Biologic Response of Menopausal Women to 17B-Estradiol

描述（由申请人提供）：尽管关于年龄依赖性改变组织对天然激素的反应的信息很少，但几条证据强烈表明，血管壁对激素的生物反应在年轻和老年绝经后妇女中可能不同。妇女健康倡议表明，绝经10年内随机接受激素治疗的妇女患冠心病（CHD）的相对风险小于1，而绝经10年以上的妇女患CHD的相对风险大于1。护士健康研究数据表明，绝经后6年内开始激素治疗的妇女比绝经后6年或更长时间开始治疗的妇女有显着降低的冠心病风险。雌激素预防动脉粥样硬化试验结果表明，雌激素治疗更有效地减少亚临床动脉粥样硬化的进展，妇女谁是随机在6年内绝经相对于那些妇女谁是10年或以上绝经后。非人类灵长类动物研究提供了病理生物学证据，表明雌激素治疗干预的最佳时间是绝经后6年内。随着进入更年期的妇女人数的迅速增加和新的激素产品进入市场，绝经后激素治疗可能会增加。了解雌激素对亚临床动脉粥样硬化进展的影响仍然是一个重要和及时的公共卫生问题，因为年轻的绝经后妇女谁有更年期症状，主要是潮红，是最有可能开始激素治疗的妇女。由于没有试验设计来直接检验外源性雌激素对动脉粥样硬化进展的影响会随着绝经后时间的推移而变化的假设，我们提出了一个双盲，采用2x2析因设计的安慰剂对照试验（治疗x绝经后时间），其中504名无心血管疾病临床证据的健康绝经后妇女将随机接受1713-雌二醇1 mg/kg，根据绝经后的年数（<6 years or >10年），治疗持续时间平均为3年（范围2 - 5年），颈动脉内膜中层厚度的变化率（一种公认的亚临床动脉粥样硬化指标）将是主要的试验终点。

DESCRIPTION(provided by applicant):Although there is little information available regarding age-dependent altered tissue responses to natural hormones, several lines of evidence strongly suggest that the biologic response of the vascular wall to hormones may differ in younger and older postmenopausal women. The Women's Health Initiative showed that women randomized to hormone therapy within 10 years of menopause had a relative risk less than 1 for coronary heart disease (CHD) compared with women more than 10 years postmenopausal who had a relative risk for CHD greater than 1. Nurse's Health Study data indicate that women who initiated hormone therapy within 6 years of menopause had a significantly lower CHD risk than did women who initiated therapy 6 or more years after menopause. Estrogen in the Prevention of Atherosclerosis Trial results show that estrogen therapy more effectively reduced the progression of subclinical atherosclerosis in women who were randomized within 6 years of menopause relative to those women who were 10 years or more postmenopausal. Non-human primate studies provide pathobiological evidence that the optimal time for intervention with estrogen therapy is within 6 years of menopause. With the rapidly growing number of women entering menopause and introduction of new hormonal products into the marketplace, postmenopausal hormone therapy is likely to increase. Understanding the effects of estrogen on the progression of subclinical atherosclerosis continues to be an important and timely public health issue since young postmenopausal women who have climacteric symptoms, predominantly flushing, are the women who are most likely to initiate hormone therapy. Since there are no trials designed to directly test the hypothesis that the effect of exogenous estrogen on the progression of atherosclerosis will vary by time since menopause, we propose a double-blind, placebo-controlled trial with a 2x2 factorial design (treatment x time since menopause) in which 504 healthy postmenopausal women without clinical evidence of cardiovascular disease will be randomized to 1713-estradiol 1 mg/day versus placebo according to their number of years since menopause, <6 years or >10 years. Treatment duration will average 3 years (,range, 2 to 5 years) and the rate of change _ carotid artery intima-media thickness, a well-established measure of subclinical atherosclerosis, will be the primary trial end point.