Elevated Endogenous Testosterone Levels are not Associated With Significant Clinical Morbidity

Objective: To investigate the association between elevated endogenous testosterone levels and deleterious effects associated with testosterone therapy. Elevated serum testosterone levels in men receiving testosterone therapy have been associated with side effects, though precise thresholds above which these occur are unknown. Data on the association between naturally elevated endogenous testosterone levels and their physiologic effects is sparse. Methods: We examined National Health and Nutrition Examination Survey data between 2011 and 2016, analyzing men aged 18 and older not on testosterone or androgen ablation therapy, excluding men who had testosterone <300 ng/dL, to compare men with elevated testosterone (>800 ng/dL) to men with normal testosterone (300-800 ng/dL). We used multivariable logistic and linear regressions for comparison. Results: After excluding men with testosterone levels <300 ng/dL, 3673 men met inclusion criterion. Only 146 (4%) of men had a testosterone >800 ng/dL. When compared to men with normal testosterone, men with high testosterone had similar rates of sleep disorders, urinary symptoms, and depression. Men with elevated testosterone had higher hematocrit regression coefficient (βi 1.30, 95% confidence interval [CI] 0.69-1.90 P < .01), AST (βi 8.48, 95% CI 0.31-16.66, P = .04) and ALT (βi 12.23, 95% CI 0.70-23.77, P = .04) compared to men with normal testosterone. Conclusion: No association was found between higher endogenous testosterone levels and adverse events associated with testosterone therapy. Men with higher testosterone had increased hematocrit, but this was not clinically significant. This challenges what is considered a safe target for testosterone therapy and prompts future prospective studies to delineate the safety of elevated endogenous and exogenous modulated levels of testosterone.