What is the next step for a patient with polycythemia (elevated red blood cell count) on testosterone replacement therapy?

Management of Polycythemia in Patients on Testosterone Therapy

For a patient with hemoglobin of 17.5 g/dL and hematocrit of 51% while on testosterone therapy (total testosterone 653 ng/dL), therapeutic phlebotomy is the recommended next step to reduce the risk of thromboembolic events. 1

Assessment of Current Status

The patient presents with:

• Hemoglobin: 17.5 g/dL (elevated)
• Hematocrit: 51% (elevated but below critical threshold)
• Total testosterone: 653 ng/dL (within therapeutic range)

Risk Stratification

This patient has secondary erythrocytosis due to testosterone therapy, which is one of the most common adverse effects of testosterone replacement therapy (TRT). While the current hematocrit of 51% is elevated, it remains below the critical threshold of 54% that would necessitate immediate discontinuation of therapy 2.

Management Algorithm

1. Immediate Intervention:

   • Therapeutic phlebotomy to reduce hematocrit 1
   • Target hematocrit below 50% to reduce cardiovascular risk

2. Medication Adjustment:

   • Consider modifying testosterone administration route
   • Injectable testosterone has higher risk of erythrocytosis (43.8% of patients) compared to transdermal preparations (15.4%) 1
   • Consider switching to transdermal testosterone if currently on injectable form

3. Risk Factor Modification:

   • Assess and address modifiable risk factors:
     • Tobacco use (increases risk by 2.2 times) 3
     • Body mass index (high BMI increases risk by 3.7 times) 3
     • Presence of pulmonary conditions 3

4. Follow-up Monitoring:

   • Recheck hemoglobin/hematocrit within 1-3 months 2
   • Continue regular monitoring every 3-6 months thereafter

Evidence Analysis

The New England Journal of Medicine guidelines define erythrocytosis as hematocrit over 52%, with recommendations for appropriate measures including therapeutic phlebotomy when erythrocytosis develops 1. While the patient's current hematocrit of 51% is below this threshold, the hemoglobin of 17.5 g/dL indicates significant erythrocytosis that warrants intervention.

Research shows that testosterone stimulates erythropoiesis through increased erythropoietin levels and decreased hepcidin, establishing a new erythropoietin/hemoglobin set point 4. This physiological mechanism explains the persistent elevation in red blood cell parameters despite continued therapy.

Important Considerations and Pitfalls

1. Phlebotomy Effectiveness: Evidence from a 2017 study suggests that repeat blood donation alone may be insufficient to maintain hematocrit below 54% in patients on TRT 5. Therefore, phlebotomy should be combined with other interventions such as dose adjustment or route modification.

2. Monitoring Limitations: Simply monitoring without intervention may be insufficient, as the probability of developing erythrocytosis increases over time (10% after 1 year, 38% after 10 years) even though the largest increase in hematocrit occurs in the first year of therapy 3.

3. Route of Administration: Injectable testosterone carries a significantly higher risk of erythrocytosis compared to transdermal preparations 1. The 2024 research indicates that therapeutic phlebotomy should be carefully considered as it may trigger biological pathways that could potentially increase thrombotic risk 6.

4. FDA Warning: The FDA label for injectable testosterone specifically lists polycythemia as an adverse reaction requiring monitoring of hemoglobin and hematocrit levels periodically in patients receiving long-term androgen administration 7.

By implementing therapeutic phlebotomy while considering medication adjustments and addressing modifiable risk factors, the risk of thromboembolic events can be minimized while maintaining the benefits of testosterone therapy for this patient.