Pathophysiology and therapeutic strategy for late reproductive aged women with PCOS

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Project Summary Polycystic ovary syndrome (PCOS) is a highly prevalent reproductive disorder characterized by hyperandrogenism (HA) and oligo/anovulation. PCOS is also associated with metabolic syndrome, obesity and insulin resistance. In young women with PCOS, several factors contribute to HA: a) excess luteinizing hormone (LH) secretion, b) abnormal ovarian steroidogenesis, c) abnormal adrenal steroidogenesis, and d) hyperinsulinemia/ insulin resistance. Of interest, HA (and menstrual function) improves with age in PCOS. However, the relative contributions of the aforementioned HA-related factors in young adult vs. late reproductive-aged women with PCOS are not known. Identifying the most important predictor(s) of HA in older women with PCOS will be critically important for devising the most relevant therapeutic strategies for older women with PCOS. While oral contraceptives (OCs) that are effective in addressing HA and menstrual dysfunction, they are also associated with adverse cardiovascular risks that may be further increased with age. Therefore, for older women with PCOS, alternative therapies (e.g., metformin) could be preferable. In young women with PCOS, metformin has been shown to be effective for treating menstrual dysfunction and biochemical HA. However, the relative desirability of OC vs. metformin is not known in older PCOS women. We propose to determine the relative contributions of four established predictors of HA (LH secretion, ovarian response to recombinant human chorionic gonadotropin administration, adrenal response to adrenocorticotropic hormone administration, and hyperinsulinemia) in older vs. young women with PCOS in a physiological study (Aim 1). We will also determine the relative desirability (as determined by quality of life assessments) of metformin vs. OCs in treating PCOS in women of late reproductive age in a randomized cross-over study (Aim 2). Successful completion of these studies will provide 1) a more complete and cohesive understanding of how the determinants of HA change with aging in PCOS; and 2) critical insight into age-relevant therapeutic strategies for older reproductive aged women with PCOS. The proposed studies in this K23 grant will be performed under the mentorship of Christopher R. McCartney, M.D., who has made significant contributions to understanding the pathophysiology of PCOS for the past 18 years. The research environment at my institution (University of Virginia) is very collaborative and supportive. With a tremendous research support and dedication from my mentor and my institution, I will continue to refine my research skills needed to become an independent clinical investigator.