Serum FGF-23 and α-Klotho Levels in Prolactinoma and Non-Tumoral Hyperprolactinemia: An Exploratory Cross-Sectional Comparative Study

Background/Objectives: This study aimed to evaluate serum fibroblast growth factor-23 (FGF-23) and α-Klotho levels in patients with prolactinoma and patients with non-tumoral hyperprolactinemia and to explore their discriminatory performance for prolactinoma. Methods: Seventy-three participants were included in this single-center, cross-sectional comparative study: non-tumoral hyperprolactinemia (n = 14), prolactinoma (n = 29), and healthy controls (n = 30). All patients with prolactinoma had received dopamine agonist therapy for at least six months. Serum FGF-23 and α-Klotho were measured by ELISA, and between-group comparisons, correlation analyses, linear regression analyses, and receiver operating characteristic (ROC) analyses were performed. Results: FGF-23 concentrations differed significantly among the groups (overall p < 0.001). Post hoc analysis showed that FGF-23 concentrations were significantly higher in the prolactinoma group [236.10 (107.70–667.90) pg/mL] than in healthy controls [138.75 (49.40–253.60) pg/mL] (adjusted p < 0.001), whereas the difference between the prolactinoma and non-tumoral hyperprolactinemia groups [166.20 (100.30–327.20) pg/mL] was not statistically significant (adjusted p = 0.075). α-Klotho concentrations were significantly higher in the prolactinoma group [2.908 (1.376–6.257) ng/mL] than in both the non-tumoral hyperprolactinemia group [2.244 (1.432–5.139) ng/mL] (adjusted p = 0.038) and healthy controls [2.204 (0.149–4.917) ng/mL] (adjusted p < 0.001). In pooled analyses, both biomarkers showed positive correlations with prolactin and weak negative correlations with hemoglobin. However, prolactin and hemoglobin were not independently associated with either biomarker after multivariable adjustment. The non-tumoral hyperprolactinemia group did not differ significantly from healthy controls for either biomarker. For distinguishing prolactinoma from non-tumoral hyperprolactinemia, the AUCs were 0.741 for FGF-23, 0.732 for α-Klotho, and 0.862 for the exploratory combined model. Conclusions: Dopamine agonist-treated prolactinoma was characterized by higher circulating FGF-23 concentrations than those in healthy controls and by higher α-Klotho concentrations than those in both healthy controls and patients with non-tumoral hyperprolactinemia. Exploratory ROC analyses suggested moderate discriminatory performance for the individual biomarkers and higher apparent performance for the combined model; however, these findings should be interpreted cautiously and require validation in larger, treatment-naïve cohorts.