Can Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping?

Birkeland KI, Stray-Gundersen J, Hemmersbach P, Hallen J, Haug E, Bahr R. Effects of rhEPO administration on serum levels of sTfR and cycling performance. Med Sci Sports Exerc 2000;32:1238–1243. ObjectiveCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? To assess the use of soluble transferrin receptor (sTfR) as an indicator of doping with recombinant erythropoietin (rhEPO) in male athletes. DesignCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? Randomized controlled double-blinded 4-week intervention and 4-week follow-up. Participants were matched in pairs for sport and training level. SettingCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? University research center, Oslo, Norway. ParticipantsCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? 20 healthy, well-trained male athletes (mean age, 24 y) from endurance sports volunteered to participate. Inclusion criteria were normal blood values (hematocrit, 38% to 45% and serum ferritin, 25 to 200 μg/L) and no risk factor for cardiovascular disease. InterventionCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? A baseline medical examination included blood and urine sampling and a maximal exercise test on a bicycle ergometer. One of each matched pair of participants was then randomly assigned to 5,000 U (181 to 232 U/kg/wk) rhEPO (Recormon, Boehringer Mannheim GmbH) or placebo (1 mL NaCl 9 g/L) subcutaneously 3 times/wk for 30 days or until hematocrit reached ≥50% in the EPO group. Both groups were given a liquid oral iron supplement (270 mg/d Fe2+). Main outcome measuresCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? Blood samples for the quantification of hemoglobin, sTfR, ferritin, and EPO were obtained 3 times/wk during the intervention, and daily for 5 days, then twice weekly during the 4-week follow-up. Serum sTfR concentration was measured by immunoassay (Orion Diagnostica). Maximal oxygen uptake (V̇O2 max) and time to exhaustion were measured postintervention, and weekly through the follow-up period. Main resultsCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? Hematocrit increased from a mean of 42.7% at baseline to ≥50% by the fifth day after treatment in all EPO-treated participants, but did not change in the control group. Mean serum levels of sTfR increased in the EPO group from 3.1 (SD, 0.9) to 6.3 (2.3) mg/L (p < 0.001) by 1 day posttreatment. The increase lasted for 2 weeks after treatment then returned progressively to baseline over the next 2 weeks. sTfR did not change in the placebo group. At the end of treatment, individual values were significantly greater than mean baseline values (all participants) for 8 of 10 men in the EPO group and for none in the control group. Mean V̇O2 max increased more from baseline to 1 day posttreatment for the EPO group than the controls (4.9 [3.2] vs. 0.6 [1.9] mL/kg/min increase; p < 0.003) and remained higher through the follow-up. Both groups increased time to exhaustion by 1 day posttreatment (EPO group: 12.8 [1.0] to 14.0 [1.4] min; p < 0.0001; and controls: 13.1[1.5] to 13.3 [1.5] min; p = 0.04). ConclusionCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? Serum levels of sTfR may be used as an indirect marker of supranormal erythropoiesis up to 1 week after administration of rhEPO. The effects of rhEPO administration on maximal oxygen uptake and increased time to exhaustion lasted at least 2 weeks longer than elevated blood levels of sTfR. Source of funding: Norwegian Olympic Committee and Confederation of Sports, Boehringer Mannheim, and Nycomed Pharma AS. For article reprint: K. I. Birkeland, Hormone Laboratory, Aker University Hospital, N-0514 Oslo, Norway. E-mail: [email protected] CommentaryCan Elevated Serum sTfR Levels Be Used To Indicate rhEPO Doping? The study by Birkeland et al. is well designed and carefully conducted. Although the purpose of the investigation was to examine a technique that might detect rhEPO use, the study is also important because it is the first randomized placebo-controlled investigation to document increases in V̇O2max and time to exhaustion resulting from rhEPO administration in well-trained endurance athletes. Use of rhEPO is generally acknowledged to confer a large advantage in endurance performance. Although its use by athletes has been banned, there is presently no effective detection technique. The use of sTfR to detect rhEPO abuse was proposed by Gareau et al., 1 and although the present study confirms their findings, it also provides some important qualifications. Birkeland et al. found that the serum level of sTfR may be used as an indirect marker of rhEPO abuse for up to 1 week following rhEPO administration. The concurrent iron supplementation taken by both the experimental and the control participants (which is probably what the athletes would do) was probably the reason that the observed difference in sTfR between the groups was less than that reported by Gareau et al. Birkeland et al. also found a substantial performance advantage for at least 2 weeks beyond the time that rhEPO use could be detected. Thus a normal value of sTfR in a doping control test would not rule out recent rhEPO use. Further, in 2 out of the 10 subjects, the level of sTfR never did increase significantly above baseline levels, and several days after cessation of rhEPO treatment only 5 of the 10 subjects exceeded the sTfR cut-off level proposed for detection. Thus testing for sTfR lacked sensitivity and specificity for detecting rhEPO abuse and, as with any currently available technique for detecting rhEPO, it would only be useful in random out-of-competition testing.

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