Review

A novel approach to improve detection of

Br J Sports Med: first published as 10.1136/bjsports-2020-103512 on 20 April 2021. Downloaded from http://bjsm.bmj.com/ on May 1, 2021 by guest. Protected by copyright.
glucocorticoid doping in sport with new guidance for
physicians prescribing for athletes
Rosa Ventura ‍ ‍,1 Peter Daley-­Yates ‍ ‍,2 Irene Mazzoni,3 Katia Collomp ‍ ‍,4,5,6
Martial Saugy,7 Frank Buttgereit ‍ ‍,8 Olivier Rabin ‍ ‍,3 Mark Stuart ‍ ‍9,10
1
Catalonian Antidoping ABSTRACT for safety or ethical reasons. These limitations
Laboratory, IMIM, Hospital The systemic effect of glucocorticoids (GCs) following certainly also apply to GCs, and currently there
del Mar Institute for Medical
Research, Barcelona, Catalunya, injectable routes of administration presents a potential is only a small number of studies in athletes that
Spain risk to both improving performance and causing harm to provide an indication that these drugs may improve
2
Clinical Pharmacology & health in athletes. This review evaluates the current GC performance.
Experimental Medicine, GSK, antidoping regulations defined by the World Anti-­Doping On this premise, and as with other substances on
Brentford, UK
3 Agency and presents a novel approach for defining the Prohibited List, the concept of potential perfor-
Science & Medicine
Department, World Anti-­Doping permitted and prohibited use of glucocorticoids in sport mance enhancement (PE) is key in the assessment of
Agency, Montreal, Quebec, based on the pharmacological potential for performance whether a drug is considered prohibited in sport;
Canada
4
enhancement (PE) and risk of adverse effects on health. ‘potential to enhance performance’ is the current
CIAMS, Université d’Orléans, Known performance-­enhancing doses of glucocorticoids standing assumption that has applied to this class of
Orléans, France
5
Université Paris-­Saclay CIAMS, are expressed in terms of cortisol-­equivalent doses and medications since their inclusion on the Prohibited
Orsay, France thereby the dose associated with a high potential for PE List in 1985, although with even less evidence then
6
Département des Analyses, for any GC and route of administration can be derived. for PE than is available today. The work presented
AFLD, Chatenay-­Malabry, France Consequently, revised and substance-­specific laboratory here acknowledges these limitations and refers to
7
REDs, Research and Expertise
reporting values are presented to better distinguish the concept of potential PE in line with the Code
in antiDoping sciences,
University of Lausanne, between prohibited and permitted use in sport. In as the level of risk this class of drugs presents to
Lausanne, Switzerland addition, washout periods are presented to enable having a meaningful physiological effect on athletic
8
Department of Rheumatology clinicians to prescribe glucocorticoids safely and to avoid performance.
and Clinical Immunology, the risk of athletes testing positive for a doping test.
Charité University Medicine, In the current International Standard of the
Berlin, Germany Prohibited Substances and Methods (the Prohib-
9
International Testing Agency, ited List), GCs are prohibited in-­competition when
Lausanne, Switzerland administered by oral, intravenous, intramuscular
10
Division of Medicine, AIMS
Centre for Metabolism and
or rectal routes, but are allowed by other routes
The aim of this review is to analyse the current of administration, where a local, non-­ systemic
Inflammation, University College
London, London, UK glucocorticoid (GC) antidoping regulations defined effect is required, including topical application
by the World Anti-­Doping Agency (WADA) and to and local injections. The ability for sports drug
Correspondence to better define the prohibited or permitted routes testing to differentiate between permitted and
Mr Mark Stuart, Centre for of administration in sport based on strong scien- prohibited routes of administration through labo-
Metabolism and Inflammation, tific and medical rationale. The approach aims to
University College London ratory methods was needed in order to distinguish
reduce the risk of misuse and abuse of this class of between doping and permitted and legitimate ther-
Division of Medicine, London
WC1E 6BT, UK; substances by athletes and present a practical frame- apeutic purposes.
​mark.​stuart.​18@​ucl.​ac.​uk work to allow for legitimate medical use. In 2004, a urinary concentration reporting
Accepted 30 March 2021
level (RL) of 30 ng/mL was initially established
INTRODUCTION as a temporary RL, based on the best but limited
GCs have been prohibited by some routes of admin- evidence at the time, to differentiate prohibited and
istration since 1985; first by the International permitted use through analysis of urine collected
Olympic Committee, and from 2004 by WADA from athletes at the time of doping control. For
under the World Anti-­ Doping Code. According the last 17 years until now, this temporary 30 ng/
to this Code, two out of three criteria must be mL RL has been applied to every type of GC drug
fulfilled to consider the inclusion of a substance in and every prohibited route of administration as a
the Prohibited List. These criteria include: (1) That possible indicator of doping. However, since its
© Author(s) (or their the substance has the potential to enhance perfor- introduction, it has been acknowledged by WADA
employer(s)) 2021. No mance; (2) Its use represents an actual or potential that this single RL lacks the required specificity to
commercial re-­use. See rights
and permissions. Published health risk; (3) Its use violates the spirit of sport. ever be an accurate indicator of potential or actual
by BMJ. When assessing a substance for the Prohibited List, doping in all cases. What was needed was a model
the most challenging criteria to determine with of laboratory GC detection that took into account
To cite: Ventura R, Daley-­ the vast differences in pharmacology, metabolism
any robust evidence-­based approach is whether a
Yates P, Mazzoni I, et al.
Br J Sports Med Epub ahead substance actually improves performance. For many and excretion rates that occur with different GC
of print: [please include Day substances on the List, this is rarely demonstrated compounds and when administered at different
Month Year]. doi:10.1136/ by double-­blind, peer-­reviewed, randomised clin- doses by a diverse range of administration routes.
bjsports-2020-103512 ical trials in athletes as this is often not permitted In addition, the most relevant marker in the urine

Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512    1

 Review
to best determine permitted or prohibited use needed to be Therapeutic use of GCs in sports

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specifically defined for each GC, whether that be the parent GCs are widely used in sports medicine, mainly to treat musculo-
compound, or a metabolite of the drug. skeletal injuries and asthma. GCs administered by local injection
After the initial introduction of the temporary RL, WADA can be an important and effective option in the treatment plan of
proceeded to sponsor a number of excretion studies which a number of musculoskeletal conditions commonly encountered
aimed to provide the evidence needed to improve the speci- in sports medicine. For example, intra-­articular GC injections
ficity of the RLs for individual drugs and the various routes of are used to treat adhesive capsulitis, where it has been shown
administration.1 As more data became available through these that a single GC injection provides faster pain relief and earlier
studies, it emerged that when GCs were administered by local improvement of shoulder function and motion compared with
injections in doses used for legitimate medical use, the concen- oral NSAIDs, and that they are effective for both short-­term and
trations found in the urine could reach levels similar to those of long-­term pain relief.23 24 Intra-­articular GC injections are also
prohibited routes, indicating systemic distribution of the drug commonly used for the treatment of bursitis in athletes.
and presenting a real risk of the athlete sample being reported Local GC injections also provide short-­ term pain relief
as an adverse analytical finding (AAF). These studies also rein- and improvement in function in subacromial impingement
forced the fact that a single RL was not suitable for all GCs and syndrome, a condition commonly observed in overhead sports,
all routes of administration. The initial results were corrobo- where athletes perform frequent and quick upper limb actions
rated and expanded on by numerous studies published thereafter causing alterations of scapular kinematics.25
which further evidenced the systemic distribution by measuring
not only urinary but also plasma concentrations of the drugs.1–20 Health risks associated with GC use
As a consequence, the status of local injections in the WADA The proven or potential risk to health of the athlete is one of
Prohibited List needed to be re-­evaluated.5–7 13 19 20 three criteria established by the Code to assess when determining
The need for reliable and practical guidance for physi- whether a substance is prohibited. Despite their excellent thera-
cians treating athletes with GCs has also been recognised by peutic effects, GCs have a relatively high potential for triggering
WADA since the first inclusion of GCs on the Prohibited List. adverse effects, particularly when administered systemically.26
When treating athletes with GCs, sports physicians are often The potential for harmful effects ultimately depends on the
faced with complex decisions in order to ensure the athlete duration of treatment, dose, route of administration and patient-­
does not test positive after being administered these drugs for specific factors.27 28 For these reasons, if athletes are taking GCs
therapeutic use. Since GCs are permitted out of competition with the intention to improve performance, shorter periods of
without restrictions, physicians are often left with the difficult administration are likely to be preferred due to a lesser incidence
task of attempting to estimate the time of elimination in order of adverse effects such as muscle wasting, and without the need
for the athlete to avoid an AAF during the next in-­competi- for tapering the dose at the end of the course.29 30
tion period, and to assess whether a Therapeutic Use Exemp- When administered as a local injection by the intra-­articular
tion is required if the drug might still be detectable at levels or periarticular route, systemic absorption occurs to some extent
above 30 ng/mL at the time of competition. With recent studies due to the high vascularity of the joint and diffusion of the
showing the vast differences in elimination times between drug into the surrounding tissue after injection. This can lead
different GCs,1–10 13 15 16 18 the extreme difficulty for physicians to adverse effects including flushing of the face, blood glucose
to make informed treatment decisions in order to comply with increase in diabetics, increase in blood pressure or palpitations,
the antidoping rules was evident. There was a pressing need for transient immunosuppression, and, rarely, water retention and
the establishment of clear and practical guidance on washout intermittent gynaecological bleeding.
periods for individual drugs and their routes to empower Locally occurring adverse effects after intra-­articular GC injec-
physicians to be able to use these drugs in the athletes they tions are rare but may include reactive synovitis, local irritation
treat, with the confidence to know that they are complying and postinjection pain, septic arthritis, cutaneous depigmenta-
with the antidoping rules. tion, tendinopathy and avascular necrosis.31–34 Adverse effects
Another limitation of the current approach was that local following local infiltrations into periarticular structures, tendon
injections of GCs can produce urinary concentrations similar to sheaths or bursae are also rare, but may include atrophy of the
those of prohibited routes due to systemic distribution of the subcutaneous tissue and cutaneous depigmentation.
drug following administration. For example, permitted intra-­
articular and periarticular administrations of triamcinolone Mechanism of the performance-enhancing effect of GCs
acetonide (TA) and betamethasone (BET) can result in similar During exercise, there is a strong stimulation of the hypothalamic-­
urine and plasma concentrations as after prohibited intramus- pituitary-­adrenal (HPA) axis, which results in a rise in baseline
cular administration of the drug,1 5 6 11 13 15 19 with no differences blood cortisol concentration, according to the intensity and the
in metabolites between these routes,6 13 making differentiation duration of the activity.35 36 Administration of oral GCs has been
by laboratory urinalysis methods currently impossible. Side shown to inhibit the HPA axis, resulting in a strong decrease
effects observed after intra-­articular administration also indicate in baseline blood cortisol concentration and an inhibition of
that systemic effects are possible after local injection.21 exercise-­induced cortisol secretion.37–42 Similar effects were not
To undertake this evaluation WADA convened a number of observed after administration via the inhaled route.43 44
expert groups to review the published literature in the field and The response of cortisol to endurance exercise results from
incorporate the pertinent published and unpublished results both the central and peripheral actions of GCs by direct and/or
to elaborate a novel approach that differentiates doping and indirect pathways, which can lead to effects including euphoria
acceptable medical use in sport.22 Through this review, washout and decrease in fatigue. In addition, GCs increase energy mobil-
periods were also established to support the use of GCs medi- isation via proteolysis and gluconeogenesis while maintaining
cally, aimed to avoid risk of a positive doping test through legit- the blood glucose level, and have a marked effect on reducing
imate medical use. inflammation.45 Any ergogenic effect produced by GCs probably

2 Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512

 Review
includes a local muscular effect of the drug rather than any direct A significant performance-­enhancing effect has been demon-

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link to the anti-­inflammatory response, but the complexity of the strated after administration of oral prednisolone (PRED) and
central and peripheral response after GC administration makes prednisone (PSONE) at 50–60 mg/day over a 7-­ day period,
the exact causal effects of PE difficult to identify. respectively, in female and male recreationally trained subjects,
during prolonged endurance exercise lasting more than
Studies of GC effects on performance 40 min.38–40 A small improvement in performance was also
A number of recent studies show that the impact of GCs on observed after administration of PSONE 60 mg/day over a 7-­day
athletic performance depends on the intensity and duration of period during repeated exercise leading to muscle fatigue and
exercise, the dose and duration of treatment and the route of exhaustion.48
administration.38–44 46–49 Results of all known studies looking However, no studies have demonstrated an improvement
at the effects of GCs on exercise performance are presented in in performance following acute systemic GC administration
table 1. Only the inhaled and oral routes of administration for (such as a single dose of 20 mg of PRED) at any intensity of
GCs have been studied to assess their effect on PE, with evidence exercise,41 42 or which examine the effect on performance by
of PE only after oral administration. combining different GCs by any route of administration. In

Table 1 Effect of GCs on exercise performance

GC molecule Study place Gender Route Mode PE
(references) (L, F) (M, F) Type of exercise (INH, PO) (A, ST) Dose and environment effects
Budesonide
Kuipers et al43 L M VO2 max INH ST (4 weeks) 800 µg/day = (Watt)
(maximal graded GC: 375±36 vs Pla: 376±25
exercise)
Hostrup et al44 L M 90% peak power output INH ST (2 weeks) 1.6 mg/day + acute terbutaline = (second)
until exhaustion Post-­GC: 214 vs pre-­GC : 203
Dexamethasone
Marquet et al37 L M VO2 max PO ST (4.5 days) 1–3 mg/day = (VO2 max) values not
(maximal graded provided
exercise)
Nordsborg et al47 L M Knee extensor exercise PO ST (5 days) 4 mg/day High intensity = (second)
until exhaustion at GC: 106±10 vs Pla: 108±9
several intensities Low intensity: + (second)
GC: 393±50 vs Pla: 294±41
Casuso et al46 L M Knee extensor exercise PO ST (5 days) 4 mg/day + (second)
F until exhaustion GC: 333±30 vs Pla: 264±21
F 20 m shuttle run Yo-­yo + (minute)
(maximal graded GC:16.1±2.9 vs Pla: 13.5±2.6
exercise) = (second)
30 m sprint test GC: 4.5±0.1 vs Pla :4.6±0.1
Prednisolone
Arlettaz et al41 L M 80%–85% VO2 max until PO A 20 mg = (minute)
exhaustion GC: 22.0±2.5 vs Pla:
21.5±2.9
Arlettaz et al42 L M 70%–75% VO2 max until PO A 20 mg = (minute)
exhaustion GC : 55.9±5.2 vs Pla:
48.8±2.9
Arlettaz et al38 L M 70%–75% VO2 max until PO ST (7 days) 60 mg/day + (minute)
exhaustion GC: 74.5±9.5 vs Pla:
46.1±3.3
Collomp et al40 L M 70%–75% VO2 max until PO  ST (7 days) 60 mg/day + + (minute)
exhaustion 2 hours training/day GC:107.0±20.7 vs Pla:
64.0±9.1
Tacey et al49 L M 4 × 4 min cycling bouts PO  A 20 mg - (kjoule)
at GC : 206 vs Pla: 217 (−5%)
90%–95% peak heart
rate
Prednisone
Le Panse et al39 L F 70%–75% VO2 max until PO  ST (7 days) 50 mg/day + (minute)
exhaustion GC: 66.4±8.4 vs Pla: 47.9±6.7
Zorgati et al48 L M Hopping until exhaustion PO ST (7 days) 60 mg/day + (peak force), = (second)
GC: 123.1±29.5 vs Pla:
119.9±24.7
Bold indicates there was a positive response in PE (performance enhancement) to emphasise the finding.
=, no change in performance.
+, significant performance improvement expressed in mean±sem.

A, acute; F, field; F, female; GC, glucocorticoid; INH, inhalation; L, laboratory; M, male; PE, performance enhancement; PO, oral; ST, short-­term.

Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512 3

 Review
addition, an impaired cycling performance has been demon- increased risk of inducing PE effects (figures 1 and 2). Using this

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strated 12 hours after acute PRED administration, suggesting approach, two categories were defined:
that any ergogenic effect obtained in the 2–3 hours after initial
administration may be reversed with GC elimination.49 1. Low-risk GC use
A significant PE effect has been confirmed after oral dexa- Low-­risk use is defined as a dose of exogenous GC (cortisol
methasone (DEX) administration of 4 mg/day over a 5-­ day equivalent dose ≤5.28 mg/day) that when added to normal
period during knee extensor and maximal graded exercises,46 47 physiological daily GC exposure (26.4 mg/day) results in a
and a small improvement in performance observed with the total exposure (endogenous + exogenous) that does not reach
same doses during repeated exercise leading to muscle fatigue supraphysiological levels (cortisol equivalent dose >32 mg/day)
and exhaustion.47 However, no PE was observed at lower doses (figure 1). In terms of adverse effects on health the extent of
of oral DEX of 1–3 mg/day over 4.5 days.46 47 HPA-­axis suppression is expected to result in <50% cortisol
No PE has been demonstrated after inhaled GCs have been suppression.
administered. Although only inhaled budesonide has been
studied, this finding is expected to apply to all inhaled GCs 2. High-risk GC use
at recommended therapeutic doses due to their relatively low High-­ risk use is defined as a dose of exogenous GC that is
systemic exposure compared with oral administration.43 44 equivalent to or greater than a dose demonstrated to be perfor-
These few studies demonstrate that under certain conditions mance enhancing (eg, DEX 4 mg, equivalent to 32.6 mg cortisol)
and routes of administration GCs can enhance sport perfor- (figure 1). This is also ≈6 times the 5.28 mg/day acceptable
mance, while under other conditions no PE effect could be dose defined above and results in a total GC exposure (26.4 mg
measured. It is conceivable that in certain circumstances, other endogenous + 32.6 mg exogenous) of ≈60 mg/day. In terms of
GCs in other doses or other sports could also potentially influ- adverse effects on health the extent of HPA-­axis suppression is
ence performance in a positive way. This concept of potential PE expected to result in ≥80%–90% cortisol suppression.
is the basis for defining the status of these drugs on the Prohib- Between these two categories, there is an intermediate risk of
ited List. adverse health effects but there are insufficient data to experi-
mentally derive the potential for PE. However, the level of risk
is anticipated to be on a continuous dose-­response scale, starting
Novel approach for defining permitted and prohibited GC use with little or no PE effects rising to a high and known PE risk.
The naturally occurring GC hormones and their synthetic Despite these limitations, this framework still allows clear guid-
analogues possess a wide range of potencies and pharmacoki- ance on acceptable low-­risk use versus unacceptable high-­risk
netic properties.50 The body produces a daily output of endog- use since many of the widely used GC doses and formulations
enous GC (cortisol), typically 18–22 mg/day51 and hence this fall into one of these categories.
amount of GC should be regarded as the normal physiological
baseline for cortisol levels in the body. The upper end of this Applying the approach to GC doses with known performance-
basal physiological range can be defined as 26.4 mg/day which enhancing effects
is 20% above the upper typical output of 22 mg/day. The supra- Clinical data confirming PE are only available for 4 mg oral DEX,
physiological threshold can be defined as >32 mg/day which is and 50 mg and 60 mg oral PRED when given over 5–7 days,
>20% above the 26.4 mg/day upper basal physiological range. based on published data as described above.38–40 46 47 Using the
Although there is no reference range for daily cortisol produc- methodology described in this article (see below) the corre-
tion, these ranges are similar to that seen for morning serum sponding cortisol equivalent doses were estimated to correspond
cortisol levels. The 20% margins allow for additional variability to 32.6 mg, 80 mg and 96 mg, respectively (figure 1), all of which
recognising that less than a 20% difference in exposure is not exceed the 32 mg/day threshold set to determine low-­risk versus
usually considered clinically relevant compared with expected high-­risk use of a GC drug in sport. These results validate that
biological variability. the new framework to determine acceptable or unacceptable GC
Administering GC drugs can result in a total GC exposure use in sport applies appropriately to drugs and doses with known
(exogenous + endogenous) that exceeds the supraphysiological PE effects and corroborates that their use is high risk and there-
threshold for daily physiological GC exposure when expressed fore unacceptable in sport.
in cortisol equivalents. Based on the studies presented above it
is generally accepted that GCs have PE potential, but it is not Methodology for determining cortisol equivalent doses
known exactly at what level total GC exposure is required to For any GC the dose can be expressed in terms of a cortisol-­
elicit a meaningful PE effect as there are insufficient data to equivalent dose and thereby the dose which exceeds 32 mg/
construct a dose-­ response relationship. However, like other day total cortisol-­equivalent exposure for any GC and route of
pharmacological actions of GCs, PE is not expected to be an all-­ administration can be determined. This approach was applied to
or-­nothing effect but rather gradually increase with increasing define the GC doses and routes of administration that should be
GC exposure, following a non-­ linear sigmoid dose-­response prohibited, or not prohibited in sport.
curve. On this basis, PE, even though initially very small, may To make this assessment it is first necessary to convert the
occur once the supraphysiological threshold for daily physiolog- administered exogenous GC dose into a cortisol-­equivalent dose
ical GC exposure is exceeded. Whereas GC drug use that does (figure 1). This was calculated as follows:52
not exceed the supraphysiological threshold of 32 mg/day, in Equation 1: Cortisol equivalent dose = CLcort . (Pr . ((FGC .
cortisol equivalents, can reasonably be regarded as not having DoseGC) / CLGC))),
significant PE potential. This gradual onset of effect is repre- where, F=the bioavailability of the systemically absorbed
sented by the gradual shading from green to red in figure 1. fraction of the dose for the route of delivery and formulation;
For any exogenous GC dose or route of administration, where Pr=relative GC potency in terms of the GC-­receptor binding
the estimated systemic exposure exceeds these limits, there is an or GC activity (cortisol=1); CL=the rate at which active GC is

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Figure 1 Physiological, supraphysiological and GC exposure with low risk and high risk of performance-­enhancing effects in mg/day shown
in cortisol equivalents. Column 1 shows the physiologically normal basal cortisol daily production rate typically 18–22 mg/day. Column 2 shows
the upper end of basal physiological range defined as 26.4 mg/day which is 20% above 22 mg/day. Column 3 depicts the supraphysiological
range of >32 mg/day which is defined as >20% above the 26.4 mg/day upper basal physiological range; exceeding this represents a continuum
for increasing the risk for performance-­enhancing and adverse health effects as shown in columns 4 and 5. The 20% margins (indicated with an
asterix * in column 4) allow for additional variability recognising that a 20% difference in exposure is not usually clinically relevant compared
with biological response variability. Column 4 shows the impact of acute administration of exogenous GC to upper basal cortisol (26.4 mg/day)
exceeding the supraphysiological range of >32 mg/day in the acute administration scenario (eg, oral dexamethasone 0.65 mg, oral prednisolone
3.3 mg, intra-­articular triamcinolone acetonide 8.5 mg). Column 5 shows the impact of the same exogenous GC doses shown in column 4 but in a
chronic administration scenario where basal endogenous GC levels are suppressed by chronic administration of high doses of exogenous GC. GC,
glucocorticoid.

cleared from the body via metabolism and/or excretion; CLcort supraphysiological GC thresholds (figure 1). These values are
is the plasma clearance of cortisol (L/h); and CLGC is the plasma not based on circulating cortisol concentrations, which can vary
clearance of the exogenous GC (L/h).50 widely throughout the day due to the pulsatile nature of cortisol
These parameters are mostly available for commonly used secretion, but nevertheless they still reflect the variability seen
GC formulations and routes of administration.50 52–77 Although in morning serum cortisol concentrations (5–25 µg/dL) that are
the bioavailability for some less common topical delivery routes used in clinical chemistry.
(eg, skin, eye, ear) and older molecules is not known, this was Higher or lower cortisol production or secretion rates and
not a significant issue since even when hypothesising 100% circulating concentrations can occur during stress, disease or
bioavailability the upper physiological exposure threshold was exercise. Consequently, some athletes may have elevated circu-
not exceeded within the approved therapeutic dose ranges lating cortisol levels during exercise,79 80 but there is no evidence
(figure 2). Similarly, for parenteral injections other than intrave- that this alters the daily cortisol production rate and therefore
nous, for example, intradermal, periarticular and intralesional, was not considered relevant to the argument for using a single
bioavailability was assumed to be 100%. supraphysiological threshold of >32 mg/day for total GC expo-
For intra-­articular injections the situation is more complex sure (endogenous + exogenous). This is a conservative position,
since they can be absorbed slowly from the injection site. because if an athlete generates increased cortisol levels during
Although 100% bioavailability may eventually be achieved, we extreme exercise and has higher endogenous GC exposure,
estimated the fraction absorbed in each 24-­hour period postdose taking exogenous GC will only result in a higher risk of PE.
from the absorption half-­life which is known in most cases. A
sensitivity analysis was also performed using different bioavail-
ability scenarios (figure 2). Consideration of cortisol suppression
The approved dose ranges for all the commonly used GC drugs, We also considered that cortisol suppression can occur following
formulations and routes of administration78 were converted into exogenous GC administration. With acute and single doses, this
cortisol equivalents using equation 1. These were compared is not important because although the body immediately starts
with the cortisol-­equivalent doses corresponding to normal and to reduce cortisol production/secretion the amount of cortisol

Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512 5

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Figure 2 Relationship between approved therapeutic dose ranges (blue bars) for various GC drugs and their corresponding doses estimated to
either produce systemic exposures above the upper physiological range for GC exposure (green bars) or estimated to have a high risk of performance-­
enhancing effects (red bars) during acute administration.* *For the intra-­articular route of administration different extents of systemic absorption in
24 hours were assumed where F is the fraction of the dose absorbed. GC, glucocorticoid.

already present in the body is not immediately removed and Establishing improved urinary RLs for GC use
hence is added to exogenous dose (figure 2). With chronic Up to now, a general urinary RL of 30 ng/mL was used to differ-
administration cortisol suppression is relevant, but not in the entiate between permitted and prohibited administrations of all
range that has a high risk of PE because the contribution of GCs. However, different studies have shown the need to estab-
the endogenous cortisol to the total GC exposure is very small lish compound-­specific RLs given the diversity of administration
(figure 2). For example, chronic administration of 20 mg/day routes and doses, as well as pharmacokinetic and pharmacody-
PRED or 4 mg/day of DEX results in 80%–90% cortisol suppres- namic properties between the different GCs.1–20
sion and the 32 mg/day total GC threshold is still exceeded with The ideal RL should not produce AAFs after permitted admin-
20 mg/day PRED and 4 mg/day DEX despite cortisol suppression istrations or negative results after prohibited use. When testing
(figure 2). athletes, the potential for AAFs after permitted administrations
for therapeutic purposes have to be precluded, therefore the
RL must be based on concentrations obtained after permitted
Results of the application of the new methodology administrations.
Oral and injectable routes (eg, intravenous, intramuscular, The compound-­ specific RL needs to be based on urinary
subcutaneous, intra-­articular) when used at their approved doses concentrations obtained after administration studies and so the
are likely to produce total GC exposures in excess of 32 mg/ RLs for GCs for which these data are available were reviewed.
day except at the lowest doses that are seldom used clinically All relevant studies are presented in table 2.1–20 For other GCs,
(figure 1). For example, doses of oral PRED (3.3 mg) and oral with limited or no data available, the RL has been maintained at
DEX (0.65 mg) and intra-­articular triamcinolone acetonide (TA, 30 ng/mL until further data are generated in the future.
1.4 mg) are estimated to produce total GC exposures at the In most of the studies, concentrations obtained after enzymatic
threshold of 32 mg/day (figure 2). hydrolysis (free and glucuronide fractions) were described. The
However, none of the inhaled, intranasal, dermal or other distribution of concentrations and the maximum concentrations
topical GCs, when used at their maximum licensed approved in urine (Cmax) after permitted administrations, obtained after
doses, would exceed the 32 mg/day threshold. the maximum daily doses recommended by manufacturers, were
Using this new methodology, the dose that corresponds with the most important data taken into consideration to define the
unacceptable use in sport was determined for most routes of compound-­specific RLs. When studies at those doses were not
known licensed GCs. This formed the basis by which the revised available or the number of volunteers was low, a conservative
specific RLs were set, which subsequently guided the establish- value was applied to the highest individual urinary concentra-
ment of washout periods. tion. The proposed RLs are summarised in table 3.

6 Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512

 Table 2 Administration studies of GCs reviewed to establish the compound-­specific reporting levels and washout periods†
Ref. Glucocorticoid Administration protocol MF Results in urine samples
Reference GC Route Dose, administration Volunteers Marker Cmean±sd (ng/ml) Cmax (ng/ml) Detection time
Budesonide (BUD)
2 Matabosch et al2 BUD Inhaled 400 ug × 3 days 8M F+G 6β-OHBUD 3.0±2.1 10.6 none
3 Coll et al3 BUD Inhaled 800 ug × 3 days 4M+4F F+G 6β-OHBUD 5.8±6.5 35.4 none
3 Coll et al3 BUD Inhaled 1600 ug × 3 days 4M F+G 6β-OHBUD 9.0±8.7 31.0 none
3 Coll et al3 BUD Intranasal 256 ug × 3 days 4M+4F F+G 6β-OHBUD 1.3±1.9 7.1 none
2.3 Matabosch et al; Coll et al2 3 BUD Oral 3 mg 10 M + 8 F F+G 6β-OHBUD 24 hours
4 Athanasiadou et al4 BUD Oral 9 mg (different hydration 7M × 3 F+G 6β-OHBUD 48 hours
protocols)
Triamcinolone acetonide (TA) and hexacetonide (THA)
5.6 Matabosch et al; Coll et al5 6 TA Intranasal 220 ug × 3 days 8M+6F F+G TA 0.8±0.9 3.6 none
11 Avois et al TA Intranasal 220 ug 5 F+G TA na* 7.0 none
11 Avois et al TA Intranasal 220 ug × 5 days 6 F+G TA na 7.0 none
5 Matabosch et al5 TA Dermatological 10 mg × 5 days 8M F+G TA 0.4±0.4 1.8 none
12 Wicka et al12 TA Dermatological 4.4 mg once a day × 3 days + 4M F+G TA na 0.8 none
4.4 mg twice a day × 3 days
5 Matabosch et al5 TA Intramuscular 20 mg 10 M F+G TA 8 days

Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512

6 Coll et al6 TA Intramuscular 40 mg 4M+4F F+G TA 11 days
6 Coll et al6 TA Intramuscular 80 mg 4M F+G TA 23 days **
11 Avois et al TA Intramuscular 80 mg 6 F+G TA 28 days ***
7 Coll et al6 THA Intra-­articular 40 mg 4M+4F F+G TA 8 days
13 Ventura et al13 TA Intra-­articular 40–80 mg 1M+3F F+G TA 3 days
1.11 Avois and Saugy; Avois et al TA Intra-­articular 40 mg 6 F+G TA 4 days
13 Ventura et al13 TA Periarticular 40–80 mg 4F F+G TA 8 days
Triamcinolone (T)
18 Chen et al18 T Oral 4 mg 4 M+8 F F+G T >24 hours
1 Avois and Saugy T Oral 16 mg 6 F+G T 48 hours
1 Avois and Saugy T Oral 16+16, 16+8, 16+0, 8+0, 8+0 6 F+G T 48 hours ****
(mg)
Betamethasone (BET)
14 Bakkene et al14 BET Dermatological 3 mg 8 F BET na 1.3 none
15 Coll et al15 BET Dermatological 10 mg once a day × 5 days 6M F+G BET 1.0±1.4 6.6 none
15 Coll et al15 BET Intranasal 320 ug × 3 days 4 M+4 F F+G BET 11.6±6.7 32.0 none
15 Coll et al15 BET Oral 0.5 mg 8M F+G BET 36 hours
1 Avois and Saugy BET Oral 2 mg 6 F+G BET 40 hours
1 Avois and Saugy BET Oral 2+2+2, 2+2+1, 2+2+0, 2+0+0, 5 F+G BET 48 hours ****
1+0+0 (mg)
14 Bakkene et al14 BET Intramuscular 5.7 mg 8 F BET 48 hours
15 Coll et al15 BET Intramuscular 6 mg 6M F+G BET 72 hours
1 Avois and Saugy BET Intramuscular 7 mg 6 F+G BET 50 hours
Continued
Review

7
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8
Review

Table 2 Continued
Ref. Glucocorticoid Administration protocol MF Results in urine samples
15 Coll et al15 BET Intramuscular 12 mg 4 M+4F F+G BET 96 hours
13 Ventura et al13 BET Intra-a­ rticular 3–12 mg 10 F F+G BET 48 hours
1 Avois and Saugy BET Intra-a­ rticular 7 mg 3 F+G BET 45 hours
13 Ventura et al13 BET Periarticular 6–12 mg 3 M+11 F F+G BET 72 hours
Dexamethasone (DEX)
1 Avois and Saugy DEX Intramuscular 7 mg 6 F+G DEX 57 hours
Prednisolone (PRED) and prednisone (PSONE)
8 Mazzarino et al8 PRED Intranasal 2 mg (two sprays three times 1 M+1 F F+G PRED, PSONE na 40, 120 none, none
a day)
14 Bakkene et al14 PRED Intraocular 0.9 mg 8 F PRED ***** na 19, na none, na
8 Mazzarino et al8 PRED Intraocular 1 mg (four drops twice per day) 1 M+1 F F+G PRED, PSONE na 50, 45 none, none
17 Coll et al17 PRED Dermatological 5 mg × 5 days 6M F+G PRED, PSONE 3.5±3.5; 3.7±3.9 12,1; 18, 0 none, none
8 Mazzarino et al8 PSONE Oral 1 mg 2F F+G PRED, PSONE 12 hours, 12 hours
8 Mazzarino et al8 PRED Oral 5 mg 2M F+G PRED, PSONE 24 hours, 12 hours
17 Coll et al17 PRED Oral 5 mg 6M F+G PRED, PSONE 8 hours, 8 hours
8 Mazzarino et al8 PSONE Oral 5 mg 2M F+G PRED, PSONE 24 hours, 12 hours
17 Coll et al17 PSONE Oral 5 mg 2M F+G PRED, PSONE 8 hours, 8 hours
14 Bakkene et al14 PRED Oral 10 mg 8 F PRED ***** 24 hours, na
17 Coll et al17 PRED Oral 10 mg 2M F+G PRED, PSONE 24 hours, 24 hours
9 Ahí et al9 PRED Oral 20 mg 1M F+G PRED, PSONE 9 hours, none
17 Coll et al17 PSONE Oral 30 mg 2M F+G PRED, PSONE 8 hours, 24 hours
9 Ahí et al9 PRED Oral 40 mg 1M F+G PRED, PSONE 14 hours, 20 hours
1 Avois and Saugy1 PRED Intramuscular 25 mg 6 F+G PRED, PSONE 10 days, 7 days
Methylprednisolone (MP)
10 Matabosch et al10 MP Dermatological 10 mg × 5 days 2M F+G MP 0.5±0.3 2.0 none
10 Matabosch et al10 MP Oral 4 mg 2M F+G MP 12 hours
16 Simoes et al MP Oral 4 mg 1M F+G MP 10 hours
10 Matabosch et al10 MP Oral 40 mg 2M F+G MP 24 hours
1 Avois and Saugy MP Intra-a­ rticular 80 mg 4 F+G MP 48 hours
*, data not available.
**, last sample collected at 23 days.
***, concentrations between 10 and 15 ng/ml up to 56 days.
****, after the last dose.
*****, only concentrations of PRED reported.
F, female; F, free fraction; G, glucurono conjugated fraction; GC, glucocorticoid; M, male; MF, metabolic fraction; 6β-OHBUD, 6β-hydroxy-b­ udesonide.

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 Review
RL of PRED and PSONE to 100 ng/mL and 300 ng/mL, respec-
Table 3 Reporting levels proposed and washout periods

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tively, to avoid an AAF after these administration routes at
recommended after administration of GCs by different routes
higher doses.
Reporting level (ng/ml) Marker For methylprednisolone (MP), only studies after dermatolog-
15 Triamcinolone acetonide ical application were available. Despite the low concentrations
30 Methylprednisolone obtained after dermatological application, the RL was main-
30 All other GCs tained at 30 ng/mL because the sensitivities after oral, intra-
45 6β-hydroxy-­budesonide muscular and intra-­articular administrations and the washout
60 Betamethasone, dexamethasone periods did not significantly change using lower RLs.
100 Prednisolone
300 Prednisone
Administration route GC Washout Establishing washout periods following administration of GCs
period After GCs administration, urinary concentrations which could
Oral All GC 3 days result in an AAF can be reached for different periods of time
Except: triamcinolone 10 days after administration depending on the GC administered and the
Intramuscular Betamethasone, dexamethasone, 5 days dose.
methylprednisolone Guidance relating to clinical use according to the manufac-
Prednisolone, prednisone 10 days turer’s licensed doses was deemed necessary to reduce the risk
Triamcinolone acetonide 60 days of AAF after medical use during an out-­of-­competition period
‘Local’ injections (intra-­ All GCs 3 days and, therefore, washout periods for oral and injectable routes
articular, periarticular, Except: triamcinolone acetonide, 10 days were defined. The washout period refers to the time taken from
peritendinous…) triamcinolone hexacetonide, the last dose to the time of the in-­competition period (midnight
prednisolone, prednisone beginning the evening of the in-­competition period) in order to
GC, glucocorticoid. reduce the GC concentration in the urine below the RLs. The
washout periods were established taking into account the time
of detection of the drugs using the new RLs established for each.
Regarding the marker of discrimination, the parent drug The maximum detection times obtained in each study are indi-
was suitable for the majority of GCs studied,5 6 13 15 17 except
cated in table 2.
for budesonide and triamcinolone hexacetonide (THA).
It is worth highlighting the long detection times obtained after
For budesonide, the metabolite 6β-hydroxy-­budesonide
intramuscular use of TA (table 2). For triamcinolone, the recom-
(6β-OHBUD) showed better balance between specificity and
mended washout period is 10 days to ensure specificity after the
sensitivity compared with the parent drug or other metabo-
maximum oral dose (table 2).
lites.2 3 THA, a pro-­drug of TA, was not detected in urine after
In order to simplify the recommendations and facilitate
administration and the active drug was selected as the marker of
the therapeutic use of GCs in out-­of-­competition periods, the
discrimination.7
washout periods were unified by administration routes and the
For all GCs, urinary concentrations after dermatological appli-
recommended values are described in table 3.
cations were very low (table 2) and, in general, data obtained
after inhaled or intranasal administrations were used to define
the RLs.
For 6β-OHBUD, data after intranasal and inhaled adminis-
DISCUSSION
Oral, intramuscular, rectal and intravenous routes have been
trations were available (table 2). Concentrations after intranasal
administration were very low. However, concentrations obtained prohibited for some time because there is clear evidence of
after inhalation steered the decision to increase the RL to 45 ng/ systemic effects which could potentially enhance performance
mL to reduce the possibility of an AAF after inhalation at high and be harmful to health. The same GC systemic concentrations
doses. as existing prohibited routes can be achieved after administra-
For TA, dermatological and intranasal administrations were tion by local injection (including periarticular, intra-­articular,
studied. After the maximum daily intranasal dose, the mean and peritendinous and intratendinous) at licensed therapeutic
median concentrations were very low, however a Cmax of 7 ng/ doses.5–7 11 13 15 19 69 81
mL was obtained. Due to these results and because concentra- The plasma and urinary concentrations of GCs obtained after
tions of TA after intramuscular administrations were very low, administration by local injection using normal licensed ther-
especially after low doses,5 6 a reduction of the RL to 15 ng/mL apeutic doses are consistent with those obtained after other
was proposed to increase the sensitivity of detection after intra- existing prohibited routes that were shown to have the potential
muscular use. to improve performance in clinical studies.
For BET, dermatological and intranasal studies were available. The systemic effect of GCs following local injectable routes
The Cmax obtained after repeated intranasal administration at of administration may therefore present a potential to both
doses below the maximum recommended daily doses suggested improve performance and cause harm to health. Consequently,
an increase of the RL to 60 ng/mL to avoid an AAF after higher all injectable routes of administration were approved for inclu-
intranasal doses. For DEX, the same criterion was proposed due sion on the 2022 WADA Prohibited List as prohibited routes of
to the similar pharmacological and pharmacokinetic properties administration for GCs during the in-­competition period.
with BET. In addition, revised and substance-­ specific laboratory RLs
For PRED and PSONE, dermatological, intraocular and based on excretion studies were recommended to be introduced
intranasal studies were available. The Cmax obtained after to better reflect the proposed approach (table 3). Revised RLs
repeated intraocular or intranasal administration using doses were proposed for the seven GCs most frequently reported as
below the maximum daily dose suggested an increase of the AAFs by antidoping laboratories up to now (table 4).

Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512 9

Review

Table 4 Adverse analytical findings (AAFs) reported for glucocorticoids 2010–2018

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Year Number of AAF % of total AAF Substance Occurrences % within drug class
2010 234 4 Budesonide* 111 47.4
Prednisolone+prednisone 39 16.7
Betamethasone 27 11.5
Prednisolone 16 6.8
Prednisone 9 3.8
Dexamethasone 8 3.4
Methylprednisolone 7 3.0
Triamcinolone acetonide 7 3.0
Triamcinolone 6 2.6
Deflazacort 3 1.3
Fluticasone propionate 1 0.4
2011 274 5 Budesonide* 113 41.2
Prednisolone+prednisone 40 14.6
Betamethasone 25 9.1
Dexamethasone 21 7.7
Prednisolone 19 6.9
Prednisone 19 6.9
Methylprednisolone 16 5.8
Triamcinolone acetonide 16 5.8
Triamcinolone 2 0.7
Fluticasone propionate 2 0.7
Deflazacort 1 0.4
2012 365 8 Budesonide* 157 43.0
Prednisolone 67 18.4
Prednisone 60 16.4
Betamethasone 30 8.2
Dexamethasone 18 4.9
Triamcinolone acetonide 16 4.4
Methylprednisolone 15 4.1
Triamcinolone 1 0.3
Fluticasone propionate 1 0.3
2013 330 6 Budesonide* 135 40.9
Prednisolone 58 17.6
Prednisone 55 16.7
Betamethasone 35 10.6
Dexamethasone 18 5.5
Methylprednisolone 14 4.2
Triamcinolone acetonide 12 3.6
Fluticasone propionate 2 0.6
Triamcinolone 1 0.3
2014 252 8 Budesonide* 74 29
Prednisolone 56 22
Prednisone 44 17
Betamethasone 34 13
Triamcinolone acetonide 16 6
Methylprednisolone 14 6
Dexamethasone 12 5
Deflazacort 1 0.4
Triamcinolone 1 0.4
2015 215 6 Prednisolone 60 28
Prednisone 52 24
Betamethasone 31 14
Dexamethasone 19 9
Methylprednisolone 19 9
Triamcinolone acetonide 17 8
Budesonide* 7 3
Continued

10 Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512

 Review

Table 4 Continued

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Year Number of AAF % of total AAF Substance Occurrences % within drug class
Deflazacort 4 2
Fluticasone propionate 3 1
Fluticasone 2 1
Triamcinolone 1 0.5
2016 184 4 Prednisolone 51 28
Prednisone 48 26
Betamethasone 29 16
Triamcinolone acetonide 18 10
Dexamethasone 13 7
Methylprednisolone 11 6
Fluticasone propionate 9 5
Deflazacort 2 1
triamcinolone 2 1
Budesonide* 1 0.5
2017 224 5 Prednisolone 70 31
Prednisone 56 25
Triamcinolone acetonide 31 14
Betamethasone 23 10
Dexamethasone 20 9
Methylprednisolone 13 6
Fluticasone propionate 4 2
Deflazacort 3 1
Budesonide* 2 1
Triamcinolone 1 0
2018 284 7 Prednisolone 77 27
Triamcinolone acetonide 72 25
Prednisone 70 25
Betamethasone 34 12
Dexamethasone 15 5
Methylprednisolone 8 3
Budesonide* 5 2
MRL revised to lower values are highlighted in pink; MRL revised to higher values are highlighted in orange.
*Note that the change in prevalence is due to change in target analyte from budesonide to N6β-hydroxy-­budesonide in 2014.

Practical implications of new RLs for laboratories new RLs were defined taking into account urinary concentra-
The combination of RLs and washout periods enables better tions obtained after allowed administrations so they ensure high
differentiation between routes of administration and provides a specificity for these administration routes. In addition, five out of
margin of safety to avoid reporting an AAF for therapeutic use the six revised RLs are higher than 30 ng/mL. For those reasons,
during in-­competition and out-­of-­competition periods. the number of in-­competition AAFs due to allowed therapeutic
Antidoping laboratories will need to update their procedures administrations is expected to be drastically reduced.
to incorporate the new RLs. Analytical difficulties are not fore- In summary, the refinement of the criteria of discrimination
seen because the new values are of the same order of magnitude, between allowed and prohibited GC use is expected to produce
although validation assays will be required. a reduction in the number of AAFs. This has previously been
The new RLs will avoid problems of results interpretation of observed with budesonide where the number of AAFs was dras-
some specific GCs. In particular, the problem of the endogenous tically reduced from 2014 when 6β-hydroxy-­budesonide was
production of PRED and PSONE at low concentrations due to introduced as a marker of oral budesonide administration by all
microbial activity in the urine samples which involved sophis- laboratories.83
ticated confirmatory procedures including isotope-­ ratio mass
spectrometer (IRMS) analysis82 is solved with the new RLs. Impact of prohibiting local injections on AAFs
The combination of the increase of RLs with defined washout
Impact of change in urinary concentration RLs on AAFs periods that take into account their elimination time of these
The total number of GC AAFs in the Anti-­Doping Administra- injections should diminish the number of AAFs, provided that
tion & Management System (ADAMS) database from 2010 to those washout periods are respected. If the athlete needs an
2018 is reasonably consistent (table 4), constituting 4%–8% of injection during a period of 3–10 days before the competition
total AAFs annually. (depending on the GC) they may apply for a retroactive Thera-
It is difficult to estimate precisely the true impact of these peutic Use Exemption (TUE) in the event of an AAF, as per the
changes on the annual number of GC AAFs, as the estimated International Standard for TUE and if granted, the presence of
concentrations are not systematically reported. However, the GC will not be prosecuted.84

Ventura R, et al. Br J Sports Med 2021;0:1–14. doi:10.1136/bjsports-2020-103512 11

 Review
In addition, data from the WADA Monitoring Programme The approach presents a vast improvement in the speci-

Br J Sports Med: first published as 10.1136/bjsports-2020-103512 on 20 April 2021. Downloaded from http://bjsm.bmj.com/ on May 1, 2021 by guest. Protected by copyright.
reporting out-­of-­competition GC use at values greater than 1 ng/ ficity of the urinary concentration RLs, to better reflect the
mL showed an incidence of less than 2% of urine samples tested unique pharmacological properties of each drug, and to more
(unpublished WADA data) confirming that there should not be a accurately distinguish between prohibited and permitted use
marked increase in the number of AAFs. in sport. Ultimately, the implementation of the new RLs will
create efficiencies in the analysis process and rationalise the
analysis by laboratories and will improve the management of
Implications for therapeutic use exemptions in sport AAFs reported for GCs. The model should overall decrease
Under the current regulation, TUEs granted for GC use by the number of AAFs reported, but better detect the actual
prohibited routes in competition represent a third of all the potential for abuse of GCs by athletes.
TUE applications granted and entered into ADAMS in 2019. With the implementation of new guidance on washout
This is the most requested class along with stimulants or periods following medical use of GCs, clinicians should be
hormone and metabolic modulators, with 22% and 13% of better informed to be able to manage the athlete’s treatment
all TUE applications, respectively. plan and minimise any risk to the athlete of failing a doping
Based on the prohibition of all injectable routes and the test after legitimate medical use.
imposed washout periods before a return to competition
requiring application for a TUE, it is anticipated that the What is already known
number of TUE applications for GCs will increase. However,
studies in this field conducted at the recent Olympic Games ►► The systemic effect of glucocorticoids following injectable
suggest a rather restricted medical need for in-­ c ompeti- routes of administration presents a potential to both improve
tion use of injectable GCs.85–87 However, the 2019 WADA performance and cause harm to health in athletes.
Monitoring Programme revealed comparable use of GCs in
competition and out of competition (unpublished WADA
data) suggesting that TUE applications for GCs may double What are the new findings
in number.
Beyond the number of TUEs, the concern that some physi- ►► All injectable routes of administration of glucocorticoids will
cians or athletes might misinterpret or ignore the new rules be prohibited in sport by the World Anti-­Doping Agency from
leading to unintentional antidoping rule violation is miti- 1 January 2022.
gated by clearer rules supported by a proactive information ►► New washout periods are presented to enable clinicians to
and education campaign launched by WADA and the anti- use glucocorticoids safely and to avoid the risk of athletes
doping organisations around the world. testing positive for a doping test.
►► New substance-­specific laboratory reporting values will better
distinguish between prohibited and permitted use in sport.
Implications for medical treatment
With the existing framework of the TUE system in place, use
for any legitimate and necessary medical treatment could still Contributors RV and PD-­Y (joint first authors) along with KRC and MS contributed
to the scientific research presented. IM, OR contributed to the WADA data presented.
be applied for through the existing TUE application process.
FB contributed to the clinical medicine aspects presented. MS contributed to the
However, the prohibition of GCs by local injection during drug reviews presented and represented the WADA Prohibited List Expert Group.
the in-­competition period, coupled with the introduction All authors collaborated and formed a consensus on the resulting conclusions and
of new washout periods, will potentially shift the preferred recommendations.
selection of type of locally injected GC when administered Funding The authors have not declared a specific grant for this research from any
near to the time of a competition event. Those GCs with funding agency in the public, commercial or not-­for-­profit sectors.
the lowest washout time after medical treatment may be Competing interests FB reports grants and personal fees from Horizon
preferred in the immediate days before the competition Therapeutics, outside the submitted work. PD-­Y reports he is a GSK employee and
period to avoid the need to apply for a TUE. For example, shareholder; GSK is a manufacturer of glucocortiocoid drug products. RV reports
that she works at an antidoping laboratory and has worked on research projects
triamcinolone by intra-­ a rticular route is currently listed funded by WADA. IM and OR are employees of WADA. KRC and MS have nothing to
on the 2019 Olympic and Paralympic Model Formulary as disclose.
an essential medicine to have available at the Olympic and Patient consent for publication Not required.
Paralympic Games for prescribing to athletes.88 But with a
Provenance and peer review Not commissioned; externally peer reviewed.
washout period of 10 days, the shift to such drugs as hydro-
cortisone or MP with a 3-­ d ay washout period might be ORCID iDs
observed. This potential shift in preference to GCs with a Rosa Ventura http://​orcid.​org/​0000-​0002-​1413-​8890
shorter washout period should be considered when selecting Peter Daley-­Yates http://​orcid.​org/​0000-​0003-​0684-​5621
Katia Collomp http://​orcid.​org/​0000-​0001-​6004-​7052
medicines for formularies for teams and major events. Frank Buttgereit http://​orcid.​org/​0000-​0003-​2534-​550X
Olivier Rabin http://​orcid.​org/​0000-​0003-​3632-​0770
Mark Stuart http://​orcid.​org/​0000-​0001-​6904-​0244
CONCLUSION
This novel approach completely redefines how GCs are
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