Low testosterone tied to increased risk for mortality, CVD events

Key takeaways:

• Men with a testosterone concentration below 7.4 nmol/L had a greater risk for mortality.
• The study “resolves previous inconsistent findings,” but more research on mechanisms are warranted, researchers said.

Men with low testosterone concentrations had a higher risk for all-cause mortality, and those with very low testosterone also had an increased risk for CVD mortality, a study in Annals of Internal Medicine showed.

“Given the effects of testosterone on male libido, virilization, and body composition ... an important question has been whether and when lower endogenous testosterone concentrations are related to poorer health outcomes,” Bu B. Yeap, MBBS, a professor in the Medical School at the University of Western Australia, and colleagues wrote.

Prior research on the associations between testosterone concentrations and mortality outcomes have reported contrasting results, according to the researchers.

Yeap and colleagues conducted a systematic review and meta-analysis of 11 prospective cohort studies with data on 24,109 community-dwelling men whose sex hormones were measured with mass spectrometry. The participants were followed for at least 5 years.

The researchers used individual patient data to examine associations between baseline testosterone hormones — including total testosterone, sex hormone-binding globulin (SHBG), dihydrotestosterone (DHT), luteinizing hormone (LH) and estradiol concentrations — with all-cause mortality, CVD mortality and incident CVD events.

Higher risks for all-cause mortality were found in men with baseline testosterone concentrations below 7.4 nmol/L, LH concentrations above 10 IU/L or estradiol concentrations below 5.1 pmol/L.

In addition, men with testosterone concentrations below 5.3 nmol/L had a higher risk for CVD mortality.

“Lower testosterone concentrations may predispose men to poorer outcomes via associations with lower muscle mass and greater adiposity and with other adverse cardiovascular risk factors,” the researchers wrote. “Very low testosterone concentrations might also be associated with other medical comorbidities and hence higher mortality rise."

Yeap and colleagues further reported that lower SHBG concentration was tied to lower risks for all-cause mortality (adjusted HR = 0.85; 95% CI, 0.77-0.95) and CVD mortality (aHR = 0.81; 95% CI, 0.65-1).

“It is possible that higher SHBG concentrations could modulate the bioavailability of testosterone to tissues,” they noted. “Alternatively, SHBG might influence risk for all-cause and CVD mortality in a manner distinct from its relationship with total testosterone, but further investigation of potential underlying nutritional or metabolic pathways would be needed.”

They also pointed out that men with lower baseline DHT concentrations had higher risks for all-cause mortality (aHR = 1.19; 95% CI, 1.08-1.3) and CVD mortality (aHR = 1.29; 95% CI, 1.03-1.61), whereas risks additionally increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had an increased risk for incident CVD events.

There were several limitations, according to the researchers. For example, because of the study’s observational nature, causality could not be determined. There may have also been residual confounding from unmeasured variables.

“Further investigation into potential underlying mechanisms for these associations is warranted,” Yeap and colleagues concluded.

In a related editorial, Bradley D. Anawalt, MD, a professor and vice chair of the department of medicine at the University of Washington, said it is “tempting” to suggest that testosterone therapy may have cardiovascular benefits “solely in patients with very low concentrations of serum total testosterone.”

“Although these epidemiologic data do not prove a causal relationship, they remind us that sex steroid hormones have complex actions and interactions in human health,” he wrote.

References:

• Anawalt B. Ann Intern Med. 2024;doi:10.7326/M24-0875.
• Yeap B, et al. Ann Intern Med. 2024;doi:10.7326/M23-2781.