Sex steroids, Sleep, and Metabolic Dysfunction in Women

女性的性类固醇、睡眠和代谢功能障碍

• 批准号: 7928876
• 负责人: DAVID A EHRMANN
• 金额: $ 121.03万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928876
• 关键词: Sex; steroids; Sleep; Metabolic; Dysfunction

The prevalence of obesity and chronic sleep loss are at record levels among Americans and evidence continues to emerge to support a causal link between the two conditions. Metabolic and cardiovascular abnormalities related to sleep disruption are particularly evident in individuals with obstructive sleep apnea (OSA), a disorder traditionally associated with male gender. While more prevalent in men, OSA is underrecognized in women in part because its clinical and polysomnographic features differ from those of men. Women with polycystic ovary syndrome (PCOS) are particularly susceptible to OSA with at least a 5-fold higher risk for its development compared to obese women without PCOS. The overarching aim of this SCOR application is to therefore establish the basis for the apparent gender difference in prevalence of OSA by focusing on the mechanistic role of sex steroids in the pathogenesis of the disorder as well as its metabolic complications. Four Projects sharing integrated hypotheses, aims, and methods, plus an Administrative Core are proposed. In Project 1 (Van Cauter. principal investigator) and Project 2 (Ehrmann. principal investigator) subjects with and without OSA will have detailed assessments of sleep, metabolic, and cardiovascular function; studies will be conducted in serum and urine for metabolomics and in fat biopsies for adipocyte function. Obese men and women with and without OSA will participate in Project 1: those with OSA will be treated with continuous positive airway pressure (CPAP) and its impact on baseline measures will be assessed. Project 2 will enroll obese women with PCOS, with and without OSA. Those with OSA will receive CPAP or will be randomized to receive depot leuprolide to suppress ovarian steroid output over 12 weeks, reassessed at 6 weeks, and then randomized (double-blind, placebo controlled) to 6 weeks of either micronized estrogen + placebo or micronized progestin + placebo. The independent effects of androgen, estrogen, and progesterone on OSA and metabolic function will be assessed. Project 3 (Mittendorfer, principal investigator) will focus on mechanisms responsible for increased plasma triglyceride (TG) concentration, a finding common to both OSA and PCOS. Studies of VLDL-TG kinetics will be undertaken before and after modulation of plasma glucocorticoid, progesterone, and testosterone concentrations. In Project 4 (Brady. principal investigator) primary human adipocytes will be prepared from fat biopsies obtained in Projects 1 - 2. Insulin sensitivity will be determined by phospho-specific immunoblotting in conjunction with glucose uptake and anti-lipolysis assays. In parallel, adipocytes from these subjects will be cultured for 1-5 days prior to metabolic assays to ascertain if removal of from circulating factors will improve insulin signaling, or if insulin resistance persists in vitro. Finally, the Administrative Core will have oversight of all Project functions; interface with the Metabolomics Laboratory at Duke University (C. Newgard, Lab Director); and coordinate meetings of the External Advisory Committee.

肥胖和慢性睡眠损失的患病率在美国人中处于创纪录的水平，并且证据继续出现，以支持两种情况之间的因果关系。在阻塞性睡眠呼吸暂停（OSA）的个体中，与睡眠中断有关的代谢和心血管异常尤为明显，这是一种传统上与男性性别有关的疾病。尽管在男性中更普遍，但OSA在女性中的认可程度不高，部分原因是其临床和多摄影学特征与男性的特征不同。与没有PCOS的肥胖女性相比，患有多囊卵巢综合征（PCOS）的女性特别容易受到OSA的影响，其发育风险至少高5倍。因此，该SCOR应用的总体目的是通过关注性类固醇在疾病发病机理及其代谢并发症中的机械作用来建立OSA患病率明显的性别差异的基础。提出了四个共享综合假设，目标和方法的项目，并提出了行政核心。在项目1（Van Cauter。首席调查员）和项目2（Ehrmann。1.Mann。Chiplann。Mangann。Mangann。Mangmann。主题）受试者和没有OSA的受试者中，将对睡眠，代谢和心血管功能进行详细评估；研究将在血清和尿液中进行代谢组学和脂肪活检以进行脂肪细胞功能。有和没有OSA的肥胖男性和女性将参加项目1：OSA的肥胖男性和女性将以持续的阳性气道压力（CPAP）对待，并评估其对基线措施的影响。项目2将在有或没有OSA的情况下将肥胖妇女纳入PCOS。患有OSA的人将接收CPAP或将被随机分配以接收leuprolide，以抑制12周内的卵巢类固醇输出，在6周时重新评估，然后随机（双盲，安慰剂控制）至6周的微管雌激素 +安慰剂 +安慰剂或Micronicized孕激素 +安慰剂。将评估雄激素，雌激素和孕酮对OSA和代谢功能的独立影响。项目3（Mittendorfer，首席研究员）将重点介绍负责增加血浆甘油三酸酯（TG）浓度的机制，这是OSA和PCOS共有的发现。在调节血浆糖皮质激素，孕酮和睾丸激素浓度之前和之后，将进行VLDL-TG动力学的研究。在项目4（Brady。首席研究者）中，将根据项目1-2获得的脂肪活检制备原代人脂肪细胞。胰岛素敏感性将通过磷酸特异性免疫印迹与葡萄糖摄取和抗激溶方法结合来​​确定。同时，在代谢测定之前将培养这些受试者的脂肪细胞1-5天，以确定从循环因子中取出是否会改善胰岛素信号传导，或者是否在体外持续胰岛素抵抗。最后，行政核心将监督所有项目功能。与杜克大学代谢组学实验室的接触（C. Newgard，实验室主任）；并协调外部咨询委员会的会议。