Polycystic ovary syndrome (PCOS) is the most common reproductive- metabolic disorder of women during their child-bearing years affecting 5-10% of this population. The major clinical features include infrequent and irregular menses, excessive hair growth and infertility as result of an ovulation and hyperandrogenism. In recent ears, late age health concerns for these patients have grown largely due to the emergence of insulin resistance and hyperinsulinemia as constitutive components of this disorder. These risks include endometrial cancer, insulin-dependent and noninsulin- dependent diabetes mellitus, hypertension, stroke and cardiovascular disease. Efforts to elucidate the pathogenesis of PCOS have demonstrated distinct abnormalities at each level of the reproductive system as reflected by increased pituitary LH secretion, excessive theca interstitial cell androgen production and arrest of ovarian follicle development. In all of these target tissues insulin had been shown in vitro to enhance cell function, including studies which have utilized both PCOS and normal ovaries. Unfortunately, corresponding in vivo human studies have not been able to corroborate the in vitro results of insulin action. The overall goal of this proposal is to examine in women with PCOS the effect of hyper- insulinemia on the functional capacity of pituitary LH secretion, theca cell androgen production and granulosa cell estrogen production. Our hypothesis is that hyperinsulinemia perpetuates the recognized abnormalities of PCOS by altering these major target tissues. Following baseline studies to determine target tissue responsiveness and sensitivity, PCOS and normal women will have their serum insulin levels raised by the hyperinsulinemic, euglycemic clamp method and the studies will be repeated. Subsequently, subjects will be treated with an insulin enhancing drug, Troglitazone, to reduce hyperinsulinemia after which they will be retested. While on Troglitazone, insulin levels will again be raised and the baseline studies repeated. The results of this vigorous and thorough proposal will allow us to identify in vivo the effects of insulin at each target tissue and determine the clinical impact of hyperinsulinemia on reproductive dysfunction in PCOS.
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