Can a smoker with documented low testosterone (two morning measurements), no untreated prostate cancer, hematocrit <55%, and no recent myocardial infarction or stroke safely start testosterone replacement therapy?

Can a Smoker Start Testosterone Replacement Therapy?

Yes, a smoker with documented hypogonadism can start testosterone replacement therapy, but smoking status must be assessed as a modifiable cardiovascular risk factor before initiating treatment, and smokers should be counseled that active smoking may negate the protective cardiovascular benefits of testosterone normalization. 1

Pre-Treatment Risk Assessment

Before offering testosterone therapy, clinicians must measure hemoglobin and assess all testosterone-deficient patients for atherosclerotic cardiovascular disease (ASCVD) risk factors, including both fixed factors (older age, male gender) and modifiable factors such as current cigarette smoking. 1 This is a strong recommendation based on Grade A evidence from the American Urological Association.

Smoking is not listed as an absolute contraindication to testosterone therapy. 1, 2 The absolute contraindications include:

• Untreated prostate cancer or elevated PSA without urological evaluation 1, 2
• Hematocrit >50-54% at baseline 1, 2
• Recent myocardial infarction or stroke within 3-6 months 1, 2
• Breast cancer 2
• Uncontrolled heart failure 2

Critical Smoking-Specific Considerations

Active smoking significantly modifies testosterone therapy outcomes. A 2017 study demonstrated that normalization of testosterone levels in current smokers was associated with decreased all-cause mortality (HR 0.563, P<.001) but showed no benefit for myocardial infarction risk (HR 1.096, P=.69), unlike nonsmokers who experienced both mortality and MI risk reduction. 3

Most concerning, current smokers with normalized testosterone levels had significantly higher rates compared to nonsmokers with normalized testosterone for:

• All-cause mortality (HR 1.242, P<.001) 3
• Myocardial infarction (HR 1.706, P=.001) 3
• Stroke (HR 1.590, P=.04) 3

Treatment Algorithm for Smokers

Step 1: Confirm Eligibility

• Two morning fasting total testosterone measurements <300 ng/dL 1, 2
• Documented hypogonadism symptoms 2
• Hematocrit <50% at baseline 1, 2
• No recent cardiovascular events within 3-6 months 1, 2
• PSA screening appropriate for age (>40 years) 1

Step 2: Mandatory Smoking Counseling

Patients who are overweight or obese should be counseled regarding weight loss programs concurrent with testosterone therapy, and lifestyle modifications including smoking cessation should be emphasized as having the potential to increase total testosterone levels and reduce cardiovascular risk. 1 High body mass index coupled with low testosterone and active smoking creates compounded cardiovascular risk. 1

Step 3: Formulation Selection

Strongly prefer transdermal testosterone gel over intramuscular injections for smokers, particularly those with cardiovascular risk factors. 4 The rationale:

• Intramuscular injections carry 43.8% risk of elevated hematocrit (>52%) 4, 2
• Transdermal preparations have only 3-18% erythrocytosis risk 4, 2
• Erythrocytosis increases blood viscosity and cardiovascular risk 4
• Recent evidence shows any increase in hematocrit after starting testosterone is associated with increased MACE risk 5

Step 4: Enhanced Monitoring Protocol

For smokers on testosterone therapy, implement more vigilant surveillance:

Initial Phase (First 3 months):

• Hematocrit at 2-3 months 1, 4
• If hematocrit >54%, intervention required (dose reduction, temporary discontinuation, or therapeutic phlebotomy) 1

Ongoing Monitoring (Every 6-12 months):

• Hematocrit measurement 1, 4
• PSA and prostate examination 1
• Lipid panel and blood pressure 4
• Cardiovascular symptom assessment 4

Step 5: Dosing Strategy

Target testosterone levels in the middle tertile of normal range (450-600 ng/dL), using minimal dosing necessary. 1 This conservative approach is particularly important in smokers given their attenuated cardiovascular benefit profile. 3

Common Pitfalls to Avoid

Do not delay treatment solely based on smoking status if the patient meets all other criteria. Smoking is a modifiable risk factor requiring counseling and monitoring, not an absolute contraindication. 1

Do not use intramuscular testosterone as first-line in smokers. The 4-fold higher erythrocytosis risk with injectable formulations compounds the already elevated cardiovascular risk from smoking. 4, 2

Do not initiate therapy if the patient had a cardiovascular event within 3-6 months. This waiting period is mandatory regardless of smoking status. 1

Do not prescribe testosterone if hematocrit is >50% at baseline. The etiology must be formally investigated before considering therapy. 1

Evidence Quality Considerations

The 2023 TRAVERSE trial provides Level 1 evidence that testosterone therapy does not increase stroke risk in appropriately selected men, even with preexisting cardiovascular disease. 4 However, this trial's applicability to active smokers requires caution, as the smoking-specific data from 2017 shows active smoking negates MI protection despite testosterone normalization. 3

The conflicting evidence from 2013 showing increased cardiovascular events with testosterone therapy 6 versus 2021 data showing no increased risk 7 highlights the importance of proper patient selection, formulation choice, and monitoring—all particularly critical in smokers. 3