The NU SCOR explores the overarching hypothesis that genetic variation resulting in hyperandrogenemia produces the phenotypic features of the polycystic ovary syndrome (PCOS) by androgen programming in utero as well as by ongoing androgen actions at critical developmental periods and in the adult. We have found sex-specific metabolic phenotypes in PCOS families, mapped several PCOS susceptibility genes, developed animal models of androgen programming and discovered that androgen-mediated estrogen resistance is an important mechanism for these androgen actions. It is clear that the genes for PCOS so far identified do not explain the high heritability of this disorder. We will investigate te mechanisms for this deficit in heritability as well as the molecular mechanisms by which estrogen resistance can produce obesity and metabolic abnormalities in PCOS. Our strategy for achieving the SCOR objectives is to directly investigate the genetic, epigenetic and hormonal determinants PCOS in three highly interactive, synergistic and interdisciplinary projects: Projects I and II are clinical research projects and Projects III will utilize a novel non-human primate model. Although each project is discrete, the proposed SCOR as a whole will continue to comprehensively investigate novel mechanisms for the pathogenesis of PCOS. Project I will test the hypothesis that rare genetic variants will account for much of the deficit in heritabilityof PCOS. We predict that we will identify rare variants in pathways implicated in the pathogenesis of PCOS in mapping of common variants, such as TGF? signaling, Wnt signaling, insulin signaling, gonadotropin action and extracellular matrix, as well as rare variants in genes in novel pathways. Project II will test the hypothesis that a significant component of the heritability of PCOS is due to epigenetic changes including variation in methylation patterns, that these changes in methylation patterns correlate with changes in expression patterns, and that these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. Project III will develop a novel non-human primate (marmoset) model of diet-induced obesity to test the hypothesis that androgenic programming of metabolic features of PCOS is mediated by induction of resistance to the actions of estradiol in target hypothalamic neurons that modulate energy homeostasis. These studies are extremely innovative, highly synergistic and likely to have a major impact on the field through elucidating the pathogenesis of PCOS and its metabolic phenotypes.

Public Health Relevance

PCOS is one of the most common endocrine disorders of reproductive age women, affecting approximately 7% of this population. It is a leading risk factor for metabolic syndrome and type 2 diabetes mellitus in adolescent as well as adult women. The NU SCOR will elucidate the causes of PCOS leading to new prevention and treatment strategies. A novel non-human primate model of obesity will be developed that will be very important for studies of the causes of this epidemic disorder.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD044405-12
Application #
8549283
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (50))
Program Officer
Eisenberg, Esther
Project Start
2002-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$1,051,976
Indirect Cost
$249,928
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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) :
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
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
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
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 106:50-55

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