Does testosterone replacement therapy increase red blood cell (RBC) count?

From the Guidelines

Yes, testosterone replacement therapy (TRT) does increase red blood cell count in most patients. This effect, called erythrocytosis or polycythemia, is one of the most common side effects of TRT, occurring in approximately 20-30% of men receiving treatment 1. The increase typically begins within 3-6 months of starting therapy and is dose-dependent, meaning higher testosterone doses generally cause greater increases in red blood cell production. This occurs because testosterone stimulates erythropoietin production in the kidneys, which then signals the bone marrow to produce more red blood cells. Some key points to consider:

• While this effect can be beneficial for men with anemia, excessive increases in red blood cell count can potentially increase blood viscosity and the risk of thrombotic events like stroke or heart attack.
• Men on TRT should have their complete blood count (CBC) monitored regularly, typically every 3-6 months during the first year of treatment and then annually thereafter.
• If hematocrit levels exceed 54%, physicians may recommend temporarily stopping TRT, reducing the dose, switching to a different formulation, or performing therapeutic phlebotomy to reduce blood thickness and associated cardiovascular risks 1. It's also worth noting that the risk of erythrocytosis may vary depending on the formulation of testosterone used, with injectable testosterone potentially carrying a higher risk compared to transdermal preparations 1. Overall, the benefits and risks of TRT should be carefully weighed and monitored in individual patients to minimize the risk of adverse effects while maximizing the potential benefits of treatment.

From the FDA Drug Label

Androgens have been reported to stimulate production of red blood cells by enhancing production of erythropoietic stimulation factor

• Testosterone replacement therapy may increase red blood cell (RBC) count by stimulating the production of erythropoietic stimulation factor.
• Patients receiving long-term androgen administration should have their hemoglobin and hematocrit levels checked periodically to detect polycythemia 2, 2.

From the Research

Testosterone Replacement Therapy and Red Blood Cell Count

• Testosterone replacement therapy (TRT) has been shown to increase red blood cell (RBC) count in several studies 3, 4, 5.
• The increase in RBC count is due to the stimulation of erythropoiesis by exogenous testosterone, which can improve oxygen transport to the body 3.
• However, excessive RBC production can lead to blood clots and severe sequelae such as heart attack, stroke, or pulmonary embolism, highlighting the need for close monitoring of hematocrit levels in TRT patients 3, 5.

Mechanisms of Testosterone-Induced Erythrocytosis

• Testosterone administration has been shown to downregulate hepatic hepcidin mRNA expression, upregulate renal erythropoietin mRNA expression, and increase erythropoietin levels, leading to increased iron incorporation into RBCs 6.
• The suppression of hepcidin expression by testosterone is independent of its effects on erythropoietin or hypoxia-sensing mechanisms 6.

Clinical Implications

• The risk of erythrocytosis and polycythemia secondary to TRT is a concern, particularly in older men and those with risk factors for veno-thrombotic events 5.
• The choice of testosterone preparation and route of administration can influence the extent of hematocrit increases, and some formulations may be safer than others in terms of minimizing hematological side effects 3, 5.
• Regular monitoring of hematocrit levels is recommended for TRT patients, particularly in the first year of therapy, although the frequency of monitoring may be reevaluated based on individual patient risk factors 4.