The Association of Reproductive Hormone Levels and All-Cause, Cancer, and Cardiovascular Disease Mortality in Men

Context: Testosterone (T) levels have been associated with mortality, but controversy exists. Objective: Our objective was to investigate associations between serum levels of total T, SHBG, free T, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up. Design: This was a prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up. Setting and Participants: A total of 5350 randomly selected men from the general population aged 30, 40, 50, 60, or 70 years at baseline participated. Main Outcomes and Measures: All-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality were the main outcomes. Results: A total of 1533 men died during the follow-up period; 428 from CVD and 480 from cancer. Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.14-1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR, 1.23; 95% CI, 1.06-1.43; HR, 1.23; 95% CI 1.06-1.43). No association to T levels was found. Higher LH levels were associated with increased cancer mortality (HR, 1.42; 95% CI, 1.10-1.84) independently of smoking status. Lower CVD mortality was seen for men with T in the highest quartile compared to lowest (HR, 0.72; 95% CI, 0.53-0.98). Furthermore, negative trends were seen for SHBG and free T in relation to CVD mortality, however insignificant. Conclusion: The observed positive association of LH and LH/T, but not T, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency.