GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile

Abstract

BackgroundGnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS.MethodsPCOS was induced in rats by oral administration of letrozole (aromatase inhibitor). Following PCOS validation, animals were assessed for gonadotropin levels and their mRNA expression. Neurotrasnmitter status was evaluated by estimating their levels, their metabolism and their receptor expression in hypothalamus, pituitary, hippocampus and frontal cortex of PCOS rat model.ResultsWe demonstrate that GnRH and LH inhibitory neurotransmitters – serotonin, dopamine, GABA and acetylcholine – are reduced while glutamate, a major stimulator of GnRH and LH release, is increased in the PCOS condition. Concomitant changes were observed for neurotransmitter metabolising enzymes and their receptors as well.ConclusionOur results reveal that increased GnRH and LH pulsatility in PCOS condition likely result from the cumulative effect of altered GnRH stimulatory and inhibitory neurotransmitters in hypothalamic-pituitary centre. This, we hypothesise, is responsible for the depression and anxiety-like mood disorders commonly seen in PCOS women.

Neuroendocrine characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

“…GnRH neurons play a role in the central regulation of fertility. A pulsatile signal of GnRH is necessary for the secretion of LH and FSH (follicle-stimulating hormone), which promotes steroidogenesis and follicular development in females (Chaudhari et al, 2018 ). In the altered hypothalamic-pituitary-gonadal axis, high levels of LH reflect increased GnRH release.…”

Animal models of polycystic ovary syndrome: A review of hormone‐induced rodent models focused on hypothalamus‐pituitary‐ovary axis and neuropeptides

“…Kiss1 mRNA expression levels in the posterior hypothalamus were higher in letrozole‐treated as compared to control rats, whereas no difference was observed in the anterior hypothalamus . Additionally, in letrozole‐treated rats, the levels of neurotransmitters that inhibit GnRH and LH release (serotonin, dopamine, GABA, and acetylcholine) were reduced whereas that of a stimulatory neurotransmitter (glutamate) was increased in the hypothalamus and pituitary …”

“…After 4 days of RU486 treatment, rats showed irregular cycles consisting of persistent estrous. [46][47][48]…”

The leaf aqueous extract of Myrianthus arboreus P. Beauv. (Cecropiaceae) improved letrozole-induced polycystic ovarian syndrome associated conditions and infertility in female Wistar rats

“…Treatments were given orally (every morning from 06: 30 a.m. to 07 h30 a.m.) for 30 consecutive days. During this treatment period, the administration of letrozole was not interrupted as the latter is a reversible aromatase inhibitor [4,22]. Thus, to maintain the cause of PCOS (aromatase inhibition) in experimental animals, letrozole was co-administered with the aqueous extract of M. arboreus leaves during the treatment period to determine whether or not the aforementioned extract could improve PCOS symptoms despite the presence of the causal element.…”