What are the treatment options for a patient with polycythemia who is on testosterone (testosterone replacement therapy)?

Management Options for Polycythemia in Patients on Testosterone Replacement Therapy

For patients with polycythemia secondary to testosterone therapy, the primary treatment options include dose reduction, changing the testosterone formulation to transdermal preparations, temporary discontinuation of therapy, or therapeutic phlebotomy when hematocrit exceeds 54%. 1

Understanding Testosterone-Induced Polycythemia

Testosterone stimulates erythropoiesis, which commonly leads to increased hemoglobin and hematocrit levels in patients on testosterone replacement therapy (TRT):

• Testosterone acts as a direct stimulus for erythropoiesis, increasing hemoglobin levels by 15-20% 1
• Polycythemia is one of the most common adverse effects of TRT 2
• While mild increases in hemoglobin can be beneficial for patients with anemia, elevation above the normal range may have serious consequences, particularly in elderly patients 1
• Increased blood viscosity can potentially aggravate vascular disease in coronary, cerebrovascular, or peripheral circulation 1

Risk Assessment and Monitoring

Before initiating treatment for polycythemia in TRT patients:

• Determine the severity of polycythemia by measuring hematocrit levels 1
• According to AUA guidelines, hematocrit >54% warrants intervention 1
• Assess for additional risk factors that may compound the risk of polycythemia:
  • Age (older patients at higher risk) 1
  • Route of testosterone administration (injectable forms carry higher risk) 1
  • Comorbid conditions like COPD or sleep apnea 1, 3
  • Smoking status 3, 4
  • BMI (higher BMI associated with increased risk) 3

Treatment Options

1. Modification of Testosterone Therapy

• Change administration route:

  • Switch from injectable to transdermal preparations, which have significantly lower rates of polycythemia 1, 4
  • Studies show polycythemia occurs in 0% of transdermal testosterone users compared to 23.3% with testosterone enanthate injections 4

• Dose reduction:

  • Lower the testosterone dose while maintaining it within therapeutic range 1
  • Target total testosterone levels in the middle tertile of the normal reference range (450-600 ng/dL) 1

• Temporary discontinuation:

  • For severe cases (hematocrit >54%), temporarily discontinue testosterone until hematocrit decreases to an acceptable level 2
  • Resume at a lower dose or different formulation once hematocrit normalizes 1

2. Therapeutic Phlebotomy

• Consider therapeutic phlebotomy for rapid reduction of hematocrit 5
• However, evidence suggests that repeat blood donation alone may be insufficient to maintain hematocrit below 54% in patients continuing TRT 5
• Should be combined with modification of testosterone therapy for optimal management 5

3. Treatment of Underlying Conditions

• Address any comorbid conditions that may exacerbate polycythemia:
  • Treatment of sleep apnea 1, 3
  • Smoking cessation 3, 4
  • Weight management for patients with high BMI 3

Clinical Decision Algorithm

1. For hematocrit 50-54%:

   • Consider changing from injectable to transdermal testosterone 1, 4
   • Reduce testosterone dose while maintaining therapeutic levels 1
   • Increase monitoring frequency (every 3 months) 1

2. For hematocrit >54%:

   • Temporarily discontinue testosterone therapy 2
   • Consider therapeutic phlebotomy 5
   • Once hematocrit normalizes, resume with transdermal formulation at lower dose 1
   • Monitor hematocrit closely after resuming therapy (initially monthly, then quarterly) 1

Important Considerations and Caveats

• Recent evidence suggests that developing polycythemia while on TRT increases the risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) in the first year of therapy (OR 1.35,95% CI 1.13-1.61) 6
• Injectable testosterone preparations are associated with significantly higher rates of polycythemia compared to transdermal formulations 1, 4
• Patients should be informed about the signs and symptoms of thromboembolic events and advised to seek immediate medical attention if these occur 2
• Regular monitoring of hematocrit is essential for all patients on TRT, with increased vigilance for those on injectable formulations 1