PCOS, Sleep Apnea, and Metabolic Risk in Women

阻塞性睡眠呼吸暂停（OSA）似乎是一个认识不足，但在发病机制的重要因素 多囊卵巢综合征（PCOS）的代谢紊乱。最近的研究结果表明， 是PCOS的两种“亚型”，即有或没有OSA，并且这两种亚型可能与 明显的代谢和内分泌改变患有OSA的PCOS女性可能有更高的风险， 糖尿病和心血管疾病比PCOS妇女没有OSA， 旨在降低OSA严重程度的干预措施。因此，本项目的主要目标是 对比这两种PCOS亚型的代谢和激素特征， PCOS患者OSA高患病率的机制，并检验持续阳性 气道压力（CPAP）治疗可以降低糖尿病和其他心血管疾病的风险， 多囊卵巢综合征合并阻塞性睡眠呼吸暂停综合征妇女的代谢异常。在具体目标1中，我们将确定PCOS女性 由于循环浓度的差异，患有OSA的人与没有OSA的人不同 雌激素和孕激素。我们将进一步测试我们的假设，通过比较刺激类固醇水平， PCOS合并和不合并OSA女性对GnRH激动剂亮丙瑞林单次给药的反应。在 具体目标2。我们将确定用雌激素治疗的多囊卵巢综合征妇女的OSA是否改善， 孕酮对于这些研究，我们将招募患有OSA的PCOS女性。受试者将接受 详细的基线代谢和代谢组学特征以及基线多导睡眠图。受试者将 然后接受单剂量的Depot-Leuprolide，以抑制卵巢产生雌激素，孕酮， 和雄激素治疗三个月给予库型亮丙瑞林后6周，受试者将 反复评估代谢、代谢组学和睡眠指标，以确定这些结果是否 会因为卵巢性类固醇的联合抑制而改变随后，将对受试者进行随机分组 以双盲安慰剂对照的方式分配至两个治疗组之一，持续6周。 治疗组为：雌激素加安慰剂或孕激素加安慰剂。在这第二个六结束时 周，受试者将重复进行代谢、代谢组学和睡眠测量。主要结局 将在治疗组内和治疗组之间比较测量值。具体目标3。我们将确定 存在于患有OSA的PCOS妇女中的代谢紊乱通过用以下药物治疗OSA而得到改善： 持续气道正压通气（CPAP）。我们的初步研究结果表明，CPAP治疗 阻塞性睡眠呼吸暂停综合征不仅在睡眠中导致皮质醇水平下降，而且在清醒时也会导致皮质醇水平下降。 这一目的将有助于验证PCOS患者OSA的纠正将导致代谢改善的假设。 这种功能至少部分归因于皮质醇循环水平的降低。

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.