Atherosclerosis Intervention with Novel Tissue Selective Estrogen Complex Therapy

项目摘要/摘要 这项拟议的试验对临床和公共卫生的影响是深远的，因为过去的科学 十年的研究证实，雌激素对女性的益处很大，但风险很低，尤其是当 开始于围绝经期或绝经后早期。然而，大多数进入的女性 更年期有子宫需要与孕激素联合治疗以对抗雌激素诱导的子宫内膜 增生症。孕激素联合治疗为绝经后激素治疗创造了一个限制因素 由于相对于单独的雌激素，传统的含有孕激素的高铁疗法具有最大的健康价值。 对女性的风险，包括静脉血栓栓塞症(VTE)和乳腺癌。但是，作为的组件， 组织选择性雌激素复合体(TSEC)是一类新的药物，雌激素现在可以通过 不含孕激素的养生法没有孕激素暴露的风险。作为一类新的创新药物， TSEC疗法为治疗更年期症状提供了一种新的方法，它与选择性的 雌激素受体调节剂(SERM)与雌激素在基础上达到最佳临床效果 组织选择性活性图谱。第三代SERM联合BZA的疗效观察 结合雌激素(CE)对乳腺、子宫内膜、骨骼、脂质生物合成和静脉血栓形成的影响 独一无二的安全性和有效性优化。一系列3期随机对照试验显示 BZA/CE(FDA批准)在预防骨质疏松症和缓解血管舒缩方面有效 阴道症状，同时确保子宫内膜安全。BZA/CE不刺激子宫内膜组织 使用BZA/CE的累积闭经率与安慰剂相当，子宫内膜的发生率也是如此 增生(1%)。此外，BZA/CE不会刺激乳房组织，也不会增加乳房X光检查 密度相对于安慰剂；VTE(深静脉血栓形成和肺栓塞)和中风的发生率 类似于安慰剂。到目前为止，已经用传统孕激素进行了随机对照试验- 基于超线程的。应用创新的无孕激素配方BZA/CE保护妇女的子宫 不切除子宫是超越传统的孕激素抗雌激素疗法的下一步 使用新的TSEC类药物为女性提供安全有效的治疗，这些药物对 动脉粥样硬化的进展尚不清楚。这项建议旨在解决我们在知识和知识方面的这一重大差距 停止这一独特的公共卫生机会。我们建议的具体目的是进行一项 360例有子宫的健康绝经后妇女的随机、双盲、安慰剂对照试验 绝经6年内及60岁以下无临床心血管疾病及 糖尿病患者随机服用BZA 20 mg/CE 0.45 mg或安慰剂，疗程2至4.5年至 确定TSEC治疗对亚临床动脉粥样硬化进展的影响 以颈动脉内膜中层厚度和颈动脉僵硬度为试验终点。

PROJECT SUMMARY/ABSTRACT The clinical and public health implications of this proposed trial are far-reaching as the science over the last decade has confirmed that estrogen provides substantial benefits with low risk to women especially when initiated in the perimenopausal or early postmenopausal period. However, the majority of women entering menopause have a uterus requiring co-treatment with progestogen to counter estrogen-induced endometrial hyperplasia. Co-treatment with progestogen creates a limiting factor for postmenopausal hormone therapy (HT) since relative to estrogen alone, traditional progestogen-containing HT regimens carry the greatest health risks for women, including venous thromboembolism (VTE) and breast cancer. However, as a component of tissue selective estrogen complex (TSEC), a new class of agents, estrogen can now be delivered in a progestogen-free regimen without risks from progestogen exposure. As a new class of innovative medications, TSEC therapy provides a novel approach for the treatment of menopausal symptoms by partnering a selective estrogen receptor modulator (SERM) with estrogen to achieve optimal clinical results based on the blended tissue-selective activity profile. The effect of combined bazedoxifene (BZA), a third generation SERM with conjugated estrogens (CE) on breast, endometrium, bone, lipid biosynthesis and venous thrombosis are unique with optimization of safety and efficacy. A series of phase 3 randomized controlled trials have shown that BZA/CE (FDA approved) is effective in preventing osteoporosis and providing relief of vasomotor and vaginal symptoms while ensuring endometrial safety. BZA/CE does not stimulate endometrial tissue and the rate of cumulative amenorrhea with BZA/CE is comparable with placebo as is the incidence of endometrial hyperplasia (<1%). In addition, BZA/CE does not stimulate breast tissue and does not increase mammographic density relative to placebo; the incidences of VTE (deep vein thrombosis and pulmonary embolism) and stroke are similar to placebo. To date, randomized controlled trials have been conducted with traditional progestogen- based HT. Deploying the innovative progestogen-free formulation of BZA/CE to protect the uterus in women without a hysterectomy is the next step beyond traditional HT (progestogen opposed estrogen therapy) in providing safe and effective therapy for women with the new TSEC class of agents, the effects of which on atherosclerosis progression are unknown. This proposal seeks to address this major gap in our knowledge and to cease upon this unique public health opportunity. The specific aim of our proposal is to conduct a randomized, double-blinded, placebo-controlled trial in 360 healthy postmenopausal women with a uterus within 6 years of menopause and less than 60 years of age without clinical cardiovascular disease and diabetes mellitus randomized to BZA 20 mg/CE 0.45 mg or placebo for a treatment period of 2 to 4.5 years to determine the effects of TSEC therapy on the progression of subclinical atherosclerosis measured as change in carotid artery intima-media thickness and carotid arterial stiffness as trial end-points.