Is testosterone replacement therapy (TRT) cardio protective?

Testosterone Replacement Therapy and Cardiovascular Protection

Based on the most recent and highest quality evidence, testosterone replacement therapy (TRT) is not cardioprotective but appears to be cardiovascularly neutral in men with hypogonadism.

Current Evidence on Cardiovascular Safety

The most recent high-quality evidence from the 2023 TRAVERSE trial demonstrated that TRT was noninferior to placebo regarding major adverse cardiovascular events in men with hypogonadism who had preexisting or high risk of cardiovascular disease 1. This large randomized controlled trial specifically designed to assess cardiovascular outcomes provides the strongest evidence to date on this question.

Earlier guidelines and studies provide additional context:

• The 2004 New England Journal of Medicine guidelines noted that men in the highest two-thirds of testosterone levels had lower relative risks of severe aortic atherosclerosis compared to men in the lowest third, suggesting testosterone may not have a deleterious cardiovascular effect 2

• The 2012 Princeton III Consensus stated that TRT may be considered for symptomatic men with testosterone levels between 231-346 ng/dL after careful discussion of risks and benefits 2

• The 2020 American College of Physicians guidelines found no evidence of increased risk for serious adverse events with TRT and noted insufficient evidence to make conclusions about mortality 2

Cardiovascular Effects of TRT

Potential Benefits

• May increase coronary artery diameter and blood flow 2
• Generally neutral effect on lipid profiles at physiologic replacement doses 2
• May improve angina-free exercise tolerance in men with chronic stable angina 2

Potential Risks

• FDA drug labeling notes that epidemiologic studies and RCTs have been inconclusive for determining cardiovascular risk 3
• Higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism observed in the testosterone group in the TRAVERSE trial 1
• Risk of venous thromboembolic events including DVT and PE 3

Clinical Approach to TRT and Cardiovascular Risk

Patient Selection

1. Confirm true hypogonadism:

   • Morning testosterone levels <300 ng/dL on two separate occasions
   • Presence of clinical symptoms of hypogonadism

2. Cardiovascular risk assessment:

   • All men with erectile dysfunction >30 years should be considered at increased CVD risk 2
   • Particular caution in patients with:
     • Congestive heart failure (risk of fluid retention) 2
     • History of venous thromboembolism 3

Treatment Recommendations

• Target testosterone levels: Mid-range (350-600 ng/dL), especially in men with heart failure 2
• Formulation selection: Consider easily titratable formulations (gel, spray, patch) rather than long-acting injectables for patients >70 years or with chronic illness 2
• Monitoring:
  • Regular hematocrit monitoring (risk of erythrocytosis) 2
  • Prostate-specific antigen testing 2
  • Cardiovascular parameters

Important Caveats

1. Not for enhancement: TRT should not be used for athletic performance enhancement 3

2. Age-related hypogonadism: The FDA has cautioned against using TRT for age-related hypogonadism alone 2

3. Duration of therapy: Beyond 6 months, TRT should be continued only if clinical benefit is observed 2

4. Individual risk factors: The decision to initiate TRT should consider the patient's specific cardiovascular risk profile

5. Patient education: Discuss potential cardiovascular risks with each patient before initiating therapy 4

In conclusion, while earlier observational studies suggested possible cardiovascular benefits of TRT, the most recent high-quality evidence indicates TRT is likely cardiovascularly neutral rather than protective in men with documented hypogonadism. The decision to initiate TRT should be based on confirmed hypogonadism with symptoms, with careful consideration of individual cardiovascular risk factors.