Abstract
This study aimed to explore the association between testosterone imbalance and the risk of depression and anxiety. Our analysis included 133,733 men aged 40-70 years from the UK Biobank. Serum testosterone, sex hormone-binding globulin, and albumin were measured at baseline, and free testosterone was calculated using the Vermeulen method. Testosterone imbalance was defined using age-specific Z-scores and categorized as low, normal, or high within six age groups (40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years). Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% CIs for incident anxiety/depression. Potential nonlinear associations between testosterone and depression/anxiety were explored using restricted cubic spline (RCS) regression. Age-stratified and sensitivity analyses were also conducted. During follow-up, 3398 participants developed anxiety and 3701 participants developed depression. In the overall population, both low and high total testosterone levels were associated with higher depression risk (HR = 1.48, 95% CI: 1.11-1.98 and HR = 1.27, 95% CI: 1.08-1.49, respectively). Free testosterone showed a stronger association with depression risk, with lower levels associated with higher risk (HR = 1.99, 95% CI: 1.35-2.93). Age-stratified analyses indicated that these associations were most pronounced among middle-aged men. RCS and interaction analyses further suggested nonlinear and age-modified relationships. Overall, both abnormally low and high testosterone levels were associated with higher depression risk, with a greater impact on middle-aged men, highlighting testosterone imbalance as a potential risk factor for male mental health.