Polycystic Ovarian Syndrome (PCOS) is a common clinical disorder affecting 6-8% of women of reproductive age. Features include anovulation and hyperandrogenemia, commonly associated with hyperinsulinemia, obesity, dyslipidemia and other manifestations of the metabolic syndrome. Plasma LH levels are elevated in up to 90% of subjects, which reflects a persistent rapid frequency of GnRH secretion. This impairs the ability to differentially secrete FSH and LH resulting in anovulatory cycles and hyperandrogenemia (HA). The etiology of the disorder is unknown, but adolescent girls with HA also demonstrate rapid GnRH pulse secretion and elevated LH, which evolves before or during pubertal maturation. In both adolescents and adults, abnormal regulation of GnRH in part reflects impaired sensitivity to progesterone (P) inhibition, a consequence of elevated androgen levels. We propose that elevated androgens prior to and during pubertal maturation, impair the normal evolution of ovarian regulation of GnRH secretion. Obesity is common in girls (approx. 1 in 5 of 6-19yo) and is associated with marked HA in 60- 90%. Thus, the recent increase in obesity may predispose to PCOS via elevated androgens impairing steroid feedback on the hypothalamus and resulting in abnormal GnRH secretion. In SA1 we aim to assess the role of plasma androgens in modifying GnRH sensitivity to negative feedback of estradiol (E2) and P in both normal and HA girls. We will assess if the normal rise in testosterone (T) is part of the normal modification of hypothalamic feedback set points during adolescence and also establish if excess androgen impairs feedback and whether this can be corrected by androgen receptor (AR) blockade or by reduction of insulin and T after treatment with metformin for 3 months. We will also examine potential mechanisms of varied hypothalamic sensitivity to HA by examining polymorphisms of the AR CAG repeat. We identified that nocturnal P secretion occurs in pre and early pubertal girls, which may represent the initiation of normal ovarian control of GnRH pulse secretion. In SA2 we assess the role of P in suppressing GnRH frequency during the day and during sleep in both normal and HA girls, and if impaired, whether this can be corrected by AR blockade. Prepubertal obesity is associated with marked elevations in T and in SA3 we explore the contribution of the adrenal gland to the production of P and excess T in early puberty, a stage when the ovary is relatively immature.
The overall goal is to establish the etiology and mechanisms of abnormal regulation of hypothalamic GnRH secretion during adolescence in girls with HA, a forerunner of adult PCOS. The prevalence of obesity in 6- 19yo girls has increased 4-fold in the past 30y and 60-90% of obese girls have HA. We also seek to identify markers allowing early identification of girls susceptible to the negative hypothalamic effects of elevated testosterone, which would allow prospective reduction in the incidence of PCOS during adulthood.
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