Hepcidin is not essential for mediating testosterone's effects on erythropoiesis.

Abstract

We have shown that testosterone administration suppresses hepcidin, stimulates iron-dependent erythropoiesis, and increases hemoglobin and hematocrit. We investigated whether testosterone-mediated suppression of hepcidin plays an essential role in mediating testosterone's stimulatory effects on erythropoiesis. We utilized two mouse models to elucidate the role of hepcidin as a mediator of testosterone's effects on erythropoiesis: First, we used a whole-body hepcidin knockout (HepKO) mouse. Because testosterone's effects on hepcidin expression are mediated through androgen receptor, we also utilized a liver-specific androgen receptor knockout mouse (L-ArKO). Effects of 6weeks of testosterone (50mg/kg weekly) administration relative to vehicle on hemoglobin and hematocrit, red blood cell indices, and markers of iron stores and availability were compared between wild-type (WT) and the two genetically modified mouse models. HepKO mice had significantly higher baseline levels of hemoglobin, hematocrit, serum and liver iron, and ferritin than WT mice. Compared to vehicle group, testosterone administration was associated with significant increases in hematocrit, hemoglobin, red cell counts, reticulocyte count, reticulocyte hemoglobin, and serum iron levels in both HepKO and WT mice. Baseline hematocrit levels did not differ between WT and L-ArKO mice. Compared to vehicle, testosterone treatment was associated with significantly greater increase in hematocrit, hemoglobin, red cell count, reticulocyte count, reticulocyte hemoglobin, and serum iron in WT and L-ArKO mice. Although hepcidin suppression by testosterone increases iron availability and erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in healthy mice.