encourage them to seek advice before stopping.

Effects of an extended flexible regimen of an oral contraceptive pill containing 20 μg ethinylestradiol and 3 mg drospirenone on menstrual-related symptoms: a randomised controlled trial

Objectives: The aim of the study was to assess the efficacy for menstrual-related symptoms of an extended flexible regimen of an oral contraceptive pill containing 20 μg ethinylestradiol and 3 mg drospirenone in comparison with a 24/4 d cyclical regimen of the same formulation.Methods: This randomised, non-inferiority, open-label, multicentre study was conducted in women aged 18–39 years. Their menstrual-related symptoms were assessed using the Penn Daily Symptom Rating (DSR17). Participants were randomised to use an extended flexible regimen of 20 μg ethinylestradiol and 3 mg drospirenone (EE/DRSPe.flex), comprising 168 consecutive days with a 4-d hormone-free interval (HFI, allowing for management of unexpected bleeding) or a conventional 24/4 cyclical regimen of the same pill (EE/DRSP24/4). The primary measure of efficacy was the percentage change in DSR17 total score from baseline to cycle 6. The secondary measures of efficacy were the percentage changes in DSR17 total score from baseline after each 28-d interval throughout the entire study and in the scores for individual DSR17 symptoms.Results: The primary analysis demonstrated that EE/DRSPe.flex was not inferior to EE/DRSP24/4 (Mean DSR17 score 9.1; 95% confidence interval (CI) − 2.5, 20.6; p = 0.123). Analysis at intervals throughout the entire evaluation period showed greater reduction in DSR17 total score for EE/DRSPe.flex than for the 24/4 regimen (p < 0.001). The decreases in individual scores for the symptoms ‘poor coordination’ and ‘depression/feeling sad/down or blue’ were greater for the extended flexible regimen than for the cyclical regimen (p < 0.05).Conclusion: The extended flexible regimen was not inferior to the 24/4 cyclical regimen in terms of the primary endpoint. It significantly improved symptoms in the interval analysis, and the effects on specific DSR17 symptoms, compared with the cyclical regimen.

PS 01-02] Combined oral contraceptive and nitric oxide synthesis inhibition synergistically causes cardiac hypertrophy and fibrosis in hypertensive insulin-resistant female rats

Objective: Combined oral contraceptive (COC) use or inhibition of nitric oxide (NO) synthesis has been shown to cause hypertension and insulin resistance. However, the concomitant effect of COC and NO deficiency on the heart is not well known. We therefore hypothesize that NO deficiency during COC treatment would lead to cardiac hypertrophy and fibrosis. Design and method: Eight-week-old female Wistar rats were randomly allotted into control, NO deficient (NG-nitro-L-arginine methyl ester: L-NAME; 20.0 mg/kg b.w.), COC-treated (1.0 μg ethinylestradiol + 5.0 μg levonorgestrel, p.o) and L-NAME+COC-treated groups. The animals were treated daily for 8 weeks. Blood pressure was estimated by tail-cuff plethysmography while insulin resistance (IR) was estimated by homeostatic model of assessment (HOMA-IR). Profibrotic (plasminogen activator inhibitor-1; PAI-1) and proinflammatory (C-reactive protein; CRP and uric acid) markers were estimated in the plasma. Cardiac histological examination was also done. Results: Results show that COC or L-NAME treatments led to increased blood pressure, HOMA-IR, PAI-1, CRP and uric acid, without significant effect on heart weight. L-NAME+COC-treated group had significantly higher blood pressure, HOMA-IR, PAI-1, CRP and heart weight than COC- or L-NAME-treated groups. Histological examination validated that NO deficiency during COC use causes cardiac hypertrophy and fibrosis. Conclusions: The present study demonstrates that COC treatment and NO deficiency synergistically causes cardiac hypertrophy which is associated with increased fibrosis and inflammation.

PS 10-02 ESTROGEN-PROGESTIN ORAL CONTRACEPTIVE CAUSES DYSLIPIDEMIA, β-CELL DYSFUNCTION AND ELEVATED PROFIBROTIC MARKERS THROUGH MINERALOCORTICOID RECEPTOR ACTIVATION

Objective: Mineralocorticoid receptor (MR) activation is involved in the pathogenesis of main components of metabolic syndrome. Combined estrogen – progestin oral contraceptives (COC), used by tens of millions of women in the world, have been associated with increased cardiometabolic risk factors. Although possible underlying mechanisms by which COC induces these risk factors have not been well elucidated. We therefore hypothesized that abnormal lipid profile and pancreatic β-cell function caused by treatment with COC steroids containing levonorgestrel and ethinylestradiol is through MR activation. Design and Method: Female Wistar rats were randomly allotted into four groups, receiving (p.o.) vehicle, COC (5.0 μg levonorgestrel and 1.0 μg ethinylestradiol) with or without MR antagonist, spironolactone (0.5 mg/kg) daily for 8 weeks. Insulin resistance (IR) and pancreatic β-cell function were estimated using the homeostatic model assessment (HOMA) of insulin resistance (HOMA-IR) and β-cell (HOMA-β) respectively. Dyslipidemia was evaluated by atherogenic lipids; triglyceride (TG)/HDL-cholesterol and total cholesterol (TC)/HDL-cholesterol ratios. Circulating profibrotic markers, plasminogen activator inhibitor – 1 (PAI-1) and glycogen synthase kinase-3 (GSK-3) were estimated by ELISA. Results: Results showed that COC treatment led to increase in HOMA-IR, HOMA-β, TC/HDL-cholesterol, TG/HDL-cholesterol, PAI-1 and GSK-3. On the other hand COC treatment caused impaired glucose tolerance. However the MR antagonist ameliorated these effects except HOMA-IR and impaired glucose tolerance. Conclusions: The result from the present study showed that COC treatment leads to abnormal atherogenic lipid and pancreatic β-cell function, which are associated with elevated circulating PAI-1 and GSK-3. The result also implies that activation of MR is probably involved in COC – induced cardiometabolic effects and reduction of PAI-1 and GSK-3 may be useful therapeutic approach for the treatment of COC – induced cardiometabolic disorders.

The effect of a drospirenone-containing combined oral contraceptive on female sexual function: a prospective randomised study

Objectives: The study investigated the effects on female sexual function of a progestogen-containing combined oral contraceptives (COCs) with an antiandrogenic profile taken in a continuous regimen.Methods: In this prospective randomised single-institution study, 80 healthy women with a monogamous partner and an active sexual life were randomised into two groups for a period of 3 months. Women in the exposed group (n = 40) took a COCs containing 30 μg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) in a 21/7 regimen. Women in the control group (n = 40) used either a barrier contraceptive method (BCM) or a natural family planning method (NFPM). Participants were asked to complete a set of validated questionnaires to assess sociodemographic variables and measure Female Sexual Function Index (FSFI).Results: The total FSFI score (p < 0.0001), as well as the desire (p = 0.04) and arousal (p = 0.03) scores, were significantly lower in the COCs group after 3 months of hormonal contraceptive use compared with baseline. Women using BCM or NFPM showed an improvement in total FSFI score (p = 0.02). Hormonal contraception with DRSP increased the likelihood of worse sexual function in the desire (odds ratio [OR] 2.47; 95% confidence interval [CI] 1.22, 4.98; p = 0.01) and arousal domains (OR 2.85; 95%CI 1.34, 5.93; p = 0.005) and in total FSFI score (OR 2.01; 95%CI 1.45, 2.79; p < 0.001). The results remained statistically significant even after adjustment for smoking status.Conclusions: The study found evidence that women taking a combined EE/DRSP COCs for 3 months may have a worsening of sexual function as measured by FSFI.

Combined Oral Contraceptives and Sexual Function in Women-a Double-Blind, Randomized, Placebo-Controlled Trial.

There is a lack of knowledge about how oral contraceptives may affect sexual function. To determine whether there is a causal effect of oral contraceptives on sexuality. We hypothesized that a widely used pill impairs sexuality. A double-blind, randomized, placebo-controlled trial. Enrollment began in February 2012 and was completed in August 2015. Karolinska University Hospital, Stockholm, Sweden. A total of 340 healthy women, aged 18-35 years, were randomized to treatment, and 332 completed the study. A combined oral contraceptive (150 μg levonorgestrel and 30 μg ethinylestradiol) or placebo for 3 months of treatment. The primary outcome was the aggregate score on the Profile of Female Sexual Function (PFSF). Secondary outcomes were the seven domains of the PFSF, the Sexual Activity Log, and the Personal Distress Scale. Overall sexual function was similar in women in the oral contraceptive and placebo groups. The PFSF domains desire (-4.4; 95% confidence interval [CI], -8.49 to -0.38; P = .032), arousal (-5.1; 95% CI, -9.63 to -0.48; P = .030), and pleasure (-5.1; 95% CI, -9.97 to -0.32; P = .036) were significantly reduced in comparison to placebo, whereas orgasm, concern, responsiveness, and self-image were similar between groups. The mean frequency of satisfying sexual episodes and personal distress were also similar between groups. This study shows no negative impact of a levonorgestrel-containing oral contraceptive on overall sexual function, although three of seven sexual function domains were adversely affected.

Combined oral contraceptive-induced hypertension is accompanied by endothelial dysfunction and upregulated intrarenal angiotensin II type 1 receptor gene expression.

Combined oral contraceptive (COC) use is associated with increased risk of developing hypertension. Activation of the intrarenal renin-angiotensin system (RAS) and endothelial dysfunction play an important role in the development of hypertension. We tested the hypothesis that COC causes hypertension that is associated with endothelial dysfunction and upregulation of intrarenal angiotensin-converting enzyme 1 (Ace1) and angiotensin II type 1 receptor (At1r). Female Sprague-Dawley rats aged 12weeks received (p.o.) olive oil (control) and a combination of 0.1μg ethinylestradiol and 1.0μg norgestrel (low COC) or 1.0μg ethinylestradiol and 10.0μg norgestrel (high COC) daily for 6weeks. Blood pressure was recorded by tail cuff plethysmography. Expression of genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. COC treatment led to increased blood pressure, circulating uric acid, C-reactive protein and plasminogen activator inhibitor-1, renal uric acid, and expression of renal Ace1 and At1r. COC treatment resulted in increased contractile responses to phenylephrine in endothelium-denuded aortic rings. Endothelium-dependent relaxation responses to acetylcholine, but not endothelium-independent relaxation responses to nitric oxide (NO) donation by sodium nitroprusside, were attenuated in COC-exposed rings. Impaired relaxation responses to acetylcholine were masked by the presence of NO synthase inhibitor (L-NAME) in the COC-exposed rings, whereas the responses to acetylcholine in the presence of selective cyclooxygenase-2 inhibitor (NS-398) were enhanced. These findings indicate that COC induces hypertension that is accompanied by endothelial dysfunction, upregulated intrarenal Ace1 and At1r expression, and elevated proinflammatory biomarkers.

Oral contraceptives versus physical exercise on cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: a randomized controlled trial.

Although oral contraceptives (OCs) are one the most widespread therapy in young polycystic ovary syndrome (PCOS) women and physical exercise represents a crucial first step in the treatment of overweight and obese PCOS, no studies were performed to compare the effects on cardiovascular risk (CVR) of OCs and physical exercise in PCOS. To compare the effects of OCs administration and physical exercise on the CVR, clinical, hormonal and metabolic parameters in PCOS women. One hundred and fifty PCOS women were enrolled and were randomized to OCs (3 mg drospirenone plus 30 μg ethinyloestradiol), structured exercise training programme (SETP) or polyvitamin tablets. The intervention phase study was of 6 months. Primary outcome was intima-media thickness (IMT) and flow-mediated dilation (FMD). Secondary outcomes were clinical, hormonal and metabolic changes. A significant reduction of IMT and a significant increase of FMD were observed in the SETP group after treatment. Compared to baseline, in the SETP group, a significant improvement in anthropometric measures, insulin sensitivity indexes, lipid profile, cardiopulmonary function, inflammatory markers and frequency of menses was observed. Oral contraceptives use was associated with a significant decrease of hyperandrogenism and a significant improvement of frequency of menses. Further, OCs use had a neutral effect on CVR risk factors. OCs effectively treat hyperandrogenism and menstrual disturbances, while SETP is more effective in improving cardiometabolic profile and cardiopulmonary function in PCOS.

Efficacy and safety of the contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive in Chinese women: a 1-year randomised trial

Objectives: The aim of the study was to assess the efficacy and tolerability of the monthly vaginal ring (NuvaRing; 15 μg ethinylestradiol [EE] and 120 μg etonogestrel per day) compared with a monophasic (21/7) combined oral contraceptive (COC) containing 30 μg EE and 3 mg drospirenone in healthy Chinese women aged 18–40 years.Methods: This was a phase III, open-label, randomised multicentre trial conducted in China. Participants received NuvaRing or COC for 13 cycles (3 weeks of ring/pill treatment followed by a 1-week ring-free/pill-free period). Contraceptive efficacy was assessed by in-treatment pregnancies and expressed by the Pearl Index (PI; number of pregnancies/100 woman-years of use). Cycle control was assessed by unscheduled (breakthrough) and absence of scheduled (withdrawal) bleeding events. Safety and tolerability were assessed throughout the study.Results: Participants were randomised either to the NuvaRing (n = 732) or to the COC (n = 214); 588 (82.4%) and 182 (78.4%) participants, respectively, completed the study. There were 10 in-treatment pregnancies in the NuvaRing group (PI 1.92; 95% confidence interval [CI] 0.92, 3.53) and five in the COC group (PI 3.12; 95% CI 1.01, 7.29). Breakthrough bleeding/spotting ranged from 18.6% (Cycle 1) to 4.2% (Cycle 11) for NuvaRing and from 21.6% (Cycle 1) to 7.9% (Cycle 11) for COC. Absence of withdrawal bleeding ranged from 8.6% (Cycle 1) to 3.0% (Cycle 11) for NuvaRing and from 14.6% (Cycle 1) to 6.4% (Cycle 5) for COC. For NuvaRing and COC, respectively, 26.6% and 25.0% of participants had treatment-related adverse events, and 7.0% and 9.1% discontinued the study as a result.Conclusions: Once-monthly NuvaRing is efficacious and safe for use in Chinese women.

Effect of Extended 30 μg Ethinyl Estradiol with Continuous Low-Dose Ethinyl Estradiol and Cyclic 20 μg Ethinyl Estradiol Oral Contraception on Adolescent Bone Density: A Randomized Trial

Study ObjectiveTo compare changes in lumbar spine bone mineral density after 12 months of a 91-day extended regimen or 28-day combined oral contraceptive with those in a healthy reference group not using hormonal contraceptives. DesignPhase 2, multicenter, open-label, randomized, controlled study. SettingForty-five academic centers, clinical research centers, and community practices in the United States. ParticipantsEight hundred twenty-nine postmenarcheal adolescent girls aged 12-18 years. InterventionsAdolescents were randomly assigned to 91-day levonorgestrel (LNG)/ethinyl estradiol (EE) extended regimen (84 days of LNG 150 μg/EE 30 μg with 7 days of EE 10 μg [LNG/EE extended regimen]) or 28 days of LNG/EE (21 days of LNG 100 μg/EE 20 μg with 7 days of placebo [LNG/EE 21/7]) for 12 months. A reference group not seeking hormonal contraception was also evaluated. Main Outcome MeasuresThe primary end point was mean percent change in lumbar spine bone mineral density measured using dual-energy x-ray absorptiometry. ResultsOf 1361 adolescents randomized/enrolled, 829 were included in the primary analysis. Mean changes in lumbar spine bone mineral density were +2.26% with LNG/EE extended regimen, +1.45% with LNG/EE 21/7, and +2.50% in the reference group. Noninferiority of the LNG/EE extended regimen compared with the reference group was shown. A statistically significant treatment difference was found between LNG/EE 21/7 and the reference group (1.05%; 95% confidence interval, 0.61%-1.49%) but not between LNG/EE extended regimen and the reference group (0.23%; 95% confidence interval, −0.20% to 0.67%). No new safety signals were noted. ConclusionCompared with the reference group, bone accrual was statistically significantly lower among LNG/EE 21/7 users but not among LNG/EE 30-μg extended regimen users. Additional research is needed to clarify the clinical relevance of these findings.

Activation of cardiac renin–angiotensin system and plasminogen activator inhibitor-1 gene expressions in oral contraceptive-induced cardiometabolic disorder

Context: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Improvement of oral contraceptive-induced glucose dysregulation and dyslipidemia by valproic acid is independent of circulating corticosterone

Context: Cardiometabolic disorders are rapidly becoming major public health challenges. Valproic acid (VPA) is a widely prescribed anticonvulsant drug. Objective: We hypothesized that treatment with VPA would improve the regulation of glucose and atherogenic dyslipidemia through reduction in circulating corticosterone. Methods: Female Wistar rats recieved (p.o.) combined oral contraceptive (COC) containing 1.0 µg ethinylestradiol plus 5.0 µg levonorgestrel and valproic acid (VPA; 20 mg) for 8 weeks. Results: Treatment with COC led to elevated fasting blood glucose, insulin, corticosterone, triglycerides (TG), TG/HDL-cholesterol ratio, insulin resistance (IR) and impaired glucose tolerance. VPA significantly attenuated the alterations induced by COC treatment, but did not affect the corticosterone level. However, VPA treatment led to significant increases in plasma insulin, corticosterone, atherogenic lipids and impaired glucose tolerance in rats not treated with COC. Conclusion: The findings in this study suggest that VPA mitigates against the development of COC-induced insulin resistance and dyslipidemia independent of elevated circulating corticosterone.

Short-Term Treatment of Bothersome Bleeding for Etonogestrel Implant Users Using a 14-Day Oral Contraceptive Pill Regimen

The etonogestrel contraceptive implant is one of the most effective contraceptives available, with a failure rate of 0.05%. Approved for 3 years of use, it has a high 2-year continuation rate (53%–90%). Up to 11.3% of women in clinical trials discontinued use of this implant before 3 years because of bothersome bleeding (prolonged bleeding and frequent episodes). This double-blind randomized, placebo-controlled trial was designed to determine whether 14 days of treatment with a combination of oral contraceptive pills (OCPs) would stop bleeding in users of the implant with bothersome bleeding. The OCP regimen was a low-dose combination of levonorgestrel and ethinyl estradiol. The primary study outcome was the proportion of women in each group who stopped bleeding during treatment and continued to report no bleeding at the end of 14 days of therapy. Prespecified secondary outcomes included number of days until temporary cessation of bleeding, number of days without bleeding during therapy, and number of days to recurrence of bleeding after therapy was discontinued. The investigators hypothesized that the intervention would result in temporary interruption of bleeding in 80% of the treatment group compared with 20% in the control group; using 80% power, a sample size of 26 women (13 in each group) was required. The study was performed according to the intention-to-treat principle. Most subjects (78%) were young white women. Baseline characteristics of groups were similar. Mean age was 21 to 22 years (range, 18–44 years). A total of 66 women were screened between November 2013 and December 2014; 32 of these were randomized to an OCP group or to a placebo group. Users of the etonogestrel implant with bothersome bleeding episodes for at least 7 consecutive days were randomized to receive 14 pills of combined OCPs (150 μg levonorgestrel and 30 μg ethinyl estradiol, n = 16, or an identical-appearing placebo, n = 16). Significantly, more women in the OCP group than in the placebo group were likely to have a temporary interruption of bleeding during the study period (14 of 16 [87.5% ± 16.2%] in the OCP group vs 6 of 16 [37.5% ± 23.7%] in the placebo group); the odds ratio was 11.7, with a 95% confidence interval of 1.9 to 70.2 (P < 0.01). Among women who had a temporary interruption of bleeding during OCP therapy, 85.7% had bleeding recurrence within 10 days after treatment ended. Use of a low-dose combination OCP in etonogestrel implant users who had reported bothersome bleeding before treatment usually stops bleeding within 14 days. However, bleeding resumes in most patients within 10 days of treatment cessation.

Comparison of two contraceptive pills containing drospirenone and 20 μg or 30 μg ethinyl estradiol for polycystic ovary syndrome

To compare the effects of 30 μg and 20 μg ethinyl estradiol (EE) among women with polycystic ovary syndrome (PCOS). In a randomized study, patients with PCOS, a history of six or fewer menstrual cycles in the previous 12 months, and abnormal body hair growth were enrolled at a center in Kolkata, India, between May 1, 2012, and January 31, 2014. Participants were randomly assigned (1:1) using a computer-generated randomization table to receive an oral contraceptive pill containing 3mg drospirenone and either 30 μg EE or 20 μg EE. Patients were followed up after 6 and 12 months. The primary outcome was the absolute change in the free androgen index. Participants were masked to group assignment but investigators were not. Analyses were by intention to treat. Overall, 112 patients were enrolled. At 6 months, the free androgen index had decreased by 4.96±6.01 among patients receiving 30 μg (n=55) and by 4.81±6.03 among those receiving 20 μg (n=57; P=0.89). At 12 months, the decrease from baseline was 5.23±5.79 with 30 μg and 4.99±5.86 with 20 μg (P=0.82). Among patients with PCOS, an oral contraceptive pill containing 20 μg EE has similar effects on androgen levels to those of a pill containing 30 μg. CTRI/2012/04/002571.

Combined oral contraceptive synergistically activates mineralocorticoid receptor through histone code modifications

Clinical studies have shown that the use of combined oral contraceptive in pre-menopausal women is associated with fluid retention. However, the molecular mechanism is still elusive. We hypothesized that combined oral contraceptive (COC) ethinyl estradiol (EE) and norgestrel (N) synergistically activates mineralocorticoid receptor (MR) through histone code modifications. Twelve-week-old female Sprague-Dawley rats were treated with olive oil (control), a combination of 0.1µg EE and 1.0µg N (low COC) or 1.0µg EE and 10.0µg N (high COC) as well as 0.1 or 1.0µg EE and 1.0 or 10.0µg N daily for 6 weeks. Expression of MR target genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. MR was quantified by western blot. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes as well as histone code modifications was analyzed by chromatin immunoprecipitation assay. Treatment with COC increased renal cortical expression of MR target genes such as serum and glucocorticoid-regulated kinase 1 (Sgk-1), glucocorticoid-induced leucine zipper (Gilz), epithelial Na+channel (Enac) and Na+–K+–ATPase subunit α1 (Atp1a1). Although COC increased neither serum aldosterone nor MR expression in kidney cortex, it increased recruitment of MR and Pol II in parallel with increased H3Ac and H3K4me3 on the promoter regions of MR target genes. However, treatment with EE or N alone did not affect renal cortical expression of Sgk-1, Gilz, Enac or Atp1a1. These results indicate that COC synergistically activates MR through histone code modifications.

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

Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary–ovarian axis and ovulation in healthy premenopausal women.Methods This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary–ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication.Results A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe.Conclusions Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.Chinese 摘要目的 这项研究的目的是评估不同剂量的雌四醇联合两种孕激素中的其中一种对垂体-卵巢轴以及健康的绝经前妇女的排卵方面的抑制疗效。方法 这是一个在18到35岁的健康女性中进行的开放的、平行的，关于II期药物剂量探索的初步研究，这些女性均有治疗前的排卵周期记录。连续三个周期的24/4-天方案,参与者接受5毫克或10毫克的雌四醇/3毫克屈螺酮;5毫克,10毫克或20毫克的雌四醇/150 μg左炔诺孕酮;或用20 μg炔雌醇/3毫克屈螺酮作比较。在第1和第3个治疗周期，通过监测卵泡的大小,血清促卵泡激素、黄体生成素、雌二醇和孕激素的水平对垂体-卵巢轴的活动和排卵进行评估。对子宫内膜厚度的评估贯穿于整个试验过程中，对排卵抑制的评估在用完药物之后。结果 总共有109名妇女参与试验。任何一个治疗组都没有出现排卵。对卵巢活动的抑制似乎与雌四醇的剂量成正比：最严重的抑制出现在20毫克的雌四醇组，与在炔雌醇/屈螺酮组观察到的情况非常相似。所有组的子宫内膜厚度的抑制程度是相同的。在最后一次积极治疗后的第17到21天之间，所有参与者均出现了治疗后的排卵。所有的试验组合均有良好的耐受性和安全性。结论 雌四醇联合一种雌激素能够充分的抑制卵巢活动，尤其是当雌四醇的剂量大于10毫克/天的时候。关键词雌四醇；雌激素；口服避孕药；排卵抑制；孕激素

Effect of mavoglurant (AFQ056) on the Pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and Levonorgestrel in healthy Women

Objective: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). Methods: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18–40 years. In Period 1, a single oral dose of an OC containing 30 μg ethinyl estradiol (EE)/150 μg levonorgestrel (LNG) was administered alone. In Period 2, OC was administered with a clinically relevant multiple-dose of 100 mg b.i.d. mavoglurant under-steady conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration and PK parameters Cmax and AUClast were estimated using noncompartmental methods. Results: The geometric mean ratios of EE PK parameters Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval [CI]: 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63 0.73), respectively. Conclusions: In conclusion, the EE PK was unchanged, whereas Cmax and AUClast of LNG was approximately 19% and 32% lower, respectively, when given with mavoglurant. Further investigation regarding the impact on contraceptive efficacy is warranted.

Reduction in the level of antibodies against heat shock proteins 60 during different hormonal protocols in postmenopausal women.

IntroductionIn current literature, the immune-inflammatory theory of atherosclerosis is widely discussed. The role of how heat shock proteins 60 (HSP60) lead to the development of the atheromatous plaque is especially underlined. The aim of the study is to estimate the influence of three hormonal protocols on behavior of antibodies against HSP60. It determines the state of endothelium in postmenopausal women.Material and methodsThe study was carried out on 90 women between 2007 and 2012. All the women were in their menopausal age (51 ± 3 years), from the south region of Poland, with a follicle stimulating hormone (FSH) level above 25 mIU/ml, and with menopausal symptoms disturbing their normal daily activity. The study was done for a period of 6 months. Three groups of 30 randomized patients were formed. In the first group we used transdermal estrogen therapy in a 37.5 µg/24 h dose combined with a 10 mg dose of dydrogesterone. In the second group we applied transdermal estrogen therapy in a 50 µg/24 h dose with 2.5 mg of oral medroxyprogesterone. In both these groups, gestagens were administered continuously. In the third group, we prescribed continuous, oral, low-dose combined estrogen-gestagen therapy with 1 mg of ethinyl estradiol and 0.5 mg of norethisterone acetate. The control group consisted of 30 volunteers who were also from the south region of Poland, in good health, with menopausal symptoms, no menstrual period for the last 12 months, selected considering their age and weight, with an FSH level above 25 mIU/ml and with normal levels of thyroid stimulating hormone (TSH) and prolactin. All patients treated and in the control group were seronegative to Chlamydia pneumonia for the entire duration of the study. In the analysis conducted, nonparametric tests were used (Mann-Whitney U test, Wilcoxon test, Kruskal-Wallis test – ANOVA).ResultsAfter 6 months of hormonal therapy, we found that all schemes of treatment promote a significant reduction in antibodies against HSP60 in all treated groups vs. the control group.ConclusionsAll of the investigated estrogen protocols have a favorable impact on the blood level of HSP60 antibodies in early postmenopausal women who have no cardiovascular risk factors. It triggers a better condition of endothelium.

Estimating systemic exposure to ethinyl estradiol from an oral contraceptive

This study was conducted to compare single-dose pharmacokinetics of ethinyl estradiol in an oral contraceptive with steady-state values and to assess whether any simpler measures could provide an adequate proxy of the "gold standard" 24-hour steady-state area under the curve (AUC) value. Identification of a simple, less expensive measure of systemic ethinyl estradiol exposure would be useful for larger studies that are designed to assess the relationship between an individual's ethinyl estradiol exposure and side-effects. We collected 13 samples over 24 hours for pharmacokinetic analysis on days 1 and 21 of the first cycle of a monophasic oral contraceptive that contained 30 μg ethinyl estradiol and 150 μg levonorgestrel in 17 nonobese healthy white women. We also conducted an abbreviated single-dose 9-sample pharmacokinetic analysis after a month washout. Ethinyl estradiol was measured by liquid chromatography-tandem mass spectrometry. We compared results of a full 13-sample steady-state pharmacokinetic analysis with results that had been calculated with the use of fewer samples (9 or 5) and after the single doses. We calculated Pearson correlation coefficients to evaluate the relationships between these estimates of systemic ethinyl estradiol exposure. The AUC, maximum, and 24-hour values were similar after the 2 single oral contraceptive doses (AUC; r=0.92). The steady-state 13-sample 24-hour AUC value was correlated highly with the average 9-sample AUC value after the 2 single doses (r=0.81; P=.0002). This correlation remained the same if the number of single-dose samples was reduced to 4, taken at time 1, 2.5, 4, and 24 hours. The 24-hour value at steady-state was correlated highly with the 24-hour steady-state AUC value (r=0.92; P<.0001). The average of the 24-hour values after the 2 single doses was also correlated quite highly with the steady-state AUC value (r=0.72; P=.0026). Limited blood sampling, including results from 2 single doses, gave highly correlated estimates of an oral contraceptive user's steady-state ethinyl estradiol exposure.