Neurotransmitter and neuromodulator imbalance in kisspeptin/GnRH regulation in rodent models of polycystic ovary syndrome and its implications for mental health disorders: A systematic review.

BACKGROUND

Polycystic ovary syndrome (PCOS) is an endocrine disease associated with hyperandrogenism, which causes infertility and often leads to mental health disorders. Although gonadotropin-releasing hormone (GnRH) neuronal dysfunction may contribute to PCOS, the pathophysiology of mood disorders associated with the syndrome remains unclear.

OBJECTIVE

We raise the question of whether imbalanced neurotransmitters controlling the mood state, such as GABA and monoamines, impact the reproductive neural circuit and may facilitate the emergence of mental health disorders in PCOS.

METHODS

We systematically reviewed gene and protein expressions, and neurotransmitter contents related to GnRH signaling in studies of rats and mice models of PCOS. Searches were conducted through PubMed and Web of Science and 52 research articles were included.

RESULTS

Our findings showed that the kisspeptinergic and noradrenergic signaling stimulates GnRH neurons in non-PCOS-like rodents. In contrast, serotonergic and GABAergic pathways exert receptor-dependent bidirectional effects, with distinct receptor subtypes mediating either inhibitory or excitatory influences. PCOS-like rodents present dysfunctional signaling to GnRH neurons, which is dependent on the PCOS model applied: i) postnatal androgenization leads to decreased kisspeptinergic, monoaminergic, and GABAergic signaling to GnRH neurons; ii) prenatal androgenization does not change kisspeptinergic signaling but monoaminergic and GABAergic alterations need further investigation in this model; iii) postnatal estrogenization results in reduced kisspeptinergic and GABAergic signaling, but the monoaminergic neurotransmission is increased in this model.

CONCLUSION

The reduction in kisspeptinergic, monoaminergic, and GABAergic neurotransmission in postnatally androgenized rats and mice suggests that pathways regulating reproduction and mood may share underlying neurobiological mechanisms under an androgenic milieu. Whether this signaling is similarly altered in PCOS patients with mental health disorders remains to be determined.