Does supplemental testosterone increase stroke risk in older men with cardiovascular disease or other vascular risk factors?

Testosterone Replacement Therapy Does Not Increase Stroke Risk

In men aged 45-80 years with confirmed hypogonadism, testosterone replacement therapy is reasonable and does not increase the risk of stroke, even in those with preexisting cardiovascular disease or multiple vascular risk factors. 1

Evidence Quality and Strength

The 2024 American Heart Association/American Stroke Association guidelines provide a Class 2a recommendation (Level of Evidence B-R) that testosterone therapy initiation or continuation does not increase stroke risk in appropriately selected men. 1 This recommendation is based primarily on the 2023 TRAVERSE trial, which represents the highest quality evidence available on this question. 1

The TRAVERSE Trial: Definitive Evidence

The TRAVERSE study enrolled 5,246 men aged 45-80 years with confirmed hypogonadism (two fasting testosterone levels <300 ng/dL plus associated symptoms) in a multicenter, randomized, double-blind, placebo-controlled noninferiority trial. 1 Critically, participants either had:

• Preexisting cardiovascular disease (coronary artery disease, cerebrovascular disease, or peripheral arterial disease), OR
• High cardiovascular risk (≥3 risk factors including hypertension, dyslipidemia, current smoking, stage 3 chronic kidney disease, diabetes, elevated C-reactive protein, age ≥65 years, or elevated coronary calcium score) 1

After a mean follow-up of 21.7 months using transdermal 1.62% testosterone gel (targeting levels 350-750 ng/dL), investigators found no significant difference in nonfatal stroke incidence between testosterone and placebo groups. 1

Historical Context and FDA Warning

The FDA issued a warning in 2015 about potential increased risk of stroke and heart attacks based on conflicting observational studies and small randomized trials. 1 However, two systematic reviews of randomized clinical trials and observational studies published before 2017 found no evidence for increased stroke risk, though they noted low-quality evidence limited definitive conclusions. 1 The TRAVERSE trial has now resolved this controversy with high-quality data. 1

Cardiovascular Effects: Neutral to Beneficial

Existing evidence suggests testosterone has neutral or possibly beneficial cardiovascular effects. 1, 2 Several key observations support this:

• Men with established cardiovascular disease documented by angiography had lower levels of free and bioavailable testosterone than men with normal angiograms. 1
• In the Rotterdam Study, men in the highest two-thirds of testosterone levels had age-adjusted relative risks of severe aortic atherosclerosis of 0.4 and 0.2 compared to men in the lowest third. 1
• Studies of testosterone replacement therapy have not demonstrated increased incidence of cardiovascular events including myocardial infarction, stroke, or angina. 1
• Men with chronic stable angina treated with transdermal testosterone showed greater angina-free exercise tolerance compared to placebo. 2

Formulation-Specific Considerations

Transdermal testosterone gel is the preferred formulation with established safety data from the TRAVERSE trial. 2 The Endocrine Society strongly prefers transdermal testosterone gel over injections or pellets, especially for patients with cardiovascular disease or risk factors. 2

Oral testosterone undecanoate is specifically contraindicated by the FDA for age-related hypogonadism due to demonstrated blood pressure increases. 2, 3

Real Risks: Erythrocytosis, Not Stroke

The primary cardiovascular concern with testosterone therapy is erythrocytosis (elevated hematocrit), not stroke. 2 Risk varies dramatically by formulation:

• Intramuscular injections: 43.8% risk of hematocrit >52% 2
• Transdermal preparations: 3-18% risk depending on dose 2
• Transdermal patches (5mg/day): 2.8% risk 2
• Transdermal gel (50mg/day): 11.3% risk 2
• Transdermal gel (100mg/day): 17.9% risk 2

Erythrocytosis increases blood viscosity and could theoretically aggravate coronary, cerebrovascular, or peripheral vascular disease, particularly in elderly patients. 2 However, despite theoretical thrombotic concerns, no testosterone-associated thromboembolic events have been reported in clinical trials to date. 2

Required Monitoring Protocol

Mandatory monitoring parameters include: 2

• Hematocrit: At 2-3 months, then every 6-12 months
• PSA and prostate examination: Every 3-6 months for first year, then annually
• Lipid panel and blood pressure: At each visit

If erythrocytosis develops, management options include: 2

• Dosage reduction
• Withholding testosterone temporarily
• Therapeutic phlebotomy
• Blood donation

Patient Selection Criteria

Testosterone therapy should only be initiated in men who meet ALL of the following criteria: 2

• Age 45-80 years
• Confirmed hypogonadism: Two separate fasting testosterone levels <300 ng/dL
• Associated symptoms: Decreased libido, erectile dysfunction, fatigue, diminished muscle mass, or reduced bone density
• Documented medical cause

Contradictory Observational Data on Endogenous Testosterone

Importantly, some observational studies show that LOW endogenous testosterone levels predict INCREASED stroke risk, which is the opposite of what would be expected if testosterone caused strokes. 4 In 3,443 community-dwelling men ≥70 years old followed for 3.5 years, total testosterone in the lowest quartile (<11.7 nmol/L) was associated with increased stroke/TIA incidence (hazard ratio 1.99) after adjusting for conventional cardiovascular risk factors. 4

However, other studies found no association between endogenous testosterone and stroke. 5 In 1,558 men from the ARIC study followed for 14.1 years, after controlling for atherosclerotic risk factors, there was no association between endogenous testosterone and incident clinical stroke or ischemic brain changes. 5

This discrepancy between observational studies of endogenous testosterone and the randomized trial of exogenous testosterone (TRAVERSE) highlights why the TRAVERSE trial provides the most reliable evidence for clinical decision-making. 1

Knowledge Gaps

The TRAVERSE study provides reassurance specifically for transdermal testosterone gel in men with confirmed hypogonadism. 1 The stroke risks for other populations using testosterone off-label are not known. 1 The effects of other testosterone formulations and routes of administration on stroke risk are not well studied. 1

Common Pitfalls to Avoid

• Do not prescribe testosterone without confirmed hypogonadism (two fasting testosterone levels <300 ng/dL plus symptoms). 2
• Avoid oral testosterone undecanoate for age-related hypogonadism due to blood pressure concerns. 2, 3
• Prefer transdermal formulations over injections to minimize erythrocytosis risk, especially in patients with cardiovascular disease. 2
• Do not skip hematocrit monitoring at 2-3 months, as erythrocytosis is the primary cardiovascular risk. 2
• Recognize that relative contraindications include hematocrit >50% at baseline, which may increase erythrocytosis and cardiovascular event risk. 2