Testosterone therapy has a long and unusually noisy evidence history: early observational signals of harm, an FDA safety communication in 2015, a decade of contested meta-analyses, and then a large dedicated safety trial. Your patients have read some of this, usually the headline version. You need the actual findings.
TRAVERSE
TRAVERSE was a randomized, double-blind, placebo-controlled non-inferiority trial of transdermal testosterone gel in more than 5,000 men aged 45 to 80 with hypogonadism and either established cardiovascular disease or high cardiovascular risk. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Testosterone was non-inferior to placebo for that endpoint.
- Primary MACE endpoint: non-inferior to placebo.
- Higher incidence in the testosterone group: atrial fibrillation, acute kidney injury, and pulmonary embolism.
- No increase in prostate cancer incidence over the trial period.
- No reduction in clinical fracture incidence; a nominally higher fracture rate was observed in the testosterone arm in the fracture substudy.
- Trial population was men with hypogonadism and elevated cardiovascular risk; findings should not be extrapolated to men without a diagnosis.
Large, dedicated, randomized double-blind placebo-controlled cardiovascular safety trial with adjudicated endpoints.
TRAVERSE was a safety trial, not an efficacy trial for cardiovascular benefit. It does not show that testosterone improves cardiovascular outcomes, does not address supraphysiologic dosing, does not address injectable formulations specifically, and does not support prescribing testosterone to men who do not meet diagnostic criteria for hypogonadism.
Following TRAVERSE, the FDA implemented class-wide labeling changes for testosterone products, including updated cardiovascular language and a requirement to address blood pressure. Labeling continues to emphasize that these products are indicated for men with hypogonadism associated with a specific medical condition, and are not indicated for age-related decline in testosterone alone.
Thrombosis and Atrial Fibrillation
The pulmonary embolism signal in TRAVERSE, alongside prior case reports and pharmacovigilance data, supports counseling patients about venous thromboembolism risk and taking a thrombophilia and prior VTE history seriously before initiating. The atrial fibrillation signal is a newer finding and warrants attention to palpitations and to pulse assessment at follow-up visits, particularly in older men and those with other AF risk factors.
What Testosterone Therapy Does and Does Not Improve
| Outcome | Effect | Evidence |
|---|---|---|
| Libido and sexual desire | Consistent improvement in hypogonadal men | High |
| Erectile function | Modest improvement; often insufficient alone in men with vascular ED | Moderate |
| Lean body mass and fat mass | Increase in lean mass, decrease in fat mass | High |
| Muscle strength | Modest improvement, greater when combined with resistance training | Moderate |
| Bone mineral density | Improves density; NOT shown to reduce clinical fractures | High for BMD, high for absence of fracture benefit |
| Mood and depressive symptoms | Small improvement in hypogonadal men; not a treatment for major depression | Moderate |
| Energy and vitality | Inconsistent; the least reliable of the reported benefits | Low to moderate |
| Progression to type 2 diabetes | T4DM showed reduced incidence alongside a lifestyle program in men with prediabetes; not an approved indication | Moderate |
| Cognition | No consistent benefit demonstrated | Moderate |
| Cardiovascular event reduction | Not demonstrated | High for absence of demonstrated benefit |
Testosterone reliably improves bone mineral density, and it did not reduce clinical fractures in TRAVERSE. Do not counsel patients that testosterone will prevent fractures. Manage osteoporosis risk in hypogonadal men with the same tools you would use in any other patient, including bone density testing and osteoporosis-specific pharmacotherapy when indicated.
The Counseling Script
"Here is where the evidence stands. In a large trial of men like you — men with confirmed low testosterone and existing heart risk — testosterone gel did not increase heart attacks, strokes, or cardiovascular death compared with placebo. That was reassuring, and it settled a question that had been open for about a decade. The same trial did find more atrial fibrillation, more blood clots in the lungs, and more kidney injury in the testosterone group, so those are real things we will watch for. Testosterone will very likely help your libido. It will help your body composition. It has not been shown to prevent fractures or heart attacks, and it is not a treatment for depression. If your energy does not improve, that tells us something useful — it means we need to look at your sleep and your mood rather than push the dose higher."
The headline in the waiting room
A 66-year-old man on testosterone gel for two years arrives with a printed article stating that testosterone 'causes blood clots and heart rhythm problems.' He has coronary artery disease with a stent placed four years ago, is on appropriate secondary prevention, and reports substantial benefit from therapy in libido and energy. He wants to know whether he should stop.
How do you counsel him?