What are the risks and benefits of testosterone supplementation for a patient with hypogonadism (low testosterone levels) who is a heavy smoker?

Testosterone Supplementation in Hypogonadal Patients Who Smoke

Recommendation Summary

Testosterone supplementation for a hypogonadal heavy smoker carries significant risks that likely outweigh potential benefits, particularly due to increased risk of erythrocytosis, cardiovascular events, and potential worsening of smoking-related health issues. 1

Risk Assessment for Testosterone Therapy in Smokers

Cardiovascular Risks

• Heavy smoking is already a significant cardiovascular risk factor, and testosterone therapy may compound this risk 1
• Testosterone therapy shows increased cardiovascular event risk during the first 12 months of treatment, particularly in men ≥65 years (risk ratio = 2.90) 2
• Different administration routes carry different cardiovascular risks:
  • Transdermal testosterone: highest risk (risk ratio = 2.80)
  • Oral testosterone: moderate risk (risk ratio = 2.28)
  • Intramuscular testosterone: lowest risk (risk ratio = 0.96) 2
• The 2023 TRAVERSE study demonstrated testosterone therapy was noninferior to placebo for major adverse cardiac events in men with hypogonadism, but showed higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism 3, 1

Hematologic Risks

• Erythrocytosis is a major concern with testosterone therapy, especially in smokers 1
• Incidence of erythrocytosis varies by formulation:
  • Nonscrotal patches: 2.8%
  • Gel preparations (50 mg/day): 11.3%
  • Gel preparations (100 mg/day): 17.9% 1
• Testosterone therapy should be withheld if baseline hematocrit exceeds 50%, and discontinued if hematocrit rises above 54% during treatment 1, 4
• Smoking independently increases hemoglobin and hematocrit levels, compounding this risk 5

Smoking-Specific Considerations

• Smoking men have 15% higher total and 13% higher free testosterone levels compared to non-smokers 5
• This elevation may mask borderline hypogonadism and complicate accurate diagnosis 5
• Smoking cessation should be strongly encouraged before considering testosterone therapy 1

Potential Benefits of Testosterone Therapy

Despite the risks, testosterone therapy may provide some benefits in hypogonadal patients:

• Improvements in erectile function and sexual desire 1, 6
• Increased bone mineral density 1, 6
• Increased lean body mass and decreased fat mass 1, 6
• Potential improvements in depressive symptoms 1, 6
• Possible improvements in energy levels and quality of life 1, 4

Monitoring Requirements if Therapy is Initiated

If testosterone therapy is deemed necessary despite the risks:

1. Baseline assessments required:

   • Total testosterone levels (morning measurements)
   • Hemoglobin/hematocrit (critical in smokers)
   • PSA for men over 40
   • Cardiovascular risk assessment
   • Digital rectal examination
   • Sleep apnea history 1, 4

2. Ongoing monitoring:

   • Testosterone levels (target: 450-600 ng/dL)
   • Hematocrit every 3-6 months (discontinue if >54%)
   • PSA every 3-6 months in first year
   • Symptom improvement assessment 4
   • More frequent monitoring of cardiovascular parameters in smokers 4

Alternative Approaches

For hypogonadal patients who smoke, consider:

1. Smoking cessation as first-line intervention before initiating testosterone therapy
2. Selective estrogen receptor modulators (e.g., clomiphene citrate) which may have lower cardiovascular risk 4
3. Aromatase inhibitors (e.g., anastrozole) to reduce conversion of testosterone to estradiol 4
4. Lifestyle modifications to naturally improve testosterone levels:
   • Weight loss
   • Regular exercise
   • Improved sleep hygiene
   • Stress reduction

Conclusion

The combination of hypogonadism and heavy smoking presents a challenging clinical scenario. The increased risks of erythrocytosis, cardiovascular events, and other adverse outcomes in a patient who already has elevated cardiovascular risk due to smoking makes testosterone supplementation potentially dangerous. Smoking cessation should be strongly encouraged before considering testosterone therapy. If testosterone therapy is deemed necessary, intramuscular formulations may carry lower cardiovascular risk than transdermal or oral preparations, but close monitoring is essential.