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 ^

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
2P50HD044405-11
Application #
8366640
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (50))
Project Start
Project End
Budget Start
2012-09-21
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$371,277
Indirect Cost
$126,674
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Torchen, Laura C; Idkowiak, Jan; Fogel, Naomi R et al. (2016) Evidence for Increased 5α-Reductase Activity During Early Childhood in Daughters of Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 101:2069-75
Dubois, Sharon L; Wolfe, Andrew; Radovick, Sally et al. (2016) Estradiol Restrains Prepubertal Gonadotropin Secretion in Female Mice via Activation of ERα in Kisspeptin Neurons. Endocrinology 157:1546-54
Navarro, Guadalupe; Xu, Weiwei; Jacobson, David A et al. (2016) Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male. Cell Metab 23:837-51
Xu, Beibei; Lovre, Dragana; Mauvais-Jarvis, Franck (2016) Effect of selective estrogen receptor modulators on metabolic homeostasis. Biochimie 124:92-7
Torchen, Laura C; Kumar, Ajay; Kalra, Bhanu et al. (2016) Increased antimüllerian hormone levels and other reproductive endocrine changes in adult male relatives of women with polycystic ovary syndrome. Fertil Steril 106:50-5
Dunaif, Andrea (2016) Perspectives in Polycystic Ovary Syndrome: From Hair to Eternity. J Clin Endocrinol Metab 101:759-68
Hayes, M Geoffrey; Urbanek, Margrit; Ehrmann, David A et al. (2016) Corrigendum: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 7:10762
Fuller, Miles; Priyadarshini, Medha; Gibbons, Sean M et al. (2015) The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis. Am J Physiol Endocrinol Metab 309:E840-51
Bethea, Cynthia L; Reddy, Arubala P; Flowers, Matthew et al. (2015) High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets. Prog Neuropsychopharmacol Biol Psychiatry 58:71-80
Dubois, Sharon L; Acosta-Martínez, Maricedes; DeJoseph, Mary R et al. (2015) Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology 156:1111-20

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