Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses

Abstract

Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial.

Purpose: To clarify associations of sex hormones with these outcomes.

Data sources: Systematic literature review to July 2019, with bridge searches to March 2024.

Study selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up.

Data extraction: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use.

Data synthesis: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events.

Limitations: Observational study design, heterogeneity among studies, and imputation of missing data.

Conclusion: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality.

Primary funding source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Figure 1.

Summary curves and forest plots for the association of baseline testosterone concentration with the relative risk of (a) all-cause mortality; b) death from cardiovascular disease (CVD); c) an incident non-fatal or fatal CVD: Model 2. Estimates control for baseline age, BMI, marital/de facto status, alcohol consumption, smoking, physical activity, total cholesterol to HDL cholesterol ratio, blood creatinine concentration, lipid medication use, hypertension and diabetes. Estimates for all-cause mortality additionally control for history of cancer at baseline. Men with prevalent CVD were excluded from the analysis of incident CVD. Dotted lines and arrowheads indicate testosterone concentrations below which the HR and the 95% CI for all-cause mortality (a) and death from CVD (b) are >1.0 (7.4 nmol/L [213 ng/dL] and 5.3 nmol/L [153 ng/dL], respectively). To convert testosterone from nmol/L to ng/dL divide by 0.0347.

Figure 2.

Summary curves and forest plots for the association of baseline SHBG concentration with the relative risk of (a) all-cause mortality; b) death from cardiovascular disease (CVD); c) an incident non-fatal or fatal CVD: Model 2. Estimates control for baseline age, BMI, marital / de facto status, alcohol consumption, smoking, physical activity, total cholesterol to HDL cholesterol ratio, blood creatinine concentration, lipid medication use, hypertension and diabetes. Estimates for all-cause mortality additionally control for history of cancer at baseline. Men with prevalent CVD were excluded from the analysis of incident CVD.

Figure 3.

Summary curves and forest plots for the association of baseline DHT concentration with the relative risk of (a) all-cause mortality; b) death from cardiovascular disease (CVD); c) an incident non-fatal or fatal CVD: Model 2. Estimates control for baseline age, BMI, marital / de facto status, alcohol consumption, smoking, physical activity, total cholesterol to HDL cholesterol ratio, blood creatinine concentration, lipid medication use, hypertension and diabetes. Estimates for all-cause mortality additionally control for history of cancer at baseline. Men with prevalent CVD were excluded from the analysis of incident CVD.