Sex differences in classic congenital adrenal hyperplasia: a multicenter, real-world analysis

Background The phenotypic variability of classic congenital adrenal hyperplasia (CAH) demands tailored management to optimize disease control and attenuate long-term consequences. Although sex-specific differences have been recognized, real-world evidence in adults remains limited and inconsistent. Therefore, this study aimed to compare the clinical, metabolic, and hormonal profiles of adult male and female patients with classic CAH and identify sex-specific predictors of biochemical control.Methods In this multicenter, real-world analysis, records from adult CAH patients followed at four Italian tertiary centers, focusing on anthropometry, glucocorticoid (GC) therapy, biochemical and hormonal parameters, were retrospectively collected. Whole cohort and sex-stratified predictors of uncontrolled disease were then identified.Results Overall, 123 patients [77 females, 30.5 (24-37) years; 46 males, 32 (23-40) years] were enrolled. Males showed greater overweight/obesity rates (75.6% vs. 46.7%, p = 0.001), BMI (26.6 vs. 24.4 kg/m2, p = 0.003) and visceral adiposity indices [waist-to-height ratio (WHtR) 0.55 vs. 0.51, p = 0.006]. GC formulations and total daily doses were comparable between the sexes. Uncontrolled disease occurred in 26.2% of males and 17.6% of females (p = 0.271). WHtR was the strongest predictor of androstenedione (beta = 0.311, p = 0.003). Sex-stratified analysis revealed that visceral adiposity and glucose metabolism abnormalities were critical predictors of poor control among males but not females.Conclusions Adult males with CAH may face a vicious cycle of adiposity-driven metabolic and hormonal dysregulation, hindering disease control; however, estrogens may counteract these effects in well-controlled females. These results advocate for prioritizing metabolic health for long-term CAH management.