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The relationship between testosterone and related hormones and cardiovascular and mortality outcomes is debated. The authors of this study obtained individual patient–level data from 9 cohort studies and aggregate data from 11 studies in total. These data enabled them to describe the associations of testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol with all-cause mortality, cardiovascular death, and incident cardiovascular events while accounting for other cardiac risk factors. 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) [ABSTRACT FROM AUTHOR]

To describe patterns of testosterone concentrations among men across a range of sociodemographic, lifestyle, and health characteristics, the authors systematically searched and obtained individual participant and aggregate data from eligible cohort studies. This study reports the findings from a 2-stage random-effects meta-analysis of 9 studies with individual patient data and 2 studies with aggregate data. Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. Purpose: To clarify factors associated with variations in sex hormone concentrations. Data Sources: Systematic literature searches (to July 2019). Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. Data Extraction: Individual participant data (IPD) (9 studies; n  = 21 074) and aggregate data (2 studies; n  = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, −0.27 nmol/L [−7.8 ng/dL] [CI, −0.71 to 0.18 nmol/L {−20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (−1.55 nmol/L [−44.7 ng/dL] [CI, −2.05 to −1.06 nmol/L {−59.1 to −30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, −2.42 nmol/L [−69.7 ng/dL] [CI, −2.70 to −2.13 nmol/L {−77.8 to −61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, −0.57 nmol/L [−16.4 ng/dL] [CI, −0.89 to −0.26 nmol/L {−25.6 to −7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (−0.51 nmol/L [−14.7 ng/dL] [CI, −0.90 to −0.13 nmol/L {−25.9 to −3.7 ng/dL}]); were former smokers (−0.34 nmol/L [−9.8 ng/dL] [CI, −0.55 to −0.12 nmol/L {−15.9 to −3.5 ng/dL}]); or had hypertension (−0.53 nmol/L [−15.3 ng/dL] [CI, −0.82 to −0.24 nmol/L {−23.6 to −6.9 ng/dL}]), cardiovascular disease (−0.35 nmol/L [−10.1 ng/dL] [CI, −0.55 to −0.15 nmol/L {−15.9 to −4.3 ng/dL}]), cancer (−1.39 nmol/L [−40.1 ng/dL] [CI, −1.79 to −0.99 nmol/L {−51.6 to −28.5 ng/dL}]), or diabetes (−1.43 nmol/L [−41.2 ng/dL] [CI, −1.65 to −1.22 nmol/L {−47.6 to −35.2 ng/dL}]). Sex hormone–binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668) [ABSTRACT FROM AUTHOR]