Neuroendocrine Effects of Androgens in Adult Polycystic Ovary Syndrome and Female Puberty

Abstract

In addition to hyperandrogenism and ovulatory dysfunction, polycystic ovary syndrome (PCOS) is characterized by neuroendocrine abnormalities including a persistently rapid gonadotropin-releasing hormone (GnRH) pulse frequency. Rapid GnRH pulsatility favors pituitary secretion of luteinizing hormone (LH) over that of follicle-stimulating hormone (FSH). Excess LH stimulates ovarian androgen production, whereas relative deficits in FSH impair follicular development. The rapid GnRH pulse frequency is a result of reduced progesterone-mediated feedback inhibition of the GnRH pulse generator secondary to infrequent luteal phase increases in progesterone, as well as reduced hypothalamic sensitivity to progesterone feedback. Progesterone sensitivity is restored by treatment with the androgen receptor blocker flutamide. As such, hyperandrogenemia appears to play an important pathophysiologic role in PCOS. Adolescent hyperandrogenemia is believed to be a precursor to adult PCOS. In addition to increased LH concentrations and pulse frequency, some girls with elevated androgen levels also demonstrate reduced hypothalamic sensitivity to progesterone feedback. We hypothesize that excess peripubertal androgens may reduce the sensitivity of the GnRH pulse generator to sex steroid inhibition in susceptible individuals, resulting in increased GnRH pulse frequency and subsequent abnormalities in gonadotropin secretion, ovarian androgen production, and ovulatory function. Over time, these abnormalities may progress to the clinical hyperandrogenism and chronic oligo-ovulation typical of adult PCOS.