Ethinylestradiol/Drospirenone

Ethinylestradiol 30microg/drospirenone 3mg (Yasmin, petibelle) [EE/DRSP] is a combined contraceptive pill (CC) for the prevention of pregnancy in women of reproductive age. Drospirenone is a novel progestogen with antimineralocorticoid, progestogenic and antiandrogenic activity. The theoretical (0-0.07) and corrected (0.41-0.71) Pearl indices and pregnancy ratios (0.3-0.84) in young, healthy women aged 18-35 years (or 18-30 years if smokers) given 13-26 cycles of EE/DRSP in large multi-center trials indicate that this CC is highly effective in preventing pregnancy. EE/DRSP is equally as effective as ethinylestradiol 30microg/desogestrel 150microg (EE/DSG; corrected Pearl index 0.28-0.41) in preventing pregnancy. EE/DRSP is generally well tolerated. The frequency and type of adverse event reported in clinical trials are typical of those observed with other CCs, and comparable to those in women receiving EE/DSG. The incidence of intermenstrual bleeding (spotting, breakthrough bleeding or both) during treatment with EE/DRSP in young, healthy women decreased rapidly after the first cycle to 9 to 18% in the second cycle and 6% after 26 cycles, indicating good cycle control. The incidence of intermenstrual bleeding was similar in recipients of EE/DSG (9 and 14% in cycle 2 and 10% in cycle 26). Bodyweight was maintained +/- 2kg in most young women who received EE/DRSP for up to 26 cycles. Neither EE/DRSP nor EE/DSG showed clinically significant effects on blood pressure. EE/DRSP improved premenstrual and menstrual symptoms (negative affect, water retention, increased appetite) compared with baseline in a noncomparative trial. A similar improvement in skin condition (acne, seborrhea) was observed in women receiving EE/DRSP or ethinylestradiol 35microg/cyproterone acetate 2mg in a randomized, double-blind trial. CONCLUSIONS: Data from several 1- to 2-year studies show that EE/DRSP is an effective oral contraceptive, with Pearl index values similar to those of established low-dose CCs. This combination is well tolerated, demonstrating good cycle control and a beneficial effect on skin condition and well-being (including some premenstrual and menstrual symptoms). EE/DRSP has demonstrated similar efficacy and tolerability to EE/DSG, but long-term clinical experience is required to establish the position of EE/DRSP among other available CCs and to clarify any potential tolerability advantages. Nevertheless, because the management of tolerability is complicated by the idiosyncratic nature of the response of women to CCs containing different progestogens, EE/DRSP appears to be a useful treatment option for women desiring oral contraception.     

Oral contraceptives and arterial hypertension

Arterial hypertension (AH) was reported for the 1st time as a side effect 5 years after the introduction of oral contraceptives (OCs) in the early 1960s. Most of the information associated with the risks of OC use was derived from the UK Royal College of General Practitioner's (RCGP) Oral Contraception Study of 1968, the UK Oxford/Family Planning Associates Contraceptive Study of 1968, and the US Walnut Creek/Kaiser Permanente Study of 1968 and 1977. These studies showed that AH and the risk of cardiovascular morbidity and mortality was significantly higher in women over 35 and who smoked because of the increased estradiol metabolism. In the 1960s the estrogen content in OCs was 50-150 mcg and the prostagen content was 10-10 mg. An average of 50 mcg estrogen and 1.5 mg of progestogen has been used since 1969. Low dose preparations in use since 1973 contain 30 mcg of estrogen and an equal dose of progestogen. The RCGP study of 1977 implicated norethisterone acetate (1, 3, and 4 mg used with 50 mcg of ethinyl estradiol EE), a progestogen, in hypertension. In a study of 78 women 15 were using an OC with 30 mcg of EE with 150 or 250 mcg of norgestrel and 63 women used a pill with 50 mcg of EE or mestranol with 1, 3, or 4 mg of norethisterone. The lower EE dose produced higher arterial pressure attributable to norgestrel. In 9 women taking OCs with 30 mcg of EE blood pressure dropped in a 1978 study of 50 women taking such low-dose pills, while the pressure increased in 100 other women taking on OC with 50 mcg of EE. Most relevant studies indicated a dose-response or type-response relationship between the progestogen component and arterial pressure. The estrogen component was also a major factor in OC-induced AH. The data implicate the involvement of the renin-angiotensin-aldosterone system, the direct effects of mineralocorticoids, and the adrenergic nervous system in the etiology of high blood pressure under OC use.     

Effects of a new hormone therapy, drospirenone and 17-beta-estradiol, in postmenopausal women with hypertension

Drospirenone (DRSP), a progestin with antialdosterone activity, has been developed for hormone therapy in combination with 17-beta-estradiol (E2) in postmenopausal women. We evaluated the antihypertensive efficacy and safety of various doses of DRSP and E2 and estradiol alone in postmenopausal women with hypertension using ambulatory and clinic blood pressure (BP) monitoring. This was a randomized, double-blind clinical trial of 3 doses of DRSP combined with estradiol, estradiol alone, and placebo in 750 postmenopausal women with stage 1 to 2 hypertension between 45 to 75 years. Ambulatory and clinic BPs, potassium, aldosterone, and lipid measurements and adverse events were evaluated in postmenopausal women with stages 1 to 2 hypertension during 8 weeks of double-blind therapy. DRSP and E2 induced dose-related reductions in the ambulatory and clinic systolic BP with physiological increases in serum aldosterone. Significant decreases in 24-hour systolic pressure were observed at doses of 2 and 3 mg of DRSP combined with estradiol but not by estradiol alone or 1 mg of DRSP with estradiol. There were no significant changes from baseline in potassium in any treatment group. Small, significant reductions in total and low-density lipoprotein cholesterol occurred on all of the active treatments, and serum triglycerides did not change. Adverse event rates were low and similar across treatment groups. In conclusion, these data show that DRSP combined with E2 significantly reduces BP in postmenopausal women with hypertension and did not induce significant increases in serum potassium. These characteristics may lead to a new benefit for this novel hormone therapy in postmenopausal women with hypertension.     

Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study

The aim of this study was to investigate the effects of the new estro-progestinic containing the antimineralcorticoid progestogen drospirenone (DRSP) in women with polycystic ovary syndrome (PCOS). Fifteen hirsute PCOS patients were treated with 30 microg ethinyl estradiol plus 3 mg DRSP for 12 cycles. Ultrasonographic pelvic exams, evaluation of hirsutism scores, and hormonal and lipid profile assays were performed at baseline and after three, six, and 12 cycles of treatment. An oral glucose tolerance test and euglycemic hyperinsulinemic clamp were also performed, except at the third cycle. The treatment was well tolerated, and all women attained satisfactory cycle control. Hirsutism significantly improved from the sixth cycle onward. Body weight and fat distribution as well as blood pressure remained stable throughout the treatment. Plasma levels of LH, testosterone, SHBG, and, consequently, the free androgen index significantly fell from the third cycle on. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone significantly decreased after six cycles. The treatment did not affect glycoinsulinemic homeostasis. A trend toward an increase was seen for total cholesterol, triglycerides, and high- and low-density lipoproteins (HDL and LDL) plasma concentrations, although all parameters remained within the normal range. No modifications in total cholesterol/HDL and HDL/LDL ratios were induced by the therapy. The ethinyl estradiol/DRSP combination seems to be effective in ameliorating clinical and hormonal features of PCOS.     

Additive effect of drospirenone/17-beta-estradiol in hypertensive postmenopausal women receiving enalapril

BACKGROUND: Aldosterone has been implicated in the pathogenesis of progressive cardiovascular disease. Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone replacement therapy (HRT) as DRSP/17beta-estradiol (DRSP/ E2). We investigated the additive effect of DRSP/E2 versus placebo on 24-h ambulatory blood pressure (BP) in postmenopausal women with hypertension treated with enalapril maleate (ENA). METHODS: This was a double-blind, randomized, two-parallel group trial. Twenty-four nonsmoking postmenopausal women receiving 10 mg of ENA twice a day before study were randomized to DRSP/E2 + ENA (n = 12) or placebo (P) + ENA (n = 12) for 14 days. Twenty-four-hour ambulatory BP, plasma renin activity, and serum aldosterone were determined at baseline and on day 14. RESULTS: Compared to placebo, 24-h mean [SD] BP in the DRSP/E2 + ENA group decreased significantly from baseline (139/80 mm Hg), systolic (-9 [51 mm Hg, P = .014) and diastolic (-5 [4] mm Hg, P = .007). Essentially no change from baseline (139/83 mm Hg) in systolic or diastolic 24-h ambulatory BP were observed in the P + ENA group. Aldosterone (mean [SD]) increased from baseline by 2.6 [4.5] ng/dL in the DRSP/E2 + ENA group, and decreased by 0.3 [5.5] ng/dL in the P + ENA group (P = .08) consistent with an antimineralocorticoid effect. CONCLUSIONS: Our results suggest a significant additive BP-lowering effect of DRSP/E2 on both systolic and diastolic BP in hypertensive postmenopausal women receiving ENA, consistent with an antimineralocorticoid effect. DRSP/E2, a HRT with antimineralocorticoid effects, could offer a novel potential mechanism for reducing cardiovascular end points in postmenopausal women.     

Effects of drospirenone/17-beta estradiol on blood pressure and potassium balance in hypertensive postmenopausal women

BACKGROUND: Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone therapy as DRSP /17-beta estradiol (DRSP/E2). Because of a significant aldosterone antagonist activity, we studied the effects of DRSP/E2 on serum potassium (K) and blood pressure (BP) in hypertensive postmenopausal women with and without diabetes mellitus. METHODS: This was a multicenter trial in postmenopausal women 44 to 70 years of age, either with type 2 diabetes mellitus (n = 82) or without type 2 diabetes mellitus (n = 148) and using an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist. Patients were randomized to 28 days of DRSP/E2 or placebo. Study endpoints were the number and percentage subjects who developed hyperkalemia (K >or= 5.5 mEq/L) and changes from baseline in clinic systolic and diastolic BP. To increase the likelihood of unmasking hyperkalemia, the nondiabetic group was also administered ibuprofen for 5 days. RESULTS: There were no statistical differences in the overall number and percentage of subjects with hyperkalemia for DRSP/E2 versus placebo. No subject had symptoms or electrocardiographic changes related to hyperkalemia. Blood pressure was reduced by -8.6/-5.8 mm Hg in patients receiving DRSP/E2 versus -3.7/-2.9 mm Hg in those receiving placebo (P < .01 for both SBP and DBP). CONCLUSIONS: In hypertensive postmenopausal women, treatment with DRSP/E2 was not associated with a greater incidence of hyperkalemia than with placebo in patients with and without type 2 diabetes mellitus and concomitant use of ACE inhibitors, angiotensin receptor antagonists, or ibuprofen. Furthermore, DRSP/E2 was found to have a significant antihypertensive effect in this high-risk population.     

Effects of 17beta-oestradiol plus different doses of drospirenone on adipose tissue, adiponectin and atherogenic metabolites in postmenopausal women

OBJECTIVE: To investigate how variation in the dose of the progestogen influence the impact of 17beta-oestradiol plus drospirenone (DRSP) treatment on adipose tissue and its secretor function with direct implications for atherogenic metabolites. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Primary care, single study site. SUBJECTS: A total of 240 healthy postmenopausal women 53-65 years old, 178 completer. INTERVENTION: Daily treatment with 1 mg 17beta-oestradiol plus 1, 2, or 3 mg DRSP, or placebo for 2 years. MAIN OUTCOME MEASURES: Absolute changes in central (CFM) and peripheral fat mass (PFM; dual-energy X-ray absorptiometry, DEXA), adipokines [interleukin (IL)-6 and adiponectin], atherogenic metabolites [triglycerides, high-density lipoprotein cholesterol (HDL-C), glucose] and blood pressure. RESULTS: Oestradiol plus 1 mg DRSP evoked significant decreases in CFM and the CFM/PFM ratio from baseline. These benefits virtually decreased with increasing dose of DRSP confounded by dose-dependent increases in CFM and PFM in smokers (P-value for trends <0.001), in whom the increases in bioavailable oestradiol were half of that in nonsmokers (P < 0.001). Treatment with 3 mg DRSP induced decreases in serum adiponectin by month 6 (P < 0.05), which persisted in nonsmokers only and led to significant increases in glucose and triglycerides and decreases in HDL-C (P < 0.05). Adiponectin in smokers normalized by the end of the study parallel with the increases in body fat mass. CONCLUSIONS: Interactions of the sex steroids with adipose tissue and its secretor function are important determinants of the overall impact of hormone therapy on cardiovascular risk. A DRSP dose up to 2 mg does not seem to exert adverse effects when combined with 1 mg 17beta-oestradiol.     

Effects of the hormone therapy,drospirenone and 17-beta estradiol,on early morning blood pressure in postmenopausal women with hypertension

Drospirenone (DRSP), is a unique progestin with antimineralocorticoid activity that has been combined with 17-β estradiol (E2) for the treatment of symptoms of the menopause in women with hypertension. We assessed the effects of DRSP/E2, E2 alone, and placebo on early morning systolic blood pressure (BP) as well as the rate of rise in systolic BP in 748 postmenopausal women with stage 1 and 2 hypertension at baseline and after 8 weeks of double-blind therapy. Patient characteristics (mean age, 56.5 years, 73% to 77% Caucasian; 13% to 17% African-American) and the clinic (152/95 mm Hg) and 24-hour BP (139/83 mm Hg) measurements were similar at baseline. The early morning systolic BP was reduced significantly on DRSP at 3 mg, 2 mg, and 1 mg with E2 compared with placebo, while E2 alone was similar to placebo. The reductions in early morning systolic BP were larger with increasing dose. Changes in the rate of rise in systolic BP between the lowest values during sleep and following a plateau period post-awakening was significant for the 3 mg DRSP group. In conclusion, DRSP/E2 induced significant reductions in early morning systolic BP in post-menopausal women. This attribute could play a potential role in reducing some of the untoward cardiac and cerebrovascular events that have been observed in studies of other progestins/estrogens in postmenopausal women.     

Dose response effect of cyclical medroxyprogesterone on blood pressure in postmenopausal women

OBJECTIVE: This study was designed to compare with placebo the dose-response effect of cyclical doses of the C21 progestogen, medroxyprogesterone acetate (MPA) on blood pressure (BP) when administered to normotensive postmenopausal women receiving a fixed mid-range daily dose of conjugated equine oestrogen (CEE). MATERIALS AND METHODS:Twenty normotensive postmenopausal women (median age 53 years) participated in the study which used a double-blind crossover design. There were four randomised treatment phases, each of 4 weeks duration. The four blinded treatments were MPA 2.5 mg, MPA 5 mg, MPA 10 mg and matching placebo, taken for the last 14 days of each 28 day treatment cycle. CEE 0.625 mg was also administered once daily as open labelled tablets to all subjects throughout the study. Clinic BP was measured weekly with the mean values of weeks 3 and 4 of each phase used for analysis. Ambulatory BP was performed in the final week of each phase. RESULTS: Compared with the placebo phase, end of phase clinic BP was unchanged by any of the progestogen treatments. There was a dose-dependent decrease in ambulatory daytime diastolic and mean arterial BP with the progestogen treatments compared with placebo (P < 0.05).CONCLUSION: In a regimen of postmenopausal hormone replacement therapy with a fixed mid-range daily dose of CEE combined with a cyclical regimen of a C21 progestogen spanning the current clinical dose range, the progestogen has either no effect or a small dose-dependent reduction in clinic and ambulatory BPs over one treatment cycle.     

Maintenance of normal circulating levels of delta 4-androstenedione and dehydroepiandrosterone in simple obesity despite increased metabolic clearance rates: evidence for a servo-control mechanism

To study the effect of obesity on the metabolism of adrenal androgens not bound to testosterone-estradiol-binding globulin, the MCRs of delta 4-androstenedione (A) and dehydroepiandrosterone (DHEA) were determined using constant infusion of unlabeled steroids to steady state in 8 normal weight and 19 obese nonhirsute eumenorrheic women. The blood production rates (PR) were calculated as the product of the MCR and the 24-h integrated serum concentrations (IC). The mean MCR and PR of A and DHEA were significantly higher in the obese women than in the normal weight women. There was, however, no difference in the mean IC of each androgen in the 2 groups. The MCR and PR of A and DHEA were each correlated with the body mass index (BMI; kilograms per m2). The MCR and PR of A and the MCR of DHEA were also correlated with the ratio of waist circumference to hip circumference (WHR). However, the PR of DHEA was not correlated with WHR. There was no correlation between the IC of either androgen and BMI or WHR. However, partial correlation analysis revealed that correction of the BMI for WHR resulted in a significant negative correlation between BMI and IC of A. We conclude that the MCR and PR of A and DHEA were increased in obese nonhirsute eumenorrheic women; there was a strong correlation between BMI and the MCR and PR of A and DHEA; upper segment obesity, as measured by WHR, was correlated with the MCR and PR of A and the MCR of DHEA, but not with the PR of DHEA; and circulating DHEA and A were maintained at normal levels in the obese eumenorrheic women despite an increase in the MCR, which suggests that a servo-mechanism is operative which registers the body size and adjusts the PR according to the MCR.     

Effects of short-term hormone replacement on serum leptin levels in postmenopausal women

OBJECTIVE: Leptin is a hormone which is secreted by adipocytes and appears to influence the reproductive axis. Previous studies have demonstrated higher leptin levels in relation to body fat mass in women compared to men, higher levels in normally cycling compared to postmenopausal women, and a decrease in leptin levels with increased age. The purpose of this study was to determine whether oestrogen replacement with or without progesterone increases serum leptin levels in postmenopausal women, independently of changes in body fat, and to determine if ageing affects leptin levels at baseline or in response to hormone replacement. PATIENTS: Twenty-one healthy postmenopausal women on no hormone replacement were studied at baseline, after 1 month of oestrogen (E2: estraderm 50 microg/day) and after a further month of oestrogen and 7 days of progesterone (P: progesterone 100 mg per vagina bid) designed to achieve physiological hormone levels. Subjects included 11 younger (45-55 years) and 10 older (70-80 years) postmenopausal women. RESULTS: The relationship between leptin and the absolute fat mass (% body fat x weight [kg]) at baseline was not different between the younger and older postmenopausal women. The adequacy of physiological hormone replacement was confirmed in all subjects. Despite the absence of an effect of hormone replacement on weight, body mass index (BMI), % and absolute fat mass (bioimpedance) or waist-hip ratio, there was an increase in serum leptin levels with hormone replacement (15.4 +/- 1.7, 17.6 +/- 1.7, and 18.1 +/- 1.6 microg/l; mean +/- SEM at baseline, with E2, and with E2 + P, respectively; P < 0.001 vs. baseline) for the group as a whole. An increase in leptin with hormonal treatment was seen in both the younger (15.1 +/- 2.1, 18.1 +/- 2.4, and 18.5 +/- 1.9 microg/l; P < 0.01) and the older (15.7 +/- 2.8, 17.0 +/- 2.5, 17.7 +/- 2.8 microg/l; P = 0.06) postmenopausal women. CONCLUSIONS: (1) Short-term physiological oestrogen replacement increases serum leptin levels in postmenopausal women independently of changes in fat mass; and (2) physiological progesterone replacement does not influence leptin levels in postmenopausal women.     

Increased C-reactive protein levels in overweight and obese women taking exogenous hormones: the United Kingdom Women's Heart Study (UKWHS)

Objective  Women's cardiovascular risk factors, including inflammatory markers such as C-reactive protein (CRP) which is emerging as a major association with cardiovascular disease (CVD) risk, can be influenced by the oral contraceptive (OC) pill in premenopausal and hormone replacement (HR) in postmenopausal women and by central adiposity which is associated with a heightened inflammatory state. The interaction between central obesity and different hormone use in both pre and postmenopausal women has not previously been reported in a study spanning the whole age range associated with hormone use.
Design  Observational, cross-sectional study.
Patients  Only healthy women were included in this study.
Measurements  A total of 21,310 women aged 30–64 employed by Marks & Spencer participated. They completed a health questionnaire and were screened for CVD risk factors including blood pressure, weight, height, waist and hip circumference, lipids and lipoproteins, CRP and fibrinogen.
Results  Compared with non-users, women who took the OC or HR had significantly higher CRP levels. This was more marked than effects on other CVD risk factors. It was further compounded by the independent effect of increased waist circumference. The CRP increase was greatest (more than twice that of nonhormone users) in premenopausal women with the highest quartile of waist circumference who took the combined contraceptive pill.
Conclusions  Women who received first the combined OC and then HR may be exposed over much of their life to high CRP levels aggravated by central obesity. The health consequences of this require further investigation.     

The effectiveness of oral cyproterone acetate in combination with ethinylestradiol in acne tarda of the facial type]

BACKGROUND: Cyproterone acetate is a potent antiandrogen with strong progestational activity. In combination with ethinyloestradiol, it has been shown to be of clinical benefit to women displaying signs of androgenization, such as acne, seborrhoea and hirsutism. In addition, this combined oestrogen/progestogen preparation provides effective contraceptive protection. OBJECTIVE: The aim of this open-label, multicentre study was to determine the efficacy and tolerability of a preparation containing cyproterone acetate and ethinyloestradiol in women with various grades of facial acne. PATIENTS: A total of 890 women aged from 15 to 50 years with grade I-IV facial acne according to the classification of Plewig and Kligman, participated in the study. METHODS: Patients received six cycles of a preparation containing 2 mg cyproterone acetate and 0.035 mg ethinyloestradiol (EE/CPA). Changes from baseline counts of individual acne lesions (open and closed comedones, papules, pustules, nodes and cysts) were monitored together with the simultaneous presence of seborrhoea and hirsutic signs. Reductions in the number of all and individual lesions were classified as: 75-100%, "very good"; 50-75%, "good"; 25-50%, "moderate"; < or = 25%, "absence of therapeutic effect". Body weight and blood pressure were recorded throughout the study. Adverse events and reasons for premature withdrawal from treatment were documented. RESULTS: A "good" or "very good" therapeutic response (i.e. reduction in the total lesion count of > 50%) was seen in 82.8% (95% CI 80.1-85.5) of patients after six cycles of EE/CPA. A similar response was achieved in the different grades of acne with a significant decrease in the number of all lesions throughout the study (p < 0.05). A greater than 50% reduction in open and closed comedones, papules, pustules, nodes and cysts was observed in 75.6%, 80.0%, 88.4% and 85.1% of patients, respectively. By the end of the study, 64.3% of women displayed a lower grade of acne and only 4.9% experienced exacerbation of the condition. EE/CPA was well tolerated, with only 3.4% of patients discontinuing treatment because of adverse events. The majority of events were described as mild, and their incidence declined as the study progressed. No clinically significant changes in blood pressure and body weight were recorded. CONCLUSION: EE/CPA is an effective treatment for acne of all grades and all types of lesion. The preparation is well tolerated and would appear to be an appropriate treatment for women with these symptoms of androgenization.     

The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study

The objective of this open, longitudinal, controlled study was to assess the effect of transdermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). Twenty-eight postmenopausal women (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80 microg/24 hr transdermal estradiol (Fematrix 80; Solvay Healthcare Ltd, Southampton, UK) and oral dydrogesterone 10 mg daily for the first 12 days of the calendar month, whereas 5 women with previous hysterectomy had 80 microg/24 hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1c), glucose/insulin ratio, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular risk. There was a significant decrease in HbA1c, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers may improve in postmenopausal women with type 2 diabetes with transdermal estradiol. This effect may have important clinical implications and it deserves further investigation in appropriately designed trials.     

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

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

Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study

BACKGROUND: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease. OBJECTIVE: We aimed to assess the effects of androgen replacement on cardiovascular risk factors. DESIGN: Thirty-seven postmenopausal women aged 42-62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo. METHODS: Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography. RESULTS: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance. CONCLUSION: This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.     

Estrogen improves abnormal norepinephrine-induced vasoconstriction in postmenopausal women.

OBJECTIVE: An exaggerated blood pressure response to mental stress in postmenopausal women has been reported but the underlying mechanism is not clear. In the present study, we examined the role of estrogen in the blood pressure response to mental stress. SUBJECTS AND METHODS: Hemodynamic responses to mental stress and constrictor responses to norepinephrine were compared in 18 premenopausal (mean +/- SD age 33 +/- 5 years), 22 postmenopausal women (62 +/- 7 years) and 13 postmenopausal women with estrogen replacement therapy (58 +/- 8 years). Premarin was infused in 10 postmenopausal women to determine whether estrogen attenuates norepinephrine-induced vasoconstriction. The hemodynamic responses to a standard mental arithmetic test were measured. Norepinephrine (12.5, 25, 50, 100 ng/min) was infused at 0.5 ml/min for 5 min via the dorsal hand vein. Norepinephrine (100 ng/min) combined with premarin (200 microg/min) was infused into the dorsal hand vein of postmenopausal women. Changes in venous diameter were measured by ultrasonography using a 7.5 MHz transducer. RESULTS: All study subjects were healthy, normotensive and had normal lipid profiles. The postmenopausal women showed a significantly greater blood pressure response to the mental arithmetic test than the premenopausal women or those taking estrogen replacement therapy (P < 0.01). Norepinephrine induced significant dose-dependent vasoconstriction in all three groups (P < 0.001). The postmenopausal women showed significantly greater constriction in response to norepinephrine than the premenopausal women and those taking estrogen replacement therapy (P = 0.02). Premarin significantly attenuated the norepinephrine-induced vasoconstriction in the postmenopausal women (P< 0.001). CONCLUSION: Healthy, normotensive postmenopausal women showed an exaggerated blood pressure response to mental stress. An increased vasoconstriction in response to norepinephrine and loss of estrogen-mediated vasodilation may contribute to the increased blood pressure response to stress in postmenopausal women without estrogen replacement therapy.     

Oral contraceptives, sex steroid-induced antibodies and vascular thrombosis: results from 1318 cases.

The role of antiethinyl estradiol antibodies (anti EE Ab) and associated risk factors was evaluated in 1318 cases of venous or arterial thrombosis in oral contraceptives (OC) users, and compared to 61 non-users and 124 healthy current users. Anti EE Ab were absent in non-users and present in 33% of healthy users and 72% of those with thrombosis, either arterial or venous. Age, duration of use, hyperlipidaemia and smoking were factors associated with thrombosis only in women with an arterial disease. While the two predominant factors, anti EE Ab and smoking may be risk factors in their own right, the combination of both was found in 47.7% of women with thrombosis. It is proposed that thrombosis associated with OC use may be explained by an immunological disease in which anti EE Ab and their complexes with the circulating synthetic hormones may be harmful to the vessels, as also suggested by the type of lesions already described in OC users. The determination of anti EE Ab in healthy users may identify a group at risk of thrombosis.     

Spotlight on Estradiol-Intranasal in the Management of Menopause

Estradiol-intranasal is a nasal spray formulation containing an aqueous solution of 17beta-estradiol that has a unique pulse-like pharmacokinetic profile. In a well designed, placebo-controlled trial estradiol-intranasal 200 to 400 microg/day significantly reduced the incidence and severity of climacteric symptoms in women with moderate to severe menopausal symptoms after 4 and 12 weeks' treatment. The efficacy of estradiol-intranasal 300 microg/day was similar to that of oral estradiol 2 mg/day in this and another double-blind placebo-controlled trial. This equivalent efficacy was maintained in a subgroup of women with initially severe symptoms, and in smokers. Reductions in the incidence of atrophic vaginal mucosa and genitourinary symptoms and increases in the karyopyknotic index achieved with estradiol-intranasal 300 microg/day were also similar to those observed with oral estradiol 2 mg/day. Assessments of the effects of estradiol-intranasal on the complications of menopause (increased risk of cardiovascular disease and osteoporosis) are ongoing; however, estradiol-intranasal (sequentially combined with a progestogen) produced significant beneficial effects on some lipid parameters and on markers of bone resorption and formation, and bone mineral density in postmenopausal women. Estradiol-intranasal had no significant effects on serum levels of most of the assessed hemostatic factors, or on angiotensinogen or insulin levels. Estradiol-intranasal 100 to 600 microg/day was generally well tolerated in clinical trials and most adverse events were mild to moderate. The most commonly reported events were nasal symptoms and mastalgia. There was no evidence of endometrial hyperplasia with up to 1 year's treatment with estradiol-intranasal 300 microg/day combined with a progestogen. The incidence of mastalgia and withdrawal or breakthrough bleeding was lower with estradiol-intranasal 300 microg/day than with oral estradiol 2 mg/day (both administered with a progestogen) in one trial. In another trial, the incidence of mastalgia was lower with estradiol-intranasal 300 microg/day than with estradiol transdermal 50microg (both administered with a progestogen). However, the overall incidence of adverse events was similar between the two treatments in this trial. In conclusion, estradiol-intranasal 200 to 400 microg/day (optimal initiating dose 300 microg/day) reduces the incidence and severity of menopausal climacteric symptoms and has a good tolerability profile. Thus, evidence to date suggests that estradiol-intranasal is a useful treatment option for menopausal symptoms.     

Pharmacodynamics and Pharmacokinetics of Oral Contraceptives Co-administered with Alosetron (Lotronex)

The 5-HT3 receptor antagonist alosetron (Lotronex) is indicated for use in women with severe, chronic, diarrhea-predominant irritable bowel syndrome (IBS) who have failed conventional therapy. Oral contraceptives (OCs) and alosetron are potential co-medications in women of childbearing age. This study assessed the effect of alosetron co-administration on pharmacodynamic markers of contraceptive efficacy, on the pharmacokinetics of estrogen and progesterone OC components, and on the activity of biochemical markers for the risk of thrombosis. This was an open label, nonrandomized two-way crossover study in 18 healthy women stabilized for 3 months on a low-dose OC containing ethinyl estradiol (EE) and levonorgestrel (LN). Alosetron had no effect on serum concentrations of luteinizing hormone (LH) or follicle-stimulating hormone. Ovarian activity grades (assessing follicle size, progesterone, and 17beta-estradiol concentrations) were similar during OC use with and without alosetron. Steady-state (Day 21) AUC24, Cmax, and tmax of both LN and EE were similar during coadministration of alosetron with an OC. Concentrations and activity of biochemical markers of thrombosis risk were not different in the presence of alosetron. These results indicate that alosetron does not alter the pharmacokinetics or pharmacodynamic markers of efficacy for a low-dose combination OC. The results also suggest that thromboembolic risk is not increased when alosetron is co-administered with an OC.