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.
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.
|Bishop, Cecily V; Xu, Fuhua; Xu, Jing et al. (2016) Western-style diet, with and without chronic androgen treatment, alters the number, structure, and function of small antral follicles in ovaries of young adult monkeys. Fertil Steril 105:1023-34|
|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-MÃ¼llerian hormone by individual macaque follicles during three-dimensional culture. Hum Reprod 30:664-74|
|Dumesic, Daniel A; Goodarzi, Mark O; Chazenbalk, Gregorio D et al. (2014) Intrauterine environment and polycystic ovary syndrome. Semin Reprod Med 32:159-65|
|Simerman, Ariel A; Perone, Marcelo J; Gimeno, MarÃa L et al. (2014) A mystery unraveled: nontumorigenic pluripotent stem cells in human adult tissues. Expert Opin Biol Ther 14:917-29|
|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|
|Keller, Erica; Chazenbalk, Gregorio D; Aguilera, Paul et al. (2014) Impaired preadipocyte differentiation into adipocytes in subcutaneous abdominal adipose of PCOS-like female rhesus monkeys. Endocrinology 155:2696-703|
|Amin, Marli; Simerman, Ariel; Cho, Michele et al. (2014) 21-Hydroxylase-derived steroids in follicles of nonobese women undergoing ovarian stimulation for in vitro fertilization (IVF) positively correlate with lipid content of luteinized granulosa cells (LGCs) as a source of cholesterol for steroid synthesis. J Clin Endocrinol Metab 99:1299-306|
|Heneidi, Saleh; Simerman, Ariel A; Keller, Erica et al. (2013) Awakened by cellular stress: isolation and characterization of a novel population of pluripotent stem cells derived from human adipose tissue. PLoS One 8:e64752|
|Chazenbalk, Gregorio; Singh, Prapti; Irge, Dana et al. (2013) Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78:920-6|
|Varlamov, Oleg; Chu, Michael P; McGee, Whitney K et al. (2013) Ovarian cycle-specific regulation of adipose tissue lipid storage by testosterone in female nonhuman primates. Endocrinology 154:4126-35|
Showing the most recent 10 out of 11 publications