Androgens stimulate erythropoiesis through the DNA‐binding activity of the androgen receptor in non‐hematopoietic cells

Background Androgens function through DNA and non‐DNA binding‐dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood. Design and methods To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA‐binding domain of the AR (ARΔZF2) with non‐aromatizable 5α‐dihydrotestosterone (5α‐DHT) or aromatizable testosterone. To distinguish direct hematopoietic and non‐hematopoietic mechanisms, we performed bone marrow reconstitution experiments. Results In wild‐type mice, 5α‐DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild‐type mice following 5α‐DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α‐DHT had no erythroid activity in ARΔZF2 mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α‐DHT, suppressed EPO levels in ARΔZF2 mice, suggesting testosterone following aromatization may oppose the erythroid‐stimulating effects of androgens. Female wild‐type mice reconstituted with ARΔZF2 bone marrow cells remained responsive to 5α‐DHT. In contrast, ARΔZF2 mice reconstituted with female wild‐type bone marrow cells showed no response to 5α‐DHT. Conclusion Erythroid promoting effects of androgens are mediated through DNA binding‐dependent actions of the AR in non‐hematopoietic cells, including stimulating EPO expression.