How Much Does Recombinant EPO Impact Performance?

In a story that has rocked the triathlon world, it has just been announced that American professional Collin Chartier tested positive for the banned substance erythropoietin – or EPO – in an out-of-competition test in February. Chartier, made miraculous strides up the ranks last year, winning the PTO US Open in Dallas.

There had been an immense amount of chatter in this space over the last day or so. And the bottom line is, doping in this manner (in addition to any manner) gives a huge competitive advantage. A clean sport is absolute paramount for fair competition, and our sport. So in this blog, I am going to do a bit of a deep dive into EPO, how it works, and the effect it has on performance – which is why it is often the drug of choice for those seeking to climb up the podium by means other than hard work and discipline in training. I have written a fair bit about EPO recently, after a couple of studies have been published demonstrating that ketone supplements can (legally) boost EPO (3, 7).

The physiology of erythropoietin (EPO): How does it work?

Erythropoietin, or EPO, is a hormone produced by the kidneys that plays a crucial role in the production of red blood cells. It signals to bone marrow to produce more red blood cells, which are responsible for carrying oxygen throughout the body. Increasing your overall red blood cell count is one of the key goals of endurance training, as more red blood cells mean more ability to carry oxygen to the muscles to support aerobic metabolism. Increasing your red blood cell count and oxygen carrying capacity is likely to increase important endurance-related variables like V̇O₂max, as your maximum ability to consume oxygen is likely limited by your ability to deliver oxygen to the working muscles (6).

Therefore, EPO is a naturally occurring hormone produced by the body, and one we want to stimulate with endurance training. However, EPO is also produced artificially; this is called recombinant EPO. Recombinant EPO is a prescription drug used for the treatment of conditions like anaemia (low red blood cell counts). Recombinant EPO is produced by inserting the gene that codes for EPO into host cells that then produce large quantities of the hormone. Recombinant EPO has the same amino acid sequence and biological activity as natural erythropoietin, and it stimulates red blood cell production in the same way. Therefore, recombinant EPO has been injected by athletes seeking to gain an unfair advantage.

If you follow professional cycling, you may be aware that EPO was widely used as a performance-enhancing drug, particularly in the 1990s. For example, Lance Armstrong was a prolific user of EPO. It was for a long time hard for the anti-doping authorities to detect because it has the same structure and appearance as the naturally occurring hormone. Modern testing methods have made it easier, however, to catch athletes taking recombinant EPO.

Does EPO doping make a difference?

Okay, so it makes sense in theory that taking recombinant EPO would improve endurance performance, and therefore confer an unfair advantage. Is there data to back this up?

In short, yes. A trial published this year found that even very small doses of recombinant EPO improved endurance performance (1). In this study, healthy, but not particularly well-trained, participants (24 males, 24 females) were randomly allocated to receive either low dose EPO or saline injections three times per week, for four weeks. Cycling time-trial performance and V̇O₂max was assessed before and after the treatment period. The performance test was time-to-complete 400 kcal of work, which in these participants required ~25 min, following an hour of submaximal riding.

Mean power output during the time-trial improved by on average ~4.1% (~10 W) in the EPO group, which meant that the participants completed the 400 kcal of work ~64 s faster following the intervention. Additionally, V̇O₂max improved by on average ~4.2% in the EPO group. No positive effects were seen in the control group. Even in relatively untrained participants, these are pretty hefty positive returns, demonstrating just how effective taking EPO can be. Think about that, 64 seconds improvement over 25 minutes of racing. Of course it's not exactly linear, as it likely has more of an effect over this duration, but still, the effect over 4 or even 8 hours of racing would be massive.

Two studies in well-trained runners have also found evidence of positive, performance-enhancing effects of taking recombinant EPO (2, 4), although it should be acknowledged that these studies had relatively weak research designs; with unmatched groups at baseline (or no control group at all). Conversely, one study in well-trained cyclists found no evidence of benefit (5), although this study has been criticised for only measuring performance after the EPO intervention, and so the magnitude of improvement could not be determined at an individual level. Of course, undertaking these studies is challenging, particularly in high-level athletes, given the intervention is a banned substance. That said, we have very strong theoretical rationale, as well as some experimental evidence, that taking EPO will vastly improve performance.

It is, however, hard to say what the magnitude of the benefit associated with taking EPO is likely to be. My guess would be that this would depend on a few factors:

1. How well-trained you are to start – it seems likely that better trained athletes who have already accrued adaptations through years of hard training would benefit less, but this may not be the case.
2. How much you take and how long you take it for – it seems likely that there will be some kind of dose-response, where more EPO, for longer, will have greater benefits. That said, there is likely a tipping point, and taking too much EPO could cause dangerously high haematocrit.
3. How much training you are doing – one of the main benefits of taking EPO is that by boosting your fitness, it allows you to train harder. So, you get the direct performance-enhancing effects of EPO, and the indirect effects by facilitating greater training-related adaptations.
4. Your event – my guess is that EPO would have greater, direct performance-enhancing effects in middle-distance events like 5 and 10ks than long-distance triathlon, as these events are probably more closely linked to your maximum capacity for oxygen delivery. That said, I would 100% still expect to see EPO boost the performance of an Ironman triathlete, but maybe to a slightly lesser extent.

 I’ll add one thought; any illegal performance benefit is too much. Races are won and lost by fine margins particularly at the elite level.

 Conclusions

It’s a disappointing day when news of a top athlete cheats in sport. We need to ensure that we as a sport take doping seriously and hold anyone involved accountable. As substances like recombinant EPO do decide the outcomes of races.

Jack Kelly from the How They Train Podcast did a "tell all interview" with Chartier. It's an interesting conversation. Check that out here.

References

1. Breenfeldt Andersen A, Graae J, Bejder J, Bonne TC, Seier S, Debertin M, Eibye K, Hostrup M, Nordsborg NB. Microdoses of recombinant human erythropoietin enhance time trial performance in trained males and females. Med Sci Sports Exerc 55: 311–321, 2023. doi: 10.1249/MSS.0000000000003052.
2. Durussel J, Daskalaki E, Anderson M, Chatterji T, Wondimu DH, Padmanabhan N, Patel RK, McClure JD, Pitsiladis YP. Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men. PLoS One 8: 1–8, 2013. doi: 10.1371/journal.pone.0056151.
3. Evans E, Walhin JP, Hengist A, Betrts JA, Dearlove DJ, Gonzalez JT. Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men [Online]. Am J Physiol - Endocrinol Metab 324: E56–E61, 2023. https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders.
4. Haile DW, Durussel J, Mekonen W, Ongaro N, Anjila E, Mooses M, Daskalaki E, Mooses K, McClure JD, Sutehall S, Pitsiladis YP. Effects of EPO on blood parameters and running performance in Kenyan athletes. Med Sci Sports Exerc 51: 299–307, 2019. doi: 10.1249/MSS.0000000000001777.
5. Heuberger JAAC, Rotmans JI, Gal P, Stuurman FE, van’t Westende J, Post TE, Daniels JMA, Moerland M, van Veldhoven PLJ, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF. Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial. Lancet Haematol 4: e374–e386, 2017.
6. Mortensen SP, Dawson EA, Yoshiga CC, Dalsgaard MK, Damsgaard R, Secher NH, González-Alonso J. Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans. J Physiol 566: 273–285, 2005. doi: 10.1113/jphysiol.2005.086025.
7. Poffé C, Robberechts R, Van Thienen R, Hespel P. Exogenous ketosis elevates circulating erythropoietin and stimulates muscular angiogenesis during endurance training overload. .