Biologic Response of Menopausal Women to 17B-Estradiol

描述(由申请人提供)：尽管几乎没有关于年龄相关的改变组织对自然激素的反应的信息，但有几条证据强烈表明，在年轻和老年绝经后妇女中，血管壁对激素的生物反应可能不同。妇女健康倡议显示，绝经后10年内随机接受激素治疗的女性患冠心病的相对风险小于1，而绝经后10年以上的女性患冠心病的相对风险大于1。护士健康研究数据显示，绝经6年内开始激素治疗的女性患冠心病的风险显著低于绝经后6年或更长时间开始治疗的女性。雌激素预防动脉粥样硬化试验结果显示，与绝经后10年或更长时间的女性相比，雌激素疗法更有效地减少了绝经6年内的女性亚临床动脉粥样硬化的进展。非人灵长类动物的研究提供了病理生物学证据，表明雌激素治疗的最佳干预时间是绝经后6年内。随着进入更年期的女性数量迅速增加，以及新的荷尔蒙产品进入市场，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而及时的公共卫生问题，因为有更年期症状(主要是潮红)的年轻绝经后妇女最有可能开始激素治疗。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不同而变化的假设，我们提出了一项双盲、安慰剂对照试验，采用2x2析因设计(治疗×绝经后时间)，其中504名没有心血管疾病临床证据的健康绝经后妇女将根据她们自绝经以来的年数被随机分成1713-雌二醇1毫克/天和安慰剂，根据她们绝经6年或10年。治疗持续时间平均为3年(范围为2至5年)，颈动脉内膜-中层厚度的变化率将是主要的试验终点，颈动脉内膜-中层厚度是公认的亚临床动脉粥样硬化的指标。

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.