The specific aim of this proposal is to elucidate the causes of the diversity in the clinical and biochemical expression of androgen excess in women. This objective will be addressed as follows: 1) By classifying hyperandrogenic women on the basis of parameters of peripheral and central androgen actions, and of associated findings such as obesity and insulin resistance. The groups thus established will be contrasted in further studies to discern whether their features are markers for distinct neuroendocrine mechanisms or simply reflect a homogeneous spectrum of androgen action. 2) By defining the mechanisms of the heterogeneous gonadotropin derangements associated with hyperandrogenism, via examining the production, availability, and utilization of androgens in relation to the pattern of gonadotropin secretion in each of the groups defined. In each, the response of gonadotropin secretion and release to alterations in the steroid environment will be examined. The specific receptor mechanisms involved in the feedback regulation of gonadotropin secretion in androgen excess will also be explored by the administration of estradiol, non-aromatizable androgen, and progesterone. 3) By defining the prevalence of insulin resistance in hyperandrogenism, and examining the role of insulin as a possible modifier of androgen action, via comparing the metabolism and utilization of androgens, the ovarian response to trophic hormones, and the regulation of gonadotropin release in hyperinsulinemic and non-hyperinsulinemic women with androgen excess. The effects will be examined of the amelioration of insulin resistance by weight reduction on the androgenic manifestations in these women. These studies promise to shed light on the control of androgen action on its target organs, both central and peripheral, and particularly on the complex interrelationship between these actions; and also to elucidate the role of insulin as a possible modifier of human reproductive function.
