Role of hyperandrogenemia in abnormal pubertal gonadotropin-releasing hormone (GnRH) secretion and development of PCOS



 DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is a prevalent reproductive disorder characterized by hyperandrogenism (HA) and oligo/anovulation with subfertility. It is also associated with obesity, insulin resistance and metabolic syndrome. PCOS is marked by excessive ovarian androgen production; ovarian HA is in part related to persistently elevated gonadotropin releasing hormone (GnRH) pulse frequency, which promotes high luteinizing hormone (LH) levels and relative follicle stimulating hormone (FSH) deficiency. The mechanisms underlying the neuroendocrine abnormalities of PCOS remain unclear. The emergence of PCOS is often traced back to puberty. Peripubertal HA is believed to represent a precursor to adult PCOS. The beginning of puberty is marked by sleep-related increases of LH pulse amplitude and frequency (mirroring GnRH pulses). Across normal pubertal maturation, there are day-night changes in LH (GnRH) pulse frequency. Although the underlying mechanisms for the diurnal changes are not known, these changes are thought to be important for appropriate gonadotropin secretion. Progesterone is the primary modulator of day-to-day GnRH pulse frequency in adult women, most notably by slowing GnRH pulse frequency (negative feedback) during the luteal phase of menstrual cycle. Our group has reported data suggesting a differential sensitivity of the GnRH pulse generator to progesterone negative feedback depending on sleep status during puberty. These data are consistent with the notion that sex steroids (e.g., progesterone) may be important regulators of daytime LH pulse frequency across puberty, while nighttime LH pulse frequency is heavily influenced by higher sleep centers (and less responsive to sex steroid feedback). The sensitivity of GnRH pulse generator to inhibition by progesterone is impaired in adults with PCOS, and this appears to be related to HA (it is reversed by androgen receptor blockade). Our preliminary data in pubertal girls suggested altered regulation of day-to-night change of LH pulse frequency that is specific to those with HA. Thus, we propose that pubertal HA may play an important role in aberrant pattern of GnRH secretion, causing LH excess and relative FSH deficiency, both of which contribute to worsening HA and disturbances of follicular development (and ovulation) as seen in PCOS. We propose the following aims to test our hypotheses. In Aim 1, we will assess the acute effect of progesterone on wake vs. sleep-related LH pulse frequency in mid- to late pubertal girls with and without HA. In Aim 2, we will assess effect of androgen receptor-blockade (spironolactone) on progesterone-associated suppression of LH pulse frequency in mid- to late pubertal girls with HA. A better understanding a potentially causal role of peripubertal HA will support the development of a rational preventive and/or treatment strategies to decrease morbidity associated with PCOS.