PILOT PROJECT - FACTORS DETERMINING OBESITY-ASSOCIATED HYPERANDROGENEMIA IN GIRLS

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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.