REGULATION OF GNRH DRIVE IN PCOS

多囊卵巢综合征(PCOS)的经典定义是卵巢起源的高雄激素血症所致的慢性无排卵。最近，多囊卵巢综合征与胰岛素抵抗和高胰岛素血症有关。由于高雄激素血症和胰岛素抵抗，它们在无排卵发生中的独立作用尚不清楚。由于安全、方便的恢复排卵疗法的发展取决于确定原因(S)，该项目的目的是阐明高雄激素血症和胰岛素抵抗在多囊卵巢综合征无排卵中独立起作用的程度。多囊卵巢综合征无排卵的直接原因是促性腺激素分泌异常，其特征是循环中的黄体生成素升高和卵泡刺激素不足以维持卵泡的生成。黄体生成素/卵泡刺激素比值改变的一个可能原因是促性腺激素释放激素脉冲频率过快(反映为黄体生成素脉冲频率增加)。为了确定PCOS患者无排卵的原因，我们将探讨高雄激素血症和高胰岛素血症在维持快速的黄体生成素脉冲频率和黄体生成素分泌减少中的作用，方法包括：[1]用雄激素受体阻滞剂氟他胺降低雄激素作用；[2]用胰岛素增敏剂曲格列酮改善胰岛素抵抗；以及[3]比较药物干预和安慰剂的效果。将对患有多囊卵巢综合征的非肥胖女性进行研究，因为这些药物更有可能降低相对瘦弱女性的雄激素作用或恢复胰岛素敏感性。对非肥胖人群的使用将对多囊卵巢综合征无排卵的发病机制提供更清晰的概念测试，这项研究的结果将直接与多囊卵巢综合征妇女不孕症的治疗相关。

Polycystic ovary syndrome (PCOS) is classically defined as chronic anovulation in the presence of hyperandrogenism of ovarian origin. More recently, PCOS has been associated with insulin resistance and hyperinsulinemia. Because hyperandrogenism and insulin resistance the independent role of each in the genesis of anovulation remains unclear. Since the development of safe and convenient therapies to restore ovulation depends on identifying the cause(s), the aim of this project is to clarify to what extent hyperandrogenism and insulin resistance independently contribute to anovulation in PCOS. The proximate cause of anovulation in PCOS is aberrant gonadotropin secretion characterized by elevated circulating LH and insufficient FSH to sustain folliculogenesis. A likely cause of the altered LH/FSH ratio is a rapid GnRH pulse frequency (as reflected by increased LH pulse frequency). To determine the cause of anovulation in women with PCOS, we will investigate the roles of hyperandrogenism and hyperinsulinemia in the maintenance of rapid LH pulse frequency and reduced LH secretion by: [1] reducing androgen action with the androgen receptor blocker, flutamide; [2] by improving insulin resistance insulin resistance with the insulin sensitizer, troglitazone; and [3] by comparing the effects of pharmacologic intervention to placebo. Non-obese women with PCOS will be studied because these pharmacological agents are more likely to reduce androgen action or restore insulin sensitivity in relatively lean women. The use of a non-obese population will afford a clearer test of concept regarding the pathogenesis of anovulation in PCOS and the results of this study will be directly relevant to the treatment of infertility in women with PCOS.