Association of testosterone and sex hormone–binding globulin with chronic liver disease outcomes across sex and menopausal status

BACKGROUND & AIMS: The influence of sex hormones on chronic liver disease (CLD) progression remains unclear, despite sex-related differences in disease susceptibility and outcomes. This study aimed to investigate the associations of total testosterone (TT) and sex hormone-binding globulin (SHBG) levels with CLD-related outcomes across sex and menopausal status. METHODS: A retrospective cohort study was conducted using UK Biobank data. Serum TT and SHBG levels were measured at baseline. Participants were followed for incident liver fibrosis and cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. Cumulative risk curve, restricted cubic spline, and multivariable Cox proportional hazards models were used to assess TT and SHBG associations with outcomes in males, premenopausal females, and postmenopausal females. RESULTS: A total of 155,997 males, 79,637 postmenopausal females, and 28,174 premenopausal females were included, with a median follow-up of 13.53 years. Cumulative risk curve showed that males had the highest risk of CLD-related outcomes (P < 0.001). Males in the highest quartile of SHBG had hazard ratios (HRs) of 3.58 for liver fibrosis and cirrhosis, 4.31 for HCC, and 5.18 for liver-related death compared to the lowest quartile. In the highest TT quartile, the HRs were 2.17 for liver fibrosis and cirrhosis, 2.22 for HCC, and 2.50 for liver-related death. In postmenopausal females, only SHBG levels were positively associated with outcomes, though weaker than males. No significant associations were observed in premenopausal females. CONCLUSIONS: Elevated TT and SHBG levels are associated with higher risks of CLD-related outcomes, particularly in males. Further studies are needed to clarify the causal roles and mechanisms.