Off-Label Testosterone Therapy Linked to Long-Term Cardiovascular Risk: Study
Germany: A retrospective real-world cohort study has found that off-label testosterone therapy in men without evidence of hypogonadism was associated with an increased risk of cardiovascular events for up to 10 years. The findings highlight the importance of prescribing testosterone only for evidence-based indications and carefully weighing potential long-term cardiovascular risks.
Testosterone therapy (TT) has become increasingly common in men without confirmed hypogonadism, despite clinical guidelines recommending treatment only after appropriate diagnostic evaluation. However, the long-term cardiovascular safety of this practice has remained uncertain. To address this question, researchers led by Hatim Kerniss from the Department of Cardiology, University Heart Centre Frankfurt, University Hospital Frankfurt, Germany, compared cardiovascular outcomes among men who initiated testosterone therapy with and without evidence of hypogonadism.
For the study, published in eBioMedicine, investigators conducted a retrospective cohort analysis using de-identified electronic health record data from 123 healthcare organizations worldwide. Men aged 30–75 years who started testosterone therapy were identified, while those with prior testosterone use or major cardiovascular or thromboembolic events during the preceding three years were excluded. After propensity score matching, 113,554 pairs of men with and without evidence of hypogonadism were followed for as long as 10 years.
The key findings were as follows:
- Among 358,957 men who initiated testosterone therapy, 127,152 (35.4%) had no documented evidence of hypogonadism before treatment.
- Men receiving testosterone therapy without evidence of hypogonadism had a 51% higher risk of major adverse cardiovascular events (MACE) than those treated for confirmed hypogonadism (16.53% vs. 11.83%).
- Off-label testosterone use was associated with a 90% higher risk of all-cause mortality.
- The risk of ischaemic stroke increased by 23%, cardiac arrest by 41%, and heart failure by 32% in men without evidence of hypogonadism.
- Although the magnitude of risk differed across racial and ethnic groups, the overall trend toward increased cardiovascular risk remained consistent.
The findings suggest that the cardiovascular safety of testosterone therapy depends on the clinical context, with greater long-term risk observed when treatment is initiated without evidence of hypogonadism rather than for confirmed deficiency.
The authors noted that the observational design, potential residual confounding, incomplete documentation of hypogonadism, and limited information on treatment duration, dose, adherence, and formulations may have influenced the findings. They emphasized that the results show an association, not causation, and that variations in prescribing practices across healthcare settings may also have contributed.
Overall, the study found that about one-third of men receiving testosterone therapy had no documented evidence of hypogonadism and experienced higher long-term cardiovascular and cerebrovascular risks. The researchers recommend adhering to guideline-based prescribing, confirming hypogonadism before treatment, and monitoring cardiovascular risk during follow-up.
Reference:
Kerniss, H., Curman, P., Olbrich, H., Kridin, K., Francis, R., Leistner, D. M., Alam, U., & Ludwig, R. J. (2026). Off-label testosterone therapy is associated with higher long-term cardiovascular risk in men. EBioMedicine, 130, 106373. https://doi.org/10.1016/j.ebiom.2026.106373
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