Off-Label Testosterone Use Linked to Higher CV Risk
Key Takeaways
- In a very large propensity score-matched TriNetX cohort of men aged 30 to 75 years prescribed testosterone, those treated without hypogonadism were associated with higher major adverse cardiovascular event risk than testosterone-treated men with hypogonadism.
- The same group also had higher all-cause mortality and higher risks across ischemic stroke, myocardial infarction, cardiac arrest, heart failure, and pulmonary embolism.
- In a 2-year sensitivity analysis, the excess risk pattern persisted for all reported outcomes except myocardial infarction and pulmonary embolism.
- Asian men had the largest reported relative increases in major adverse cardiovascular events and all-cause mortality, whereas Black men had the smallest reported increases.
In a retrospective cohort study using the TriNetX global collaborative network, Kerniss and colleagues in EBioMedicine studied men aged 30 to 75 years who were prescribed testosterone beginning in 2006. Men were classified as having hypogonadism if they had at least one symptom of testicular hypofunction, a total testosterone concentration of 300 ng/dL or less, or a free testosterone concentration of 60 pg/mL or lower. The comparison paired testosterone-treated men with hypogonadism against testosterone-treated men without hypogonadism, and the primary endpoint was major adverse cardiovascular events (MACE), a composite of myocardial infarction, ischemic stroke, cardiac arrest, and all-cause mortality. Propensity score matching yielded 113,554 men in each cohort.
After matching, testosterone-treated men without hypogonadism had higher risk of MACE than testosterone-treated men with hypogonadism, with a hazard ratio of 1.51 (95% CI 1.46-1.56; P < .001). They also had higher all-cause mortality, with a hazard ratio of 1.9 (95% CI 1.8-2; P < .001). The overall pattern indicated a heavier event burden in the non-hypogonadism group.
Median follow-up was 1,448 days in the hypogonadism cohort and 697 days in the non-hypogonadism cohort. Despite that difference, the non-hypogonadism group also had higher risks of ischemic stroke, myocardial infarction, cardiac arrest, heart failure, and pulmonary embolism. In a 2-year sensitivity analysis, the excess-risk pattern remained for all reported outcomes except myocardial infarction and pulmonary embolism, and subgroup analyses showed the largest relative increases among Asian men and the smallest among Black men.
This retrospective observational comparison does not establish causality, and it compared two groups already receiving testosterone rather than testosterone exposure vs no testosterone exposure. The unequal follow-up durations remain part of the interpretation, and the available source context does not provide fuller detail on exposure characteristics or event adjudication. In investigator comments on diagnostic evaluation and follow-up, the authors linked the findings to patient profile and diagnostic status at testosterone initiation and distinguished confirmed hypogonadism from treatment of aging-related symptoms without adequate evaluation.
The authors concluded that testosterone prescribing without meeting the study’s hypogonadism criteria was associated with higher cardiovascular and mortality risk than testosterone use in men who met those criteria. They called for prospective registries, target-trial emulations, and more detailed analyses of dose, formulation, achieved testosterone levels, hematocrit changes, duration of exposure, and cardiovascular risk profiles. The subgroup signal in Asian men was presented as requiring confirmation.
Clinician Questions
How was hypogonadism defined in men receiving testosterone therapy in this TriNetX analysis?
In this TriNetX analysis of men receiving testosterone therapy, hypogonadism was defined as at least one symptom of testicular hypofunction, a total testosterone concentration of 300 ng/dL or less, or a free testosterone concentration of 60 pg/mL or lower. The cardiovascular comparison therefore separated testosterone-treated men who met any of those criteria from testosterone-treated men who did not.
What did the primary cardiovascular endpoint include for testosterone-treated men with and without hypogonadism?
For testosterone-treated men with and without hypogonadism, major adverse cardiovascular events were defined as a composite of myocardial infarction, ischemic stroke, cardiac arrest, and all-cause mortality. That definition clarifies that the primary comparison captured both fatal and nonfatal events rather than a single ischemic outcome.
Did shorter follow-up change the cardiovascular risk pattern seen with testosterone use without hypogonadism?
When follow-up was limited to 2 years, testosterone use without hypogonadism remained associated with higher risk for all reported outcomes except myocardial infarction and pulmonary embolism. That sensitivity analysis helps interpret the main findings in light of the unequal median follow-up between the two testosterone-treated cohorts.
What questions remain after the reported subgroup differences in Asian and Black men receiving testosterone?
Among men receiving testosterone therapy, the study reported the largest relative increases in major adverse cardiovascular events and all-cause mortality among Asian men without hypogonadism and the smallest increases among Black men without hypogonadism. The authors said the Asian signal requires confirmation and identified biological susceptibility, body composition, pharmacokinetics, prescribing patterns, and residual confounding as possible explanations that remain unresolved.