Does exogenous testosterone raise hematocrit by stimulating erythropoiesis and altering iron metabolism?

Exogenous testosterone administration is well-documented to increase hematocrit levels through the stimulation of erythropoiesis. This physiological response is primarily driven by a dual-action mechanism involving the modulation of erythropoietin (EPO) signaling and the regulation of systemic iron metabolism.

Clinical effectiveness and dose-dependency

The impact of testosterone on hematocrit is highly dose-dependent and most pronounced in men or those undergoing gender-affirming therapy.

• Erythrocytosis incidence: Pathological elevation of hematocrit is recognized as the most frequent adverse event in men receiving testosterone replacement therapy.
• Observations in women: In female populations, such as postmenopausal women treated for hypoactive sexual desire disorder, significant increases in hematocrit are rarely observed. This is attributed to the lower physiological or low-supraphysiological doses typically prescribed (e.g., 75–100 mg pellets), which do not always reach the threshold required for clinically significant erythrocytosis.
• Physiological set-point: Testosterone recalibrates the EPO-hemoglobin set point, leading to sustained increases in red blood cell production as long as therapy continues.

Mechanistic explanations

Testosterone influences red blood cell production through two interconnected pathways that increase both the proliferative signal and the necessary raw materials (iron).

• EPO signaling: Testosterone directly stimulates the production of serum EPO. This increases signaling through the JAK2/STAT5 pathway in erythroid progenitors, driving their proliferation and differentiation into mature red blood cells.
• Hepcidin suppression: Testosterone is a potent suppressor of hepatic hepcidin, the master regulator of iron homeostasis. It inhibits hepcidin transcription both directly (via the androgen receptor and BMP/Smad signaling) and indirectly (via erythroferrone).
• Iron mobilization: Reduced hepcidin levels prevent the degradation of ferroportin, the cell's iron exporter. This facilitates the release of iron from storage sites, such as splenic macrophages and the liver, and increases dietary iron absorption in the gut.
• Substrate availability: Studies using stable isotopes confirm that this mobilized iron is actively incorporated into new hemoglobin. This is evidenced by a decrease in ferritin (stored iron) alongside an increase in transferrin saturation and serum iron.

Bottom line

The claim is strongly supported by scientific evidence. Exogenous testosterone raises hematocrit by increasing EPO-driven red blood cell production and suppressing hepcidin to ensure sufficient iron availability. While this effect is a consistent clinical concern at higher doses, it is less frequently observed at the lower doses typically used in female clinical contexts.