Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by hyperandrogenism and infertility and is commonly associated with increased rates of mental health disorders. Dysfunction of gonadotropin-releasing hormone (GnRH) neurons has been proposed as one contributor to PCOS pathophysiology. However, the neurobiological basis linking reproductive circuit alterations and mood changes in PCOS is not fully understood. The review synthesized available rodent-model data on neurotransmitters and neuromodulators that regulate GnRH and could intersect with mood-regulating systems.
The review asked whether imbalances in neurotransmitters known to influence mood—specifically GABA and monoamines—affect the reproductive neural circuit centered on kisspeptin/GnRH regulation and whether such imbalances might facilitate the emergence of mental health disorders in PCOS.
The authors conducted a systematic review of studies assessing gene and protein expression and neurotransmitter contents related to GnRH signaling in rats and mice modeling PCOS. Searches were carried out in PubMed and Web of Science. A total of 52 primary research articles met inclusion and were analyzed for patterns of neurotransmitter and neuromodulator changes linked to kisspeptinergic and other inputs to GnRH neurons.
Findings from non-PCOS-like rodents
In control (non-PCOS-like) rodent models, kisspeptinergic and noradrenergic signaling generally act to stimulate GnRH neurons.
Serotonergic and GABAergic pathways demonstrate receptor-dependent, bidirectional effects on GnRH neurons: distinct receptor subtypes can mediate either inhibitory or excitatory influences on GnRH cell activity.
Findings across PCOS-like rodent models
The review identified model-specific patterns of altered signaling to GnRH neurons:
Postnatal androgenization: This model shows decreased kisspeptinergic, monoaminergic, and GABAergic signaling directed to GnRH neurons. The authors interpret these concurrent reductions as evidence that androgen exposure postnatally can suppress multiple neurotransmitter systems that regulate both reproduction and mood.
Prenatal androgenization: In prenatally androgenized rodents, kisspeptinergic signaling was reported as not changed. The review indicates that alterations in monoaminergic and GABAergic systems in this model remain unclear or require further investigation based on the available studies.
Postnatal estrogenization: Rodents exposed to estrogen postnatally exhibited reduced kisspeptinergic and GABAergic signaling to GnRH neurons, while monoaminergic neurotransmission appeared increased in this model.
Overall interpretation of results
The pattern that emerges—particularly from postnatally androgenized animals—is a coordinated reduction in pathways that regulate both GnRH-driven reproductive function and neurotransmitter systems implicated in mood regulation. This convergence suggests potential shared neurobiological mechanisms by which an androgenic milieu could impact reproductive and affective outcomes.
The systematic review concludes that PCOS-like rodent models display dysfunctional signaling to GnRH neurons in a manner that depends on the specific model used. Postnatal androgenization consistently produced reductions in kisspeptinergic, monoaminergic, and GABAergic neurotransmission, implying overlapping neural mechanisms for reproduction and mood under androgen excess. Whether similar signaling alterations are present in human PCOS patients who experience mental health disorders remains to be determined.
The rodent data highlight the importance of kisspeptin and multiple neurotransmitter systems (GABA, monoamines, noradrenaline, serotonin) in coupling reproductive neuroendocrine regulation with circuits that influence mood. Translational studies are needed to test whether the model-specific alterations described here occur in humans with PCOS and comorbid psychiatric conditions.
The review underscores heterogeneity across preclinical models: different timing and type of steroid exposure (prenatal vs postnatal, androgen vs estrogen) produce distinct neurochemical outcomes. Future preclinical work should continue to clarify monoaminergic and GABAergic changes in prenatal androgenization models and to map receptor-subtype-specific effects of serotonergic and GABAergic inputs to GnRH neurons.
The authors note that direct extrapolation to patients is not yet supported by the reviewed animal studies; targeted clinical and translational research is required to establish whether these neural alterations underlie the increased prevalence of mood disorders in people with PCOS.
Note on reporting
Details such as specific genes, proteins, numerical effect sizes, or study-level quality assessments were not provided in the abstract summary. For those specifics, readers should consult the full systematic review and the 52 included primary studies.