ExcelMale Consensus
Testosterone therapy started without a confirmed low-testosterone diagnosis carries measurably higher heart risk. A 2026 study of 358,957 men found that men who began TRT with no biochemical or clinical sign of hypogonadism had a 51% higher rate of major cardiac events and nearly double the death rate over 10 years, compared with men treated for genuine deficiency.
The single most protective step you can take is confirming a true deficiency with lab testing before your first injection, then monitoring hematocrit and blood pressure while you stay on treatment. One caveat matters: "no documented deficiency" is not the same as "normal testosterone," and some of that higher-risk group were likely using supraphysiologic or performance doses, not physiological replacement.
Key Takeaways
- Men who started TRT without evidence of low testosterone had a MACE hazard ratio of 1.51 and an all-cause mortality hazard ratio of 1.90 versus men treated for confirmed hypogonadism.
- Roughly one in three testosterone prescriptions (35.4%) in the study went to men with no documented deficiency.
- The excess risk showed up as stroke, cardiac arrest, and heart failure more than heart attack, which points to blood thickening and fluid retention as the likely mechanisms. A baseline hematocrit above 50% raised the danger further.
- The signal held when the analysis was restricted to men with actual documented lab values (HR 1.52), so it is not simply a coding artifact.
- "Off-label" here is a proxy for non-guideline prescribing, not proof of eugonadism. Supraphysiologic and performance-pattern use may account for part of the excess risk.
- For men with a real, lab-confirmed deficiency, testosterone remains a reasonable treatment when monitored.
About one in three men who start testosterone therapy have no lab evidence that their testosterone was ever low. That number comes from a 2026 analysis of 358,957 men across 123 health systems, and it reframes a question our community has argued about for years. The safety of off-label testosterone therapy, meaning testosterone started without a documented deficiency, is a different question from whether testosterone is safe in general. When researchers separated men by why they started, the men taking it without a medical reason on record had worse cardiovascular outcomes over the following decade. This article walks through what that study found, why the biology behind it makes sense, where the interpretation gets complicated, and how to tell which side of the line you fall on.
What Did the 2026 Study Find About Off-Label Testosterone and Heart Risk?
Men who started testosterone without documented hypogonadism had a 51% higher rate of major cardiac events and nearly double the death rate over 10 years compared with matched men treated for confirmed deficiency. The study, published by Kerniss and colleagues in EBioMedicine, used de-identified health records from the TriNetX Global Collaborative Network. Researchers followed 358,957 men aged 30 to 75 who started testosterone therapy, then split them into two groups. One group had documented hypogonadism, meaning a total testosterone at or below 300 ng/dL, a free testosterone at or below 60 pg/mL, or a coded diagnosis of testicular hypofunction. The other group had none of that on record. About 35.4% of men, 127,152 of them, fell into that second off-label group.
The two groups did not look alike at baseline. Men with confirmed hypogonadism were actually sicker to start, with more obesity (23.2% versus 6.5%) and more hypertension (39.1% versus 14.0%). To make a fair comparison, researchers used 1:1 propensity-score matching, pairing men with nearly identical age, weight, and comorbidity profiles. That produced 113,554 matched pairs followed for up to 10 years.
Here is where it gets uncomfortable for the off-label group. Even after matching away those baseline differences, the men who started testosterone without a diagnosis did worse:
| Outcome | Off-Label Risk | On-Label Risk | Hazard Ratio (95% CI) |
|---|---|---|---|
| MACE (primary) | 16.53% | 11.83% | 1.51 (1.45-1.56) |
| All-cause mortality | 10.71% | 5.99% | 1.90 (1.80-2.00) |
| Cardiac arrest | 1.23% | 0.95% | 1.41 (1.23-1.61) |
| Heart failure | 8.60% | 7.23% | 1.32 (1.26-1.39) |
| Ischaemic stroke | 3.84% | 3.29% | 1.23 (1.14-1.33) |
| Myocardial infarction | 4.32% | 4.16% | 1.10 (1.02-1.17) |
MACE, short for major adverse cardiovascular events, bundles heart attack, ischaemic stroke, cardiac arrest, and death into one composite. The off-label group hit that composite 4.7 percentage points more often in absolute terms. The mortality gap is the one that stops most people: 10.71% versus 5.99%, a near doubling of the death rate.
Read the hazard ratios alongside the absolute numbers, because they tell slightly different stories. The mortality gap is large in both. The stroke and heart-failure gaps are real and statistically solid, but the absolute differences are smaller: about half a percentage point for stroke over a full decade. The composite is driven more by death than by any single vascular event.
To check that these signals were real and not an artifact of messy data, the researchers ran a negative control. They looked at acute appendicitis, which has no plausible connection to testosterone. The result came back null (HR 0.88), which means the data was not simply inflating every outcome. They also re-ran the analysis restricted to men with actual documented testosterone lab values rather than diagnostic coding alone. The MACE signal held at HR 1.52, which answers the obvious objection that the whole finding is just miscoded records. And because the two groups were followed for different lengths of time (a median of 697 days off-label versus 1,448 on-label), the authors repeated the analysis in a fixed 2-year window; the association was numerically stronger, not weaker. The heart signals stood on their own.
Why Would Testosterone Raise Heart Risk in Men Who Don't Need It?
The excess risk clusters in outcomes tied to blood flow and pressure rather than slow arterial plaque, which points to blood thickening, higher blood pressure, and fluid retention as the drivers. The pattern of injuries tells the story. Heart attack risk mostly washed out in a sensitivity analysis that excluded the first 90 days (the hazard ratio dropped to 0.996), while stroke, cardiac arrest, and heart failure stayed elevated. That distribution argues against slow arterial plaque buildup as the main driver. It points instead toward blood flow and blood pressure problems that can appear faster.
Three mechanisms fit that picture. The first is erythrocytosis, an overproduction of red blood cells that testosterone reliably stimulates. Thicker blood is harder to push through vessels, which raises the odds of clotting, stroke, and sudden cardiac arrest. The second is blood pressure, since exogenous testosterone can nudge vascular tension upward, and sustained higher pressure strains the heart's chambers over time. Fluid retention rounds it out: the body holds extra salt and water, which raises the total volume the heart has to move with every beat. None of these mechanisms depend on plaque. All of them get worse when testosterone levels run high rather than merely normal.
A man with true hypogonadism who is brought back to a physiological range is filling an empty tank. A man with normal levels who adds testosterone is overfilling one, and the overflow is where these hemodynamic stresses come from.
The study found a specific red flag that ties this together. Men in the off-label group who started with a baseline hematocrit above 50%, meaning their blood was already thick before the first dose, had an even higher risk of MACE (HR 1.12) and heart attack (HR 1.27) than off-label men with hematocrit in the normal 41 to 50% band. Starting testosterone on top of already-concentrated blood adds pressure to a system that is straining. This is exactly why hematocrit sits near the top of every monitoring checklist for men on TRT.
Does "Off-Label" Mean These Men Had Normal Testosterone?
No, and this is the caveat that changes how you should read the whole study. The authors are explicit that the absence of a documented deficiency is a proxy for prescribing that fell outside guideline-based diagnostic workup, not proof that these men were eugonadal. Structured health records do not reliably capture the timing of a blood draw, whether it was fasting, assay quality, or repeat confirmatory testing. Some men labeled off-label may have had a true deficiency that simply was never coded properly.
The other direction matters more for the ExcelMale audience. The off-label group almost certainly includes men using testosterone in ways that look nothing like physiological replacement: supraphysiologic doses, cycling, formulation switching, and non-medical or performance-related use. The authors say this directly, and they note that supraphysiologic anabolic-androgenic steroid exposure is already linked to dyslipidemia, blood pressure elevation, erythrocytosis, and accelerated coronary disease. If a meaningful share of the off-label group was running high doses rather than replacing a deficiency, that alone could explain part of the excess risk.
This is the honest read: the study does not prove that a normal-testosterone man on a carefully dosed replacement protocol faces the same 51% risk bump. It proves that men who started outside a documented diagnosis, as a group, did worse, and that group is a mix of the under-tested and the over-dosed. If you are running a physiological dose and holding your hematocrit and blood pressure in range, you are not the average member of that high-risk group. The number to respect is not the headline hazard ratio; it is the mechanism, because erythrocytosis and blood pressure do not care what your prescription paperwork says.
Does the Heart Risk From Testosterone Differ by Race or Ethnicity?
Yes, and the spread is wider than most people would guess. The direction held across every group, but the magnitude varied a lot when researchers stratified by race and ethnicity.
| Group | MACE Hazard Ratio | Mortality Hazard Ratio |
|---|---|---|
| Asian | 2.39 | 2.98 |
| White | 1.49 | 1.99 |
| Hispanic/Latino | 1.49 | 1.82 |
| Black/African American | 1.31 | 1.51 |
Asian men carried by far the steepest risk. Their mortality hazard ratio of 2.98 means the death rate nearly tripled with off-label use. Heart attack risk was significantly raised only in Asian men (HR 2.38) and marginally in White men, while it did not reach significance in Black or Hispanic/Latino men. The authors flag the Asian findings as exploratory, since Western health databases hold smaller numbers of Asian patients, so the confidence intervals are wider. Still, the size of the signal is hard to dismiss and argues for more research in non-Western populations.
Age shifted the pattern too. Younger men showed higher proportional risk for the sudden events, stroke and cardiac arrest. Older men saw the risk land more heavily as all-cause mortality, likely because testosterone-driven cardiovascular stress compounds with age-related frailty. A 38-year-old and a 68-year-old on the same off-label prescription face different odds, and different kinds of danger.
How Do You Know If You Actually Qualify for Testosterone Therapy?
You qualify when two separate early-morning blood draws show a total testosterone at or below 300 ng/dL or a free testosterone at or below 60 pg/mL, alongside symptoms. This is the practical fork in the road. The entire safety gap in the study came down to one thing: whether there was real evidence of deficiency before treatment started. So the question worth answering before your first prescription is whether you meet the diagnostic bar that both the Endocrine Society and the American Urological Association set.
A guideline-concordant diagnosis needs biochemical confirmation. Testosterone follows a daily rhythm, so the sample should come from an early-morning draw, and a single low reading is not enough. Guidelines call for at least two separate morning measurements before anyone commits you to lifelong therapy. Symptoms alone do not qualify you, because fatigue and low libido have long lists of causes that have nothing to do with testosterone.
The reason this matters goes back to the 2015 FDA safety communication, which stated plainly that testosterone products are not approved for low testosterone caused by aging alone. The Kerniss data is the real-world receipt for that warning. When a man with normal levels takes testosterone to chase energy or gym performance, he is not correcting a deficiency, and the study suggests he pays for it in cardiovascular risk. If your labs are normal and you feel off, the more useful path is finding out why, rather than overriding a system that is already working.
What Monitoring Lowers Your Heart Risk on TRT?
A baseline workup, a 90-day recheck, and annual monitoring of hematocrit and blood pressure are the steps that lower risk. For men who do have a confirmed deficiency, testosterone is still a reasonable treatment. The reassurance from the TRAVERSE trial, a large randomized study, applies to exactly this group: hypogonadal men who were monitored. Monitoring is the part that does the work.
Start with a full baseline. Before the first dose, that means a hematocrit measurement and an honest cardiovascular risk assessment, including blood pressure and personal and family cardiac history. If your baseline hematocrit is already above 50%, that is a reason to pause and address it first rather than push ahead.
Build in a 90-day check. The study showed that heart attack risk tended to settle after the early window, but stroke and heart failure risk did not fade on their own. An early review lets your provider catch rising hematocrit or climbing blood pressure before either turns into an event. If your red blood cell count is trending up, options include lowering the dose, adjusting the injection frequency, or therapeutic phlebotomy.
Then keep it going. Annual monitoring of hematocrit, blood pressure, and cardiovascular symptoms should continue for as long as you are on treatment. This is not box-checking. The men who ran into trouble in this study were, disproportionately, the ones treated without a diagnosis and, by extension, often without this kind of structured follow-up.
Frequently Asked Questions
Does testosterone therapy cause heart attacks?
Not clearly, based on this data. Heart attack risk was only marginally raised in the off-label group and became statistically neutral once the first 90 days were excluded. The stronger and more persistent signals were for stroke, cardiac arrest, and heart failure, which suggests blood thickening and fluid shifts rather than heart-attack-style plaque rupture.
Is TRT safe if my testosterone is genuinely low?
For men with lab-confirmed hypogonadism who are monitored, the evidence is reassuring. The TRAVERSE trial found no increase in major cardiac events for treated hypogonadal men versus placebo. The higher risk in the 2026 study fell on men who started therapy without any documented deficiency.
Why does the same drug help one man and harm another?
Because context changes the biology. Replacing testosterone that is truly missing returns the body to its normal range. Adding testosterone to a man who already has normal levels pushes him above it, and the excess is what drives erythrocytosis, higher blood pressure, and fluid retention. Higher doses widen that gap further.
What hematocrit level is too high to start testosterone?
The study flagged a baseline hematocrit above 50% as a threshold where MACE and heart attack risk climbed further. Many clinicians treat a hematocrit over 50 to 54% as a reason to hold or adjust therapy and to investigate the cause before continuing.
How often should I get blood work on TRT?
A reasonable rhythm is a baseline panel, a follow-up around 90 days, and annual testing after that. Hematocrit, testosterone, and blood pressure belong on every check, with more frequent testing if your hematocrit runs high or your dose changes.
Conclusion
One detail in this study rarely makes it into the headline. The off-label men were the healthier group at the start, with less obesity and less hypertension, and they still died at nearly twice the rate once the follow-up played out. That inversion is the whole point. A clean baseline did not protect them, because their starting health was never the source of the danger.
The likeliest explanation sits in the group's composition: it blends men who were never properly tested with men running doses no doctor would call replacement. If you are weighing testosterone and your labs have never actually shown a deficiency, that is the number to sit with before you start. For a deeper look at the blood markers that matter most on therapy, our guide on managing TRT side effects and the community's ongoing discussion of the TRAVERSE trial and the FDA label change are both good next stops.
Key References
Kerniss H, Curman P, Olbrich H, et al. Off-label testosterone therapy is associated with higher long-term cardiovascular risk in men. EBioMedicine. 2026;130:106373. Redirecting
Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy (TRAVERSE). New England Journal of Medicine. 2023;389(2):107-117. https://doi.org/10.1056/NEJMoa2215025
Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. The Lancet Healthy Longevity. 2022;3(6):e381-e393. Redirecting
Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism. 2018;103(5):1715-1744. https://doi.org/10.1210/jc.2018-00229
Corona G, Rastrelli G, Sparano C, et al. Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis. Expert Opinion on Drug Safety. 2024;23(5):565-579. https://doi.org/10.1080/14740338.2024.2337741
Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. The Journal of Urology. 2018;200(2):423-432. https://doi.org/10.1016/j.juro.2018.03.115
U.S. Food and Drug Administration. FDA drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging. 2015. FDA.gov
Related ExcelMale Forum Discussions
Testosterone and Cardiovascular Risk: The TRAVERSE Trial and the New FDA Label Change. Community breakdown of the randomized trial that reassured monitored hypogonadal men, plus what the updated FDA label actually says.
Testosterone Therapy and Heart Health: Large Study Finds No Mortality Risk, But Raises Arrhythmia Concerns. A meta-analysis of 23 randomized trials showing neutral mortality but a signal for cardiac arrhythmias, which lines up with the hemodynamic risks discussed here.
Cardiovascular Safety of Testosterone Replacement Therapy in Men. A longer-running thread that collects the major cardiovascular studies as they have come out, useful for seeing how the evidence has moved.
Medical Disclaimer
This article is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before starting or modifying any hormone therapy or medical treatment.
About the Author
By Nelson Vergel | B.S. Chemical Engineering, MBA | Founder, ExcelMale.com | 34+ years on TRT | NIH and FDA advisory panel service | Author: Testosterone: A Man's Guide, Beyond Testosterone, The hCG Advantage, and From Pills to Implants. Updated August 2026.
Editor's note (August 2026 update): This revision adds the study's laboratory-anchored and 2-year sensitivity analyses, clarifies that "off-label" is a proxy for non-guideline prescribing rather than confirmed normal testosterone, and corrects the reference and author details.
About ExcelMale
ExcelMale.com is a men's health community founded by Nelson Vergel, with more than 24,000 members and over 20 years of archives covering testosterone replacement, hormone optimization, fertility, and men's sexual health.
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