What are the risks of testosterone replacement therapy (TRT) in heavy smokers?

Risks of Testosterone Replacement Therapy in Heavy Smokers

Heavy smokers undergoing testosterone replacement therapy (TRT) face significantly increased risks of myocardial infarction and all-cause mortality compared to nonsmokers, even when testosterone levels are normalized. 1

Cardiovascular Risks

• Heavy smoking negates the potential cardiovascular protective effects of TRT, with smokers showing a 70% higher risk of myocardial infarction compared to nonsmokers with normalized testosterone levels 1
• While TRT may have neutral or possibly beneficial cardiovascular effects in nonsmokers, this benefit is not observed in heavy smokers 2, 1
• Smokers with normalized testosterone levels still have 24% higher all-cause mortality compared to nonsmokers with normalized testosterone 1

Hematologic Effects

• Erythrocytosis (elevated red blood cell count) is a significant risk with TRT, occurring in:
  • 3-18% of patients using transdermal formulations 2
  • Up to 44% of patients receiving injectable testosterone 2
• This risk is particularly concerning in smokers who may already have elevated hematocrit levels due to chronic carbon monoxide exposure 3
• Monitoring hematocrit/hemoglobin is essential, with temporary discontinuation of TRT or dose reduction recommended if levels rise above the reference range 3

Prostate Effects

• All men receiving TRT require careful monitoring for prostate cancer through:
  • Baseline and follow-up PSA measurements 3
  • Regular digital rectal examinations 3
• Consider prostate biopsy for PSA increases of ≥1.0 ng/mL in one year or if PSA rises above 4.0 ng/mL 3
• While the absolute risk of prostate cancer with TRT remains controversial, proper monitoring is essential 2

Sleep Apnea

• TRT can exacerbate existing sleep apnea or contribute to its development, particularly in men with other risk factors 3, 2
• Smokers often have compromised respiratory function, making this risk especially relevant 3
• Assessment for sleep apnea symptoms should be performed before initiating TRT and at follow-up visits 3

Other Significant Risks

• Fluid retention may be problematic, particularly in smokers with compromised cardiovascular function 3, 2
• Testicular atrophy and infertility are common due to gonadotropin suppression 2
• Stroke risk is 59% higher in smokers with normalized testosterone compared to nonsmokers with normalized testosterone 1

Monitoring Recommendations for Heavy Smokers

• Baseline assessment should include:

  • Cardiovascular risk assessment 3, 2
  • PSA and digital rectal examination 3
  • Hematocrit/hemoglobin 3
  • Assessment for sleep apnea 3
  • Voiding symptoms evaluation 3

• Follow-up monitoring:

  • First follow-up at 1-2 months to assess efficacy 3
  • Subsequent monitoring every 3-6 months for the first year, then annually 3
  • More frequent monitoring of hematocrit may be warranted in smokers 2
  • Low threshold for cardiovascular evaluation 3, 1

Formulation Considerations

• Oral testosterone preparations should be avoided due to hepatotoxicity risk 3, 2
• For smokers with cardiovascular concerns, consider easily titratable formulations (gels, patches) rather than long-acting injectables 3, 2
• Target testosterone levels should be in the mid-range (350-600 ng/dL) rather than high-normal, particularly in those with cardiovascular risk factors 3

Key Pitfalls to Avoid

• Failing to recognize that normalized testosterone levels do not provide the same cardiovascular protection in smokers as in nonsmokers 1
• Inadequate monitoring of hematocrit, which can lead to hyperviscosity and increased thrombotic risk 3, 2
• Overlooking the potential exacerbation of sleep apnea, which is already more common in smokers 3, 2
• Neglecting to counsel patients that smoking cessation would significantly improve their risk profile with TRT 1