The overall goal of the proposed studies is to determine the molecular mechanism involved in the transformation of normal theca-interstitital cells into androgen hypersecreting cells and the subsequent impairment of the growth and development of ovarian follicles resulting in anovulation. Ovarian hyperandrogenism has been recognized as a major causative factor for anovulation. Although not present in all hyperandrogenic anovulatory conditions, a subset of patients with anovulation has been shown to be insulin resistant with a resultant increase in insulin levels. These conditions are associated with theca-cell hyperplasia, hyperandrogenism and anovulation.
Aim 1 of the proposed studies will examine the molecular basis for insulin and LH action in stimulating theca-interstitial cell androgen production.
This aim will be accomplished by examining the mechanisms involved in the cholesterol transport system via induction of plasma lipoprotein receptors. More specifically, it is proposed to examine the involvement of the transcription factor, Sterol Response Element Binding Protein which regulates the expression of cholesterol responsive genes in the theca-interstitial cells in response to LH and insulin.
In Aim 2, theca-interstitial cell hyperplasia will be examined by determining the regulation of cell cycle at the G1/S interphase by insulin alone or in the presence of LH.
Aim 3 will examine the inhibitory effect of androgens on ovarian follicular growth involving mTOR. This will be accomplished by identifying the signalling pathways involved in the action of mTOR-mediated regulation of granulosa cell growth and development in response to FSH and insulin. The specific step(s) in this pathway affected by dihydrotestosterone will also be determined. It is expected that the studies proposed in this application will help delineate the molecular basis for the secretion of excess androgens by the theca-interstitial cells and the destructive effect these androgens produce in preparing the ovarian follicles for ovulation. The results will have direct bearing on the understanding of the pathophysiology of androgen excess disorders like polycystic ovarian syndrome. Since polycystic ovarian syndrome is one of the most common causes of infertility in women, the proposed study is expected to generate valuable information that may have relevance in the understanding of this complex disorder.
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