Sex steroids, Sleep, and Metabolic Dysfunction in Women

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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.