REGULATION OF GNRH DRIVE IN PCOS

多囊卵巢综合征（PCOS）被经典地定义为卵巢源性高雄激素症存在的慢性无排卵。最近，多囊卵巢综合征与胰岛素抵抗和高胰岛素血症有关。由于高雄激素和胰岛素抵抗各自在无排卵发生中的独立作用尚不清楚。由于开发安全便捷的恢复排卵的治疗方法取决于确定原因，本项目的目的是阐明高雄激素和胰岛素抵抗在多大程度上独立促进PCOS的无排卵。PCOS无排卵的直接原因是促性腺激素分泌异常，其特征是循环LH升高和FSH不足以维持卵泡发生。LH/FSH比值改变的一个可能原因是GnRH脉冲频率加快（反映为LH脉冲频率增加）。为了确定PCOS女性无排卵的原因，我们将研究高雄激素血症和高胰岛素血症在维持黄体生成素快速脉冲频率和减少黄体生成素分泌中的作用：用雄激素受体阻滞剂氟他胺降低雄激素的作用；胰岛素增敏剂曲格列酮改善胰岛素抵抗；[3]通过比较药物干预和安慰剂的效果。非肥胖的多囊卵巢综合征女性将被研究，因为这些药物更有可能降低雄激素作用或恢复相对苗条的女性的胰岛素敏感性。使用非肥胖人群将为PCOS无排卵的发病机制提供更清晰的概念测试，本研究的结果将与PCOS妇女不孕不育的治疗直接相关。

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.