The TRAVERSE trial results published in 2023 substantially clarified the clinical picture around testosterone replacement therapy for men with clinical hypogonadism. The 5,246-patient randomized controlled trial specifically examined cardiovascular safety of TRT in men with confirmed hypogonadism and cardiovascular risk factors — the population where TRT decisions had been most complicated by earlier concerning observational data.
Two years after publication, the trial has meaningfully shaped clinical practice. This piece examines what the data actually shows, how it should be interpreted, and what remains unresolved despite the substantial evidence advance.
What TRAVERSE Actually Studied
The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men) enrolled 5,246 men aged 45-80 with confirmed hypogonadism (testosterone below 300 ng/dL) and documented cardiovascular disease or high cardiovascular risk. Participants were randomized to testosterone gel or placebo gel with follow-up over average 22 months.
The primary endpoint was major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Additional endpoints examined other cardiovascular outcomes, prostate outcomes, hematologic outcomes, and various safety measures.
The Primary Cardiovascular Findings
The primary cardiovascular outcome showed non-inferiority of testosterone versus placebo. Major adverse cardiovascular events occurred at similar rates in both groups (7.0% testosterone vs 7.3% placebo).
This was the finding TRAVERSE was designed to establish or refute. Previous concerns about TRT cardiovascular safety based on observational data and smaller trials had created substantial uncertainty. TRAVERSE addressed this concern with adequately powered randomized controlled evidence.
The clinical implication: for men with confirmed clinical hypogonadism and elevated cardiovascular risk, TRT does not appear to increase cardiovascular events. This substantially resolves what had been a significant safety concern.
The Secondary Findings That Nuance the Picture
Several secondary findings complicate simple positive interpretation:
Higher pulmonary embolism rates — TRT group had higher rates of pulmonary embolism (0.9% vs 0.5%). This is meaningful safety signal warranting individual patient risk assessment.
Higher acute kidney injury rates — TRT group had higher rates of acute kidney injury (2.3% vs 1.5%). Mechanism uncertain but signal is meaningful.
Higher atrial fibrillation rates — TRT group had modestly higher atrial fibrillation rates in some subgroups.
Hematologic effects — Predictable hematocrit elevation with TRT confirmed. This warrants monitoring particularly in patients at baseline hematocrit elevation risk.
No prostate cancer increase — Prostate cancer rates were similar between groups. This addresses another historical concern.
Modest testosterone level increases — Average testosterone increase in treatment group was modest (from about 227 to 350 ng/dL average). This reflects real-world dosing practices rather than aggressive supraphysiological dosing.
Who Benefits Actually
The TRAVERSE data supports TRT for specific patient population:
Men with confirmed clinical hypogonadism — Testosterone below 300 ng/dL on multiple confirmatory measurements plus documented symptoms of hypogonadism.
Men whose symptoms significantly affect quality of life — Symptomatic patients benefit meaningfully. Asymptomatic testosterone deficiency (biochemical without symptoms) has weaker treatment case.
Men who have failed lifestyle intervention — Substantial testosterone improvement is often achievable through resistance training, sleep optimization, weight loss, and other lifestyle interventions. TRT is more clearly indicated after lifestyle optimization has failed to resolve symptoms.
Men able to maintain injection or gel compliance — TRT requires ongoing compliance with prescribed regimen. Patients unable to maintain compliance often do worse than untreated patients due to inconsistent hormonal state.
Who TRT Is Not Appropriate For
Several populations should not receive TRT despite marketing pressure:
Men with age-appropriate testosterone (400-600 ng/dL) with vague symptoms — This population has been substantially over-treated in optimization-focused practice. TRAVERSE addressed hypogonadal men, not this population.
Men with active or recent prostate cancer — Ongoing contraindication despite TRAVERSE showing no cancer development difference in previously cancer-free population.
Men with untreated severe sleep apnea — TRT can worsen sleep apnea and pulmonary considerations.
Men with polycythemia risk — Baseline hematocrit elevation risk warrants caution.
Men seeking fertility preservation — TRT typically suppresses fertility. Patients desiring fertility should consider alternative approaches or specific TRT-fertility protocols.
TRAVERSE substantially resolved the primary cardiovascular safety question that had constrained TRT prescribing for years. It did not eliminate all safety considerations, and it did not extend supporting evidence beyond the specific patient population studied.
The Off-Label Optimization Question
TRAVERSE evidence does not extend to off-label TRT use for optimization in eugonadal men (normal testosterone levels). This distinction matters substantially.
Men with age-appropriate testosterone levels seeking supraphysiological levels for optimization purposes:
- Are not the population TRAVERSE studied
- May not benefit as substantially since starting from adequate testosterone rather than deficient state
- Face potentially higher risk from supraphysiological levels than TRAVERSE data addresses
- Include population where earlier concerning signals may still apply
The optimization TRT market continues expanding despite weaker evidence base than TRAVERSE established for hypogonadal treatment. Consumers considering off-label optimization TRT should understand that TRAVERSE evidence doesn't apply to their specific situation.
The Monitoring Requirements
Appropriate TRT requires substantial monitoring:
Baseline evaluation — Complete testosterone workup including confirmatory testing, hematocrit, PSA, sleep apnea evaluation, cardiovascular risk assessment.
Early monitoring — Testosterone levels, hematocrit, PSA, sleep quality within 3-6 months of initiation.
Ongoing monitoring — Testosterone levels, hematocrit, PSA at regular intervals during ongoing treatment.
Response assessment — Symptom response evaluation to guide continuation, dose adjustment, or discontinuation decisions.
Adverse effect monitoring — Pulmonary symptoms, kidney function, cardiovascular symptoms, sleep quality changes.
TRT programs providing minimal monitoring should be approached with skepticism. Appropriate TRT is more medical management than pharmaceutical convenience.
The Delivery Method Considerations
TRT can be delivered through multiple routes:
Injectable testosterone — Various injectable formulations (cypionate, enanthate, undecanoate). Different pharmacokinetic profiles suit different patient situations.
Topical gels — Daily topical application. Convenient but requires attention to transfer risk to family members.
Pellets — Subcutaneous implantation providing sustained release for 3-6 months.
Nasal formulations — Multiple daily application with distinctive pharmacokinetic profile.
Oral testosterone — Historically problematic but newer formulations (Jatenzo, Kyzatrex) have addressed earlier concerns.
Delivery method choice should reflect patient preference, adverse effect profile, and specific clinical circumstances.
The Long-Term Question
TRAVERSE follow-up was 22 months average. Longer-term (5-10+ years) data continues developing. Extended follow-up may reveal effects that shorter follow-up doesn't capture.
The lifetime commitment aspect of TRT should be understood by patients starting treatment. Discontinuation after extended TRT produces temporary hypogonadal state that may take substantial time to resolve.
The Realistic Frame
TRAVERSE has substantially clarified TRT clinical picture for the specific patient population studied — men with confirmed hypogonadism and elevated cardiovascular risk. For this population, TRT appears reasonably safe from cardiovascular perspective and provides meaningful clinical benefit.
The trial did not establish safety or benefit for optimization use in eugonadal men. It did not eliminate all safety considerations even for hypogonadal population. It did not shorten monitoring requirements.
For patients considering TRT, the practical approach involves proper diagnostic workup to establish hypogonadal status, lifestyle optimization before or during pharmaceutical intervention, appropriate monitoring throughout treatment, and realistic expectations about ongoing commitment TRT represents.
The evidence for appropriate TRT use is stronger than it was pre-TRAVERSE. The evidence for optimization TRT in eugonadal men remains weaker than commercial promotion suggests. Distinguishing between these situations produces better clinical decisions.
Dr. Marcus Wren has no financial relationships with any pharmaceutical company mentioned in this article. TimesWriter editorial standards require disclosure of author conflicts of interest.