TY - JOUR
T1 - Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men
T2 - Individual Participant Data Meta-analyses
AU - Yeap, Bu B
AU - Marriott, Ross J
AU - Dwivedi, Girish
AU - Adams, Robert J
AU - Antonio, Leen
AU - Ballantyne, Christie M
AU - Bauer, Douglas C
AU - Bhasin, Shalender
AU - Biggs, Mary L
AU - Cawthon, Peggy M
AU - Couper, David J
AU - Dobs, Adrian S
AU - Flicker, Leon
AU - Handelsman, David J
AU - Hankey, Graeme J
AU - Hannemann, Anke
AU - Haring, Robin
AU - Hsu, Benjumin
AU - Martin, Sean A
AU - Matsumoto, Alvin M
AU - Mellström, Dan
AU - Ohlsson, Claes
AU - O'Neill, Terence W
AU - Orwoll, Eric S
AU - Quartagno, Matteo
AU - Shores, Molly M
AU - Steveling, Antje
AU - Tivesten, Åsa
AU - Travison, Thomas G
AU - Vanderschueren, Dirk
AU - Wittert, Gary A
AU - Wu, Frederick C W
AU - Murray, Kevin
PY - 2024/6
Y1 - 2024/6
N2 - 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).
AB - 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).
KW - Humans
KW - Male
KW - Cardiovascular Diseases/mortality
KW - Testosterone/blood
KW - Sex Hormone-Binding Globulin/analysis
KW - Estradiol/blood
KW - Cause of Death
KW - Luteinizing Hormone/blood
KW - Dihydrotestosterone/blood
KW - Incidence
KW - Risk Factors
KW - Aged
KW - Middle Aged
U2 - 10.7326/M23-2781
DO - 10.7326/M23-2781
M3 - Review article
C2 - 38739921
SN - 0003-4819
VL - 177
SP - 768
EP - 781
JO - Annals of Internal Medicine
JF - Annals of Internal Medicine
IS - 6
ER -
