Obstructive sleep apnea (OSA) appears to be an underrecognized, yet significant factor in the pathogenesis of metabolic derangements in polycystic ovary syndrome (PCOS). Recent findings suggest that there may be two """"""""subtypes"""""""" of PCOS, i.e. with or without OSA, and these two subtypes may be associated with distinct metabolic and endocrine alterations. PCOS women with OSA may be at much higher risk for diabetes and cardiovascular disease than PCOS women without OSA and may benefit from therapeutic interventions targeted to decrease the severity of OSA. Thus, a major goal of the present project is to contrast the metabolic and hormonal features of these two subtypes of PCOS, explore causative mechanisms for the high prevalence of OSA in PCOS, and test the hypothesis that continuous positive airway pressure (CPAP) treatment may decrease the risk of diabetes and other cardiovascular and metabolic abnormalities in PCOS women with OSA.
In Specific Aim 1 we will determine if women with PCOS who have OSA differ from those without OSA as a consequence of differences in circulating concentrations estrogen and progesterone. We will further test our hypothesis by comparing stimulated steroid levels in response to a single dose of the GnRH agonist leuprolide in PCOS women with and those without OSA.
In Specific Aim 2. we will determine if OSA improves in women with PCOS treated with estrogen or, progesterone. For these studies, we will enroll women with PCOS who have OSA. Subjects will have a detailed baseline metabolic and metabolomic profile together with a baseline polysomnogram. Subjects will then receive a single dose of depot-leuprolide in order to suppress ovarian production of estrogen, progestin, and androgen over a period of 3 months. Six weeks after administration of depot-leuprolide, subjects will have repeated assessment of metabolic, metabolomic, and sleep measures to determine if these outcomes are altered by the combined suppression of ovarian sex steroids. Subsequently, subjects will be randomized in a double-blind placebo controlled fashion to one of two treatment arms for a period of six weeks. Treatment arms are: estrogen plus placebo or progesterone plus placebo. At the end of this second six weeks, subjects will have metabolic, metabolomic, and sleep measures repeated. Primary outcome measures will be compared both within and between treatment arms.
In Specific Aim 3. we will determine if metabolic disturbances present in PCOS women with OSA are ameliorated by the treatment of OSA with continuous positive airway pressure (CPAP). Results of our preliminary studies indicate that CPAP treatment of OSA results in attenuation of cortisol levels not only during sleep, but throughout waking hours as well.
This aim will serve to test the hypothesis that correction of OSA in PCOS will lead to improved metabolic function which can be attributed, at least in part, to a reduction in circulating levels of cortisol.
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