Results from a recent study suggest that the effects of rEPO on hematocrit can be further enhanced with the addition of anabolic steroids. The anabolic steroids increase the sensitivity of erythroid progenitors to rEPO.
The magnitude of performance enhancement so far attributed to rEPO is significant in a sport where several seconds can be the difference between winning a race and being an also-ran. An athlete who participated in Ekblom's study compared taking rEPO with being hooked up to a turbo engine. In the world of sports these sort of comments have as much effect, or more, than results from any well-controlled study published in a leading medical or scientific journal.
Side Effects of rEPO
No drug is without risk and rEPO is no exception. Patients who receive the drug for legitimate medical reasons have experienced myalgias accompanied with a flu-like syndrome. This syndrome is usually mild and transient. Hypertension has also been reported as a common problem in kidney dialysis patients receiving rEPO. In a small number of these patients the elevated blood pressure has progressed to hypertensive encephalopathy and seizures.
Changes in blood pressure have also been observed in healthy individuals. Berglund and Ekblom administered small doses of rEPO to 15 healthy male subjects for a period of six weeks. Significant increases in hemoglobin and hematocrit were observed. The average hematocrit level rose from 44.5% to 49.7%. Resting blood pressure was unchanged. However, during submaximal exercise at 200 watts, the average systolic blood pressure increased from a baseline of 177 mm Hg to
191 mm Hg after rEPO treatment.
Hypertension is believed to be related to the viscosity of the blood which increases along with hematocrit. As hematocrit rises the thicker blood perfuses organs at a slower rate and is more prone to clotting. This increases the risk for heart attack and stroke. Although never conclusively linked to rEPO, eighteen world-class Dutch and Belgium cyclists have suffered deaths of cardiac origin. One who died was Johannes Draaijer of Holland, who seven months earlier had finished 20th in the Tour de France.
Whether these deaths were related to rEPO may never be known. Despite that, athletes who inject the drug put themselves at considerable risk for cardiac and cerebrovascular side effects. When rEPO is given to patients with kidney disease the doses are controlled to result in a hematocrit of 30-33 percent. An athlete has a much higher baseline hematocrit (usually 40-48% for men and 36-42% for women). Athletes using rEPO may raise their hematocrit levels as high as 60 percent. During competition the hematocrit may rise even higher due to fluid loss. The effects of rEPO on hematocrit can continue for up to ten days following injection which can put the athlete at risk well after the competition is over. This inability to limit the increase in hematocrit makes rEPO potentially more dangerous than blood doping.
Deterring rEPO Use In Athletics
The potential effects of rEPO on hematocrit and athletic performance are similar to blood doping, a procedure already banned by the International Olympic Committee (IOC). This led the IOC, and subsequently the National Collegiate Athletic Association, to ban the use of rEPO. Banning the drug and detecting rEPO users, however are very different.
Detection of rEPO is difficult for a number of reasons. First the drug is virtually indistinguishable from the natural occurring hormone found in all individuals. To overcome this limitation some have proposed having the manufacturer of rEPO add a chemical to the drug solution that would be a "marker" that would distinguish it from natural erythropoeitin. Unfortunately, adding a detection chemical to rEPO would increase the risk that kidney patients receiving the drug would accumulate the marker. Any marker used would need to have a long half-life putting these patients at additional risk for toxicity.
Another approach to identifying rEPO in the body is to modify the structure enough to make it detectable from the natural form yet not change the structure so much as to lose the pharmacological action. Although this is potentially possible, even slight structural changes in the compound may cause the body to identify the drug as a "foreign" protein and reject it resulting in severe allergic reactions. The nearly identical structure of rEPO is why the drug is so well tolerated by patients.
Marking rEPO, either by addition of a chemical or by altering the structure, is unlikely to be pursued since it could put patients who the drug is intended for at additional risk.
A second limitation in detecting rEPO is that the drug produces minute and short-lived increases in erythropoeitin concentrations. The rise in erythropoeitin after rEPO injection does not exceed normal range making any such test non-definitive. In addition, the increase in erythropoeitin lasts only about 24 hours even though the effects on red blood cell mass last for several weeks. Athletes, therefore could administer rEPO a week before competition. improve their performance and not have any detectable change in erythropoeitin levels.
Rather than attempting to detect rEPO, some sports medicine experts suggest measuring hematocrit and disqualifying those athletes with a level that is too high. The difficulty in this method is determining the cut-off point between normal and artificial. This level would need to take in consideration athletes who live or train at high altitudes and would have a higher hematocrit level than normal. Very possibly the level chosen would be sufficiently high to allow some athletes to still be able to use rEPO. This would result in a detection procedure similar to that for caffeine, where athletes can take the drug and get the performance benefits without running a significant risk of being caught.
All of the solutions for detecting rEPO share a fundamental problem. Each of these methods would require a blood sample from the athlete being tested. At present, the only biologic fluid used for drug testing in athletics is urine. Drawing blood samples, whether during in-season training or at a competitive event, will require athletic organizations to carefully examine the associated philosophical and logistic issues.
Even if an effective detection method is developed, detection alone may not solely deter the use of rEPO. Educating athletes, coaches, parents and others responsible for the well-being of the athlete is important. The educational message should not only focus on the possible risks associated with the drug, but also how using rEPO (or any other performance-enhancing drug) is contrary to the very nature of sport. Sports should encourage and reward natural physical excellence, not behaviors that risk the health and welfare of the participants.
The author wishes to acknowledge the contributions made by Kimberly L. Bergman.
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