Hyperkisspeptinemia and hypothalamic-pituitary-gonadal axis uncoupling in hemodialysis patients: clinical evidence suggestive of central desensitization.

BACKGROUND: Reproductive and sexual dysfunction (uremic hypogonadism) are pervasive in maintenance hemodialysis (MHD) patients, yet the underlying neuroendocrine mechanisms remain poorly understood. Kisspeptin is the master upstream regulator of the hypothalamic-pituitary-gonadal (HPG) axis. We hypothesized that uremia-induced kisspeptin accumulation is associated with HPG axis uncoupling through central desensitization. METHODS: In this cross-sectional study, 69 MHD patients and 20 age-matched healthy controls (HCs) were recruited. All participants were rigorously screened to exclude active inflammation and primary gonadal disease. Serum kisspeptin, gonadotropins, and sex steroids were quantified. Mediation analysis was performed to elucidate the pathophysiological pathway between kisspeptin and erectile dysfunction (ED) in males. RESULTS: Serum kisspeptin was profoundly elevated in MHD patients versus HCs (median, 30.35 vs 9.02 ng/ml; P < .001). In uremic females, despite profound hypoestrogenism and massive kisspeptin stimuli, compensatory gonadotropin surges were blunted (follicle-stimulating hormone: P = .138; luteinizing hormone: P = .149), suggesting potential pituitary desensitization. In uremic males, kisspeptin independently predicted decreased testosterone (β = -0.045, P = .046) after adjusting for age, C-reactive protein, and diabetes. Mediation analysis revealed a mediation pattern consistent with testosterone-mediated effects of kisspeptin's impact on erectile function (indirect effect P = .046; direct effect P = .081), suggesting that kisspeptin accumulation may be associated with ED exclusively by suppressing the HPG axis. Serum kisspeptin predicted moderate-to-severe ED (area under the curve 0.734, 95% confidence interval: 0.596-0.872). CONCLUSIONS: The marked hyperkisspeptinemia and concurrent HPG axis uncoupling observed in uremic patients are clinically suggestive of central neuroendocrine desensitization. Serum kisspeptin may serve as a novel exploratory functional proxy for the severity of uremic endocrine disruption, offering a potential target for therapeutic intervention.