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Here, we evaluate whether exposure to altitude-induced hypoxia (2,320\u2009m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants ( n = 39) were randomly assigned to 20\u2009IU\u00b7kg body wt<jats:sup>\u22121<\/jats:sup> rHuEPO or placebo injections every second day for 3\u2009wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE ( P \u2264 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE ( P &lt; 0.05) and hepcidin levels ( P &lt; 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin ( P &lt; 0.05) and ERFE ( P \u2264 0.001) parallel with increases in hematocrit ( P &lt; 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found ( R<jats:sup>2<\/jats:sup> = 0.13, P &lt; 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context. <\/jats:p>","DOI":"10.1152\/ajpregu.00070.2021","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T15:54:20Z","timestamp":1624463660000},"page":"R152-R161","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial"],"prefix":"10.1152","volume":"321","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-3009","authenticated-orcid":true,"given":"Andreas","family":"Breenfeldt Andersen","sequence":"first","affiliation":[{"name":"Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4714-1981","authenticated-orcid":true,"given":"Thomas 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