EPO in Athletes: Erythropoietin Levels, Clinical Interpretation, and the Doping Divide
Table of Contents
Introduction
EPO in athletes sits at a contested intersection of sports medicine, clinical diagnosis, and anti-doping science. Endurance athletes speak of “natural EPO elevation” from altitude camps as a badge of physiological adaptation. Anti-doping authorities track it as the gateway to blood manipulation.
Erythropoietin has also become widely known to the public through high-profile doping cases, particularly in endurance sports such as cross-country skiing, where its misuse has been repeatedly exposed. At the same time, erythropoietin has an established and legitimate role in clinical medicine. Its primary therapeutic use is in the treatment of anemia associated with chronic kidney disease, where impaired endogenous EPO production leads to reduced red blood cell formation. Outside of this indication, the clinical use of erythropoietin is relatively limited and typically restricted to specific conditions such as chemotherapy-related anemia.
EPO in Athletes: What Erythropoietin Is and How It Works
Erythropoietin is a glycoprotein hormone consisting of 165 amino acids, produced predominantly by peritubular interstitial cells in the renal cortex and medulla, with approximately 15% synthesized in the liver [1]. Its primary function is to stimulate erythropoiesis — acting on erythroid progenitor cells in bone marrow to drive red blood cell production — in direct response to tissue hypoxia.
The molecular switch controlling EPO production is the hypoxia-inducible factor (HIF) system. The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production, with HIF serving as the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia [2]. When oxygen delivery falls short, HIF-mediated signaling drives EPO output upward. More EPO → more red blood cells → more oxygen-carrying capacity.
In a study of 39 male athletes measured at the start of a training season, EPO concentrations were significantly higher than in a sedentary male control group — median 12.65 mIU/mL versus 5.74 mIU/mL (p = 0.001) — compared to 34 healthy non-training controls [3].
In my own clinical work, erythropoietin is something I encounter relatively infrequently outside of a specific patient group. Most often, it comes up in the context of patients with chronic kidney disease, where declining renal function leads to reduced endogenous EPO production and a gradual drop in hemoglobin levels. These cases are typically managed within nephrology or specialized care settings, rather than general practice.
From a practical standpoint, what I more commonly see is the monitoring phase: patients with worsening renal parameters whose hemoglobin trends are followed over time, with the question of initiating erythropoiesis-stimulating therapy arising as anemia develops. It is rarely an immediate decision, but rather part of a longitudinal clinical assessment.
Outside of this context, the use of exogenous erythropoietin in routine clinical practice is limited. For most clinicians working outside nephrology or oncology, it is not a medication encountered on a regular basis.
Altitude Training and EPO in Athletes
Altitude training’s central rationale is the deliberate exploitation of the HIF-EPO axis. The elevated erythropoietin production in hypoxia is a key factor in achieving enhanced hematological variables, with the magnitude of EPO increase and acceleration of erythropoiesis depending on the duration of exposure and degree of hypoxia [4]. During altitude training, EPO levels increase significantly after the first to third days and nights at altitude, after which erythropoietin gradually falls but remains above initial values for a period before returning toward baseline [4]. This mechanism is central to understanding EPO in athletes, particularly in the context of altitude training and endurance performance.
A 2025 systematic review and meta-analysis found that altitude training significantly increased hemoglobin concentration compared to low-altitude training (SMD = 0.7, 95% CI: 0.27–1.13, p = 0.03), with subgroup analysis indicating that the Live High–Train High approach and interventions lasting longer than three weeks yielded the most pronounced effects [5]. It is worth noting that altitude-induced increases in plasma erythropoietin also interact closely with blood volume changes that athletes experience during heavy training — elevated hemoglobin readings do not always mean more red cell mass.
The Live High–Train Low strategy — sleeping at altitude, training at lower elevations — was developed to combine the hypoxic erythropoietin stimulus with high-quality training. This approach is legal, physiologically grounded, and used in endurance sports from middle-distance running to cycling.
In endurance sports such as cross-country skiing, altitude training has become a well-established part of preparation, and Nordic athletes — including Finnish skiers — are often associated with its systematic use. In practice, athletes travel to mountainous environments well in advance of competition and remain there long enough to induce measurable hematological adaptations before returning to sea level for racing. The observed increase in hemoglobin is driven, at least in part, by hypoxia-induced stimulation of the HIF–EPO pathway, which promotes red blood cell production over time.
When Erythropoietin Testing Is Clinically Warranted
It is worth emphasizing that erythropoietin is not a first-line investigation in the evaluation of anemia or routine blood count abnormalities. In clinical practice, it is typically reserved for more specialized settings and used selectively as part of a broader diagnostic workup. The two situations in which it is most commonly considered are the evaluation of persistent or unexplained anemia, and the assessment of suspected polycythemia, where EPO levels can help guide further investigation.
Anemia workup. Erythropoietin is most useful when the cause of anemia is not immediately clear from a standard blood panel. When a patient presents with low hemoglobin, a reduced or inappropriately normal EPO level may point toward diminished renal erythropoietin production or primary bone marrow pathology rather than iron deficiency or blood loss, where EPO is typically elevated.
Iron deficiency complicates this picture in an important way. Hepcidin, the peptide hormone that regulates systemic iron metabolism, decreases in response to erythropoiesis by facilitating increased iron efflux from ferroportin into circulation — but during exercise, there is an alarming increase in the expression of hepcidin resulting in a negative iron balance in athletes [6]. If you want to understand exactly how hepcidin timing affects iron absorption in training, that mechanism is covered in depth in a separate article. The clinical implication here is that iron deficiency can limit erythropoietic output regardless of EPO level, because the bone marrow lacks the raw substrate for hemoglobin synthesis.
Polycythemia workup. Elevated hemoglobin and hematocrit triggers a standard clinical question in any patient: is this physiological or pathological? A suppressed erythropoietin level supports polycythemia vera (PV), while elevated EPO points more toward secondary causes such as hypoxemia, OSA, or EPO-secreting tumors. However, a 2019 retrospective study of 138 patients found important limitations: of 75 patients with confirmed PV, 32% had EPO levels within the normal range, and erythropoietin level positively correlated with obesity and smoking status, making it an unreliable diagnostic marker in those patients [7]. Positive JAK2V617F mutation demonstrated a strong predictive value for PV (OR 670.5, p = 0.006), supporting the central role of JAK2 mutation testing in the diagnostic workup of suspected PV [7].
At this point, it is important to emphasize a common misconception encountered in practice. As a clinician, I often find myself having to remind athletes and coaches that erythropoietin is not a clinically meaningful marker of athletic performance. In athletes, there is generally no indication to measure EPO levels in the context of performance assessment or training optimization. EPO testing belongs strictly to the clinical domain, where it is used as part of the diagnostic evaluation of specific medical conditions. In other words, sport itself is not a valid reason to measure EPO — testing is justified only when there is a clear clinical indication related to disease.
Erythropoietin Doping in Athletes: Detection and the Biological Passport
Recombinant human erythropoietin (rHuEPO) became readily available in Europe in the late 1980s, and its use in sports was banned in the early 1990s [8]. Its initial medical application was treating anemia in chronic renal dysfunction, and erythropoietin is a naturally produced glycoprotein hormone that stimulates erythropoiesis by acting on erythroid progenitor cells [1]. The performance rationale for its misuse is well documented. A 2025 systematic review of 10 trials in well-trained endurance athletes found that regardless of the total dose administered, rHuEPO consistently improved total hemoglobin mass, hemoglobin concentration, and hematocrit, alongside VO2max and VO2peak [1].
However, evidence for rHuEPO’s impact on submaximal performance parameters remains inconclusive, and improvements are almost exclusively seen during maximal exercise intensities, which may be less relevant to actual competition conditions [8].
Detection approaches. Anti-doping methods can distinguish recombinant from endogenous erythropoietin using specialized laboratory techniques, though the detection window is limited, and athletes using microdosing protocols have historically been able to exploit this narrow window.
The response was the development of longitudinal monitoring. Blood transfusions and erythropoiesis stimulating agents such as erythropoietin are among the primary targets of the Athlete Biological Passport (ABP); biomarkers connected to the haematopoietic system — particularly haemoglobin concentration and reticulocytes — are monitored over time using mathematical models to identify patterns suspicious of doping [9]. Rather than trying to catch the drug itself, the ABP tracks whether an athlete’s markers deviate from their own established individual baseline — a far harder target to evade.
Altitude training is considered one of the main confounding factors in the variability of the ABP model, as the associated changes in haemoglobin, reticulocyte percentage, and related markers resulting from hematological adaptation to the hypoxic condition may result in the individual limits of the ABP being exceeded [10]. This is precisely why altitude exposure is an important factor in ABP interpretation — legitimate physiological erythropoietin rises from altitude present differently in longitudinal context compared to typical blood doping patterns.
Erythropoietin has also been central to some of the most well-known doping cases in endurance sports — something many will recall from cross-country skiing, particularly the 2001 World Championships in Lahti involving Finnish athletes. In that case, several athletes tested positive for the use of hydroxyethyl starch (HES), a plasma volume expander used to dilute blood parameters. At the time, advances in anti-doping testing made it possible to reliably detect such agents, which played a key role in the sanctions that followed. Its misuse increases red blood cell production and can lead to a rise in hematocrit, which is one of the key markers monitored in anti-doping. In response, various masking strategies have been used, including the administration of plasma volume expanders such as HES to dilute blood parameters. The detection of such agents was later incorporated into anti-doping protocols, and their use has contributed to several high-profile sanctions as testing methods improved.
Conclusion
Erythropoietin sits at a unique intersection of physiology, clinical medicine, and sports ethics. In athletes, it represents a natural adaptive signal — rising with hypoxic exposure, interacting with iron availability, and contributing to the body’s capacity to transport oxygen. In clinical practice, however, it remains a targeted diagnostic tool, used selectively to clarify underlying disease processes rather than to assess performance.
At the same time, erythropoietin has played a central role in the history of endurance sport doping, driving both performance enhancement strategies and the evolution of increasingly sophisticated detection methods. The development of longitudinal monitoring through the Athlete Biological Passport reflects a shift away from single-point measurements toward individualized biological patterns, highlighting just how complex the interpretation of hematological data has become.
For clinicians, coaches, and athletes alike, the key takeaway is this: erythropoietin cannot be understood in isolation. Its meaning depends entirely on context — physiological, clinical, or regulatory. Interpreting EPO correctly requires not just a number on a lab report, but an understanding of the underlying biology, the clinical picture, and the broader framework in which that number exists.
About the Author
Dr. Antti Rintanen, MD, MSc (IEM)
Dr. Antti Rintanen is a licensed medical doctor from Finland with a Master’s degree in Industrial Engineering and Management. He has a research background in orthopedic surgery and public health economics, and extensive clinical experience across both public hospitals and private healthcare providers. A former World Champion in Taekwon-Do and multiple-time World Cup titleholder in kickboxing, Dr. Rintanen brings a unique perspective bridging clinical medicine and elite athletic performance. He is the founder of drantti.com, a platform dedicated to providing clear, reliable, and evidence-based medical information.
Connect with Dr. Rintanen on LinkedIn
Bibliography
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