Testosterone Replacement Therapy Does Not Increase Stroke Risk in Appropriately Selected Men
In men aged 45-80 years with confirmed hypogonadism, testosterone replacement therapy is reasonable and does not increase the risk of stroke, based on the highest quality evidence from the 2023 TRAVERSE trial and 2024 American Heart Association/American Stroke Association guidelines. 1
Evidence Quality and Strength
The 2023 TRAVERSE study provides definitive level 1 evidence that resolved years of controversy. This multicenter, randomized, double-blind, placebo-controlled noninferiority trial enrolled 5,246 men aged 45-80 years with confirmed hypogonadism (two fasting testosterone levels <300 ng/dL plus symptoms) who either had preexisting cardiovascular disease or were at high risk. 1 Participants received daily transdermal 1.62% testosterone gel (dose-adjusted to target 350-750 ng/dL) or placebo for a mean of 21.7 months. 1
The trial found no significant difference in nonfatal stroke incidence between testosterone and placebo groups, effectively addressing the FDA's 2015 safety concerns. 1, 2
Patient Selection Criteria
Testosterone therapy should be initiated only in men who meet ALL of the following criteria:
- Age 45-80 years 1
- Confirmed hypogonadism: Two separate fasting testosterone levels <300 ng/dL AND associated symptoms (diminished libido, erectile dysfunction, reduced energy, depressed mood, or decreased muscle mass) 1
- Documented medical cause: Hypogonadism due to testicular, pituitary, or hypothalamic pathology—NOT simply age-related decline alone 1, 3
Cardiovascular Risk Context
The evidence demonstrates a neutral to potentially beneficial cardiovascular effect:
- No increased stroke risk was observed even in men with preexisting cerebrovascular disease, coronary artery disease, or peripheral arterial disease 1
- No increased risk in men with ≥3 cardiovascular risk factors including hypertension, dyslipidemia, diabetes, or chronic kidney disease 1
- Earlier observational data suggesting harm has been superseded by this higher-quality randomized controlled trial evidence 1, 2
Important Caveats and Monitoring
Timing Considerations
One observational study suggested elevated risk in the first 6 months to 2 years of therapy, particularly in men aged 45-59 years. 4 However, this conflicts with the TRAVERSE trial findings and represents lower-quality evidence. The guideline recommendation based on TRAVERSE takes precedence. 1
Formulation Matters
- Transdermal testosterone gel (as used in TRAVERSE) is the preferred formulation with established safety data 1, 5
- Injectable testosterone shows similar safety in younger healthy men without significant risk factors 6
- Oral testosterone undecanoate is specifically contraindicated by the FDA for age-related hypogonadism due to demonstrated blood pressure increases 5
Required Monitoring
The FDA label mandates monitoring for: 3
- Venous thromboembolic events: Evaluate any symptoms of DVT (leg pain, edema, warmth, erythema) or PE (acute shortness of breath) and discontinue if suspected 3
- Erythrocytosis: Monitor hematocrit, as this is the primary mechanism for potential cardiovascular effects (3-18% risk with transdermal, up to 44% with injections) 1, 5
- Prostate safety: Though not directly related to stroke, requires ongoing surveillance 3, 2
Clinical Bottom Line
The 2024 AHA/ASA guidelines provide a Class 2a recommendation (Level of Evidence B-R) that testosterone therapy initiation or continuation is reasonable and does not increase stroke risk in appropriately selected men. 1 This represents the most authoritative current guidance, superseding the FDA's 2015 safety warning that was based on lower-quality observational data and small trials. 1
The key is proper patient selection: confirmed hypogonadism with documented medical cause, not simply treating age-related testosterone decline. 1, 3