In a male with established coronary artery disease, what evidence supports testosterone replacement therapy and what are the risks of withholding it in symptomatic hypogonadism?

Testosterone Replacement Therapy in Men with Coronary Artery Disease

In men with established coronary artery disease and symptomatic hypogonadism (confirmed by two fasting testosterone levels <300 ng/dL), testosterone replacement therapy is safe and does not increase cardiovascular risk, based on the definitive 2023 TRAVERSE trial, and should be offered using transdermal formulations to improve quality of life and sexual function while avoiding the higher erythrocytosis risk of injectable preparations. 1

Evidence Supporting TRT Safety in CAD Patients

The 2023 TRAVERSE trial provides the highest-quality evidence for cardiovascular safety in exactly this population 1:

• 5,246 men aged 45-80 years with preexisting cardiovascular disease or high cardiovascular risk were randomized to transdermal testosterone gel versus placebo 1
• Primary cardiovascular events (death, MI, stroke) occurred in 7.0% of testosterone-treated patients versus 7.3% of placebo patients (hazard ratio 0.96,95% CI 0.78-1.17), demonstrating noninferiority 1
• Mean treatment duration was 21.7 months with 33 months follow-up 1

Additional supportive evidence shows:

• Men with established cardiovascular disease have lower testosterone levels than men with normal angiograms, suggesting testosterone deficiency may contribute to CAD rather than cause it 2
• In the Rotterdam Study, men in the highest two-thirds of testosterone levels had relative risks of severe aortic atherosclerosis of 0.4 and 0.2 compared to the lowest third 2
• 22 men with chronic stable angina treated with transdermal testosterone had greater angina-free exercise tolerance than placebo controls 2

Benefits of TRT in Symptomatic Hypogonadism

The American College of Physicians 2020 guidelines found moderate-certainty evidence for 2:

• Small improvement in sexual function (SMD 0.35, CI 0.23-0.46) 2
• Small improvement in quality of life (SMD 0.33 lower on AMS scale, CI 0.50-0.16), though driven primarily by sexual function improvements 2
• Small improvement in erectile function (SMD 0.27, CI 0.09-0.44) 2

Observational data spanning up to 10.3 years showed no increased risk for mortality, cardiovascular events, prostate cancer, or venous thromboembolism 2

Risks of Withholding TRT in Symptomatic Hypogonadism

Untreated hypogonadism in men with CAD perpetuates a harmful metabolic state:

• Low testosterone is associated with obesity, metabolic syndrome, type 2 diabetes, and altered lipid profiles—all contributing to increased cardiovascular disease risk 3
• 40% of male type 2 diabetics with CAD have hypogonadism (testosterone <3 ng/mL) versus only 14% of controls, with positive correlation between hypogonadism and CAD (r=0.177, P=0.030) 4
• Testosterone deficiency has a detrimental effect on vascular health, quality of life, and increased mortality 3
• Longer durations of testosterone therapy in observational studies were associated with greater health benefits and reduced cardiovascular risk 3

Critical Implementation Algorithm

Step 1: Confirm Hypogonadism

• Obtain two separate fasting morning testosterone levels <300 ng/dL 5, 1
• Document symptoms: decreased libido, erectile dysfunction, fatigue, diminished muscle mass 5

Step 2: Choose Transdermal Formulation

• Strongly prefer transdermal testosterone gel over injections for all patients with cardiovascular disease 6, 5
• Transdermal preparations carry 3-18% erythrocytosis risk versus 43.8% with intramuscular injections 6, 5
• Target mid-normal testosterone levels of 500-600 ng/dL 6

Step 3: Baseline Assessment

• Hematocrit/hemoglobin (withhold if hematocrit >50%) 6, 5
• PSA and digital rectal examination 5
• Document cardiovascular status 1

Step 4: Monitoring Schedule

• Hematocrit at 2-3 months, then every 6-12 months 6, 5
• PSA and prostate examination every 3-6 months for first year, then annually 5
• If hematocrit rises >52%, reduce dose, withhold temporarily, or perform therapeutic phlebotomy 5

Important Caveats and Contradictory Evidence

One conflicting study requires acknowledgment:

• A 2013 retrospective VA cohort study of 8,709 men who underwent coronary angiography found testosterone therapy associated with increased risk of composite endpoint (mortality, MI, stroke) with hazard ratio 1.29 (CI 1.05-1.58) 2, 7
• However, this study was retrospective with significant confounding, and the definitive prospective TRAVERSE trial directly contradicts these findings 1
• The FDA issued a 2015 safety warning based on retrospective data, but the 2023 TRAVERSE trial provides level 1 evidence of safety 2, 6, 1

Additional monitoring concerns:

• Higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism observed in TRAVERSE testosterone group—monitor for these complications 1
• Physiologic replacement doses show neutral effects on lipid profiles (HDL unchanged in 15 of 18 studies), but supraphysiologic doses can reduce HDL 2

Absolute Contraindications

• Active prostate cancer 5
• Hematocrit >50% at baseline 6, 5

The evidence overwhelmingly supports offering TRT to symptomatic hypogonadal men with CAD using transdermal formulations, with the TRAVERSE trial definitively establishing cardiovascular safety in this exact population. 1