Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS)

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is the leading cause of anovulatory subfertility.Increased gonadotrophin releasing hormone (GnRH) pulsatility in the hypothalamus results in preferential luteinizing hormone (LH) secretion from the pituitary gland, leading to ovarian hyperandrogenism and oligo/anovulation.The resultant hyperandrogenism reduces negative feedback from sex steroids such as oestradiol and progesterone to the hypothalamus, and thus perpetuates the increase in GnRH pulsatility. GnRH neurons do not have receptors for oestrogen, progesterone, or androgens, and thus the disrupted feedback is hypothesized to occur via upstream neurons. Likely candidates for these upstream regulators of GnRH neuronal pulsatility are Kisspeptin, Neurokinin B (NKB), and Dynorphin neurons (termed KNDy neurons). Growing insight into the neuroendocrine dysfunction underpinning the heightened GnRH pulsatility seen in PCOS has led to research on the use of pharmaceutical agents that specifically target the activity of these KNDy neurons to attenuate symptoms of PCOS. This review aims to highlight the neuroendocrine abnormalities that lead to increased GnRH pulsatility in PCOS, and outline data on recent therapeutic advancements that could potentially be used to treat PCOS. Emerging evidence has investigated the use of neurokinin 3 receptor (NK3R) antagonists as a method of reducing GnRH pulsatility and alleviating features of PCOS such as hyperandrogenism. We also consider other potential mechanisms by which increased GnRH pulsatility is controlled, which could form the basis of future avenues of research.

Systemic and local pharmacological effects of melatonin targeting polycystic ovary syndrome based on network pharmacology

“…Intrinsic alterations in ovarian function, characterized by hyperandrogenemia and oligo/anovulation, are considered the direct culprits of PCOS (2). Growing insights into the neuroendocrine system underpinning the heightened gonadotrophin-releasing hormone (GnRH) pulsatility observed in PCOS have shed light on the causes or underlying biological alterations (3). Increased GnRH pulsatility promotes the secretion of luteinizing hormone (LH), which in turn stimulates ovarian androgen secretion.…”

Neurokinin 1/3 receptor antagonists for menopausal women: A current systematic review and insights into the investigational non-hormonal therapy

“…[25,26] NKB, a member of the tachykinin family of peptides, is encoded by TAC3 genes in humans and preferentially binds to NK3R. [27][28][29][30][31] Evidence suggests that NKB/NK3R signaling pathways play a pivotal role in central neuroendocrine pathways in human reproduction. [15,[32][33][34] Additionally, it has been found that kisspeptin, a neuropeptide that regulates the hypothalamic-pituitary-gonadal axis, works in concert with NKB in modulating reproductive functions.…”

The Application of Complementary and Alternative Medicine in Polycystic Ovary Syndrome Infertility

“…It is one of the most common causes of infertility in women of childbearing age. It is usually associated with reproductive complications (irregular menstruation, ovulation dysfunction, and pregnancy complications), metabolic disorders (type 2 diabetes and cardiovascular disease), and even psychological risk factors [1][2][3][4]. Depending on the population investigated and the diagnostic criteria used, the prevalence of PCOS ranges from 6% to 15% and approximately 75% of women with PCOS su er from infertility due to ovulation disorders, which makes infertility an urgent problem for PCOS patients [5][6][7].…”