Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women. Essentially all suffer from excess ovarian androgen production which causes hirsutism and likely perpetuates multiple reproductive and metabolic disruptions associated with the disorder, including altered pituitary gonadotropin secretion, morphologic and functional ovarian abnormalities, altered adipose distribution, insulin resistance, and dyslipidemia. However, a comprehensive understanding of the mechanisms that dictate androgen overproduction is lacking, which may account for inconsistencies between measures of androgen excess and clinical presentation in individual cases. The need for detailed translational studies is underscored by the limited response to treatment of androgen excess in these patients. We hypothesize that in PCOS theca cell (TC) androgen production is influenced by a variety of extra- as well as intra-ovarian factors, although the relationships among these factors are not well understood. Accordingly, we will assess in detail the impact of increased LH secretion, in vivo and in vitro paracrine influences by the granulosa cell (GC), and the role of hyperinsulinemia on TC function. In addition, consideration of altered steroidogenic pathways to hyperandrogenemia will be explored with respect to the integrity of GC function, adrenal androgen production, and insulin secretion, all of which are implicated in androgen overproduction in PCOS. Initially, the ED{50} for hCG-stimulated TC response will be determined and subsequently used to test the roles of LH secretion including pulsatile release, FSH-stimulated GC paracrine factors, and increased (insulin infusion) and decreased (diazoxide) insulin levels. Delta-4 and -5 steroid pathways will be assessed among PCOS women that exhibit high and normal 17OHP responses to hCG relative to contributions of GCs (FSH stimulation), adrenal androgens (ACTH infusion), and insulin (diazoxide) that may be responsible of this disparity. In vitro, we will assess the molecular and cellular paracrine mechanisms by which GC-derived inhibin and kit ligand enhance TC androgen production using the human TC/GC primary co-culture system. The proposed studies will begin to delineate the multiple influences that drive excess ovarian androgen production and, hopefully, provide insight into novel and targeted treatment modalities for women suffering from PCOS.
A major feature of the PCOS phenotype is ovarian androgen excess, treatment for which is suboptimal. A detailed understanding of the mechanisms responsible for androgen production in women with PCOS is lacking. This proposal is designed to determine the relative roles of increased LH secretion, TC responsiveness, GC paracrine factors, hyperinsulinemia, and adrenal androgens with the intention of providing new approaches to therapy for women suffering from this disorder.
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