National Centers for Translational Research in Reproduction and Infertility
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Testosterone-GnRH Frequency and the Evolution of PCOS in Adolescence

University of Virginia

PI:  C. R. McCartney

Polycystic ovary syndrome (PCOS) affects approximately 8% of reproductive-aged women and is marked by hyperandrogenism and oligo/anovulation (with subfertility). 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.

Our primary goal is to understand the ontogeny of PCOS across pubertal development, especially with regard to abnormal gonadotropin-releasing hormone (GnRH) and gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) secretion. We will address two key gaps in knowledge: (1) How do the neuroendocrine abnormalities of PCOS (e.g., rapid GnRH pulse frequency and excessive LH secretion) develop during puberty? (2) Why does HA begin and progress in girls who go on to develop PCOS?

In brief, our working model for the pubertal development of PCOS in obese girls is as follows: Progesterone (P4) negative feedback is an important contributor to day-night differences of GnRH secretion during puberty, but HA antagonizes P4 negative feedback on the GnRH pulse generator. Entering neuroendocrine puberty in the setting of relative HA (initially of adrenal origin) promotes an abrupt transition to high 24-h GnRH pulse frequency: this favors LH over FSH secretion, which promotes ovarian HA and interferes with follicular development. In addition to disrupting P4 negative feedback,- HA antagonizes sex steroid positive feedback at the pituitary, leading to defective LH surges. Together, these neuroendocrine abnormalities support a progression to adolescent/adult PCOS.

The proposed project involves clinical research studies designed to elucidate the role of P4 in directing daynight differences of GnRH pulse frequency during puberty in normal girls (Aim la); the role of testosterone (and HA) in modifying day-night regulation of GnRH pulse frequency (Aims lb and 1c); the role of HA in disrupting sex steroid positive feedback (LH surge generation) in late pubertal girls (Aim 2); and the sources and determinants of HA in some pubertal girls with obesity (Aim 3). 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 strategies.