Off-Label Testosterone Linked to Higher CV Risk in Men

Key Takeaways

• In a large matched TriNetX cohort of testosterone-treated men aged 30 to 75 years, major adverse cardiovascular events were reported more often when testosterone was prescribed without documented hypogonadism than when men met hypogonadism criteria.
• All-cause mortality was 90% higher and statistically significant in men prescribed testosterone without hypogonadism.
• Ischemic stroke, myocardial infarction, cardiac arrest, heart failure, and pulmonary embolism were also reported more often in the group prescribed testosterone without hypogonadism.
• The higher-risk pattern largely persisted in the 2-year sensitivity analysis, and for MACE and all-cause mortality the largest relative increases were seen in Asian men.

Testosterone use often enters a clinical gray zone when men present with aging-related symptoms, fatigue, reduced vitality, or reduced physical performance before biochemical hypogonadism has been documented. In that setting, the unresolved question is whether cardiovascular risk differs when treatment starts outside formal hypogonadism criteria rather than after those criteria are met. That question was examined in a matched cohort of testosterone-treated men drawn from a large health network.

Kerniss et al. in EBioMedicine reported a retrospective cohort study using the TriNetX global collaborative network to identify men aged 30 to 75 years who were prescribed testosterone beginning in 2006, with propensity score matching creating two groups of 113,554 men.

Hypogonadism was defined as at least one symptom of testicular hypofunction plus total testosterone of 300 ng/dL or less or free testosterone of 60 pg/mL or lower. The primary outcome was major adverse cardiovascular events (MACE), defined as myocardial infarction, ischemic stroke, cardiac arrest, and all-cause mortality, and the comparison was testosterone use with documented hypogonadism versus testosterone prescribed without hypogonadism.

Compared with matched men with hypogonadism using testosterone, men prescribed testosterone without hypogonadism had higher risk for MACE (HR 1.51; 95% CI 1.46-1.56; P < .001) and all-cause mortality (HR 1.90; 95% CI 1.8-2.0; P < .001). Mortality was the strongest individual signal reported.

Ischemic stroke, myocardial infarction, cardiac arrest, heart failure, and pulmonary embolism were also reported more often in the group prescribed testosterone without hypogonadism. In the cohort’s follow-up and subgroup analyses, median follow-up was 1,448 days in the hypogonadism group versus 697 days in the group without hypogonadism, and the higher-risk pattern persisted at 2 years for all reported outcomes except myocardial infarction and pulmonary embolism. Relative increases were greatest in Asian men and smallest in Black men.

This retrospective, propensity-matched observational comparison does not show that prescribing testosterone outside hypogonadism criteria caused the excess risk, and the unequal follow-up further complicates interpretation. The report did not provide details on testosterone dose, formulation, achieved levels, or outcome adjudication. The investigators said the subgroup pattern, particularly in Asian men, raises questions about biological susceptibility, body composition, pharmacokinetics, prescribing patterns, or residual confounding and needs confirmation.

The study suggests that cardiovascular risk with testosterone may vary by the medical profile present at treatment initiation, with higher observed risk among men prescribed testosterone without documented hypogonadism than among matched testosterone-treated men who met hypogonadism criteria. The investigators also called for large prospective registry studies and real-world target-trial emulations with attention to dose, formulation, achieved testosterone levels, hematocrit changes, duration of exposure, and cardiovascular risk profiles.

Clinician Questions

What comparison does this testosterone cohort actually address?

The cohort compared testosterone-treated men who met the reported definition of hypogonadism with testosterone-treated men prescribed testosterone without hypogonadism. It did not compare testosterone use with no testosterone exposure, so the finding addresses how cardiovascular risk varied by the medical profile present at treatment initiation among men who were already prescribed testosterone.

Which racial-ethnic subgroup showed the largest relative increase in cardiovascular risk with testosterone prescribed without hypogonadism?

Asian men without hypogonadism had the highest relative increases, with MACE HR 2.39 and all-cause mortality HR 2.98.

Black men without hypogonadism had the lowest relative increases, with MACE HR 1.31 and all-cause mortality HR 1.51. Investigators said these subgroup signals raise questions and need confirmation in dedicated studies.

What follow-up questions did investigators raise after this testosterone safety analysis?

Investigators called for large prospective registry studies and real-world target-trial emulations to confirm the findings, with attention to testosterone dose and formulation, achieved testosterone levels, hematocrit changes, duration of exposure, cardiovascular risk profiles, and the pronounced signal seen in Asian men.