Sex steroids, Sleep, Body Fat, and Plasma Triglycerides in Women

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Increased plasma triglyceride (TG) concentration is a common feature of the metabolic abnormalities associated with obesity and a major risk factor for cardiovascular disease. Obesity is a major risk factor for two conditions that appear to be increasing in prevalence in women: the polycycstic ovary syndrome (PCOS) and sleep disordered breathing. PCOS affects 5-8% of women. Sleep disordered breathing affects up to 10% of women. Obstructive sleep apnea (OSA) is the most common cause for sleep disordered breathing and particularly prevalent in obese women with PCOS (~50%). Both PCOS and OSA augment the increase in plasma TG concentration associated with obesity, and the effects of PCOS and OSA on plasma TG concentration appear to be additive. The mechanisms responsible for the adverse effects of PCOS and OSA on plasma TG metabolism are not known. The primary goal of this project, therefore, is to determine the mechanisms responsible for the increase in plasma TG concentration in obese women with PCOS and OSA. It is our general hypothesis that alterations in the hormonal milieu that are characteristic of PCOS (hyperandrogenemia and progesterone deficiency) and OSA (hypercortisolemia) are, at least in part, responsible for the increase in plasma TG concentration in obese women with PCOS and OSA. Furthermore, we hypothesize that the hormonal aberrations, characteristic of PCOS and OSA, are particularly harmful to obese, compared with lean, women. To test our hypotheses, we will measure the rates of hepatic VLDL-TG and VLDL-apoB-100 secretion, VLDL-TG plasma clearance rate, and factors that may affect VLDL-TG plasma clearance (i.e., the concentrations of VLDL-apoC-ll, VLDL-apoC-lll, VLDL- apoE) in four groups of subjects: i) obese women with OSA (butnot PCOS); ii) obese women with PCOS (but not OSA); iii)obese women without PCOS or OSA; and iv) lean women without PCOS or OSA, both before and after interventions that will alter plasma testosterone, progesterone, and glucocorticoid availability. A better understanding of the mechanisms responsible for plasma TG homeostasis could lead to more effective treatment strategies for women with OSA and PCOS.