Background Sex hormones have been associated with the risk of hyperuricemia (HUA) and gout in observational studies, but the potential causal relationships between sex hormones and risk of HUA and gout remain largely unclear. This study aimed to further investigate the mechanism underlying the causality between sex hormones, HUA, and gout in different genders. Methods We used sex‐specific genome‐wide association study (GWAS) data for European populations. The genetic correlation between sex hormones and serum urate or gout was analyzed using linkage disequilibrium score regression (LDSC). Two‐sample Mendelian randomization (MR) analysis assessed the causality between sex hormones (total testosterone ToT, bioavailable testosterone BioT, SHBG, estradiol, age at menarche, and age at menopause) and serum urate or gout, followed by sex‐stratified analysis. Colocalization analysis examined shared genetic variants between sex hormones and outcomes. Sensitivity analyses were additionally performed to address potential pleiotropy. A two‐step MR was conducted to evaluate the mediation effects of circulating metabolites linking sex hormones with serum urate. Results Genetic correlation analysis revealed moderate associations between sex hormones and serum urate/gout. MR analysis indicated a significant association between genetically predicted ToT and increased serum urate levels among women ( β : 0.035, 95% CI: 0.006–0.063, and p = 0.018). Mediation analysis suggested that androstenediol (3β, 17β) disulfate (2) partially mediated the effect of ToT on serum urate levels, with a mediation proportion of 28.4%. Conclusions These findings provide robust evidence that sex hormones influence urate metabolism with significant sex‐specific differences, suggesting tailored interventions for HUA, especially in European women with hyperandrogenism.
Li et al. (Thu,) studied this question.