Ovarian hyperandrogenism is one of the most common endocrinopathies of reproductive age women. Proposed etiologic mechanisms for this common clinical syndrome include primary abnormalities of the hypothalamic-pituitary unit, the ovary and the adrenal gland. A unique opportunity to identify a specific molecular cause of ovarian hyperandrogenism is provided by the observation that hyperinsulinemia is commonly associated with hyperandrogenism. The objective of this proposal is to test the hypothesis that insulin and insulin-like growth factors (IGFs) regulate ovarian androgen production and metabolism in women. Preliminary evidence indicates that insulin, IGF-1 and LH stimulate androgen production in incubations of minced human ovarian stroma and theca. To further explore these effects the following experiments are planned: 1) determination of detailed dose-response curves for insulin, IGF-1 and LH stimulation of thecal and stomal androgen production, 2) determination of the effects of insulin, IGF-1 and LH on androgen production in theca obtained from healthy or atretic follicles, 3) analysis of the binding characteristics of insulin and IGFs to insulin receptors, and IGF-1 receptors in ovarian theca and stroma, 4) analysis of the effects of insulin and IGFs on specific enzymes of thecal androgen biosynthesis (e.g. 17B - hydroxysteroid dehydrogenase), 5) use dot blots to probe ovarian tissue for the presence of mRNA for the insulin and IGF-1 receptors. Preliminary evidence indicated that the oral administration of 100 gms of glucose to hyperinsulinemic-hyperandrogenic women produces an acute rise in serum androstenedione, testosterone and dihydrotestosterone. To test the effects of insulin and glucose on circulating androstenedione and testosterone, the following experiments are planned: 1) examine the effects of 50 gm, 100 gm and 200 gm or oral glucose; and 25 gm and 50 gm of intravenous glucose on circulating insulin and androgens, 2) directly test the effects of hyperinsulinemia on circulating insulin by using a euglycemic clamp; and 3) directly test the effects of hyperglycemia on circulating androgens by using a hyperglycemic clamp. These experiments should yield important information concerning the role of metabolic factors in the regulation of ovarian androgen production and metabolism.
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