ABSTRACT

Sport is the organized playing of competitive games according to rules. Hence doping represents drug cheating, a fraud on competitors, the sport, and the public. The charter of the World Anti-doping Agency (WADA) forms a harmonized Code that authorizes an annually updated list of prohibited doping substances and methods, accrediting national anti-doping labs around the world, and establishing the Court of Arbitration for Sports as the “Supreme Court” to settle global disputes related to doping. Sports performance has 4 major components: skill, strength, endurance, and recovery, with each sport employing a distinct combination of these elements. These performance characteristics also correspond to the most potent and effective forms of doping. Sports requiring explosive power including combat and collision sports are most susceptible to androgen doping through their effect on increasing muscle mass and strength whereas sports that require endurance are most enhanced by hemoglobin (blood) doping which increases oxygen delivering capacity to exercising tissues. Performance in sports involving intense physical activity or training may possibly be enhanced by growth hormone and its secretagogues through speeding of tissue recovery from injury though convincing evidence is lacking. Hormones remain the most potent and widely detected doping agents being responsible for about 2/3 of anti-doping rule violations detected by increasingly sophisticated detection methods. At present, the vast majority of positives are still due to a wide variety of androgens, including natural, marketed, and illicit synthetic steroidal and non-steroidal (e.g. SARMs) androgens, while the peptide hormones (erythropoiesis stimulating agents, growth hormone and its secretagogues) and autologous blood transfusion remain difficult to detect. Although chronic pharmacological use of glucocorticoids is likely deleterious to muscle function and sports performance, short-term use of high doses may be potentially ergogenic through mental effects of blunting of fatigue perception. Use of thyroid hormones is not prohibited but is likely counterproductive in creating loss of muscle mass and strength due to hyperthyroidism. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Across the world, sport is a ubiquitous human social activity that forms a unique intersection of health, recreation, entertainment and industry (1). It is both a major economic activity as well as a profound influence on social behavior of individuals at home, work, and play. One practical and concise definition of sport is the organized playing of competitive games according to rules. In that context, rule breaking is cheating to achieve an unfair competitive advantage whether it involves using illegal equipment, match fixing, banned drugs or any other prohibited means.

The illicit use of banned drugs (doping) to influence the outcome of a sporting contest, constitutes a fraud against competitors, spectators, sport, sponsors, and the public no different from other personal, professional, or commercial frauds. While performance enhancement is almost invariably the intent of cheating, impairing performance is also well known in horse racing and even, rarely, in human elite sports (e.g. drink-spiking of banned drugs, injurious physical assaults). Rules of sporting contests may change by agreement, but once set, represents the boundaries of fair competition. Nevertheless, fairness is an elastic, socially constructed concept which may change gradually over time. For example, a century ago deliberate training itself was considered an ungentlemanly breach of fairness as competition was then envisaged as a contest based solely on natural endowments. Similarly, some sports once maintained a distinction between amateurs and professionals. The philosophical foundations of the concept of fairness is a deep and complex issue (2, 3) where the focus has been mainly on distributive justice with an implicit goal of equality of outcomes. Less attention has been given to the philosophical basis of fair competition in sport where the prior distribution of talent and training and the outcome of contests are intended to provide equality of opportunity, but not of outcome, between contestants.

Naïve arguments are made that deny doping is cheating, or unsafe or violates the spirit of sport and asserting that drugs should be freely available or under medical supervision (4-6). However, removing prohibition on doping would immediately render drug taking as pervasive as training in elite sport extending to promising underage and sub-elite athletes. Ensuing demands on doctors to prescribe excessive, often massive, drug doses without medical indications would be unprofessional, unethical, and unsafe. This could convert sporting participation into a potentially dangerous rather than a healthy activity. In practice, creating enforceable boundaries for drugs in sport is unavoidable whether it is prohibition or, even under the most idealistic libertarian scenarios, by age or dosage. Within the limitations of unverifiable self-report regarding an illicit activity (7, 8), surveys indicate athletes support antidoping testing mainly to prevent cheating but also to promote safety (9-11). Motivating factors for, and routes by which athletes get involved in doping are complex but include the use of non-banned nutritional supplements as a gateway to doping (12) and the suspicion of athletes or their entourage that their rivals may be using illicit drugs, the so-called “false consensus belief” (7, 13-15). These philosophical issues are not considered further here and, recognizing that sport requires concrete, practical decisions, the establishment and enforcement of agreed rules is the basis of fair competition. An excellent discussion of the logic and morality of a decisive antidoping approach from an ethicist with extensive experience in sports anti-doping is recommended (16).

It is well understood that individual human genetic endowments are unequal, and, among these, sporting prowess is at least partly genetically determined (17). However, little is still known of the genotype-phenotype correlations that underlie beneficial genetic endowments for sports performance. Natural genetic advantages are recognized in height (tallness for basketball, shortness for jockeys and motor-cycle riders) and hereditary erythrocytosis where a high circulating hemoglobin (due to a high affinity erythropoietin (EPO) receptor (18)) for endurance sports, or conversely genetic disadvantage such as the common α-actinin-3 deletion genetic polymorphism which limits anaerobic, explosive power (19). More examples of genetic (dis)advantages for sports performance are likely to be identified as genomics continues to expand our understanding of the biological basis of health, including natural human sporting prowess. In the context of sports doping, however, a person’s genetic endowment is a given creating a natural boundary whereby the use of exogenous drugs or chemicals (including DNA) may constitute drug cheating or doping.

WORLD ANTI-DOPING AGENCY (WADA) AND THE GLOBAL ANTI-DOPING REGULATORY ENVIRONMENT

Cheating is as old as sport itself, yet the present endemic of doping using pharmaceutical drugs to boost sports performance is largely a Cold War legacy. Eastern European national doping programs were established by governments aiming to achieve a short-cut propaganda victory over their Western rivals, a challenge quickly reciprocated and then taken up by individual coaches and athletes. Starting with power sports (20), the epidemic became entrenched as an endemic in sufficiently affluent circles. In 1967, following the introduction of anti-doping rules by some sports federations, the International Olympic Committee (IOC) established its Medical Commission, which published their first list of prohibited substances. During the 1970’s the IOC Medical Commission took an increasingly active role by banning androgens which required developing standardized, valid methods to detect and deter androgen doping. After discarding alternatives such as immunoassays and blood sampling, in the 1980s mass spectrometry (MS)-based tests became (21) and remain the standard for detecting synthetic androgens in urine.

In 1999, the IOC established the WADA based in Montreal to be equally supported by governments and sporting organizations with its charter, the WADA Code, representing a harmonized set of global anti-doping rules introduced in 2004, revised in 2009 and every 6 years thereafter (2015, 2021, and scheduled for 2027) (22). WADA also publishes an annually updated Prohibited List of Substances and Methods, accredits national anti-doping labs together with their operational anti-doping testing framework and established the Court for Arbitration in Sport (CAS) to settle anti-doping legal disputes as sport’s “Supreme Court”. The WADA Code has been adopted by over 660 sporting organizations including all Olympic and Paralympic organizations and National Anti-Doping Organizations as well as most non-Olympic International and National Sports Federations. The WADA Code prohibits substances or methods which meet 2 of 3 criteria comprising:

i.

enhance performance (cheating),

ii.

harmful to health (safety) or

iii.

violate the spirit of sport (unsporting).

A key feature of the WADA Code is its strict liability provision. This makes each athlete personally responsible to ensure no prohibited substances enter their body so that detection of any prohibited substances in their body constitutes an antidoping rule violation (ADRV), regardless of intent, fault, negligence, or knowing use as well as refusal or avoidance of testing or possession, attempts, trading, and tampering with banned drugs.

Although the primacy of penalizing cheating is widely understood, implementing these criteria encounter ethical and practical difficulties in proving ergogenic effects of increasing numbers of illicit and/or non-approved substances. These substances have unknown safety so that human testing is not feasible making athlete safety an important consideration.

Sanctions involve suspension from any elite competitive sport and extend to support personnel and teams. Suspensions, once 2 years are now 4 years since adoption of the 2015 Code. This is generally believed to be longer than the ergogenic benefits of doping, although recent evidence suggests that androgen effects on muscle may create durable or even permanent effects (23), which might argue for much longer or permanent banning of androgen doping violators.

The Prohibited List bans, at any time either in or out of competition, the use of performance enhancing hormones, including androgens, EPO, and growth hormone and related substances or drugs which stimulate endogenous production of these hormones (Table 1). Among the 15 categories of prohibited substances (12) and methods (3), hormones feature prominently in S1 (anabolic agents, mainly androgens), S2 (peptide hormones, growth factors, related substances and mimetics), S4 (hormone and metabolic modulators), and S9 (glucocorticoids) with S1 and S2 having important “catch-all” provision for unnamed but related substances “with similar chemical structure or biological effects”. In addition, the S0 category bans non-approved substances, those without current regulatory approval for human therapeutic use. The prominence of hormones is reinforced by the WADA laboratory statistics for anti-doping tests where hormones remain the most frequently detected banned drugs (Table 2). In 2017, of over 322,000 anti-doping tests ~1.5% were positive with 61% due to hormones, the vast majority (~99%) due to androgens. These findings confirm that the detection of androgen doping is effective whereas the low rate of detection of hemoglobin or growth hormone doping may reflect the limitations of available tests for peptides and peptide hormones which require blood rather than conventional urine sampling and feature low sensitivity and brief windows of detection, rather than their lack of abuse. Further use of out-of-competition testing and blood samples together with more sensitive detection tests with longer windows of detection are required particularly for peptide hormones.

The prevalence of doping in elite sports as an illicit activity with drastic consequences for athletes admitting guilt remains difficult to quantify using laboratory-based testing, inference from performance, or self-report questionnaires (24). The most promising methods appear to be questionnaires using the unrelated question random response methodology (25). This methodology was developed to estimate the prevalence of sensitive, disapproved, or illicit activities by asking the sensitive personal questions masked by mixing them with unrelated non-sensitive questions in an anonymized framework. This provides overall prevalence self-report estimates of the target activities without allowing for individual identification of answers. One study of two elite athletic competitions provided estimates of 43.6% and 57.1% for recent (last year) and 70.1% of ever use of banned doping methods (26). However, another study using the same methodology found markedly lower prevalence estimates of 0.7% to 11.9% for recent use of banned doping (27). The discrepancies between these prevalence estimates requires further clarification. A significant limitation of these methods is their reliance on the athlete’s perception of banned methods. For example, whether “banned drugs” are interpreted as including the widely used (but non-banned) nutritional supplements which athletes are urged to avoid for fear of adulteration with unlabeled banned substances.

COMPONENTS OF SPORTS PERFORMANCE AND DOPING

Sports performance has 4 major dimensions – skill, strength, endurance, and recovery (Figure 1). High performance in any sport requires a characteristic blend of these dimensions although individual sports differ widely in that balance. Similarly, the major ergogenic drug classes have distinctive effects aligned predominantly along one of these dimensions so that the most effective ergogenic drug classes used in doping are dictated by these dimensions of sports performance (Figure 2). While every sport requires an acquired skill, some are largely or solely based on skill and concentration (e.g. board games, target shooting, car driving, and motor-cycle riding) and may benefit from drugs that reduce anxiety, tremor, inattention, or fatigue. Sports that are highly dependent on explosive, short-term anaerobic power (sprinting, throwing, boxing, wrestling) are typically ones which favor a stocky, muscular build, and are most susceptible to androgen-induced increases in muscle mass and strength. Other sports with an emphasis on aerobic effort and endurance (e.g. long distance or duration events), characteristically favored by a lean build, may be boosted by hemoglobin doping (blood transfusion, EPO and its analogs, or mimetics). Finally, sports that depend on recovery from major injury or recurrent minor injury during intensive training, notably combat or collision sports, may benefit from tissue proliferative and remodeling effects of growth hormone and various growth factors.

Figure 1.

Components of Sports Performance.

Figure 2.

Drugs that Enhance Sports Performance.

ANDROGENS

Although the ergogenic effects of androgens were discovered empirically soon after the identification of testosterone as the principal male androgen of testicular origin in 1935 (32), their applications to elite sport performance were mainly developed during the Cold War by trial and error experiments undertaken on unknowing elite athletes (20, 33, 34); however, the scientific basis of androgen doping was only objectively proven in the 1990’s. Until that time, the settled consensus was that exogenous androgens had no effect in eugonadal men whose androgen receptors were already saturated by endogenous testosterone (T) (20, 35, 35). The then alleged benefits of androgen doping were misattributed placebo responses together with training and nutritional effects. Using an exemplary placebo-controlled, randomized clinical trial design with a wide range of testosterone doses, Bhasin et al showed that T increased muscle mass and strength in eugonadal young men to a similar extent as exercise alone and with additive effects when combined with exercise (37) (figure 3). Subsequent dose-response studies showed that administration of T increased muscle mass and strength by 10% without and 20-37% with exercise (where exercise alone increased them by 10-20%) together with additive effects from 3% increase in circulating hemoglobin. These benefits extended from below to well above physiological T doses or blood levels without evidence of plateau (38, 39) and regardless of age (40).

Figure 3.

Biological Basis of Androgen Doping.

Androgen doping may be either direct or indirect (Table 3, figure 4). Direct androgen doping involves administration of testosterone, natural or synthetic androgens whereas indirect androgen doping includes a variety of non-androgenic drugs which increase endogenous T. Direct androgen doping originally involved all pharmaceutically marketed natural (T, DHT, nandrolone) and synthetic androgens but has extended to non-marketed designer and nutraceutical androgens as well as pro-androgens (androstenedione, DHEA) and the new class of non-steroidal androgens (selective androgen receptor modulators, SARM (41)). Indirect androgen doping involves use of hCG, LH, anti-estrogens (estrogen receptor blockers, aromatase inhibitors), opioid antagonists and neurotransmitters involved in neuroendocrine regulation of endogenous LH and T secretion (42-45).

Figure 4.

Direct and Indirect Androgen Doping.

Detection of direct androgen doping using steroids of known chemical structure is highly effective using gas or liquid chromatography MS (46-48) . Traces of synthetic androgens or their metabolites may remain detectable for periods up to months after last administration (49). Recent developments including the ability to detect testosterone esters in serum or dried blood spots (50-56) and identification of long-term metabolites has further widened the detection windows for synthetic androgens (57-63). Challenges to detection of synthetic androgens have included the development of non-marketed designer and nutraceutical androgens, the use of natural androgens and pro-androgens, masking methods, restricting use to out-of-competition training or micro-dosing. Designer and nutraceutical androgens are typically non-marketed synthetic androgens based on structures and synthesis methods recovered from expired patent literature of the 1960-70’s. These are now synthesized by unregulated chemical manufacturers without Good Manufacturing Practice (GMP) licensing advertising and sold over the internet or over-the-counter as nutritional supplements, which may contain undeclared steroids (64). However, once the chemical structures of any synthetic androgens are known, they are easily detectable although the sheer profusion of such chemicals represents an ongoing challenge. Nevertheless, despite their novelty, there is little evidence that designer androgens have been used after they are discovered so that there is a high likelihood of detection. As a result, virtually all ongoing androgen ADRVs are still due to conventional marketed synthetic androgens.

HEMOGLOBIN (BLOOD) DOPING

Hemoglobin doping involves either direct blood transfusion or indirect methods of increasing hemoglobin via stimulating erythropoiesis by administration of erythropoietin, its analogs or mimetics (see excellent reviews (148, 149)) (Table 4). Boosting hemoglobin is advantageous in aerobic, endurance sports such as road cycling, distance running, and cross-country skiing. Maximal oxygen consumption (Vo₂), a rate-limiting factor in aerobic exercise, principally determined by cardiac output and blood oxygen transfer with a lesser contribution from tissue oxygen transfer (150). Experiments on exercise tolerance and blood transfusion were first reported in 1945 (151, 152) but the scientific basis of hemoglobin doping via enhanced tissue oxygen transfer was firmly established in 1972 by the work of Ekblom et al reporting experiments in healthy volunteers who underwent venesection and/or re-transfusion of 1, 2 or 3 units (400 mL) of blood with repeated testing of maximal exercise-induced oxygen consumption before and after each procedure (153). This proved unequivocally that the maximal oxygen consumption was highly correlated with acute changes in hemoglobin (figure 5). Subsequently, during the 1970-80’s before its banning in 1988, blood transfusion became a prevalent surreptitious practice in road cycling and cross-country skiing and the apparently low prevalence among distance runners may be an underestimation (154). Modeling of historical performance in European road cycling from 1993 onwards shows a unique progression averaging an improvement of 6.4% corresponding closely with the performance enhancement (6-7%) due to rhEPO administration, which is sustained for at least 4 weeks after administration (155-157).

Figure 5.

Biological Basis of Blood Doping.

GROWTH HORMONE

Growth hormone (GH) is a tissue growth promoter in children but after puberty it is predominantly a metabolic hormone although latent tissue growth promoting effects may be unleashed under non-physiological circumstances, such as during recovery from tissue injury. There is consistent anecdotal evidence that GH has been used in elite sports for decades (218). Nevertheless, ergogenic effects of GH remain unproven and largely speculative as discussed in excellent recent reviews (219-221). Claims of GH benefits in sport have included increases in muscle mass and strength, especially in conjunction with androgens, and/or improved tissue healing with more rapid recovery from either major injuries or minor repetitive injuries, such as from intense physical training allowing for more effective training. The biological basis of ergogenic effects of GH has been tested in these two different scenarios with largely inconclusive findings.

Evidence for direct enhancement of athletic performance by GH has been investigated in two well-controlled RCTs with a primary focus on athletic performance. In one study, 96 recreational sub-elite athletes (63 male, 33 female, mean age 28 yr) were administered 8 weeks of daily sc injections of GH or placebo with the men also having weekly im injections of T enanthate or saline placebo for the last 5 weeks (222). GH increased lean (muscle) mass (by +2.7 kg) and reduced fat mass (by -1.4 kg) while T increased lean mass (alone by +2.4 kg, by +5.8 kg with GH). The effects of GH were marginally significant for anaerobic sprint capacity (by +3.9%, p=0.05) when pooling male and female participants but this was due to significant effects in men only (by +5.5% alone and +8.3% with GH). However, there were no significant effects on maximal Vo₂ consumption, dead lift or jump height (222). A second study involved 30 healthy non-athletes (15 male, 15 female, mean age 25 yr) who were administered daily sc injections of GH at high (4.6 mg/day) or low (2.3 mg/day) doses or placebo (223). There was no significant effect on muscle mass or maximal Vo₂ consumption. Additional controlled studies of GH effects but with less focus on athletic performance have also shown that (a) a single dose of GH (~0.8 mg) in 9 recreational athletes did not affect maximal Vo₂ or power output in repeated 30 min bursts of bicycle ergometry (224), (b) short term (6 days), low dose GH (~1.7 mg/day) treatment of 48 male androgen abusers withdrawn from androgens for 12 weeks significantly increased maximal Vo₂ more than placebo (225), (c) daily sc injections of a GH receptor antagonist (pegvisomant) or placebo for 16 days to 20 sedentary men did not change maximal Vo₂ although time to exhaustion at 90% maximal Vo₂ was reduced (226) and (d) 4 weeks of daily sc injections of GH (~5 mg/day) increased whole body protein synthesis (227), lipolysis and glucose uptake (228) with uncertain significance for athletic performance. Overall, these studies indicate that GH has, at most, a modest ergogenic effect in men only and there through enhancing T effects. That is consistent with the fact that young women have markedly greater growth hormone secretion than young men so that growth hormone cannot explain the sex differences in athletic performance (229). A meta-analysis concluded that “… GH administration … does not increase either muscle strength or aerobic exercise capacity in healthy, young subjects” (230).

It is also claimed that GH may enhance injury healing, thereby facilitating more intensive training and/or recovery from muscle, connective tissue or bone injury, notably in contact sports. This claim is difficult to evaluate and no well-controlled studies of recovery from sports injuries or tolerance of training intensity in elite athletes are reported. The most germane surrogate evidence available arises from investigations on the use of GH in recovery from injuries due to burns, fracture, or for wound healing. A recent Cochrane meta-analysis review of GH treatment effects on recovery from burns injury and healing of donor skin graft sites suggests that GH has a small benefit in skin healing with large burns and reduced hospital stay but there was no benefit in reducing mortality or scarring and adverse effects, notably hyperglycemia, were increased (231). In practice, the increased mortality due to administration of high dose GH in critical illness (232) has led to GH treatment not being widely adopted in clinical practice of treatment of burns. Similarly, the only well controlled study of GH effects on bone healing from fracture reported that, among over 400 patients with tibial fractures treated for up to 16 weeks with GH (1, 2 or 4 mg/day) or placebo, there was no benefit of GH for overall healing (233). Finally, while there are numerous experimental studies of GH or growth factors on wound healing in animal models a wide variety of findings are reported with detrimental, neutral or beneficial effects but no well-controlled human studies are available. In summary, the available evidence for improved tissue repair or regeneration is minimal.

Important caveats on interpreting these few well-designed studies are that the effects of higher GH and T doses, as used in doping, have not been studied so that more potent higher dose and/or interactive effects cannot be excluded in the absence of well controlled, high dose, placebo-controlled studies. Nevertheless, the hypothesis that high dose GH exposure would enhance muscular function is inconsistent with the experience of acromegaly in which patients experience much higher (25-100 times) growth hormone exposure than doses that can be ethically administered to healthy human volunteers (234) yet characteristically display muscular weakness rather than increased muscle size or strength (235). Anti-doping science history suggests that caution is required before rejecting evidence for claimed ergogenic effects without investigations replicating the pharmacological doses used.

Furthermore, safety analysis is not feasible based on the few, small, short-term studies of GH’s potential ergogenic effects; however, there are significant safety concerns about the long-term risk of cancer following GH administration. Even standard therapeutic GH doses administered to GH deficient children are associated with increased risk of second cancers in some (236-238) but not all (239) follow-up studies although these risks appear largely confined to survivors of childhood cancers and its treatment which render them GH deficient (240-243). Although the significant cancer risk based on uncontrolled observational cohort data using standard GH doses remains contentious (244, 245), the long-term risks of much higher GH doses used illicitly by athletes must be viewed with significant concern.

Detection of GH doping remains difficult (246). A major challenge is the non-glycosylated primary structure of recombinant and endogenous 22 kDa GH, that lack the distinctive side-chain carbohydrate differences of exogenous glycoproteins EPO or hCG which provide a convenient basis for sensitive molecular detection tests. Nevertheless, minor infidelities in commercial manufacturing of GH may incorporate distinctive non-natural chemical features proving an exogenous origin (247-249) although these findings have not been developed into detection tests. Challenges to the detection of GH doping arise from the physiological pattern of endogenous GH secretion with its intermittent, pulsatile pattern subject to prominent influence of exercise, stress, and nutritional effects together with GH’s brief circulating half-life and low urine concentrations (250, 251). Like other major doping classes, there are both direct and indirect forms of GH doping, involving either direct administration of GH or IGF-I or their analogs and indirect GH doping involving drugs that aim to increase endogenous GH and IGF-I secretion (Table 5). Detection of a range of gonadotrophin and growth hormone releasing factor analogs has been reported (252, 253).

The first test to detect administration of exogenous GH, the 22kD recombinant form of human GH, was based on blood sampling to measure the ratio of circulating isoforms of GH recognizing the fact that the pituitary secretes not only the major 22 kD isoform (65-80%) but also a variety of minor isoforms including a wide variety of minor isoforms and their multimeric variants (254). Administration of exogenous GH suppresses endogenous pituitary GH secretion leading to a predominance of circulating 22 kD GH. This is the basis for the GH isoform ratio test whereby a serum sample is measured by two different GH immunoassays, one with predominant 22 kD GH specificity (“rec” assay) and the other recognizing the broad spectrum of pituitary GH isoforms (“pit” assay) and the ratio of results (“rec”/”pit” ratio) is an index to detect administration of exogenous recombinant GH (250, 255). This ratio test then serves to detect administration of exogenous recombinant human 22kD GH analogous to detect exogenous T by the urine T/E ratio and exogenous insulin by analysis of serum C peptide (256). The differential GH isoform ratio test has undergone extensive validation involving standardization of the two GH immunoassays with distinctive immunoreactivities to quantify 20kD and 22kD epitopes as well as its application to various populations of elite athletes and evaluating physiological factors which might impact on the validity of test read-out. A strength of this test is that it is aimed at the exogenous doping agent itself, although it cannot definitively distinguish it from its endogenous counterpart. The major limitations of this differential isotope ratio test are its narrow window of detection (24-36 hours post administration) and its inability to detect indirect GH doping. While pituitary-derived human GH might not be detected, human pituitary GH, once obtained from national scale pituitary collection and purification programs, has not been available since 1985 when its risks of Creutzfeldt-Jakob disease were identified (257, 258) with recombinant human GH replacing pituitary-extracted GH worldwide. This differential isoform test was first introduced for the 2004 Olympics (259) and led in 2010 to the first successful detection of out of competition GH doping (260).

A complementary detection test with a wider window of detection has been developed based on biomarkers of GH action. This uses two serum biomarkers of tissue GH effects, circulating IGF-1 as a short-term marker of hepatic GH action, and N-terminal peptide of procollagen type III (PIII-NP) as a long-term marker of GH-dependent collagen synthesis. In a study of 102 recreational athletes (53 male, 49 female, mean age 25 years, from 4 different European cities) randomly assigned to self-inject 2.7 mg or 5.4 mg GH or placebo once daily, measurement of serum IGF-1 and PIII-NP by specific immunoassays were able to correctly classify 86% of samples from males and 60% of samples from female using an empirical linear discriminant analysis of log-transformed serum IGF-1 and PIII-NP at the specificity of 1:10,000 required for a WADA biomarker threshold (261). Subsequent studies have shown that additional collagen biomarkers, N-terminal propeptide and C-terminal telopeptide of type I collagen, further widen the window of detection for GH administration (262, 263). This multiplex biomarker test, based on using standardized immunoassay antibodies, requires establishment of reliable reference range with specificity (false positive detection rate) of no more than 1:10,000 incorporating the impact of gender and age, although exercise, injury, ethnicity and sports type appear not to be confounding influences. Modifications of the analyte profile to include fibronectin 1 were recently proposed (264). The statistical properties of this GH biomarker test and its reliance on large sample size for reliable assignment of confidence limits has been reported (265). The two GH doping tests, the differential isoform and biomarker approaches, are considered ultimately complementary (266). The application of both tests in a longitudinal analysis has high, if not perfect, detection capability for GH doping when used in an ABP format (267).

Therapeutic Use Exemption (TUE) allowing athletes to use GH when medically necessary may be permitted for evidence of pre-pubertal GH deficiency and for some cases of non-GH deficient short stature (268); however, a TUE is unlikely to be acceptable for GH administration to adults when GH is a metabolic, rather than a growth promoting hormone as it is in children.

GLUCOCORTICOIDS

Glucocorticoids have many medical uses in the general community and consequently are often used by athletes; however, supraphysiological doses of synthetic glucocorticoids are performance enhancing and they are prohibited during competition under the WADA Code. Physiological glucocorticoid replacement therapy for primary or secondary adrenal insufficiency and for congenital adrenal hyperplasia are well known but infrequent indications among elite athletes. These are acceptable under a Therapeutic Use Exemption where the athlete has a proven medical need for such treatment.

Much more frequent is the use of pharmacological doses of synthetic glucocorticoids for anti-inflammatory and/or immunosuppressive effects for a wide variety of diseases. Such pharmacological glucocorticoid therapeutics, typically using supraphysiological oral or parenteral administration, considered necessary for medical care is not prohibited by WADA outside of competition. However, as supraphysiological glucocorticoid doses over days to a week have proven ergogenic effects (288, 289), consequently they are prohibited for use in competition (290). The ergogenic mechanism is unclear but likely involves acute mood elevation to blunt fatigue perception and/or metabolic effects improving muscle force energetics and efficiency and these effects are evident in short-term (days), but not single dose, studies (288). Use in competition is defined as oral or parenteral (injection by all routes) delivery on the day of the event (defined as starting from the midnight before the day of competition) and prohibited usage can be detected by the measured glucocorticoid concentrations exceeding drug-specific thresholds from defined by pharmacologically established washout periods for each drug (288, 291-293).

THYROID HORMONES

Thyroid hormones (TH), thyroxine (T4) and its more potent metabolite, triiodothyronine (T3), have long been reported as used by some athletes but TH are not prohibited in sport. Unlike androgens and glucocorticoids, there is not only no evidence that THs are ergogenic, but the available evidence suggests that supraphysiological exogenous TH ingestion, beyond physiological replacement doses, is likely to be detrimental to exercise performance in creating a hyperthyroidal state detrimental to health and exercise performance (294). Hence in the absence of any plausible ergogenic effects, TH are not prohibited in sport.

Advocacy for TH use mostly arises in bodybuilding street folklore but lacks objective or even plausible supportive evidence for performance enhancement. The wished-for objectives include weight loss or improved body composition (reducing fat rather than muscle), overcoming reduced circulating T3 and/or boosting androgen effects, increasing alertness, and other extrapolated in vitro biochemical effects; however, none of these has sound physiological basis or empirical evidence in humans. On the contrary the likelihood is that exogenous TH use, beyond replacement doses, would be detrimental to exercise performance (294). Supraphysiological TH doses are likely to create hyperthyroidism which would be detrimental to health and exercise performance including creating muscular weakness and adverse metabolic effects. Low serum T3 in athletes are likely the result of intense training and/or nutritional deficits, termed the Reduced Energy Deficiency in Sports (REDS) (295, 296), a variant of non-thyroidal illness syndrome and not hypothyroidism warranting TH treatment (297). One study of 500 Australian athletes reported that there was minimal use of TH declared on their doping control forms, completed at each antidoping test, nor any biochemical evidence of TH abuse (298).

Detection of TH doping would be difficult to achieve. Detecting TH doping would most likely be feasible by using blood samples, including dried blood spots, to measure serum TSH as an index of thyroidal status, together with serum T4 and T3 concentrations. This would be most effective when deployed in an Athletes Biological Passport (ABP) Bayesian format, whereby serial measurements within an individual provide sensitive detection of significant suppression of serum TSH. An alternative has been proposed based on measuring multiple biologically inactive metabolites of T4 and T3 to potentially serve as biomarkers of exogenous TH administration. However, available evidence from a study of one individual administered TH and observations from athlete samples comparing those who did and did not declare TH use on their Doping Control Forms (299), has not established that inactive metabolites can distinguish between endogenous and exogenous sources of TH, requiring substantial further research to evaluate its potential to detect TH doping.

PROGRESS, GAPS, AND FUTURE PROSPECTS

Anti-doping science continues to make major progress over recent decades especially since the advent of WADA with its harmonization and focus on deterrence through standardized testing. Progress from improved MS-based testing methodologies and instrumentation, summarized annually in the major antidoping science journal, Drug Testing and Analysis (300), is evident from the increasing numbers of ADRV findings among frozen stored urine samples now banked for 10 years from previous Olympics. Like any efforts to combat human malfeasance, the quest for drug-free and safe sport requires ongoing vigilance and continual renewal of intelligence-based detection testing. While great progress has been made in the two canonical forms of doping, androgen and hemoglobin doping, human ingenuity continually finds way to challenge the testing just as traditional frauds are supplanted by cyber-crime and ingenious computer hacking. It is important to bear in mind that the winning margin (defined as the difference in performance between gold and silver medals, getting a medal or not, making a final or not in the Olympic athletic or swimming events) is <1% (299) so even small systematic advantages may be important motives and unfair advantages for doping.

The major gaps remaining in anti-doping science are (a) the lack of a definitive test for autologous blood transfusion, (b) need for more sensitive detection tests for peptide hormone doping with wider windows of detection and (c) more economical, affordable, and robust sample handling and storage procedures including dried blood spot sampling. These challenges must be met by adapting novel technologies such as quantitative proteomics, genomics, and metabolomics as well as implementing more out of competition blood testing. Such progress depends on innovative applied research which is supported by WADA, Partnership for Clean Competition, and certain national anti-doping organizations together with regular peer-review research granting agencies. Finally, the development of effective forensic intelligence investigations, focused on non-laboratory elements of doping including the acquisition, possession, and distribution of prohibited substances, involving analysis of suspicious movements and communications of athletes and coaches, is a slow, complex and costly process but which can have salutary effects (e.g. for road cycling in the Lance Armstrong case; the Russian national doping schemes), is proving a valuable complementary approach as an adjunct to effective laboratory testing.

REFERENCES

1.

Handelsman, D.J. & Gooren, L.J. Hormones and sport: physiology, pharmacology and forensic science. Asian J Androl 10, 348-50 (2008). [PubMed: 18385896]

2.

Rawls, J. Justice as Fairness: A Restatement (Belknap, Harvard University Press, Cambridge, MA, 2001).

3.

Ryan, A. Fairness and philosopy. Social Research 73, 597-606 (2006).

4.

Wiesing, U. Should performance-enhancing drugs in sport be legalized under medical supervision? Sports Med 41, 167-76 (2011). [PubMed: 21244107]

5.

Shuster, S. & Devine, J.W. The banning of sportsmen and women who fail drug tests is unjustifiable. J R Coll Physicians Edinb 43, 39-43 (2013). [PubMed: 23516691]

6.

Savulescu, J., Creaney, L. & Vondy, A. Should athletes be allowed to use performance enhancing drugs? BMJ 347, f6150 (2013). [PubMed: 24149520]

7.

Uvacsek, M. et al. Self-admitted behavior and perceived use of performance-enhancing vs psychoactive drugs among competitive athletes. Scand J Med Sci Sports 21, 224-34 (2011). [PubMed: 19903314]

8.

Petroczi, A. et al. Incongruence in doping related attitudes, beliefs and opinions in the context of discordant behavioural data: in which measure do we trust? PLoS One 6, e18804 (2011). [PMC free article: PMC3082532] [PubMed: 21541317]

9.

Dunn, M., Thomas, J.O., Swift, W., Burns, L. & Mattick, R.P. Drug testing in sport: the attitudes and experiences of elite athletes. Int J Drug Policy 21, 330-2 (2010). [PubMed: 20079619]

10.

Bloodworth, A.J., Petroczi, A., Bailey, R., Pearce, G. & McNamee, M.J. Doping and supplementation: the attitudes of talented young athletes. Scand J Med Sci Sports 22, 293-301 (2012). [PubMed: 20973831]

11.

Lamberti, N. et al. Antidoping attitudes among elite athletes: a cross sectional study in biathlon using a suitably developed questionnaire. J Sports Med Phys Fitness 57, 610-623 (2017). [PubMed: 27139792]

12.

Backhouse, S.H., Whitaker, L. & Petroczi, A. Gateway to doping? Supplement use in the context of preferred competitive situations, doping attitude, beliefs, and norms. Scand J Med Sci Sports 23, 244-52 (2013). [PubMed: 22092778]

13.

Morente-Sanchez, J. & Zabala, M. Doping in sport: a review of elite athletes’ attitudes, beliefs, and knowledge. Sports Med 43, 395-411 (2013). [PubMed: 23532595]

14.

Petroczi, A., Mazanov, J., Nepusz, T., Backhouse, S.H. & Naughton, D.P. Comfort in big numbers: Does over-estimation of doping prevalence in others indicate self-involvement? J Occup Med Toxicol 3, 19 (2008). [PMC free article: PMC2553062] [PubMed: 18775068]

15.

Dunn, M., Thomas, J.O., Swift, W. & Burns, L. Elite athletes’ estimates of the prevalence of illicit drug use: evidence for the false consensus effect. Drug Alcohol Rev 31, 27-32 (2012). [PubMed: 21450047]

16.

Thomas H. Murray. Good Sport (Oxford University Press, 2018).

17.

Eynon, N. et al. Genes and elite athletes: a roadmap for future research. J Physiol 589, 3063-70 (2011). [PMC free article: PMC3145924] [PubMed: 21540342]

18.

de la Chapelle, A., Traskelin, A.L. & Juvonen, E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A 90, 4495-9 (1993). [PMC free article: PMC46538] [PubMed: 8506290]

19.

Berman, Y. & North, K.N. A gene for speed: the emerging role of alpha-actinin-3 in muscle metabolism. Physiology (Bethesda) 25, 250-9 (2010). [PubMed: 20699471]

20.

Wade, N. Anabolic Steroids: Doctors Denounce Them, but Athletes Aren’t Listening. Science 176, 1399-403 (1972). [PubMed: 17834639]

21.

Ljungqvist, A. Half a century of challenges. Bioanalysis 4, 1531-3 (2012). [PubMed: 22831467]

22.

WADA. (WADA, Montreal, 2025).

23.

Egner, I.M., Bruusgaard, J.C., Eftestol, E. & Gundersen, K. A cellular memory mechanism aids overload hypertrophy in muscle long after an episodic exposure to anabolic steroids. J Physiol 591, 6221-30 (2013). [PMC free article: PMC3892473] [PubMed: 24167222]

24.

de Hon, O., Kuipers, H. & van Bottenburg, M. Prevalence of doping use in elite sports: a review of numbers and methods. Sports Med 45, 57-69 (2015). [PubMed: 25169441]

25.

Lensveldt-Mulders, G.J.L., Hox, J.J., van der Heijden, P.G.M. & Maas, C.J.M. Meta-analysis of randomized response research. Socieological Methods & Research 33, 319-48 (2005).

26.

Ulrich, R. et al. Doping in Two Elite Athletics Competitions Assessed by Randomized-Response Surveys. Sports Med 48, 211-219 (2018). [PubMed: 28849386]

27.

Schroter, H. et al. A Comparison of the Cheater Detection and the Unrelated Question Models: A Randomized Response Survey on Physical and Cognitive Doping in Recreational Triathletes. PLoS One 11, e0155765 (2016). [PMC free article: PMC4878800] [PubMed: 27218830]

28.

WADA. (2014).

29.

Di Luigi, L. et al. The use of prohibited substances for therapeutic reasons in athletes affected by endocrine diseases and disorders: the therapeutic use exemption (TUE) in clinical endocrinology. J Endocrinol Invest 43, 563-573 (2020). [PubMed: 31734891]

30.

Allan, C.M. et al. Estradiol induction of spermatogenesis is mediated via an estrogen receptor-{alpha} mechanism involving neuroendocrine activation of follicle-stimulating hormone secretion. Endocrinology 151, 2800-10 (2010). [PMC free article: PMC2875821] [PubMed: 20410197]

31.

WADA Medical Information to Support the Decisions of TUECs - Androgen Deficiency-Male Hypogonadism 2015 https://www​.wada-ama​.org/en/resources/science-medicine​/medical-information-to-support-the-decisions-of-tuecs-adrenal#​.VDhr4Bb92-Q.

32.

David, K., Dingemanse, E., Freud, J. & Laqueur, E. Uber krystallinisches mannliches Hormon aus Hoden (Testosteron), wirksamer als aus Harn oder aus Cholestrin bereitetes Androsteron. Hoppe Seylers Zeischrift Physiologische Chemie 233, 281-2 (1935).

33.

Yesalis, C.E., Courson, S.P. & Wright, J.E. in Anabolic Steroids in Sports and Exercise (ed. Yesalis, C.E.) 51-71 (Human Kinetics, Champaign, IL, 2000).

34.

Franke, W.W. & Berendonk, B. Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clinical Chemistry 43, 1262-79 (1997). [PubMed: 9216474]

35.

Ryan, A.J. Anabolic steroids are fool’s gold. Fed Proc 40, 2682-8 (1981). [PubMed: 6269903]

36.

Elashoff, J.D., Jacknow, A.D., Shain, S.G. & Braunstein, G.D. Effects of anabolic-androgenic steroids on muscular strength. Annals of Internal Medicine 115, 387-393 (1991). [PubMed: 1830732]

37.

Bhasin, S. et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. New England Journal of Medicine 335, 1-7 (1996). [PubMed: 8637535]

38.

Woodhouse, L.J. et al. Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab 284, E1009-17 (2003). [PubMed: 12517741]

39.

Storer, T.W. et al. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab 88, 1478-85 (2003). [PubMed: 12679426]

40.

Bhasin, S. et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 90, 678-88 (2005). [PubMed: 15562020]

41.

Thevis, M. & Schanzer, W. Detection of SARMs in doping control analysis. Mol Cell Endocrinol 464, 34-45 (2018). [PubMed: 28137616]

42.

Stenman, U.H., Hotakainen, K. & Alfthan, H. Gonadotropins in doping: pharmacological basis and detection of illicit use. Br J Pharmacol 154, 569-83 (2008). [PMC free article: PMC2439513] [PubMed: 18414398]

43.

Handelsman, D.J. Indirect androgen doping by oestrogen blockade in sports. Br J Pharmacol 154, 598-605 (2008). [PMC free article: PMC2439522] [PubMed: 18500381]

44.

Handelsman, D.J. Clinical review: The rationale for banning human chorionic gonadotropin and estrogen blockers in sport. J Clin Endocrinol Metab 91, 1646-53 (2006). [PubMed: 16478815]

45.

Mauras, N., Rogol, A.D. & Veldhuis, J.D. Appraising the instantaneous secretory rates of luteinizing hormone and testosterone in response to selective mu opiate receptor blockade in late pubertal boys. J Androl 8, 203-9 (1987). [PubMed: 3040654]

46.

Kicman, A.T. Pharmacology of anabolic steroids. Br J Pharmacol 154, 502-21 (2008). [PMC free article: PMC2439524] [PubMed: 18500378]

47.

Thevis, M. & Schanzer, W. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators. Handb Exp Pharmacol, 99-126 (2010). [PubMed: 20020362]

48.

Ponzetto, F. et al. High-resolution mass spectrometry as an alternative detection method to tandem mass spectrometry for the analysis of endogenous steroids in serum. J Chromatogr B Analyt Technol Biomed Life Sci 1052, 34-42 (2017). [PubMed: 28346887]

49.

Palonek, E. et al. Atypical excretion profile and GC/C/IRMS findings may last for nine months after a single dose of nandrolone decanoate. Steroids 108, 105-11 (2016). [PubMed: 26853157]

50.

Mazzarino, M. et al. Liquid vs dried blood matrices: Application to longitudinal monitoring of androstenedione, testosterone, and IGF-1 by LC-MS-based techniques. J Pharm Biomed Anal 242, 116007 (2024). [PubMed: 38367516]

51.

Forsdahl, G. et al. Detection of testosterone esters in blood. Drug Test Anal 7, 983-9 (2015). [PubMed: 26695486]

52.

Van Renterghem, P. et al. Validation of an ultra-sensitive detection method for steroid esters in plasma for doping analysis using positive chemical ionization GC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 1141, 122026 (2020). [PubMed: 32109748]

53.

Langer, T. et al. Analysis of Testosterone Esters in Serum and DBS Samples-Results From an Interlaboratory Study. Drug Test Anal 17, 1817-1821 (2025). [PubMed: 40138730]

54.

Miyamoto, A., Ota, M., Sato, M. & Okano, M. Simultaneous detection of testosterone, nandrolone, and boldenone esters in dried blood spots for doping control in sports by liquid chromatography-tandem mass spectrometry. Drug Test Anal 17, 42-55 (2025). [PubMed: 38520227]

55.

Solheim, S.A. et al. Stability and detectability of testosterone esters in dried blood spots after intramuscular injections. Drug Test Anal 14, 1926-1937 (2022). [PubMed: 33733610]

56.

Ponzetto, F. et al. LC-MS/MS measurement of endogenous steroid hormones and phase II metabolites in blood volumetric absorptive microsampling (VAMS) for doping control purposes. Clin Chim Acta 557, 117890 (2024). [PubMed: 38537673]

57.

Sobolevsky, T. & Rodchenkov, G. Detection and mass spectrometric characterization of novel long-term dehydrochloromethyltestosterone metabolites in human urine. J Steroid Biochem Mol Biol 128, 121-7 (2012). [PubMed: 22142641]

58.

Sobolevsky, T. & Rodchenkov, G. Mass spectrometric description of novel oxymetholone and desoxymethyltestosterone metabolites identified in human urine and their importance for doping control. Drug Test Anal 4, 682-91 (2012). [PubMed: 22945829]

59.

Thevis, M., Piper, T., Beuck, S., Geyer, H. & Schanzer, W. Expanding sports drug testing assays: mass spectrometric characterization of the selective androgen receptor modulator drug candidates RAD140 and ACP-105. Rapid Commun Mass Spectrom 27, 1173-82 (2013). [PubMed: 23650030]

60.

Rzeppa, S. & Viet, L. Analysis of sulfate metabolites of the doping agents oxandrolone and danazol using high performance liquid chromatography coupled to tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1029-1030, 1-9 (2016). [PubMed: 27394004]

61.

Liu, J. et al. Combined chemical and biotechnological production of 20betaOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT). J Inorg Biochem 183, 165-171 (2018). [PubMed: 29544993]

62.

Esquivel, A., Alechaga, E., Monfort, N. & Ventura, R. Sulfate metabolites improve retrospectivity after oral testosterone administration. Drug Test Anal 11, 392-402 (2019). [PubMed: 30362276]

63.

Esquivel, A. et al. Evaluation of sulfate metabolites as markers of intramuscular testosterone administration in Caucasian and Asian populations. Drug Test Anal 11, 1218-1230 (2019). [PubMed: 30932347]

64.

Kohler, M. et al. Confiscated black market products and nutritional supplements with non-approved ingredients analyzed in the Cologne Doping Control Laboratory 2009. Drug Test Anal 2, 533-7 (2010). [PubMed: 21204286]

65.

Handelsman, D.J. & Bermon, S. Detection of testosterone doping in female athletes. Drug Test Anal 11, 1566-1571 (2019). [PubMed: 31454165]

66.

Saugy, M., Lundby, C. & Robinson, N. Monitoring of biological markers indicative of doping: the athlete biological passport. Br J Sports Med 48, 827-32 (2014). [PubMed: 24659506]

67.

Xue, Y. et al. Adaptive evolution of UGT2B17 copy-number variation. Am J Hum Genet 83, 337-46 (2008). [PMC free article: PMC2556428] [PubMed: 18760392]

68.

Schulze, J.J. et al. Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation. J Clin Endocrinol Metab 93, 2500-6 (2008). [PubMed: 18334593]

69.

Schulze, J.J. et al. Substantial advantage of a combined Bayesian and genotyping approach in testosterone doping tests. Steroids 74, 365-8 (2009). [PubMed: 19056415]

70.

Sottas, P.E., Saugy, M. & Saudan, C. Endogenous steroid profiling in the athlete biological passport. Endocrinol Metab Clin North Am 39, 59-73, viii-ix (2010). [PubMed: 20122450]

71.

Martin-Escudero, P. et al. Impact of the UGT2B17 polymorphism on the steroid profile. Results of a crossover clinical trial in athletes submitted to testosterone administration. Steroids 141, 104-113 (2019). [PubMed: 30503386]

72.

Okano, M. & Shiomura, S. Effectiveness of blood steroidal passport markers for detecting testosterone abuse in Asians. Drug Test Anal 16, 595-603 (2024). [PubMed: 37848395]

73.

Tretzel, L. et al. Use of dried blood spots in doping control analysis of anabolic steroid esters. J Pharm Biomed Anal 96, 21-30 (2014). [PubMed: 24713476]

74.

Salamin, O. et al. Comparison of three different blood matrices for the quantification of endogenous steroids using UHPLC-MS/MS. Drug Test Anal 14, 1920-1925 (2022). [PubMed: 36208447]

75.

Vernec, A.R. The Athlete Biological Passport: an integral element of innovative strategies in antidoping. Br J Sports Med 48, 817-9 (2014). [PubMed: 24659508]

76.

Equey, T. et al. Longitudinal Profiling of Endogenous Steroids in Blood Using the Athlete Biological Passport Approach. J Clin Endocrinol Metab 108, 1937-1946 (2023). [PubMed: 36794909]

77.

Moreillon, B. et al. Variability of the urinary and blood steroid profiles in healthy and physically active women with and without oral contraception. Drug Test Anal 15, 324-333 (2023). [PubMed: 36414566]

78.

Shackleton, C.H., Roitman, E., Phillips, A. & Chang, T. Androstanediol and 5-androstenediol profiling for detecting exogenously administered dihydrotestosterone, epitestosterone, and dehydroepiandrosterone: potential use in gas chromatography isotope ratio mass spectrometry. Steroids 62, 665-73 (1997). [PubMed: 9381514]

79.

Piper, T. & Thevis, M. Applications of Isotope Ratio Mass Spectrometry in Sports Drug Testing Accounting for Isotope Fractionation in Analysis of Biological Samples. Methods Enzymol 596, 403-432 (2017). [PubMed: 28911778]

80.

Piper, T. et al. Determination of 13C/12C ratios of endogenous urinary steroids: method validation, reference population and application to doping control purposes. Rapid Commun Mass Spectrom 22, 2161-75 (2008). [PubMed: 18536069]

81.

Cawley, A.T., Trout, G.J., Kazlauskas, R., Howe, C.J. & George, A.V. Carbon isotope ratio (delta13C) values of urinary steroids for doping control in sport. Steroids 74, 379-92 (2009). [PubMed: 19056414]

82.

Van Renterghem, P., Van Eenoo, P., Sottas, P.E., Saugy, M. & Delbeke, F. Subject-based steroid profiling and the determination of novel biomarkers for DHT and DHEA misuse in sports. Drug Test Anal 2, 582-8 (2010). [PubMed: 21204290]

83.

Polet, M. et al. Prevalence of nandrolone preparations with endogenous carbon isotope ratios in Australia. Drug Test Anal 16, 1345-1349 (2024). [PubMed: 38342098]

84.

Hullstein, I., Sagredo, C. & Hemmersbach, P. Carbon isotope ratios of nandrolone, boldenone, and testosterone preparations seized in Norway compared to those of endogenously produced steroids in a Nordic reference population. Drug Test Anal 6, 1163-9 (2014). [PubMed: 25388436]

85.

Brailsford, A.D., Majidin, W.N.M., Wojek, N., Cowan, D.A. & Walker, C. IRMS delta values ((13) C) of nandrolone and testosterone products available in the UK: Implications for anti-doping. Drug Test Anal 10, 1722-1727 (2018). [PubMed: 30381908]

86.

Brooker, L. et al. Stable carbon isotope ratio profiling of illicit testosterone preparations—domestic and international seizures. Drug Test Anal 6, 996-1001 (2014). [PubMed: 25139646]

87.

Cawley, A. et al. Stable isotope ratio profiling of testosterone preparations. Drug Test Anal 2, 557-67 (2010). [PubMed: 20967879]

88.

Van Renterghem, P., Van Eenoo, P., Sottas, P.E., Saugy, M. & Delbeke, F. A pilot study on subject-based comprehensive steroid profiling: novel biomarkers to detect testosterone misuse in sports. Clin Endocrinol (Oxf) (2011). [PubMed: 21521264]

89.

Jardines, D. et al. Longitudinal evaluation of the isotope ratio mass spectrometric data: towards the ‘isotopic module’ of the athlete biological passport? Drug Test Anal 8, 1212-1221 (2016). [PubMed: 27732769]

90.

de la Torre, X., Jardines, D. & Botre, F. Evaluation of longitudinal (13) C isotope ratio mass spectrometric data in antidoping analysis. Drug Test Anal 14, 1877-1890 (2022). [PubMed: 35738893]

91.

Piper, T., Emery, C. & Saugy, M. Recent developments in the use of isotope ratio mass spectrometry in sports drug testing. Anal Bioanal Chem 401, 433-47 (2011). [PubMed: 21448602]

92.

Piper, T., Emery, C., Thomas, A., Saugy, M. & Thevis, M. Combination of carbon isotope ratio with hydrogen isotope ratio determinations in sports drug testing. Anal Bioanal Chem 405, 5455-66 (2013). [PubMed: 23568614]

93.

Thevis, M., Piper, T., Horning, S., Juchelka, D. & Schanzer, W. Hydrogen isotope ratio mass spectrometry and high-resolution/high-accuracy mass spectrometry in metabolite identification studies: detecting target compounds for sports drug testing. Rapid Commun Mass Spectrom 27, 1904-12 (2013). [PubMed: 23939956]

94.

Kicman, A.T. et al. Criteria to indicate testosterone administration. Br J Sports Med 24, 253-64 (1990). [PMC free article: PMC1478898] [PubMed: 2097025]

95.

Palonek, E., Gottlieb, C., Garle, M., Bjorkhem, I. & Carlstrom, K. Serum and urinary markers of exogenous testosterone administration. J Steroid Biochem Mol Biol 55, 121-7 (1995). [PubMed: 7577715]

96.

Goebel, C. et al. Screening for testosterone abuse in male athletes using the measurement of urinary LH, a revision of the paradigm. Drug Test Anal 1, 511-7 (2009). [PubMed: 20355166]

97.

Akram, O.N. et al. Evaluation of androgenic activity of nutraceutical-derived steroids using mammalian and yeast in vitro androgen bioassays. Anal Chem 83, 2065-74 (2011). [PubMed: 21329390]

98.

Handelsman, D.J. & Heather, A. Androgen abuse in sports. Asian J Androl 10, 403-15 (2008). [PubMed: 18385902]

99.

Zierau, O., Lehmann, S., Vollmer, G., Schanzer, W. & Diel, P. Detection of anabolic steroid abuse using a yeast transactivation system. Steroids 73, 1143-7 (2008). [PubMed: 18550137]

100.

Houtman, C.J. et al. Detection of anabolic androgenic steroid abuse in doping control using mammalian reporter gene bioassays. Anal Chim Acta 637, 247-58 (2009). [PubMed: 19286037]

101.

Cadwallader, A.B., Lim, C.S., Rollins, D.E. & Botre, F. The androgen receptor and its use in biological assays: looking toward effect-based testing and its applications. J Anal Toxicol 35, 594-607 (2011). [PMC free article: PMC4729460] [PubMed: 22080898]

102.

Death, A.K., McGrath, K.C., Kazlauskas, R. & Handelsman, D.J. Tetrahydrogestrinone is a potent androgen and progestin. J Clin Endocrinol Metab 89, 2498-500 (2004). [PubMed: 15126583]

103.

McRobb, L. et al. Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay. Journal of Steroid Biochemistry and Molecular Biology 110, 39-47 (2008). [PubMed: 18395441]

104.

Thevis, M., Geyer, H., Tretzel, L. & Schanzer, W. Sports drug testing using complementary matrices: Advantages and limitations. J Pharm Biomed Anal 130, 220-230 (2016). [PubMed: 27040951]

105.

Kintz, P. Testing for anabolic steroids in hair: a review. Leg Med (Tokyo) 5 Suppl 1, S29-33 (2003). [PubMed: 12935548]

106.

Deng, X.S., Kurosu, A. & Pounder, D.J. Detection of anabolic steroids in head hair. J Forensic Sci 44, 343-6 (1999). [PubMed: 10097359]

107.

Kintz, P., Cirimele, V., Sachs, H., Jeanneau, T. & Ludes, B. Testing for anabolic steroids in hair from two bodybuilders. Forensic Sci Int 101, 209-16 (1999). [PubMed: 10404632]

108.

Kintz, P., Cirimele, V., Jeanneau, T. & Ludes, B. Identification of testosterone and testosterone esters in human hair. J Anal Toxicol 23, 352-6 (1999). [PubMed: 10488923]

109.

Hold, K.M., Borges, C.R., Wilkins, D.G., Rollins, D.E. & Joseph, R.E., Jr. Detection of nandrolone, testosterone, and their esters in rat and human hair samples. J Anal Toxicol 23, 416-23 (1999). [PubMed: 10517545]

110.

Gaillard, Y., Vayssette, F., Balland, A. & Pepin, G. Gas chromatographic-tandem mass spectrometric determination of anabolic steroids and their esters in hair. Application in doping control and meat quality control. J Chromatogr B Biomed Sci Appl 735, 189-205 (1999). [PubMed: 10670734]

111.

Gaillard, Y., Vayssette, F. & Pepin, G. Compared interest between hair analysis and urinalysis in doping controls. Results for amphetamines, corticosteroids and anabolic steroids in racing cyclists. Forensic Sci Int 107, 361-79 (2000). [PubMed: 10689587]

112.

Cirimele, V., Kintz, P. & Ludes, B. Testing of the anabolic stanozolol in human hair by gas chromatography-negative ion chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 740, 265-71 (2000). [PubMed: 10821413]

113.

Kintz, P., Cirimele, V. & Ludes, B. Discrimination of the nature of doping with 19-norsteroids through hair analysis. Clin Chem 46, 2020-2 (2000). [PubMed: 11106346]

114.

Kintz, P., Cirimele, V., Dumestre-Toulet, V. & Ludes, B. Doping control for nandrolone using hair analysis. J Pharm Biomed Anal 24, 1125-30 (2001). [PubMed: 11248508]

115.

Dumestre-Toulet, V., Cirimele, V., Ludes, B., Gromb, S. & Kintz, P. Hair analysis of seven bodybuilders for anabolic steroids, ephedrine, and clenbuterol. J Forensic Sci 47, 211-4 (2002). [PubMed: 12064656]

116.

Kintz, P., Cirimele, V., Dumestre-Toulet, V., Villain, M. & Ludes, B. Doping control for methenolone using hair analysis by gas chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 766, 161-7 (2002). [PubMed: 11820291]

117.

Bresson, M., Cirimele, V., Villain, M. & Kintz, P. Doping control for metandienone using hair analyzed by gas chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 836, 124-8 (2006). [PubMed: 16597518]

118.

Gambelunghe, C. et al. Analysis of anabolic steroids in hair by GC/MS/MS. Biomed Chromatogr 21, 369-75 (2007). [PubMed: 17294499]

119.

Deshmukh, N., Hussain, I., Barker, J., Petroczi, A. & Naughton, D.P. Analysis of anabolic steroids in human hair using LC-MS/MS. Steroids 75, 710-4 (2010). [PubMed: 20435054]

120.

Strano-Rossi, S. et al. Screening for exogenous androgen anabolic steroids in human hair by liquid chromatography/orbitrap-high resolution mass spectrometry. Anal Chim Acta 793, 61-71 (2013). [PubMed: 23953207]

121.

Kintz, P., Cirimele, V. & Ludes, B. Physiological concentrations of DHEA in human hair. J Anal Toxicol 23, 424-8 (1999). [PubMed: 10517546]

122.

Kintz, P., Cirimel, V., Devaux, M. & Ludes, B. Dehydroepiandrosterone (DHEA) and testosterone concentrations in human hair after chronic DHEA supplementation. Clin Chem 46, 414-5 (2000). [PubMed: 10733296]

123.

Rambaud, L. et al. Development and validation of a multi-residue method for the detection of a wide range of hormonal anabolic compounds in hair using gas chromatography-tandem mass spectrometry. Anal Chim Acta 586, 93-104 (2007). [PubMed: 17386700]

124.

Deshmukh, N.I., Barker, J., Petroczi, A. & Naughton, D.P. Detection of testosterone and epitestosterone in human hair using liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 67-68, 154-8 (2012). [PubMed: 22559991]

125.

Segura, J., Pichini, S., Peng, S.H. & de la Torre, X. Hair analysis and detectability of single dose administration of androgenic steroid esters. Forensic Sci Int 107, 347-59 (2000). [PubMed: 10689586]

126.

Brown, H.G. & Perrett, D. Detection of doping in sport: detecting anabolic-androgenic steroids in human fingernail clippings. Med Leg J 79, 67-9 (2011). [PubMed: 21673061]

127.

Anizan, S. & Huestis, M.A. The potential role of oral fluid in antidoping testing. Clin Chem 60, 307-22 (2014). [PMC free article: PMC4545493] [PubMed: 24153253]

128.

Schonfelder, M. et al. Potential detection of low-dose transdermal testosterone administration in blood, urine, and saliva. Drug Test Anal 8, 1186-1196 (2016). [PubMed: 27723957]

129.

Chiodini, I., Ramos-Rivera, A., Marcus, A.O. & Yau, H. Adrenal Hypercortisolism: A Closer Look at Screening, Diagnosis, and Important Considerations of Different Testing Modalities. J Endocr Soc 3, 1097-1109 (2019). [PMC free article: PMC6500795] [PubMed: 31069279]

130.

Welker, K.M. et al. A comparison of salivary testosterone measurement using immunoassays and tandem mass spectrometry. Psychoneuroendocrinology 71, 180-8 (2016). [PubMed: 27295182]

131.

Thevis, M., Krug, O., Geyer, H. & Schanzer, W. Expanding analytical options in sports drug testing: Mass spectrometric detection of prohibited substances in exhaled breath. Rapid Commun Mass Spectrom 31, 1290-1296 (2017). [PMC free article: PMC5519941] [PubMed: 28508503]

132.

Schonfelder, M. et al. Gene expression profiling in human whole blood samples after controlled testosterone application and exercise. Drug Test Anal 3, 652-60 (2011). [PubMed: 22031502]

133.

Young, J. et al. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology 97, 193-202 (2013). [PMC free article: PMC3902960] [PubMed: 22377698]

134.

George, J.T. et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab 96, E1228-36 (2011). [PMC free article: PMC3380939] [PubMed: 21632807]

135.

Dhillo, W.S. et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 90, 6609-15 (2005). [PubMed: 16174713]

136.

Colpaert, T., Risseeuw, M., Deventer, K. & Van Eenoo, P. Investigating the detection of the novel doping‐relevant peptide kisspeptin‐10 in urine using liquid chromatography high‐resolution mass spectrometry. Biomed Chromatogr 38, e5946 (2024). [PubMed: 38978171]

137.

Zvereva, I., Dudko, G. & Dikunets, M. Determination of GnRH and its synthetic analogues’ abuse in doping control: Small bioactive peptide UPLC-MS/MS method extension by addition of in vitro and in vivo metabolism data; evaluation of LH and steroid profile parameter fluctuations as suitable biomarkers. Drug Test Anal 10, 711-722 (2018). [PubMed: 28777889]

138.

Judák, P., Esposito, S., Coppieters, G., Van Eenoo, P. & Deventer, K. Doping control analysis of small peptides: A decade of progress. J Chromatogr B Analyt Technol Biomed Life Sci 1173, 122551 (2021). [PubMed: 33848801]

139.

Görgens, C., Guddat, S., Thomas, A. & Thevis, M. Recent improvements in sports drug testing concerning the initial testing for peptidic drugs (< 2 kDa) - sample preparation, mass spectrometric detection, and data review. Drug Test Anal 10, 1755-1760 (2018). [PubMed: 30239151]

140.

Braunstein, G.D., Rasor, J., Danzer, H., Adler, D. & Wade, M.E. Serum human chorionic gonadotropin levels throughout normal pregnancy. Am J Obstet Gynecol 126, 678-81 (1976). [PubMed: 984142]

141.

Gandy, H.M. in Endocrinology of Pregnancy (eds. Fuchs, F. & Klopper, A.) 123-56 (Harper & Row, Hagerstown, Maryland, 1977).

142.

Woldemariam, G.A. & Butch, A.W. Immunoextraction-tandem mass spectrometry method for measuring intact human chorionic gonadotropin, free beta-subunit, and beta-subunit core fragment in urine. Clin Chem 60, 1089-97 (2014). [PMC free article: PMC4334569] [PubMed: 24899693]

143.

Butch, A.W. & Woldemariam, G.A. Urinary human chorionic gonadotropin isoform concentrations in doping control samples. Drug Test Anal 8, 1147-1151 (2016). [PubMed: 27594536]

144.

Butch, A.W., Ahrens, B.D. & Avliyakulov, N.K. Urine reference intervals for human chorionic gonadotropin (hCG) isoforms by immunoextraction-tandem mass spectrometry to detect hCG use. Drug Test Anal 10, 956-960 (2018). [PubMed: 29098788]

145.

Handelsman, D.J. et al. Effects of recombinant human LH and hCG on serum and urine LH and androgens in men. Clinical Endocrinology 71, 417-28 (2009). [PubMed: 19170708]

146.

Handelsman, D.J. et al. Detection and effects on serum and urine steroid and LH of repeated GnRH analog (leuprolide) stimulation. J Steroid Biochem Mol Biol 141, 113-20 (2014). [PubMed: 24495617]

147.

Graham, M.R. et al. Counterfeiting in performance- and image-enhancing drugs. Drug Test Anal 1, 135-42 (2009). [PubMed: 20355187]

148.

Elliott, S. Erythropoiesis-stimulating agents and other methods to enhance oxygen transport. Br J Pharmacol 154, 529-41 (2008). [PMC free article: PMC2439521] [PubMed: 18362898]

149.

Reichel, C. & Gmeiner, G. Erythropoietin and analogs. Handb Exp Pharmacol, 251-94 (2010). [PubMed: 20020369]

150.

di Prampero, P.E. & Ferretti, G. Factors limiting maximal oxygen consumption in humans. Respir Physiol 80, 113-27 (1990). [PubMed: 2218094]

151.

Pace, N., Consolazio, W.V. & Lozner, E.L. The effect of transfusions of red blood cells on the hypoxia tolerance of normal men. Science 102, 589-91 (1945). [PubMed: 17843173]

152.

Pace, N., Lozner, E.L. & et al. The increase in hypoxia tolerance of normal men accompanying the polycythemia induced by transfusion of erythrocytes. Am J Physiol 148, 152-63 (1947). [PubMed: 20283143]

153.

Ekblom, B., Goldbarg, A.N. & Gullbring, B. Response to exercise after blood loss and reinfusion. J Appl Physiol 33, 175-80 (1972). [PubMed: 5054420]

154.

Hoberman, J. History and prevalence of doping in the marathon. Sports Med 37, 386-8 (2007). [PubMed: 17465615]

155.

Birkeland, K.I. et al. Effect of rhEPO administration on serum levels of sTfR and cycling performance. Med Sci Sports Exerc 32, 1238-43 (2000). [PubMed: 10912888]

156.

Ashenden, M.J. et al. A comparison of the physiological response to simulated altitude exposure and r-HuEpo administration. J Sports Sci 19, 831-7 (2001). [PubMed: 11695504]

157.

Russell, G., Gore, C.J., Ashenden, M.J., Parisotto, R. & Hahn, A.G. Effects of prolonged low doses of recombinant human erythropoietin during submaximal and maximal exercise. Eur J Appl Physiol 86, 442-9 (2002). [PubMed: 11882931]

158.

Nelson, M., Popp, H., Sharpe, K. & Ashenden, M. Proof of homologous blood transfusion through quantification of blood group antigens. Haematologica 88, 1284-95 (2003). [PubMed: 14607758]

159.

Cartron, J.P. & Colin, Y. Structural and functional diversity of blood group antigens. Transfus Clin Biol 8, 163-99 (2001). [PubMed: 11499957]

160.

Giraud, S., Robinson, N., Mangin, P. & Saugy, M. Scientific and forensic standards for homologous blood transfusion anti-doping analyses. Forensic Sci Int 179, 23-33 (2008). [PubMed: 18514452]

161.

Voss, S.C., Thevis, M., Schinkothe, T. & Schanzer, W. Detection of homologous blood transfusion. Int J Sports Med 28, 633-7 (2007). [PubMed: 17614019]

162.

Manokhina, I. & Rupert, J.L. A DNA-based method for detecting homologous blood doping. Anal Bioanal Chem (2013). [PubMed: 23842898]

163.

Stampella, A. et al. Application of DNA-based forensic analysis for the detection of homologous transfusion of whole blood and of red blood cell concentrates in doping control. Forensic Sci Int 265, 204-10 (2016). [PubMed: 27175858]

164.

Giraud, S., Sottas, P.E., Robinson, N. & Saugy, M. Blood transfusion in sports. Handb Exp Pharmacol, 295-304 (2010). [PubMed: 20020370]

165.

Segura, J., Monfort, N. & Ventura, R. Detection methods for autologous blood doping. Drug Test Anal 4, 876-81 (2012). [PubMed: 22407819]

166.

Donati, F. et al. Detecting Autologous Blood Transfusion in Doping Control: Biomarkers of Blood Aging and Storage Measured by Flow Cytofluorimetry. Curr Pharm Biotechnol 19, 124-135 (2018). [PubMed: 29621963]

167.

Doctor, A. & Spinella, P. Effect of processing and storage on red blood cell function in vivo. Semin Perinatol 36, 248-59 (2012). [PMC free article: PMC3404625] [PubMed: 22818545]

168.

Monfort, N., Ventura, R., Balcells, G. & Segura, J. Determination of five di-(2-ethylhexyl)phthalate metabolites in urine by UPLC-MS/MS, markers of blood transfusion misuse in sports. J Chromatogr B Analyt Technol Biomed Life Sci 908, 113-21 (2012). [PubMed: 23040990]

169.

Pottgiesser, T. et al. Hb mass measurement suitable to screen for illicit autologous blood transfusions. Med Sci Sports Exerc 39, 1748-56 (2007). [PubMed: 17909402]

170.

Morkeberg, J. et al. Detecting autologous blood transfusions: a comparison of three passport approaches and four blood markers. Scand J Med Sci Sports 21, 235-43 (2011). [PubMed: 19903320]

171.

Pottgiesser, T., Echteler, T., Sottas, P.E., Umhau, M. & Schumacher, Y.O. Hemoglobin mass and biological passport for the detection of autologous blood doping. Med Sci Sports Exerc 44, 835-43 (2012). [PubMed: 21988933]

172.

Ashenden, M., Gough, C.E., Garnham, A., Gore, C.J. & Sharpe, K. Current markers of the Athlete Blood Passport do not flag microdose EPO doping. Eur J Appl Physiol 111, 2307-14 (2011). [PubMed: 21336951]

173.

Gatterer, H. et al. Low-dose carbon monoxide inhalation to increase total hemoglobin mass and endurance performance: scientific evidence and implications. Front Physiol 15, 1490205 (2024). [PMC free article: PMC11519625] [PubMed: 39473608]

174.

Kannan, M. & Atreya, C. Differential profiling of human red blood cells during storage for 52 selected microRNAs. Transfusion 50, 1581-8 (2010). [PubMed: 20158686]

175.

Pottgiesser, T. et al. Gene expression in the detection of autologous blood transfusion in sports—a pilot study. Vox Sang 96, 333-6 (2009). [PubMed: 19254233]

176.

Sottas, P.E., Robinson, N. & Saugy, M. The athlete’s biological passport and indirect markers of blood doping. Handb Exp Pharmacol, 305-26 (2010). [PubMed: 20020371]

177.

Sottas, P.E., Robinson, N., Rabin, O. & Saugy, M. The athlete biological passport. Clin Chem 57, 969-76 (2011). [PubMed: 21596947]

178.

Pottgiesser, T. & Schumacher, Y.O. Current strategies of blood doping detection. Anal Bioanal Chem (2013). [PubMed: 23934350]

179.

Cazzola, M. A global strategy for prevention and detection of blood doping with erythropoietin and related drugs. Haematologica 85, 561-3 (2000). [PubMed: 10870110]

180.

Parisotto, R. et al. A novel method utilising markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes. Haematologica 85, 564-72 (2000). [PubMed: 10870111]

181.

Parisotto, R. et al. Detection of recombinant human erythropoietin abuse in athletes utilizing markers of altered erythropoiesis. Haematologica 86, 128-37 (2001). [PubMed: 11224480]

182.

Gore, C.J. et al. Second-generation blood tests to detect erythropoietin abuse by athletes. Haematologica 88, 333-44 (2003). [PubMed: 12651273]

183.

Malcovati, L., Pascutto, C. & Cazzola, M. Hematologic passport for athletes competing in endurance sports: a feasibility study. Haematologica 88, 570-81 (2003). [PubMed: 12745277]

184.

Sharpe, K., Ashenden, M.J. & Schumacher, Y.O. A third generation approach to detect erythropoietin abuse in athletes. Haematologica 91, 356-63 (2006). [PubMed: 16503554]

185.

Sottas, P.E. et al. Statistical classificiation of abnormal blood profiles inathletes. International Journal of Biostatistics 2, 3 (2006).

186.

WADA Athlete Biological Passport: Operating guidelines and compilation of required elements. Verson 3.1 2012 http://www​.wada-ama.org​/Documents/Science_Medicine​/Athlete_Biological_Passport​/WADA-ABP-Operating-Guidelines_v3.1-EN.pdf.

187.

Breenfeldt Andersen, A., Nordsborg, N.B., Bonne, T.C. & Bejder, J. Contemporary blood doping-Performance, mechanism, and detection. Scand J Med Sci Sports 34, e14243 (2024). [PubMed: 36229224]

188.

Ekblom, B. & Berglund, B. Effect of erythropoeitin administration on maximal aerobic power in man. Scandanavian Journal of Medicine and Science in Sport 1, 88-93 (1991).

189.

Jelkmann, W. Biosimilar recombinant human erythropoietins (“epoetins”) and future erythropoiesis-stimulating treatments. Expert Opin Biol Ther 12, 581-92 (2012). [PubMed: 22471247]

190.

Catlin, D.H., Fitch, K.D. & Ljungqvist, A. Medicine and science in the fight against doping in sport. J Intern Med 264, 99-114 (2008). [PubMed: 18702750]

191.

Lopez, B. The invention of a ‘drug of mass destruction’: deconstructing the EPO myth. Sport in History 31, 84-109 (2011).

192.

Lasne, F. & de Ceaurriz, J. Recombinant erythropoietin in urine. Nature 405, 635 (2000). [PubMed: 10864311]

193.

Lasne, F., Martin, L., Crepin, N. & de Ceaurriz, J. Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones. Anal Biochem 311, 119-26 (2002). [PubMed: 12470670]

194.

Lasne, F., Thioulouse, J., Martin, L. & de Ceaurriz, J. Detection of recombinant human erythropoietin in urine for doping analysis: interpretation of isoelectric profiles by discriminant analysis. Electrophoresis 28, 1875-81 (2007). [PubMed: 17503402]

195.

Leuenberger, N., Reichel, C. & Lasne, F. Detection of erythropoiesis-stimulating agents in human anti-doping control: past, present and future. Bioanalysis 4, 1565-75 (2012). [PubMed: 22831473]

196.

Breidbach, A. et al. Detection of recombinant human erythropoietin in urine by isoelectric focusing. Clin Chem 49, 901-7 (2003). [PubMed: 12765986]

197.

Wickramasinghe, S. & Medrano, J.F. Primer on genes encoding enzymes in sialic acid metabolism in mammals. Biochimie 93, 1641-6 (2011). [PubMed: 21689720]

198.

Reverter-Branchat, G. et al. Detection of erythropoiesis-stimulating agents in a single dried blood spot. Drug Test Anal 10, 1496-1507 (2018). [PubMed: 29877055]

199.

Durussel, J. et al. Blood transcriptional signature of recombinant human erythropoietin administration and implications for antidoping strategies. Physiol Genomics 48, 202-9 (2016). [PubMed: 26757800]

200.

Beuck, S., Schanzer, W. & Thevis, M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test Anal 4, 830-45 (2012). [PubMed: 22362605]

201.

La Merie Publishing Blockbuster Biologics 2012 2013 http://www​.pipelinereview.com/.

202.

Imagawa, S. et al. Does k-11706 enhance performance and why? Int J Sports Med 28, 928-33 (2007). [PubMed: 17497587]

203.

Richardson, R.S., Tagore, K., Haseler, L.J., Jordan, M. & Wagner, P.D. Increased VO2 max with right-shifted Hb-O2 dissociation curve at a constant O2 delivery in dog muscle in situ. J Appl Physiol (1985) 84, 995-1002 (1998). [PubMed: 9480962]

204.

Pagel, P.S. et al. RSR13, a synthetic modifier of hemoglobin-oxygen affinity, enhances the recovery of stunned myocardium in anesthetized dogs. J Pharmacol Exp Ther 285, 1-8 (1998). [PubMed: 9535987]

205.

Breidbach, A. & Catlin, D.H. RSR13, a potential athletic performance enhancement agent: detection in urine by gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom 15, 2379-82 (2001). [PubMed: 11746905]

206.

Thevis, M., Krug, O. & Schanzer, W. Mass spectrometric characterization of efaproxiral (RSR13) and its implementation into doping controls using liquid chromatography-atmospheric pressure ionization-tandem mass spectrometry. J Mass Spectrom 41, 332-8 (2006). [PubMed: 16421876]

207.

Casadevall, N. et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 346, 469-75 (2002). [PubMed: 11844847]

208.

Macdougall, I.C. et al. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int 81, 727-32 (2012). [PubMed: 22336988]

209.

Unger, E.F., Thompson, A.M., Blank, M.J. & Temple, R. Erythropoiesis-stimulating agents—time for a reevaluation. N Engl J Med 362, 189-92 (2010). [PubMed: 20054037]

210.

Bennett, C.L. et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299, 914-24 (2008). [PubMed: 18314434]

211.

Strippoli, G.F., Navaneethan, S.D. & Craig, J.C. Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev, CD003967 (2006). [PubMed: 17054191]

212.

Tonia, T. et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 12, CD003407 (2012). [PMC free article: PMC8145276] [PubMed: 23235597]

213.

Rampling, M.W. Hyperviscosity as a complication in a variety of disorders. Semin Thromb Hemost 29, 459-65 (2003). [PubMed: 14631545]

214.

Kovesdy, C.P. & Kalantar-Zadeh, K. Iron therapy in chronic kidney disease: current controversies. J Ren Care 35 Suppl 2, 14-24 (2009). [PubMed: 19891681]

215.

Gagnon, D.R., Zhang, T.J., Brand, F.N. & Kannel, W.B. Hematocrit and the risk of cardiovascular disease—the Framingham study: a 34-year follow-up. Am Heart J 127, 674-82 (1994). [PubMed: 8122618]

216.

Danesh, J., Collins, R., Peto, R. & Lowe, G.D. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 21, 515-20 (2000). [PubMed: 10775006]

217.

Braekkan, S.K., Mathiesen, E.B., Njolstad, I., Wilsgaard, T. & Hansen, J.B. Hematocrit and risk of venous thromboembolism in a general population. The Tromso study. Haematologica 95, 270-5 (2010). [PMC free article: PMC2817030] [PubMed: 19833630]

218.

Holt, R.I., Erotokritou-Mulligan, I. & Sonksen, P.H. The history of doping and growth hormone abuse in sport. Growth Horm IGF Res 19, 320-6 (2009). [PubMed: 19467612]

219.

Liu, H. et al. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med 148, 747-58 (2008). [PubMed: 18347346]

220.

Baumann, G.P. Growth hormone doping in sports: a critical review of use and detection strategies. Endocr Rev 33, 155-86 (2012). [PubMed: 22368183]

221.

Holt, R.I.G. & Ho, K.K.Y. The Use and Abuse of Growth Hormone in Sports. Endocr Rev 40, 1163-1185 (2019). [PubMed: 31180479]

222.

Meinhardt, U. et al. The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial. Ann Intern Med 152, 568-77 (2010). [PubMed: 20439575]

223.

Berggren, A. et al. Short-term administration of supraphysiological recombinant human growth hormone (GH) does not increase maximum endurance exercise capacity in healthy, active young men and women with normal GH-insulin-like growth factor I axes. J Clin Endocrinol Metab 90, 3268-73 (2005). [PubMed: 15784718]

224.

Irving, B.A. et al. The effects of time following acute growth hormone administration on metabolic and power output measures during acute exercise. J Clin Endocrinol Metab 89, 4298-305 (2004). [PubMed: 15328062]

225.

Graham, M.R. et al. Short-term recombinant human growth hormone administration improves respiratory function in abstinent anabolic-androgenic steroid users. Growth Horm IGF Res 17, 328-35 (2007). [PubMed: 17512232]

226.

Goto, K., Doessing, S., Nielsen, R.H., Flyvbjerg, A. & Kjaer, M. Growth hormone receptor antagonist treatment reduces exercise performance in young males. J Clin Endocrinol Metab 94, 3265-72 (2009). [PubMed: 19549743]

227.

Healy, M.L. et al. High dose growth hormone exerts an anabolic effect at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab 88, 5221-6 (2003). [PubMed: 14602753]

228.

Healy, M.L. et al. Effects of high-dose growth hormone on glucose and glycerol metabolism at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab 91, 320-7 (2006). [PubMed: 16263834]

229.

Handelsman, D.J., Hirschberg, A.L. & Bermon, S. Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance. Endocr Rev 39, 803-829 (2018). [PMC free article: PMC6391653] [PubMed: 30010735]

230.

Hermansen, K., Bengtsen, M., Kjaer, M., Vestergaard, P. & Jorgensen, J.O.L. Impact of GH administration on athletic performance in healthy young adults: A systematic review and meta-analysis of placebo-controlled trials. Growth Horm IGF Res 34, 38-44 (2017). [PubMed: 28514721]

231.

Breederveld, R.S. & Tuinebreijer, W.E. Recombinant human growth hormone for treating burns and donor sites. Cochrane Database Syst Rev 12, CD008990 (2012). [PubMed: 23235668]

232.

Takala, J. et al. Increased mortality associated with growth hormone treatment in critically ill adults New England Journal of Medicine 341, 785-92 (1999). [PubMed: 10477776]

233.

Raschke, M. et al. Effects of growth hormone in patients with tibial fracture: a randomised, double-blind, placebo-controlled clinical trial. Eur J Endocrinol 156, 341-51 (2007). [PubMed: 17322494]

234.

van den Berg, G., Frolich, M., Veldhuis, J.D. & Roelfsema, F. Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab 79, 1706-15 (1994). [PubMed: 7989479]

235.

Fuchtbauer, L. et al. Muscle strength in patients with acromegaly at diagnosis and during long-term follow-up. Eur J Endocrinol 177, 217-226 (2017). [PubMed: 28566445]

236.

Sklar, C.A. et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 87, 3136-41 (2002). [PubMed: 12107213]

237.

Ergun-Longmire, B. et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab 91, 3494-8 (2006). [PubMed: 16822820]

238.

Carel, J.C. et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab 97, 416-25 (2012). [PubMed: 22238382]

239.

Mo, D., Hardin, D.S., Erfurth, E.M. & Melmed, S. Adult mortality or morbidity is not increased in childhood-onset growth hormone deficient patients who received pediatric GH treatment: an analysis of the Hypopituitary Control and Complications Study (HypoCCS). Pituitary (2013). [PMC free article: PMC4159575] [PubMed: 24122237]

240.

Swerdlow, A.J., Higgins, C.D., Adlard, P. & Preece, M.A. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet 360, 273-7 (2002). [PubMed: 12147369]

241.

Wilton, P., Mattsson, A.F. & Darendeliler, F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr 157, 265-70 (2010). [PubMed: 20400105]

242.

Mackenzie, S. et al. Long-term safety of growth hormone replacement after CNS irradiation. J Clin Endocrinol Metab 96, 2756-61 (2011). [PubMed: 21715535]

243.

Woodmansee, W.W. et al. Incidence of second neoplasm in childhood cancer survivors treated with GH: an analysis of GeNeSIS and HypoCCS. Eur J Endocrinol 168, 565-73 (2013). [PubMed: 23359434]

244.

Jenkins, P.J., Mukherjee, A. & Shalet, S.M. Does growth hormone cause cancer? Clin Endocrinol (Oxf) 64, 115-21 (2006). [PubMed: 16430706]

245.

Holly, J. & Perks, C. Growth hormone and cancer: are we asking the right questions?*. Clin Endocrinol (Oxf) 64, 122-4 (2006). [PubMed: 16430707]

246.

Ho, K.K. & Nelson, A.E. Growth hormone in sports: detecting the doped or duped. Horm Res Paediatr 76 Suppl 1, 84-90 (2011). [PubMed: 21778756]

247.

Hepner, F., Cszasar, E., Roitinger, E. & Lubec, G. Mass spectrometrical analysis of recombinant human growth hormone (Genotropin®) reveals amino acid substitutions in 2% of the expressed protein. Proteome Sci 3, 1 (2005). [PMC free article: PMC549540] [PubMed: 15707495]

248.

Hepner, F., Csaszar, E., Roitinger, E., Pollak, A. & Lubec, G. Mass spectrometrical analysis of recombinant human growth hormone Norditropin reveals amino acid exchange at M14_V14 rhGH. Proteomics 6, 775-84 (2006). [PubMed: 16372270]

249.

Jiang, H., Wu, S.L., Karger, B.L. & Hancock, W.S. Mass spectrometric analysis of innovator, counterfeit, and follow-on recombinant human growth hormone. Biotechnol Prog 25, 207-18 (2009). [PubMed: 19224592]

250.

Bidlingmaier, M. & Strasburger, C.J. Growth hormone. Handb Exp Pharmacol, 187-200 (2010). [PubMed: 20020365]

251.

Bosch, J. et al. Analysis of urinary human growth hormone (hGH) using hydrogel nanoparticles and isoform differential immunoassays after short recombinant hGH treatment: preliminary results. J Pharm Biomed Anal 85, 194-7 (2013). [PMC free article: PMC5557414] [PubMed: 23954438]

252.

Memdouh, S., Gavrilovic, I., Ng, K., Cowan, D. & Abbate, V. Advances in the detection of growth hormone releasing hormone synthetic analogs. Drug Test Anal 13, 1871-1887 (2021). [PubMed: 34665524]

253.

Judak, P., Esposito, S., Coppieters, G., Van Eenoo, P. & Deventer, K. Doping control analysis of small peptides: A decade of progress. J Chromatogr B Analyt Technol Biomed Life Sci 1173, 122551 (2021). [PubMed: 33848801]

254.

Bidlingmaier, M. et al. High-sensitivity chemiluminescence immunoassays for detection of growth hormone doping in sports. Clin Chem 55, 445-53 (2009). [PubMed: 19168559]

255.

Bidlingmaier, M. & Manolopoulou, J. Detecting growth hormone abuse in athletes. Endocrinol Metab Clin North Am 39, 25-32, vii (2010). [PubMed: 20122447]

256.

Marks, V. Murder by insulin: suspected, purported and proven-a review. Drug Test Anal 1, 162-76 (2009). [PubMed: 20355194]

257.

Will, R.G. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br Med Bull 66, 255-65 (2003). [PubMed: 14522863]

258.

Brown, P. et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55, 1075-81 (2000). [PubMed: 11071481]

259.

Barroso, O., Schamasch, P. & Rabin, O. Detection of GH abuse in sport: Past, present and future. Growth Horm IGF Res 19, 369-74 (2009). [PubMed: 19482501]

260.

Travis, J. Pharmacology. Growth hormone test finally nabs first doper. Science 327, 1185 (2010). [PubMed: 20203018]

261.

Powrie, J.K. et al. Detection of growth hormone abuse in sport. Growth Horm IGF Res 17, 220-6 (2007). [PubMed: 17339122]

262.

Nelson, A.E. et al. Pharmacodynamics of growth hormone abuse biomarkers and the influence of gender and testosterone: a randomized double-blind placebo-controlled study in young recreational athletes. Journal of Clinical Endocrinology and Metabolism 93, 2213-22 (2008). [PubMed: 18381573]

263.

Krusenstjerna-Hafstrom, T. et al. Biochemical markers of bone turnover in tibia fracture patients randomly assigned to growth hormone (GH) or placebo injections: Implications for detection of GH abuse. Growth Horm IGF Res 21, 331-5 (2011). [PubMed: 21963127]

264.

Sieckmann, T. et al. Longitudinal studies of putative growth hormone (GH) biomarkers and hematological and steroidal parameters in relation to 2 weeks administration of human recombinant GH. Drug Test Anal 12, 711-719 (2020). [PubMed: 32115881]

265.

Liu, W. et al. Comparison of normal distribution-based and nonparametric decision limits on the GH-2000 score for detecting growth hormone misuse (doping) in sport. Biom J 63, 187-200 (2021). [PubMed: 33164238]

266.

Barroso, O., Handelsman, D.J., Strasburger, C. & Thevis, M. Analytical challenges in the detection of peptide hormones for anti-doping purposes. Bioanalysis 4, 1577-90 (2012). [PubMed: 22831474]

267.

Equey, T. et al. Application of the Athlete Biological Passport Approach to the Detection of Growth Hormone Doping. J Clin Endocrinol Metab 107, 649-659 (2022). [PubMed: 34726230]

268.

Allen, D.B. et al. Human GH Use By Athletes With Short Stature Without GH Deficiency: Therapeutic Use Exemptions. J Clin Endocrinol Metab 110, e2088-e2091 (2025). [PubMed: 39760205]

269.

Williams, R.M., McDonald, A., Savage, M.O. & Dunger, D.B. Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX. Expert Opin Drug Metab Toxicol 4, 311-24 (2008). [PubMed: 18363546]

270.

Guha, N. et al. IGF-I abuse in sport. Curr Drug Abuse Rev 2, 263-72 (2009). [PubMed: 20443773]

271.

Ernst, S. & Simon, P. A quantitative approach for assessing significant improvements in elite sprint performance: has IGF-1 entered the arena? Drug Test Anal 5, 384-9 (2013). [PubMed: 22930482]

272.

Thomas, A., Kohler, M., Schanzer, W., Delahaut, P. & Thevis, M. Determination of IGF-1 and IGF-2, their degradation products and synthetic analogues in urine by LC-MS/MS. Analyst 136, 1003-12 (2011). [PubMed: 21157622]

273.

Hess, C. et al. Simultaneous determination and validated quantification of human insulin and its synthetic analogues in human blood serum by immunoaffinity purification and liquid chromatography-mass spectrometry. Anal Bioanal Chem 404, 1813-22 (2012). [PubMed: 22865008]

274.

Guha, N. et al. Biochemical markers of recombinant human insulin-like growth factor-I (rhIGF-I)/rhIGF binding protein-3 (rhIGFBP-3) misuse in athletes. Drug Test Anal (2013). [PubMed: 24173773]

275.

Guha, N., Cowan, D.A., Sonksen, P.H. & Holt, R.I. Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection. Anal Bioanal Chem 405, 9669-83 (2013). [PubMed: 23934394]

276.

Matheny, R.W., Jr., Nindl, B.C. & Adamo, M.L. Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology 151, 865-75 (2010). [PMC free article: PMC2840678] [PubMed: 20130113]

277.

Esposito, S., Deventer, K. & Van Eenoo, P. Characterization and identification of a C-terminal amidated mechano growth factor (MGF) analogue in black market products. Rapid Commun Mass Spectrom 26, 686-92 (2012). [PubMed: 22328223]

278.

Thevis, M., Thomas, A. & Schanzer, W. Insulin. Handb Exp Pharmacol, 209-26 (2010). [PubMed: 20020367]

279.

Anderson, L.J., Tamayose, J.M. & Garcia, J.M. Use of growth hormone, IGF-I, and insulin for anabolic purpose: Pharmacological basis, methods of detection, and adverse effects. Mol Cell Endocrinol 464, 65-74 (2018). [PMC free article: PMC5723243] [PubMed: 28606865]

280.

Thomas, A. & Thevis, M. Analysis of insulin and insulin analogs from dried blood spots by means of liquid chromatography-high resolution mass spectrometry. Drug Test Anal 10, 1761-1768 (2018). [PubMed: 30298989]

281.

Thomas, A., Krombholz, S., Breuer, J., Walpurgis, K. & Thevis, M. Insulin-mimetic peptides in sports drug testing. Drug Test Anal 15, 1468-1476 (2023). [PubMed: 37691519]

282.

Thomas, A. & Thevis, M. Recent advances in the determination of insulins from biological fluids. Adv Clin Chem 93, 115-167 (2019). [PubMed: 31655729]

283.

Thomas, A., Yang, R., Petring, S., Bally, L. & Thevis, M. Simplified quantification of insulin, its synthetic analogs and C-peptide in human plasma by means of LC-HRMS. Drug Test Anal 12, 382-390 (2020). [PubMed: 31930697]

284.

Smith, R.G. Development of growth hormone secretagogues. Endocr Rev 26, 346-60 (2005). [PubMed: 15814848]

285.

Hersch, E.C. & Merriam, G.R. Growth hormone (GH)-releasing hormone and GH secretagogues in normal aging: Fountain of Youth or Pool of Tantalus? Clin Interv Aging 3, 121-9 (2008). [PMC free article: PMC2544358] [PubMed: 18488883]

286.

Thomas, A., Walpurgis, K., Krug, O., Schanzer, W. & Thevis, M. Determination of prohibited, small peptides in urine for sports drug testing by means of nano-liquid chromatography/benchtop quadrupole orbitrap tandem-mass spectrometry. J Chromatogr A 1259, 251-7 (2012). [PubMed: 22901302]

287.

Thomas, A., Delahaut, P., Krug, O., Schanzer, W. & Thevis, M. Metabolism of growth hormone releasing peptides. Anal Chem 84, 10252-9 (2012). [PubMed: 23101768]

288.

Ventura, R. et al. A novel approach to improve detection of glucocorticoid doping in sport with new guidance for physicians prescribing for athletes. Br J Sports Med (2021). [PubMed: 33879477]

289.

Riiser, A., Stensrud, T. & Andersen, L.B. Glucocorticoids and physical performance: A systematic review with meta-analysis of randomized controlled trials. Front Sports Act Living 5, 1108062 (2023). [PMC free article: PMC10076788] [PubMed: 37033881]

290.

Vernec, A. et al. Glucocorticoids in elite sport: current status, controversies and innovative management strategies-a narrative review. Br J Sports Med 54, 8-12 (2020). [PMC free article: PMC6923944] [PubMed: 31326919]

291.

Coll, S. et al. Elimination profiles of prednisone and prednisolone after different administration routes: Evaluation of the reporting level and washout periods to ensure safe therapeutic administrations. Drug Test Anal 13, 571-582 (2021). [PubMed: 33161623]

292.

Coll, S. et al. Elimination profiles of betamethasone after different administration routes: Evaluation of the reporting level and washout periods to ensure safe therapeutic administrations. Drug Test Anal 13, 348-359 (2021). [PubMed: 32949107]

293.

Derendorf, H., Möllmann, H., Grüner, A., Haack, D. & Gyselby, G. Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration. Clin Pharmacol Ther 39, 313-7 (1986). [PubMed: 3948470]

294.

Gild, M.L., Stuart, M., Clifton-Bligh, R.J., Kinahan, A. & Handelsman, D.J. Thyroid Hormone Abuse in Elite Sports: The Regulatory Challenge. J Clin Endocrinol Metab 107, e3562-e3573 (2022). [PMC free article: PMC9387720] [PubMed: 35438767]

295.

Mountjoy, M. et al. 2023 International Olympic Committee’s (IOC) consensus statement on Relative Energy Deficiency in Sport (REDs). Br J Sports Med 57, 1073-1097 (2023). [PubMed: 37752011]

296.

Dipla, K., Kraemer, R.R., Constantini, N.W. & Hackney, A.C. Relative energy deficiency in sports (RED-S): elucidation of endocrine changes affecting the health of males and females. Hormones (Athens) 20, 35-47 (2021). [PubMed: 32557402]

297.

Fliers, E. & Boelen, A. An update on non-thyroidal illness syndrome. J Endocrinol Invest (2020). [PMC free article: PMC8285315] [PubMed: 33320308]

298.

Handelsman, D.J. et al. Thyroid Hormone Abuse Among Elite Athletes. J Endocr Soc 7, bvad027 (2023). [PMC free article: PMC9989342] [PubMed: 36896254]

299.

Martínez Brito, D., Leogrande, P., de la Torre, X., Romanelli, F. & Botrè, F. Characterization of the thyroid hormones level in urine by liquid chromatography coupled to mass spectrometry focus in the antidoping field. Drug Test Anal 17, 868-881 (2025). [PubMed: 39180509]

300.

Thevis, M., Kuuranne, T. & Geyer, H. Annual Banned-Substance Review 17^th Edition-Analytical Approaches in Human Sports Drug Testing 2023/2024. Drug Test Anal 17, 1417-1442 (2025). [PMC free article: PMC12319490] [PubMed: 39731401]