NSA Volume 15 Issue 1 Bibliography Introduction
Selected and annotated bibliography 52:
EPO Doping
by Jürgen Schiffer
What is erythropoietin?
Erythropoietin (EPO) is a glycopeptid hormone, which controls the formation of red blood cells (erythrocytes) in the stem cells of the bone marrow depending on oxygen requirements. EPO is produced chiefly in the kidney tissue.
EPO is composed of amino acids. At four places in the protein chain there are links with different glycosidic residues. Because of the variety of these sugar residues there are different EPO forms, whose physiological effects are comparable although their physical and chemical characteristics are somewhat different.
The genetically engineered recombinant human erythropoietin (in the presented literature abbreviated as: rHuEPO, r-HuEPO, rhu-EPO, rhEPO or rEPO) is identical with natural EPO as far as the amino acid structure is concerned. However, there are slight differences in the sugar chains. These differences also have an effect on the physical and chemical behaviour of the molecule. For example, there are differences in the electrical charges of the various EPO forms.
(See e.g. Breidbach, ch. 1; Eckardt, ch. 1; Fandrey/Jelkmann, ch. 1; Gambrell/
Lombardo, ch. 1; Jelkmann, ch. 1; Schänzer, ch. 1; Breidbach/Schänzer, ch. 3.)
Historical aspects of human recombinant erythropoietin in sport
1977 Purified EPO is isolated from human urine for the first time.
1985 EPO gene is cloned.
1987 Recombinant EPO is first available in Europe.
1987-1990 A number of deaths of competitive Dutch and Belgian cyclists is linked to EPO use (see Gambrell/Lombardo, ch. 1; Rossi et al., ch. 1; Deacon/Gains, ch. 3).
1988 Fédération Internationale de Ski (FIS) classifies EPO as a doping substance.
1989 Recombinant EPO is approved by the FDA for manufacture.
1990 EPO is banned by the IOC.
1993-1994 The IAAF introduces blood sampling during eight World Cup Meetings (see Birkeland/Donike et al., ch. 3).
1997 The Union Cycliste Internationale (UCI) and the Fédération Internationale de Ski (FIS) accept random blood testing before competition and fix maximum haematocrit and haemoglobin values. However, these blood values are not controlled to prove the athlete guilty of doping but to protect his or her health against possible damage caused by elevated haematocrit and haemoglobin values (see Schänzer, ch. 1; Hartmann et al., ch. 3; Schmidt, ch. 3; Vergouwen et al., ch. 3).
1998 The discovery of EPO in a Festina team car during the Tour de France leads to a doping scandal, which is covered extensively in the press.
1999 Work to develop a reliable EPO test in time for Sydney 2000 is intensified.
Effects of EPO
EPO stimulates the maturation of reticulocytes to erythrocytes in the stem cells of the bone marrow. The increase in the number of erythrocytes leads to an increase in the amount of storable oxygen per blood volume portion and, in connection with this, to the improvement of oxygen transport capacity and an increase in endurance performance. A similar effect is achieved through altitude training.
(See e.g. Breidbach, ch. 1; Gambrell/Lombardo, ch. 1; Schänzer, ch. 1; Rendic, ch. 2.)
In which cases is rhEPO normally used in medicine?
As EPO is produced by the kidneys, people suffering from chronic renal failure are anaemic. While patients with total renal failure were treated with blood transfusions and erythrocyte concentrates until the end of the eighties, they have been treated with rhEPO since the approval of this medicament in 1989. In a lot of cases anaemias of a different genesis can also be improved by rhEPO. The fact that rhEPO therapy induces an additional stimulation of erythropoesis, even in the case of a completely intact endogenous EPO production, is utilized with autologous blood donors. As an alternative to erythrocyte transfusion, high rhEPO doses are also effective as an antianaemic in the case of chronic polyarthritis, AIDS, tumors and surgery. A still unclear side effect of therapeutic rhEPO administration is increased blood pressure.
(See e.g. Breidbach, ch. 1; Eckardt, ch. 1; Fandrey/Jelkmann, ch. 1; Jelkmann, ch. 1; Mandin, ch. 2)
In which sports or sport events is rhEPO used as a doping substance?
Because of its side effects on the oxygen storage and transport capacity the administration of rhEPO leads to increased performance in sports which benefit from the aerobic metabolism. These are, for example, running distances from 800m on as well as all disciplines of cross-country skiing and cycle racing.
(See Breidbach, ch. 1.)
How is rhEPO administered?
In haemodialysis patients rhEPO is normally administered intravenously. However, rhEPO can also be injected subcutanously.
(See Gambrell/Lombardo, ch. 1.)
What are the risks of rhEPO administration?
RhEPO is a well-tolerated medicament, which has almost no adverse effects. However, if rhEPO is administered in an excessively high dosage and in an uncontrolled way, the result is an increase in blood viscosity and thus a high risk of coronary and cerebral vascular occlusions.
The risks associated with the intake of too much rhEPO even increase when training is done at altitude or in the case of dehydration.
(See e.g. Breidbach, ch. 1; Gambrell/Lombardo, ch. 1; Schänzer, ch. 1; Shaskey/
Green, ch. 1; Stricker, ch. 1.)
Is it possible to detect forbidden rhEPO intake?
At present there is no method available for clear detection of EPO doping in athletes. Since natural and recombinant EPO have an identical amino acid structure, recombinant EPO is virtually indistinguishable from the natural hormone.
Current tests involve the use of either direct or indirect methods.
Direct methods for the detection of EPO aim at identifying slight differences between the genetically engineered and the natural EPO. Researchers have, for example, tried to utilize the electrical charge differences between human and recombinant EPO to separate the two forms of EPO by means of suitable separation methods (e.g. capillary electrophoresis). Although this separation is basically possible, great volumes of urine (up to 1 litre) are needed.
Therefore, at present, indirect detection processes, which require only small amounts of urine or blood, are favoured. Indirect methods for EPO detection are for example:
The definition of reference areas. This means that an increased EPO concentration in blood or urine must be distinguished from a physiological or pathological increase. However, working with reference values is only possible if the variation range of the standard EPO values is very narrow so that the EPO concentrations after EPO administration can be distinguished from the reference values. These conditions are fulfilled when blood is used.
The measurement of biochemical factors whose concentration in blood depends on the EPO concentration. This applies, for example, to the serum concentration of soluble transferrin receptor (sTfR), which is increased following rhEPO administration. However, the sTfR concentration is also increased after altitude training.
The determination of fibrin and fibrinogen degradation products in urine after EPO administration.
(See e.g. Breidbach, ch. 1; Schänzer, ch. 1; Birkeland/Fiskum et al., ch. 3; Breidbach/Schänzer, ch. 3; Brisson et al., ch. 3; Conconi et al., ch. 3; Emslie et al., ch. 3; Gareau et al., ch. 3; Hemmersbach et al., ch. 3; Wide et al., ch. 3.)
How is EPO misuse controlled at the moment?
As it is almost impossible at present to clearly verify the administration of exogenous EPO, physiological blood parameters which change after EPO administration are controlled. The International Cycling Federation (UCI), for example, uses maximum haematocrit values (50.0 vol% for men) while the International Skiing Federation (FIS) uses maximum haemoglobin values (16.5g% for women and 18.5g% for men) as a criterion. If these values are exceeded prior to a competition, the respective athlete is excluded from the competition for reasons of health protection. However, both haematocrit and haemoglobin values are influenced by many factors. They can be considerably altered, for example, after only moderate endurance exercise, and they vary from athlete to athlete. It is therefore not possible to regard haematocrit values higher than 50.0 vol% as a clear indication of rhEPO doping.
(See e.g. Breidbach, ch. 1; Schänzer, ch. 1; Hartmann et al., ch. 3; Vergouwen et al., ch. 3.)
About this bibliography
The following bibliography is the second one dealing with doping in NSA. The first one, which covered all aspects of doping, was published in NSA 2/1999. The present bibliography is an extract from the data contained in the literature databases SPOLIT of the Federal Institute of Sports Science (BISp) in Cologne, the database of the Sport Research and Information Centre (SIRC) in Ottawa/Canada, the database of the National Library of Medicine, MEDLINE, as well as of the data stored in the Web of Science of the Institute for Scientific Information (ISI) in Philadelphia/USA. The documents were retrieved using the keyword combination "erythropoietin" and "doping, performance, sport, training".
This bibliography includes altogether 108 documents about EPO doping. It is subdivded into three chapters:
General or comprehensive articles and books dealing with erythropoietin: 44 documents
Publications focussing on the effects of erythropoietin: 21 documents
Articles about EPO detection: 43 documents.
The division between these chapters is only approximate because there are fluent transitions between the the chapters. Chapter 1 is also used as a reservoir for publications which could not clearly be allocated to one chapter.
Chapter 1 (part 1 A-M)
Chapter 1 (part 2 N-Z)
Chapter 2 (part 1 A-K)
Chapter 2 (part 2 L-Z)
Chapter 3 (part 1 A-C)
Chapter 3 (part 2 D-N)
Chapter 3 (part 3 O-Z)
