Neuroendocrine mechanisms responsible for elevated gonadotrophin‐releasing hormone and luteinising hormone pulses in polycystic ovary syndrome

Abstract Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in premenopausal individuals with ovaries worldwide. Despite the diagnostic features of anovulation, ovarian cysts, and hyperandrogenemia, which indicate that ovary dysfunction is the cause of the syndrome, changes in central neuroendocrine circuits are a significant cause of PCOS pathology. Specifically, cells in the hypothalamus have a diminished ability to transmit negative feedback signals from gonadal sex steroid hormones to gonadotropin‐releasing hormone (GnRH) neurons. This results in an elevated frequency of pulsatile hypothalamic GnRH and pituitary luteinizing hormone (LH) secretion, leading to ovarian hyperandrogenism and ovulatory dysfunction. In recent years, preclinical research in animal models has rapidly advanced our understanding of the neural mechanisms underlying GnRH pulse generation with the identification of KNDy cells—a unique cell population in the hypothalamus expressing the neuropeptides kisspeptin, neurokinin B and dynorphin. As a result, therapeutics targeting KNDy cell signaling have emerged as a promising avenue for treating GnRH/LH hypersecretion in PCOS patients. However, the precise central changes underpinning impaired negative feedback regulation of GnRH pulse generation in PCOS patients are still unclear. Evidence from both the clinic and animal models suggests that changes in the regulation of KNDy cells may be directly responsible for elevated GnRH and LH pulse frequency in PCOS. However, other cell populations regulating GnRH secretion may also be involved. This review provides an overview of our current understanding of the aetiology and contribution of neuroendocrine dysfunction in PCOS pathology. It also examines the evidence for neural mechanisms underlying GnRH/LH hypersecretion, which may serve as central targets in developing novel treatments. Finally, this review highlights key knowledge gaps that are hindering the development of preventive and curative interventions.