ROLE OF ANDROGENS IN THE NEUROENDOCRINE DYSFUNCTION OF NASCENT PCOS

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Hyperandrogenic polycystic ovary syndrome (PCOS) affects approximately 8-10% of reproductive-aged women. PCOS is a major cause of infertility and poor gynecological health, and it is associated with obesity, insulin resistance/hyperinsulinemia, type 2 diabetes, and endometrial cancer. The underlying causes of PCOS remain unclear, but puberty is a critical developmental window during which the pathophysiology of PCOS unfolds. Peripubertal hyperandrogenemia (HA) can represent a precursor to full-blown PCOS, and HA is very common (~ 60% overall) in peripubertal girls with obesity. Thus, the study of peripubertal girls with obesity provides an opportunity to evaluate the causes and consequences of peripubertal HA, in addition to providing key insights into how asymptomatic HA progresses to full-blown PCOS. This proposal is designed to elucidate how PCOS begins and develops across puberty, primarily focusing on the role of abnormal gonadotropin- releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) secretion. More specifically, this proposal will address the following working model regarding the emergence of neuroendocrine abnormalities in PCOS: (1) peripubertal HA (from any source) leads to abnormal sleep-wake patterns of LH (GnRH) pulse frequency—namely, high 24-hour frequency without normal sleep-wake changes—which contributes to LH excess, ovarian HA, FSH deficiency, and anovulation; (2) peripubertal HA also antagonizes estrogen- (and progesterone-) induced gonadotropin surge generation—another impediment to the establishment of cyclic ovulatory function. Aim 1 of the proposed project involves clinical research studies designed to assess the following: if acute progesterone suppression of wake LH pulse frequency is impaired in girls with HA (Aim 1a); if androgen-receptor blockade (spironolactone) improves progesterone-suppression of wake LH pulse frequency in girls with HA (Aim 1b); if spironolactone alone normalizes sleep-wake LH/FSH secretion in girls with HA (Aim 1c); and if daily (morning) low-dose progesterone administration normalizes sleep-wake LH/FSH secretion in girls with HA (a pilot trial of therapeutic plausibility; Aim 1d). Aim 2 of the proposed project involves clinical research studies designed to: assess progesterone augmentation of gonadotropin secretion in late pubertal girls with HA (Aim 2a); evaluate the ability of androgen-receptor blockade to normalize progesterone augmentation of gonadotropin secretion in PCOS (Aim 2b); and assess potential impairments in estradiol augmentation of gonadotropin release in PCOS (Aim 2c). These human studies will provide insight into mechanisms underlying the development of abnormal gonadotropin secretion in nascent PCOS. These studies will synergize with the basic studies of Projects II and III to help elucidate the pubertal ontogeny of PCOS, all with a view to developing rational preventive and/or treatment strategies.