How is polycythemia (increased red blood cell count) managed in patients undergoing testosterone (male hormone) therapy?

From the Guidelines

Polycythemia in patients on testosterone therapy should be managed through regular blood monitoring, therapeutic phlebotomy, and possible testosterone dose adjustments, with a focus on preventing hematocrit levels from exceeding 54%. According to the most recent guideline evidence 1, patients should undergo a baseline measurement of hemoglobin/hematocrit before commencing testosterone therapy, and if the hematocrit exceeds 50%, clinicians should consider withholding testosterone therapy until the etiology is formally investigated.

While on testosterone therapy, a hematocrit level greater than 54% warrants intervention, such as dose reduction or temporary discontinuation 1. The primary intervention for symptomatic polycythemia or when hematocrit exceeds 54% is therapeutic phlebotomy, which involves removing 1 unit or approximately 500mL of blood. This procedure can be repeated every 2-3 months as needed.

Key considerations in managing polycythemia in patients on testosterone therapy include:

• Regular monitoring of hematocrit and hemoglobin levels before starting therapy, then every 3-6 months during the first year, and annually thereafter
• Temporarily discontinuing testosterone therapy if hematocrit exceeds 54% until levels normalize
• Adjusting the testosterone regimen, including reducing the dose, changing from intramuscular to transdermal formulations, or extending the interval between doses
• Maintaining adequate hydration and avoiding smoking as supportive measures
• Referring patients to a hematologist if polycythemia persists despite these interventions to rule out other causes.

It is essential to note that polycythemia occurs because testosterone stimulates erythropoiesis in the bone marrow, increasing red blood cell production, and this side effect is more common with injectable testosterone formulations and in older patients 1.

From the FDA Drug Label

1. 3 Polycythemia

Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events.

Management of polycythemia in patients undergoing testosterone therapy involves:

• Monitoring hematocrit levels before starting treatment, 3 to 6 months after initiation, and then annually
• Lowering or discontinuing testosterone if hematocrit levels become elevated
• Stopping therapy until hematocrit decreases to an acceptable concentration if it becomes elevated 2

From the Research

Management of Polycythemia in Testosterone Therapy

• Polycythemia, or increased red blood cell count, is a common adverse effect of testosterone replacement therapy (TRT) that may predispose patients to adverse vascular events 3.
• Current guidelines recommend regular laboratory monitoring and discontinuing TRT or reducing the dose if the hematocrit exceeds 54% (hemoglobin ≥180 g/L) 3, 4.
• The evidence for secondary polycythemia causing harm during testosterone therapy is scarce, and hematocrit-based cutoffs appear to be arbitrarily chosen 5.
• Patient-specific factors should be considered when choosing an appropriate testosterone therapy dosage and modality, and providers should decrease or discontinue therapy if the patient's hematocrit exceeds 54% until the hematocrit normalizes 4.

Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism

• Secondary polycythemia in men receiving testosterone therapy increases the risk of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE) in the first year of therapy 6.
• Men with polycythemia had a higher risk of MACE/VTE than men who had normal hematocrit while on testosterone therapy (OR 1.35,95% CI 1.13-1.61, p <0.001) 6.
• Developing polycythemia while on testosterone therapy is an independent risk factor for MACE and VTE in the first year of therapy 6.

Prevention and Treatment of Erythrocytosis

• Erythrocytosis occurs in trans men using testosterone, with a prevalence of 11% (hematocrit > 0.50 L/L), 3.7% (hematocrit > 0.52 L/L), and 0.5% (hematocrit > 0.54 L/L) 7.
• Tobacco use, long-acting undecanoate injections, age at initiation of hormone therapy, body mass index (BMI), and pulmonary conditions are associated with erythrocytosis and polycythemia vera 7.
• A reasonable first step in the care for trans men with erythrocytosis while on testosterone is to advise them to quit smoking, switch to a transdermal administration route, and lose weight if BMI is high 7.