Central Regulation of PCOS: Abnormal Neuronal-Reproductive-Metabolic Circuits in PCOS Pathophysiology

Abstract

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. PCOS patients are characterized by hyperandrogenemia, anovulation, and metabolic dysfunction. Hypothalamus-pituitary-ovary axis imbalance is considered as an important pathophysiology underlying PCOS, indicating that central modulation, especially the abnormal activation of hypothalamic GnRH neurons plays a vital role in PCOS development. Increased GnRH pulse frequency can promote LH secretion, leading to ovarian dysfunction and abnormal sex steroids synthesis. By contrast, peripheral sex steroids can modulate the action of GnRH neurons through a feedback effect, which is impaired in PCOS, thus forming a vicious cycle. Additionally, hypothalamic GnRH neurons not only serve as the final output pathway of central control of reproductive axis, but also as the central connection point where reproductive function and metabolic state inter-regulate with each other. Metabolic factors, such as insulin resistance and obesity in PCOS patients can regulate GnRH neurons activity, and ultimately regulate reproductive function. Besides, gut hormones act on both brain and peripheral organs to modify metabolic state. Gut microbiota disturbance is also related to many metabolic diseases and has been reported to play an essential part in PCOS development. This review concludes with the mechanism of central modulation and the interaction between neuroendocrine factors and reproductive or metabolic disorders in PCOS development. Furthermore, the role of the gut microenvironment as an important part involved in the abnormal neuronal-reproductive-metabolic circuits that contribute to PCOS is discussed, thus offering possible central and peripheral therapeutic targets for PCOS patients.

Keywords: gut microbiota; hypothalamus–pituitary–ovary axis; metabolic disorders; ovarian dysfunction; polycystic ovary syndrome.

Figure 1

Central regulation of PCOS. Hypothalamic GnRH pulse mediates regulation of LH and FSH synthesis, which plays an important role in PCOS pathophysiology. This process is modulated by central regulators including KNDy neurons, POMC neurons, and neurotransmitters. In addition, peripheral factors including abnormal ovarian hormone levels, metabolic disorders, and gut microbiota dysbiosis also contribute to PCOS development by acting on their receptors expressed in hypothalamic neurons. Moreover, central regulators and peripheral factors interact with each other and form an abnormal neuronal–reproductive–metabolic circuit, thus promoting PCOS development. GnRH, Gonadotropin-releasing hormone; KNDy neurons, kisspeptin/NKB/dynorphin A neurons; POMC neurons, Pro-opiomelanocortin neurons; GABA, γ-aminobutyric acid; GLP-1, Glucagon-like peptide-1; IR, Insulin receptor; LepR, Leptin receptor; AR, Androgen receptor; GLP-1R, Glucagon-like peptide-1 receptor; AMHR, Anti-Müllerian hormone receptor; LH, Luteinizing hormone; FSH, Follicle stimulating hormone; AMH, Anti-Müllerian hormone; SHBG, Sex hormone-binding globulin; IL-22, Interleukin 22; SCFAs, Short-chain fatty acids.