Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous syndrome of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Most PCOS women also have insulin resistance (IR) beyond that predicted by body mass index (BMI), increasing the risk for diabetes. Although many PCOS women are overweight, in nonobese PCOS women, breakdown of lipids (lipolysis) is decreased in subcutaneous (SC) abdominal fat cells (adipocytes), causing enlarged SC abdominal adipocytes that correlate in size with IR. This finding may be due to androgen excess, since androgen decreases lipolysis and inhibits SC abdominal adipogenesis, whereby adipose stem cells become preadipocytes and differentiate to adipocytes. Thus, androgen excess in PCOS may decrease numbers of adipocytes in SC abdominal adipose and reduce capacity of this adipose to safely store fat. When energy intake exceeds this capacity, SC abdominal adipocytes may overfill with lipid, mobilizing free fatty acids to ectopic locations (lipotoxicity), promoting IR and ovarian dysfunction. We hypothesize that androgen excess in lean PCOS women decreases adipogenic differentiation and increases adipocyte lipid content in a constrained SC abdominal adipose store, inducing lipotoxicity, IR and ovarian dysfunction. If so, antiandrogen therapy with flutamide for 6 months to lean PCOS women should improve SC abdominal adipogenesis, insulin sensitivity and ovarian function and morphology. We will 1) compare differences in SC abdominal adipogenesis in lean PCOS women vs. age- and BMI matched controls;2) examine the effect of 6-month fiutamide therapy in lean PCOS women on SC abdominal adipogenesis, body fat distribution, metabolic function and ovarian folliculogenesis;and 3) determine the underlying mechanisms whereby androgen inhibits adipogenesis. Understanding if androgen excess in lean PCOS women disrupts SC abdominal adipogenesis to impair ovarian function will establish a crucial link between adipogenic and ovarian dysfunction, allowing development of new clinical strategies that improve reproduction in PCOS women and enhance safety of ovulation-inducing agents during infertility therapy.

Public Health Relevance

Women with polycystic ovary syndrome (PCOS) have androgen excess, ovarian dysfunction and abnormal glucose metabolism. Their elevated androgen levels may impair subcutaneous (SC) abdominal fat storage, mobilizing fatty acids and substances from fat to other tissues, disrupting ovarian function and glucose metabolism. Blocking excess androgen action with the antiandrogen flutamide in lean PCOS women may restore SC abdominal fat storage, ovulation and metabolism, improving reproduction in PCOS women and enhancing safety of ovulation-inducing agents in those individuals who need them.

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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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-Müllerian 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, María 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

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