Erythropoietin

Abstract

Total hemoglobin (Hb) mass is an important determinant of aerobic power. The glycoprotein erythropoietin (Epo) promotes the production of red blood cells (RBCs). The present article reviews the regulation of erythropoiesis and ways of its manipulation. The various Epos, e.g. recombinant human (rh)Epo and (epoetin), and their long-acting analogues can be misused by cheating athletes, but the drugs are detectable by chemical tests, because their glycan isoform structures differ from those of endogenous Epo. Still, anti-doping control has become more difficult, since additional erythropoiesis-stimulating agents have become available (Epo mimetics, activin inhibitors, and small-molecule chemical drugs activating EPO expression). A major problem is created by hypoxia-inducible factor (HIF) stabilizers (e.g. α-ketoglutarate competitors and Co2+ salt) which activate HIFs and thus increase EPO expression. Direct EPO transfer is theoretically also possible but medically little advanced. To overcome weaknesses of direct testing of biological fluids, the World Anti-Doping Agency has implemented the Athlete Biological Passport for continuous monitoring of RBC parameters of athletes. Blood doping is assumed when distinct parameters (blood Hb concentration and reticulocytes) change in a nonphysiological way.

Combined administration of microdoses of growth hormone and erythropoietin: Effects on performance and evaluation of GH detection capability using anti‐doping methods

“…This reflected the time needed for the erythroid progenitors CFU-E activated by EPO to be differentiated into young reticulocytes. 22 The maximal increase was seen 3 days after the end of the lower to the pre-treatment values were seen, but only 3 subjects were tested. One would have been flagged by the ABP model below the 99% specificity lower limit ( Figure S2).…”

Annual banned‐substance review: analytical approaches in human sports drug testing

“…[26] Among these, erythropoiesisstimulating agents (ESAs), particularly erythropoietin (EPO) and its derivatives have represented the most frequently detected prohibited substances in section S2 over the past years, [86] debatably due to the purported as well as proven performanceenhancing effects of the glycoprotein. [87] The EPO-induced increase in endurance performance, particularly concerning time-toexhaustion, was recently corroborated in a placebo-controlled study using EPO injections of low (2500 IU), medium (5000 IU), or high (10000 IU) dosage every 2-3 days over a period of 4 weeks, [88] where improvements in time-to-exhaustion experiments were found to be dose-dependent but, notably, not exclusively related to hematopoietic factors. Irrespective of the underlying performance-enhancing mechanisms, doping controls for EPO and related substances are essential for a comprehensive antidoping fight, [89] and test methods are subject of continuous optimization.…”

“…The relevance of the emerging class of therapeutics referred to as hypoxia-inducible factor (HIF) stabilizers both in a clinical and anti-doping context is continuously growing. [87] Particularly HIF prolylhydroxylase inhibitors (PHIs) have been pursued as promising drug candidates, [93][94][95] and despite the fact that clinical approvals have not yet been issued, first adverse analytical findings (AAFs) with HIF PHIs were reported in 2015/2016. FG-4592 (roxadustat, Figure 3) was detected in doping control samples in France as identified by means of LC-MS/MS targeting the intact drug.…”

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

“…In turn, JAK2 phosphorylates the cytoplasmic tail of EPOR, providing multiple docking sites for signal-transducing proteins, which subsequently lead to STAT-5 phosphorylation [91]. Additionally, it was shown that the phosphatidylinositol-3-kinase/protein kinase B (PI-3k/AKT) and mitogen-associated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathways can also be activated in this way [92].…”