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Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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).
Additional Info
Disclosure statements are available on the authors' profiles:
Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses
Ann. Intern. Med 2024 May 14;[EPub Ahead of Print], BB Yeap, RJ Marriott, G Dwivedi, RJ Adams, L Antonio, CM Ballantyne, DC Bauer, S Bhasin, ML Biggs, PM Cawthon, DJ Couper, AS Dobs, L Flicker, DJ Handelsman, GJ Hankey, A Hannemann, R Haring, B Hsu, SA Martin, AM Matsumoto, D Mellström, C Ohlsson, TW O'Neill, ES Orwoll, M Quartagno, MM Shores, A Steveling, Å Tivesten, TG Travison, D Vanderschueren, GA Wittert, FCW Wu, K MurrayFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Low Testosterone Levels and Mortality Risk
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. Studies were chosen that used mass spectrometry for hormone testing, which is more accurate than other studies that have used immunoassays. The investigators evaluated several hormones and compared them with all-cause mortality, cardiovascular death, and cardiovascular events.
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. High SHBG levels were associated with more cardiovascular events and all-cause mortality.
The best way to reduce this risk is to increase the body’s innate production of testosterone. If there is primary gonadal failure (high luteinizing hormone), then giving testosterone is necessary. But most men have modifiable risk factors that, if addressed, can increase T. Giving T externally in shots, gels, or patches will reduce this innate production.
The SHIP study showed that men who maintained healthy lifestyle habits slowed the normal decline in testosterone with aging.1 And a recent 2024 study showed that giving men with hypogonadism and prediabetes testosterone did not reduce the risk of progressing to diabetes.2 Before we consider giving T, the goal should be addressing underlying causes. Being overweight, excessive alcohol use, and metabolic dysfunction are significant.
Health is more about what you do than what you take.
References