Induction of Erythroferrone in Healthy Humans by Micro-Dose Recombinant Erythropoietin or High-Altitude Exposure

Induction of Erythroferrone in Healthy Humans by Micro-Dose Recombinant Erythropoietin or High-Altitude Exposure / Paul Robach, Elena Gammella, Stefania Recalcati, Domenico Girelli, Annalisa Castagna, Matthieu Roustit, Carsten Lundby, Anne-Kristine Lundby, Pierre Bouzat, Samuel Vergès, Guillaume Séchaud, Pierluigi Banco, Mario Uhr, Catherine Cornu, Pierre Sallet, Gaetano Cairo. - (Haematologica (2020) 1 (9 January); p. 1-20).

  • PMID: 31919080.
  • DOI: 10.3324/haematol.2019.233874


The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEPO) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEPO, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker.

Original document


Research / Study
9 January 2020
Banco, Pierluigi
Bouzat, Pierre
Cairo, Gaetano
Castagna, Annalisa
Cornu, Catherine
Gammella, Elena
Girelli, Domenico
Lundby, Anne-Kristine
Lundby, Carsten
Recalcati, Stefania
Robach, Paul
Roustit, Matthieu
Sallet, Pierre
Séchaud, Guillaume
Uhr, Mario
Vergès, Samuel
Other organisations
Athletes For Transparency (AFT)
Centre Hospitalier Universitaire de Grenoble-Alpes (CHUGA) - Grenoble Alpes University Hospital
Ecole Nationale de Ski et d'Alpinisme (ENSA) - National School of Mountain Sports
Københavns Universitetshospital - Copenhagen University Hospital
Università degli Studi di Milano (UniMi) - University of Milan
Università degli Studi di Verona - University of Verona
Université Grenoble Alpes (UGA) - Grenoble Alps University
Analytical aspects
Testing method development
Erythropoietin (EPO)
High altitude training
Document category
Scientific article
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Date generated
14 January 2020
Date of last modification
11 November 2020
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