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Erythropoietin and rEPO explained: A doctor and medical researcher discusses the drug behind Jose Uzcategui’s positive test

What is recombinant human erythropoietin (rEPO)? What does it do? A doctor and medical researcher discusses the facts.

Jose Uzcategui v Caleb Plant - Press Conference Photo by John McCoy/Getty Images
John Hansen joined Bad Left Hook as a staff writer in 2021 and co-hosts the "Prophets of Goom" podcast.

This time last week, Jose Uzcategui was on schedule for a title eliminator fight against David Benavidez. Uzcátegui (31-4, 26 KO), a former IBF super middleweight champion, would have headlined a Showtime main event, and potentially put himself in line for another shot at a championship belt.

Then, he took a drug test.

Uzcategui tested positive for recombinant erythropoietin (rEPO), leading to his removal from the fight and Kyrone Davis stepping in as his replacement. But, what is erythropoietin? What does it do, and why is it a banned substance?

To get a better understanding of the drug, and how it might work as a performance enhancer for a fighter, we spoke to Dr. Dion Diep, Physical Medicine and Rehabilitation Resident at the University of Toronto, and one of the authors of a 2020 study on the athletic performance enhancing effects of erythropoietin.

Dr. Diep has no first-hand knowledge of Uzcátegui’s test results, or any role in his testing or treatment. But, he’s an amateur boxer, and a researcher that has studied and analyzed “the ergogenic benefits of recombinant human erythropoietin (rHuEPO).” Dr. Diep was kind enough to explain what that sort of sentence means to a layperson, and to talk through the current understanding of how erythropoietin functions as a performance enhancer in various types of athletic activity.

Among the highlights of our conversation: Testing is precise enough that recombinant erythropoietin isn’t going to be confused for something naturally produced by the body. rEPO is not the sort of thing that would end up in someone’s system by accident or coincidence. And, between cycling and combat sports, you’ve probably heard of at least one or two athletes that have used this substance before.

A transcript of our conversation, edited for length and clarity, follows.

BAD LEFT HOOK: You’re unique among our explainer experts so far, in that you actually are quite familiar with, and have a connection to, the world of boxing. We’re going to spend a lot of time talking about erythropoietin, and about your medical and research background. But, why don’t you start off by telling us a little about your connection with the sport?

DR. DION DIEP: I’ve actually been boxing for the last 10 years, and I’m actively training for my next amateur fight. It gives me a good perspective of not just the health consequences of boxing, but the patient perspective behind it, too. It lets me see both sides.

I’ve tried to tie my personal and professional interests together. Throughout medical school and residency, I volunteered at a lot of local, provincial, national, and international boxing events as part of the medical team. We would be at events like the 2017 Canadian National Championships, conducting pre-bout and post-bout assessments and even suturing athletes after sustaining lacerations. We were most recently at the Pan-American Games in Lima, Peru back in 2019, and the European Games in Belarus the same year.

Outside of boxing competitions and medicals, I also try to promote the sport to people who generally wouldn’t be exposed to it. I am the founder and head coach of the University of Toronto boxing club. It’s a fully student-run club where we try to promote both the sweet science and our passion for general fitness to promote student wellness. It’s been going strong; we have about 50 members right now.

I also have a strong passion for research. My research interests include sports medicine, pain, and rehabilitation. I’ve completed many doping studies investigating the athletic performance potential of various substances. Not just erythropoietin, but also drugs like marijuana, glucocorticoids, testosterone, and pseudoephedrine. I have also investigated various approaches of alternative medicine to treat common musculoskeletal and neurological injuries.

I have to ask, before we go any further: What’s your weight class as an amateur? People are going to want to know, as soon as they see your answer, what class you fight in.

[Laughs] Well, right now, I walk around at 155 pounds at 5 feet 11 inches. AIBA changed their weight classifications this year, and welterweight is now 147, so that’s my goal. [NOTE: Boxing Canada formerly classified welterweight as a max of 152 lbs/69 kg] I want to cut as little water as possible so I’m constantly in a caloric deficit until I reach my goal.

I suppose that if you’re trying to stay mentally sharp to diagnose patients for your job, you don’t want to be dehydrated, fatigued, and generally addled from a weight cut, right?

That is definitely right.

Before we get into the specifics of your research and conclusions, I want to get some basic information out of the way. Can you give us a brief overview of what erythropoietin is? What does it do, and what sort of “legitimate” medical purpose does it serve?

The entire premise behind erythropoietin doping revolves around the red blood cell. These are the cells in your blood that contribute to its red color. The scientific name for it is the “erythrocyte.” Red blood cells circulate throughout your body with the purpose of collecting oxygen from your lungs, and to carry this to the other cells and tissues, most notably the muscle cells, throughout your body.

Muscle cells use oxygen to produce energy and also expend waste products during this process. It’s your red blood cell that ultimately helps with that storage and transport. This is where erythropoietin comes in, because it is a hormone that’s found naturally in the body which stimulates red blood cell production. In theory, having more red blood cells would increase one’s body’s capacity to transport oxygen and eliminate waste products.

Now, it’s important to distinguish between erythropoietin that occurs naturally, and then the recombinant human erythropoietin, which is made artificially.

Let me interrupt to make sure we’re clear about that distinction. Uzcategui’s failed test was reportedly for “rEPO”. Just to make sure, is that another layman’s term for something that also has a more precise medical name? Is there any difference between “rEPO” and the “rHuEPO” you discuss in your research study?

There’s currently no consensus in the scientific community for how to use these acronyms. They’re similar ways of describing the same thing. The acronym “rHuEPO” just stands for recombinant human erythropoietin, while “rEPO” stands for recombinant erythropoietin.

The main take-home point here is that it’s artificial as opposed to the one that’s made naturally in your body. The artificial version has been used as a medical therapeutic, but also as a potential doping strategy.

The whole history behind rHuEPO starts in the 1980s when it was first advertised to treat different medical conditions such as chronic kidney disease or kidney failure. The reason why it’s used for that is because your kidneys produce EPO; therefore, if you have damage to your kidneys, you risk lowering your natural EPO production factory. With less natural EPO, you get lower red blood cell counts and to avoid this you supplement your deficient EPO production with rHuEPO.

rHuEPO is also commonly seen used in cancer patients on chemotherapy drugs as well as patients using certain HIV drugs. Such drugs can suppress production of red blood cells, therefore rHuEPO is used to give your body a boost in red blood cell production.

You mention in the study that this particular substance already has a certain level of notoriety in the world of sports. Any specific examples or incidents that people might remember?

[Laughs] Yes, in the study, I start the first paragraph with a ‘hook’ referring to Lance Armstrong. I think his case certainly contributed to the drug’s notoriety, given the amount of publicity that went with it. He most famously publicized it when he admitted to using it in multiple Tours de France.

In combat sports, we have examples of athletes using it as well. Notable mentions include Shane Mosely in 2003 against Oscar De La Hoya. Also, from a fight I saw in person: TJ Dillashaw vs. Henry Cejudo. While he didn’t win, it still likely gave Dillashaw an advantage.

Hopefully, I’m not using a label that’s scientifically invalid… But, just to make sure we’re putting things in terms that people will recognize: We’ve heard the phrase “blood doping” in connection to those cycling scandals. Would this sort of rEPO usage fall in that category?

I like to think of the phrase “blood doping” as a big umbrella category covering various strategies to increase your red blood cell count. A few subcategories would include rHuEPO, altitude training, and blood transfusions. These forms of “blood doping” all work to increase your red blood cell count, but in slightly different ways.

rHuEPO increases red blood cell production through the drug itself. Meanwhile, altitude training works by having athletes train in low oxygen settings. Your body is always trying to keep a balance, so it tries to compensate for the low oxygen levels by increasing your natural EPO production, thus raising red blood cell levels. Finally, blood transfusions describe the practice of taking out blood pre-competition, and then storing it so that you can reintroduce it into the body shortly before competition.

I’m glad you mentioned something like altitude training, because failed tests can often lead to athletes or their handlers offering an “innocent” explanation about accidental ingestion, tainted food, or supplements that caused an unintentional contact with a banned substance. How does this substance end up in someone’s body? Is there any possible “innocent” way an athlete could end up with enough rEPO in their system to exceed World Anti-Doping standards and fail a VADA test?

WADA has done a lot of excellent work and put a lot of funding into making sure the tests for detecting rHuEPO are valid and reliable. Valid, meaning that it’s measuring what it is supposed to measure. And reliable, meaning that the results are reproducible and robust.

rHuEPO is tested in the urine. rHuEPO, while similar to EPO, still has a slightly different chemical structure such that it can be separated and reliably distinguished in well studied detection tests. A normal pee sample would just have EPO, such that you wouldn’t see the drug finding in someone who hasn’t actually used rHuEPO. There are no established natural mimickers of rHuEPO. You can’t sniff, snort, or inhale rHuEPO through second-hand methods, and rHuEPO is not typically associated with other intravenous illicit drug use. It’s a long-winded way of saying it, but if you find that substance in the urine, it’s more than likely intentional.

So, how do you take it? Is it injected? Is it an oral thing? How does someone get it in their body?

The bioavailability of it, which is a fancy way to describe how much of a substance gets into your bloodstream after passing through your stomach and liver, is poor. As a result, it’s mainly taken intravenously or subcutaneously through injections.

IV means “intravenous,” which is through the vein. It goes directly into the blood, and concentrates the EPO very quickly. Subcutaneous means injecting it into the fatty tissue just under your skin. Then it slowly dissolves into your bloodstream.

The only legitimate way I could think of someone having rHuEPO in their system would be if they had a therapeutic use exemption. WADA introduced this to allow people with genuine medical conditions to access medications warranted by a medical professional. Athletes with kidney issues or on red blood cell suppressing medications may need rHuEPO. But, even then, there wouldn’t be a clear advantage as it would be monitored very closely to ensure the right balance between treating their medical condition, but stopping before you may expect to see any performance enhancing effects.

We’ll talk more about general side effects a little later, but I wanted to ask now about a specific incident related to Uzcategui. He produced a strange, reddish urine sample on fight night prior to a March 2018 rematch against Anthony Dirrell. Could something like that potentially be a side effect of rEPO use?

That’s a good question, and my short answer is: most likely, no.

There are case reports that have shown an increased bleeding risk in people with primary medical conditions that cause naturally higher levels of red blood cells. However, it’s still an uncommon finding. And it’s really hard to make any conclusive statements as to what’s actually caused it. Any murky, reddish color in the urine is most likely blood. And, blood in the urine is quite nonspecific as to what might have caused it.

In a relatively young, high-level athlete, blood in the urine would first make me suspect an infectious cause, like a urinary tract infection or an STI. It could also be related to trauma. Uzcategui exercises much more than the average person, which can place strain on the kidneys which have to filter excess waste products. Additionally, direct trauma to the kidneys and the bladder from constantly receiving punches in sparring and competition could do the trick.

With all of that as a foundation, I’d like to open it up a bit so you can talk about your specific research. I’ll be candid, and admit that I don’t have the background to fully interpret and comprehend concepts like Maximal vs. Submaximal oxygen consumption, or the “Borg Scale Rating of Perceived Exhaustion.” I gave it my best shot, but I think it would help tremendously if you tried to explain in your own simplified words: What did you find about how useful this is as a performance enhancer, and under what conditions or circumstances would it be significantly helpful as a booster of athletic performance?

Before I answer that question, it would probably help to explain the methodology behind the research. The results are directly dependent on how the research was conducted.

Okay, let me ask you a different question about methodology. One of the things I was impressed by was how you boiled down over 2800 different studies down to ten that you used to draw conclusions. Is that a better place to start?

That’s right. The study we did was a systematic review and meta-analysis. In research there are hierarchies of evidence commonly taught to be shaped as a pyramid. The higher you get into the pyramid, the greater the confidence you can have about the conclusions drawn.

At the bottom of the pyramid, you have things like case studies, where you may be studying just one person. Then as you move up, you reach controlled studies, where you look at two different groups and compare them based on which drug each group received respectively. Then, we get into randomized control studies, where you randomly assign people into different groups to balance out their baseline characteristics. For instance, some people will be bigger, stronger, or better trained than others, which can affect how well they respond to the drug of interest. But, if you randomize people into both drug and placebo groups, then both groups should in theory have similar baseline characteristics, assuming there are enough people in the study. There are often many randomized controlled studies trying to answer the same question, but unfortunately come to different conclusions based on the characteristics of its design. Finally, near the top of the pyramid are systematic reviews and meta-analyses. These studies summarize all of the randomized control trials to try and finally reach a consensus.

That’s what we did. And to do it, we had to first look at all of the different types of studies out there. The only limitation that we had was that they needed to be in the English language. Despite that, we still found over 2,800 studies that were relevant, and we distilled it down to ten. The reason it was those ten and not any more was because of the strict criteria we used to select for eligible studies. To truly isolate the effects of rHuEPO, we wanted to remove any possible confounders. As a result, every single study had to have an rHuEPO group and a placebo group. If there was no placebo group, it was eliminated. Because there were a lot of studies in the past that just said “here are ten people, let’s give them all EPO and see before and after if they do better!” And, of course they’re going to do better, because the placebo effect is very real and it was not controlled for.

And, I assume, because the repeated process of the athletic test they’re doing would lead to improvement through practice?

Exactly. It’s the repeated test bias that you’re identifying there. These are the things we need to control for, and we try to control for as many as possible. However, we kept our parameters for “athletic performance” very broad.

We ended up with ten studies, and we found that there was a high likelihood of performance enhancing effects from erythropoietin. However, these results apply to the limited settings that were used in each study. What I mean by this is that every study but one measured performance enhancing effects in a very controlled, laboratory environment. The subjects were often on a stationary bike in a very artificial environment, and that simply isn’t the best setting to measure true athletic performance as opposed to a real-life competition.

That is not to say that the differences found between the rHuEPO and placebo groups are not valid. The improvements to maximal exercise performance found in favor of rHuEPO groups should not be ignored. There was considerable evidence that groups who received rHuEPO could perform better in all out sprints, longer distances, and also got tired less quickly.

If you don’t mind, I’d like to try and put that in a more direct sports context, at least as far as you’re comfortable generalizing. If the most significant results are in high impact, high intensity performance situations, how does that carry over to specific sports where that would have a notable performance enhancing benefit?

It seems like, if I’m understanding correctly, a sprinter, or a time trial cyclist, someone constantly going at full effort, would potentially see substantial value. But, in a sport like soccer or basketball, where there are short bursts of maximum intensity but we see a more measured baseline of exertion for the majority of the event, would this substance be as helpful for increasing performance?

Before I get into specific sports, we probably ought to talk about the three energy systems that the body has, and how EPO affects these systems. That way, we have a similar process in reasoning so we can draw conclusions.

The first is your anaerobic system, which provides immediate short-term energy over periods of time measured in seconds. That’s the energy system you use when you do Olympic weightlifting, shot-put, or javelin throwing. Then you have your glycolytic system, which quickly provides energy for seconds to a minute and is used for track, swimming, rowing, or cycling-type sprints. Finally, there’s the aerobic system, which provides energy more efficiently but at a slower rate. Unlike the other systems, the aerobic system is directly dependent on oxygen, and therefore there is potential to enhance this system by increasing your red blood cell count

To get back to the original question: in theory, rHuEPO would be less helpful for sports like weightlifting, shot put, and 100 meter sprints. Meanwhile, sports like long-distance running, cycling, and triathlons would see the most benefit from its use. Boxing in particular has a high aerobic demand and, in theory, rHuEPO would certainly improve one’s physical performance. However, even if it is used in less applicable sports, not everything is black and white, and sports will often still require you to use your aerobic system. Any advantage, albeit small, may be the difference between a gold and silver medal, a win or a loss.

I want to refer to a quote from your published study:

With regard to policy implications, it is important to acknowledge that a substance’s potential to enhance performance is only one of the three criteria that WADA considers when determining its inclusion in the prohibited list. Doping policymakers must also examine any health risks to athletes and potential violations to the ‘spirit of sport’. Therefore, even if one of these dimensions is inconclusive, prohibition may still be justifiable

Even if someone tries to potentially dispute the usefulness or impact of rEPO, the spirit seems very clear. If this is in your system, it seems like you’re clearly trying to gain an advantage.

That’s right. In fact, even if there’s the potential for benefit or harm, it’s already enough grounds to justify a ban.

And, not to try and oversimplify or generalize the results of your study, but it seems quite clear that evidence shows performance enhancing benefits coming from the use of erythropoietin, right?

That’s right, though again, these results are taken from very limited settings. rHuEPO can enhance physical performance in limited, but precise laboratory settings. Meanwhile, physical performance is often a predictor of improved athletic performance in real life settings. Therefore, it’s beyond a reasonable doubt that rHuEPO has the potential to improve one’s athletic performance.

While there is no direct evidence that rHuEPO makes you a better boxer since there have been no studies on it in that specific setting, it is still reasonable to extrapolate the results of these laboratory-based studies to boxing itself. For instance, rHuEPO has been shown to improve VO2 max, which is a strong surrogate measure for performance in almost every type of sport, including boxing.

I doubt that an athlete or a trainer engaging in this sort of doping is doing the same sort of clinical study that you did to evaluate risks and potential performance gains. But, the assumption of use would be, post-cycling scandals, that there is a benefit to be had here. How has our understanding of this, either medically or popularly in the world of athletics, changed over the 5-10 years?

I actually think this is a very common issue in medical research. It often takes a lot of time to definitively prove anything in medical research, such that by the time there is strong evidence, the harm has already been done. In this case, coaches and athletes know if a substance helps them through anecdotal experience, and word travels much faster than research progress.

One thing I’d suggest for readers to look into is WADA’s Athlete Biological Passport. What it does is, instead of taking pee or blood tests and getting snapshots of where an athlete is at those fixed moments in time, the athletes get their blood tested at regular intervals to track the trends of those test results. There’s always going to be a new potential performance-enhancing drug. Like I’ve mentioned previously, the science of testing and evaluating the drug will lag behind. You may not be able to detect it, or determine if it has a big performance-enhancing impact or not, but it’s still being used.

By having this passport, you can see fluctuations in blood markers that performance-enhancing drugs often target. Therefore, even without seeing the actual drug itself, you can have a raised index of suspicion that something odd is going on. If one day your hemoglobin, which is a marker for your red blood cells, is 120, and then the next day it’s at 160, it’s still not grounds for a suspension or to say definitively that there’s an illicit drug involved. But, it can be grounds to raise the index of suspicion and say, “perhaps we do some more investigations.”

Are there any notable contemporaneous side effects, or known long-term consequences from the use of rEPO?

Short term side effects can include very non-specific things like nausea, headaches, or dizziness. There are no scientific studies out there that talk about the long-term consequences of rHuEPO use in athlete populations. However, there is extensive research on the effects of rHuEPO on different medical conditions, specifically chronic kidney disease. rHuEPO increases your red blood cell count, which can predispose patients to higher risks of blood clots, heart attacks, and stroke.

You come from a boxing background. You train and fight on the amateur level. You work with fighters; you work on the medical and support team at boxing events. What is your take? I mean, I’m assuming you’re not on recombinant EPO, right?

[Laughs for 6 seconds] Who knows? [Makes a playful face]

[Laughing] Well, I’m asking you! YOU should know!

No, I’m just kidding.

So, it’s something you avoid despite the potential benefit it could have. How do you interpret or handle a hypothetical situation with a boxer you know or you’re working with who wants to go down this path? I’m not asking you to be Nancy Reagan, but this is a pretty clear “Say No To Drugs” type of situation, right?

That is certainly the route I’d take when counselling patients on its use.

However, I do acknowledge that medicine isn’t black and white. As a clinician, you have to take into account your duty as a medical professional, your patient’s perspective, and also the perspective of society and organizing bodies as a whole. The key to this balance comes to transparent and clear communication. You want to ensure your patient is aware of your perspective as a physician to first do no harm to the patient. There are clear risks of rHuEPO use to not just my patient, but my patient’s opponents.

There is also the legal element of prescribing performance-enhancing drugs that makes it more murky. While it’s safe to say I won’t be prescribing any performance-enhancing drugs, it is still important to always listen to your patient and understand their perspective to build a trusting relationship. This is especially important as patients can find other unauthorized and potentially dangerous sources to get access, so I would want to take a harm-reduction approach by being open-minded and counsel my patient around these dangerous possibilities. It’s also important to know that there are WADA created resources like the Sports Physicians Tool Kit for difficult situations like these, which I would certainly refer to.

Any other final thoughts or things you’d like to add? Maybe a specific fight date when our Canadian readers can come out and cheer you on?

Hopefully, I’ll fight sometime in January or February. Things are a bit shut down due to COVID right now, so I’m mostly working on keeping in shape and getting enough sparring in to stay sharp.

Finally, I’d like to thank one of my most influential mentors. His name is Dr. Kien Trinh, and he was the lead author of the study. I was very lucky as a 17 or 18 year old undergraduate student to have gotten into his research lab. He’s the medical director of Boxing Canada, and it was under him that I was able to learn so much about doping and how it relates to boxing legislation, and to work with so many boxers from a medical perspective.

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