Kisspeptin mediates the impact of chronic psychological stress on reproductive and metabolic dysregulation in polycystic ovary syndrome: evidence from human and rat models

Polycystic ovary syndrome (PCOS) and mental health disorders have high rates of co-occurrence. Although the precise pathophysiological mechanisms remain unknown, the observed changes in those conditions may be modulated by kisspeptin (Kiss1), a protein that regulates energy metabolism. The aim of this study was to investigate whether Kiss1 plays an important role in linking dysfunctional reproductive processes and abnormalities in energy metabolism in PCOS, both in humans and using a rat model of PCOS combined with chronic unpredictable mind stress (CUMS). In 27 women with PCOS and 11 controls, fasting insulin (INS), blood glucose, Kiss1, and monoamine neurotransmitter levels were measured. For the animal experiments, the 16 rats were divided into control, PCOS, CUMS, and PCOS + CUMS groups to assess changes in behaviour, reproductive endocrine function, glucose metabolism, and granulosa cell apoptosis, as well as alterations in the expression levels of Kiss1, Kiss1 receptor (Kiss1R), and gonadotropin-releasing hormone (GnRH) in hypothalamic tissues and changes in INS-like growth factor 1 (IGF-1) and IGF-binding protein 1 (IGFBP-1) levels in ovarian tissues. The body mass index, fasting INS levels, homeostatic model assessment of insulin resistance (HOMA-IR) index, and serum Kiss1 levels were significantly elevated in women with PCOS compared to the values in the healthy controls, whereas serum monoamine neurotransmitters levels were lower. Kiss1 levels negatively correlated with monoamine neurotransmitter concentrations and positively correlated with both INS levels and the HOMA-IR index. In the PCOS+CUMS model rats, reproductive endocrine dysfunction, abnormal glucose metabolism, and depressive-like behaviours were observed; these changes were accompanied by upregulated expression of Kiss1 and gonadotropin-releasing hormone (GnRH), downregulated IGF-1 levels, and increased ovarian granulosa cell apoptosis. CUMS exposure reduces monoamine neurotransmitter levels in PCOS, weakening Kiss1’s inhibitory effects., while regulating ovarian IGF-1 expression may promote granulosa cell apoptosis and reduce INS sensitivity, aggravating reproductive endocrine disorders and abnormal glucose metabolism in patients with PCOS-related psychological stress.