Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New erythropoietin/hemoglobin Set Point

J Gerontol A Biol Sci Med Sci. 2014 Jun;69(6):725-35. doi: 10.1093/gerona/glt154. Epub 2013 Oct 24.

Abstract

Background: The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear.

Methods: We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months.

Results: The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range.

Conclusions: Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.

Keywords: Erythropoietin; Ferritin.; Hepcidin; Testosterone.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Androgens / administration & dosage
  • Androgens / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Erythropoiesis / drug effects*
  • Erythropoietin / blood*
  • Follow-Up Studies
  • Hemoglobins / drug effects
  • Hemoglobins / metabolism
  • Hepcidins / antagonists & inhibitors*
  • Hepcidins / blood
  • Humans
  • Male
  • Middle Aged
  • Mobility Limitation*
  • Polycythemia / blood
  • Polycythemia / drug therapy*
  • Polycythemia / etiology
  • Radioimmunoassay
  • Testosterone / administration & dosage*
  • Testosterone / pharmacokinetics
  • Treatment Outcome

Substances

  • Androgens
  • Hemoglobins
  • Hepcidins
  • Erythropoietin
  • Testosterone