Sex steroids, Sleep, and Metabolic Dysfunction in Women

描述（由首席研究员提供）：肥胖和慢性睡眠不足的患病率在美国达到了创纪录的水平，并且不断有证据支持这两种情况之间的因果关系。与睡眠中断相关的代谢和心血管异常在阻塞性睡眠呼吸暂停（OSA）患者中尤为明显，这是一种传统上与男性相关的疾病。虽然OSA在男性中更为普遍，但在女性中未得到充分认识，部分原因是其临床和多导睡眠图特征与男性不同。患有多囊卵巢综合征（PCOS）的女性特别容易患阻塞性睡眠呼吸暂停，与没有多囊卵巢综合征的肥胖女性相比，其发展风险至少高出5倍。因此，本SCOR应用的总体目标是通过关注性类固醇在该疾病发病机制及其代谢并发症中的机制作用，为OSA患病率的明显性别差异建立基础。四个项目共享整合的假设、目标和方法，外加一个行政核心。在项目1 （Van Cauter）。首席研究员)和项目2 (Ehrmann。研究人员将对有或没有OSA的受试者进行详细的睡眠、代谢和心血管功能评估；将在血清和尿液中进行代谢组学研究，并在脂肪活检中进行脂肪细胞功能研究。有或无OSA的肥胖男性和女性将参加项目1:OSA患者将接受持续气道正压通气（CPAP）治疗，并评估其对基线测量的影响。项目2将招募患有多囊卵巢综合征的肥胖女性，伴或不伴阻塞性睡眠呼吸暂停。阻塞性睡眠呼吸暂停患者将接受CPAP治疗，或在12周内随机接受赖丙利酯治疗，以抑制卵巢类固醇分泌，在6周时重新评估，然后随机（双盲，安慰剂对照）至6周微粉雌激素+安慰剂或微粉黄体酮+安慰剂。将评估雄激素、雌激素和孕激素对OSA和代谢功能的独立影响。项目3 （Mittendorfer，首席研究员）将重点研究血浆甘油三酯（TG）浓度升高的机制，这是OSA和PCOS的共同发现。在调节血浆糖皮质激素、孕酮和睾酮浓度之前和之后，将进行VLDL-TG动力学研究。在项目4(布雷迪。原代人脂肪细胞将从项目1 - 2中获得的脂肪活检中制备。胰岛素敏感性将通过磷酸特异性免疫印迹结合葡萄糖摄取和抗脂解测定来确定。同时，这些受试者的脂肪细胞将在代谢试验前培养1-5天，以确定从循环因子中去除是否会改善胰岛素信号，或者胰岛素抵抗是否在体外持续存在。最后，行政核心将监督所有项目职能；杜克大学代谢组学实验室的接口（C. Newgard，实验室主任）；协调外部咨询委员会的会议。

DESCRIPTION (provided by principal investigator): 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.