Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells

Aging Cell

Wen Guo³  Eric Bachman³  Michelle Li³  Cindy N. Roy¹  Jerzy Blusztajn⁴  Siu Wong³  Stephen Y. Chan⁶  Carlo Serra³  Ravi Jasuja³  Thomas G. Travison³  Martina U. Muckenthaler⁵  Elizabeta Nemeth² 

[1] Division of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, MD, USA;Center for Iron Disorders, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Claude D. Pepper Older Americans Independence Center, Boston Medical Center, Boston, MA, USA;Woods Hole Oceanographic Institution, Woods Hole, MA, USA;Department of Molecular Medicine, University of Heidelberg, Otto-Meyerhof-Zentrum, Heidelberg, Germany;Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

关键词: aging;    antiaging;    steroids;    endocrinology;    sex hormones;   

DOI  :  10.1111/acel.12052

来源: Wiley

【 摘 要 】

Summary

Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferrin saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound ⁵⁸Fe, the amount of ⁵⁸Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to bone morphogenetic protein (BMP)-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. In conclusion, testosterone inhibits hepcidin transcription through its interaction with BMP/Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.

【 授权许可】

Unknown   
© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland