Associations of Testosterone and Related Hormones with Cardiovascular Mortality and Incident Cardiovascular Disease in Men

Annals of Internal Medicine: Published May 2024

Testosterone (T) levels slowly decline as we age, and serum hormone-binding globulin (SHBG) levels gradually increase. As SHBG increases, there is less T available to the tissues. There are several conditions that reduce levels of T; these include being overweight, having metabolic dysfunction, liver disease, and using too much alcohol. Common medications that also lower T include opioids, steroids, and high-dose statins.

This study used an individual participant data meta-analysis to evaluate 24,109 men from 11 cohort studies.

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In this meta-analysis of prospective cohort studies, low testosterone levels were associated with an increased risk of all-cause and cardiovascular disease mortality among aging men.

Low T levels (<7.4 nmol/L [<213 ng/dL]) had the strongest correlation with all-cause mortality. Levels had to drop lower to <5.3 nmol/L (<153 ng/dL) to be associated with higher cardiovascular mortality.

In addition, high luteinizing hormone levels or low estradiol levels were associated with an increased risk of all-cause mortality.

These findings suggest that low testosterone levels and primary hypogonadism may portend an increased risk of adverse cardiovascular events and all-cause mortality among men.

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.

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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.

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