Neuroendocrine dysfunction in polycystic ovary syndrome

Abstract

Polycystic ovarian syndrome (PCOS) is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Neuroendocrine abnormalities including increased gonadotropin-releasing hormone (GnRH) pulse frequency, increased luteinizing hormone (LH) pulsatility, and relatively decreased follicle stimulating hormone contribute to its pathogenesis. HA reduces inhibition of GnRH pulse frequency by progesterone, causing rapid LH pulse secretion and increasing ovarian androgen production. The origins of persistently rapid GnRH secretion are unknown but appear to evolve during puberty. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. However, even early pubertal girls with HA have increased LH pulsatility and enhanced daytime LH pulse secretion, indicating the abnormalities may begin early in puberty. Decreasing sensitivity to progesterone may regulate normal maturation of LH secretion, potentially related to normally increasing levels of testosterone during puberty. This change in sensitivity may become exaggerated in girls with HA. Many girls with HA-especially those with hyperinsulinemia-do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA and the development of PCOS.

Fig. 1

Late evening [surrogate for daytime] and overnight luteinizing hormone (LH) pulse frequency characteristics in obese [defined as body-mass-index percentile- for-age >95] (solid) and non-obese (open) girls stratified by breast Tanner stage. Overnight LH pulse frequency is similar throughout pubertal maturation in nonobese girls. *p<0.05 compared to baseline sample. ^ap<0.05 compared to non-obese girls. Modified with permission from McCartney CR, Prendergast KA, Blank SK, Helm KD, Chhabra S, Marshall JC. Maturation of luteinizing hormone (gonadotropin-releasing hormone) secretion across puberty: evidence for altered regulation in obese peripubertal girls. J Clin Endocrinol Metab 2009;94:56–66 [24]; Copyright 2009, The Endocrine Society.

Fig. 2

The percent change in luteinizing hormone (LH) pulse frequency per 11 h following 7 days of oral estradiol and progesterone in breast Tanner stage 1–2 normal control (NC) (A), Tanner 3–5 NC (B), and hyperandrogenemic (HA) (C) adolescent girls. The data are plotted as a function of mean plasma progesterone on day 7. The Tanner 1–2 subjects are labeled with the Tanner stages of the individual subjects. The shaded areas represent the ranges of responses to 7 days of oral estradiol and progesterone in NC adult women. T = testosterone. Modified with permission from Blank SK, McCartney CR, Chhabra S, Helm KD, Eagleson CA, Chang RJ, et al. Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls—implications for regulation of pubertal maturation. J Clin Endocrinol Metab 2009:94;2360–6 [25]; Copyright 2009, The Endocrine Society.

Fig. 3

(A) Schematic representation of testosterone levels and hypothesized changes in hypothalamic sensitivity to feedback inhibition by sex steroids in normal and hyperandrogenemic (HA) adolescent girls during puberty. (B) Schematic representation of the evolution in 24-h patterns of gonadotropin-releasing hormone (GnRH; solid line) and sex steroids (dashed line) during puberty in normal (top) and HA (bottom) girls. Shaded areas represent periods of sleep. Modified from Blank SK, McCartney CR, Marshall JC. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum Reprod Update 2006;12(4):351–361 by permission of Oxford University Press [50].

Fig. 4

Schema of proposed effects of hyperandrogenemia (HA) on gonadotropin-releasing hormone (GnRH) secretion and subsequent luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production during puberty in susceptible adolescent girls. E₂, estradiol; P, progesterone. Modified with permission from Blank SK, McCartney CR, Helm KD, Marshall JC. Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty. Semin Reprod Med 2007;25:352–359 [51].