Neuroendocrine Actions of Androgens in Females

Northwestern University, Evanston IL

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Abstract

Hyperandrogenemia, LH excess, hyperinsulinemia, and impaired pancreatic beta cell function are core features of the polycystic ovarian disease (PCOS) that can be experimentally induced in female rhesus monkeys by prenatal androgenization We will thus use the prenatally androgenized female monkey to study the pathogenesis of these PCOS symptoms. We hypothesize that prenatal androgenization "programs" subsequent 1) hyperactivity of the "hypothalamic" GnRH pulse generator", leading to LH excess, and 2) hypersecretion of insulin and impaired insulin secretory responses to glucose. In Aim 1of the proposed studies, GnRH release will be monitored in adult, prenatally androgenized monkeys to determine if these animals exhibit hyperactivity of the GnRH pulse generator. A series of studies will then be performed to test the idea that the effects of androgens are mediated by modulation of ATP-sensitive potassium channels (KATP channels). The KATP channels appear to regulate secretion in both GnRH neurons and pancreatic beta cells, and we have obtained evidence that androgens suppress KATP channel expression. We will therefore test the idea that the effects of prenatal androgen exposure on LH and insulin secretions are mediated by suppression of KATP channel expression and/or activity. It will specifically be determined whether KATP channel subunits are expressed in GnRH neurons in the female rhesus monkey (Aim 2), and if prenatal androgenization leads to suppression of KATP channel expression in both hypothalamus and pancreas (Aim 3). We will then determine if modulation of KATP channel activity in vivo is functionally linked to GnRH pulsatility, and whether prenatal androgenization reduces the activity of these channels (Aim 4). In Aim 5 a transgenic mouse will be developed in which dominant negative KATP channels will be targeted to GnRH neurons, to determine if the experimental suppression of KATP channel activity in GnRH neurons results in LH excess. These experiments will provide the first direct assessment of the neuroendocrine consequences of prenatal and androgenization, and will est the hypothesis that the ability of prenatal androgenization to induce PCOS symptoms is mediated by a suppression of KATP channel activity. A clearer understanding of the pathogenesis of PCOS symptoms will hopefully prompt exploration of new therapies for this common, yet perplexing reproductive and metabolic disorder.