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.     

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.     

17-beta-estradiol therapy lessens angina in postmenopausal women with syndrome X

Objectives. We sought to investigate the hypothesis that estrogen replacement therapy ameliorates symptoms in postmenopausal women with syndrome X.Background. Syndrome X (angina pectoris, positive findings on exercise electrocardiography and normal results on coronary angiography) frequently occurs in menopausal women. This observation, in conjuction with the known vasoactive properties of estrogens, suggests that estrogen depletion may contribute to the pathogenesis of syndrome X in some women.Methods. Twenty-five postmenopausal patients with syndrome X completed a double-blind, placebo-controlled study of the effect of 17-beta-estradiol cutaneous patches (100 μg/24 h) on the frequency of chest pain and on exercise tolerance. Patients were randomly assigned to receive either placebo or 17-beta-estradiol patches for 8 weeks and were then crossed over to the other treatment.Results. During the placebo phase, patients had a mean of 7.3 episodes of chest pain/10 days. A reduction to 3.7 episodes/10 days was observed during the 17-beta-estradiol phase (p < 0.05). No significant differences were observed between the effects of 17-beta-estradiol and placebo on exercise duration or the results of other cardiologic investigations.Conclusions. Estrogen replacement reduces the frequency of chest pain and may be a useful new therapeutic option for treating postmenopausal women with syndrome X.     

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.     

The effect of 17 beta-estradiol on MCP-1 serum levels in postmenopausal women

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is considered a propagator of atherosclerosis and a key modulator of monocyte activity. Hormone replacement therapy (HRT) is currently being investigated as a means towards prevention of atherosclerosis. We aimed to assess (1) the range of circulating MCP-1 levels in postmenopausal women, (2) the correlation between MCP-1 and atherosclerotic burden, and (3) the effects of commencement and discontinuation of HRT on MCP-1 serum levels. METHODS: This clinical prospective trial investigated 51 postmenopausal women at increased risk for cardiovascular events who were randomized to receive either no HRT or 1 mg 17 beta-estradiol continuously plus sequential progestagen over 1 year. Intima-media thickness (IMT) of carotid and femoral arteries was measured by ultrasound. Serum levels of MCP-1 and cellular adhesion molecules were measured by ELISA. RESULTS: At baseline, MCP-1 levels and overall mean maximum IMT correlated (r=0.589; P<0.0001, Pearson's coefficient). MCP-1 levels in serum gradually decreased after 3, 6, and 12 months of HRT by 16.8 +/- 15.7% at 12 months (P<0.0001, MANOVA). Similarly, all cellular adhesion molecules decreased significantly by 6-12%. After 12 months, women decided whether to continue or discontinue treatment. At 18 months, in women discontinuing HRT (n=17), MCP-1 levels rose by 21 +/- 20% (P=0.003), but remained lowered in women continuing HRT. CONCLUSION: Our observations indicate that 17 beta-estradiol may have an antiatherosclerotic effect by reducing MCP-1 serum levels and cell adhesion molecules.     

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.     

Short-term effects of low-dose estrogen/drospirenone vs low-dose estrogen/dydrogesterone on glycemic fluctuations in postmenopausal women with metabolic syndrome

This study aims to compare the effects of low-dose emidrate estradiol/drospirenone (E2/DRSP) vs low-dose emidrate estradiol/dydrogesterone (E2/DG) combination on the mean amplitude of glycemic excursions (MAGE) value in postmenopausal women affected by metabolic syndrome (MS). One hundred sixty postmenopausal women were recruited to receive a treatment with oral doses of E2/1 mg plus drospirenone/2 mg (E2/DRSP group) or oral dose of E2/1 mg plus dydrogesterone/5 mg (E2/DG group) for 6 months. At enrollment and after 6 months, anthropometric, metabolic, and inflammatory parameters have been assessed. MAGE, evaluated during 48-h continuous subcutaneous glucose monitoring (CSGM), allowed us to assess daily glucose fluctuations at baseline and after 6 months. After hormone therapy, both groups showed a significant decline in fasting plasma glucose levels (p < 0.05), while only E2/DRSP group showed a statistically significant decline in waist circumferences, post-prandial glycemia, LDL, plasma triglycerides, MAGE, HOMA index, and plasma IL-6 (p < 0.05) levels. In the whole population (n = 160), after 6 months of indicated therapy, changes in fasting plasma glucose and PAI-1 levels correlated with the changes in MAGE values, while only in E2/DRSP group that MAGE reduction was positively associated with a stronger decrease in waist circumferences, triglycerides, and TNF-α plasma levels. The independent effect of hormone therapy (HT) on reduction in MAGE value has been tested in three different multiple linear regression models. HT resulted to be associated with MAGE, independent of other confounding variables. Although both groups had a decline in fasting plasma glucose, only drospirenone treatment revealed positive effects on glycemic excursions and insulin sensitivity, induced favorable changes in lipid profile, and showed an improvement of inflammatory indices in postmenopausal women with MS.     

Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women

OBJECTIVES:; The aim of the present study was to assess whether optimized antihypertensive treatment is effective in modifying endothelial function and whether an improvement in flow-mediated vasodilation (FMD) in response to treatment, as an expression of reversible endothelial dysfunction, could predict a more favorable prognosis in a population of postmenopausal women. BACKGROUND: Hypertensive postmenopausal women have been shown to have abnormal endothelium-dependent vascular function. However, FMD may change over time, according to antihypertensive treatment; the prognostic value of these changes has not been investigated. METHODS: A total of 400 consecutive postmenopausal women with mild-to-moderate hypertension and impaired FMD underwent ultrasonography of the brachial artery at baseline and after six months, while optimal control of blood pressure was achieved using antihypertensive therapy. They were then followed up for a mean period of 67 months (range 57 to 78). Endothelial function was measured as FMD of the brachial artery, using high-resolution ultrasound. RESULTS: After six months of treatment, FMD had not changed (< or = 10% relative to baseline) in 150 (37.5%) of 400 women (group 1), whereas it had significantly improved (>10% relative to baseline) in the remaining 250 women (62.5%) (group 2). During follow-up, we noticed 32 events (3.50 per 100 person-years) in group 1 and 15 events (0.51 per 100 person-years) in group 2 (p < 0.0001). CONCLUSIONS: This study demonstrates that a significant improvement in endothelial function may be obtained after six months of antihypertensive therapy and clearly identifies patients who possibly have a more favorable prognosis.     

Bone mass and bone modelling markers in hypertensive postmenopausal women

Numerous phosphocalcium alterations associated with bone mineral density in hypertension have been described, but very few studies assess them. This study assesses bone mass in hypertensive postmenopausal women and the hypertension influence determining both calcium homeostasis and bone turnover markers. Blood and urine samples were analysed for calcium metabolism-related parameters. Densitometry studies were conducted in the lumbar spine (L2-L4). Hypertensive osteoporotic women--selected from 82 women, with 22% osteoporosis prevalence, similar to the rate for the same age in the Spanish population--had significantly higher levels of body mass index (29+/-4 vs 26+/-4, P=0.019), calciuria (293+/-146 vs 210+/-116 mg/24 h, P=0.023) and calcium/creatinine ratio (0.33+/-0.2 vs 0.22+/-0.1 P=0.003) vs hypertensive nonosteoporotic women. No relation was found between systolic and diastolic blood pressure with bone mass. However, there was a negative osteocalcin correlation (r=-0.386, P=0.0001, and r=-0.242, P=0.033). Calciuria is associated with bone mass decrease in hypertensive women, and there is no relation between bone mass and blood pressure.     

行激素补充疗法的绝经后妇女子宫内膜安全性监测

目的　探讨应用激素补充疗法(HRT)的绝经后妇女子宫内膜安全性的监测方法。　方法　对60例绝经后行HRT妇女进行血清雌二醇(E2)测定;阴道B超(TVS)监测子宫体积和子宫内膜厚度;对部分患者行子宫内膜的病理学检查和雌激素受体(ER)、孕激素受体(PR)半定量检测。　结果　应用HRT后,子宫内膜明显增厚,均值从2.8mm升至3.9mm(P＜0.05);E2显著上升,由(20.6±6.9)ng/L升至(33.8±11.7)ng/L（P＜0.01）;子宫内膜厚度与E2呈正相关关系(r=0.94,P＜0.01);20例送检内膜中,2例简单型增生过长,1例复杂型增生过长,余为萎缩型;ER(+)19例,ER(++)1例;PR均为(+)。　结论　根据临床表现,并结合血清E2和TVS检测子宫内膜厚度,可对子宫内膜安全性进行初步评估;当E2＞45ng/L,子宫内膜厚度≥5mm时,则需进一步行子宫内膜病理学检查和ER测定。