Understanding Testosterone Replacement: Insights from the TRAVERSE Trial

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Testosterone

Why the TRAVERSE Trial Was Needed

For decades, testosterone replacement therapy (TRT) has been prescribed to men with clinically low testosterone levels to address symptoms such as fatigue, low libido, depressed mood, and reduced muscle mass.

But in the early 2010s, TRT use expanded far beyond men with classical hypogonadism. Direct-to-consumer advertising, “Low T clinics,” and off-label prescribing led to a sharp rise in prescriptions, particularly in middle-aged and older men who often had cardiovascular risk factors.

At the same time, a number of observational studies (2010–2014) suggested possible harm, linking TRT with heart attacks, strokes, and death [1,2]. These studies, however, had profound methodological flaws: many men included did not have hypogonadism, data were retrospective, and results were confounded by age, obesity, and comorbidities. Yet, they were influential enough that the FDA added a boxed warning in 2015 about cardiovascular risk, creating fear and uncertainty among physicians and patients.

Many clinicians argued for years, the evidence simply did not support the claim that testosterone was harmful to the heart. Meta-analyses repeatedly failed to confirm increased cardiovascular risk [3]. What was needed was a large, rigorous randomised trial. The FDA mandated such a study, and thus was born TRAVERSE (Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy Response in hypogonadal men).

What Was the TRAVERSE Trial, and Why It Matters

The TRAVERSE trial was a landmark, FDA-mandated, randomised, double-blind, placebo-controlled study of over 5,200 hypogonadal men aged 45–80 with documented testosterone levels under 10.4 nmol/L. Importantly, this was a high-risk population – every participant had existing cardiovascular disease or significant cardiovascular risk factors, making the results especially powerful and clinically relevant [4]. The trial followed men for nearly 3 years, making it by far the most definitive study of TRT safety ever conducted.

The Answer: TRT is Safe for the Heart

  • The primary outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) occurred in 7.0% of men on testosterone vs. 7.3% on placebo – proving noninferiority [4].
  • In other words: TRT did not increase cardiovascular risk, even in older men with high baseline risk. This is an enormously reassuring result that finally puts to rest a decade of misplaced fear.

Other Observations

While cardiovascular safety was clear, the trial did note slight imbalances:

  • Atrial fibrillation (3.5% vs. 2.4%)
  • Acute kidney injury (2.3% vs. 1.5%)
  • Pulmonary embolism (0.9% vs. 0.5%)

These signals warrant monitoring, but the trial was not powered to establish causality for these uncommon events. Prudence suggests vigilance, not alarm.

On the positive side:

  • TRT significantly improved anemia correction and boosted energy levels [4,5].
  • A slightly higher fracture rate was observed (3.5% vs. 2.5%), likely reflecting increased activity and falls rather than weakened bone [4].
  • Importantly, prostate outcomes were reassuring: there was no excess of prostate cancer, no signal for disease progression, and no meaningful difference in PSA-related events [4,6,7]. This aligns perfectly with decades of evidence showing that physiologic testosterone replacement does not cause prostate cancer [7].

Regulatory Impact: A Landmark Shift

In February 2025, following TRAVERSE, the FDA removed its boxed warning about cardiovascular risk from testosterone labels [8]. This is a historic moment. For years, men and doctors have hesitated to pursue therapy out of fear. The FDA’s reversal validates what science and clinical experience had long suggested: TRT is safe for appropriately diagnosed men.

The FDA also required labels to include TRAVERSE data and added a caution about potential increases in blood pressure – an area worth monitoring [8].

Bottom Line: Where We Stand Now

Benefits

  • Cardiovascular reassurance – TRT is safe for the heart, even in men at elevated risk [4,9].
  • Prostate reassurance – no evidence of increased cancer or progression [7].
  • Clinical gains – correction of anemia, improved energy, better quality of life [4,5].

Areas for Caution

  • Monitor for atrial fibrillation, kidney events, and thromboembolic disease [4].
  • Encourage safe mobility to reduce fracture risk.
  • Long-term safety beyond ~3 years is still being studied [4].

Clinical Guidance

  • Use TRT for men with confirmed hypogonadism, not for nonspecific symptoms in men with normal T.
  • Continue regular monitoring: hematocrit, PSA, cardiovascular risk, and blood pressure [6,7].
  • Avoid under-treatment of men who truly qualify – outdated fears should no longer be a barrier [9].

Final Word (from an Androgen Society perspective)

The TRAVERSE trial is the final nail in the coffin of the myth that testosterone therapy is dangerous for the heart or the prostate. For too long, men with genuine hypogonadism have been denied therapy out of misplaced fear. It is time to move forward with confidence: treating hypogonadal men helps, it does not harm.

References

  1. Vigen R, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.
  2. Finkle WD, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805.
  3. Xu L, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomised trials. BMC Med. 2013;11:108.
  4. N Engl J Med. 2023;389:107-117. (TRAVERSE trial primary publication).
  5. Snyder PJ, et al. Effects of testosterone treatment in older men. J Clin Endocrinol Metab. 2017;102(2):583–593.
  6. Morgentaler A, Rhoden EL. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2006;355:1821–1828.
  7. Morgentaler A, et al. Testosterone therapy and prostate cancer: an updated review. Eur Urol. 2016;70(1):9–21.
  8. FDA Drug Safety Communication. FDA updates labeling for testosterone products. February 2025.
  9. Saad F, et al. Androgen Society Position Paper on cardiovascular risk with testosterone therapy. Mayo Clin Proc. 2022;97(1):34–48.

 

Think You May Have Low Testosterone?

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Please answer YES or NO to the following questions:
1. Do you have a decrease in libido (sex drive)?*
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3. Do you have a decrease in strength and/or endurance?*
4. Have you lost height?*
5. Have you noticed a decreased "enjoyment of life"?*
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7. Are your erections less strong?*
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9. Are you falling asleep after dinner?*
10. Has there been a recent deterioration in your work performance?*

Scoring If you answered YES to Question 1 or 7, or to more than three questions overall, you may have low testosterone. This does not confirm a diagnosis - only a blood test and clinical evaluation can do that.
Next Steps If your responses suggest possible low testosterone: Speak with your doctor. Consider having your testosterone levels measured with a morning blood test. Do not start therapy without proper medical evaluation.
Disclaimer: The ADAM questionnaire is for screening purposes only and should not replace medical advice, diagnosis, or treatment.