What are the cardiovascular risks associated with testosterone therapy in patients with hypogonadism?

Cardiovascular Effects of Testosterone Therapy

Testosterone therapy in hypogonadal men has conflicting evidence regarding cardiovascular risk, with current data suggesting a neutral or potentially beneficial effect on cardiovascular outcomes when used appropriately in properly diagnosed patients.

Current Understanding of Cardiovascular Risk

Testosterone therapy's cardiovascular effects have been subject to significant debate and conflicting evidence:

• The FDA required labeling changes in 2015 to inform healthcare professionals and patients about possible increased risk of heart attack and stroke with testosterone use for age-related hypogonadism 1
• However, multiple medical associations and societies, supported by various safety data, maintain that testosterone replacement therapy may have cardiometabolic benefits when properly prescribed 1
• The American College of Physicians' 2020 evidence review concluded that evidence is inadequate to make definitive conclusions about long-term cardiovascular harms of testosterone treatment 1

Risk Stratification by Administration Route

Different testosterone formulations appear to have varying cardiovascular risk profiles:

• Injectable testosterone may carry greater cardiovascular risk compared to transdermal preparations 1

  • This may be related to fluctuating testosterone levels with injections (peaks and valleys) versus more stable levels with transdermal formulations
  • Injectable testosterone users spend more time in both supratherapeutic and subtherapeutic ranges 1

• Transdermal preparations (gels, patches) provide more consistent testosterone levels but have other limitations including:

  • Risk of transfer to others
  • Variable absorption
  • Higher cost 1

Cardiovascular Effects by Evidence Quality

Established Effects

• Fluid retention: May occur with testosterone therapy, particularly concerning in patients with pre-existing cardiac, renal, or hepatic disease 2
• Erythrocytosis: Dose-dependent effect (2.8-17.9% incidence) that can increase blood viscosity 3

Emerging Evidence

• Lipid profiles: Most studies show neutral effects with physiologic replacement doses 1

  • Supraphysiologic doses may lower HDL levels
  • Physiologic doses often show minimal or no reduction in HDL, sometimes with beneficial reduction in total cholesterol 1

• Coronary blood flow: Some evidence suggests testosterone may increase coronary artery diameter and blood flow 1

Monitoring Recommendations

For patients receiving testosterone therapy, cardiovascular monitoring should include:

1. Baseline assessment of cardiovascular risk factors before initiating therapy 3
2. Regular monitoring of:
   • Blood pressure
   • Hemoglobin/hematocrit (discontinue if Hct >54%) 3
   • Lipid profile
3. Testosterone level monitoring:
   • 2-3 months after treatment initiation
   • After any dose change
   • Every 6-12 months once stable 1
   • Target mid-normal range (450-600 ng/dL) 3

Special Considerations

• Patients with pre-existing cardiovascular disease: Exercise caution, though some evidence suggests testosterone may be safely considered in men with appropriately diagnosed hypogonadism even with concurrent cardiovascular risk factors 4

• Elderly patients: May have higher cardiovascular risk with testosterone therapy, requiring more careful monitoring 5

• Timing of measurements for injectable testosterone: Levels should be measured midway between injections 1

Future Research

The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) began enrollment in 2018 to evaluate testosterone therapy's effects on cardiovascular outcomes over 5 years 1. This large, prospective trial should provide more definitive evidence on long-term cardiovascular safety.

Clinical Decision Algorithm

1. Confirm true hypogonadism: Morning total testosterone <300 ng/dL on at least two separate occasions with consistent symptoms 3
2. Assess cardiovascular risk: Evaluate pre-existing conditions, baseline lipids, blood pressure
3. Choose appropriate formulation:
   • For patients with cardiovascular risk factors: Consider transdermal preparations for more stable levels
   • For patients with minimal cardiovascular risk: Either formulation may be appropriate
4. Monitor closely:
   • Testosterone levels (target 450-600 ng/dL)
   • Hematocrit (discontinue if >54%)
   • Cardiovascular symptoms
5. Reassess benefit vs. risk periodically, especially in elderly patients or those with pre-existing cardiovascular disease