Testosterone replacement therapy (TRT) has cleared its largest cardiovascular safety hurdle, but whether TRT is safe long term depends on how you define the timeframe. At Longevity Benchmark, we separate what clinical research supports from marketing claims across men's health platforms. The single largest safety trial, TRAVERSE, showed that testosterone was noninferior to placebo for major adverse cardiac events over a mean of 27.1 months. That evidence prompted the U.S. Food and Drug Administration (FDA) in February 2025 to remove the cardiovascular boxed warning from all testosterone products.
The Verdict
What The Largest Safety Trial Measured
The TRAVERSE trial established that testosterone replacement therapy does not increase major adverse cardiovascular events compared to placebo over an average follow-up of 27.1 months. The trial was published in the New England Journal of Medicine in 2023. Investigators randomized 5,246 men aged 45 to 80 years across multiple medical centers. Participants had pre-existing cardiovascular disease or elevated cardiac risk. Each participant also had documented hypogonadal symptoms. They had two separate fasting testosterone concentrations below 10.4 nmol/L.
Men received daily transdermal 1.62% testosterone gel or a matching placebo gel. Clinicians adjusted the active dose to keep testosterone between 12 nmol/L and 26 nmol/L. The mean treatment duration was 27.1 months. TRAVERSE used a noninferiority design. Noninferiority means the trial was designed to show testosterone was not worse than placebo by more than a pre-set margin. It was not designed to show that testosterone improved cardiac outcomes.
A primary cardiovascular event occurred in 182 men (7.0%) on testosterone and 190 men (7.3%) on placebo. The hazard ratio was 0.96 with a 95% confidence interval of 0.78 to 1.17. This confirmed noninferiority with P<0.001. The trial also evaluated prostate safety. There was no increase in prostate-related events, including prostate cancer. PSA monitoring is still standard on therapy, though the USPSTF, the AUA and the American Cancer Society each set a different starting age for screening.
The Boxed Warning That Came Off, And The One That Went On
On 28 February 2025, the FDA announced class-wide labeling updates for all prescription testosterone products. The agency removed language from the Boxed Warning regarding adverse cardiovascular outcomes. The FDA stated that TRAVERSE showed no increase in adverse cardiovascular outcomes for hypogonadal men. Package inserts now incorporate the complete TRAVERSE trial results.
Regulators also addressed blood pressure. The FDA added product-specific data for products with completed ambulatory blood pressure monitoring (ABPM) studies. Products without completed ABPM studies received a new warning regarding blood pressure elevation. The agency retained its Limitation of Use language for age-related hypogonadism. The official label still does not endorse testosterone for normal aging.
The Three Signals That Did Move
While TRAVERSE cleared testosterone on primary cardiovascular outcomes, several secondary endpoints showed statistically significant increases. That moved the question off heart attacks. Nonfatal arrhythmias requiring intervention occurred in 5.2% of the testosterone group versus 3.3% on placebo (P=0.001). Atrial fibrillation developed in 3.5% of men taking testosterone compared to 2.4% taking placebo (P=0.02). Acute kidney injury occurred in 2.3% of the testosterone cohort versus 1.5% in the placebo cohort (P=0.04). Pulmonary embolism was recorded in 0.9% of testosterone users compared to 0.5% on placebo. These signals warrant careful clinical monitoring over time.
| Outcome | Testosterone group | Placebo group | Documented Finding |
|---|---|---|---|
| Primary cardiovascular events | 7.0% (182 men) | 7.3% (190 men) | Hazard ratio 0.96 (95% CI 0.78 to 1.17; P < 0.001 for noninferiority) |
| Nonfatal arrhythmias requiring intervention | 5.2% | 3.3% | Statistically significant increase (P = 0.001) |
| Atrial fibrillation | 3.5% | 2.4% | Statistically significant increase (P = 0.02) |
| Acute kidney injury | 2.3% | 1.5% | Statistically significant increase (P = 0.04) |
| Pulmonary embolism | 0.9% | 0.5% | Observed secondary safety finding |
| Prostate-related events and prostate cancer | No increase observed | No increase observed | No significant difference between groups |
Twenty-Seven Months Is Not Thirty Years
The average duration of treatment in the TRAVERSE trial was 27.1 months. A study running under three years leaves multi-decade safety unexamined. Many men start therapy in midlife. They often plan to stay on treatment for decades. Controlled trials stop far earlier. This creates an evidence gap. It is not proof of harm. The data do not show that prolonged therapy causes cumulative toxicity. Controlled evidence simply ends before year three.
Prescribers must weigh symptomatic benefits against unstudied cumulative exposure over time. Our guide on TRT after 50 outlines how clinicians approach treatment in older adults. Broader physiological context is covered in our review of age-related testosterone decline.
Why The Label Still Will Not Endorse Age-Related Low Testosterone
The FDA maintained its Limitation of Use statement to emphasize that testosterone is not approved for age-related decline. The agency did not expand indications to cover normal aging. TRAVERSE enrolled a very specific patient group. Every participant had documented symptoms, two low fasting readings under 10.4 nmol/L, and elevated cardiovascular risk. The trial did not enroll men who had borderline readings without symptoms. Prescribing testosterone for age-related low testosterone remains off-label use. A clinical evaluation requires confirming genuine deficiency before considering medication. Our overview of signs of low testosterone details how clinicians assess characteristic symptoms.
What Long-Term Use Puts On A Monitoring List
Clinical trial data and revised product inserts direct prescribers to monitor blood pressure, renal markers, and cardiac rhythm during treatment. Surveillance focuses on the specific signals identified in TRAVERSE.
- Blood pressure surveillance. The FDA blood-pressure warning directs prescribers to monitor blood pressure regularly, particularly in light of ambulatory blood pressure monitoring findings on modern formulations.
- Renal function tracking. Because acute kidney injury occurred in 2.3% of testosterone patients versus 1.5% on placebo in TRAVERSE, clinicians monitor kidney biomarkers as covered in our guide to TRT and kidney function.
- Cardiac rhythm assessment. Given the statistically higher rates of atrial fibrillation and nonfatal arrhythmias, clinicians evaluate unexplained palpitations, lightheadedness, or pulse irregularities.
- Haematocrit surveillance. No haematocrit figure from TRAVERSE appears on this page, and the detail prescribers monitor is covered in our guide to high haematocrit on TRT.
- Overall side effect review. Routine surveillance allows clinicians to evaluate clinical tolerance over time, guided by our broader review of TRT side effects and risks.
Who Should Not Read This As Reassurance
The TRAVERSE findings apply strictly to diagnosed hypogonadal men and do not provide blanket reassurance for every individual. Certain groups face clinical considerations that fall outside the trial results.
- Men with borderline, age-related decline without symptoms. Men whose lower readings reflect natural aging without symptoms fall outside the trial population.
- Men seeking to preserve fertility. Fertility is not an outcome TRAVERSE reported, and the trial evidence on this page does not answer it. Men who plan to conceive should raise it with a specialist, and our guide to TRT and fertility covers what the question involves.
- Men with previous thromboembolic events. TRAVERSE recorded pulmonary embolism in 0.9% of testosterone recipients versus 0.5% on placebo. Men with a personal history of deep vein thrombosis or pulmonary embolism require specialist evaluation rather than assuming clean clearance.
What Would Change This Assessment
Three developments would change the current medical consensus regarding lifelong testosterone therapy.
- Controlled trials extending past three years. A prospective controlled trial running five to ten years would provide concrete data on cumulative cardiovascular, vascular, and tissue exposure.
- Replication of rhythm and renal signals. Dedicated trials clarifying whether atrial fibrillation and acute kidney injury represent direct drug effects or population artifacts would sharpen prescribing guidelines.
- Regulatory re-evaluation of age-related indications. If future clinical evidence prompts the FDA to revise its position on age-related hypogonadism, prescribing indications would fundamentally change.
If you are weighing a programme that expects to keep you on testosterone for years, ask the prescriber which of those three questions they monitor for, and compare that answer against our comparison of doctor-led TRT programs.
Frequently Asked Questions
Is TRT safe to stay on for life?
The long-term safety of staying on TRT for life has not been established in multi-decade clinical trials. The largest randomized safety trial, TRAVERSE, evaluated testosterone replacement therapy over an average duration of 27.1 months. It found that testosterone was noninferior to placebo for major adverse cardiac events in men with hypogonadism and elevated cardiovascular risk. However, that trial followed patients for less than three years. It also identified higher rates of atrial fibrillation, nonfatal arrhythmias, and acute kidney injury in the testosterone arm. Additionally, the FDA introduced new warnings regarding elevated blood pressure. A 27-month study cannot prove safety across thirty or forty years of continuous use. Men considering lifelong therapy should view this as an evidence gap rather than proof of harm. Ongoing surveillance by a licensed physician is necessary.
Did the FDA remove the heart warning from testosterone?
Yes, on 28 February 2025, the FDA announced class-wide labeling changes removing the cardiovascular boxed warning from all prescription testosterone products. The decision was based on results from the TRAVERSE trial, which showed no increase in major adverse cardiovascular outcomes among hypogonadal men taking testosterone compared to placebo. However, the FDA did not issue an unconditional clearance for all risks. At the same time it removed the heart attack and stroke warning, the agency added new warnings regarding elevated blood pressure for all testosterone products. It also mandated that prescribing information include product-specific data from ambulatory blood pressure monitoring studies. The FDA also maintained its existing Limitation of Use statement for age-related low testosterone.
What did the TRAVERSE trial actually find?
The TRAVERSE trial evaluated 5,246 men aged 45 to 80 with hypogonadism and elevated cardiovascular risk to determine if testosterone was noninferior to placebo. Over an average follow-up of 27.1 months, a primary cardiovascular event occurred in 7.0% of men receiving testosterone gel and 7.3% receiving placebo. This confirmed that testosterone was noninferior to placebo for major cardiovascular events. The trial also observed no increase in prostate cancer or other prostate-related events. However, TRAVERSE identified several secondary safety signals. Men receiving testosterone experienced higher rates of nonfatal arrhythmias (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), and acute kidney injury (2.3% vs 1.5%). Pulmonary embolism occurred in 0.9% versus 0.5%.
Does TRT raise blood pressure?
Yes, clinical evidence indicates that testosterone can raise blood pressure, prompting the FDA to add new warnings to testosterone labels in February 2025. In its class-wide labeling update, the agency added product-specific data from ambulatory blood pressure monitoring (ABPM) studies for products that had completed them. For products without completed ABPM studies, the FDA required a new warning about potential blood pressure increases. The FDA announcement does not publish the wording of that new warning, and no monitoring interval appears on this page. The label change does establish that blood pressure is now a labelled consideration on every testosterone product.
Does long-term TRT cause atrial fibrillation?
Clinical trial evidence shows an association between testosterone therapy and an increased rate of atrial fibrillation, though lifelong risk remains unstudied. In the TRAVERSE study, atrial fibrillation occurred in 3.5% of men assigned to transdermal testosterone compared to 2.4% assigned to placebo over a mean of 27.1 months. That difference was statistically significant. Nonfatal arrhythmias requiring medical intervention also occurred more frequently in the testosterone group (5.2% vs 3.3%). Because TRAVERSE was limited to under three years, researchers do not yet know whether this arrhythmia risk persists, worsens, or plateaus over decades of continuous therapy. The trial counted arrhythmia events that warranted intervention, and what to do about a rhythm symptom on treatment is a conversation for the prescribing clinician.
Is TRT safe for men with existing heart disease?
The TRAVERSE trial specifically enrolled men with pre-existing cardiovascular disease or multiple cardiovascular risk factors, and it found no increase in major adverse cardiac events compared to placebo over 27.1 months. Primary cardiac events occurred in 7.0% of testosterone users and 7.3% of placebo users, meeting the statistical standard for noninferiority. Based on these findings, the FDA removed the cardiovascular boxed warning from testosterone products in February 2025. However, men with heart disease still face elevated risks of arrhythmias and atrial fibrillation, which occurred more often with testosterone in the trial. They also require careful blood pressure management due to the newly added FDA blood pressure warnings. Treatment decisions for men with established cardiovascular disease require close physician supervision.
Does the FDA approve testosterone for age-related low testosterone?
No, the FDA does not approve prescription testosterone products for age-related low testosterone. In its February 2025 labeling update, the FDA explicitly retained its Limitation of Use language regarding age-related hypogonadism. The agency's announcement does not publish the wording of that Limitation of Use, so this page does not quote it. The retention means the label still does not endorse testosterone for low testosterone that is simply age-related. Furthermore, the TRAVERSE trial studied symptomatic men with two fasting testosterone draws below 10.4 nmol/L and established cardiovascular disease or elevated cardiac risk. It did not evaluate men with mild, asymptomatic declines in hormone levels. Prescribing testosterone solely for age-related decline remains an off-label clinical practice that requires careful risk-benefit discussion with a healthcare provider.