The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS)

Abstract

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women.

Keywords: GABA; GnRH; Kiss1; Kisspeptin; LH; PCOS; androgen; brain; neuroendocrine; pulses.

Figure 1

Changes in the brain and neuroendocrine reproductive axis in PCOS women and PCOS-like animal models. Clinical studies demonstrate very high circulating LH levels in PCOS individuals, and this is recapitulated in the prenatally androgenized (PNA) and letrozole (LET) preclinical animal models. These high-frequency LH pulses contribute to thecal cell hyperplasia and stimulate increased production and secretion of ovarian androgens, contributing to hyperandrogenemia. The elevated LH levels and LH pulse frequency seen in PCOS and the PCOS animal models point to an upstream hyperactive GnRH neural circuit. In PNA mice and mice prenatally treated with AMH (PAMH), there is an increased firing rate of GnRH neurons. PNA mice also exhibit an increase in upstream GABAergic postsynaptic currents (PSCs). There is also impaired sex steroid negative feedback observed in PNA models and PCOS women, and this may be mediated by alterations in afferent hypothalamic GABA neurons, at least in PNA mice. In relation to this, progesterone receptor (PR) expression is decreased in ARN GABA neurons in PNA mice and in the mediobasal hypothalamus of LET mice. Alongside GABA, there is also an increase in ARN KNDy cells and ARN Kiss1 and Tac2 mRNA levels in PNA and LET PCOS models, possibly providing an increase in excitatory signals to GnRH neurons. Refer to the article text for discussion on species differences and specific brain parameters that have not yet been assessed in different models. [LH—luteinizing hormone; PNA—prenatally androgenized animals; LET—letrozole-treated PCOS models; H—human/clinical data from PCOS women].