The TRAVERSE Trial Explained

Quick Reference Card

Overview / What Is the TRAVERSE Trial?

The Basics

For years, one question hung over every conversation about testosterone therapy: does it increase the risk of heart attack or stroke? This question shaped prescribing decisions, influenced insurance coverage, and caused real anxiety for millions of men with low testosterone who might otherwise have benefited from treatment.

The TRAVERSE trial was designed specifically to answer that question. It is the largest clinical trial ever conducted to assess the cardiovascular safety of testosterone replacement therapy, enrolling more than 5,200 men across 316 sites in the United States. The trial took years to complete and produced results that have fundamentally changed how the medical community thinks about the relationship between testosterone therapy and heart health.

What makes TRAVERSE particularly significant is why it happened. In 2010, a small study of older, frail men (the TOM trial) was stopped early because more cardiovascular events occurred in the testosterone group than the placebo group. In 2013, a controversial observational study (the Vigen study) suggested testosterone therapy might increase the risk of heart attack and stroke. These studies, despite their significant limitations, prompted the FDA to add a boxed warning (the most serious type of drug warning) to all testosterone products in 2015.

That warning weighed heavily on clinical practice. Many physicians became reluctant to prescribe testosterone, even to men who clearly needed it. Some insurers used the warning to deny coverage. Men with genuine hypogonadism went untreated because of a safety concern that had never been properly tested in a large, well-designed trial.

The FDA itself recognized this gap and requested that testosterone manufacturers conduct a cardiovascular outcomes trial. TRAVERSE was the result. Published in the New England Journal of Medicine in June 2023, its findings provided the clearest evidence to date that testosterone therapy, when used as indicated for men with hypogonadism, does not increase the risk of major adverse cardiovascular events.

In February 2025, the FDA responded by removing the cardiovascular boxed warning from all testosterone products. This is one of the most significant regulatory changes in the history of testosterone therapy.

The Science

The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men) was a phase 4, multicenter, randomized, double-blind, placebo-controlled, noninferiority, event-driven trial conducted at 316 sites across the United States [1].

The trial was mandated by the FDA following the 2014 Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, which was convened in response to increased reports of stroke, myocardial infarction, and death in men receiving FDA-approved testosterone products [2].

Two key studies drove the FDA's concern. The Testosterone in Older Men (TOM) trial (Basaria et al., 2010) was a small study of 209 mobility-limited men aged 65 and older that was terminated early due to an excess of cardiovascular events in the testosterone group (23 vs 5, P = 0.05), though the study was not powered for cardiovascular outcomes and the population was uniquely frail [3]. The Vigen et al. study (2013), a retrospective observational analysis of VA medical records, reported increased risk of cardiovascular events with testosterone prescriptions, though it was subsequently criticized for methodological errors including misclassification of events and exclusion of relevant data [4].

In contrast, the European Medicines Agency (EMA) reviewed the same body of evidence and concluded there was "no consistent evidence of an increased risk of heart problems with testosterone medicines" [5].

TRAVERSE enrolled 5,246 men aged 45-80 years who had preexisting cardiovascular disease or were at high risk for cardiovascular disease and who reported symptoms of hypogonadism. Enrollment required two fasting serum testosterone levels below 300 ng/dL (10.4 nmol/L). Participants were randomized 1:1 to receive daily transdermal 1.62% testosterone gel or matching placebo gel, with dose titration to maintain serum testosterone between 350 and 750 ng/dL. Randomization was stratified by the presence or absence of preexisting cardiovascular disease [1].

The trial was designed as a noninferiority trial with the primary composite endpoint of major adverse cardiovascular events (MACE): death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The prespecified noninferiority margin was a hazard ratio upper bound of 1.20. The trial was event-driven, designed to conclude after 256 primary composite endpoint events had occurred [1].

Medical / Chemical Identity

The TRAVERSE trial used transdermal testosterone gel rather than intramuscular injections. This was a deliberate design choice: gel delivery provides relatively stable testosterone levels (avoiding the pronounced peak-trough dynamics of injectable formulations) and allowed for dose titration in a blinded fashion. The gel was dose-adjusted in 20.25 mg increments, starting from 20.25 mg and ranging up to 101.25 mg (1.25 g to 6.25 g of gel) to maintain testosterone within the 350-750 ng/dL target range [1].

Mechanism of Action / Pathophysiology

The Basics

To understand what TRAVERSE was testing, it helps to understand why cardiovascular safety was a concern in the first place.

Testosterone has wide-ranging effects throughout the body. Beyond its role in sexual function and muscle maintenance, it influences the cardiovascular system in several ways. Testosterone affects how the body produces red blood cells, how blood vessels dilate and contract, how the heart muscle functions, and how the body manages inflammation and cholesterol levels.

The concern about heart risk arose because testosterone can increase red blood cell production (which thickens the blood and could theoretically raise the risk of blood clots), may affect heart rhythm, and has complex effects on cholesterol profiles. Some observational studies suggested these effects might translate into more heart attacks and strokes, though the data were inconsistent.

On the other side of the equation, low testosterone itself is associated with increased cardiovascular risk. Men with untreated hypogonadism have higher rates of metabolic syndrome, type 2 diabetes, obesity, and cardiovascular disease. This created a genuine clinical dilemma: is the condition (low testosterone) or the treatment (testosterone replacement) the greater cardiovascular risk?

TRAVERSE was designed to answer the treatment side of that question. By comparing testosterone to placebo in a population already at high cardiovascular risk, it could detect whether testosterone therapy added meaningful cardiovascular danger above and beyond what these men were already experiencing.

The Science

The cardiovascular effects of testosterone are mediated through multiple pathways, creating a complex risk-benefit picture that prior observational data could not resolve [6].

Testosterone stimulates erythropoiesis through direct effects on erythroid progenitor cells and by suppressing hepcidin, the principal regulator of iron homeostasis. This leads to increased hemoglobin and hematocrit, which, when excessive (hematocrit >54%), has been theorized to increase blood viscosity and thrombotic risk [7]. However, the TRAVERSE trial's hematologic sub-analysis found no association between on-treatment hematocrit changes and MACE risk (HR 0.97, 95% CI 0.92-1.02) or venous thromboembolism risk (HR 0.94, 95% CI 0.84-1.05) in the context of transdermal gel therapy [8].

Testosterone modulates vascular function through endothelial nitric oxide synthase (eNOS) activation and calcium channel modulation, generally promoting vasodilation. The aromatization of testosterone to estradiol via CYP19A1 (aromatase) provides additional cardioprotective effects through estrogen receptor-mediated pathways [6].

The immunomodulatory effects of testosterone are relevant to cardiovascular risk: a 2025 TRAVERSE sub-analysis demonstrated that testosterone increased circulating neutrophils and monocytes while decreasing lymphocytes and platelets. Increases in neutrophil (OR 1.32, 95% CI 1.01-1.73) and monocyte (OR 1.39, 95% CI 1.08-1.79) counts were associated with increased venous thromboembolism risk, suggesting a potential mechanism for the observed increase in thromboembolic events [9].

Pathway & System Visualization

Pharmacokinetics / Hormone Physiology

The Basics

Understanding the testosterone delivery method used in TRAVERSE is important for interpreting its results. The trial used a topical testosterone gel (AndroGel 1.62%), applied daily to the skin. This delivery method produces relatively stable testosterone levels throughout the day, without the dramatic peaks and troughs that characterize weekly or biweekly injections.

In TRAVERSE, participants had a median baseline testosterone of 227 ng/dL. After treatment, the median testosterone level throughout the study ranged between 300 and 400 ng/dL, with a median increase of approximately 148 ng/dL at 12 months. The mean daily dose of testosterone was 65 mg of gel.

These levels are important context. Many men receiving TRT through injection protocols achieve trough testosterone levels of 600-1000 ng/dL or higher, well above the levels achieved in TRAVERSE. Whether the trial's safety findings apply to these higher levels is an area of ongoing discussion among clinicians and researchers.

The Science

Transdermal testosterone gel (1.62%) delivers testosterone through the stratum corneum into the systemic circulation, producing a pharmacokinetic profile characterized by steady-state testosterone concentrations with relatively low peak-to-trough fluctuation compared to intramuscular depot formulations [10].

In TRAVERSE, dose titration in 20.25 mg increments (gel volumes of 1.25-6.25 g) was performed to maintain serum testosterone within the target range of 350-750 ng/dL. Testosterone levels were measured 24 (+/-2) hours after the last dose application. The achieved testosterone levels were modest: median values throughout the study ranged from 300-400 ng/dL, representing a median increase of approximately 148 ng/dL from a baseline median of 227 ng/dL [1].

This difference in achieved testosterone levels between TRAVERSE and common clinical practice represents one of the most important considerations when interpreting the trial's findings. Transdermal gel absorption is variable between individuals (influenced by body composition, skin thickness, application site, and physical activity), and adherence to daily application can be lower than injection protocols [10].

Research & Clinical Evidence

The Basics

The TRAVERSE trial is best understood in the context of a decades-long debate about testosterone and heart health. Before TRAVERSE, the evidence was a patchwork of small studies, observational analyses, and expert opinions that pointed in contradictory directions.

The story goes roughly like this: for years, doctors observed that men with low testosterone seemed to have worse cardiovascular outcomes. Low testosterone was associated with metabolic syndrome, type 2 diabetes, obesity, and increased cardiovascular mortality. Several observational studies suggested that treating low testosterone might actually protect the heart. Then, between 2010 and 2014, a few studies raised alarm. The TOM trial was stopped early due to more cardiovascular events in older, frail men receiving testosterone. The Vigen study suggested increased cardiovascular risk with testosterone prescriptions. These findings, while limited by small sample sizes and significant methodological issues, prompted the FDA to issue safety warnings.

What the field lacked was a large, properly designed clinical trial specifically built to answer the cardiovascular safety question. That is what TRAVERSE provided.

The headline finding: testosterone therapy was non-inferior to placebo for major adverse cardiovascular events. In plain terms, men receiving testosterone had the same rate of heart attacks, strokes, and cardiovascular deaths as men receiving a placebo gel. The cardiovascular event rate was 7.0% in the testosterone group versus 7.3% in the placebo group over approximately three years.

But TRAVERSE also revealed that the cardiovascular picture is more nuanced than a simple "safe or not" question. Several secondary findings warrant attention.

The Science

Cardiovascular Safety (Primary Endpoint)

The primary composite MACE endpoint occurred in 182 participants (7.0%) in the testosterone group and 190 (7.3%) in the placebo group, yielding a hazard ratio of 0.96 (95% CI: 0.78-1.17, P < 0.001 for noninferiority). The upper bound of the 95% confidence interval (1.17) was below the prespecified noninferiority margin of 1.20, confirming noninferiority [1].

Individual MACE components showed similar rates between groups. Cardiovascular death was numerically lower in the testosterone group (HR 0.84, 95% CI 0.63-1.12), though this did not reach statistical significance [1].

Secondary Adverse Events

Despite the reassuring primary endpoint, TRAVERSE identified statistically significant increases in several secondary adverse events in the testosterone group [1]:

• Atrial fibrillation: 91 (3.5%) vs 63 (2.4%), P = 0.02
• Non-fatal arrhythmias warranting intervention: 134 (5.2%) vs 87 (3.3%), P = 0.001
• Acute kidney injury: 60 (2.3%) vs 40 (1.5%), P = 0.04
• Pulmonary embolism: 23 (0.9%) vs 12 (0.5%)
• Total venous thromboembolic events: 44 (1.7%) vs 30 (1.2%)

An independent validation study using the TriNetX Research Network (n = 2,134 per cohort) confirmed the increased AKI risk (RR 1.53, 95% CI 1.07-2.18) but did not confirm a statistically significant increase in atrial fibrillation (RR 1.48, 95% CI 0.93-2.37) [11].

Sexual Function Sub-Study

Among 1,161 men with low libido, testosterone therapy was associated with significantly greater improvement in sexual activity compared to placebo (estimated mean between-group difference 0.49 acts/day at 6 months, P = 0.011). Treatment effects were sustained at 24 months. TRT improved hypogonadal symptoms and sexual desire but did not improve erectile function [12].

Fracture Sub-Study

In a pre-specified fracture analysis (n = 5,204, median follow-up 3.19 years), clinical fractures occurred in 91 participants (3.50%) in the testosterone group versus 64 (2.46%) in the placebo group (HR 1.43, 95% CI 1.04-1.97). This finding was unexpected, as prior studies (TTrials Bone Trial, T4Bone) had demonstrated improvements in bone mineral density with testosterone therapy. The JAMA editorial suggested the increased fractures may reflect increased physical activity in a previously sedentary, high-risk population. Non-high-impact (fragility) fractures did not increase significantly (HR 1.32, 95% CI 0.94-1.86) [13].

Prostate Safety

No increase in prostate cancer, high-grade prostate cancer, acute urinary retention, or surgical procedures for BPH was observed [14].

Anaemia Correction

Among 815 participants (15.7%) with anaemia at baseline, testosterone corrected anaemia in 41.0% vs 27.5% with placebo at 6 months. Improved hemoglobin levels correlated with energy level improvements. Among those without baseline anaemia, fewer testosterone-treated men developed anaemia during the study [15].

Diabetes Prevention

When analyzed among the approximately 30% of participants without baseline diabetes, testosterone therapy was associated with a 22.5% reduction in progression to new-onset diabetes (P = 0.029). However, the authors noted that 25% of testosterone-group participants failed to reach the normal testosterone range, suggesting the diabetes prevention effect may be underestimated in this trial [16].

Depression

Depression was recorded in approximately 50% of participants. Modest improvement in depression scores and Aging Males' Symptoms (AMS) scores were observed in those with mild to moderate depression [17].

Evidence & Effectiveness Matrix

The evidence matrix below presents TRAVERSE-specific findings across the 18 TRT symptom/outcome categories. Because TRAVERSE was a safety trial (not a treatment efficacy trial), evidence strength reflects the trial's contribution to understanding each outcome rather than a comprehensive efficacy assessment.

Categories scored (Evidence Strength): 18
Categories with community data: 6
Categories not scored (insufficient data): 0 (all scored for Evidence Strength; 10 marked N/A for community-reported effectiveness)

Benefits & Therapeutic Effects

The Basics

TRAVERSE was designed as a safety trial, not a benefits trial. Its primary purpose was to determine whether testosterone therapy causes cardiovascular harm, not to measure how much it helps. That said, the seven sub-studies that emerged from the trial paint a detailed picture of what testosterone therapy did and did not accomplish in this population.

The benefits observed in TRAVERSE were real but generally modest. Sexual desire improved, but erectile function did not. Anaemia was corrected in a meaningful proportion of men. The progression from prediabetes to diabetes was reduced. Mild to moderate depression showed some improvement. These findings are consistent with what smaller trials have shown: testosterone therapy helps many symptoms, but it is not a cure-all, and the degree of improvement depends on the severity of the deficiency and the nature of the symptom.

One way to think about the TRAVERSE benefits data: the men in this trial were older (average age 63), had multiple serious health conditions (70% had diabetes, most had cardiovascular disease or risk factors), and achieved relatively modest testosterone levels on gel therapy. For younger, healthier men with more severe hypogonadism receiving treatment to higher testosterone targets, the benefits could reasonably be expected to be more pronounced.

What TRAVERSE establishes most convincingly is that these benefits can be pursued without a meaningful increase in the risk of heart attack, stroke, or cardiovascular death.

The Science

The efficacy endpoints of TRAVERSE, assessed through nested sub-studies, demonstrated the following therapeutic effects [12][13][14][15][16][17]:

Sexual function: Among 1,161 men with baseline low libido, testosterone therapy produced a statistically significant improvement in sexual activity (0.49 additional acts/day at 6 months, omnibus test P = 0.011) that was maintained at 24 months. The lack of improvement in erectile function (as measured by IIEF-EF) is consistent with the study population: mean age 65, 70% with diabetes, and extensive vascular comorbidities contributing to erectile dysfunction through mechanisms independent of androgen status [12].

Anaemia correction: Testosterone corrected existing anaemia in 41.0% vs 27.5% of men at 6 months. Anaemia was identified in 15.7% of the study population. Improved haemoglobin correlated with improvements in energy levels, establishing a mechanistic link between haematological response and symptomatic benefit [15].

Diabetes prevention: Among participants without baseline diabetes (~30% of total), testosterone therapy reduced progression to diabetes by 22.5% (P = 0.029). This effect was observed despite likely undertreating: 25% of participants failed to reach normal testosterone levels, and the median increase was only 9.3 to 12.9 nmol/L. The T4DM trial, which achieved higher testosterone levels with undecanoate injections, showed a more robust 41% reduction [16].

Reading about the potential benefits gives you a framework for what to look for. Tracking whether those benefits are actually showing up in your own experience turns hope into evidence. Doserly lets you monitor the specific outcomes that matter most to you, from energy and libido to mood and body composition, building a personal record of how your testosterone therapy is working.

When it's time for your next provider appointment, you'll have concrete data showing which symptoms have improved, which haven't changed, and when shifts started happening. That kind of detail makes follow-up conversations more productive and dose adjustments more precise.

Risks, Side Effects & Safety

The Basics

The TRAVERSE trial's most important contribution to TRT safety is its primary finding: testosterone therapy did not increase the rate of heart attacks, strokes, or cardiovascular deaths compared to placebo in men with hypogonadism who already had cardiovascular disease or were at high risk for it. This is genuinely reassuring news, and it directly led to the FDA removing its most serious safety warning from testosterone products in February 2025.

But the headline finding does not tell the whole story. TRAVERSE also identified several secondary safety signals that deserve attention.

More men in the testosterone group developed atrial fibrillation (an irregular heart rhythm) than in the placebo group: 3.5% vs 2.4%. More men experienced acute kidney injury: 2.3% vs 1.5%. And more men developed blood clots in the lungs (pulmonary embolism): 0.9% vs 0.5%. These are not common events, and the absolute risk differences are small, but they are statistically significant and clinically meaningful.

Perhaps the most surprising safety finding came from the fracture sub-study: men receiving testosterone actually had more fractures than men receiving placebo (3.5% vs 2.5%), despite prior research showing that testosterone improves bone density. The leading explanation is that testosterone improved energy and activity levels in previously sedentary men, leading to more falls and injuries before the bone-strengthening benefits had time to develop.

What does all of this mean for someone considering TRT? It means the cardiovascular safety picture is considerably better than the previous FDA warnings suggested, but it does not mean TRT is risk-free. The secondary findings reinforce the importance of medical monitoring and individualized risk assessment.

The Science

Cardiovascular Safety (Primary Endpoint)

The primary composite MACE endpoint demonstrated noninferiority: HR 0.96 (95% CI: 0.78-1.17, P < 0.001 for noninferiority). In absolute terms, 182 of 2,601 testosterone-treated men (7.0%) experienced a MACE event compared to 190 of 2,603 placebo-treated men (7.3%) over a mean follow-up of 33 months. This represents an absolute risk difference of approximately 3 fewer events per 1,000 men treated (not statistically significant). Cardiovascular mortality was numerically lower in the testosterone group (HR 0.84, 95% CI 0.63-1.12), though this did not reach statistical significance [1].

Atrial Fibrillation and Arrhythmias

New-onset atrial fibrillation occurred in 91 testosterone-treated men (3.5%) vs 63 placebo-treated men (2.4%), P = 0.02. The absolute risk difference is approximately 11 additional cases per 1,000 men treated. Non-fatal arrhythmias requiring intervention: 134 (5.2%) vs 87 (3.3%), P = 0.001. An independent validation study (TriNetX, n = 2,134 per cohort) did not confirm a statistically significant increase in AF (RR 1.48, 95% CI 0.93-2.37), suggesting this finding may be population-specific or require longer follow-up to confirm [1][11].

Venous Thromboembolism

Total VTE events: 44 (1.7%) vs 30 (1.2%), representing a 46% relative increase. Pulmonary embolism: 23 (0.9%) vs 12 (0.5%). The absolute risk increase for VTE is approximately 5 additional events per 1,000 men treated. A 2025 hematologic sub-analysis found that testosterone-induced increases in neutrophil and monocyte counts were associated with VTE risk (neutrophils: OR 1.32; monocytes: OR 1.39), suggesting an immunomodulatory mechanism [1][9].

Acute Kidney Injury

AKI occurred in 60 testosterone-treated men (2.3%) vs 40 placebo-treated men (1.5%), P = 0.04. The absolute risk difference is approximately 8 additional cases per 1,000 men treated. This finding was confirmed by the TriNetX validation study (RR 1.53, 95% CI 1.07-2.18) [1][11].

Polycythemia and Hematocrit

Only 6 participants in TRAVERSE exceeded the hematocrit threshold of 54% at the lowest testosterone dose and had their medication discontinued. Time-dependent Cox models found no association between on-treatment hematocrit changes and MACE risk (HR 0.97, 95% CI 0.92-1.02) or VTE risk (HR 0.94, 95% CI 0.84-1.05). This finding is specific to transdermal testosterone gel; the authors explicitly noted these findings may not apply to self-administered injection regimens, which produce higher peak testosterone and hematocrit levels [8].

Prostate Safety

No increased incidence of prostate cancer, high-grade prostate cancer, acute urinary retention, or surgical procedures for benign prostatic hyperplasia was observed in the testosterone group [14].

Fractures

Clinical fractures: 91 (3.50%) vs 64 (2.46%), HR 1.43 (95% CI 1.04-1.97). This finding was surprising given prior evidence of BMD improvement with testosterone. Non-high-impact fractures: HR 1.32 (95% CI 0.94-1.86), not statistically significant. The study did not include pre/post BMD measurement [13].

Being informed about potential risks is important. Being able to track and document any side effects you actually experience is what turns awareness into safety. Doserly lets you log side effects as they happen, with timestamps and severity ratings, so nothing falls through the cracks between appointments.

If you're noticing acne, water retention, mood changes, or any other shift, having a documented timeline helps your provider distinguish between expected adjustment effects and signals that warrant a protocol change. The app also tracks your hematocrit and PSA values over time, alerting you when levels approach thresholds that need attention.

Dosing & Treatment Protocols

The Basics

TRAVERSE used a specific treatment protocol that is important to understand when interpreting its results.

All testosterone was delivered as a daily topical gel (AndroGel 1.62%), applied to the skin. The dose was adjustable in five levels, starting from 20.25 mg and going up to 101.25 mg of testosterone daily. The average daily dose was about 65 mg.

The goal was to keep testosterone levels between 350 and 750 ng/dL. In practice, the typical post-treatment testosterone level achieved was in the 300-400 ng/dL range, which many clinicians would consider a conservative replacement level.

This protocol differs significantly from what many men experience in clinical practice, where injection-based TRT (using testosterone cypionate or enanthate, typically 100-200 mg per week) often achieves trough testosterone levels of 500-900 ng/dL or higher. Whether TRAVERSE's safety findings fully apply to these higher-dose injection protocols is a question the trial cannot directly answer.

The Science

TRAVERSE Protocol:

• Formulation: Transdermal testosterone gel, 1.62% (AndroGel)
• Application: Daily, topical
• Dose range: 20.25 mg to 101.25 mg daily (5 dose levels, titrated in 20.25 mg increments)
• Gel volume: 1.25 g to 6.25 g daily
• Mean daily dose: 65 mg
• Target testosterone range: 350-750 ng/dL
• Achieved median testosterone: 300-400 ng/dL (24 hours post-application)
• Baseline median testosterone: 227 ng/dL
• Median testosterone increase at 12 months: 148 ng/dL [1]

The mean treatment duration was 21.7 months, though 59.8% of participants had discontinued by month 48. Similar discontinuation rates were observed in the placebo group, suggesting adherence challenges were not specific to testosterone but reflected broader trial participation factors [1].

What to Expect (Timeline)

TRAVERSE was a safety trial rather than a treatment timeline study, but the sub-study publications provide some guidance on the temporal course of treatment effects observed over the trial period:

• Months 0-6: Testosterone levels rise to target range. Sexual desire improvements become apparent. Anaemia correction observed in 41% of those with baseline anaemia. Hematocrit begins to increase (monitored per protocol).
• Months 6-12: Sexual activity improvements statistically significant (0.49 acts/day vs placebo at 6 months, maintained at 12 months). Energy improvements associated with anaemia correction. Modest depression score improvements in mild/moderate cases.
• Months 12-24: Sexual function benefits maintained at 24 months. Diabetes prevention effect measurable (22.5% reduction in progression).
• Months 24-33+: Cardiovascular safety confirmed over mean 33-month follow-up. Fracture incidence difference becomes apparent by year 3 (3.8% cumulative in testosterone group vs 2.8% in placebo).
• Ongoing: Long-term effects beyond 33 months not captured by TRAVERSE. Some experts note this follow-up period may be insufficient to detect slowly developing cardiovascular effects or longer-term benefits.

Individual timelines vary substantially based on baseline testosterone level, severity of symptoms, delivery method, dose, age, and comorbidities. TRAVERSE findings reflect a specific population (older men with significant comorbidities receiving gel therapy) and may not match the experience of younger, healthier men receiving injectable TRT.

Knowing what to expect is helpful. Documenting your own journey week by week creates something even more valuable, a personal timeline that captures exactly how your testosterone therapy is unfolding. Doserly's symptom journal lets you record changes as they happen, building a detailed record from your first injection.

The early weeks of TRT can feel uncertain. Having a clear log of what's changing, and what hasn't shifted yet, helps you stay grounded in your actual progress rather than relying on memory. When you look back after three months, you'll see how far you've come in ways that are easy to forget without documentation.

Fertility Preservation & HPG Axis

TRAVERSE did not specifically evaluate fertility endpoints. The trial enrolled men aged 45-80, most of whom were not pursuing fertility. However, the physiological principle that exogenous testosterone suppresses the HPG axis and spermatogenesis remains applicable to all testosterone formulations, including the transdermal gel used in TRAVERSE.

Men considering TRT who may want biological children in the future should discuss fertility preservation strategies with their provider before initiating treatment. Options include sperm banking, HCG co-administration, or consideration of SERMs (clomiphene, enclomiphene) as an alternative to exogenous testosterone for men where fertility preservation is a priority.

For detailed fertility information, see: Fertility Preservation on TRT

Interactions & Compatibility

This section is abbreviated for this educational guide. The TRAVERSE trial's primary contribution is not interaction data but rather cardiovascular safety evidence that informs prescribing decisions across all testosterone formulations.

Key considerations from TRAVERSE for drug interactions:

• Anticoagulants: The observed increase in VTE and PE in TRAVERSE (absolute risk ~5 additional VTE events per 1,000 men) may warrant additional caution in men on anticoagulant therapy or with prior thromboembolic events.
• Antiarrhythmic medications: The observed increase in atrial fibrillation (absolute risk ~11 additional AF cases per 1,000 men) is relevant for men with existing arrhythmia histories.
• Diabetes medications: The 22.5% reduction in diabetes progression in TRAVERSE suggests that men on diabetes medications may require dose adjustments if initiating TRT.

For comprehensive interaction information, see: TRT for Beginners | TRT Blood Work Guide

Decision-Making Framework

TRAVERSE contributes important evidence to the TRT decision-making process. Before this trial, the FDA's boxed warning created a significant barrier to prescribing, particularly for men with cardiovascular risk factors, the very population that TRAVERSE was designed to study.

What TRAVERSE tells us about the decision to start TRT:

The trial demonstrates that for men aged 45-80 with hypogonadism (confirmed by two fasting testosterone levels below 300 ng/dL with symptoms) who have cardiovascular disease or cardiovascular risk factors, transdermal testosterone therapy does not increase the risk of major adverse cardiovascular events over approximately three years.

What TRAVERSE does not tell us:

• Whether injectable testosterone (which achieves higher testosterone levels than gel) carries the same cardiovascular safety profile
• Whether TRT is safe for men without significant cardiovascular risk factors (TRAVERSE specifically enrolled high-CV-risk men)
• Whether TRT is safe beyond 33 months of follow-up
• Whether TRT provides cardiovascular protection (noninferiority is not the same as benefit)
• Whether men with age-related testosterone decline (as opposed to pathological hypogonadism) receive the same risk-benefit balance

Questions to ask your provider about TRAVERSE:

• "Does the TRAVERSE trial apply to my specific situation (age, health conditions, planned testosterone formulation)?"
• "Given that TRAVERSE used gel and achieved testosterone levels of 300-400 ng/dL, how do its findings apply to the treatment protocol you're recommending?"
• "What monitoring should I have based on the secondary findings from TRAVERSE (atrial fibrillation, kidney function, blood clots, fracture risk)?"
• "How do the TRAVERSE diabetes prevention findings factor into my care, given my metabolic health status?"

Administration & Practical Guide

This section is abbreviated for this educational guide. TRAVERSE used daily transdermal testosterone gel (AndroGel 1.62%), applied topically. The practical administration aspects of various testosterone formulations are covered in detail in the following guides:

• Testosterone Injections Guide
• Testosterone Gels & Topicals Guide
• Oral Testosterone Guide

Monitoring & Lab Work

TRAVERSE provides important data on monitoring protocols during TRT:

Pre-TRT baseline labs (as used in TRAVERSE):

• Two fasting serum testosterone levels below 300 ng/dL (10.4 nmol/L), confirming hypogonadism
• Cardiovascular risk assessment (TRAVERSE enrolled only men with established CVD or high CV risk)
• Complete blood count with hematocrit
• PSA (age-appropriate)

Monitoring insights from TRAVERSE:

• Hematocrit: Only 6 of 5,204 participants exceeded the 54% threshold on gel therapy. Importantly, no association between on-treatment hematocrit changes and MACE or VTE risk was found. However, the study authors cautioned these findings apply to transdermal gel and may not apply to injection protocols, which produce higher hematocrit elevations.
• PSA: No increased prostate cancer incidence observed, supporting the current guideline recommendation for standard PSA monitoring rather than additional screening beyond normal protocols.
• Cardiovascular monitoring: TRAVERSE demonstrated noninferiority for MACE, but the secondary findings (increased AF, AKI, PE) suggest that cardiovascular rhythm assessment, kidney function monitoring, and awareness of thromboembolic symptoms should be part of routine TRT follow-up.

For comprehensive monitoring protocols, see: TRT Blood Work Guide

Estrogen Management on TRT

TRAVERSE did not specifically evaluate estradiol levels or aromatase inhibitor use as outcomes. The trial used transdermal gel, which generally produces less aromatization-related estrogen elevation than injectable formulations due to the more stable testosterone levels.

For detailed estrogen management information, see: Estrogen Management on TRT

Stopping TRT / Post-Cycle Considerations

TRAVERSE provides limited data relevant to stopping TRT. The high discontinuation rate (59.8% by month 48) is noteworthy, though similar rates were observed in the placebo group, suggesting the discontinuation reflected general trial fatigue rather than TRT-specific tolerability issues.

The trial did not evaluate HPG axis recovery after testosterone discontinuation. For information on stopping TRT and post-cycle recovery, see: Stopping TRT & Post-Cycle Recovery

Special Populations & Situations

TRAVERSE provides valuable data for several special populations:

Men with Cardiovascular Disease

TRAVERSE specifically enrolled men with preexisting cardiovascular disease or high cardiovascular risk. The primary finding (MACE noninferiority) directly applies to this population. The ACC perspective notes that this population represents the group for whom cardiovascular safety evidence was most urgently needed [18].

Older Men (45-80)

The TRAVERSE cohort had a mean age of 63 years. Findings apply most directly to men in this age range. The fracture sub-study finding (increased fractures) may be particularly relevant for older men at risk of falls. Providers should consider fall risk assessment when initiating TRT in older patients.

Men with Type 2 Diabetes

Approximately 70% of TRAVERSE participants had diabetes at baseline. The 22.5% reduction in progression from prediabetes to diabetes among those without baseline diabetes provides evidence that TRT may offer metabolic benefits in this population [16].

Men with Anaemia

Anaemia was present in 15.7% of TRAVERSE participants and was effectively corrected by testosterone therapy (41% vs 27.5%), with associated energy improvements. This suggests screening for anaemia as part of hypogonadism evaluation [15].

Men with Depression

Depression was recorded in approximately 50% of TRAVERSE participants. Modest improvements were observed in mild to moderate cases, supporting screening for depression in hypogonadal men [17].

Regulatory, Insurance & International

TRAVERSE has had a direct and profound impact on testosterone regulation:

United States (FDA)

• February 28, 2025: FDA issued class-wide labeling changes for all testosterone products based on TRAVERSE results and ABPM study data [2].
• Boxed Warning removal: Language related to increased risk of adverse cardiovascular outcomes removed from all testosterone product labels. This warning had been in place since 2015.
• Limitation of Use retained: The distinction between FDA-approved treatment of classical hypogonadism and off-label treatment of age-related testosterone decline remains on all labels.
• TRAVERSE results added: All testosterone product labels now include the trial's cardiovascular safety data.
• Blood pressure warning added: Based on separate ABPM studies (not TRAVERSE), warnings about increased blood pressure added or expanded for all products.
• Schedule III classification: Testosterone remains a Schedule III controlled substance. A December 2025 FDA expert panel unanimously supported removing remaining prostate-related warnings, and some panel members discussed potential reclassification of testosterone's scheduling status, though this is a separate and lengthy regulatory process.

International Impact

The European Medicines Agency (EMA) had previously concluded (prior to TRAVERSE) that there was no consistent evidence of increased cardiovascular risk with testosterone. TRAVERSE results align with this earlier assessment. The European Expert Panel for Testosterone Research issued a 2025 position statement concluding testosterone therapy is safe from a cardiovascular standpoint when prescribed to appropriately selected patients [19].

FAQ

What was the TRAVERSE trial?
TRAVERSE was the largest randomized controlled trial ever conducted to determine whether testosterone replacement therapy increases the risk of heart attacks, strokes, or cardiovascular death. It enrolled more than 5,200 men across 316 sites in the United States and was published in the New England Journal of Medicine in 2023.

What did the TRAVERSE trial find?
The trial found that testosterone therapy was non-inferior to placebo for major adverse cardiovascular events (heart attacks, strokes, cardiovascular death). In simpler terms, men receiving testosterone had the same rate of these events as men receiving a placebo gel. The event rate was 7.0% in the testosterone group versus 7.3% in the placebo group over approximately three years.

Why was the TRAVERSE trial conducted?
The FDA requested the trial in 2014 after earlier, smaller studies raised concerns about cardiovascular risk with testosterone therapy. These concerns led to a boxed warning (the most serious type of drug warning) being placed on all testosterone products in 2015.

Did the FDA change the testosterone warning because of TRAVERSE?
Yes. In February 2025, the FDA removed the boxed warning related to cardiovascular risk from all testosterone products, citing TRAVERSE results. This is one of the most significant regulatory changes in the history of testosterone therapy.

Does TRAVERSE prove TRT is completely safe?
No. TRAVERSE demonstrated non-inferiority for major cardiovascular events, which is not the same as proving comprehensive safety. The trial identified increased rates of atrial fibrillation, acute kidney injury, pulmonary embolism, and fractures in the testosterone group. These secondary findings, while involving small absolute risk differences, warrant continued monitoring.

Does TRAVERSE apply to injectable testosterone?
The trial used transdermal testosterone gel (not injections) and achieved relatively modest testosterone levels (typically 300-400 ng/dL). Whether the findings fully apply to injectable protocols that achieve higher testosterone levels is an area of ongoing discussion. No comparable RCT exists for injectable testosterone.

What about the increased fracture risk?
The TRAVERSE fracture sub-study found that men receiving testosterone had more clinical fractures than those receiving placebo (3.5% vs 2.5%). This finding surprised researchers, as prior studies had shown testosterone improves bone density. The leading explanation is that testosterone improved energy and activity in previously sedentary men, leading to more falls before bone-strengthening effects could develop.

Does TRAVERSE apply to younger men?
TRAVERSE enrolled men aged 45-80 with cardiovascular disease or risk factors. Its findings apply most directly to this population. Younger, healthier men considering TRT can take some reassurance from the results, but the trial does not directly address their specific risk profile.

What about TRT and prostate cancer?
TRAVERSE found no increase in prostate cancer or prostate-related events in the testosterone group. This aligns with the growing body of evidence that testosterone replacement at physiological levels does not increase prostate cancer risk.

Should the TRAVERSE findings change how I talk to my doctor about TRT?
TRAVERSE provides evidence that should reduce the cardiovascular safety concern that previously dominated many TRT conversations. It enables a more balanced discussion focused on whether you have genuine hypogonadism, what benefits you might expect, and what monitoring is appropriate for your specific situation. It does not eliminate the need for individualized assessment and medical supervision.

Myth vs. Fact

Myth: "TRT causes heart attacks."
Fact: The TRAVERSE trial, the largest RCT designed to assess cardiovascular outcomes with TRT, found no increase in major adverse cardiovascular events (heart attacks, strokes, cardiovascular death) in men with hypogonadism and preexisting or high cardiovascular risk (HR 0.96, 95% CI: 0.78-1.17). In absolute terms, 182 of 2,601 testosterone-treated men (7.0%) experienced a cardiovascular event versus 190 of 2,603 placebo-treated men (7.3%) [1]. The FDA removed the cardiovascular boxed warning from all testosterone products in February 2025 based on these results [2].

Myth: "The old studies proving TRT is dangerous were solid science."
Fact: The studies that triggered the 2015 FDA warning had significant limitations. The TOM trial (2010) was a small study of 209 frail, mobility-limited men aged 65+ that was not designed or powered to assess cardiovascular outcomes [3]. The Vigen study (2013) was a retrospective observational analysis subsequently criticized for methodological errors including data misclassification [4]. Neither represented the quality of evidence that a properly designed cardiovascular outcomes trial like TRAVERSE provides.

Myth: "TRAVERSE proved TRT is perfectly safe."
Fact: TRAVERSE demonstrated non-inferiority for major cardiovascular events, which is an important but specific finding. The trial also identified statistically significant increases in atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%), pulmonary embolism (0.9% vs 0.5%), and clinical fractures (3.5% vs 2.5%) [1][13]. Non-inferiority for one endpoint does not equal comprehensive safety across all outcomes.

Myth: "TRAVERSE means any dose of testosterone at any level is safe."
Fact: TRAVERSE used transdermal gel achieving median testosterone levels of 300-400 ng/dL, well below the levels commonly achieved with injectable TRT protocols. Whether the cardiovascular safety findings apply to injection protocols targeting 600-1200 ng/dL has not been tested in a comparable RCT. TRAVERSE's findings should not be extrapolated to supraphysiological dosing.

Myth: "TRT causes prostate cancer."
Fact: TRAVERSE found no increase in prostate cancer, high-grade prostate cancer, acute urinary retention, or BPH-related surgical procedures in the testosterone group over a median follow-up of 3.19 years. This is consistent with the saturation model hypothesis and the growing evidence base that physiological testosterone replacement does not increase prostate cancer risk [14].

Myth: "High hematocrit on TRT means you're going to have a blood clot."
Fact: In TRAVERSE, time-dependent Cox models found no association between on-treatment hematocrit changes and MACE risk (HR 0.97, 95% CI 0.92-1.02) or VTE risk (HR 0.94, 95% CI 0.84-1.05). Only 6 participants exceeded the 54% hematocrit threshold. However, these findings apply specifically to transdermal gel therapy and may not apply to injection protocols that produce greater hematocrit elevations [8].

Myth: "TRT makes your bones stronger, so you'll have fewer fractures."
Fact: Despite prior studies showing testosterone improves bone mineral density, the TRAVERSE fracture sub-study found an increased incidence of clinical fractures in the testosterone group (3.5% vs 2.5%, HR 1.43). The likely explanation is increased physical activity in previously sedentary men, leading to more falls. Non-fragility fractures drove the difference; fragility fractures did not increase significantly [13].

Myth: "Once you start TRT, you can never stop."
Fact: This is a nuanced topic not directly addressed by TRAVERSE. The high discontinuation rate (59.8% by month 48, with similar rates in the placebo group) shows that many participants stopped treatment without catastrophic consequences. However, whether HPG axis function recovers after stopping TRT depends on the underlying cause of hypogonadism, duration of use, age, and other factors. TRAVERSE does not provide data on recovery outcomes.

Myth: "TRT clinic protocols are validated by TRAVERSE."
Fact: Many TRT clinics use injection-based protocols targeting testosterone levels of 800-1200 ng/dL or higher. TRAVERSE used transdermal gel achieving levels of 300-400 ng/dL. The trial validated the cardiovascular safety of modest testosterone replacement via gel, not the aggressive optimization protocols used by some clinics. The distinction matters.

Sources & References

Landmark Trial

[1] Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389:107-117. doi:10.1056/NEJMoa2215025

Government/Institutional Sources

[2] U.S. Food and Drug Administration. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-class-wide-labeling-changes-testosterone-products

Pre-TRAVERSE Studies

[3] Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363:109-122. doi:10.1056/NEJMoa1000485

[4] Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.

[5] European Medicines Agency. No consistent evidence of an increased risk of heart problems with testosterone medicines. November 2014.

Mechanism and Hematology

[6] Kloner RA, Carson C 3rd, Dobs A, et al. Testosterone and cardiovascular disease. J Am Coll Cardiol. 2016;67(5):545-557.

[7] Bachman E, Travison TG, Basaria S, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin. J Clin Endocrinol Metab. 2014;99(11):3972-3979.

[8] Pencina KM, et al. Efficacy of testosterone replacement therapy in correcting anaemia in men with hypogonadism. JAMA Network Open. 2023;6(10):e2340030. doi:10.1001/jamanetworkopen.2023.40030

TRAVERSE Sub-Studies and Related Analyses

[9] TRAVERSE hematologic sub-analysis: Association of testosterone-induced increase in neutrophil and monocyte counts with thromboembolic events. 2025. PMID: 40246046.

[10] Swerdloff RS, Wang C, Cunningham G, et al. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab. 2000;85(12):4500-4510.

[11] Validation study: Association of testosterone replacement therapy with atrial fibrillation and acute kidney injury. J Sex Med. 2024;21(12). PMID: 39487489.

[12] Pencina KM, et al. Effect of testosterone replacement therapy on sexual function and hypogonadal symptoms in men with hypogonadism. J Clin Endocrinol Metab. 2023. doi:10.1210/clinem/dgad484

[13] Snyder PJ, et al. Testosterone treatment and fractures in men with hypogonadism. N Engl J Med. 2024;390:203-211. doi:10.1056/NEJMoa2308836

[14] Bhasin S, et al. Prostate safety events during testosterone replacement therapy in men with hypogonadism: a randomized clinical trial. JAMA Network Open. 2023;6(12):e2348692. doi:10.1001/jamanetworkopen.2023.48692

[15] Pencina KM, et al. Efficacy of testosterone replacement therapy in correcting anaemia in men with hypogonadism. JAMA Network Open. 2023;6(10):e2340030.

[16] Bhasin S, Lincoff AM, et al. Effect of testosterone on progression from prediabetes to diabetes in men with hypogonadism: a substudy of the TRAVERSE randomized clinical trial. JAMA Intern Med. 2024. doi:10.1001/jamainternmed.2023.7862

[17] Bhasin S, et al. Depressive syndromes in men with hypogonadism in the TRAVERSE trial: response to testosterone replacement therapy. J Clin Endocrinol Metab. 2024. doi:10.1210/clinem/dgae026

Expert Perspectives and Guidelines

[18] American College of Cardiology. Journal Scan: Cardiovascular safety of testosterone-replacement therapy. June 20, 2023. https://www.acc.org/Latest-in-Cardiology/Journal-Scans/2023/06/20/14/42/cardiovascular-safety-of-testosterone

[19] Zitzmann M, Rastrelli G, Murray RD, et al. Cardiovascular safety of testosterone therapy: insights from the TRAVERSE trial and beyond. A position statement of the European Expert Panel for Testosterone Research. Andrology. 2025. doi:10.1111/andr.13849

[20] Hackett G, Ramachandran S. Making sense of the TRAVERSE trials. Androgen Society. https://www.androgensociety.org/learning-resources/traverse

Related Trial Data

[21] Bhasin S, Lincoff AM, Basaria S, et al. Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: rationale and design of the TRAVERSE study. Am Heart J. 2022;245:41-50.

[22] Wittert G, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM). Lancet Diabetes Endocrinol. 2021. doi:10.1016/S2213-8587(20)30367-3

Clinical Guidelines

[23] Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.

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