ArticleLiterature Review

Erythropoietin doping in cycling: Lack of evidence for efficacy and a negative risk-benefit

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

AIM & METHODS: Imagine a medicine that is expected to have very limited effects based upon knowledge of pharmacology and (patho)physiology, is studied in the wrong population, with low quality studies that use a surrogate endpoint that relates to the clinical endpoint in a partial manner at most. Such a medicine would surely not be recommended. Recombinant human erythropoietin (rHuEPO) use to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to look at the evidence for these ergogenic properties of this drug normally used to treat anaemia in chronic renal failure patients. RESULTS: The results of this literature search show there is no scientific basis to conclude rHuEPO has performance enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side-effects have not been adequately researched for this population but appear to be worrying at least. CONCLUSIONS: rHuEPO use in cycling is rife but scientifically unsupported by evidence and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well controlled trial in athletes under real life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification that this would eradicate its use.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... However, systematic evidence that this translates into a positive effect on performance is limited. 77,78 • Birkeland et al. 79 demonstrated an increase in both haematocrit and VO 2max following administration of rhEPO over 4 weeks in a double-blind placebo-controlled study with only a small cohort of trained cyclists (n = 10). This period was needed to demonstrate a large treatment effect [42.7 vs. 50.8% ...
... 83 Cardiac side effects occurring in athletes with 'haematologic doping' (especially if they are dehydrated and exposed to strenuous exercise) are secondary to the circulatory overload, induced by the increased erythroid mass, increased blood viscosity, and altered endothelial and platelet function with possible thromboembolic events and hypertension during effort. 70,77 Additionally, it increases blood viscosity, coagulation, and platelet reactivity leading to an increased risk of thrombosis. 84 Some case reports of thromboembolic events as well as acute coronary syndrome with intraventricular thrombus in athletes following rhEpo doping have been reported. ...
... It was suggested that this effect is dose-dependent. 120 Table 2 Adverse cardiovascular effect of common legal nutritional supplements in sports [65][66][67][68][69][70]74,75,77 Caffeine alone has been shown to be effective for the improvement of aerobic capacity in endurance athletes 119 but the 'more is better' philosophy, when applied to caffeine use in sports, may result in side effects that outweigh the performance benefits. Optimal performance benefits are usually achieved with intakes of 3-6 mg/kg (approximately 2-4 cups) and side effects become more common with caffeine doses over 9 mg/kg of body mass. ...
Article
The use of substances and medications with potential cardiovascular effects among those practicing sports and physical activity has progressively increased in recent years. This is also connected to the promotion of physical activity and exercise as core aspects of a healthy lifestyle, which has led also to an increase in sport participation across all ages. In this context, three main users' categories can be identified, (i) professional and amateur athletes using substances to enhance their performance, (ii) people with chronic conditions, which include physical activity and sport in their therapeutic plan, in association with prescribed medications, and (iii) athletes and young individuals using supplements or ergogenic aids to integrate their diet or obtaining a cognitive enhancement effect. All the substances used for these purposes have been reported to have side effects, among whom the cardiovascular consequences are the most dangerous and could lead to cardiac events. The cardiovascular effect depends on the type of substance, the amount, the duration of use, and the individual response to the substances, considering the great variability in responses. This Position Paper reviews the recent literature and represents an update to the previously published Position Paper published in 2006. The objective is to inform physicians, athletes, coaches, and those participating in sport for a health enhancement purpose, about the adverse cardiovascular effects of doping substances, commonly prescribed medications and ergogenic aids, when associated with sport and exercise.
... A qualitative systematic review of the available literature was performed in 2012 to examine the evidence for the performance enhancing properties of rHuEPO in cyclists. [4] The review demonstrated that the characteristics of the study populations differed from the population suspected of rHuEPO abuse. Studies did not use well-trained cyclists, still less elite or world-class cyclists. ...
... A review of the available literature showed that, after initial years of training, well-trained athletes maintain a plateau in their VO2,max, but continue to improve their performance. [4] This indicates that the difference between effects on VO2,max between the NeoRecormon and placebo group in well-trained cyclists might be smaller. The smaller the size of the difference, the larger the sample size must be to detect a significant difference. ...
... A qualitative systematic review of the available literature was performed in 2012 to examine the evidence for the performance enhancing properties of rHuEPO in cyclists. [4] The review demonstrated that the characteristics of the study populations differed from the population suspected of rHuEPO abuse. rHuEPO studies often used untrained or moderately trained cyclists. ...
Data
Full-text available
Study protocol CHDR1514. (PDF)
... However, this is only one part of the story because we could also ask whether it is necessary or scientifically sound to apply clinical pharmacological standards to the testing of performanceenhancing effects of substance classes, as we argue below. The review by Heuberger and Cohen [2] is partially reliant on the outcome of a study by the same group that investigated the performance-enhancing effect of erythropoietin (EPO) on cycling in a time trial and a typical mountainstage race [5]. Interestingly, their study conducted in the typical fashion of a randomized controlled trial against placebo failed to demonstrate an effect, while suggesting effects on surrogate parameters of performance in the same manner as other previous studies. ...
... Moreover, if these outcome measures are not tested in an elite cohort subjected to factors that typically accompany EPO use, such as losing weight, as well as increasing the duration and intensity, and modifying the structure of training sessions, how could they be regarded as more valid outcome measures than, for instance, maximal oxygen consumption or submaximal performance traits related to lactate steady state measured in a laboratory test? In other words, the EPO study by Heuberger et al. [5] may have had an excellent internal validity but its external validity might have been so low that a presumably negative outcome should not be accorded great significance. Doping experts in the field certainly are aware of some practical advantages of administering EPO to cyclists. ...
... The problem here is that Heuberger et al. [5] apply inductive reasoning for verifying a performance-enhancing effect of a very concrete doping procedure. This assumes that dopers behave like patients who would subsequently receive EPO prescribed under medical supervision. ...
... To reach some solid, yet preliminary answers concerning the validity of the SPA, we therefore decided to statistically estimate the ergogenic effects of RBC–augmenting doping agents on riders' aerobic performances and the corresponding improvements in cycling speeds by conducting a meta–analysis of epo studies [36]. Kuipers [13] already contended that effects of RBC–doping aids on cyclists' maximal aerobic power output (W map ) are overestimated, while Heuberger et al. [53] even maintain that the epo doping – aerobic performance hypothesis is not supported by empirical evidence. In our meta–analysis, we evaluated findings of seventeen laboratory studies and assessed effect sizes (unbiased d, r and r 2 ) of the epo–stimulated increases in VO 2max and W map . ...
... However, Hopkins et al. [52] strongly warn against directly generalizing this increase to actual races. Additionally, Heuberger et al. [53] and Lodewijkx et al. [36] argue that the epo/blood doping– aerobic performance relationship suffers from external, ecological, and predictive validity problems. For instance, the relationship becomes very limited if we consider the well–known fact that elite athletes, such as professional cyclists, are estimated to be able to exercise at peak VO 2max levels for approximately ten minutes before reaching the different stages in the lactate threshold [54]. ...
... Nevertheless, we argue that awareness of our empirical observations and their implications would greatly contribute to the exchange of evidence–based pros and cons in the sometimes frenzied, societal discussions about the effects of doping in the cycling world, set in motion by the Armstrong affair. Moreover, Kuipers [13] and Heuberger et al. [53] might not be mistaken in their final conclusion that the doping problem in professional cycling indeed rests on superstition, hearsay, insufficient knowledge, medical malpractice, and lack of (opposing) empirical evidence. On balance, the sportive feats demonstrated by riders in the years of the 'epo epidemic' were not exceptional at all, despite their doping use. ...
Article
Full-text available
The massive doping schemes that surfaced in professional cycling suggest that riders' performances, realized in the controversial 'epo era' (>1990), are a cut above achievements delivered by their forerunners. We examined this superior performances assumption (SPA) by conducting six historic studies, which all scrutinized archival records of winning riders' stage race and time trial performances demonstrated in the three European Grand Tours (Tour de France, Giro d'Italia, and Vuelta a España; 1903–2013), including Lance Armstrong's wins. Findings revealed that all riders' wins in the epo years are no exception to the variability in speed progress observed in the three races over time and none of their achievements proved to be outliers. This also holds true for Armstrong's performances. These findings agree with results of a meta–analysis of epo studies we conducted, indicating that the ergogenic effects of epo and blood doping on riders' aerobic performances and associated cycling speeds are overrated. In conclusion, we argue that our observations render the SPA doubtful. They also made us realize that arguments used in contemporary discussions about effects of doping in cycling often involve psychological biases, false reasoning, and fabrications. They are presented in the closing sections of this contribution.
... The rHuEPO is one of the most widely used drugs to improve performance in sport by increasing the circulating red blood cells and the consequent oxygen delivery to muscles [7,27]. Sports authorities prohibited the use of rHuEPO in 1988. ...
... Sports authorities prohibited the use of rHuEPO in 1988. Athletes who abuse erythropoietin consider only the benefit to performance and usually ignore the potential short-and long-term liabilities [8,9,27]. The artificial increase in red blood cells count and hematocrit, further enhanced by dehydratation during prolonged exercise, predisposes to thromboembolic complications which might be connected to sudden death in sport practice [10]. ...
... But, parallel to this therapeutic use, its administration in sports as doping has unfortunately spread. Indeed, some athletes use recombinant human erythropoietin illicitly, at high doses, to boost the delivery of oxygen to the tissues and enhance their performance in endurance sports [7][8][9]27,28]. However, serious problems can arise with administration of rHuEPO. ...
Article
Although many studies highlight how long-term moderate dose of Recombinant Human Erythropoietin (rHuEPO) treatments result in beneficial and antioxidants effects, few studies take into account the effects that short-term high doses of rHuEPO (mimicking abuse conditions) might have on the oxidative stress processes. Thus, the aim of this study was to investigate the in vivo antioxidant activity of rHuEPO, administered for a short time and at high doses to mimic its sports abuse as doping. Male Wistar healthy rats (n = 36) were recruited for the study and were treated with three different concentrations of rHuEPO: 7.5, 15, 30 μg/kg. Plasma concentrations of erythropoietin, 8-epi Prostaglandin F2α, plasma and urinary concentrations of NOx were evaluated with specific assay kit, while hematocrit levels were analyzed with an automated cell counter. Antioxidant activity of rHuEPO was assessed analyzing the possible variation of the plasma scavenger capacity against hydroxylic and peroxylic radicals by TOSC (Total Oxyradical Scavenging Capacity) assay. Statistical analyses showed higher hematocrit values, confirmed by a statistically significant increase of plasmatic EPO concentration. An increase in plasma scavenging capacity against peroxyl and hydroxyl radicals, in 8-isoprostane plasmatic concentrations and in plasmatic and urinary levels of NOX were also found in all the treated animals, though not always statistically significant. Our results confirm the literature data regarding the antioxidant action of erythropoietin administered at low doses and for short times, whereas they showed an opposite incremental oxidative stress action when erythropoietin is administered at high doses.
... They argue that time trial performances are nearly perfectly and linearly related to riders' maximal oxygen uptake (VO 2 max) and the corresponding power output (W). Therefore, they assessed time differences between the first-, second-, and fiftieth-ranking riders in the trials and compared their results to data relating to the proposed ergogenic effects of epo, reported by Heuberger et al. (2012). In strong disagreement with conclusions drawn by Perneger, Lippi et al., and the CIRC-report, they maintain that the (assumed) illicit use of epo doping conceivably could still have led to performance enhancement in the trials since 2000. ...
... None of riders' achievements in the epo years proved to be outliers. What is more, Lodewijkx (2014) argued that the findings of his research agreed with results of two metaanalyses of epo studies (Heuberger et al., 2012;Lodewijkx, Brouwer, Kuipers & Van Hezewijk, 2013) from which the authors concluded that the performance-enhancing effects of red blood cell-augmenting doping agents (i.e., epo and blood doping) on riders' aerobic performances and associated speeds realized in actual races are far from decisive and most probably are overrated. ...
... However, in their systematic meta-analysis of seventeen epo studies, reported 6-7% improvements in VO 2 max and 7-8% increases in the related power output measure (W). Last, in their qualitative meta-analysis, Heuberger et al. (2012) arrived at 7-9.7% increases in VO 2 max due to epo treatment. The same scholars, however, are very critical about the epo doping-performance relationship. ...
Research
Full-text available
The 2015 report of the Cycling Independent Reform Commission (CIRC) contends that cyclists’ use of epo doping resulted in 10-15% performance gains in the epo era (late 1980s-2001), suggesting that performances delivered in cycling races in these years will be superior to preceding years (the SPA, or superior performances assumption). Due to progressively stricter anti-doping testing in the 2000-2010s, the report further states that riders’ performances in this period decreased relative to the epo years (the DPA, or decline in performances assumption). We examined both assumptions by subjecting winning riders’ mean km/h performances, realized in time trials on flat and rolling courses in the Tour de France (1934-2013), to time-series analyses (ARIMA). We additionally assessed annual progress rates in performance (%) by computing differences in riders’ mean km/h per year. ARIMA explained R2 = 0.996 of the variation in the rates. Cyclical performance sequences (partial ρlag 2= -0.87, p ≤ 0.001) indicated that decisions of the Tour organizers to regularly alternate the lengths of the trials accounted for differences in riders’ achievements. As a single variable, competition year explained 92% (r = 0.96) in these differences with an annual growth of 0.45% (p ≤ 0.01). Larger distances weakly and negatively influenced riders’ progress in performance, b = -2% (p = 0.08). The epo vs. non-epo years yielded no significant growth differences, b = 0.10% (p = 0.74), while the progress in the 2000-2010s did not decline compared to the foregoing years, b = 0% (p = 0.93). Strongly contradicting the CIRC-report, the rapid growth in performance did not start in the 1990s, but in the 1980s. A significant quadratic relationship (R2 = 0.50, p ≤ 0.05) further revealed a reversal of the SPA and DPA: Riders’ progress in performance flattened after the mid-1990s and improved again in the 2010s. Speculatively, findings suggest that the use of epo doping might have blocked riders’ performances. This would explain why riders’ time trial feats tend to improve in the 2010s, that is, after the introduction and subsequent successful deterrent effect of the Athlete Biological Passport in professional road racing. Keywords: Doping; Performance enhancement; Professional cycling; Time trials
... Non-HIF pathways that can alter EPO production include kinase C, GATA-2, nuclear factor kappa B (NFB) pathways (7,9). Baseline EPO concentration can raise up to 1000 fold in hypoxic conditions (10). In healthy individuals, reference EPO range is usually between 1 and 27 mU/ml, while patients with chronic kidney disease (CKD) can have much higher values, but inappropriately low related to the degree of anaemia, and with inadequate response to it because of the resistance (9). ...
... First erythroid progenitor cell expressing EPO receptor is colony forming unit erythroid cell (CFU-E), which further proliferates and differentiates, until 16 mature erythrocytes occur (1,10,13). In the state of intensive erythropoiesis the need of iron for haemoglobin (Hb) synthesis is elevated. ...
... This type of training and EPO both stimulate a shift in skeletal muscle, from a fast glycolytic to a slower oxidative phenotype, by inducing mitochondrial biogenesis, which also improves aerobic exercise capacity (28,31,32). Haemoglobin concentration rises because of increased erythrocytes mass, and decreased plasma volume during exercise (10). Altitude exposure is a well known legal stimulus of erythropoiesis. ...
Article
Full-text available
Erythropoietin is a hormone that promotes the formation of red blood cells by the bone marrow. In adults it is mainly produced by the kidneys as a response to hypoxia. Besides its main role, it also acts as antiapoptotic, anti-inflammatory and cytoprotective agent. Furthermore, it is produced in many non-hematopoietic tissues where it acts locally, stimulating angiogenesis. Erythropoietin binds cytokine receptors on target cells, such as erythrocyte precursor cells, neurons, glial and endothelial cells, cardiomyocytes, myocytes etc. The discovery of synthetic erythropoietin forms, in the late eighties of the last century, has significantly improved treatment outcome of patients with anaemia related to chronic diseases, especially chronic renal failure. Renal anaemia is multifactorial, but predominantly a consequence of erythropoietin deficiency. Today, three generations of erythropoiesis stimulating agents are available, differing in glycosylation pattern, molecular size, half-life and modes of administration and dosage. In anaemic patients this therapy significantly improves their quality of life, but may also have serious, potentially dangerous adverse effects. Synthesis of recombinant human erythropoietin, on the other hand, has improved possibilities for manipulations in sport, in the field of blood doping. Erythropoietin administration in athletes increases their maximum oxygen consumption capacity, improves endurance and performance, especially in aerobic exercise. This seriously undermines the spirit of sport, and also endangers athletes' health. Different anti-doping tests have been developed and used, still with limited success. At the same time, new illicit ways of malpractice are developing, such as variuos models of gene doping. Therefore, providing new models of anti-doping tests and strategies, together with better health control of athletes, still remains a considerable challenge.
... How can we settle these findings with generally shared opinions concerning, for instance, the proposed powerful ergogenic effects of epo doping on cyclists' performances? Our reply would be that this relationship is overvalued (Kuipers, 2006;Lodewijkx, Brouwer, Kuipers, & Van Hezewijk, 2013) and might even lack scientific evidence (Heuberger et al., 2012). To critically examine the strength of this relationship, conducted a meta-analysis on the findings of seventeen laboratory studies that hitherto investigated this relationship. ...
... However, we emphasize that this slight increase is solely restricted to laboratory situations. It is a well-known fact that such improvements cannot be directly extrapolated to multi-stage cycling races that last three weeks (Heuberger et al. 2012;Hopkins, Hawley, & Burke, 1999;. All these observations imply that judgments pertaining to the strong ergogenic effects of epo doping on aerobic exercise capacity are far from conclusive. ...
... In their meta-analysis, questioned the validity and generality of findings of the epo laboratory studies in which nearly 90% of the participants were non-athletes. Consistent with suggestions put forward by Joyner and Coyle (2008) and Heuberger et al. (2012) future research should concentrate on studying effects of banned doping aids in professional cyclists performing in real or simulated competitions. Perhaps, the ensuing results would provide some definite answers to the issues raised by our study. ...
Article
Full-text available
Studies examining effects of doping in professional road racing building on archival records of the three major European stage races — the Tour de France, Giro d'Italia, and Vuelta a España — concluded that riders' final performances in the 'epo era' (> 1990) strongly improved, yet declined since 2004. However, these observations can be criticized on methodological grounds. First, the current study concentrates on the criterion used in these 'historic' studies to indirectly examine effects of doping agents on riders' speed, arguing that time trial performances are more valid than final performances to evaluate these effects. Second, we will pay attention to an informal logical flaw — the Texas sharpshooter fallacy — which may have biased findings and conclusions presented in the studies. To empirically substantiate our critique, we analyzed mean kilometers per hour (km/h) performances realized by winning riders in all time trials on flat and rolling terrain in the three tours (1933–2013, N = 325). Regression analyses revealed no evidence for non–linear in– or decreases in riders' speed beyond the 1990s, but a straightforward linear progress over time of b = 0.16 km/h per year (R 2 = 0.50, p ≤ .001). Findings corroborate our comments on previous archival studies and qualify opinions about effects of the 'epo epidemic' on cyclists' achievements, since the time trial performances delivered in these years are no exemption to the observed linear progress in speed.
... They argue that time trial performances are nearly perfectly and linearly related to riders' maximal oxygen uptake (VO 2 max) and the corresponding power output (W). Therefore, they assessed time differences between the first-, second-, and fiftieth-ranking riders in the trials and compared their results to data relating to the proposed ergogenic effects of epo, reported by Heuberger et al. (2012). In strong disagreement with conclusions drawn by Perneger, Lippi et al., and the CIRC-report, they maintain that the (assumed) illicit use of epo doping conceivably could still have led to performance enhancement in the trials since 2000. ...
... None of riders' achievements in the epo years proved to be outliers. What is more, Lodewijkx (2014) argued that the findings of his research agreed with results of two metaanalyses of epo studies (Heuberger et al., 2012;Lodewijkx, Brouwer, Kuipers & Van Hezewijk, 2013) from which the authors concluded that the performance-enhancing effects of red blood cell-augmenting doping agents (i.e., epo and blood doping) on riders' aerobic performances and associated speeds realized in actual races are far from decisive and most probably are overrated. ...
... However, in their systematic meta-analysis of seventeen epo studies, reported 6-7% improvements in VO 2 max and 7-8% increases in the related power output measure (W). Last, in their qualitative meta-analysis, Heuberger et al. (2012) arrived at 7-9.7% increases in VO 2 max due to epo treatment. The same scholars, however, are very critical about the epo doping-performance relationship. ...
Research
Full-text available
The 2015 report of the Cycling Independent Reform Commission (CIRC) contends that cyclists’ use of epo doping resulted in 10-15% performance gains in the epo era (late 1980s-2001), suggesting that performances delivered in cycling races in these years will be superior to preceding years (the SPA, or superior performances assumption). Due to progressively stricter anti-doping testing in the 2000-2010s, the report further states that riders’ performances in this period decreased relative to the epo years (the DPA, or decline in performances assumption). We examined both assumptions by subjecting winning riders’ mean km/h performances, realized in time trials on flat and rolling courses in the Tour de France (1934-2013), to time-series analyses (ARIMA). We additionally assessed annual progress rates in performance (%) by computing differences in riders’ mean km/h per year. ARIMA explained R2 = 0.996 of the variation in the rates. Cyclical performance sequences (partial ρlag 2= -0.87, p ≤ 0.001) indicated that decisions of the Tour organizers to regularly alternate the lengths of the trials accounted for differences in riders’ achievements. As a single variable, competition year explained 92% (r = 0.96) in these differences with an annual growth of 0.45% (p ≤ 0.01). Larger distances weakly and negatively influenced riders’ progress in performance, b = -2% (p = 0.08). The epo vs. non-epo years yielded no significant growth differences, b = 0.10% (p = 0.74), while the progress in the 2000-2010s did not decline compared to the foregoing years, b = 0% (p = 0.93). Strongly contradicting the CIRC-report, the rapid growth in performance did not start in the 1990s, but in the 1980s. A significant quadratic relationship (R2 = 0.50, p ≤ 0.05) further revealed a reversal of the SPA and DPA: Riders’ progress in performance flattened after the mid-1990s and improved again in the 2010s. Speculatively, findings suggest that the use of epo doping might have blocked riders’ performances. This would explain why riders’ time trial feats tend to improve in the 2010s, that is, after the introduction and subsequent successful deterrent effect of the Athlete Biological Passport in professional road racing. Keywords: Doping; Performance enhancement; Professional cycling; Time trials
... Recently, Heuberger et al., have also concluded from reviewing the literature that there is no scientific basis to assume that rhEpo has performance-enhancing properties in elite cyclists [20]. According to these investigators, only five of 23 substance classes on the WADA Prohibited List [3] show robust evidence of having the ability to enhance sports performance, namely anabolic agents, β 2 -adrenergic agonists, stimulants (amphetamines, methylphenidate) glucocorticoids and β-blockers [21]. ...
... Increased RBC concentrations are associated with an elevation in Hct, which in previously anemic patients predisposes to CHF, MI, seizures and pulmonary embolism [78]. The side effects of the use of ESAs in athletes have not been extensively researched [20]. There was rumor that rhEpo was responsible for the cardiac death of 18 young Dutch and Belgian cyclists in the late 1980s and early 1990s. ...
Article
Full-text available
The total mass of hemoglobin (Hb mass) correlates with the rate of maximal O 2 uptake (VO 2max). Recombinant human erythropoietin (rhEpo) and other erythropoiesis stimulating agents (ESAs) increase the number of circulating red blood cells (RBCs), Hb mass and hematocrit (Hct). ESAs are misused by cheating athletes to increase Hb mass. The World Anti-Doping Agency (WADA) has prohibited the misuse of ESAs. VO 2max is also dependent on the cardiac output and the rate of peripheral O 2 extraction. Preclinical studies purported non-erythropoietic cytoprotective effects of ESAs in the cardiovascular system. However, none or very little Epo receptor protein (EpoR) is expressed by normal cardiovascular tissues. Placebo-controlled clinical trials have failed to confirm beneficial health effects of ESAs in patients with cardiac diseases other than increases in Hb levels. High-dose rhEpo treatment did not improve clinical outcomes of patients with heart failure, coronary syndrome, acute myocardial infarction or cardiac arrest. ESA doping may exert indirect cardiovascular effects associated with greater training loads in consequence of the increased arterial O 2 content. However, along with Hct, blood viscosity and peripheral flow resistance increase possibly causing arterial hypertension and disturbances in the microcirculation. Thus, rhEpo derivatives devoid of erythropoietic activity have attracted interest, such as asialo-Epo, carbamoylated Epo (CEPO), and ARA290. The tissue-protective effects of these compounds are proposedly mediated by a heterodimeric receptor composed of one EpoR molecule and one β common receptor molecule (syn.: CD131), called the innate repair receptor (IRR). Asialo-Epo and CEPO are specified in WADA's list as prohibited substances. However, none of the non-erythropoietic compounds has proved performance-enhancing potential in humans.
... Hence, rHuEpo is, allegedly, frequently subjected to abuse by athletes. Despite this overwhelming evidence, some authors continue to question the ergogenic potential of rHuEpo administration in elite athletes and contend that the performance-enhancing effect of rHuEpo is likely to be small or even non-existent (10,11). In the most recent of these studies, Heuberger et al (10) reported that rHuEpo administration enhanced O 2 max by 10% in well-trained cyclists but did not improve performance during submaximal exercise test or road race performance. ...
... Despite the overwhelming scientific evidence to support the ergogenic effects of rHuEpo, some question the application of these primarily laboratory findings to real-life competitive conditions or races involving elite athletes (10,11). For example, Heuberger et al (10) reported that while performance was enhanced in laboratory-based high intensity tests, endurance and road race performances were similar between rHuEpo and placebo groups questioning a multitude of findings which state otherwise (1)(2)(3)(4)(5)(6)(7)(8). ...
Article
Introduction: Recombinant human erythropoietin (rHuEpo) administration enhances oxygen carrying capacity and performance at sea level. It remains unknown whether similar effects would be observed in chronic altitude-adapted endurance runners. The aim of this study was to assess the effects of rHuEpo on haematological and performance parameters in chronic altitude-adapted endurance runners as compared to sea level athletes. Methods: Twenty well-trained Kenyan endurance runners (KEN) living and training at ~2,150 m received rHuEpo injections of 50 IU[BULLET OPERATOR]kg-1 body mass every 2 days for 4 weeks and responses compared to another cohort (SCO) that underwent an identical protocol at sea level. Blood samples were obtained at baseline, during rHuEpo administration and 4 weeks after the final injection. A maximal oxygen uptake ( O2max) test and 3,000 m time trial was performed before, immediately after and 4 weeks after the final rHuEpo injection. Results: Haematocrit (HCT) and haemoglobin concentration (HGB) were higher in KEN compared to SCO prior to rHuEpo but similar at the end of administration. Prior to rHuEpo administration, KEN had higher V˙O2max and faster time trial performance compared to SCO. Following rHuEpo administration, there was a similar increase in V˙O2max and time trial performance in both cohorts; most effects of rHuEpo were maintained 4 weeks after the final rHuEpo injection in both cohorts. Conclusion: Four weeks of rHuEpo increased the HGB and HCT of Kenyan endurance runners to a lesser extent than in SCO (~17% vs ~10%, respectively) and these alterations were associated with similar improvements in running performance immediately after the rHuEpo administration (~5%) and 4 weeks after rHuEpo (~3%).
... In a recent review counting only findings from (i) double-blind, randomized controlled trials that were (ii) performed in trained subjects, and (iii) measured relevant sporting performance outcomes as evidence for performanceenhancing effects, Heuberger and Cohen [27] concluded that only five out of the 23 substance classes prohibited by WADA show evidence of having the ability to enhance actual sports performance. For instance, although EPO is often cited as a paradigmatic example of a performance-enhancing drug, these authors argue that there is a lack of high quality evidence for its performance-enhancing effects in elite athletes [27,28]. ...
... EPO administration can clearly increase performance without the need to train, at least in non-athletes". Furthermore, they also note that a similar effect has been observed in trained cyclists [28]. 10 In contrast, they suggest that "training is crucial to making significant changes in performance using tDCS" [11]. ...
Article
Full-text available
There is increasing interest in using neuro-stimulation devices to achieve an ergogenic effect in elite athletes. Although the World Anti-Doping Authority (WADA) does not currently prohibit neuro-stimulation techniques, a number of researchers have called on WADA to consider its position on this issue. Focusing on trans-cranial direct current stimulation (tDCS) as a case study of an imminent so-called ‘neuro-doping’ intervention, we argue that the emerging evidence suggests that tDCS may meet WADA’s own criteria (pertaining to safety, performance-enhancing effect, and incompatibility with the ‘spirit of sport’) for a method’s inclusion on its list of prohibited substances and methods. We begin by surveying WADA’s general approach to doping, and highlight important limitations to the current evidence base regarding the performance-enhancing effect of pharmacological doping substances. We then review the current evidence base for the safety and efficacy of tDCS, and argue that despite significant shortcomings, there may be sufficient evidence for WADA to consider prohibiting tDCS, in light of the comparable flaws in the evidence base for pharmacological doping substances. In the second half of the paper, we argue that the question of whether WADA ought to ban tDCS turns significantly on the question of whether it is compatible with the ‘spirit of sport’ criterion. We critique some of the previously published positions on this, and advocate our own sport-specific and application-specific approach. Despite these arguments, we finally conclude by suggesting that tDCS ought to be monitored rather than prohibited due to compelling non-ideal considerations.
... The performance-enhancing effect is attributed to improvements in the blood O 2 carrying capacity because an increase in maximum O 2 uptake (VO 2max ) by 5-10 % was observed after 4 weeks of treatment (Russell et al. 2002;Thomsen et al. 2007). However, a recent qualitative systematic review questions its effectiveness in elite cyclists (Heuberger et al. 2013). Endurance competitions are performed at a wide range of submaximum intensities rather than at intensities near V O 2max . ...
... This finding indicates that endurance exercise training is only a small and slow stimulus for erythropoietic activity in trained athletes (Prommer et al. 2008) in contrast to untrained subjects (Sawka et al. 2000). The increase of total haemoglobin mass or the blood O 2 carrying capacity is an important factor for increasing V O 2max but neither parameter correlates with the improved endurance performance observed in elite athletes (Heuberger et al. 2013). ...
Article
Full-text available
Purpose: Erythropoietin (EPO) controls red cell volume (RCV) and plasma volume (PV). Therefore, injecting recombinant human EPO (rhEPO) increases RCV and most likely reduces PV. RhEPO-induced endurance improvements are explained by an increase in blood oxygen (O2) transport capacity, which increases maximum O2 uptake ([Formula: see text]O2max). However, it is debatable whether increased RCV or [Formula: see text]O2max are the main reasons for the prolongation of the time to exhaustion (t lim) at submaximal intensity. We hypothesized that high rhEPO doses in particular contracts PV such that the improvement in t lim is not as strong as at lower doses while [Formula: see text]O2max increases in a dose-dependent manner. Methods: We investigated the effects of different doses of rhEPO given during 4 weeks [placebo (P), low (L), medium (M), and high (H) dosage] on RCV, PV, [Formula: see text]O2max and t lim in 40 subjects. Results: While RCV increased in a dose-dependent manner, PV decreased independent of the rhEPO dose. The improvements in t lim (P +21.4 ± 23.8 %; L +16.7 ± 29.8 %; M +44.8 ± 62.7 %; H +69.7 ± 73.4 %) depended on the applied doses (R (2) = 0.89) and clearly exceeded the dose-independent [Formula: see text]O2max increases (P -1.7 ± 3.2 %; L +2.6 ± 6.8 %; M +5.7 ± 5.1 %; H +5.6 ± 4.3 %) after 4 weeks of rhEPO administration. Furthermore, the absolute t lim was not related (R (2) ≈ 0) to RCV or to [Formula: see text]O2max. Conclusions: We conclude that a contraction in PV does not negatively affect t lim and that rhEPO improves t lim by additional, non-hematopoietic factors.
... Hence, on this basis, the present work has been performed to study the ex vivo effects of rhEPO in a small cohort of young and healthy individuals (15 males and 14 females). Platelet reactivity and aggregation patterns which, in turn, may cause thrombotic disorders [3], have been evaluated. ...
... The available literature does not have the appropriate information to conclude that rHuEPO enhances worldclass cycling performance, as tackled by the systematic review of Heuberger and colleagues. 2 The oxygencarrying capacity of blood is critically important for endurance exercise 3 and the new red blood cells produced by rHuEPO treatment increase the body's maximum oxygen uptake (VO 2 max), which is the gross criterion of performance capacity of the cardiopulmonarymetabolic system. The effect of rHuEPO on professional cyclists has, for obvious reasons, never been scientifically documented in depth with standard clinical trials. ...
... We did this trial 1 to add to the limited scientific evidence regarding rHuEPO in sports. 2 Some of our methods have not been used before, and the combination of several modalities (maximal, submaximal, and road race www.thelancet.com/haematology Vol 4 October 2017 e463 ...
... In particular, the erythropoietin (EPO) gene can be abused in gene doping because EPO and EPO-related formulations had history that it is frequently used in doping to enhance the endurance performance of athletes in cycling, boxing, athletics, and rowing [12][13][14][15][16]. Thus, EPO and EPO-related formulations are included on the "International Standard Prohibited List" [3] published by WADA. ...
Preprint
The World Anti-Doping Agency (WADA) has prohibited gene doping in the context of progress in gene therapy. In addition, there is a risk of the EPO gene being applied in gene doping among athletes. Along with this, development of a gene-doping test has been underway in worldwide. Here, we had two purposes: to develop a robust gene doping mouse model using the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to prove gene doping using this model. The rAdV including the hEPO gene were injected intravenously to transfer the gene to the liver. After injection, the mice developed significantly increased red blood cell counts in whole blood and increased gene expressions of hematopoietic markers in the spleen, indicating successful development of the gene doping model. Next, we detected direct and indirect proof of gene doping in whole blood DNA and RNA using qPCR assay and RNA sequencing. Proof was detected in one drop of whole blood DNA and RNA over a long period; furthermore, the overall RNA expression profiles significantly changed. Therefore, we have advanced detection of hEPO gene doping in humans.
... In our aim to evaluate the effect of recombinant human erythropoietin (rHuEpo) administration on endurance performance we collected the evidence coming only from empirical trial. We did not include review and metanalysis studies on this topic because they do not provide new data; furthermore, some have structural bias and lack conclusive statements [31,32,33]. ...
Article
Full-text available
The present review provides a comprehensive overview on the erythropoietic and non-erythropoietic effects of rHuEpo on human sport performance, paying attention to quantifying numerically how rHuEpo affects exercise performance and describing physiological changes regarding the most important exercise variables. Much attention has been paid to treatment schedules, in particular, to assess the effects of microdoses of rHuEpo and the prolonged effects on sport performance following withdrawal. Moreover, the review takes into account non-erythropoietic ergogenic effects of rHuEpo, including cognitive benefits of rHuEpo. A significant increase in both Vo2max and maximal cycling power was evidenced in studies taken into account for this review. rHuEpo, administered at clinical dosage, may have significant effects on haematological values, maximal and submaximal physiological variables, whereas few reports show positive effects on exercise perfomance. However, the influence of micro-dose rHuEpo on endurance performance in athletes is still unclear and further studies are warranted.
... In a study looking at cyclists, EPO was found to increase hematocrit by close to 20%, with significant increases in endurance measures. 40 While the exercise benefits of EPO are real, so too are the serious side effects that can accompany its use. They include injection site reaction, nausea, headache, dizziness, arthralgias, increased blood pressure, and increased blood viscosity, which can lead to stroke, myocardial infarction, and even death. ...
Article
Full-text available
The preparticipation evaluation (PPE) is a widely used tool for detecting health conditions that may delay or disqualify athletic participation. The medical interview is the most valuable tool for identifying athletes who may be at increased risk for injury. Physical examination is tailored to identifying cardiac abnormalities or factors that may place an athlete at increased risk for injury. Although practiced in Europe, universal cardiac screening with electrocardiography is not currently recommended in the United States largely due to the high rate of false-positive results. Neuropsychological testing for management of concussion and laboratory testing for sickle cell trait may be indicated in select groups of athletes. Health care providers should view the PPE as a chance for anticipatory guidance and athlete-directed health counseling. Despite widespread acceptance of the PPE, the quality of such examinations varies significantly, which is an area for possible improvement and further research. © 2015 The Author(s).
... However, the evidence for the performanceenhancing effects of rHuEPO in high-level competitive sports is rather scarce. The evidence constitutes of small, often uncontrolled studies, 4 in arguably unrepresentative populations and is often inappropriately expressed only in exercise parameters that mainly evaluate maximal exercise performance. These tests are often of incremental intensity or at a very high intensity, and therefore lead to exhaustion, usually within 20 min. ...
Article
Background Substances that potentially enhance performance (eg, recombinant human erythropoietin [rHuEPO]) are considered doping and are therefore forbidden in sports; however, the scientific evidence behind doping is frequently weak. We aimed to determine the effects of rHuEPO treatment in well trained cyclists on maximal, submaximal, and race performance and on safety, and to present a model clinical study for doping research on other substances. Methods We did this double-blind, randomised, placebo-controlled trial at the Centre for Human Drug Research in Leiden (Netherlands). We enrolled healthy, well trained but non-professional male cyclists aged 18–50 years and randomly allocated (1:1) them to receive abdominal subcutaneous injections of rHuEPO (epoetin β; mean dose 6000 IU per week) or placebo (0·9% NaCl) for 8 weeks. Randomisation was stratified by age groups (18–34 years and 35–50 years), with a code generated by a statistician who was not masked to the study. The primary outcome was exercise performance, measured as maximal power output (Pmax), maximal oxygen consumption VO2 max, and gross efficiency in maximal exercise tests with 25 W increments per 5 min, as lactate threshold and ventilatory threshold 1 (VT1) and 2 (VT2) at submaximal levels during the maximal exercise test, and as mean power, VO2, and heart rate in the submaximal exercise tests at the highest mean power output for 45 min in a laboratory setting and in a race to the Mont Ventoux (France) summit, using intention-to-treat analyses. The trial is registered with the Dutch Trial Registry (Nederlands Trial Register), number NTR5643. Findings Between March 7, 2016, and April 13, 2016, we randomly assigned 48 participants to the rHuEPO group (n=24) or the placebo group (n=24). Mean haemoglobin concentration (9·6 mmol/L vs 9·0 mmol/L [estimated difference 0·6, 95% CI 0·4 to 0·8]) and maximal power output (351·55 W vs 341·23 W [10·32, 3·47 to 17·17]), and VO2 max (60·121 mL/min per kg vs 57·415 mL/min per kg [2·707, 0·911 to 4·503]) in a maximal exercise test were higher in the rHuEPO group compared with the placebo group. Submaximal exercise test parameters mean power output (283·18 W vs 277·28 W [5·90, −0·87 to 12·67]) and VO2 (50·288 mL/min per kg vs 49·642 mL/min per kg [0·646, −1·307 to 2·600]) at day 46, and Mont Ventoux race times (1 h 40 min 32 s vs 1 h 40 min 15 s [0·3%, −8·3 to 9·6]) did not differ between groups. All adverse events were grade 1–2 and were similar between both groups. No events of grade 3 or worse were observed. Interpretation Although rHuEPO treatment improved a laboratory test of maximal exercise, the more clinically relevant submaximal exercise test performance and road race performance were not affected. This study shows that clinical studies with doping substances can be done adequately and safely and are relevant in determining effects of alleged performance-enhancing drugs. Funding Centre for Human Drug Research, Leiden.
... In a recent meta-analysis of research regarding the relationship between EPO and aerobic performance, for instance, Lodewijkx, Brouwer, Kuipers, and Hezewijk (2013) argued that the extant research is 'contradictory' and 'inconclusive'. So, for example, although several physiological effects have been attributed to EPO (see Jelkmann, 2007), it has also been said that 'there is no scientific basis to conclude rHuEPO has performance enhancing properties in elite cyclists' (see Heuberger et al., 2013), as well, perhaps, as other athletes. Along with broader patterns of uncertainty and contestation, claims about the 'effects' of EPO often vary. ...
... Erythropoietin-receptor agonists, such as recombinant human erythropoietins (rHuEPOs), stimulate erythropoiesis and thereby increase haemoglobin levels, which potentially increases oxygen carrying capacity and hence improves endurance performance. However, a systematic review of the literature by Heuberger et al. concluded that there was a lack of evidence for efficacy on endurance performance [31]. Of the 13 available reviewed studies, only 5 had a placebo-controlled and double-blind design [32][33][34][35][36], all showing similar effects of rHuEPOs in both trained and untrained subjects. ...
Article
Full-text available
The World Anti-Doping Agency is responsible for maintaining a Prohibited List that describes the use of substances and methods that are prohibited for athletes. The list currently contains 23 substance classes, and an important reason for the existence of this list is to prevent unfair competition due to pharmacologically enhanced performance. The aim of this review was to give an overview of the available evidence for performance enhancement of these substance classes. We searched the scientific literature through PubMed for studies and reviews evaluating the effects of substance classes on performance. Findings from double-blind, randomized controlled trials were considered as evidence for (the absence of) effects if they were performed in trained subjects measuring relevant performance outcomes. Only 5 of 23 substance classes show evidence of having the ability to enhance actual sports performance, i.e. anabolic agents, β2-agonists, stimulants, glucocorticoids and β-blockers. One additional class, growth hormone, has similar evidence but only in untrained subjects. The observed effects all relate to strength or sprint performance (and accuracy for β-blockers); there are no studies showing positive effects on reliable markers of endurance performance. For 11 classes, no well-designed studies are available, and, for the remaining six classes, there is evidence of an absence of a positive effect. In conclusion, for the majority of substance classes, no convincing evidence for performance enhancement is available, while, for the remaining classes, the evidence is based on a total of only 266 subjects from 11 studies.
... Due to this clear, performance-enhancing effect, the use of rHuEpo by athletes has been banned by the World Anti-Doping Agency (WADA). Conversely, several recent studies have suggested that the improvements seen in laboratory-based assessments (e.g., V O 2max ) do not translate to real-world improvements in performance (13,14). Athletes have now evolved doping practices to use low doses of rHuEpo to elicit small hematological responses and reduce the presence of rHuEpo in their urine (15). ...
Article
Full-text available
Frequent, low doses of recombinant human erythropoietin (rHuEpo) have been shown to increase the oxygen carrying capacity of an athlete and enhance endurance performance, although its effect on repeated sprint ability (RSA) remains unknown. If the mechanisms behind improved RSA performance reside within the augmented O 2 carrying capacity, then carbon monoxide (CO) inhalation should inhibit RSA. Purpose: The aim of this study was to assess the effects on maximal oxygen uptake (V-O 2max) and RSA of two interventions known to differentially influence blood oxygen carrying capacity. Methods: Fourteen endurance-trained individuals were administered microdoses of rHuEpo (20-40 IU · kg -1) or placebo twice per week for 7 wk using a randomized, crossover design. V-O 2max and RSA were measured at baseline and after rHuEpo administration. Total hemoglobin mass (tHb-mass) was measured twice at baseline (14 and 7 d before the first injection), three times during rHuEpo administration (10, 24, and 38 d after the first rHuEpo injection) and twice after the cessation of rHuEpo administration (7 and 21 d after the final injection) using the optimized CO rebreathing method. V-O 2max and RSA also were assessed in a separate cohort of 11
... Despite the overwhelming scientific evidence to support the ergogenic effects of rHuEpo, some question the appli- cation of these primarily laboratory findings to real-life competitive conditions or races involving elite athletes (10,11). For example, Heuberger et al (10) reported that while performance was enhanced in laboratory-based high- intensity tests, endurance and road race performances were similar between rHuEpo and placebo groups questioning a multitude of findings which state otherwise (1-8). ...
Article
Background: Recombinant human erythropoietin (rHuEPO) is frequently abused by athletes as a performance-enhancing drug, despite being prohibited by the World Anti-Doping Agency. Although the methods to detect blood doping, including rHuEPO injections, have improved in recent years, they remain imperfect. Methods: In a proof-of-principle study, we identified, replicated and validated the whole-blood transcriptional signature of rHuEPO in endurance-trained Caucasian males at sea-level (n = 18) and Kenyan endurance runners at moderate altitude (n = 20), all of whom received rHuEPO injections for four weeks. Results: Transcriptional profiling shows that hundreds of transcripts were altered by rHuEPO in both cohorts. The main regulated expression pattern, observed in all participants, was characterised by a "rebound" effect with a profound up-regulation during rHuEPO and a subsequent down-regulation up to four weeks post administration. The functions of the identified genes were mainly related to the functional and structural properties of the red blood cell. Of the genes identified to be differentially expressed during and post rHuEPO, we further confirmed a whole blood 34-transcript signature that can distinguish between samples collected pre, during and post rHuEPO administration. Conclusion: By providing biomarkers that can reveal rHuEPO use, our findings represent a substantial advance in the development of new enhanced and robust methods for the detection of blood doping.
... The use of rHuEPO by athletes is generally based on the notion that increasing hematocrit levels (i.e., increasing the ratio between the volume of red blood cells and total blood volume) increases the amount of oxygen available for the muscles, thereby increasing performance. However, there is currently no clear evidence to suggest that this is the case in elite cyclists (Heuberger et al. 2013). ...
Article
Full-text available
Recombinant human erythropoietin (rHuEPO) has been used as a performance‐enhancing agent by athletes in a variety of sports. The resulting increase in hematocrit levels leads to increased blood viscosity and can affect blood flow, potentially increasing the athlete's risk of developing health complications. However, the actual effects of using rHuEPO on microvascular blood flow and post‐occlusive reactive hyperemia are currently unknown. We therefore evaluated the effect of rHuEPO on the cutaneous microcirculation in well‐trained cyclists using laser speckle contrast imaging (LSCI). This study was part of a randomized, double‐blind, placebo‐controlled, parallel trial designed to investigate the effects of rHuEPO in 47 well‐trained adult cyclists (age 18–50 years). Subjects received a weekly dose of either rHuEPO or placebo for 8 weeks, and LSCI was performed at baseline, after a maximal exercise test in week 6, and before maximal exercise in week 8. Endpoints included basal blood flux, maximum post‐occlusion reperfusion, and time to return to baseline. Despite an increase in hematocrit levels in the rHuEPO‐treated group, we found no statistically significant difference in microvascular function measured between the rHuEPO‐treated group and the placebo group. Our results suggest that the increased hematocrit levels in rHuEPO‐treated well‐trained cyclists are not associated with changes in microvascular blood flow or post‐occlusive reactive hyperemia measured using LSCI. The results of this study suggest that increased hematocrit levels in rHuEPO‐treated well‐trained cyclists are not associated with changes in microvascular blood flow or post‐occlusive reactive hyperemia measured using LSCI.
... In view of the weakness of evidence of the performance-enhancing properties of ESAs [10], Heuberger et al. [11] anew studied the effects of rhEpo treatment (w6000 IU per week, SC, for 8 weeks) in a double-blinded, randomized, placebo-controlled trial on 48 male amateur cyclists. The primary outcomes were maximal power output, _ VO 2 max , and gross efficiency in maximal exercise tests with 25 W increments per 5 min, as lactate threshold and ventilator thresholds 1 (VT1; a measure of aerobic exercise) and 2 (VT2) at submaximal levels during the maximal exercise test, and as mean power, _ VO 2 , and heart rate in the submaximal exercise tests at the highest mean power output for 45 min in a laboratory setting and in a mountain race. ...
Preprint
This review focuses on discoveries regarding doping with recombinant human erythropoietin (rhEpo) and other erythropoiesis stimulating agents (ESAs), reported since 2017. While ESAs are known to increase Hbmass, O2 max and maximal power output unresolved questions have remained with respect to their effects on endurance performance. ESAs are detectable by electrophoresis or isoelectric focusing and immunoblotting of urine (or blood) samples. The methods have undergone some improvements. Novel erythropoietic substances will become available in the near future. Analytical methods are already available for the detection of Epo-mimetic peptides, HIF-stabilizers and activin type II receptor ligand traps. The "Athlete Biological Passport" (ABP) is an indirect instrument in anti-doping efforts. Additional hematologic parameters such as hepcidin and erythroferrone may strengthen the ABP approach. Abstract This review focuses on discoveries regarding doping with recombinant human erythropoietin (rhEpo) and other erythropoiesis stimulating agents (ESAs), reported since 2017. While ESAs are known to increase Hb mass , O 2 max and maximal power output unresolved questions have remained with respect to their effects on endurance performance. ESAs are detectable by electrophoresis or isoelectric focusing and immunoblotting of urine (or blood) samples. The methods have undergone some improvements. Novel erythropoietic substances will become available in the near future. Analytical methods are already available for the detection of Epo-mimetic peptides, HIF-stabilizers and activin type II receptor ligand traps. The "Athlete Biological Passport" (ABP) is an indirect instrument in anti-doping efforts. Additional hematologic parameters such as hepcidin and erythroferrone may strengthen the ABP approach. 3
... Dosing aimed to reach a target Hb of 10-15% increase compared to the baseline Hb value, similar to previous studies investigating effects of rHuEPO on performance. 16 The first four injections contained 5000 IU per injection and the dose was modulated by an un-blinded, non-study related physician to 6000IU, 8000IU or 10000IU in the final four weeks in case the Hb level was below the target range, doses similar to known practices in professional cycling. 17 When the Hb was in the target range 2000IU was administered. ...
Article
Full-text available
Recombinant human erythropoietin (rHuEPO) is used as doping a substance. Anti‐doping efforts include urine and blood testing and monitoring the Athlete Biological Passport (ABP). Data on the performance of these methods are incomplete, therefore this study aimed to evaluate the performance of two common urine assays and the ABP. In a randomized, double‐blinded, placebo‐controlled trial, 48 trained cyclists received a mean dose of 6000 IU rHuEPO (epoetin β) or placebo by weekly injection for 8 weeks. Seven timed urine and blood samples were collected per subject. Urine samples were analysed by sarcosyl‐PAGE and isoelectric focusing methods in the accredited DoCoLab in Ghent. A selection of samples, including any with false presumptive findings, underwent a second sarcosyl‐PAGE confirmation analysis. Haematological parameters were used to construct a module similar to the ABP and analysed by two evaluators from an Athlete Passport Management Unit. Sensitivity of the sarcosyl‐PAGE and isoelectric focusing assays for the detection of erythropoietin abuse were 63.8% and 58.6%, respectively, with a false presumptive finding rate of 4.3% and 6%. None of the false presumptive findings tested positive in the confirmation analysis. Sensitivity was highest between 2‐6 days after dosing, and dropped rapidly outside this window. Sensitivity of the ABP was 91.3%. Specificity of the urine assays was high, however, the detection window of rHuEPO was narrow, leading to questionable sensitivity. The ABP, integrating longitudinal data, is more sensitive, but there are still subjects that evade detection. Combining these methods might improve performance, but will not resolve all observed shortcomings.
... Strictly speaking erythropoietin controls oxygen delivery to tissues (Jelkmann 2011;Bunn 2013), this oxygen delivery being a product of the oxygen tension and hemoglobin level in the blood. However, in a normal population of individuals, all living at the same altitude, there is a uniform oxygen tension in terms of erythropoietin physiology, and so in these circumstances erythropoietin is responsible for maintaining hemoglobin levels (Jelkmann 2011;Heuberger et al. 2013). ...
Article
Full-text available
Abstract Hemoglobin levels are believed to be regulated as per a set point model of regulation. This model of regulation, by which specific levels of a parameter are targeted and defended by physiological systems, implies a particular population correlation between the parameter and its controlling hormone. Empirical population correlations of other parameters and their controlling hormones, have denied the presence of such set point‐based regulation. To assess if hemoglobin is regulated according to a set point model we performed a systematic search of PubMed/MEDLINE and Web of Science identifying relevant reports published up to November 2018. Population hemoglobin/erythropoietin level correlations were retrieved, and these empirically derived correlations were compared with the positive correlation implied by a set point model of regulation. Authors of papers containing potentially suitable data were contacted with requests for further analyses, and a meta‐analysis was performed. Twelve correlations between hemoglobin and erythropoietin levels from eleven papers were analyzed. None of these correlations were significantly positive, three, restricted to the normal range of hemoglobin, were significantly negative. All but one of the other correlations showed a negative trend. New analyses of previously published data sets resulted in similar findings. In particular a new analysis of large data sets of males (n = 2417) and females (n = 2592) with normal range hemoglobin levels, revealed significantly negative correlations. A meta‐analysis of our results indicated that the data overall are not consistent with a positive relationship between hemoglobin and erythropoietin (P
... As summarised in a paper by Heuberger and colleagues, Epo administration in untrained or trained athletes elevates haemoglobin by up to 12% and haematocrit by up to 19%, the effects associated with an increase in VO2max and significant improvement in endurance measures. 57 Prolonged administration of Epo improved submaximal exercise performance by about 50%, independently of the increase in VO2max. 58 Similar approaches of doping include altitude training and blood transfusions. ...
Article
Doping in sport is a widespread problem not just among elite athletes, but even more so in recreational sports. In scientific literature, major emphasis is placed on doping detection, whereas detrimental effects of doping agents on athlete's health are seldom discussed. Androgenic anabolic steroids are well known for their positive effects on muscle mass and strength. Human growth hormone also increases muscle mass, although majority of that is an increase in extracellular fluid and not the functional muscle mass. In recreational athletes, growth hormone does not have major effect on muscle strength, power or aerobic capacity, but stimulates anaerobic exercise capacity. Erythropoietin administration increases oxygen carrying capacity of blood improving endurance measures, whereas systemic administration of beta-adrenergic agonists may have positive effect on sprint capacity, and beta-adrenergic antagonists reduce muscle tremor. Thus, there are certain drugs that can improve selective aspects of physical performance. However, most of the doping agents exert serious side effects, especially when used in combination, at high doses, and for long duration. The extent of long-term health consequences is difficult to predict but likely to be substantial, especially when gene doping is considered. This review summarises main groups of doping agents used by athletes, with main focus on their effects on athletic performance and adverse effects.
... When EPO appeared on the market, endurance athletes were quick to adopt its use, because it circumvented the complexity of altitude training. Again it was observed that the effects of EPO not only varied with dosage but also among individuals, and a debate on its effectiveness for elite performance is still ongoing (Clark et al. 2017;Hardeman et al. 2014;Heuberger et al. 2013;Trinh et al. 2020). EPO is not the only substance with different effects between persons. ...
Article
One of the claims sometimes advanced in favour of anti-doping is that allowing doping would lead to a uniform increase in performance in comparison to no doping. The idea is that if all athletes would use doping, this would just shift the playing field to a higher level without a change in ranking, but at a higher health cost. In this paper, we critique this contention. We first develop our theoretical framework, with reference to the so-called Red Queen effect. We then argue that, if doping were allowed, Red Queen effects would not be the rule. We also show that to some extent Red Queen effects would occur, but these would not necessarily be morally problematic. We end by developing an argument in favour of a more liberal approach of doping, since such would allow escaping from today's runaway effects of anti-doping efforts.
... Recombinant human erythropoietin (rHuEPO) is on the World Anti-Doping Agency's Prohibited List as it is considered to possess performance enhancing properties and represents a potential health risk to athletes (World Anti-Doping Agency 2018). Effects on actual performance, however, are not indisputably proven in athletes (Heuberger et al. 2013). Moreover, in a recent study we found that although rHuEPO treatment improved laboratory tests of maximal exercise, more relevant endurance performance variables such as time trial and road race performance remained unchanged (Heuberger et al. 2017). ...
Article
Full-text available
PurposeRecombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations.Methods This double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18–50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-β; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort.ResultsrHuEPO increased P-selectin (+ 7.8% (1.5–14.5), p = 0.02) and E-selectin (+ 8.6% (2.0–15.7), p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0–24.3%), p = 0.0004) higher E-selectin and 32.1% ((4.6–66.8%), p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group.Conclusion In conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use.
... There is also a severe risk of hypercoagulability with risk of pulmonary embolism, myocardial infarction and formation of peripheral thromboembolisms. Cases of sudden death have been reported that are probably related to the above-mentioned adverse effects 39,43 . ...
Article
The use of doping has been banned for almost a century due to the risk involved to the athlete's health. Since then, the crite-rion of prohibiting substances has been reinforced to improve performance, becoming a rarely controversial issue nowadays. However, opinions defending the liberalization of doping has been sometimes given based on various arguments. One of the most common is the impossibility of completely eradicating doping and that this can be safe, from the point of view of health, if it is done by qualified doctors.This paper presents the arguments against the liberalization of doping from a medical point of view, contemplating various aspects.Those related to the use of substances such as: lack of clear criteria for inclusion in the list of prohibited substances and the unclear margin between the use of medication for treatment and for doping. Arguments related to health protection such as: the risk of sport for the athlete, the healthy sport, doping substances have few health risks, the use of medications, allow genetic doping because it is inevitable, risks of self-medication or use of me-dication without a prescription.Arguments related to sports performance such as: Doping products do not improve performance, doping is comparable to other performance improvement techniques, match genetic differences among athletes.And other arguments such as: prohibition favours doping, the control of doping increases the risks of doping itself, the high cost of anti-doping fight or the few anti-doping resources.The proposal for liberalization of doping under medical control is analyzed and discussed as well as the effects of liberalization on children and adolescents. At the end the medical ethical aspects related to doping are presented to conclude with the opposition of the medical profession against doping and its liberalization.
... In the wake of Amgen's approval of rHuEPO in 1989 for patients with end-stage renal anemia [39], rHuEPO was quickly abused by athletes seeking the benefits of improved oxygen-carrying capacity, predominantly in aerobic-dominated sports [3-5, 40, 41]. Despite its infamous history of abuse, perhaps the most noticeable example being the Festina affair of the 1998 Tour de France [42], some have questioned the ergogenic potential of rHuEPO on 'real-life' performance [6,[43][44][45]; most recently in light of a heavily debated RCT that reported no effect of rHuEPO (mean dose: 6000 IU/ wk for 8 weeks) on road race cycling performance or during a laboratory time trial compared to a placebo group [46]. Though criticized for utilizing a post-only design without pre-intervention road race measurement and standardization among other concerns [47][48][49][50][51][52], the study is among the few RCTs that have assessed the effect of rHuEPO on 'real-life' sport-specific performance. ...
Article
Full-text available
Some have questioned the evidence for performance-enhancing effects of several substances included on the World Anti-Doping Agency’s Prohibited List due to the divergent or inconclusive findings in randomized controlled trials (RCTs). However, inductive statistical inference based on RCTs-only may result in biased conclusions because of the scarcity of studies, inter-study heterogeneity, too few outcome events, or insufficient power. An abductive inference approach, where the body of evidence is evaluated beyond considerations of statistical significance, may serve as a tool to assess the plausibility of performance-enhancing effects of substances by also considering observations and facts not solely obtained from RCTs. Herein, we explored the applicability of an abductive inference approach as a tool to assess the performance-enhancing effects of substances included on the Prohibited List. We applied an abductive inference approach to make inferences on debated issues pertaining to the ergogenic effects of recombinant human erythropoietin (rHuEPO), beta2-agonists and anabolic androgenic steroids (AAS), and extended the approach to more controversial drug classes where RCTs are limited. We report that an abductive inference approach is a useful tool to assess the ergogenic effect of substances included on the Prohibited List—particularly for substances where inductive inference is inconclusive. Specifically, a systematic abductive inference approach can aid researchers in assessing the effects of doping substances, either by leading to suggestions of causal relationships or identifying the need for additional research.
... The erythropoietin (EPO) gene has been identified as a target for abuse in gene doping because EPO-and EPO-related formulations have been frequently used in doping to enhance the endurance performance of athletes in cycling, boxing, athletics, and rowing [12][13][14][15][16], and EPO and EPO-related formulations are included on the International Standard Prohibited List [3] published by WADA. According to the Wiley database on Gene Therapy Trials Worldwide [17], recombinant adenovirus (rAdV) is the most frequently used vector in clinical trials for gene therapy. ...
Article
Full-text available
Despite the World Anti-Doping Agency (WADA) ban on gene doping in the context of advancements in gene therapy, the risk of EPO gene-based doping among athletes is still present. To address this and similar risks, gene-doping tests are being developed in doping control laboratories worldwide. In this regard, the present study was performed with two objectives: to develop a robust gene-doping mouse model with the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to identify gene doping by using this model. The rAdV including the hEPO gene was injected intravenously to transfer the gene to the liver. After injection, the mice showed significantly increased whole-blood red blood cell counts and increased expression of hematopoietic marker genes in the spleen, indicating successful development of the gene-doping model. Next, direct and potentially indirect proof of gene doping were evaluated in whole-blood DNA and RNA by using a quantitative PCR assay and RNA sequencing. Proof of doping could be detected in DNA and RNA samples from one drop of whole blood for approximately a month; furthermore, the overall RNA expression profiles showed significant changes, allowing advanced detection of hEPO gene doping.
... Other exclusion criteria of our study such as history of malignancy or epilepsy are also explained by the spectrum of undesired effects of EPO. 8 Professional or semiprofessional sports activities belong to the exclusion criteria because EPO has been misused for doping, especially to enhance endurance of elite cyclists. 9 Additionally, pure red cell aplasia has been described as a rare but potentially fatal side effect of EPO. It is caused by neutralising antibodies induced by repetitive exposure to subcutaneous but eventually also intravenous EPO formulations. ...
Article
Full-text available
Introduction Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. Methods and analysis Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. Ethics and dissemination TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Trial registration number NCT01962571.
Article
Full-text available
This archival study (N = 100) compared Lance Armstrong's time trial wins to victories demonstrated by all former multiple Grand Tour winners (1949–1995; Coppi, Anquetil, Merckx, Hinault, Indurain) and by riders who won similar races in the three major European Grand Tours (Tour de France, Giro d'Italia, and Vuelta a España) from 2006 to 2013, who were either involved in doping affairs or not. Regression analyses yielded a non–significant M = 142 seconds difference between Armstrong vs. the aggregated other riders (∆R 2 = .001, p = .20). The effect emerged after controlling for the influence of competition year (b = -12.23 s per year, ∆R 2 = .045, p ≤ .001) and trial distances (b = 84.64 s per kilometer trial distance, ∆R 2 = .933, p ≤ .001) on the variation in riders' speed. Furthermore, Armstrong along with other riders who were suspended for doping use or who acknowledged having used doping in the 2006– 2013 periods did not outperform riders who were not involved in doping affairs during the same years (M = -68 s, ∆R 2 = .01, p = .35). Findings disprove the argument from ignorance, a false logic which refers to the often heard opinion that cyclists' performances over time (including Armstrong's wins) are mainly determined by their use of increasingly potent doping aids. However, in contrast to this logic, the distances of the time trials constitute the main determinant of riders' performances rather than the year in which they competed, and riders engaged in doping affairs did not significantly outperform riders who were not.
Article
Doping is defined by the World Anti-Doping Agency as the occurrence of an anti-doping rule violation. These violations are mainly materialised by the content of the Prohibited List International Standard. A substance or method may be put on the prohibited list if it meets any two of the following three criteria: (1) the potential to enhance sport performance; (2) representing a potential health risk to the athlete; and (3) a determination that it violates the ‘spirit of sport’. The concept of the ‘spirit of sport’ is explained in the fundamental rationale for the World Anti-Doping Code. This means that the decision that doping violates a fundamental principle of sport has already been made. One may not agree with this decision, but apparently there is some ‘spirit of sport’ that is deemed worthy of protection. As such, this concept is present in all anti-doping rules and regulations, and also in all discussions on the Prohibited List. But this concept is subsequently offered as a potential criterion to add substances or methods to the prohibited list as well. It is unsatisfactory to call something both fundamental and optional. It is proposed in this article to eliminate the ‘spirit of sport’ clause as an optional criterion in the determination whether a substance should be prohibited or not. This will focus discussions regarding the contents of the Prohibited List on the potentially performance-enhancing and health risk properties, which will guide doping-related discussions towards the core of what the concept of ‘doping’ should be.
Chapter
Different studies have shown that the respiratory system can limit exercise performance. The maximal duration of exercise at 90–95% of maximal work capacity (Wmax) was reduced in subjects who had fatigued their respiratory muscles just prior to the exercise test by either breathing against an inspiratory load (8) or by hyperventilating at 66% of their maximal voluntary ventilation (MVV) for 150 min (9). Respiratory endurance training in turn increased exercise duration at 64% of peak oxygen consumption (VO2) in sedentary subjects (2) and at 77% ̇VO2,peak in trained subjects (1), whereas exercise duration at 90–95% Wmax was the same as before respiratory training (5, 10). These conflicting results with respect to improvement of endurance by respiratory training may result either from different workloads at which subjects were exercising or from different respiratory training regimes. For example, subjects breathing against resistance can improve respiratory muscle strength whereas subjects performing isocapnic hyperpnea increase respiratory endurance (7). It also seems possible that the specific breathing pattern adopted during the respiratory training could influence the pattern adopted during subsequent exercise. This would be of importance because breathing slowly and deeply is more efficient than rapid shallow breathing during exercise.
Article
Forecasting seasonal snow cover is useful for planning resources and mitigating natural hazards. We present a link between the North Atlantic Oscillation (NAO) index and days of snow cover in Scotland between winters beginning from 1875 to 2013. Using broad (5 km resolution), national scale data sets like UK Climate Projections 2009 (UKCP09) to extract nationwide patterns, we support these findings using hillslope scale data from the Snow Survey of Great Britain (SSGB). Currently collected snow cover data are considered using remotely sensed satellite observations, from moderate-resolution imaging spectroradiometer; but the results are inconclusive due to cloud. The strongest correlations between the NAO index and snow cover are found in eastern and southern Scotland; these results are supported by both SSGB and UKCP09 data. Correlations between NAO index and snow cover are negative with the strongest relationships found for elevations below 750 m. Four SSGB sites (two in eastern Scotland, two in southern Scotland) were modelled linearly with resulting slopes between −6 and −16 days of snow cover per NAO index integer value. This is the first time the relationship between NAO index and snow cover duration has been quantified and mapped in Scotland.
Chapter
Der Missbrauch von Medikamenten und die Anwendung unerlaubter Methoden zum Zwecke der Leistungssteigerung findet nicht nur im Leistungssport statt, sondern stellt auch im Breiten- und Freizeitsport ein relevantes Problem dar. Doping gilt als Verursacher von Gesundheitsschäden. Für das Herz-Kreislauf-System ist hierbei unter der Einnahme verschiedener Dopingsubstanzen ein breites Spektrum an unerwünschten Wirkungen beschrieben. Diese umfassen unter anderem die Entwicklung einer Myokardhypertrophie, das Auftreten von Arrhythmien, eine Dyslipoproteinämie, proatherogene Effekte bis hin zum Myokardinfarkt und den plötzlichen Herztod. Die Kenntnis des Nebenwirkungsprofils der einzelnen Dopingsubstanzen besitzt auch in der täglichen klinischen Praxis eine besondere Bedeutung, da es bei differenzialdiagnostischen Überlegungen mitberücksichtigt werden muss.
Chapter
A primary indication for red blood cell (RBC) transfusion is to prevent the adverse effects of inadequate tissue oxygenation when hemoglobin (Hgb) is low and physiological mechanisms to compensate for diminished oxygen delivery are inadequate. Indications for transfusion have historically been guided by Hgb concentration. The conundrum facing researchers and healthcare providers is to identify the point when critical tissue oxygen delivery is impaired to the extent that transfusion is required in a patient while avoiding unnecessary transfusion. This article will review basic physiological responses to RBC loss and indications for RBC transfusion in patients with acute and chronic anemia and conclude with a discussion of alternatives to transfusion.
Article
Full-text available
Determination of the heart rate recovery (HRR) after the session of a physical activity, represents the valuable parameter for the investigation of autonomic balance and its dynamic in the general population, but also in the population of elite athletes. However, the methodology for its determination and analysis is still not entirely specified. It is necessary to define an adequate protocol of cardiopulmonary exercise test, by choosing an adequate ergometer (treadmill, ergo-bicycle or step bench). Organization of recovery period (active or passive), after the session of exercise is also very important, because its protocol interfered significantly with the value of HRR. Interpretation of obtained HRR values varies a lot, and researcher has freedom to choose the most adequate way, in accordance with the objectives of his study. Following paper represents a short review of determination, interpretation and analysis of HRR, followed by the latest recommendations.
Research
Full-text available
The report of the Cycling Independent Reform Commission (CIRC; Marty, Nicholson, & Haas, 2015) concluded that cyclists' use of red blood cell (RBC)-augmenting doping aids resulted in 10-15% improvement in performance in the 'epo era' (1990-1999). Hence, the superior performances assumption (SPA) expects that cyclists' performances realized in races in these years will be far better compared to foregoing and successive years. To extend and validate previous research, in two studies we reappraised the SPA using alternative dependent variables. Study 1 examined annual progress rates in winning riders' km/h and time performances realized in the French stage race Paris-Nice from 1933 to 2016. Study 2 assessed riders' power-to-weight ratio (W/kg) delivered in the time trial up Col d'Èze, since 1969 often the final stage in Paris-Nice. Findings of Study 1 produced no evidence that riders in the epo era raced strikingly faster than riders in other time periods. Moreover, riders' first-ranking performances did not constitute outliers and the progress in performance they demonstrated did not depart from the variation in progress observed in Paris-Nice from 1933 onward. Regarding Study 2, the choice of W/kg as an alternative measure to evaluate the SPA did not challenge, but rather substantiated findings observed in previous archival studies. After controlling for the robust influence of trial distances on winning riders' climbing achievements findings revealed a reversal of the SPA. Riders in the epo era did not deliver faster, but rather slower performances compared to riders in the pre-epo and post-epo years. Findings, underlying assumptions, and methodological weaknesses of both studies are discussed extensively.
Technical Report
Full-text available
Drawing on conclusions of the Cycling Independent Reform Commission (CIRC; Marty, Nicholson, & Haas, 2015), the current study investigated whether cyclists' first-ranking performances delivered in professional one-day races in the epo era (the 1990s) were faster compared to achievements realized by riders in the 1980s, the 2000s, and 2010s. To examine this research question we designed a 12 (Time Periods: 1892-2017) × 12 (One-Day Races: Omloop Het Nieuwsblad-Il Lombardia) factorial between-subjects study with nonequivalent groups. The sample (N = 1111 races) consisted of eleven one-day classic races (Omloop Het Nieuwsblad, Milan-San Remo, Gent-Wevelgem, Tour of Flanders, Paris-Roubaix, Amstel Gold Race, Flèche Wallone, Liège-Bastogne-Liège, Paris-Bruxelles, Paris-Tours, Il Lombardia) as well as the World Championship for professional riders. Mean km/h performances realized by winning riders from the outset of the races to 2017 served as the dependent variable. We tested the research question by classical NHST analyses as well as Bayesian analyses. When considering the evolution in riders' achievements over the years the results of the (Bayesian) correlation and regression analyses indicated that, except for the Amstel Gold Race, riders' mean km/h performances showed a gradual linear increase in speed. When confining our analyses to the 1980s and the ensuing decades the results produced by the (Bayesian) regression analyses showed moderate to extremely strong linear increases in speed in seven of the twelve races. Besides, pairwise comparisons revealed small, but nonsignificant increases in speed in the same time periods in three of the remaining races. The two exceptions to the linear progress in performances in the years between 1980 and 2017 are Il Lombardia and the Amstel Gold Race. All these statistical observations strongly reject the suggestion that riders demonstrated a conspicuous, discontinuous jump in speed in the 1990s and a decline in their performances in the decades thereafter. In the discussion we contend that our findings agree with recent criticism on the theoretical model underlying research into the performance-enhancing effects of red blood cell-augmenting doping aids. We further argue that the consistency in contradictory findings concerning these effects and the reproducibility of these findings across a variety of archival, laboratory , field, and meta-analytical studies strongly qualify conclusions put forward in the CIRC-report. The findings also suggest that these performance-enhancing effects are doubtful.
Chapter
Side effects of commonly prescribed cardiac medications such as anti-arrhythmics have specific implications for athletic performance in athletes with cardiovascular disease. Similarly, non-cardiac medications such as stimulants and anti-depressants may have more pronounced side effects in the setting of athletic activity due to the combination of endogenous and exogenous sympathetic stimulation and altered thermoregulation. This chapter is a summary of the available literature on (a) the implications of prescription medications, both cardiac and non-cardiac, on cardiovascular performance and cardiovascular health of athletic persons, and (b) the implications of potentially performance enhancing drugs known to be widely used by elite and recreational athletes on cardiovascular performance and cardiovascular health.
Article
Full-text available
Introduction Athletes have attempted to glean the ergogenic benefits of recombinant human erythropoietin (rHuEPO) since it became available in the 1980s. However, there is limited consensus in the literature regarding its true performance-enhancing effects. In fact, some studies suggest there is no conclusive evidence; therefore, it is necessary to evaluate and quantify the strength of the evidence. Objective To determine the effects of erythropoietin on enhancing athletic performance. Design At least two independent reviewers conducted citation identification through abstract and full-text screening, and study selection, and extracted raw data on demographics, descriptions of interventions and all outcomes to predesigned abstraction forms. Outcomes were stratified by treatment periods and dosages. Study quality was assessed using the Cochrane Risk of Bias Tool and Cochrane Grading of Recommendations Assessment Development and Education (GRADE) scale. Where appropriate, quantitative analysis was performed. Data sources EMBASE, MEDLINE and SPORTDiscus were searched from their inception to January 2020. Eligibility criteria Trials that examined any enhancement in sport in healthy participants aged 18–65 using rHuEPO compared with placebo were included. Results Overall, there is low-to-moderate quality evidence suggesting rHuEPO may be more beneficial than placebo in enhancing haematological parameters, pulmonary measures, maximal power output and time to exhaustion independent of dosage. However, these improvements are almost exclusively seen during maximal exercise intensities, which may be less relevant to athletic competition conditions. Conclusion Due to heterogeneity among trials, more high-quality randomised controlled trials with larger sample sizes in conditions that mirror actual competition are needed to further elucidate these effects.
Article
Full-text available
The creation of WADA contributed to harmonization of anti-doping and changed doping behavior and prevalence in the past 22 years. However, the system has developed important deficiencies and limitations that are causing harm to sports, athletes and society. These issues are related to the lack of evidence for most substances on the Prohibited List for performance or negative health effects, a lack of transparency and accountability of governance and decision-making by WADA and the extension of anti-doping policies outside the field of professional sports. This article tries to identify these deficiencies and limitations and presents a plea for more science, better governance and more education. This should lead to a discussion for reform among stakeholders, which should cover support of a new Prohibited List by actual research and evidence and introduce better governance with accountable control bodies and regulation. Finally, comprehensive education for all stakeholders will be the basis of all future positive improvements.
Article
Full-text available
Purpose: Splenic contraction induced by repeated apneas has been shown to increase oxygen availability. Our aim was to determine whether repeated maximal voluntary apnea enhances the performance of cyclists in a subsequent 4-km time trial. Methods: Seven male cyclists [age: 27.1 ± 2.1 years; height: 182 ± 8 cm; body mass: 74.8 ± 9.2 kg; peak oxygen uptake: 56.9 ± 6.6 mL min(-1) kg(-1) (mean ± SD)] performed a 4-km time trial on an ergometer with and without four prior maximal bouts of apnea interspersed with 2 min of recovery. Results: The average power output during the time trial was similar with (293 ± 48 W) and without (305 ± 42 W) prior apnea (P = 0.11, d = 0.27). The spleen was reduced in size after the fourth bout of apnea (-12.4 ± 9.0 %), as well as one (-36.6 ± 10.3 %) and 10 min (-19.5 ± 17.9 %) after the time trial, while with normal breathing the spleen was smaller one (-35.0 ± 11.3 %) and 10 min (-23.4 ± 19.7 %) after the time trial. Heart rate; oxygen uptake and carbon dioxide production; tissue oxygen saturation; and the lactate concentration, pH, oxygen saturation, level of hemoglobin and hematocrit of the blood were similar under both conditions. Conclusions: Our present findings reveal that four apneas by cyclists prior to a 4-km time trial led to splenic contraction, but no change in mean power output, the level of hemoglobin, hematocrit, oxygen saturation of the m. vastus lateralis or oxygen uptake.
Article
Full-text available
LUCÍA, A., J. HOYOS, M. PÉREZ, A. SANTALLA, and J. L. CHICHARRO. Inverse relationship between V̇O2max and economy/efficiency in world-class cyclists. Med. Sci. Sports Exerc., Vol. 34, No. 12, pp. 2079–2084, 2002. Purpose: To determine the relationship that exists between V̇O2max and cycling economy/efficiency during intense, submaximal exercise in world-class road professional cyclists. Methods: Each of 11 male cyclists (26 ± 1 yr (mean ± SEM); V̇O2max: 72.0 ± 1.8 mL·kg−1·min−1) performed: 1) a ramp test for V̇O2max determination and 2) a constant-load test of 20-min duration at the power output eliciting 80% of subjects’ V̇O2max during the previous ramp test (mean power output of 385 ± 7 W). Cycling economy (CE) and gross mechanical efficiency (GE) were calculated during the constant-load tests. Results: CE and GE averaged 85.2 ± 2.3 W·L−1·min−1 and 24.5 ± 0.7%, respectively. An inverse, significant correlation was found between 1) V̇O2max (mL·kg−0.32·min−1) and both CE (r = −0.71;P = 0.01) and GE (−0.72;P = 0.01), and 2) V̇O2max (mL·kg−1·min−1) and both CE (r = −0.65;P = 0.03) and GE (−0.64;P = 0.03). Conclusions: A high CE/GE seems to compensate for a relatively low V̇O2max in professional cyclists.
Article
Full-text available
The aim of this review is to provide greater insight and understanding regarding the scientific nature of cycling. Research findings are presented in a practical manner for their direct application to cycling. The two parts of this review provide information that is useful to athletes, coaches and exercise scientists in the prescription of training regimens, adoption of exercise protocols and creation of research designs. Here for the first time, we present rationale to dispute prevailing myths linked to erroneous concepts and terminology surrounding the sport of cycling. In some studies, a review of the cycling literature revealed incomplete characterisation of athletic performance, lack of appropriate controls and small subject numbers, thereby complicating the understanding of the cycling research. Moreover, a mixture of cycling testing equipment coupled with a multitude of exercise protocols stresses the reliability and validity of the findings. Our scrutiny of the literature revealed key cycling performance-determining variables and their training-induced metabolic responses. The review of training strategies provides guidelines that will assist in the design of aerobic and anaerobic training protocols. Paradoxically, while maximal oxygen uptake (VO2max) is generally not considered a valid indicator of cycling performance when it is coupled with other markers of exercise performance (e.g. blood lactate, power output, metabolic thresholds and efficiency/economy), it is found to gain predictive credibility. The positive facets of lactate metabolism dispel the ‘lactic acid myth’. Lactate is shown to lower hydrogen ion concentrations rather than raise them, thereby retarding acidosis. Every aspect of lactate production is shown to be advantageous to cycling performance. To minimise the effects of muscle fatigue, the efficacy of employing a combination of different high cycling cadences is evident. The subconscious fatigue avoidance mechanism ‘teleoanticipation’ system serves to set the tolerable upper limits of competitive effort in order to assure the athlete completion of the physical challenge. Physiological markers found to be predictive of cycling performance include: (i) power output at the lactate threshold (LT2); (ii) peak power output (Wpeak) indicating a power/weight ratio of ≥5.5 W/kg; (iii) the percentage of type I fibres in the vastus lateralis; (iv) maximal lactate steady-state, representing the highest exercise intensity at which blood lactate concentration remains stable; (v) Wpeak at LT2; and (vi) Wpeak during a maximal cycling test. Furthermore, the unique breathing pattern, characterised by a lack of tachypnoeic shift, found in professional cyclists may enhance the efficiency and metabolic cost of breathing. The training impulse is useful to characterise exercise intensity and load during training and competition. It serves to enable the cyclist or coach to evaluate the effects of training strategies and may well serve to predict the cyclist’s performance. Findings indicate that peripheral adaptations in working muscles play a more important role for enhanced submaximal cycling capacity than central adaptations. Clearly, relatively brief but intense sprint training can enhance both glycolytic and oxidative enzyme activity, maximum short-term power output and VO2max. To that end, it is suggested to replace ~15% of normal training with one of the interval exercise protocols. Tapering, through reduction in duration of training sessions or the frequency of sessions per week while maintaining intensity, is extremely effective for improvement of cycling time-trial performance. Overuse and over-training disabilities common to the competitive cyclist, if untreated, can lead to delayed recovery.
Article
Full-text available
Purpose: Between inefficient training and overtraining, an appropriate training stimulus (in terms of intensity and duration) has to be determined in accordance with individual capacities. Interval training at the minimal velocity associated with VO 2max (vVO 2max ) allows an athlete to run for as long as possible at VO 2max . Nevertheless, we don't know the influence of a defined increase in training volume at vVO 2max on aerobic performance, noradrenaline, and heart rate. Methods: Eight subjects performed 4 wk of normal training (NT) with one session per week at vVO 2max , i.e., five repetitions run at 50% of the time limit at vVO 2max , with recovery of the same duration at 60% vVO 2max , They then performed 4 wk of overload training (OT) with three interval training sessions at vVO 2max . Results: Normal training significantly improved their velocity associated with VO 2max (20.5 ± 0.7 vs 21.1 ± 0.8 km.h - 1 , P = 0.02). As a result of improved running economy (50.6 ± 3.5 vs 47.5 ± 2.4 mL.min -1 .kg -1 . P = 0.02), VO 2max was not significantly different (71.6 ± 4.8 vs 72.7 ± 4.8 mL.min -1 .kg -1 ). Time to exhaustion at vVO 2max ). was not significantly different (301 ± 56 vs 283 ± 41 s) as was performance (i.e., distance limit run at vVO 2max : 2052.2 ± 331 vs 1986.2 ± 252.9 m). Heart rate at 14 km.h - decreased significantly after NT (162 ± 16 vs 155 ± 18 bpm. P < 0.01). Lactate threshold remained the same after normal training (84.1 ± 4.8% vVO 2max ). Overload training changed neither the performance nor the factors concerning performance. However, the submaximal heart rate measured at 14 kmh -1 decreased after overload training (155 ± 18 vs 150 ± 15 bpm). The maximal heart rate was not significantly different after NT and OT (199 ± 9.5, 198 ± 11, 194 ± 10.4, P = 0.1 Resting plasma norepinephrine (veinous blood sample measured by high pressure liquid chromatography), was unchanged (2.6 vs 2.4 nm.L - 1 , P = 0.8). However, plasma norepinephrine measured at the end of the vVO 2max test increased significantly (11. 1 vs 26.0 nm.L - 1 , P = 0.002). Conclusion: Performance and aerobic factors associated with the performance were not altered by the 4 wk of intensive training at vVO 2max despite the increase of plasma noradrenaline.
Article
Full-text available
The glycoprotein hormone erythropoietin regulates the level of oxygen in the blood by modulating the number of circulating erythrocytes, and is produced in the kidney1–4 or liver5,6 of adult and the liver7,8 of fetal or neonatal mammals. Neither the precise cell types that produce erythropoietin nor the mechanisms by which the same or different cells measure the circulating oxygen concentration and consequently regulate erythropoietin production (for review see ref. 9) are known. Cells responsive to erythropoietin have been identified in the adult bone marrow10, fetal liver11 or adult spleen12. In cultures of erythropoietic progenitors, erythropoietin stimulates proliferation and differentiation to more mature red blood cells. Detailed molecular studies have been hampered, however, by the impurity and heterogeneity of target cell populations and the difficulty of obtaining significant quantities of the purified hormone. Highly purified erythropoietin may be useful in the treatment of various forms of anaemia, particularly in chronic renal failure13–15. Here we describe the cloning of the human erythropoietin gene and the expression of an erythropoietin cDNA clone in a transient mammalian expression system to yield a secreted product with biological activity.
Article
Full-text available
Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased. Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue.
Article
Full-text available
ABSTRACT: Erythropoietin (EPO) is the major hormone stimulating the production and differentiation of red blood cells. EPO is used widely for treating anemia of critical illness or anemia induced by chemotherapy. EPO at pharmacological doses is used in this setting to raise hemoglobin levels (by preventing the apoptosis of erythroid progenitor cells) and is designed to reduce patient exposure to allogenic blood through transfusions. Stroke, heart failure, and acute kidney injury are a frequently encountered clinical problem. Unfortunately, in the intensive care unit advances in supportive interventions have done little to reduce the high mortality associated with these conditions. Tissue protection with EPO at high, nonpharmacological doses after injury has been found in the brain, heart, and kidney of several animal models. It is now well known that EPO has anti-apoptotic effects in cells other than erythroid progenitor cells, which is considered to be independent of EPOs erythropoietic activities. This review article summarizes what is known in preclinical models of critical illness and discusses why this does not correlate with randomized, controlled clinical trials.
Article
Full-text available
Recombinant human erythropoietin (EPO) increases exercise capacity by stimulating erythropoiesis and subsequently enhancing oxygen delivery to the working muscles. In a large dose, EPO crosses the BBB and may reduce central fatigue and improve cognition. In turn, this would augment exercise capacity independent of erythropoiesis. To test this hypothesis, 15 healthy young men (18-34 years old, 74 + or - 7 kg) received either 3 days of high-dose (30,000 IU/day; n = 7) double-blinded placebo controlled or 3 mo of low-dose (5,000 IU/wk; n = 8) counter-balanced open but controlled administration of EPO. We recorded exercise capacity, transcranial ultrasonography-derived middle cerebral artery blood velocity, and arterial-internal jugular venous concentration differences of glucose and lactate. In addition, cognitive function, ratings of perceived exertion, ventilation, and voluntary activation by transcranial magnetic stimulation-induced twitch force were evaluated. Although EPO in a high dose increased cerebrospinal fluid EPO concentration approximately 20-fold and affected ventilation and cerebral glucose and lactate metabolism (P < 0.05), 3 days of high-dose EPO administration had no effect on cognition, voluntary activation, or exercise capacity, but ratings of perceived exertion increased (P < 0.05). We confirmed that 3 mo of administration of EPO increases exercise capacity, but the improvement could not be accounted for by other mechanisms than enhanced oxygen delivery. In conclusion, EPO does not attenuate central fatigue or change cognitive performance strategy, suggesting that EPO enhances exercise capacity exclusively by increased oxygen delivery to the working muscles.
Article
Full-text available
Erythropoietin (Epo) is the primary hormone that stimulates erythroid proliferation and differentiation through its cell surface receptor (EpoR) on erythroid progenitor cells. Previous studies have suggested that the bone marrow plays an important role in Epo's elimination. The changes in the EpoR mRNA levels and Epo's clearance in the bone marrow of 11 newborn lambs were studied to elucidate the role of EpoR in Epo's clearance under anemic conditions. Epo mRNA levels were measured by real-time polymerase chain reaction, and relative expression of EpoR was calculated by using the comparative CT method. The glyceraldehyde-3-phosphate dehydrogenase housekeeping gene was chosen as a control gene for the calculations. All lambs showed significant increase in bone marrow EpoR mRNA levels after phlebotomy-induced anemia. Epo's clearance determined from simultaneous pharmacokinetic studies with 125I-recombinant human Epo showed a significant increase after phlebotomy-induced anemia that was similar to the increase in EpoR. By day 28 after phlebotomy, EpoR mRNA levels and Epo clearance had returned toward baseline. These results indicate that the changes in Epo's clearance are not caused by body growth but result from significant changes in the pool of EpoR. A linear mixed-effect model was used to evaluate the quantitative relationship between EpoR and Epo's clearance. This analysis demonstrated a highly significant positive linear correlation between EpoR and Epo clearance. Together, these findings provide strong evidence that receptor-mediated Epo clearance is an important route for Epo's elimination.
Article
Full-text available
Safety concerns have arisen about the possibility of erythropoiesis-stimulating agents (ESAs) promoting tumor growth and increasing the incidence of venous thromboembolic events (VTEs). Because of the reported presence of erythropoietin receptors (EPORs) on tumor cells, it was questioned if ESAs had the potential for promoting tumor growth through stimulation of EPORs and tumor vessels and/or enhanced tumor oxygenation. Studies have shown that EPOR mRNA can be isolated from tumor cells, but the presence of EPOR protein has not yet been proven because of a lack of specific antibodies against EPORs. It is questionable whether EPORs on tumor cells are functional and there is no evidence that ESAs (within the approved indication in patients receiving chemotherapy) can stimulate EPORs on tumor cells in vivo. VTEs are frequent in cancer patients, resulting from the effects of malignant disease, cancer treatments, and comorbidities. VTEs are a leading cause of death in cancer patients. There are concerns about ESAs and a possible higher risk for VTEs and shorter survival in cancer patients. The higher risk for VTEs associated with ESAs appears to be a class effect, but the risk may be particularly pronounced when ESAs are used off label, as seen in clinical trials that targeted hemoglobin levels higher than those recommended by current ESA labeling and trials that enrolled patients who were not anemic at baseline. ESA treatment should be used within labeling confines.
Article
Full-text available
Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo. At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01) in EPO transfected obese mice; thus the mice weighed 21.9±0.8 g (control, normal diet,) 21.9±1.4 g (EPO, normal diet), 35.3±3.3 g (control, high-fat diet) and 28.8±2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass. The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles. In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.
Article
Full-text available
Erythropoietin (EP) exerts its effects on erythropoiesis by binding to a cell surface receptor. We examined EP receptor expression during normal human erythroid differentiation and maturation from the burst-forming unit-erythroid (BFU-E) to the reticulocyte level. In contrast to previous studies, we assessed EP receptor number and affinity in erythroid precursors immunologically purified from fresh bone marrow aspirates or fetal liver samples and in reticulocytes purified from peripheral blood. EP receptors were quantitated by equilibrium binding experiments with 125I EP. We found that purified primary erythroblasts from both adult and fetal sources exhibited a single high-affinity (kd 100 pmol/L) binding site for EP under our experimental conditions, and 135 or 250 receptors per cell, respectively. Reticulocytes were devoid of EP receptors. We compared these data to in vitro-derived BFU-E progeny at both early and late stages of maturation. Cultured BFU-E progeny also displayed a single class of receptors of slightly lower affinity (210 to 220 pmol/L). Preparations enriched in colony-forming units-erythroid (CFU-E) and proerythroblasts (day 9 BFU-E progeny) displayed approximately 1,100 receptors per cell, whereas populations containing mature erythroblasts (day 14 BFU-E progeny) exhibited approximately 300 receptors per cell. Furthermore, information from binding experiments was complemented by autoradiography in both enriched BFU-E preparations, cultured BFU-E progeny (days 9 and 14), and marrow mononuclear cells. These studies are consistent with a peak in EP receptor expression at the CFU-E/proerythroblast stage and a decrease with further maturation to undetectable levels at the reticulocyte stage. These data examining EP receptor characteristics on freshly isolated erythroid precursor cells complement previous data on EP receptor biology using culture-derived erythroblasts.
Article
In situ hybridization was used to quantitate the cells that produce erythropoietin (EP) in the renal cortices of mice with varying severities of acute anemia and of mice recovering from severe, acute anemia. The number of EP-producing cells in the renal cortex increased in an exponential manner as hematocrit was decreased. Individual EP- producing cells had very similar densities of silver grains in autoradiograms regardless of whether they were from normal mice or from slightly, moderately or severely anemic animals. With increasingly severe anemia, total renal EP mRNA levels and serum EP concentrations showed increases that correlated with the number of renal EP-producing cells. These results indicate that as mice become more anemic, additional cells are recruited to produce EP rather than the cells already producing EP being stimulated to increase their individual production. In mildly and moderately anemic animals, small clusters of EP-producing cells were found in the inner cortex with large areas of cortex containing no EP-producing cells. In severely anemic mice, EP- producing cells were found throughout the inner cortex with only a very few found scattered in the outer cortex and outer medulla. The data indicate that only a subset of total renal interstitial cells produce EP. During recovery from severe, acute anemia, the numbers of EP- producing cells decreased exponentially as hematocrits rose and correlated with decreases in total renal EP mRNA and serum EP concentrations. These results suggest that following an acute blood loss and during the recovery from a blood loss, the capacity to deliver oxygen, as represented by hematocrit, is the major regulator of EP production.
Article
Erythropoietin (EP) exerts its effects on erythropoiesis by binding to a cell surface receptor. We examined EP receptor expression during normal human erythroid differentiation and maturation from the burst- forming unit-erythroid (BFU-E) to the reticulocyte level. In contrast to previous studies, we assessed EP receptor number and affinity in erythroid precursors immunologically purified from fresh bone marrow aspirates or fetal liver samples and in reticulocytes purified from peripheral blood. EP receptors were quantitated by equilibrium binding experiments with 125I EP. We found that purified primary erythroblasts from both adult and fetal sources exhibited a single high-affinity (kd 100 pmol/L) binding site for EP under our experimental conditions, and 135 or 250 receptors per cell, respectively. Reticulocytes were devoid of EP receptors. We compared these data to in vitro-derived BFU-E progeny at both early and late stages of maturation. Cultured BFU-E progeny also displayed a single class of receptors of slightly lower affinity (210 to 220 pmol/L). Preparations enriched in colony-forming units-erythroid (CFU-E) and proerythroblasts (day 9 BFU-E progeny) displayed approximately 1,100 receptors per cell, whereas populations containing mature erythroblasts (day 14 BFU-E progeny) exhibited approximately 300 receptors per cell. Furthermore, information from binding experiments was complemented by autoradiography in both enriched BFU-E preparations, cultured BFU-E progeny (days 9 and 14), and marrow mononuclear cells. These studies are consistent with a peak in EP receptor expression at the CFU-E/proerythroblast stage and a decrease with further maturation to undetectable levels at the reticulocyte stage. These data examining EP receptor characteristics on freshly isolated erythroid precursor cells complement previous data on EP receptor biology using culture-derived erythroblasts.
Article
Detailed studies to analyze the early events of erythropoietin (Ep) secretion and clearance were performed in a rat model using a double antibody radioimmunoassay. Ep clearance was determined following intravenous injection of 1 mL of Ep-rich plasma, 1,080 mU/mL, obtained from phlebotomized rats. Analysis revealed a disappearance curve that conformed to a two-compartment model with an alpha half-life t1/2 of 3.6 minutes and a beta t1/2 of 86 minutes. The volume of distribution was similar to the calculated plasma volume. In anephric animals, there was no change in the plasma clearance rate or the volume of distribution. Rapid Ep secretion was elicited by a single 15 mL/kg phlebotomy (hematocrit decrement 45% to 30%), so that levels reached 20 to 30 times baseline (524 +/- 76 v 24 +/- 7 mU/mL) at five hours, whereas they plateaued for at least 33 hours. The increase in the rate of secretion was geometric, from 9.9 mU/h baseline secretion to 429 mU/h. These data identify a very sensitive and rapidly responsive system for Ep modulation in the rat.
Article
A recent study in dogs suggested that erythropoietin (EPO) not only promotes the synthesis of increased numbers of reticulated platelets but that these newly produced platelets are hyperreactive compared with controls. Because of the increasing use of EPO in the perioperative setting, we characterized the effects of EPO on platelet reactivity in healthy human volunteers. In a randomized, controlled trial, we studied the effects of EPO on platelet reactivity, thrombopoiesis, and endothelial activation in circumstances similar to those of autologous blood donation. Thirty healthy male volunteers received placebo or EPO (100 or 500 U/kg of body weight given intravenously) three times a week for 2 weeks and underwent phlebotomy on days 8 and 15. Thrombin receptor–activating peptide induced expression of P-selectin, and CD63 increased 2- to 3-fold during EPO treatment. The enhanced platelet reactivity was also reflected by a 50% increase in soluble P-selectin in plasma. Plasma E-selectin levels increased in a dose-dependent fashion by more than 100% during EPO treatment, indicating substantial activation of endothelial cells. A 10% to 20% increase in platelet counts was observed in both EPO groups on day 5. In the placebo group, platelets increased only several days after the first phlebotomy. The increase in platelet counts was not reflected by changes in the amounts of reticulated platelets or circulating progenitor cells. In summary, we found that EPO markedly enhances endothelial activation and platelet reactivity, which may adversely affect patients at cardiovascular risk. However, the increased platelet reactivity could be exploited in patients with platelet dysfunction.
Article
CO2 is generated when lactate is increased during exercise because its [H'] is buffered primarily by HCO: (22 ml for each meq of lactic acid). We developed a method to detect the anaerobic threshold (AT), using computerized regression analysis of the slopes of the CO, uptake (ko,) vs. 0, uptake (VO,) plot, which detects the beginning of the excess CO, output generated from the buffering of [H'], termed the V-slope method. From incremental exercise tests on 10 subjects, the point of excess CO, output (AT) predicted closely the lactate and HCO: thresholds. The mean gas exchange AT was found to correspond to a small increment of lactate above the mathematically defined lactate threshold [0.50 t 0.34 (SD) meq/l] and not to differ significantly from the estimated HCO: threshold. The mean VO, at AT computed by the V-slope analysis did not differ significantly from the mean value determined by a panel of six experienced reviewers using traditional visual methods, but the AT could be more reliably determined by the V-slope method. The respiratory compensation point, detected separately by examining the minute ventilation vs. VCO~ plot, was consistently higher than the AT (2.51 t 0.42 vs. 1.83 t 0.30 l/min of VOW). This method for determining the AT has significant advantages over others that depend on regular breathing pattern and respiratory chemosensitivity.
Conference Paper
Purpose: The purpose of this study was to assess research aimed at measuring performance enhancements that affect success of individual elite athletes in competitive events. Analysis: Simulations show that the smallest worthwhile enhancement of performance for an athlete in an international event is 0.7-0.4 of the typical within-athlete random variation in performance between events. Using change in performance in events as the outcome measure in a crossover study, researchers could delimit such enhancements with a sample of 16-65 athletes, or with 65-260 in a fully controlled study. Sample size for a study using a valid laboratory or field test is proportional to the square of the within-athlete variation in performance in the test relative to the event; estimates of these variations are therefore crucial and should be determined by repeated-measures analysis of data from reliability studies for the test and event. Enhancements in test and event may differ when factors that affect performance differ between test and event; overall effects of these factors can be determined with a validity study that combines reliability data for test and event. A test should be used only if it is valid, more reliable than the event, allows estimation of performance enhancement in the event, and if the subjects replicate their usual training and dietary practices for the study; otherwise the event itself provides the only dependable estimate of performance enhancement. Publication of enhancement as a percent change with confidence limits along with an analysis for individual differences will make the study more applicable to athletes. Outcomes can be generalized only to athletes with abilities and practices represented in the study. Conclusion: estimates of enhancement of performance in laboratory or field tests in most previous studies may not apply to elite athletes in competitive events.
Article
LUCÍA, A., J. HOYOS, A. SANTALLA, M. PÉREZ, and J. L. CHICHARRO. Kinetics of V̇O2 in professional cyclists. Med. Sci. Sports Exerc., Vol. 34, No. 2, pp. 320–325, 2002. Purpose: To analyze the kinetics of oxygen uptake (V̇O2) in professional road cyclists during a ramp cycle ergometer test and to compare the results with those derived from well-trained amateur cyclists. Methods: Twelve professional cyclists (P group; 25 ± 1 yr; maximal power output (Wmax), 508.3 ± 9.3 watts) and 10 amateur cyclists (A group; 22 ± 1 y; Wmax, 429.9 ± 8.6 watts) performed a ramp test until exhaustion (power output increases of 25 watts·min−1). The regression lines of the V̇O2:power output (W) relationship were calculated for the following three phases: phase I (below the lactate threshold (LT)), phase II (between LT and the respiratory compensation point (RCP)), and phase III (above RCP). Results: In group P, the mean slope (ΔV̇O2:ΔW) of the V̇O2:W relationship decreased significantly (P < 0.01) across the three phases (9.9 ± 0.1, 8.9 ± 0.2, and 3.8 ± 0.6 mL O2·watts−1· min−1 for phases I, II, and III, respectively). No significant differences (P > 0.05) were found between phases I and II (P > 0.05) in group A, whereas ΔV̇O2:ΔW significantly increased in phase III (P < 0.01), compared with phase II (10.2 ± 0.3, 9.2 ± 0.4, and 10.1 ± 1.1 mL O2·watts−1· min−1 in phases I, II, and III, respectively). The mean value of ΔV̇O2:ΔW for phase III was significantly lower in group P than in group A (P < 0.01). Conclusion: Contrary to the case in amateur riders, the rise in V̇O2 in professional cyclists is attenuated at moderate to high workloads. This is possibly an adaptation to the higher demands of their training/competition schedule.
Article
The purpose of this study was to investigate the effect of infusion of 400 mL of red blood cells (RBCs) on 10-km track race time, submaximal heart rate, hematocrit, 2,3-diphosphoglycerate, and partial pressure of oxygen at 50% hemoglobin saturation. Six highly trained, male, distance runners twice donated a unit of RBCs, which was frozen for subsequent reinfusion. Eleven weeks after the second donation, they undertook a series of three competitive 10-km races on a standard 400-m track: before infusion, after 100 mL of saline solution, and after 400 mL of autologous, previously frozen deglycerolized RBCs. All subjects took all trials in this double-blind, placebo, crossover, experimental design. Running time was recorded at each 400-m split, and blood was collected prior to each trial. The data were analyzed by analysis of variance. Results following the RBC infusion showed a significantly higher hematocrit concentration, a significantly faster 10-km run, a nonsignificant decrease in submaximal heart rate (10 beats per minute), and no significant changes in either 2,3-diphosphoglycerate or partial pressure of oxygen at 50% hemoglobin saturation. Erythrocythemia induced by the infusion of 400 mL of autologous packed RBCs effectively increased performance capacity in a 10-km track race, probably due to an increase in oxygen delivery to the working muscles. (JAMA 1987;257:2761-2765)
Article
The purpose of this study was to investigate the validity of the ventilatory response during incremental exercise as indication of endurance performance during prolonged high-intensity exercise under field test conditions in elite cyclists. The ventilatory threshold (VT) was assessed in 14 male elite cyclists (age 22.4 ± 3.4 years, height 181 ± 6 cm, weight 69.2 ± 6.8 kg, V̇O2max 69 ± 7 ml·min-1·kg-1) during an incremental exercise test (20 W·min-1). Heart rate and oxygen uptake were assessed at the following ventilatory parameters: 1. Steeper increase of VCO2 as compared to V̇O2 (V-slope-method); 2. Respiratory exchange ratio (RQ) = 0.95 and 1.00; 3. VE/V̇O2 increase without a concomitant VE/VCO2 (VE/V̇O2 method). Three weeks following the laboratory tests, the ability to maintain high-intensity exercise was determined during a 40 km time trial on a bicycle. During this time trial the mean heart rate (HR(TT)) and the road racing time (TT) were assessed. The V-slope-method and the VE/V̇O2 method showed significant correlations with TT (V-slope: r = -0.82; p < 0.001; 90% interval of confidence = ± 82 sec; VE/V̇O2: r = -0.81; p < 0.01; 90% interval of confidence = ± 81 sec). Heart rate at the ventilatory parameters and at the maximum heart rate (HR(max)) showed significant correlations with HR(TT). The V-slope-method is the preferred method to predict heart rate during prolonged high-intensity exercise (r = 0.93; p < 0.0001; 90% interval of confidence: ± 4.8 beats·min-1). For predicting heart rate during prolonged high-intensity exercise using an incremental exercise test (20 W·min-1), without the knowledge of ventilatory parameters, we recommend using the regression formula: H(TT) = 0.84·H(max) + 14.3 beats·min-1 (r = 0.85; p < 0.001).
Article
The purpose of this paper is to review the physiological determinants of endurance exercise performance by using the data of the World Record holder for the women’s marathon (PR), to illustrate the link between an athlete’s physiology and success in distance running. The maximal oxygen (O2) uptake, O2 cost of running at sub-maximal speeds (running economy), and blood lactate response to exercise can all be determined using standard physiology laboratory exercise tests and the results used to track changes in ‘fitness’ and to make recommendations for future training. PR’s data demonstrate a 15% improvement in running economy between 1992 and 2003 suggesting that improvements in this parameter are very important in allowing a distance runner to continue to improve their performance over the longer-term. PR’s data demonstrate how 15 years of directed training have created the ‘complete’ female distance runner and enabled the setting of an extraordinary World record of 2:15:25 for the Marathon.
Article
The human erythropoietin gene has been isolated from a genomic phage library by using mixed 20-mer and 17-mer oligonucleotide probes. The entire coding region of the gene is contained in a 5.4-kilobase HindIII-BamHI fragment. The gene contains four intervening sequences (1562 base pairs) and five exons (582 base pairs). It encodes a 27-amino acid signal peptide and a 166-amino acid mature protein with a calculated Mr of 18,399. The erythropoietin gene, when introduced into Chinese hamster ovary cells, produces erythropoietin that is biologically active in vitro and in vivo.
Article
We assessed the possibility of using soluble transferrin receptor (sTfR) as an indicator of doping with recombinant erythropoietin (rhEPO). A double-blind, placebo-controlled study was conducted with the administration of 5,000 U of rhEPO (N = 10) or placebo (N = 10) three times weekly (181-232 U x kg(-1) x wk-1) for 4 wk to male athletes. We measured hematocrit and the concentration of hemoglobin, sTfR, ferritin, EPO, and quantified the effects on performance by measuring time to exhaustion and maximal oxygen uptake (VO2max) on a cycle ergometer. Hematocrit increased from 42.7 +/- 1.6% to 50.8 +/- 2.0% in the EPO group, and peaked 1 d after treatment was stopped. In the EPO group, there was an increase in sTfR (from 3.1 +/- 0.9 to 6.3 +/- 2.3 mg x L(-1) , P < 0.001) and in the ratio between sTfR and ferritin (sTfR-ferritin(-1)) (from 3.2 +/- 1.6 to 11.8 +/- 5.1, P < 0.001). The sTfR increase was significant after 1 wk of treatment and remained so for 1 wk posttreatment. Individual values for sTfR throughout the study period showed that 8 of 10 subjects receiving rhEPO, but none receiving placebo, had sTfR levels that exceeded the 95% confidence interval for all subjects at baseline (= 4.6 mg x L(-1)). VO2max increased from 63.6 +/- 4.5 mL x kg(-1) x min(-1) before to 68.1 +/- 5.4 mL x kg(-1) x min(-1) 2 d post rhEPO administration (7% increase, P = 0.001) in the EPO group. Hematocrit, sTfR, sTfR-ferritin(-1), and VO2max did not change in the placebo group. Serum levels of sTfR may be used as an indirect marker of supranormal erythropoiesis up to 1 wk after the administration of rhEPO, but the effects on endurance performance outlast the increase in sTfR.
Article
The effects of subcutaneous injections of human erythropoietin (rhEpo) on the circulatory response to submaximal and maximal exercise were studied in healthy male subjects (n=15). Hemoglobin concentration [Hb] increased from 152 g · l−1 to 169 g · l−1 and in parallel maximal aerobic power (Vo2max) increased from 4.52 to 4.88 l · min−1. There were no significant changes in heart rate, ventilation and blood lactate concentration during the exhausting run. Compared with infusion of red blood cells, there was no significant difference in the increase in Vo2max per gram increase in [Hb]. Systolic blood pressure at 200 W increased from before rhEpo treatment to afterwards. It was concluded that slow (rhEpo treatment) and acute (red blood cell reinfusion) increase of [Hb] resulted in similar increase in Vo2max.
Article
1The pharmacokinetics of recombinant human erythropoietin (rHuEpo) were initially determined in two healthy volunteers after a single subcutaneous dose (50 u kg−1). Twenty subjects then received repeated subcutaneous administrations of high dose (200 u kg−1) rHuEpo and 10 subjects received placebo. An immunoradiometric assay was used to measure the concentrations of erythropoietin (Epo) in serum and urine. 2Serum Epo concentration-time profiles were best described by a one-compartment open model with zero-order input. The mean elimination half-life (±s.d.) was 42.0±34.2 h. Clearance, uncorrected for bioavailability, was 0.05±0.01 l h−1 kg& minus;1. Erythropoietin concentrations returned to normal