• Open Access

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

Authors

  • Wen Guo,

    Corresponding author
    • 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
    Search for more papers by this author
  • Eric Bachman,

    1. 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
    Search for more papers by this author
  • Michelle Li,

    1. 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
    Search for more papers by this author
  • Cindy N. Roy,

    1. Division of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • Jerzy Blusztajn,

    1. Woods Hole Oceanographic Institution, Woods Hole, MA, USA
    Search for more papers by this author
  • Siu Wong,

    1. 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
    Search for more papers by this author
  • Stephen Y. Chan,

    1. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
    Search for more papers by this author
  • Carlo Serra,

    1. 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
    Search for more papers by this author
  • Ravi Jasuja,

    1. 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
    Search for more papers by this author
  • Thomas G. Travison,

    1. 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
    Search for more papers by this author
  • Martina U. Muckenthaler,

    1. Department of Molecular Medicine, University of Heidelberg, Otto-Meyerhof-Zentrum, Heidelberg, Germany
    Search for more papers by this author
  • Elizabeta Nemeth,

    1. Center for Iron Disorders, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Search for more papers by this author
  • Shalender Bhasin

    Corresponding author
    • 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
    Search for more papers by this author

Correspondence

Shalender Bhasin, Director, Boston Claude D. Pepper Older Americans Independence Center, Director, Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA. Tel.: 617 525 9040; fax: 617 638 8217; e-mail: bhasin@bu.edu

and

Wen Guo, Research Program in Men's Health: Aging and Metabolism, Brigham and Women' Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA. Tel.: 617 525 9044; fax: 617 638 8217; e-mail: wguo@bu.edu

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.

Ancillary