Understanding the Rise of Off-Label Testosterone Use

In recent years, testosterone therapy (TT) has transitioned from a niche treatment for pathological hypogonadism to a widely marketed solution for age-related vitality concerns. While clinical guidelines emphasize that therapy should only be initiated for patients with both symptoms and biochemically confirmed low testosterone, a significant portion of prescriptions occur outside these boundaries. This trend has sparked intense debate regarding the long-term safety of such interventions. A groundbreaking study by Kerniss H et al. has recently shed light on the potential off-label testosterone therapy risks, revealing that men who initiate treatment without clear evidence of hypogonadism face substantially higher cardiovascular hazards. As practitioners in India encounter more patients seeking testosterone for non-specific symptoms like fatigue or decreased libido, understanding these risks becomes a clinical necessity. The study underscores a critical distinction between replacement therapy for a deficiency and supplementation for lifestyle enhancement, suggesting that the cardiovascular profile of testosterone is highly dependent on the baseline hormonal status of the patient.

Methodology of the Global EHR Analysis

To investigate these outcomes, researchers conducted a massive retrospective real-world cohort study utilizing de-identified electronic health record (EHR) data from 123 healthcare organizations globally. The study population included 358,957 men between the ages of 30 and 75 who initiated testosterone therapy. A crucial component of the study design was the implementation of a three-year pre-index washout period, which served to exclude individuals with prior testosterone use or major cardiovascular events. This rigorous exclusion criteria allowed the researchers to isolate the effects of therapy initiation more accurately. Using 1:1 propensity-score matching, they compared 113,554 men who had no evidence of hypogonadism at baseline with an equal number of men who had clinical evidence of the condition. By following these cohorts for up to ten years, the investigators were able to observe long-term trends that smaller, shorter randomized controlled trials often miss. This large-scale, real-world approach provides a sobering look at how testosterone behaves in a diverse, unselected population over a full decade of exposure.

Quantifying Major Adverse Cardiovascular Events

The findings regarding major adverse cardiovascular events (MACE) were particularly striking. In the cohort without evidence of hypogonadism, the 10-year cumulative incidence of MACE was 16.53%, compared to only 11.83% in the matched group with confirmed hypogonadism. This translates to a hazard ratio (HR) of 1.51, indicating a 51% higher risk for those using the hormone off-label. Specifically, the data revealed that the lack of a biological indication for therapy significantly predisposes patients to ischemic stroke, cardiac arrest, and heart failure. These results suggest that when testosterone is introduced into a system that already possesses physiological levels of the hormone, it may disrupt cardiovascular homeostasis. While the recent TRAVERSE trial demonstrated cardiovascular non-inferiority for testosterone in hypogonadal men, the Kerniss study highlights that those same safety signals do not apply to the off-label population. Consequently, clinicians must prioritize diagnostic accuracy before prescribing, as the safety profile of the drug appears to shift dramatically when the underlying pathology of hypogonadism is absent.

Off-label Testosterone Therapy Risks and Mortality

Beyond non-fatal cardiovascular events, the study identified a profound impact on all-cause mortality. Men who initiated testosterone without a clinical diagnosis of hypogonadism experienced nearly double the risk of death compared to their hypogonadal counterparts, with a hazard ratio of 1.90. This mortality signal was consistent across various secondary outcomes, including a 41% higher risk of cardiac arrest and a 32% higher risk of heart failure. Interestingly, the researchers utilized acute appendicitis as a negative-control outcome and found no association, which reinforces the validity of the cardiovascular findings. Furthermore, the study noted that while race-stratified estimates varied in magnitude, the direction of the risk remained consistent across different ethnicities. This suggests a fundamental biological response to exogenous testosterone that transcends demographic boundaries. Therefore, the decision to prescribe testosterone must be viewed as a high-stakes clinical intervention rather than a simple wellness supplement, particularly given the potential for increased long-term mortality in men who do not truly require hormone replacement.

Clinical Implications for the Indian Context

In the Indian healthcare landscape, the prevalence of hypogonadism among men over 40 is estimated to be between 20% and 29%. However, the market for testosterone products is growing rapidly, often driven by aggressive direct-to-consumer marketing and the easy availability of supplements. Indian practitioners frequently face pressure from patients to prescribe testosterone for functional symptoms associated with obesity or type 2 diabetes. While these comorbidities can lower testosterone levels, the Kerniss study suggests that unless there is clear evidence of a pathological deficiency, the risks of therapy may outweigh the benefits. Moreover, the heterogeneity of cardiovascular risk across different populations means that Indian men, who already face a high baseline risk for metabolic syndrome and early-onset coronary artery disease, must be evaluated with extreme caution. Local professional bodies, including the RSSDI, emphasize that testosterone should not be used as a primary treatment for metabolic conditions without a confirmed androgen deficiency. Consequently, thorough biochemical screening and cardiovascular risk surveillance are essential components of modern men’s health management.

Guidelines for Biologically Informed Prescribing

Moving forward, the primary takeaway for medical educators and clinicians is the need for biologically informed prescribing. This involves a two-step verification process: identifying consistent signs and symptoms of androgen deficiency and confirming these with at least two separate morning fasting total testosterone measurements. If levels are borderline, clinicians should consider measuring free or bioavailable testosterone, especially in patients with conditions that alter sex hormone-binding globulin. Once therapy is initiated, long-term cardiovascular monitoring is imperative. This includes regular assessment of blood pressure, lipid profiles, and hematocrit levels, as erythrocytosis is a known side effect that can contribute to thromboembolic events. Furthermore, patients should be educated about the potential long-term risks if they choose to pursue therapy without a clear medical need. Ultimately, the goal is to ensure that testosterone remains a valuable tool for those who suffer from clinical hypogonadism while protecting the broader population from the unintended cardiovascular consequences of off-label use. The evidence now clearly indicates that for testosterone therapy, context is everything.

Frequently Asked Questions

How does off-label use differ from indicated testosterone therapy?

Indicated testosterone therapy is prescribed to men who demonstrate both clinical symptoms and biochemical evidence of low testosterone, typically caused by primary or secondary hypogonadism. In contrast, off-label use involves prescribing the hormone to men with normal levels who may be experiencing symptoms like fatigue or muscle loss due to aging or lifestyle factors. The recent study suggests that this distinction is vital, as off-label use is linked to significantly higher cardiovascular risks.

What are the specific cardiovascular risks associated with non-hypogonadal use?

According to the data, men using testosterone without a confirmed diagnosis of hypogonadism face a 51% higher risk of major adverse cardiovascular events (MACE). This includes significantly elevated rates of ischemic stroke, heart failure, and cardiac arrest. Additionally, the risk of all-cause mortality is nearly doubled (HR 1.90). These risks likely stem from the physiological disruption caused by adding exogenous hormones to a system that already has adequate natural testosterone levels.

What should a clinician do before prescribing testosterone to a patient?

Clinicians must follow a rigorous diagnostic protocol. First, they should confirm the presence of symptoms like low libido or erectile dysfunction. Second, they must obtain at least two morning fasting total testosterone levels that are unequivocally low. If the levels are borderline, evaluating free testosterone is recommended. This thorough process ensures that only men with true clinical hypogonadism receive the therapy, thereby minimizing the potential for long-term cardiovascular harm and mortality observed in off-label populations.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Kerniss H et al. Off-label testosterone therapy is associated with higher long-term cardiovascular risk in men. EBioMedicine. 2026 Jul 09. doi: undefined. PMID: 42424704.

Bhasin S et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.

Lincoff AM et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117.