Diseases associated with hyperandrogenemia and obesity profoundly impact women's health, including fertility. Ovarian dysfunction and menstrual irregularity are commonly associated with hyperandrogenemia (notably in polycystic ovarian syndrome, PCOS), but it remains unclear which alterations are a cause versus effect of androgen action. Recent studies suggest that obesity-related factors, such as adipokines and inflammatory cytokines, also impair ovarian function, but direct evidence from primates is limited. Based on preliminary data, and the validation of primate models (chronically testosterone, T-exposed, and western style diet, WSD-treated monkeys), longitudinal studies on peri-pubertal to young adult, female rhesus macaques are designed to test the hypothesis that hyperandrogenemia or diet alone leads to abnormalities in follicular/oocyte development and uterine structure-function, which when combined will further impair reproductive potential.
The specific aims are to evaluate the effects of chronic (beginning just prior to menarche through young adulthood;years 1-4 of grant) T exposure and WSD, alone and in combination, on ovarian folliculogenesis and oocyte/embryo quality (AIM 1), plus menstrual cyclicity and uterine structure function (AIM 2);to identify the direct actions of androgen and adipokines on the primate follicle and oocyte at specific stages (preantral, small antral, preovulatory) of folliculogenesis (AIM 3);and to determine if the effects of T exposure, and/or WSD, on ovarian and uterine structure-function are reversible (AIM 4). Longitudinal studies will use circulating patterns and levels of hormones, sophisticated imaging (3-D Doppler and contrast-enhanced """"""""microbubble"""""""" ultrasound, MRI) plus follicular and uterine biopsies to monitor ovarian and uterine structure-function. Ovaries will also be obtained for acute (cumulus-oocyte complexes) and longterm (3-D alginate-encapsulated follicles) studies of androgen and lipokine actions. The project group will work closely with the NHP Core, which will maintain monkeys (n=12/grp) in each of the four groups (Control, T, WSD, and T + WSD treatment), and ultimately test the fertility of treated animals, prior to evaluation of reversibility of treatment effects in year 5. We will interact with Projects I and III (primate studies) and Project IV (clinical protocols) to integrate our observations with those on macaque hypothalamus-pituitary and adipose/liver function, and to relate our findings to clinical scenarios. Important, new information will accrue on the actions of androgen and obesity-related factors on ovarian and uterine structure-function, relevant to the etiology and treatment of clinical disorders, e.g., PCOS, and associated infertility.

Public Health Relevance

This collaborative effort between primate ovarian and uterine biologists, and imaging specialists, in consultation with infertility clinicians, will provide important new information on the actions of androgen and obesity-related factors on ovarian follicular/oocyte quality and uterine structure-function. This project (in synergy with Projects I and III) will use a primate model to improve our understanding of the etiology and treatment of women's health disorders associated with hyperandrogenemia and/or obesity, e.g., polycystic ovarian syndrome, and associated infertility.

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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Special Emphasis Panel (ZHD1-DSR-L (55))
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Oregon Health and Science University
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Rodrigues, J K; Navarro, P A; Zelinski, M B et al. (2015) Direct actions of androgens on the survival, growth and secretion of steroids and anti-Müllerian hormone by individual macaque follicles during three-dimensional culture. Hum Reprod 30:664-74
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