Even if you’re not into sport, you’d be hard pressed not to have heard about EPO – short for erythropoietin. On a simplistic level, most understand EPO is a substance that occurs naturally in the body and regulates the ‘oxygen carrying’ capacity of blood. But to be more precise, EPO is a glycoprotein, mainly involved in a process called erythropoiesis. Erythropoiesis is the name given to the process of regeneration of erythrocytes (i.e. red blood cells). With red blood cells only having a life span of about 120 days; erythropoiesis is essential to maintain normal red blood cell levels. Without EPO, your body simply can’t produce the red bloods cells it needs to carry out normal function. But with the use of synthetic EPO, the percentage of red blood cells in whole blood (termed hematocrit) can be boosted well above ‘normal’.

EPO Function & History

The first type of synthetic EPO became available in 1989 and was originally developed for individuals with kidney disease. Kidney organs are the primary producers of EPO, with severe forms of kidney disease often resulting in anemia due to lack of EPO production. EPO is still used today in medicine for a variety of surgical and clinical conditions. However, aware its potential use to artificially boost performance, the International Olympic Committee (IOC) prohibited EPO use in 1990. This was despite the fact there was no test was available to detect its use. It took till the turn of the century in 2000 for the first verified test for detection of EPO to appear. The test has since been refined and improved to keep up with developments in use of different synthetic varieties of EPO.

How EPO Works

As far as athletes are concerned, use of synthetic EPO offers a means to increase arterial/blood oxygen content, which in turn leads to an increase in maximal oxygen uptake. Endurance sports such as swimming, running, rowing and cycling stand to benefit most from an increase in maximal oxygen uptake as this is one of the limiting factors for performance. An additional benefit of EPO use is once administration is discontinued, red blood cells only return to their original levels very slowly, i.e. about a month18. This effectively means an “open window” may exist where there is no evidence of EPO misuse but where performance is still enhanced. Furthermore, the enhanced red blood 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 EPO misuse18.

Scientific vs Anecdotal Evidence for Benefits of EPO in Elite Athletes

Interestingly, one of the most recently published scientific reviews addressing the question of whether EPO can enhance performance in elite cyclists’ concluded that there is no scientific basis upon which to conclude that EPO can enhance performance in elite cyclists18. One of the main limiting factors cited in this study is the lack of studies specifically measuring the effect of EPO on elite cyclists; like those in the Tour de France for example. This is certainly a major consideration as such athletes are thought to be among the major users of EPO18, 19.

In contrast to this study’s findings, testimonies of multiple riders affidavits from the highly publicised USADA reasoned decision against Lance Armstrong, site an increase speed of the ‘peleton’ in 1995 due to the onset of widespread use of EPO. Many riders’ affidavits cite difficulty in maintaining competiveness in 1995 relative to the previous year. Moreover, many of the rider’s affidavits make admissions to the effect that use of EPO was necessary to stay competitive in the sport of professional cycling. So it would certainly appear, contrary to the recent study in the British Journal of Clinical Pharmacology, that there is a wealth of subjective and anecdotal evidence suggesting EPO can improve performance in elite cyclists.

EPO Improves Exercise Performance in Healthy Individuals

It’s important to point out that there is a wealth of studies showing that use of synthetic EPO can improve a number of variables associated with endurance exercise performance in normal or recreationally active individuals18. This is most likely due to the fact that such subjects are much easier to recruit than elite athletes for the purpose of scientific studies. One reason for the discrepancy between the scientific versus anecdotal benefits of EPO use in elite athletes is thought to be the particular measures used to gauge improved performance in such studies. One such example is VO2max.

Effect of EPO on VO2max in Elite Athletes

Contrary to popular belief, VO2max has very limited predictive value for endurance performance in elite athletes1-7. This can mean that EPO could be benefiting performance, but the improvement may not be detected when only measuring VO2max. Studies show that successful endurance athletes reach high VO2max values after initial years of training, but they subsequently maintain a plateau in their VO2max8-10. However, these athletes still continue to improve through changes in measures such as lactate threshold via improvements in buffering capacity11-12. Lastly, studies show that during the course of a three week stage race, cyclists only spend between 1-2 hours actually working at or above their VO2max13. So it’s easy to see why VO2max may not be the best measure to detect improvements in performance resulting from use of synthetic EPO.

Monitoring and Detection of EPO

On December 1st, 2009, the World Anti-Doping Authority (WADA) implemented a new system to combat drug use in sport called the Athlete Biological Passport (ABP). The ABP is based on the monitoring of selected parameters over time that indirectly reveal the effect of doping, as opposed to the traditional direct detection of doping by analytical means. As stated previously, it wasn’t until 2000 that a verified test for detecting use of synthetic EPO was available. This permitted the use of EPO to go largely undetected for close to a decade. Current tests for EPO use urine samples and therefore, back-dated testing can be performed on frozen urine sample stored for years. This has permitted the detection of a large number of positive tests for EPO from the early 90's right through to now; culminating in the highly publicised Lance Armstrong case.

Evasion of EPO Detection

It is widely reported that the testing window in which EPO can be detected is very narrow, i.e. in the vicinity of 12 hours, and therefore, the techniques used to evade detection center largely around the time of administration of EPO. Because drug testing at night is very uncommon, the USADA report mentions that riders would normally administer small doses EPO at night, so that by the morning they would be ‘clean’ so to speak. The other technique used to evade positive EPO detection centred on the form of administration, i.e. intravenous versus subcutaneous. Intravenous administration of EPO leads to much quicker elimination, and as such was the method of choice to improve the chances of evading drug tests19. This practise of doping EPO is commonly collectively referred to as 'microdosing' and is considered the most effective means of evading EPO detection via drug testing.

Testing for EPO

The methods and systems developed for evasion of positive EPO drug tests are so advanced that athletes, doctors and coaches have been reported to have developed techniques that decrease the likelihood of detection even when a sample is taken at an opportune time while using synthetic EPO. As stated in the USADA report19, these techniques take advantage of the fact that:

“…the EPO testing method works through separating and measuring the quantity (known as “intensity”) of various types of EPO and comparing the ratio of EPO bands in what is known as the “basic” region (where the bands tend to be caused by the administration of synthetic EPO) to bands in the acidic region (where the bands are naturally produced). However, because the test operates by measuring a ratio, the test can be fooled to a degree by increasing the amount of EPO in the acidic region (i.e., those produced naturally), which can be accomplished by stimulating natural production of EPO either through going to altitude or by sleeping in an altitude tent (also known as a “hypoxic chamber”).

Such techniques add to the difficulty and complexity for doping authorities to catch athletes using synthetic EPO. At the time of writing, news has just been released of a new test able to detect the use of microdosing of EPO with an accuracy of close to 100%20. As this test undergoes appropriate verification, it is expected to have a major impact on stamping out illicit use of synthetic EPO.

Adverse Effects of EPO Use

While much of the press tends to focus on the possible performance enhancing effects of synthetic EPO; its use does carry some significant detrimental side effects and risks. Use of synthetic EPO essentially leads to a thickening of the blood, which can have a flow-on effect in terms of risk of particular diseases such as heart attacks and strokes, which are associated with increased risk of blood clotting. Moreover, when exercising in a dehydrated state and at high altitude, use of synthetic EPO can significantly increase the risk of blood clotting (i.e. thrombosis) because under such conditions blood is inherently thicker.

This risk of thrombosis is evidenced by a published case report involving a professional cyclist who presented with blood clotting in the brain and thereafter confessed to 3 months of 2000IU synthetic EPO use every two days, in combination with 15 days of growth hormone and continuous high doses of vitamin A and E14.  It is also known that the artificially high hematrocrit values obtained with use of synthetic EPO can predispose one to heart failure, myocardial infarction, seizures and pulmonary embolism (a blockage of the main artery of the lung) 15, 16.

A condition called pure red cell aplasia (PRCA) in which the bone marrow ceases to produce red blood cells has also been known to arise with the use of a particular brand of synthetic EPO called Eprex®17. This condition is triggered when the body starts making antibody’s to the synthetic EPO. This risk is thought to be associated with the improper handling and storage of synthetic EPO preparations, which are the exact circumstances that surroung its secret and illicit use in sport.

Natural Alternatives to EPO

One of the most common questions that surface in regards to EPO is what are some natural alternatives? Unfortunately, there are very few supplements which have been shown to increase hemoglobin or hematocrit, with the exception of beetroot. Beetroot is one of the highest natural sources of nitrate, and studies show supplementation (via beetroot juice) results in increases in haemoglobin. This effect is thought to be due to nitrate's ability to boost nitric oxide (NO) levels. It has been suggested that elevated NO availability may improve oxygen delivery to muscle tissue; resulting in greater metabolic efficiency. This is the reason that nitric oxide supplements are sometimes suggested as an alternative to EPO. Because one of nitric oxide's main roles is in the regulation of blood flow, nitric oxide supplements can be likened to EPO in that they can help improve blood flow, which inadvertently improves oxygen delivery to muscle tissue.

Summary

In summary the total body of evidence suggests that both recreational and elite athletes stand to benefit significantly from the use of synthetic EPO, however, the drug was not designed for use by athletes and its use in such individuals does come with significant medical risks. While no nutritional supplements have been directly compared with EPO, nitrate and nitric oxide supplements offer a viable, safer alternative.

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