Polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that occurs in 5-10% of premenopausal women, often producing both infertiliy and increased risk of metabolic and cardiovascular disease. The combined evidence obtained by our core investigators strongly supports our central hypothesis that PCOS has a genetic basis linked to excess androgen production, and that the androgen excess programs the pathogenesis ofthe disorder. Common metabolic features of PCOS include obesity, insulin resistance, and hyperinsulinemia, and our studies in rodents and monkeys have revealed that prenatal androgen excess can program development of these metabolic PCOS symptoms. Since many of these same PCOS features develop in estrogen- or estrogen receptor alpha (ERa)-deficient rodents, and following ERa targeting in the hypothalamus, and since prenatal androgen exposure induces resistance to many hypothalamic acfions of estradiol (E2), we have proposed the novel hypothesis that androgenic programming of metabolic features of PCOS is mediated by induction of hypothalamic resistance to E2. However, the mechanisms by which E2 may act in the hypothalamus to regulate energy homeostasis, metabolism, adiposity, and body weight in women and non-human primates remains largely unknown, and the ability of androgens to program altered hypothalamic E2 responsiveness remains untested. We will therefore determine the effects of E2 on energy homeostasis, metabolism, and adiposity in ovariectomized marmosets. We will utilize ER-specific agonist treatments to determine which ER isoform mediates E2 effects on metabolism in this primate. In a second experiment we will use adeno-associated viral vectors to knock-down ERa in hypothalamic target nuclei to ascertain the importance of discrete neuronal ER populations in the regulation of body weight and metabolism by E2. Finally, we will determine whether prenatal and postnatal androgen excess induces metabolic features of PCOS in marmosets, and whether any such effects are mediated by induction of resistance to E2 actions.

Public Health Relevance

These studies will provide the first information in any primate on the mechanisms by which E2 may act in the hypothalamus to regulate metabolism and body weight, and test whether androgens may program resistance to these actions to produce the metabolic features of PCOS. Our findings may thereby prompt development of new ER-based therapeutic strategies to prevent the development of metabolic disease, such as tvoe 2 diabetes, in PCOS ^

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Abbott, David H; Vepraskas, Sarah H; Horton, Teresa H et al. (2018) Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation. Neuroendocrinology 107:133-146
Kraynak, Marissa; Colman, Ricki J; Flowers, Matthew T et al. (2018) Ovarian estradiol supports sexual behavior but not energy homeostasis in female marmoset monkeys. Int J Obes (Lond) :
Gorsic, Lidija K; Kosova, Gulum; Werstein, Brian et al. (2017) Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:2862-2872
Abbott, D H; Rayome, B H; Dumesic, D A et al. (2017) Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys. Hum Reprod 32:923-936
Sam, Susan; Vellanki, Priyathama; Yalamanchi, Sudha K et al. (2017) Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome. Metabolism 71:125-131
True, Cadence; Abbott, David H; Roberts Jr, Charles T et al. (2017) Sex Differences in Androgen Regulation of Metabolism in Nonhuman Primates. Adv Exp Med Biol 1043:559-574
Kraynak, Marissa; Flowers, Matthew T; Shapiro, Robert A et al. (2017) Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys. Am J Physiol Endocrinol Metab 313:E507-E514
Gibson-Helm, Melanie; Teede, Helena; Dunaif, Andrea et al. (2017) Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:604-612
Dunaif, Andrea (2016) Perspectives in Polycystic Ovary Syndrome: From Hair to Eternity. J Clin Endocrinol Metab 101:759-68
Abbott, David H; Levine, Jon E; Dumesic, Daniel A (2016) Translational Insight Into Polycystic Ovary Syndrome (PCOS) From Female Monkeys with PCOS-like Traits. Curr Pharm Des 22:5625-5633

Showing the most recent 10 out of 123 publications