Associations of T and Related Hormones With All-Cause and Cardiovascular Mortality and Incident CVD in Men

[madman]

Big one from Dr. Yeap and numerous heavyweights in the field!




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, 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.








*In conclusion, we found that the testosterone concentration below which men had higher risk for all cause mortality was 7.4 nmol/L (213 ng/dL). This adds to information on reference ranges based on distributions of testosterone in selected samples of healthy men (5, 7). Higher SHBG concentrations were associated with higher all-cause mortality, which may be related to its role as the major binding protein for sexsteroids in the circulation. We found a U-shaped association of DHT with all-cause and CVD-related mortality risks, which were higher at lower and very high DHT concentrations. Men with very low DHT concentrations also had increased risk for incident CVD events. Further investigation into potential underlying mechanisms for these associations is warranted.

 

[madman]

*Higher SHBG concentrations were associated with higher all-cause mortality, which may be related to its role as the major binding protein for sexsteroids in the circulation.

*We found a U-shaped association of DHT with all-cause and CVD-related mortality risks, which were higher at lower and very high DHT concentrations. Men with very low DHT concentrations also had increased risk for incident CVD events. Further investigation into potential underlying mechanisms for these associations is warranted.

 

[madman]

Table. Summary Estimates of Hazard Ratios for All-Cause Mortality, CVD Death, and Incident CVD Events, by Quintiles of Total Testosterone, SHBG, LH, DHT, and Estradiol Concentrations, and Estimated Relative Heterogeneity*

 

[madman]

Figure 1. Summary curves and forest plots for the association of baseline testosterone concentration with relative risk for all-cause mortality (top), CVD death (middle), and incident CVD events (bottom): model 2.

 

[madman]

Figure 2. Summary curves and forest plots for the association of baseline SHBG concentration with relative risk for all-cause mortality (top), CVD death (middle), and incident CVD events (bottom): model 2.

 

[madman]

Figure 3. Summary curves and forest plots for the association of baseline DHT concentration with relative risk for all-cause mortality(top), CVD death (middle), and incident CVD events (bottom): model 2.