Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause

描述(申请人提供)：心血管疾病(CVD)是导致女性死亡的主要原因，目前在美国，由于更年期后心血管风险的更大负担，导致女性死亡的人数多于男性。抑郁症会使患心血管疾病的风险增加两倍。了解抑郁症和心血管疾病之间的联系对女性来说特别重要，因为她们患抑郁症的比例是男性的两倍。停用雌激素不仅会增加女性患心血管疾病的风险，还会导致抑郁症。这项计划中的研究将在围绝经期停用E2的背景下，研究心血管疾病和抑郁症共同的生物介质(炎症、内皮功能障碍、心脏自主神经调节障碍和代谢障碍)。对应激的心血管、神经内分泌和炎症反应的增强也定义了一种风险，并对上述风险的介体产生了不利影响。虽然雌二醇对抑郁症和心血管疾病常见的风险介质以及应激反应有有益的影响，而且在减轻抑郁症状方面也是有效的，但对雌二醇的心脏保护和抗抑郁反应都有很大的不同。这项计划中的研究旨在确定一种风险概况，以预测E2在预防围绝经期妇女心血管风险进展和出现抑郁症方面的最大好处。基于心血管疾病和抑郁的共同危险因素，我们预测，有反复抑郁病史的围绝经期妇女将比从未抑郁的妇女表现出更大的心血管风险进展，并在12个月内遭受更多抑郁，并显示出E2对心血管的好处。共有320名符合E2候选条件的围绝经期妇女(年龄45-55岁；稻草期-1)将被研究。根据SCID访谈，一半(n=160)的患者将有反复抑郁的病史(2+次抑郁发作，1+必须是重度抑郁)，但处于缓解期(2年，目前CES-D评分d8)，160名将被招募为从未抑郁的围绝经期妇女(也是CES-D d8)。在进行医学和精神病学评估，包括评估终生创伤暴露后，女性将接受基线心血管风险描述测试，其中包括：1)心脏自主神经张力--由压力感受器敏感性定义，包括非侵入性测量心率和血压节拍变化；2)应激反应-基于对Trier社会应激测试的心血管(血压和血管阻力)、神经内分泌(皮质醇)和炎症(IL-6)反应的综合评分；3)内皮功能-基于超声测量反应性充血期间血流介导的臂动脉扩张；5)代谢风险--根据符合代谢综合征的标准或口服葡萄糖耐量试验表现出胰岛素抵抗来确定。然后，采用双盲程序，受试者将被随机分为172-E2透皮贴剂(每天100微克)或安慰剂，为期12个月，接受主动ERT的女性将每3个月服用微粒化黄体酮(P)(3个月中有2个月给予安慰剂P)，接受安慰剂ERT的女性将每月服用安慰剂P。在干预期间，受试者将定期接受抑郁、依从性、生命体征和副作用的评估。在治疗期的第6个月和第12个月，将重复在基线评估时进行的所有心血管程序。这是一项机械性研究，旨在研究未经治疗的围绝经期妇女超过12个月的心血管风险进展的预测因素(复发性抑郁史)和调节因素(创伤暴露)，以及E2治疗对抑郁和心血管风险有益影响的中介因素(应激反应谱)。这项研究的结果旨在确定行为或生物干预的潜在目标，并提供可以在生活的其他阶段发生的抑郁中进行检验的机械性假设，以及帮助推进个体化医学的目标。 公共卫生相关性：尽管心血管疾病和抑郁症在妇女中的流行率和人力成本很高，但很少有已知的中介或预测因子在围绝经期期间增加这些相互关联的疾病的风险。这些预测因子(如抑郁史)、调节因子(如终生创伤暴露)、生物标记物(如胰岛素抵抗)或介体因子(如应激反应)的存在将确定干预目标，并可能影响数百万妇女的生活和健康。此外，识别与短期ERT相关的益处预测因素将推进个体化用药的目标。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in women, and currently kills more women than men in the U.S. due to the greater burden of cardiovascular risk after menopause. Depression increases risk for CVD by two-fold. Understanding the depression-CVD link has particular relevance for women since they suffer from depression at a rate twice that of men. Estrogen (E2) withdrawal not only increases cardiovascular risk in women, but is also involved in depression. The planned study will examine the biological mediators of risk that are common to both CVD and depression (inflammation, endothelial dysfunction, cardiac autonomic dysregulation, and metabolic disturbance) within the context of E2 withdrawal during the perimenopause. Heightened cardiovascular, neuroendocrine and inflammatory reactivity to stress also define a profile of risk and adversely impacts the mediators of risk described above. While E2 is associated with beneficial effects on the mediators of risk common to depression and CVD and on stress reactivity, and is also effective in reducing depressive symptoms, there is substantial variance in both the cardioprotective and antidepressant responses to E2. The planned research intends to identify a profile of risk that would predict the greatest benefits of E2 in the prophylaxis of the progression of cardiovascular risk and appearance of depression in perimenopausal women. Based on the shared mediators of risk for CVD and depression, we predict that perimenopausal women with histories of recurrent depression will show greater progression of cardiovascular risk and suffer from more depression over 12 months than never depressed women, and show cardiovascular benefit of E2. A total of 320 perimenopausal women (45-55 years of age; STRAW stage-1) who are eligible candidates for E2 will be studied. Based on SCID interview, one half (n=160) will have a history of recurrent depression (2+ depressive episodes, 1+ must be major depression), but in remission (>2 yrs and with current CES-D score d 8) and 160 will be recruited as never depressed perimenopausal women (also CES-D d 8). Following medical and psychiatric evaluation, including assessment of lifetime trauma exposure, women will be tested for baseline cardiovascular risk profiles which include: 1) Cardiac Autonomic Tone - defined by baroreceptor sensitivity involving the non-invasive measurement of HR and beat-to-beat change in BP; 2) Stress Reactivity - based on a composite score involving cardiovascular (blood pressure and vascular resistance), neuroendocrine (cortisol), and inflammatory (IL-6) responses to the Trier Social Stress Test; 3) Endothelial Function - based on ultrasound measurement of flow mediated dilatation of the brachial artery during reactivity hyperemia; and 5) Metabolic Risk - determined based on meeting standard criteria for the metabolic syndrome or exhibiting insulin resistance in response to the oral glucose tolerance test. Using double-blind procedures, subjects will then be randomized to either transdermal 172-E2 (100ug/day) or placebo for 12 months, and micronized progesterone (P) will be given every 3 months to women on active ERT (placebo P given on 2 out of 3 months) and placebo P will be given every month to women on placebo ERT. Subjects will be assessed at regular intervals during the intervention for depression, compliance, vitals, and side effects. At months 6 and 12 of the treatment period, all cardiovascular procedures conducted at the baseline assessment will be repeated. This is a mechanistic study designed to examine the predictors (history of recurrent depression) and moderators (trauma exposure) of cardiovascular risk progression in untreated perimenopausal women over 12 months, and the mediators (stress reactivity profile) of the beneficial effects of E2 treatment on depression and cardiovascular risk. The results of this study are intended to identify potential targets for behavioral or biological intervention and provide mechanistic hypotheses that can be tested in depressions that occur during other stages of life as well as help advance the goals of individualized medicine. PUBLIC HEALTH RELEVANCE: Despite the prevalence and human costs of cardiovascular disease and depression in women, there are few known mediators or predictors of the increased risk of these inter-related disorders during the perimenopause. The existence of such predictors (e.g., history of depression), moderators (e.g., lifetime trauma exposure), biomarkers (e.g., insulin resistance) or mediators (e.g. stress reactivity) would identify targets for intervention and potentially influence the lives and health of millions of women. Additionally, identification of predictors of benefits associated with short-term ERT would advance the goal of individualized medicine.