What is the mechanism by which testosterone supplementation stimulates an increase in red blood cell (RBC) count?

Mechanism of Testosterone-Induced Erythrocytosis

Testosterone supplementation stimulates red blood cell (RBC) production primarily by inhibiting hepcidin transcription, which increases iron availability for erythropoiesis, and by enhancing erythropoietin production. 1

Primary Mechanisms

Testosterone affects erythropoiesis through several pathways:

1. Hepcidin Suppression

   • Testosterone downregulates hepatic hepcidin mRNA expression 2
   • This inhibition occurs through testosterone's interaction with BMP/Smad signaling in the liver
   • Androgen receptor (AR) associates with Smad1 and Smad4, reducing their binding to bone morphogenetic protein response elements in the hepcidin promoter 2
   • Reduced hepcidin leads to increased iron availability for erythropoiesis

2. Enhanced Iron Metabolism

   • Testosterone increases serum iron and transferrin saturation 2
   • Upregulates splenic ferroportin expression, reducing iron retention in the spleen
   • Improves iron incorporation into red blood cells 2
   • Reduces serum ferritin by 32% within 3 months of treatment initiation 3

3. Erythropoietin Stimulation

   • Testosterone upregulates renal erythropoietin mRNA expression 2
   • Increases circulating erythropoietin levels
   • This effect is independent of the hepcidin suppression mechanism

4. Direct Effects on Erythroid Progenitors

   • Testosterone directly stimulates erythroid progenitor cell proliferation 4
   • Enhances proliferation of late BFU-E (burst-forming unit-erythroid) more than CFU-E (colony-forming unit-erythroid) 4
   • Requires activation of specific androgen nuclear receptors in erythroid cells 4

Clinical Manifestations

The erythropoietic effects of testosterone are significant and measurable:

• Hemoglobin levels increase by 15-20% in boys at puberty, paralleling increasing testosterone levels 1
• Adult men have higher hemoglobin levels than adult women 1
• Hypogonadal men have lower hemoglobin levels than age-matched controls 1, 5
• Testosterone therapy can increase RBC count by 9%, hematocrit by 4%, and hemoglobin by 8% over 12 months 3

Route of Administration and Risk

The risk of erythrocytosis varies by administration route:

• Injectable testosterone carries a higher risk of erythrocytosis (43.8% with intramuscular injections vs. 15.4% with transdermal patches) 1
• Erythrocytosis risk correlates with testosterone dosage (2.8% with 5mg/day patches vs. 17.9% with 100mg/day gel preparations) 1
• Erythrocytosis is associated with supraphysiologic levels of bioavailable testosterone 1

Clinical Implications and Monitoring

• Elevated hematocrit above normal range can increase blood viscosity and potentially aggravate vascular disease 1, 6
• Higher risk in patients with conditions predisposing to increased hematocrit (e.g., COPD) 1
• Regular monitoring of hematocrit/hemoglobin is essential during testosterone therapy 1
• Management options for erythrocytosis include dosage reduction, temporary discontinuation, therapeutic phlebotomy, or blood donation 1

Important Molecular Insight

Interestingly, the erythropoietic effect of testosterone does not require conversion to dihydrotestosterone (DHT) via 5α-reductase. Studies using finasteride (a 5α-reductase inhibitor) showed that testosterone stimulates erythropoiesis and alters iron homeostasis independently of DHT 3.

This comprehensive understanding of testosterone's effect on erythropoiesis explains why erythrocytosis is one of the most common side effects of testosterone replacement therapy, particularly in older men and with injectable formulations.