Polycystic ovary syndrome (PCOS) is a common disorder of women marked by hyperandrogenemia (HA) and ovulatory dysfunction. Additionally, PCOS is associated with obesity and other metabolic abnormalities (e.g., insulin resistance). A number of pathophysiological mechanisms underlie PCOS. Neuroendocrine abnormalities play a significant role in most women with PCOS. PCOS is associated with relative resistance of the gonadotropin releasing hormone pulse generator to negative feedback by progesterone and estradiol: this defect appears to be a result of HA, and can also occur in adolescents with HA. We have hypothesized that peripubertal HA can promote the development of PCOS in part via induction of hypothalamic resistance to negative feedback. However, the cause of peripubertal HA remains unknown. Obesity is a well-recognized pathophysiological factor in the HA of adult PCOS;and recent data demonstrate that peripubertal obesity is associated with HA. However, the mechanisms underlying the relationship between peripubertal obesity and HA?and the marked variability of androgens observed among obese girls?are unknown. Preliminary data suggests that obese pre- and early pubertal girls with high androgen levels also exhibit greater degrees of insulin resistance compared to obese girls with lower androgens.
Aim 1 of this pilot project involves detailed assessments of insulin resistance and LH pulsatility in obese peripubertal girls, and its primary goal is to define the importance of insulin resistance in causing HA in obese peripubertal girls. Secondarily, the contributions of elevated LH in obesity-associated HA across puberty will be assessed. Characterization of the factors underlying peripubertal HA may permit prediction of which pre- and early pubertal girls will subsequently go on to develop symptoms of PCOS. The goal of Aim 2 is to investigate other factors that may plausibly contribute directly to HA in peripubertal girls, including insulin-like growth factor-l [IGF-I], cytokines, and adipokines. In this setting, potential confounding factors (e.g., insulin, LH) will be carefully assessed. Data generated by this project will prompt novel future U54 studies to investigate the complex interactions among metabolic and classical endocrine pathways that lead to PCOS.

Public Health Relevance

The polycystic ovary syndrome (PCOS) is a highly-prevalent disorder of women that is marked by reproductive and metabolic abnormalities. PCOS is associated with obesity and often begins in adolescence. However, the cause of adolescent PCOS remains unknown. Through this project, the role of peripubertal obesity in the development of hyperandrogenemia and PCOS will be investigated.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD028934-20
Application #
8446136
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
20
Fiscal Year
2013
Total Cost
$108,521
Indirect Cost
$73,393
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Huizhen; Larson, Melissa; Jablonka-Shariff, Albina et al. (2014) Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice. Proc Natl Acad Sci U S A 111:5735-40
Torchen, Laura C; Fogel, Naomi R; Brickman, Wendy J et al. (2014) Persistent apparent pancreatic ?-cell defects in premenarchal PCOS relatives. J Clin Endocrinol Metab 99:3855-62
Liu, D M; Torchen, L C; Sung, Y et al. (2014) Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. Hum Reprod 29:2764-72
Collins, Jessicah S; Beller, Jennifer P; Burt Solorzano, Christine et al. (2014) Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia. J Clin Endocrinol Metab 99:2887-96
Roland, Alison V; Moenter, Suzanne M (2014) Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: insight from animal models. Front Neuroendocrinol 35:494-511
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
Pike, Jack W; McDowell, Erin; McCahan, Suzanne M et al. (2014) Identification of gene expression changes in postnatal rat foreskin after in utero anti-androgen exposure. Reprod Toxicol 47:42-50
Garcia, Thomas X; Costa, Guilherme M J; Fran├ža, Luiz R et al. (2014) Sub-acute intravenous administration of silver nanoparticles in male mice alters Leydig cell function and testosterone levels. Reprod Toxicol 45:59-70
Lu, Guanyi; Su, Gang; Zhao, Yunge et al. (2014) Dietary phytoestrogens inhibit experimental aneurysm formation in male mice. J Surg Res 188:326-38
Anderson, Amy D; Solorzano, Christine M Burt; McCartney, Christopher R (2014) Childhood obesity and its impact on the development of adolescent PCOS. Semin Reprod Med 32:202-13

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