Metabolic‐endocrine correlates of gut‐brain axis mediators in polycystic ovary syndrome: A case–control study

Polycystic ovary syndrome (PCOS) is increasingly recognized as a neuro-metabolic disorder involving disrupted signaling between the brain-gut axis and reproductive system. Peptides such as kisspeptin, ghrelin, serotonin, and peptide tyrosine tyrosine (PYY) are emerging as integrators of metabolic and endocrine function, yet their coordinated alterations in PCOS and relevance to metabolic risk remain underexplored. Therefore, we investigated the combined pattern of serum kisspeptin, ghrelin, serotonin, and PYY in PCOS, and their associations with metabolic and hormonal indices. In this case-control study, a total of 190 women aged 18-40 years were included between June 2023 and June 2024, comprising 96 women diagnosed with PCOS according to 2003 Rotterdam criteria and 94 age-matched healthy controls. Serum levels of kisspeptin, ghrelin, serotonin, and PYY were measured using ELISA. Secondary assessments included clinical, metabolic, hormonal, and inflammatory parameters. Women with PCOS had significantly higher serum kisspeptin levels and lower ghrelin and serotonin levels compared to controls (p < .05), while PYY levels were similar between the groups. Kisspeptin was inversely correlated with ghrelin (r = -.237, p = .003) and serotonin (r = -.303, p < .001). These peptides also showed significant associations with metabolic indices such as fasting insulin, glucose, HOMA-IR, triglyceride-glucose (TyG), and TyG-BMI ratios. In regression models adjusted for BMI, lower ghrelin (OR = 0.661, p = .008) and serotonin (OR = 0.814, p = .016) levels were independently associated with higher odds of PCOS. Exploratory receiver operating characteristic (ROC) analysis showed that kisspeptin demonstrated moderate discriminatory performance for PCOS (AUC = 0.768; 95% CI: 0.696-0.839), with 82.4% sensitivity and 59% specificity, whereas ghrelin, serotonin, and PYY showed lower AUCs, reflecting limited stand-alone discriminatory ability. Elevated kisspeptin with concomitant reductions in ghrelin and serotonin define a reproducible peptide signature in PCOS, linking neuroendocrine perturbations to measurable metabolic risk, independent of obesity. While kisspeptin shows greater biological separation between groups, none of the peptides alone are sufficient for diagnostic classification; instead, they indicate the central role of hypothalamic-gut axis dysfunction, particularly in lean PCOS phenotypes.