Sex steroids, Sleep, and Metabolic Dysfunction in Women

肥胖和慢性睡眠不足的患病率在美国人中处于创纪录的水平，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患有阻塞性睡眠呼吸暂停（OSA）的个体中尤其明显，OSA是一种传统上与男性相关的疾病。虽然OSA在男性中更普遍，但在女性中未被充分认识，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OSA，与没有PCOS的肥胖女性相比，其发展风险至少高出5倍。因此，SCOR应用的首要目标是通过关注性类固醇在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。四个项目共享综合假设，目标和方法，加上一个行政核心。在项目1（货车Cauter.主要研究者）和项目2（埃尔曼。将对患有和不患有OSA的受试者进行睡眠、代谢和心血管功能的详细评估;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。患有和不患有OSA的肥胖男性和女性将参加项目1：患有OSA的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PCOS的肥胖女性，伴或不伴OSA。OSA患者将接受CPAP治疗，或随机接受长效亮丙瑞林治疗，以抑制卵巢类固醇输出，持续12周，在6周时重新评估，然后随机（双盲，安慰剂对照）接受6周微粉化雌激素+安慰剂或微粉化炔雌醇+安慰剂治疗。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，主要研究者）将重点关注导致血浆甘油三酯（TG）浓度升高的机制，这是OSA和PCOS的共同发现。将在调节血浆糖皮质激素、孕酮和睾酮浓度前后进行VLDL-TG动力学研究。在项目4（布雷迪。主要研究者）将从项目1 - 2中获得的脂肪活检组织中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结合葡萄糖摄取和抗脂解测定来确定。同时，将这些受试者的脂肪细胞培养1-5天，然后进行代谢试验，以确定从循环因子中去除是否会改善胰岛素信号传导，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功能;与杜克大学代谢组学实验室（C。Newgard，实验室主任）;并协调外部咨询委员会的会议。

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.