Recent study reports "weak evidence supporting EPO use for improved athletic performance"
A lesson on "absence of evidence is not evidence of absence"
A recent review article in the journal Sports Health claims that the available evidence does not support that erythropoietin (EPO) improves endurance performance.
Where do I even begin?
EPO is a hormone produced in the kidney responsible for increasing red blood cells. We all have, and need, a certain amount of EPO in our body to support our health. Red blood cells carry oxygen and without oxygen there is no life.
Oxygen is also critical to endurance performance, and the more we can take in from the air, pump through our bloodstream, and deliver to our muscles, the faster we can run, cycle, row, swim, etc. One of the primary physiological adaptations to endurance training is an increase in red blood cell volume, hemoglobin mass (the protein in red blood cells that carries oxygen), and maximal oxygen uptake.
Further manipulation of this system being regular training is an attractive avenue to improve performance. One way is to train at altitude, since low blood oxygen levels will stimulate EPO production (see diagram above). Another is blood transfusions or directly injecting EPO. Cycling clear has a long history of this, and several cases of athletes in recent years getting caught are also notable.
As an aside, anyone who knows me knows that I have a longstanding personal interest in the science of performance enhancing drugs (PEDs). I simply find the physiology very interesting and believe we need more research on how these substances work.Historically, it is difficult to study these various drugs in a traditional setting because of ethical and safety issues. Most universities and organizations are hesitant to approve or fund research projects where you provide subjects banned substances and test their performance. Also, we care about the effects in elite athletes the most, and they are unlikely to volunteer since they would get banned from their sport.
My take is that people are taking them anyway, so it is in the best interest of sports medicine, training, and research staff to know everything about how these things work.
Blood Transfusions
Blood transfusions are a form of blood doping where you remove your own blood, freeze the red cells for a few weeks, then re-infuse them after a period of time while your red blood cell status returns to normal.
One study in distance runners removed 450mL of blood two times separated by 8 weeks (900mL total). After the second blood removal, the athletes kept training normally for 11 weeks. Then, they received an infusion of either 1) their previously removed red blood cells, or 2) saline, followed by a 10km time-trial and other testing. A few days later they received another infusion of the opposite treatment. So those who got saline the first time now got the red blood cells, and vice versa, followed by another 10km time trial.
Whether you got red blood cell infusion the first time or second time, 10km time improved by about 1 minute, which is substantial. Another study around the same time found similar results. This time it was a 15km race in cross country skiers where performance improved 5% immediately after re-infusing red blood cells, and was still 3% better than baseline two weeks later.
Another study in the 80’s found an improvement in 5 mile treadmill time.
Okay. Clearly transfusions work. That’s why people do it. But the study I mentioned in the title was referring to recombinant human erythropoietin (rHuEPO). It’s not the same as taking out your own blood and re-infusing later on. Here, you are injecting the EPO hormone.
EPO
EPO synthesized back in the 1980’s by a pharmaceutical company since it has several medical uses for certain diseases. It didn’t take long for it to make its way into sport given its potent effects on raising red blood cell count. It was banned in the early 1990s but adequate testing didn’t come about until the 2000s, which is why the mid to late 1990s was the heyday of blood doping, particularly in cycling.
Often, you will see the drug written as rHuEPO (recombinant human erythropoietin).In 2017, a study got a lot of press that was really the first rigorous experiment to test EPO in well-trained athletes (cyclists). They either doped or got placebo for 8 weeks, along with substantial lab testing and a race up a mountain frequently seen in the Tour de France.
VO2max and maximal power output on the bike improved by ~10% in the EPO group and 4-5% in the placebo, so a 5-6% additional benefit of EPO. However, race time was not different between groups. The conclusion of the study was essentially that while EPO improved some things during lab testing, it may not translate to real-life scenarios and that “the effect is at best very small”.
I agree with others that there are some flaws in that interpretation (read here). In elite athletes, a 5% boost in VO2max and power output is monumental. It seems small, but when you’re very fit, improvements that large are hard to come by. Elite athletes dedicate their entire professional careers for improvements of 1% or less.
The lack of a difference on the race up the mountain also shouldn’t be the end-all be-all. It’s only one day and a lot of other factors go into performance like nutrition, hydration, sleep, and pacing/drafting that are present in actual races. Also, cycling races are often several days, so we can’t discount that EPO would not be beneficial when you stack a bunch of those races multiple days in a row. But I do like that they included something beyond just the lab.
What do other studies say?
Several other studies have also looked at EPO and performance in well-trained, but not elite, athletes. The figure below is from a study showing EPO improves VO2max and time-to-exhaustion in cyclists.
Recently, we saw a similar effect VO2max in Kenyan runners along with better performance in a 3000m time-trial by 27 seconds on average. For reference, 2 miles is 3200m, so on an outdoor track, 3000m is half a lap shorter than 2 miles.
Refuting the claim that there is limited evidence supporting that EPO improves performance
Now, the recent review article did acknowledge that EPO improves VO2max and power output. The point they tried to make was that these lab measures have not been shown to translate into real-world performance. Since we’re talking about published research here, I’ll ignore the numerous athletes who confirm it helped them race bikes or run faster and confine my argument to published research.
Let’s look at a quote from their study :
Two studies evaluating race performance times have found minimal, if any, benefits of rHuEPO on performance (8,22).What are those references, number 8 and 22?
I have already introduced you to number 8 two figures above. In that study, the athletes rode a bike where the resistance (power) was increased every 2 minutes until they could not continue. The EPO group went from 12 min 48 sec to 14 min after doping. The placebo group went from 13 min 6 sec to 13 min 18 sec after the same period.
That is a 1 min 12 sec versus a 12 sec improvement. While I agree that these types of tests are not the best for looking at sports-relevant performance for various reasons, I do believe it is representative of a relevant physiologic improvement. The ability to maintain a given power output for 60 seconds longer would certainly pay dividends at the end of a race when you’re maximally pushing to the finish line.
How about reference 22 (read here)? They used a 3000m time trial as a performance test on an indoor track and tested a group of experienced runners (group 1) and a group of young fit men but not necessarily experienced runners (group 2). Let’s look at the results.
Group 1 ran 32 seconds faster immediately after EPO. 4 weeks later (after stopping EPO) they still ran 19 seconds faster. Group 2 ran 36 seconds faster and then 26 seconds faster. The authors of this study concluded:
In conclusion, relative to baseline, running performance was
significantly improved following 4 weeks of rHuEpo administra-
tion in trained men and remained significantly elevated 4 weeks
after administration by approximately 6% and 3%, respectively.
These performance effects coincided with significantly rHuEpo-
induced elevated VO2 max and Hbmass.Honestly, I don’t think the authors of the recent review article actually read these two papers they cited because their interpretation is simply wrong. They also did not cite the first one I mentioned in the Kenyan athletes.
Absence of evidence is not evidence of absence
With performance enhancing drugs, it’s often hard to know exactly what they do since research is difficult to conduct, and pretty much impossible to conduct in elite athletes where these things really matter.
Saying that there is limited evidence that EPO, or any PED for that matter, improves performance is a bit disingenuous in my mind. Obviously there is limited evidence because most athletes are either not going to willing take EPO, or sign up for an EPO research study, for the fear of being banned or that information being disclosed to the public.
That does not mean it fails to enhance performance. Absence of evidence is not evidence of absence. You can’t say something is/isn’t true based solely on the fact the information is not available. The weird thing is that even in this case there are several lines of evidence showing it does improve performance, so I’m not sure how the authors came to that conclusion.
Unfortunately in the PED world we often have to rely on anecdotes or studies in non-elite athletes, and don’t have rigorous science in world-class performers. However, there are some initiatives that may change this soon.
References
Performance-Enhancing Drugs in Healthy Athletes: An Umbrella Review of Systematic Reviews and Meta-analyses. Sports health, 16(5), 695–705. https://doi.org/10.1177/19417381231197389
Brien, A. J., & Simon, T. L. (1987). The effects of red blood cell infusion on 10-km race time. JAMA, 257(20), 2761–2765.
The effect of induced erythrocythemia upon 5-mile treadmill run time. Medicine and science in sports and exercise, 13(3), 169–175.
Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial. The Lancet. Haematology, 4(8), e374–e386. https://doi.org/10.1016/S2352-3026(17)30105-9
Erythropoietin on cycling performance. The Lancet. Haematology, 4(10), e459–e460. https://doi.org/10.1016/S2352-3026(17)30147-3
Effects of EPO on Blood Parameters and Running Performance in Kenyan Athletes. Medicine and science in sports and exercise, 51(2), 299–307. https://doi.org/10.1249/MSS.0000000000001777
Effect of rhEPO administration on serum levels of sTfR and cycling performance. Medicine and science in sports and exercise, 32(7), 1238–1243. https://doi.org/10.1097/00005768-200007000-00009
Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men. PloS one, 8(2), e56151. https://doi.org/10.1371/journal.pone.0056151