Hyperandrogenemia, Diet and Female Reproductive Health

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SUMMARY/ABSTRACT The Oregon National Primate Research Center (ONPRC) at the Oregon Health & Science University (OHSU) proposes to renew its P50 National Center for Translational Research in Reproduction and Infertility (NCTRI) that addresses the effects of hyperandrogenemia and obesity on female reproductive health. Progress in years 01-05 identified metabolic, adipose tissue, ovarian and uterine lesions, as well as subfertility, following chronic testosterone and/or a western-style diet (WSD) treatment of female macaques beginning at puberty through young adulthood. Further studies are proposed to determine if: (1) the effects become more pronounced as treatment continues into adulthood, and (2) the effects are, at least in part, reversed by removal of treatment. Three research projects use the nonhuman primate model at ONPRC, and one project focuses on the specific population of normal weight women with polycystic ovary syndrome (PCOS) at UCLA. Project I, “Metabolic and Adipose Responses to Hyperandrogenemia and Diet” is a collaboration between Drs. C. Roberts, C. True and O. Varlamov. Project II, “Ovarian Structure-Function: Influence of Androgen and Diet”, includes Drs. J. Hennebold, R. Stouffer and S, Chavez. Project III, “Effects of Androgen and Diet on Uterine-Placental Function”, involves Drs. O. Slayden, A. Frias and L. Myatt. Project IV, “Androgen Excess Causes Adipogenic Dysfunction in PCOS Women”, incorporates a consortium with Drs. D. Dumesic and G. Chazenbalk in the Department of Ob-Gyn, UCLA. Projects I-III will be supported by a nonhuman primate (NHP) Core (O. Slayden, Supervisor) operating as a closed resource. This Core will maintain four treatment groups of female rhesus monkeys (control, testosterone or T-treated, WSD-treated and T+WSD) for two additional years, including a fertility trial. Then procedures testing the effects of removal of T and WSD will be supported, including another fertility trial. The Administrative Core (Drs. R. Stouffer and J. Hennebold) will direct the NCTRI activities and promote interactions with other centers and NICHD officers. The Outreach Core (D. Gordon and Dr. M. Zelinski) will increase public awareness and understanding of reproductive health research. Important new information will accrue on the actions of androgen and diet-related factors, individually and in combination, relevant to the etiology of fertility disorders, such as PCOS. Also, the reversibility data will provide insight on the possible efficacy of novel treatments, including epigenetic changes that may limit therapies. The estimated prevalence of infertility in the human population is 9%, with mounting evidence that hyperandrogenemia or obesity alone lead to reproductive dysfunction, and combine to further impair fertility. However, the causes versus effects of androgen, particularly as related to reproductive dysfunction, are controversial. Mechanistic studies in primates and normal-weight PCOS women will discern between the roles of chronic androgen exposure and diet, and offer insight into improving therapy for infertility.