What is the relationship between testosterone and polycythemia (excessive red blood cell count)?

From the Guidelines

Testosterone therapy is associated with an increased risk of polycythemia, a condition characterized by an excessive production of red blood cells, and patients should be monitored regularly for this potential side effect. The relationship between testosterone and polycythemia is well-established, with higher testosterone levels stimulating erythropoiesis and leading to increased hemoglobin levels 1. This is evident in the natural increase in hemoglobin levels in boys at puberty, parallel to rising serum testosterone levels, and the higher hemoglobin levels in adult men compared to adult women.

Key Considerations

• The risk of polycythemia is greater with injectable testosterone compared to transdermal formulations, with studies indicating that injectable testosterone is associated with the greatest treatment-induced increases in hemoglobin and hematocrit 1.
• Patients on testosterone therapy should have their hematocrit levels monitored regularly, typically every 3-6 months during the first year of treatment and then annually thereafter.
• If hematocrit rises above 54%, testosterone therapy should be temporarily discontinued until levels normalize, and therapeutic phlebotomy may be necessary to quickly reduce hematocrit in symptomatic patients.
• Switching from intramuscular to transdermal testosterone formulations can help reduce polycythemia risk, as transdermal forms produce more stable hormone levels with fewer peaks.

Mechanism and Patient Education

The mechanism behind testosterone-induced polycythemia involves direct stimulation of erythropoietin production in the kidneys and enhanced iron utilization for hemoglobin synthesis. Patients should be educated about symptoms of polycythemia, including headache, dizziness, and fatigue, and advised to maintain adequate hydration to reduce blood viscosity. According to the most recent guideline, patients should be informed that testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms, but also carries the risk of polycythemia 1.

From the FDA Drug Label

Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia. Laboratory tests: Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-term androgen administration.

The relationship between testosterone and polycythemia is that testosterone may cause polycythemia, which is an excessive red blood cell count. This is indicated by the need to check hemoglobin and hematocrit levels periodically in patients receiving long-term androgen administration to detect polycythemia 2. Additionally, polycythemia is listed as a possible hematologic adverse reaction to testosterone therapy 2.

From the Research

Relationship Between Testosterone and Polycythemia

The relationship between testosterone and polycythemia is a significant concern in the medical field, particularly for individuals undergoing testosterone replacement therapy (TRT). Key findings from various studies include:

• Polycythemia is a common adverse effect of TRT, which may predispose patients to adverse vascular events 3.
• The development of secondary polycythemia during testosterone therapy is associated with an increased risk of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE) 4.
• Different testosterone formulations have varying influences on the development of secondary polycythemia, with intramuscular testosterone cypionate (TC) increasing hematocrit (Hct) by 3.24% compared to intranasal testosterone gel (Natesto) 5.

Risk of Polycythemia with Different Testosterone Formulations

The risk of polycythemia varies with different formulations of testosterone therapy:

• Intramuscular testosterone enantate has a higher proportion of patients with polycythemia (23.3%) compared to transdermal testosterone (0%) 6.
• Intramuscular testosterone undecanoate has a lower risk of polycythemia (15%) compared to intramuscular testosterone enantate, but higher than transdermal testosterone 6.
• Transdermal testosterone has been shown to have a lower risk of polycythemia compared to intramuscular formulations 5, 6.

Monitoring and Management of Polycythemia

Regular monitoring of hematocrit is crucial for individuals treated with testosterone, particularly those on intramuscular formulations:

• Current guidelines recommend regular laboratory monitoring and discontinuing TRT or reducing the dose if the hematocrit exceeds 54% 3.
• Phlebotomy or blood donation may be insufficient to maintain a hematocrit below 54% in some individuals 3.
• Adjusting testosterone dosing, stopping therapy, or ordering a phlebotomy may be necessary to manage secondary polycythemia 7.