Effects of peroral and transdermal oestrogen replacement therapy on glucose and insulin metabolism

OBJECTIVE: Conflicting data have been reported previously on the effects of oestrogen replacement therapy on glucose tolerance, and the effects on glycosylated haemoglobin GHbA(1c) have been studied only among diabetics. The objective of this study was to evaluate the effects on glucose and insulin metabolism among nondiabetic women and to compare the outcomes of peroral and transdermal modes of administration. DESIGN: The effects of peroral oestradiol valerate 2 mg/day with placebo gel were compared to those of transdermal 17 beta-oestradiol gel (1 mg oestradiol/day) and placebo tablets in a randomised, double-blind, double-dummy study for six months. PATIENTS: Seventy-nine hysterectomised, nondiabetic postmenopausal women, 39 women in the peroral oestrogen group and 40 in the gel group. MEASUREMENTS: Oral glucose tolerance tests (OGTT) with blood glucose, serum C-peptide and insulin determinations were performed. GHbA(1c), IGF-I and IGFBP-1 were measured at baseline and after six months of therapy. In addition, insulin sensitivity and insulin secretion indices were obtained from OGTT. RESULTS: A small significant reduction in the GHbA(1c) concentration was observed during both peroral (P < 0.05) and transdermal oestrogen therapy (P < 0.05). However, no effect on insulin sensitivity was observed. The response to a standard 75 g oral glucose load was similar in the study groups. Compared with the baseline values, the area under the curve for C-peptide decreased by 8% both in the peroral group (P < 0.05) and in the gel group (P < 0.01). The fasting and postchallenge glucose and insulin levels or insulin release indices were not significantly altered. Peroral oestrogen decreased IGF-I and increased IGFBP-1, but these findings were not associated with the changes in glucose metabolism. CONCLUSIONS: Neither peroral nor transdermal oestradiol replacement therapy seemed to induce any negative effects on glucose metabolism over a time period of 6 months.     

Double-blind randomized placebo-controlled study of transdermal estrogen replacement therapy on hypertensive postmenopausal women

We investigated the effects of transdermal 17β-estradiol, combined with standard antihypertensive therapy, on the modification of the cardiovascular risk profile in hypertensive postmenopausal women. In a randomized, double-blind, placebo-controlled study, we enrolled 200 postmenopausal women with mild to moderate hypertension. Patients received 17β-estradiol (50 μg/day, transdermal) and norethisterone acetate (2.5 mg/day, orally) or placebo. At baseline serum total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose, and fibrinogen plasma levels were measured and all subjects underwent complete M-mode and 2-D echocardiograms, which were repeated after 6, 12, and 18 months of hormonal replacement therapy. Compared with placebo, all values decreased significantly except for HDL cholesterol. In both groups, no modifications were observed in echocardiographic parameters, except for left ventricular mean diastolic and systolic wall thickness and left ventricular mass index, which showed a significant decrease in both groups. The reduction was greater in the treated group; the percentage of patients with left ventricular hypertrophy was 46% before randomization and 17.2% after 18 months of treatment (P < .0001), whereas in group II the percentage was 48% at baseline and 31.5% after 18 months (P < .05).In conclusion, transdermal 17β-estradiol, associated with antihypertensive therapy, may contribute to the reduction of cardiovascular risk profile in hypertensive postmenopausal women.     

Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion

OBJECTIVE: To evaluate the impact on glucose and insulin metabolism of transdermal estrogen patches before and after the addition of cyclic dydrogesterone in postmenopausal women. DESIGN: We studied 21 postmenopausal women seeking treatment for symptomatic menopause. All patients received transdermal 50 micrograms/day estradiol for 24 weeks. After 12 weeks of treatment, 10 mg/day dydrogesterone were added. METHODS: During both regimens, insulin and C-peptide plasma concentrations were evaluated after an oral glucose tolerance test (OGTT); insulin sensitivity was evaluated by a hyperinsulinemic euglycemic clamp technique. Insulin and C-peptide response to OGTT were expressed as area under the curve (AUC) and as incremental AUC; insulin sensitivity was expressed as mg/kg body weight. Fractional hepatic insulin extraction (FHIE) was estimated by the difference between the incremental AUC of the C-peptide and insulin divided by the incremental AUC of the C-peptide. Plasma hormone and lipid concentrations were assessed at baseline and at 12 and 24 weeks of treatment. RESULTS: Nine patients proved to be hyperinsulinemic and 12 were normoinsulinemic. Transdermal estrogen treatment significantly decreased the insulin AUC (P < 0.05) and the insulin incremental AUC in hyperinsulinemic patients; addition of dydrogesterone further decreased both the AUC and incremental AUC of insulin. Estrogen alone and combined with dydrogesterone evoked a significant increase in C-peptide AUC in hyperinsulinemic (79.2%) and normoinsulinemic (113%) patients. The treatment increased the values for FHIE and insulin sensitivity in all patients (P < 0.04) and in the hyperinsulinemic group (P < 0.01), whereas it did not affect such parameters in normoinsulinemic patients. CONCLUSIONS: Transdermal estrogen substitution alone and combined with cyclical dydrogesterone may ameliorate hyperinsulinemia in a selected population of postmenopausal women.     

Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women

OBJECTIVES: We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women. BACKGROUND: Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism. METHODS: In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured. RESULTS: Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis. CONCLUSIONS: In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.     

Effects of transdermal estrogen replacement on parathyroid hormone secretion

The effect of transdermal 17 beta-estradiol replacement on ionized calcium and PTH levels was examined in 15 postmenopausal women. After baseline studies in the fasting state, the effect of a calcium infusion on PTH levels was studied. Estrogen replacement resulted in a fall in fasting resting ionized calcium and a rise in PTH levels. After calcium infusion there was no change in the shape of the relationship between plasma calcium and PTH. The level of nonsuppressible PTH secretion was not altered. Transdermal estrogen did not alter basal vitamin D-binding protein levels, 25-hydroxyvitamin D levels, or calcitriol levels. We conclude that the effect of transdermal estrogen replacement on PTH secretion is completely explained by the lowering of ionized calcium, causing a rise in PTH secretion. Thus, with this route of estrogen replacement, there is no necessity to postulate a direct effect of 17 beta-estradiol on the parathyroid gland.     

Oral but not transdermal estrogen replacement therapy changes the composition of plasma lipoproteins

The role of hormone replacement therapy and estrogen replacement therapy (ERT) in cardiovascular disease prevention has not been unambiguously defined yet. The metabolic effects of estrogens may vary depending upon the route of administration. Therefore, we compared the impact of unopposed oral or transdermal ERT on plasma lipids and lipoproteins in 41 hysterectomized women. This was an open-label, randomized, crossover study (with 2 treatments and 2 periods). The 41 hysterectomized women were randomized to receive oral or transdermal 17β-estradiol in the first or second of two 12-week study periods. Plasma lipid and lipoprotein levels were assayed before and after each treatment using standard automated methods. Lipid content of lipoprotein subclasses was assessed by sequential ultracentrifugation. The atherogenic index of plasma (AIP) was calculated as log(triglyceride [TG]/high-density lipoprotein [HDL] cholesterol). The difference between the 2 forms of administration was tested using a linear mixed model. The change from baseline for each of the forms was tested using paired t test. Oral ERT resulted in a significant increase in HDL cholesterol and apolipoprotein A-I levels, whereas it significantly decreased total and low-density lipoprotein (LDL) cholesterol and increased TG concentrations. Transdermal ERT had no such effect. Oral ERT led to a significant TG enrichment of HDL (0.19 ± 0.06 vs 0.27 ± 0.07 mmol/L, P < .001) and LDL particles (0.23 ± 0.08 vs 0.26 ± 0.10 mmol/L, P < .001) compared with baseline, whereas transdermal therapy did not have any effect on lipoprotein subclasses composition. The difference between the 2 treatments was statistically significant for HDL-TG and LDL-TG (0.27 ± 0.07 vs 0.19 ± 0.05 mmol/L, P < .001 and 0.26 ± 0.10 vs 0.22 ± 0.07 mmol/L, P< .001, respectively). The transdermal but not oral ERT significantly reduced the AIP compared with baseline (−0.17 ± 0.26 vs −0.23 ± 0.25, P = .023), making the difference between the therapies statistically significant (−0.23 ± 0.25 vs −0.18 ± 0.22, P = .017). Oral administration of ERT resulted in TG enrichment of LDL and HDL particles. Transdermal ERT did not change the composition of the lipoproteins and produced a significant improvement of AIP. Compared with transdermal ERT, orally administered ERT changes negatively the composition of plasma lipoproteins.     

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作为雌激素缺乏患者的主要治疗手段的雌激素替代治疗疗效确切,可明显改善临床预后。但作为绝经后骨质疏松的预防要严格掌握其适应证和用药方法,定期权衡利弊,防止不良反应的发生。1雌激素的来源女性体内的雌激素主要由卵巢分泌,肾上腺分泌只占其中很少部分,但也有一部分由激素前体在脂肪、肝脏等外周组织转换而来。育龄妇女的卵巢分泌雌二醇(estradiol)和雌酮(estrone),各占体内总生成量的95%和60%。卵巢排卵后形成的黄体也能分泌雌二醇和雌酮。妇女血液中的雌二醇约40%与性激素结合球蛋白(SHBG)结合,58%与血清白蛋白结合,游离部分仅占1%~…     

雌激素替代治疗对绝经后女性血脂代谢及血浆内皮素的影响

目的 探讨雌激素替代治疗(ERT)对绝经妇女血脂及血浆内皮素的影响。方法 选择自然停经妇女60例,其中30例用ERT,另30例用安慰剂治疗30天。治疗前后均检测促卵泡激素(FSH)、雌二醇(E_2)、孕酮(P)、睾酮(T)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)及血浆内皮素-1(ET-1)。结果 ERT组妇女血清E_2水平较治疗前明显升高,P、T水平无明显变化,TC、TG及LDL-C下降,HDL-C升高,ET-1水平显著下降;安慰剂组妇女上述指标均无显著变化。线性相关分析显示:绝经妇女E_2与TC、TG、LDL-C及ET-1负相关,与HDL-C正相关;TC与ET-1明显正相关。结论 ERT能改善绝经妇女血脂代谢和降低其血浆内皮素-1水平。两者相互促进和补充,从而发挥心血管保护作用。     

雌激素替代疗法对绝经后妇女血清血管 紧张素转化酶及血脂代谢的影响

目的　探讨雌激素替代疗法 (ERT)对绝经后妇女血清血管紧张素转化酶 (ACE)含量及血脂代谢的影响。方法　测定 30例健康绝经后妇女应用ERT(治疗组 )前及应用ERT 14周后血清ACE、雌二醇 (E2 )及血清甘油三酯 (TG)、总胆固醇 (TC)、高密度脂蛋白胆固醇 (HDL C)、低密度脂蛋白胆固醇 (LDL C)、脂蛋白 (a) [Lp(a) ]含量 ,并与 30例健康绝经后妇女应用安慰剂 (对照组 )进行对照。结果　对照组应用安慰剂前后 ,ACE及血脂各项含量无变化 ;治疗组应用ERT后 ,ACE含量明显降低且与E2 呈负相关 ,血清TC、LDL C及Lp(a)含量降低 ,HDL C含量升高 ,TG无变化。结论　绝经后妇女补充雌激素 ,可通过降低血清ACE水平及改善血脂代谢共同发挥对心血管系统的保护作用。     

Hormonal replacement therapy and lipid metabolism in women on hemodialysis with secondary to uremia estrogen deficiency

It has been reported that postmenopausal women taking hormonal replacement therapy (HRT) are at reduced risk for cardiovascular disease mainly because of favorable changes in serum LDL- and HDL-cholesterol. However, the therapy is also known to increase hepatic triglyceride production. Cardiovascular events are the leading cause of death in patients on dialysis and lipid abnormalities are common. The aim of the study was to evaluate the influence of HRT on lipid metabolism in premenopausal women undergoing hemodialysis with premature oestrogen withdrawal. 25 hemodialyzed women, aged 37 +/- 9 years (19-44 years) with serum 17 beta-estradiol < 30 pg/ml were divided into: group I (n = 13) treated with transdermal HRT (estradiol with cyclic norethisterone acetate--Estracomb TTS 50/0.25; Novartis), and control group II (n = 12). Before the treatment serum LDL-cholesterol concentrations were increased in 24% and serum triglycerides in 40% of patients, whereas HDL-cholesterol was decreased in 72% of patients. During one year, in group I a noticeable, 15% increase in serum HDL-cholesterol was observed from 0.90 +/- 0.23 to 1.04 +/- 0.19 mmol/l (34.8 +/- 8.8 to 39.8 +/- 7.4 mg/100 ml; p < 0.01). It was parallel to the increase in serum 17 beta-estradiol concentrations (from 20.5 +/- 8.91 to 50.3 +/- 17.20 pg/ml; p < 0.01). Serum LDL-cholesterol and triglycerides did not change significantly. In the control group all those values remained unchanged. CONCLUSIONS: In hemodialysis women with premature estrogen deficiency the transdermal cyclic HRT leads to the clinically important increase in serum HDL-cholesterol without significant changes in serum triglyceride concentrations and could be beneficial in reducing cardiovascular risk in this population.     

Menopausal estrogen replacement therapy and breast cancer

We conducted a meta-analysis of the literature concerning breast cancer and estrogen replacement therapy. The overall relative risk of breast cancer associated with this therapy was 1.07. However, the variation of the estimated risks among the studies was far greater than could plausibly be explained by chance alone. To explain this variation, we looked at the effects of type, duration, and dosage of treatment. Overall, women who took 0.625 mg/d or less of conjugated estrogens had a risk of breast cancer that was 1.08 times that of women who did not receive this therapy (95% confidence interval [CI], 0.96 to 1.2). The relative risks from these individual studies of low-dosage therapy did not differ significantly from each other. Women who took 1.25 mg/d or more of conjugated estrogens had a breast cancer relative risk of 2.0 or less in all studies. However, the variation in observed risks at this higher dosage was significant. This implies that other risk factors varied among these studies, making it difficult to estimate the overall risk associated with this dosage. The relative risk of breast cancer associated with estrogen replacement therapy among women with a history of benign breast disease was 1.16 (95% CI, 0.89 to 1.5). The combined results from multiple studies provide strong evidence that menopausal therapy consisting of 0.625 mg/d or less of conjugated estrogens does not increase breast cancer risk.     

Transdermal estrogen replacement therapy and vasomotor response

Previous studies have shown that acute administration of estrogen improves endothelial function in postmenopausal women, but there has been little investigation of the chronic effects of transdermal estrogen replacement therapy. The present study assessed the effect of transdermal estrogen replacement therapy (0.025 mg / day for 4 weeks, the normally applied dosage in Japan) on flow-mediated endothelium-dependent vasodilation of the brachial artery (B-mode ultrasound) and forearm cutaneous blood flow (laser Doppler flowmetry), and plasma hormonal and lipid levels in 12 normolipidemic postmenopausal women. Neither resting vascular diameter, flow-mediated vasodilation, nor time to peak vasodilation, showed significant changes after the estrogen therapy. In contrast, resting forearm cutaneous blood flow decreased significantly after the estrogen therapy. The time to the peak reactive hyperemia in the forearm skin was slightly shortened, and the % change in reactive hyperemia decreased slightly after the therapy. These findings seemed to reflect the inhibition of hot-flush symptoms associated with vasomotor abnormalities in cutaneous tissue. The lack of improvement in flow-mediated vasodilation of the brachial artery despite the inhibitory effect on cutaneous vasomotor abnormalities may be related to the low plasma estradiol concentration obtained with the present transdermal therapy (42.4+/-15.2 pg / ml), a finding which supports the estrogen threshold hypothesis in hormone replacement therapy.     

雌激素替代治疗对绝经后妇女冠心病者血脂代谢及抗氧化作用的研究

对32例绝经后妇女（PMW）冠心病患者（CHD组）进行雌激素替代治疗（ERT），以观察对其血脂代谢及机体抗氧化水平的影响。另选取绝经后健康妇女30例为对照组。CHD组口服尼尔雌醇（CEE3）每月2次，每次2mg，连用6个月，分别于用药前、用药后3个月及6个月检测总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL－C）、低密度脂蛋白胆固醇（LDL－C）、脂蛋白（a）［LP（a）］、氧化修饰低密度脂蛋白（Ox－LDL）、丙二醛（MDA）及超氧化物歧化酶（SOD）。结果表明ERT前CHD组与对照组比较LP（a）、Ox－LDL及MDA水平明显升高（P＜0．05），而SOD总活力显著降低；CHD组于ERT后TC无明显变化，TG呈升高趋势（P＞0.05），而LDL-C、TC／HDL－C和LDL－C／HDL－C显著下降（P＜0．01），LP（a）也明显降低（P＜0．05），而HDL－C显著上升（P＜0．01）；血浆Ox－LDL、血清MDA显著下降（P＜0．01），血清SOD总活力明显上升（P＜0．05），提示ERT不仅能显著改善PMW之CHD患者血脂紊乱，而且能有效地提高机体抗氧化水平。     

雌激素替代疗法的经验与评议

雌激素替代疗法的经验与评议伍汉文原发性骨质疏松包括妇女绝经后骨质疏松及男女７０岁以后的老年性骨质疏松，已成为很常见的病。随着社会发展、寿龄延长，此病的患病率将日益增多。我们用ＱＤＲ４５００Ａ型双能Ｘ线骨密度仪检查４０岁以上女性８００人，发现达到ＷＨＯ...     

Decreased mortality in users of estrogen replacement therapy

In a prospective study of 8881 postmenopausal female residents of a retirement community in southern California, we evaluated in detail the relationship between estrogen use and overall mortality. After 7 1/2 years of follow-up, there had been 1447 deaths. Women with a history of estrogen use had 20% lower age-adjusted, all-cause mortality than lifetime nonusers (95% confidence interval, 0.70 to 0.87). Mortality decreased with increasing duration of use and was lower among current users than among women who used estrogens only in the distant past. Current users with more than 15 years of estrogen use had a 40% reduction in their overall mortality. Among oral estrogen users, relative risks of death could not be distinguished by specific dosages of the oral estrogen taken for the longest time. Women who had used estrogen replacement therapy had a reduced mortality from all categories of acute and chronic arteriosclerotic disease and cerebrovascular disease. This group of women had a reduced mortality from cancer, although this reduction was not statistically significant. The mortality from all remaining causes combined was the same in estrogen users and lifetime nonusers.