Effect of different hormone replacement therapy regimens on circadian blood pressure profile and active renin in postmenopausal women

Hormone replacement therapy (HRT) was considered as main prevention of cardiovascular disease (CVD) in postmenopausal women. Mechanisms of vasoprotective effect of this treatment are complex. However, recent data give rise to some uncertainties about HRT benefits and risks. Little is known about the effects of oral and transdermal HRT regimens on the renin-angiotensin-aldosterone system (RAS) and blood pressure (BP). This 3-month study comprised 28 menopausal women (age range 45-55 years) divided into two groups: Group 1: 12 normotensive women with natural occurrence of menopause receiving oral treatment with Climen^® (Schering) containing estradiol valerate and cyproterone acetate; Group 2: 16 normotensive women with surgically induced menopause receiving transdermal application of Climara^® (Schering) containing 17β-estradiol. There were no significant differences in office BP before and after treatment with Climara or Climen. However, ambulatory monitoring showed a significant fall in systolic BP (day-time, night-time and total 24-h) when estradiol alone was used. A similar trend towards lower values of systolic BP that was significant only for the night-time BP was observed after treatment with Climen. There were no significant changes in diastolic BP after both treatment regimens. Heart rate (day-time and 24-h) was significantly lower after transdermal estradiol treatment. There was no significant change in active renin after both treatment regimens. The present study showed that both treatment regimens resulted in lower ambulatory BP in normotensive postmenopausal women with more notable reduction in night-time BP. Increase in nocturnal dipping may account in part for the beneficial cardiovascular effects of HRT including decreased end-organ damage.     

Ambulatory blood pressure monitoring and active renin in menopausal women treated with amlodipine and hormone replacement therapy.

The aim of this study was to follow up the effect of an 8-week treatment with amlodipine given alone or in combination with hormone replacement therapy (HRT) on blood pressure and active renin in postmenopausal women with mild to moderate arterial hypertension using both conventional clinical blood pressure measurements and ambulatory blood pressure monitoring. Twenty-nine hypertensive menopausal women were divided randomly into two groups according to the treatment regimens: amlodipine and amlodipine plus HRT. The combination with HRT led to normalization of 24-h and daytime systolic and diastolic blood pressure. In contrast to the group treated with amlodipine alone, where a significant fall only of systolic night-time blood pressure was observed, in the group treated with amlodipine plus HRT both systolic and diastolic night-time blood pressure decreased significantly. Active renin did not change significantly after treatment in both groups. Triglycerides decreased significantly and high-density lipoprotein-cholesterol increased significantly only after amlodipine treatment. There were no significant differences in serum total cholesterol and low-density lipoprotein-cholesterol after HRT plus amlodipine. In conclusion, amlodipine is effective in reducing blood pressure in postmenopausal women. The maintenance of a normal circadian blood pressure pattern was influenced by HRT.     

Ambulatory blood pressure monitoring and active renin in menopausal women treated with amlodipine and hormone replacement therapy

The aim of this study was to follow up the effect of an 8-week treatment with amlodipine given alone or in combination with hormone replacement therapy (HRT) on blood pressure and active renin in postmenopausal women with mild to moderate arterial hypertension using both conventional clinical blood pressure measurements and ambulatory blood pressure monitoring. Twenty-nine hypertensive menopausal women were divided randomly into two groups according to the treatment regimens: amlodipine and amlodipine plus HRT. The combination with HRT led to normalization of 24-h and daytime systolic and diastolic blood pressure. In contrast to the group treated with amlodipine alone, where a significant fall only of systolic night-time blood pressure was observed, in the group treated with amlodipine plus HRT both systolic and diastolic night-time blood pressure decreased significantly. Active renin did not change significantly after treatment in both groups. Triglycerides decreased significantly and high-density lipoprotein-cholesterol increased significantly only after amlodipine treatment. There were no significant differences in serum total cholesterol and low-density lipoprotein-cholesterol after HRT plus amlodipine. In conclusion, amlodipine is effective in reducing blood pressure in postmenopausal women. The maintenance of a normal circadian blood pressure pattern was influenced by HRT.     

绝经后妇女应用不同性激素治疗方案的效果观察

目的比较小剂量的性激素治疗方案（HT）对健康的绝经后妇女总的效果，同时观察中药一坤泰胶囊的临床作用，以期寻找防治绝经后骨丢失的优化方案。方法本研究为随机、开放、平行对照的临床试验，时间1年。征集2002年4月至2003年3月在北京协和医院就诊的41—65岁的绝经后妇女136例，分4组：A组：戊酸雌二醇1．0me,／d＋醋甲羟孕酮（MPA）2mg／d；B组：结合型雌激素（倍美力）0．45mg／d＋MPA2mg／d；C组：7-甲异炔诺酮（利雏爱）1．25mg／d；D组：坤泰胶囊4粒日3次口服。同时各组研究对象均加服元素钙400me／d和雏生素D200IU／d。监测治疗前后腰椎（L24）、股骨颈的骨密度（BMD）、骨代谢指标和血脂水平的变化，及Kupperman评分、副反应的发生情况。结果用药期间，无一例研究对象发生临床骨折。124BMD在4个组的改变率分别为：（2．91±3．58）％、（2．44±3．20）％、（2．48±3．43）％、（-0．97±3．50）％，HT组间差别无显著性，而D组显著低于其他组（P〈0．01），而股骨颈BMD的变化各组间差别无显著性（P〉0．05）。Kupperman评分的下降在治疗后的任何时点HT组均优于D组。血脂的改变在HT组各有差别，出血、乳胀的发生A组和B组相似，多于C组，D组最少。结论3种临床常用的小剂量HT方案对绝经后健康妇女的疗效相似，而副反应和对血脂的影响不尽相同。中药坤泰不能阻止绝经后骨量的丢失，但在一定程度上能改善绝经症状。     

Effect of hormone replacement therapy on glucose tolerance in postmenopausal women.

Oral glucose tolerance tests were performed on 50 symptomatic postmenopausal women before and after three months of hormone replacement therapy. All patients were randomly allocated to one of five groups treated with various synthetic or so-called naturally occurring oestrogens. Therapy produced a significant deterioration of carbohydrate tolerance with sequential preparations containing 100 microgram of ethinyl oestradiol or graduated doses of mestranol up to 50 microgram. The conjugated equine oestrogen (1.25 mg daily) and oestrogen valerate (2 mg daily) treated groups did not show abnormal glucose tolerance. The decreased glucose tolerance may be due as much to dosage levels as to any metabolic characteristics of the various oestrogens prescribed.     

Optimizing continuous-combined hormone replacement therapy for postmenopausal women: a comparison of six different treatment regimens

OBJECTIVE: We sought to determine the optimum estradiol valerate-medroxyprogesterone acetate regimens for efficacy and safety. STUDY DESIGN: We performed a 24-month, randomized, double-blind phase II study. Four hundred nineteen women who were postmenopausal for at least 3 years were placed in six parallel treatment groups and received 1 or 2 mg estradiol valerate with either 2.5 or 5 mg medroxyprogesterone acetate. In two groups the dose of estradiol valerate was increased from 1 to 2 mg estradiol valerate after 6 months. RESULTS: A marked improvement of climacteric symptoms was observed, and most women had no bleeding even during the first 3 months of treatment. The best bleeding pattern was achieved with 1 mg estradiol valerate and 2.5 or 5 mg medroxyprogesterone acetate, and in most groups the bleeding pattern improved over time. No cases of hyperplasia were observed. CONCLUSION: All regimens alleviated climacteric symptoms and provided excellent bleeding control, even during the early weeks of treatment. A choice of various dose combinations offers flexibility of dosing, thus enabling therapy to be tailored to the needs of individual women.     

Randomized comparison between orally and transdermally administered hormone replacement therapy regimens of long-term effects on 24-hour ambulatory blood pressure in postmenopausal women

OBJECTIVE: The aim of this study was to assess whether oral delivery and transdermal delivery of sequential combined hormone replacement therapy have similar effects on systemic blood pressure, as measured by 24-hour automated ambulatory recordings. STUDY DESIGN: Eighty-two healthy postmenopausal women, of whom 73 completed the study, were randomly assigned to start hormone replacement therapy with either orally (n = 38) or transdermally (n = 35) administered medication. Ambulatory blood pressure was recorded for a 24-hour period before the start of hormone replacement therapy and again 2 and 6 months later. Analysis of variance was used for data analysis. RESULTS: Hormone replacement therapy by both oral and transdermal routes was associated with slight but nonsignificant drops in mean 24-hour systolic and diastolic ambulatory blood pressure. Daytime systolic ambulatory blood pressure (mean +/- SE) fell significantly (P <.05) and similarly at 2 months in the oral (3.8 +/- 0.2 mm Hg) and transdermal (4.0 +/- 0.3 mm Hg) treatment groups. The daytime ambulatory blood pressure remained significantly lower than baseline at 6 months in the oral treatment group (-3.6 +/- 0.3 mm Hg), whereas the fall at 6 months in the transdermal group (-3.1 +/- 0.3 mm Hg) was not significant. Mean daytime diastolic ambulatory blood pressure was reduced in both the oral (-1.8 +/- 0.8 mm Hg) and transdermal (-3.5 +/- 0.7 mm Hg; P <.05) treatment groups at 2 months but not at 6 months. Nighttime ambulatory blood pressures in both groups remained unaffected by hormone replacement therapy. CONCLUSION: Sequential combined hormone replacement therapy delivered by both oral and transdermal routes caused significant falls in the daytime ambulatory blood pressure of normotensive postmenopausal women at 2 months of treatment. This fall persisted as long as 6 months of treatment in the oral treatment group but not in the transdermal treatment group.     

绝经后妇女激素补充治疗后同型半胱氨酸及超声心动图改变的初步观察

目的　观察绝经后妇女激素补充治疗 (HRT)后血浆总同型半胱氨酸 [H(e) ]及超声心动图的改变。方法　将受试者分为 4组。Ⅰ组、Ⅱ组为自然绝经妇女 ,各 30例 ,其中Ⅰ组给予HRT(结合雌激素 0 6 2 5mg d ,安宫黄体酮 2mg d ,或者每月后 14d加安宫黄体酮 4mg d) 3个月 ;Ⅱ组不给予HRT ,为对照 ;Ⅲ组 2 0例 ,为已接受HRT1 5年的绝经后妇女 ;Ⅳ组 2 0例 ,为从未应用HRT的绝经后妇女。Ⅰ组、Ⅱ组受试者于接受HRT前及接受HRT 3个月后测定H(e) ;Ⅲ组、Ⅳ组受试者测定H(e) ,并行超声心动图检查。结果　Ⅰ组、Ⅱ组接受HRT 3个月前后H(e)无明显变化 ,Ⅰ组接受HRT前为(9 3± 2 5 ) μmol L ,Ⅱ组为 (9 4± 2 9) μmol L ;Ⅰ组接受HRT后H(e)为 (9 1± 2 8) μmol L ,Ⅱ组为(9 8± 3 6 ) μmol L。两组比较 ,差异无显著性 (P >0 0 5 )。Ⅲ组H(e)明显低于Ⅳ组 ,分别为 (8 0±1 3) μmol L及 (10 3± 3 2 ) μmol L。两组比较 ,差异有显著性 (P <0 0 5 )。Ⅲ组、Ⅳ组的超声心动图检查结果无明显改变。结论　短期应用HRT对H(e)无明显改善 ,长期应用HRT可降低H(e)水平。绝经后妇女应用HRT 1 5年 ,未见超声心动图有明显变化。     

Effect of hormone replacement therapy and calcitonin on bone mass in postmenopausal women.

A total of 104 postmenopausal women were randomly assigned to different therapeutic regimens: (a) calcitonin, (b) estrogen/progestogen (HRT) plus calcitonin, (c) estrogen/progestogen (HRT), (d) and the control group. The bone mass of the lumbar vertebrae of all patients was assessed with a dual beam photon absorptiometer (Norland GD 153). The 73 patients who completed the 1-yr study showed that postmenopausal bone loss could be prevented by either estrogen/progestogen (HRT) or calcitonin. In addition, the combination of hormonal replacement therapy and calcitonin not only prevented post-menopausal bone loss but resulted in a significant 10% gain in bone mass (P < 0.001).     

Effects of raloxifene therapy on plasma renin and aldosterone levels and blood pressure in postmenopausal women.

OBJECTIVE: Blood pressure, which generally increases after menopause, is one of the best tools to characterize cardiovascular disease. The renin-aldosterone system plays a role in determining cardiovascular risk and the role of estrogen in the regulation of angiotensinogen gene expression and serum levels is well known. Raloxifene can induce endothelium-dependent vasodilation without affecting endothelium-independent vasorelaxation. The aim of the study was to investigate the effects of raloxifene on the renin-aldosterone system and blood pressure in postmenopausal women. DESIGNS: Forty women, 54-59 years of age, in physiological menopause for 6 months to 4 years, were enrolled in the study and treated with raloxifene 60 mg/day for 6 months. All had blood pressure less than 130/85 mm Hg at the start of the study. The women were divided into two groups: the first (group A; 20 women) with normal blood pressure and the second (group B; 20 women) with previous high blood pressure treated with antihypertensive drugs, not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RESULTS: No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 6 months of raloxifene use. There was a slight reduction in PRA (11+/-4% for group A and 13+/-5% for group B) and in plasma levels of aldosterone (3.6+/-0.5% and 4.6+/-0.5%, respectively) with respect to basal values, but neither change was statistically significant. CONCLUSIONS: The results of the present study show that raloxifene at 60 mg/day dose is well tolerated and has no clinical impact on blood pressure, PRA or aldosterone in postmenopausal women.     

Effects of raloxifene therapy on plasma renin and aldosterone levels and blood pressure in postmenopausal women

Objective.?Blood pressure, which generally increases after menopause, is one of the best tools to characterize cardiovascular disease. The renin–aldosterone system plays a role in determining cardiovascular risk and the role of estrogen in the regulation of angiotensinogen gene expression and serum levels is well known. Raloxifene can induce endothelium-dependent vasodilation without affecting endothelium-independent vasorelaxation. The aim of the study was to investigate the effects of raloxifene on the renin–aldosterone system and blood pressure in postmenopausal women.

Designs.?Forty women, 54–59 years of age, in physiological menopause for 6 months to 4 years, were enrolled in the study and treated with raloxifene 60 mg/day for 6 months. All had blood pressure less than 130/85 mm Hg at the start of the study. The women were divided into two groups: the first (group A; 20 women) with normal blood pressure and the second (group B; 20 women) with previous high blood pressure treated with antihypertensive drugs, not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Results.?No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 6 months of raloxifene use. There was a slight reduction in PRA (11±4% for group A and 13±5% for group B) and in plasma levels of aldosterone (3.6±0.5% and 4.6±0.5%, respectively) with respect to basal values, but neither change was statistically significant.

Conclusions.?The results of the present study show that raloxifene at 60 mg/day dose is well tolerated and has no clinical impact on blood pressure, PRA or aldosterone in postmenopausal women.     

Effect of oestrogen replacement therapy on blood coagulation factors in postmenopausal women

Natural oestrogens “Premarin”, (Ayerst, conjugated equine oestrogens) “Harmogen”, (Abbott, piperazine oestrone sulphate) and “Progynova” (Schering, oestradiol valerate) alone and in combination with proestational agents such as “Primolut N”, (Schering, norethisterone) “Neogest”, (Schering, norgestrel), “Norgeston”, (Schering, levonorgestrel), “Duphaston” (Duphar, dydrogesterone) did not have adverse effects on clotting factors. One patient developed deep vein thrombosis following treatment using “Progynova” (oestradiol valerate) alone and a second patient suffered from mild myocardial infarction following the use of “Premarin” (conjugated equine oestrogens) alone.     

An objective and subjective assessment of uterine blood loss in postmenopausal women on hormone replacement therapy.

OBJECTIVE: To determine the volume of withdrawal blood loss in women taking hormone replacement therapy (HRT). DESIGN: Prospective randomized double blind cross-over trial. SUBJECTS: Twenty-nine postmenopausal women, with climacteric symptoms. INTERVENTIONS: The women were treated with cycles of 2 mg oestradiol valerate for 21 days combined with either 250 micrograms levonorgestrel or 10 mg medroxyprogesterone acetate, for the last ten days. Each woman was randomly allocated to one of the preparations and switched to the other after four months. MAIN OUTCOME MEASURES: Uterine blood loss was estimated by the alkaline haematin method. Bleeding patterns were recorded specifying the number of days with bleeding and subjective rating of the amount of blood lost. RESULTS AND CONCLUSIONS: The mean uterine blood loss was 35.2 ml and was equivalent to the normal menstrual blood loss. There was no significant difference between therapies but the women themselves considered that they bled more heavily when taking the levonorgestrel combination. The intraindividual variation in blood loss was small, independent of preparation taken, but the variation between individuals was large. Withdrawal bleeding started 2-3 days earlier when the women used the medroxyprogesterone acetate compared to the levonorgestrel formulation.     

Effect of hormone replacement therapy on insulin secretion and insulin sensitivity in postmenopausal diabetic women.

The aim of the present study was to evaluate the effect of three different combinations of hormone replacement therapy (HRT) on insulin secretion, peripheral insulin sensitivity, serum lipid levels and parameters of oxidative stress. Seven type II diabetic women of mean age 55.4 +/- 4.7 years, who had been menopausal for an average of 5 years, were enrolled in the study. Phases of insulin secretion--first (FPIS) and second (SPIS)--and the area under the curve (AUC) for insulin secretion were studied during an intravenous glucose tolerance test (IVGTT). Insulin sensitivity was determined using the manual euglycemic-hyperinsulinemic clamp technique. Three different HRT combinations were applied consecutively for 3-month periods: estradiol valerate plus cyproterone acetate (Climen); transdermal 17 beta-estradiol (System TTS 50) plus dydrogesterone (Duphaston) 10 mg daily for 10 days a month; oral 17 beta-estradiol plus dydrogesterone (Femoston) for 14 days a month. A group of nine women with normal glucose tolerance (according to World Health Organization criteria during a 75-g oral glucose tolerance test (OGTT)), of mean age 50.1 +/- 8.2 years and mean body mass index 24.60 +/- 2.01 kg/m2, were also studied, and served as a control group. Insulin secretion improved significantly after Climen: FPIS increased by 16% and SPIS by 44%. Insulin sensitivity increased by 50% after Systen TTS 50 + Duphaston; fasting hyperinsulinemia was normalized and total antioxidant capacity of the serum (TAOCS) was significantly raised (p < 0.01). Femoston led to an increase in insulin sensitivity (by 23%) and in TAOCS (p < 0.05), while fasting hyperinsulinemia remained unchanged. HRT should be prescribed in type II diabetic postmenopausal women because of its favorable effect on existing pathophysiological defects. Cyproterone acetate should be preferred in cases with a predominant beta-cell insulin secretion defect, while dydrogesterone in combination with a transdermal estrogen should be recommended in cases with leading insulin resistance.     

Peripheral blood lymphocyte subpopulations of postmenopausal women with hormone replacement therapy]

The effect of hormone replacement therapy on cellular immunity of postmenopausal women was studied by flow cytometry (FACS). Lymphocyte subsets in peripheral blood before and after hormonal replacement therapy (HRT) were measured. After 6 months of HRT with the sequential combined drug Klimonorm(R) (2 mg estradiol valerate and 0,15 mg levonorgestrel) the cytotoxic T-cells (CD8) were reduced and the CD4/CD8 ratio was increased significantly (p < 0,05).     

Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding

Objective: To compare the effects of frequently used two different regimens of combined continuous hormone replacement therapy; 0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA) and 1 mg 17β estradiol (E2) + 0.5 mg norethindrone acetate (NETA), on endometrial histopathology and postmenopausal uterine bleeding. Materials and methods: Two hundred and forty-six outpatient subjects aged 41–57 years were enrolled in the study conducted at the menopause clinic between November 2003 and November 2004. One hundred and thirty-nine patients were assigned to receive 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA), whereas 107 patients were to receive 17β estradiol + 0.5 mg norethindrone acetate (E2/NETA). Inclusion criteria of the study were: normal values of endometrial thickness at basal evaluation, women with intact uterus, at least 12 months of amenorrhea, normal vaginal smear, bilateral mammography and biochemical blood parameters. All women were questioned every 3 months for vaginal bleeding/spotting. Endometrial sampling was performed by Pipelle catheter in the 12th month of therapy. Results: For the first 3 months, vaginal bleeding/spotting rate for the CEE/MPA group was 38.7%, whereas it was higher (45%) in the E2/NETA group. For the second 3-month period, vaginal bleeding/spotting frequencies were 41.1 and 37.8%, respectively. In the third 3-month period 30.6 and 29.6%, and in the fourth 3-month period, 18.5 and 12.5% of the patients reported vaginal bleeding or spotting. None of the results of endometrial sampling have shown findings of cancer histopathology. Conclusion: Compared to CEE/MPA regimen, E2/NETA therapy has not shown more favorable effects on postmenopausal bleeding abnormalities. Irregular endometrial proliferation was seen more with the E2/NETA regimen.     

Transdermal hormone replacement therapy in postmenopausal women with uterine leiomyomas.

OBJECTIVE: To evaluate the effects of transdermal hormone replacement therapy (HRT) on uterine and leiomyoma size and on uterine bleeding patterns in postmenopausal women with uterine leiomyomas. METHODS: The required sample size was calculated to be 30 subjects per group to detect an effect on the size of one standard deviation (SD) with an alpha value of 0.05 (two-sided) and a power 1 - delta = 0.8. At the end of the study, the power analysis showed a value of beta = 0.826. Seventy postmenopausal women with uterine leiomyomas were enrolled and treated for 12 cycles of 28 days each with transdermal 17 beta-estradiol (E(2)) patches plus oral medroxyprogesterone acetate continuously added (group A) or with calcium carbonate (group B). At entry and every three cycles, uterine and leiomyoma dimensions were measured by transvaginal ultrasonography. To evaluate the effect of transdermal HRT on the characteristics of uterine bleeding, 35 healthy postmenopausal women without uterine leiomyomas (group C) were enrolled and treated with the same regimen as group A. A daily diary was used to record the abnormal uterine bleeding episodes, and a rank scale was used to assess the severity of bleeding. RESULTS: There were no significant changes in mean uterine or leiomyoma size between groups A and B, or in each group compared with basal values. No significant difference was detected between groups A and C in uterine bleeding patterns. CONCLUSION: Transdermal HRT did not increase the size of uterine leiomyomas or affect uterine bleeding patterns in postmenopausal women.     

Compliance with hormone replacement therapy in postmenopausal Sicilian women

OBJECTIVE: To verify the compliance with hormone replacement therapy (HRT) over 2 years in a population of postmenopausal women in East Sicily. STUDY DESIGN: Patients starting hormonal therapy for the first time were enrolled in this study. A telephone survey was then conducted after 3, 6, 12 and 24 months and the reasons for any discontinuation were recorded. RESULTS: Of a total of 138 women who agreed to be enrolled in this prospective longitudinal study 72 were still taking the treatment after 1 year and only 56 at the end of the study, although only three patients reported that they had experienced no benefit. CONCLUSIONS: Type of work, surgical menopause and previous use of oral contraceptives were significantly statistically associated with better HRT compliance. Side effects and fear of breast cancer, which we maintain is exaggerated by the women and their family doctors, were the commonest reasons for early discontinuation of the hormonal treatment.