Sex hormones, obesity, and risk of cholecystectomy in men and women: a population-based prospective study and mediation analysis

Background: Obesity affects hormone metabolisms and contributes to gallstone disease more strongly in women than in men. This study assessed the sex-specific associations between serum levels of sex hormone-binding globulin (SHBG) and testosterone and risk of cholecystectomy, and their mediation role in the obesity-cholecystectomy association. Methods: Included were 176,909 men and 160,147 women from the UK Biobank. Serum SHBG and total testosterone were measured by immunoassay. Incident cases of cholecystectomy for gallstone disease were identified using hospital inpatient records. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) of cholecystectomy associated with the serum hormones. A mediation analysis was performed to estimate the proportion of the obesity-cholecystectomy association potentially mediated by the two sex hormones. Results: A total of 2877 men and 4607 women underwent cholecystectomies during the follow-up. Regardless of sex, higher levels of SHBG were associated with a lower risk of cholecystectomy. The HRs of cholecystectomy comparing the highest with the lowest quartiles of SHBG were 0.68 (95% CI: 0.59-0.77) in men (P-trend <0.001) and 0.39 (95% CI: 0.36-0.53) in women (P-trend <0.001). Higher levels of testosterone were associated with a higher risk of cholecystectomy in women (HRQ4 vs. Q1 = 1.28; 95% CI: 1.18-1.39; P-trend <0.001) but not in men (P-trend = 0.12). In women, it was estimated that 14.71% and 2.74% of the association between obesity and cholecystectomy was significantly medicated by SHBG and testosterone, respectively. 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. Both hormones mediate the obesity-cholecystectomy association in women.