The complex relationship between testosterone imbalance and the risk of depression and anxiety in men

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.