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-dependant 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 (AR(ZF2) ) with non-aromatizable 5alpha-dihydrotestosterone (5alpha-DHT), or aromatizable testosterone. To distinguish direct hematopoietic and non-hematopoietic mechanisms we performed bone marrow reconstitution experiments. RESULTS: In wild-type mice, 5alpha-DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild-type mice following 5alpha-DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5alpha-DHT had no erythroid activity in AR(ZF2) mice, proving the importance of DNA binding by the AR. Paradoxically testosterone, but not 5alpha-DHT, suppressed EPO levels in AR(ZF2) mice, suggesting testosterone following aromatization may oppose the erythroid-stimulating effects of androgens. Female wild-type mice reconstituted with AR(ZF2) bone marrow cells remained responsive to 5alpha-DHT. In contrast, AR(ZF2) mice reconstituted with female wild-type bone marrow cells showed no response to 5alpha-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.