What are the risks of testosterone-induced polycythemia (excessive red blood cell production) with early signs of hyperviscosity syndrome (increased blood thickness)?

From the Guidelines

Testosterone-induced polycythemia with early hyperviscosity syndrome requires immediate discontinuation of testosterone therapy and therapeutic phlebotomy to reduce hematocrit levels. The patient should undergo phlebotomy to remove 450-500 mL of blood, potentially repeated weekly until hematocrit falls below 50% [ 1 ]. Hydration should be increased to 2-3 liters of water daily to reduce blood viscosity. Low-dose aspirin (81 mg daily) may be considered to reduce thrombotic risk. Once stabilized, if testosterone therapy is still indicated, it should be restarted at a lower dose with more frequent monitoring of complete blood counts every 3-4 months. Alternative testosterone formulations like transdermal gels may produce less dramatic increases in hematocrit than injectable forms [ 1 ].

Key Considerations

• Testosterone stimulates erythropoiesis in the bone marrow, increasing red blood cell production [ 1 ].
• When hematocrit rises above 54%, blood viscosity increases exponentially, raising the risk of thrombotic events including stroke, myocardial infarction, and deep vein thrombosis.
• Patients should be educated about symptoms requiring immediate attention: headache, blurred vision, dizziness, or shortness of breath.
• Prior to commencing testosterone therapy, all patients should undergo a baseline measurement of hemoglobin/hematocrit [ 1 ].

Management Strategies

• Discontinue testosterone therapy immediately if hematocrit exceeds 54% [ 1 ].
• Consider alternative testosterone formulations that may produce less dramatic increases in hematocrit.
• Monitor complete blood counts every 3-4 months once testosterone therapy is restarted at a lower dose.

From the Research

Testosterone-Induced Polycythemia

• Testosterone replacement therapy (TRT) can lead to polycythemia, a condition characterized by an increased concentration of red blood cells in the blood 2, 3, 4, 5, 6.
• Polycythemia is a common adverse effect of TRT and may predispose patients to adverse vascular events, such as major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE) 2, 4.
• The risk of developing polycythemia is higher in men undergoing TRT, with short-acting injectable formulations having the highest associated incidence 5.

Diagnosis and Monitoring

• Current guidelines recommend regular laboratory monitoring and discontinuing TRT or reducing the dose if the hematocrit exceeds 54% (hemoglobin ≥180 g/L) 2.
• However, the evidence for secondary polycythemia causing harm during TRT is scarce, and the hematocrit-based cutoffs present in multiple guidelines appear to be arbitrarily chosen 3.
• A study found that men with polycythemia had a higher risk of MACE/VTE than men who had normal hematocrit while on TRT 4.

Mechanisms and Risk Factors

• The mechanisms explaining the relation between TRT and erythrocytosis include the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors 5.
• High blood viscosity increases the risk for potential vascular complications involving the coronary, cerebrovascular, and peripheral vascular circulations 5.
• Men with low to low-normal levels of testosterone have a documented benefit from hormone replacement, but the risks associated with androgen replacement need further examination 6.

Treatment and Prevention

• Adjusting TRT dosing, stopping therapy, ordering a phlebotomy, or recommending a combination of these are common interventions upon diagnosis of secondary erythrocytosis 3.
• However, the data supporting varying interventions upon diagnosis of secondary erythrocytosis are limited, and further research is needed to fully evaluate the hematological side effects associated with TRT 3, 6.