BIRKELAND, K. I., J. STRAY-GUNDERSEN, P. HEMMERSBACH, J. HALLÉN, E. HAUG, and R. BAHR. Effect of rhEPO administration on serum levels of sTfR and cycling performance. Med. Sci. Sports Exerc., Vol. 32, No. 7, pp. 1238-1243, 2000.
Purpose: We assessed the possibility of using soluble transferrin receptor (sTfR) as an indicator of doping with recombinant erythropoietin (rhEPO).
Methods: A double-blind, placebo-controlled study was conducted with the administration of 5000 U of rhEPO (N = 10) or placebo (N = 10) three times weekly (181-232 U·kg-1·wk-1) for 4 wk to male athletes. We measured hematocrit and the concentration of hemoglobin, sTfR, ferritin, EPO, and quantified the effects on performance by measuring time to exhaustion and maximal oxygen uptake (V̇O2max) on a cycle ergometer.
Results: Hematocrit increased from 42.7 ± 1.6% to 50.8 ± 2.0% in the EPO group, and peaked 1 d after treatment was stopped. In the EPO group, there was an increase in sTfR (from 3.1 ± 0.9 to 6.3 ± 2.3 mg·L-1, P < 0.001) and in the ratio between sTfR and ferritin (sTfR·ferritin-1) (from 3.2 ± 1.6 to 11.8 ± 5.1, P < 0.001). The sTfR increase was significant after 1 wk of treatment and remained so for 1 wk posttreatment. Individual values for sTfR throughout the study period showed that 8 of 10 subjects receiving rhEPO, but none receiving placebo, had sTfR levels that exceeded the 95% confidence interval for all subjects at baseline (= 4.6 mg·L-1). V̇O2max increased from 63.6 ± 4.5 mL·kg-1·min-1 before to 68.1 ± 5.4 mL·kg-1·min-1 2 d post rhEPO administration (7% increase, P = 0.001) in the EPO group. Hematocrit, sTfR, sTfR·ferritin-1, and V̇O2max did not change in the placebo group.
Conclusion: Serum levels of sTfR may be used as an indirect marker of supranormal erythropoiesis up to 1 wk after the administration of rhEPO, but the effects on endurance performance outlast the increase in sTfR.
New developments in pharmacology and medical therapeutics regularly lead to the misuse of these agents to improve performance in sport. Soon after recombinant human erythropoietin (rhEPO) became available for the treatment of anemia, rumors began to circulate that it was being misused in endurance sports (8). The peptide hormone has therefore been prohibited by the International Olympic Committee since 1990 (16), although no analytical method has been available to detect its misuse. Since then, many methods for the detection of rhEPO administration have been explored (4). These include direct proof of rhEPO administration with identification of rhEPO in blood or urine (20,21) and indirect parameters of stimulated erythropoiesis like the reticulocyte count and the number of hypochromic macrocytes (6) and the serum level of soluble transferrin receptor (sTfR) (1,2,7,13,14). Gareau and coworkers (13) showed previously that high-dose, short-term rhEPO treatment resulted in a significant increase in the serum concentration of sTfR and the ratio between sTfR and ferritin, and recently they confirmed this using lower doses during longer term (1). The authors suggested that an elevated serum level of sTfR or sTfR·ferritin-1 may be used to indicate doping with rhEPO.
An additional problem to the development of a test for rhEPO administration in athletes is the possibility that the duration of the effect on performance is greater than the duration of any hematological changes associated with rhEPO misuse. The probable mechanism for the improvement in performance from the use of rhEPO is a stimulation of erythropoiesis that increases circulating red cell mass, hemoglobin concentration, and arterial oxygen content (11,12). This increase in arterial oxygen content leads to an increase in maximal oxygen uptake in well-trained athletes (9,10,19). For athletic events dependent on maximal oxygen uptake, performance is enhanced (5,22). Once rhEPO administration is discontinued, red cell mass gradually returns to its original state, but this may take weeks (10). As a result, an open window may exist where there is no evidence of rhEPO misuse but where performance is enhanced. Furthermore, the enhanced red cell mass may allow the athlete to sustain a greater training stimulus, which could produce a subsequent improvement in performance potentially quite remote in time from when there is evidence of rhEPO misuse.
The aim of the present study was to document sTfR changes during 4 wk of administration of moderate doses of rhEPO in healthy, well-trained, male athletes in a double-blind, placebo-controlled manner. We also wanted to quantify the effects of rhEPO administration on maximal oxygen uptake. Finally, we wanted to establish the time course of changes in maximal oxygen uptake and sTfR after rhEPO administration to determine at what time during the doping process sTfR can be used to reflect rhEPO misuse.