Since the first Olympic Games in ancient Greece, elite athletes have sought ways to gain a competitive edge over equally skilled opponents. This practice has only accelerated in modern times, and recombinant human erythropoietin (EPO) is the latest in a long line of such ergogenic tools. In this article, we explore the original clinical uses of EPO, as well as delve into how its manipulation evolved into a performance-enhancing biologic. We also touch on the various detection methods used by anti-doping agencies.
The Physiological Functions of Erythropoietin
The chemical known as erythropoietin (EPO) drives red blood cell production in the body in a process called hematopoiesis. Produced by the kidneys, this hormone signals the bone marrow to produce more red blood cells, which in turn carry oxygen throughout the body.
The presence of 4 key conditions can trigger the release of EPO:
- Hypoxia: Low levels of oxygen detected in body tissues, which serves as a direct stimulus for the kidneys.
- Anemia: Low hemoglobin levels — a reduced number of functioning red blood cells – which in turn will limit their oxygen-carrying abilities.
- Decreased blood flow to the kidneys: Poor renal circulation limits the local oxygen supply.
- Increased oxygen demand: A rise in metabolic needs, such as when training or simply spending prolonged amounts of time in a high-altitude environment.
Recombinant Human Erythropoietin Enters the Athletic Arena
In 1989, the Food and Drug Administration (FDA) approved the first use of recombinant human erythropoietin to treat renal anemia. Producing recombinant EPO requires inserting a gene that codes for EPO into host cells, which can then produce large quantities of the hormone. Recombinant EPO has an amino acid sequence and biological activity identical to naturally occurring erythropoietin, and it stimulates red blood cell production in the same way.
Within a short time, elite endurance athletes capitalized on its potential as an undetectable performance-enhancing agent. Recombinant human erythropoietin allegedly improves a variety of cardiopulmonary variables that, over time and with repeated use, can enhance endurance performance. This appealed particularly to athletes competing in cycling, swimming, distance running and, of course, triathletes and Iron Man participants. By increasing the body’s erythrocyte count, elevating hemoglobin levels, and enhancing oxygen delivery to tissues, both endurance and aerobic performance seemed to take off.
Assessing the Magnitude of the Improvement
As personal trainers and coaches know, responses to applied stimuli vary greatly among individual athletes. Recombinant human EPO falls into this same category, making it difficult to pinpoint the exact magnitude of the benefit. Most likely, it depends upon several factors:
- The status of the athlete: better trained athletes who have already accrued years of adaptations typically benefit less.
- Quantity/duration of use: some kind of dose-response situation probably exists; however, so too may a tipping point, after which time athletes may experience a dangerously high hematocrit.
- The volume of one’s training: since taking recombinant human EPO boosts fitness levels, most athletes find they can train harder for a longer duration, thereby deriving greater overall benefits.
- The nature of the sport: runners of middle-distance events like 5Ks and 10Ks will reap more benefit than long-distance triathletes, as these events tie in more directly to the body’s maximum capacity for oxygen delivery. While EPO will definitely boost the performance of an Ironman triathlete, the effect may seem less by comparison.
The Submaximal Effort: Conflicting Outcomes
As with many research studies, data surrounding the use of recombinant human EPO tends to yield conflicting reports. While some labs found no definitive performance-enhancing effects in elite cyclists despite increases in hemoglobin and VO2 max, other researchers concluded that the benefits also extended to maximal power output and time to exhaustion.
However, subjects have tended to observe these improvements almost exclusively during maximal exercise intensities. In reality, even during high-level athletic competitions, participants tend to perform at a lower intensity. The performance benefit during a maximal test may not translate to what an athlete would experience during competition. Further research will no doubt determine if using EPO can also improve submaximal parameters, which can also definitely serve as major determinants of performance in endurance sports.
The Legal Conundrum
The term “blood doping” refers to the use of any substance, prohibited under the World Anti-Doping Agency (WADA), that can lead to an increase in the number of red blood cells in the body. Despite this, athletes have found ways to abuse recombinant human erythropoietin; in doing so, they challenge regulatory agencies and undermine the spirit of fair competition.
Although anti-doping agencies have developed tests to detect EPO use, problems remain. The current battery of tests cannot readily differentiate between exogenous and endogenous EPO. One research study sought to investigate indirect detection of EPO use by searching for blood markers of altered erythropoiesis. This proved potentially effective for identifying both current and recent users of recombinant human erythropoietin.
Micro-Dosing
With improved direct and indirect detection methods, many athletes have changed course and adopted microdosing, or reduced the amplitude of their blood doping regimen. Research studies in this area remain scarce. However, three randomized, placebo-controlled trials found that infusing as little as 130 ml. of red blood cells, or injecting 9 IU per kg. of body weight of EPO three times per week for 4 weeks, improved endurance performance by anywhere from 4%–6%. The mechanism responsible for this performance-enhancing effect remains the same; the difference lies in detection.
Blood doping in microdoses challenges indirect detection by the Athlete Biological Passport. The fundamental principle of the Athlete Biological Passport (ABP) is to monitor selected biological variables over time that indirectly reveal the effects of doping, rather than attempting to detect the doping substance itself. Depending on the timing of the blood sample, 20- 60% of individuals are identified.
Meanwhile, novel biomarkers continue to emerge, and some may add value for detecting micro-doping, such as immature reticulocytes and the iron-regulatory hormones hepcidin and erythroferrone.
Such indirect methods can often catch doping even after the banned substance has left the body. The time EPO remains in the body depends on many factors, including dose, frequency, route of administration, and the EPO formulation used. Future studies will no doubt seek out additional biomarkers for this specific purpose.
Risk versus Reward
Athletes who take EPO to enhance performance do so at their own risk. Sadly, some may not fully understand the many potential health complications which may accompany their decision.
The World Anti-Doping Agency fully discloses how EPO can dangerously thicken an athlete’s blood, potentially leading to heart disease, increased strain on the heart, cerebral and/or pulmonary embolism, blood clotting, and stroke. It also carries risks of developing serious autoimmune diseases.
These risks are exacerbated by dehydration, a condition that easily occurs during endurance exercise. By further concentrating the blood, these scenarios can arise much faster.
Between the late 1980’s and 1990, and again between 2003 and 2004, a number of EPO-related deaths occurred among elite European cyclists, leading to these time periods earning the nickname “the EPO Era”. Media reports said cyclists would often get up to move around in the middle of the night to keep their arteries from clogging with thickened blood. Some athletes developed such clogged arteries that they would fall asleep after a hard ride and never wake up.
The Hedonic Effect of EPO Abuse
A unique study of elite athletes using recombinant human erythropoietin examined how the substance affected their self-esteem and perception of physical prowess. Scientists conducted the study over three consecutive periods: the 2 weeks before the injections, the 6 weeks of injections, and the 4 weeks after stopping the injections. They also assessed aerobic capacity before and after 4 weeks of treatment.
As expected, data indicated a significant increase in the athletes’ aerobic physical fitness, but also noted an uptick in their perceived physical condition, which may have led to a stronger commitment to training. The scientists felt that the injections presented what they called a dangerous hedonic effect linked to endurance training.
The hedonic effect of recombinant human erythropoietin refers to a psychological boost, akin to a heightened sense of physical well-being, which in turn encourages athletes to commit more strongly to training. Specifics include the following:
- Perceived Improvement: Athletes noticed a subjective rise in their physical abilities, sometimes even before major physiological changes fully take hold.
- Behavioral Reinforcement: This rewarding sensation acts as a psychological hook, driving a deeper emotional commitment to rigorous endurance workouts.
- The Dangerous Aspect: By reinforcing the psychological drive to continue doping or overtraining, the athlete unwittingly increases mental reliance on the substance. As this dynamic begins to mask inherent fatigue, health problems ensue.
Why Does WADA Allow Altitude Training?
Altitude training, which athletes use to naturally increase red blood cell production, does not appear on WADA’s list of prohibited actions. However, spending extended periods in high-altitude, low-oxygen environments will naturally increase the body’s production of EPO, stimulating red blood cell production.
After several weeks, this can increase hemoglobin levels, which we have now learned can significantly benefit athletic performance upon returning to sea level. WADA has not banned pre-competition altitude training, since it does not involve the external administration of recombinant human EPO and, as such, does not hold any promise of success. Some elite athletes see major increases in red blood cell count, while others experience fatigue, sleep disruption, or no benefit at all.
Altitude training varies by athlete, but the most popular approach involves living and doing low-intensity cardio at about 2300 meters above sea level, paired with high-intensity training at about 1250 meters above sea level. This dynamic seems to enable athletes to maintain any acquired maximal augmentations in total hemoglobin mass while reducing the performance impairment of high-intensity sessions performed at moderate altitude (athletes sometimes will experience periods of “detraining” if they live and train at moderate altitudes).
Because altitude training may affect an athlete’s blood cell parameters in ways similar to those observed after blood doping, current detection methods appear unable to distinguish altitude training from blood doping. This conundrum makes interpreting an athlete’s biological passport difficult. The only difference seems to lie in the inherent dangers. Injecting synthetic EPO artificially thickens the blood to a precarious level, raising the risk of strokes, heart attacks, and death. In contrast, while it may offer a performance advantage, training at high elevations remains self-limiting; the body easily returns to homeostasis upon a return to sea level.
Points to Ponder
Young users typically minimize the known health risks associated with performance-enhancing substances, which puts them at particular risk for future use and subsequent harm. Many athletes just starting out on the competitive path may not have heard of recombinant human erythropoietin, let alone its inherent dangers. Early recognition by physicians, parents, and coaches, followed by honest education and “thoughtful discouragement”, might serve as a useful strategy to dissuade adolescents from even considering this type of supplementation.
References
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usada.org/spirit-of-sport/blood-doping-epo-faq/
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hematology.org/about/history/50-years/milestones-erythropoietin
