The unifying hypothesis of the NU SCOR continues to be that genetic variation resulting in hyperandrogenemia causes many of the phenotypic features of PCOS by prenatal androgen programming as well as by continued androgen excess in the adult. The following exciting findings from the initial award period support this hypothesis: 1) a major PCOS susceptibility variant, allele 8 (A8) of D19S884, has been mapped to intron 55 of the fibrillin-3 gene, 2) a distinctive metabolic phenotype, hepatic insulin resistance, is associated with the A8 variant;3) prenatal androgen excess causes LH secretory defect, insulin resistance and increased visceral adiposity, all features of PCOS, in animal models;4) LH secretory changes result from decreased expression of hypothalamic potassium sensitive ATP (KATP) channels that modulate gonadotropin releasing hormone (GnRH) secretion. Prenatal androgen exposure induces resistance to estrogen-mediated increases in KATP channel expression that occur through induction of progesterone receptor expression. 5) Prenatal androgens also decrease expression of KATP channels in pancreatic /Beta-cells providing one potential mechanism for the metabolic phenotype. Project 1 will investigate the mechanisms of hepatic insulin resistance associated with the A8 genotype in women with PCOS including the role of androgens. Potential sex-specific effects will be investigated in male first degree relatives with A8 genotype. Project 2 will investigate the impact of variation in D19S884 on parameters of glycemic control and pregnancy outcome in mothers and their infants from a large multiethnic population, including the possible association of D19S884 allelic variation with androgen levels in this non-PCOS population. In addition, the potential role of fibrillin-3 itself in the pathogenesis of PCOS will be investigated by examining the TGF/B signaling pathway, which is potentially modulated by this molecule. Project 3 is a new project that will investigate the cellular and molecular mechanisms of androgen action on pancreatic B-cells. Project 4 will pursue the mechanisms that may mediate androgen programming of the distinctive metabolic phenotype associated with A8, in particular, the hypothesis androgen exposure produces the metabolic defects of PCOS by programming resistance to estrogen's metabolic actions in the brain or periphery.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD044405-08
Application #
7678046
Study Section
Special Emphasis Panel (ZRG1-HOP-U (40))
Program Officer
Parrott, Estella C
Project Start
2002-09-27
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
8
Fiscal Year
2009
Total Cost
$1,157,399
Indirect Cost
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
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
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
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

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