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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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University of California San Diego
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Sen, Supriya; Langiewicz, Magda; Jumaa, Hassan et al. (2015) Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology 61:171-83
Glidewell-Kenney, Christine A; Trang, Crystal; Shao, Paul P et al. (2014) Neurokinin B induces c-fos transcription via protein kinase C and activation of serum response factor and Elk-1 in immortalized GnRH neurons. Endocrinology 155:3909-19
Thackray, Varykina G (2014) Fox tales: regulation of gonadotropin gene expression by forkhead transcription factors. Mol Cell Endocrinol 385:62-70
Breen, Kellie M; Mellon, Pamela L (2014) Influence of stress-induced intermediates on gonadotropin gene expression in gonadotrope cells. Mol Cell Endocrinol 385:71-7
Collins, Jessicah S; Beller, Jennifer P; Burt Solorzano, Christine et al. (2014) Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia. J Clin Endocrinol Metab 99:2887-96
McGee, W K; Bishop, C V; Pohl, C R et al. (2014) Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys. Am J Physiol Endocrinol Metab 306:E1292-304
Ahow, Maryse; Min, Le; Pampillo, Macarena et al. (2014) KISS1R signals independently of G?q/11 and triggers LH secretion via the ?-arrestin pathway in the male mouse. Endocrinology 155:4433-46
Tolson, Kristen P; Garcia, Christian; Yen, Stephanie et al. (2014) Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Invest 124:3075-9
Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam et al. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513:436-9
Di Giorgio, Noelia P; Semaan, Sheila J; Kim, Joshua et al. (2014) Impaired GABAB receptor signaling dramatically up-regulates Kiss1 expression selectively in nonhypothalamic brain regions of adult but not prepubertal mice. Endocrinology 155:1033-44

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