Sex-specific associations of SHBG, testosterone, and obesity with cholecystectomy risk: a population-based cohort study

Abstract Background Gallstone disease exhibits a marked sex difference. While obesity and female sex hormones are known risk factors, the role of sex hormone-binding globulin (SHBG) and testosterone in gallstone-related risk, and whether they mediate the association between obesity and gallbladder disease, remain unclear. Methods We included 176,909 men and 160,147 women from the UK Biobank. Serum SHBG and testosterone were measured using immunoassays. Incident cholecystectomy cases were identified through hospital records. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Mediation analyses were performed to assess the contribution of SHBG and testosterone to the obesity-cholecystectomy association. Results A total of 2,877 men and 4,607 women underwent cholecystectomy. Higher SHBG levels were associated with a lower risk of cholecystectomy in both sexes, with a stronger association in women (HR Q4 vs. Q1 = 0.40, 95% CI: 0.36–0.43) than in men (HR Q4 vs. Q1 = 0.67, 95% CI: 0.59–0.77). Elevated testosterone levels were associated with an increased risk of cholecystectomy only in women (HR Q4 vs. Q1 = 1.28; 95% CI: 1.18–1.38). Obesity exhibited a stronger association with cholecystectomy in women than in men. In women, SHBG mediated 14.7% and 20.0% of the associations between general and abdominal obesity and cholecystectomy, respectively, whereas testosterone mediated smaller proportions (2.7% and 1.8%). No significant mediation was observed in men. Conclusions SHBG levels are inversely associated with risk of cholecystectomy in both sexes, whereas higher testosterone levels are associated with a higher risk of cholecystectomy only in women. SHBG and, to a lesser extent, testosterone accounted for a modest proportion of the obesity-cholecystectomy association in women.