What is the management of elevated hematocrit (Hct) in a patient on testosterone therapy with normal testosterone levels?

Management of Elevated Hematocrit in Testosterone Therapy with Normal Testosterone Levels

For patients on testosterone therapy with normal testosterone levels who develop elevated hematocrit, temporarily discontinue testosterone therapy until hematocrit normalizes, then consider dose reduction or switching to a different formulation with lower erythrocytosis risk when restarting therapy. 1

Understanding the Problem

Erythrocytosis (elevated hematocrit) is the most common adverse effect of testosterone therapy, with risk varying significantly by administration route:

• Injectable testosterone: 43.8% risk
• Transdermal patches: 15.4% risk
• Gels: 2.8-17.9% risk (dose-dependent) 1

Even when testosterone levels are within normal range, the stimulation of erythropoiesis can occur through multiple mechanisms:

• Initial rise in erythropoietin (EPO)
• Establishment of a new EPO/hemoglobin 'set point'
• Decrease in hepcidin (master iron regulator protein) 2

Clinical Significance

Elevated hematocrit increases blood viscosity, potentially raising the risk of thromboembolic events, particularly in patients with pre-existing cardiovascular risk factors 1. The FDA label specifically warns that increases in hematocrit may require lowering or discontinuation of testosterone therapy 3.

Management Algorithm

1. Monitoring Parameters

• Check hematocrit prior to initiating treatment
• Recheck 1-2 months after initiation
• Monitor every 3-6 months during the first year
• Continue annual monitoring thereafter 1, 3

2. Intervention Thresholds

• When hematocrit exceeds 50%: Withhold testosterone therapy 1
• When hematocrit exceeds 54%: Immediate intervention required 1, 4

3. Management Steps

Step 1: Temporarily Discontinue Therapy

• Stop testosterone therapy until hematocrit normalizes 1, 4

Step 2: Consider Therapeutic Phlebotomy

• If clinically indicated (especially with significantly elevated hematocrit)
• Recheck hematocrit within 1-2 months after phlebotomy 1
• Important caveat: Evidence supporting phlebotomy efficacy and safety in testosterone-induced erythrocytosis is limited; phlebotomy may lower tissue oxygen and deplete iron stores, potentially increasing thrombotic risk 2

Step 3: Restart with Modifications

• Consider dose reduction when restarting therapy 1
• Consider switching to a different formulation with lower erythrocytosis risk:
  • Transdermal patches have shown significantly lower hematocrit increases compared to intramuscular testosterone cypionate/enanthate 5
  • Gels generally have lower risk than injectable formulations 1, 6

Special Considerations

1. Patient-specific risk factors that may increase erythrocytosis risk:

   • Advanced age
   • Higher waist circumference (obesity)
   • Larger increases in testosterone levels
   • Functional vs. classical hypogonadism 6

2. Formulation considerations:

   • Long-acting testosterone undecanoate injections lead to higher rates of hematocrit >50% compared to testosterone gel 6
   • However, injectable formulations may be more effective at treating anemia in hypogonadal patients 6

3. Monitoring frequency:

   • More frequent monitoring may be necessary for patients using injectable testosterone or those with risk factors for erythrocytosis 1, 5

Common Pitfalls to Avoid

1. Ignoring elevated hematocrit: Even with normal testosterone levels, elevated hematocrit increases thrombotic risk and requires intervention 1, 3

2. Automatic phlebotomy: While mentioned in guidelines, evidence for phlebotomy efficacy is limited, and it may have its own risks 2

3. Failing to adjust therapy: Simply restarting the same testosterone formulation at the same dose after hematocrit normalizes may lead to recurrent erythrocytosis 1

4. Overlooking other cardiovascular risk factors: Testosterone therapy may increase risk of cardiovascular events, particularly in patients with pre-existing risk factors 1, 3