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.
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