Prevalence of GC use in the general and athletic populations

GCs are one of the most widely used and effective medication classes in the general population and are available in a variety of pharmaceutical formulations (eg, injections, tablets, creams, eye-drops, ear drops, inhalers and nasal sprays).1 Administered for both their systemic and local effects, GCs are used globally in a wide array of clinical specialities, primarily for their anti-inflammatory and immunosuppressive properties. In some settings, the medical use of oral GCs appears to have increased in recent years as GCs are an accessible and affordable alternative to targeted but costlier medications. Prevalence of systemic use predominately for short-term use varies between 1% and 3%2 3 although ranged as high as 17.1% in a recent study of adults in France.4 Oral GCs are commonly used in many countries as part of first-line treatment in some infectious disease settings (acute otitis media, pharyngitis) although determining efficacy is still an area of active investigation.5 6 A large survey of adults in 48 western European centres found that a median 3.5% of respondents were currently using asthma medications (many of which include inhaled GCs), with a prevalence of 80% in those experiencing recent asthma attacks.7 The Global Initiative for Asthma GINA 2018 report recommends early use of inhaled GCs in asthma management8 although there is no accompanying prevalence data.

In athlete populations, there is an increased prevalence of musculoskeletal injuries and asthma9 10 and therefore frequent legitimate therapeutic GC use would not be surprising. Nevertheless, there is a scarcity of prevalence estimates in athlete populations. An analysis of abbreviated TUEs where the IOC was notified of GC use by athletes in advance of Olympic Games in the 1990s and early 2000s suggests that at least 5% to 12% of competitive elite athletes were treated with GCs by all routes, predominantly inhaled .11 In a recent unpublished international survey of medical doctors working with elite athletes, over 85% reported that they have at least occasionally administered injectable GCs as part of their normal practice (personal communication, Dr David Hughes, Australian Institute of Sport).

Anti-doping regulations

GCs, administered by certain routes, were first prohibited in sport by the IOC in 1985 and have been prohibited by WADA since its initial List, published in 2004. Substances or methods are considered for inclusion in the List if they meet two out of the following three criteria as stated in the World Anti-Doping Code: (1) potential to enhance, or enhances sport performance; (2) represents an actual or potential health risk to the athlete; (3) violates the spirit of sport.12 GCs are prohibited in-competition when administered by ‘systemic’ (oral, rectal, intramuscular or intravenous) routes.13 Administration by all other routes (including intra-articular and other periarticular injections) is regarded as local administration and are not prohibited in-competition. GC administration by any route is not prohibited out-of-competition (OOC).

Regardless of the specific GC substance and their individual pharmacological characteristics, a presumptive adverse analytical finding (AAF) is reported by WADA-accredited laboratories when the urinary levels of in-competition samples exceed a 30 ng/mL reporting level. Pharmacokinetics of GCs is complex and influenced by the formulation, type of esterification and salt, administration route, site and method of administration. Accordingly, while the laboratory reporting limit may demonstrate the presence of a GC, it cannot necessarily indicate if the administration was in-competition or OOC or likely to have a pharmacological or ergogenic effect. Any physician or athlete will be unsure when to stop using systemic GCs before the in-competition period to avoid exceeding the reporting limit. To further complicate the pharmacokinetic picture, intra-articular injections may give rise to systemic levels and physicians may inadvertently mischaracterise the site of injection in the absence of radiological or ultrasound guidance. Substance-specific reporting limit refinements are an area of active discussion and research among WADA-appointed experts and are beyond the scope of this paper.

Do systemic GCs enhance performance?

Some athletes have undoubtedly attempted to harness the purported performance-enhancing effects of systemic GCs that they perceive to be beneficial in their particular sporting discipline. However, the complex and pleiotropic mechanisms of GC action suggest that these medications are an unwieldy tool for the athlete seeking to gain a performance advantage and are considered to be a less popular component of doping regimens than in the past.14 Some patients and athletes reported experiencing euphoria following systemic administration.15 However, the scientific evidence supporting measurable euphoria in clinical populations is equivocal and the interpretation of the data is complicated by the association of confounding chronic pain.16 17

There is no evidence of performance-enhancing effects from short-term use of systemic GCs.18–22 There are randomised double-blind cross-over studies which suggest that athletes can exploit high-dose week-long courses of oral GCs to improve their submaximal intensity exercise performance for brief periods of time.23 24 These dosages would be easily detected during anti-doping tests, if taken in-competition. The precise mechanism for this effect is unclear but suggested to result from a combination of effects on metabolism, muscle, inflammation and the nervous system. This drug effect was shown in one study of male athletes whose training was tightly periodised alongside oral GC use.24 Exploiting this type of performance-enhancing regimen while effectively avoiding adrenal insufficiency and detection by standard in-competition doping controls would require meticulous medical supervision. It may also require more complex and exotic pharmacological manipulation of the hypothalamic–pituitary–adrenal axis than that offered by prescription GCs.25

Athletes and doctors have described inappropriate methods whereby systemic GC use, restricted nutrition and low-intensity training might be combined OOC to lose weight and preserve muscle mass.26 However, given the widely understood protein-catabolic functions of GCs,27 28 this doping mechanism remains speculative and controversial. Furthermore, efficacy may be dependent on the use of GCs as part of a complex cocktail that includes other prohibited but poorly detected hormones such as insulin.29

Recent accounts of systemic GC’s supposed potency have come from athletes who have also confessed to concurrent use of other performance-enhancing methods and substances, including anabolic agents such as testosterone.14 30 31 Such GC regimens may only have relevance in a small subset of sporting disciplines, such as in the steep mountain stages of cycling’s Grand Tours, where athletes might be willing to accept compromise in their training regimens or absolute power output in the pursuit of a superior power to weight ratio. OOC use would still necessitate a prolonged continuation of GC use into the competition period to avoid adrenal insufficiency due to feedback mechanisms. Prolonged GC use carries well-known medical risks, some of which could permanently diminish athletic performance.32

Health risks, adverse events and negative effects on performance

Treatment with GCs for many conditions has a long history and a reasonable safety profile. High doses or chronic use of systemic GCs pose some risk to the health of the athlete. Careful examination, diagnosis and deliberation by the physician is paramount and the benefits of treatment need to be weighed against potential risks and adverse effects. Potential performance enhancement use, described above and thought to be restricted to specific sport contexts with high-dose GC use, is also potentially associated with significant risks to the health of an athlete.

Adverse events with well-established causal associations to clinically appropriate GC use touch on virtually every human system, range from acute to chronic negative health outcomes and include adrenal insufficiency, immunodeficiency, osteoporosis, muscle wasting, tendon/fascia failure, avascular necrosis of the femoral head, various electrolyte, nutrient and other metabolic imbalances, glaucoma and cataracts. Perhaps because GCs are such common and clinically versatile medications, some physicians may overestimate their therapeutic value and underestimate the severity of associated adverse events.33 34 Even a single intra-articular injection could result in clinically significant adrenal insufficiency leading to malaise, electrolyte imbalance and immunosuppression for several weeks.35–37

Importantly, the aetiology of these symptoms may be unrecognised by the athlete and medical personnel, particularly in a sporting context where athletes train at high intensity and symptoms can masquerade as fatigue related to overtraining. Furthermore, an athlete who suffers trauma or serious injury may be at increased risk for adrenal crisis due to the hypothalamic–pituitary–adrenal suppression from prior GC use. This could be particularly problematic if the athlete fails to disclose this prior use.

Both the efficacy and potential harm of intra-articular injections are highly debated. Evidence from a recent prospective sham-controlled study in patients with osteoarthritis suggested that frequent triamcinolone knee injections, delivered according to a predetermined schedule, failed to effectively manage long-term pain and led to a statistically significant reduction in cartilage thickness.38 Nevertheless, medical society recommendations, as well as a comprehensive meta-analysis support the efficacy and safety of the very same intervention,39 40 strongly suggesting that judicious use of intra-articular injections in appropriate patients and circumstances can yield positive outcomes. There is a lack of published evidence on safety or harm of intra-articular GC use in athletic populations, and further research is urgently required due to the ubiquitous use of intra-articular GCs.

Policies to ensure the appropriate use of GCs

Despite concerns of possible abuse for a competitive advantage or potential detrimental effects on athlete health, GCs are widely used in sport for legitimate therapeutic reasons. Understanding that the List is harmonised across all sports from Archery to Wakeboarding, doping with GCs is not a concern where the purported benefits of high-dose GC use (prolonged power output at submaximal exercise intensities or aggressive catabolic weight management) are unlikely to be performance enhancing. Therefore, an AAF for GC would not likely be associated with any doping intent. The use of systemic GCs in many sports must be considered in a different light than in high-risk sports such as cycling, where abuse is well-documented and scientific evidence provides some support.

Mindful of the specific challenges posed by GC use in sport, sporting and anti-doping organisations have introduced innovative policies and are strengthening existing regulations to address the reasonable therapeutic use of GCs.

TUEs: a critical part of GC regulation

Athletes subject to doping control who are legitimately treated with prohibited routes of GCs in or very near to sporting competition may be permitted to use the medication if granted a TUE. However to avoid abuse, specific and strictly enforced rules are described in the International Standard for TUEs (ISTUE) and the World Anti-Doping Code for athletes seeking a TUE.12 44 ISTUE Article 4.1 lays out four strict criteria, all of which must be met in the estimation of a TUE Committee (TUEC) composed of physicians with expertise in the areas of medicine relevant to the application. Contrary to occasional reports in the media of rampant TUE abuse, TUEs are seldom sought by elite athletes.45 The number of TUEs in the last four Olympic Games has remained steady at approximately 1.2% (WADA data, confirmed by the IOC). Importantly, when granted, a TUE for a GC directly relates to individual medical needs and generally is narrowly limited in dose, frequency and duration of use. Anecdotal stories of cheating with GC TUEs are mostly reported in cycling and have been less common in the last 5 years. This may be due to a better understanding by athletes of the medication’s benefit–risk relationship, the more stringent application of the rules and investigative follow-up of AAFs.

Due to the value of systemic GCs in the treatment of many medical conditions common in athletes (eg, exacerbations of asthma, sinusitis, musculoskeletal injuries, acute allergic reactions and inflammatory bowel disease (IBD)), this class of prohibited substances consistently makes up the largest share of granted TUEs, according to recent statistics collected from WADA’s Anti-Doping Administration and Management System (ADAMS) database (see figure 1).

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Figure 1

The percentage of TUEs that were entered in the WADA’s ADAMS database prospectively and retroactively. It also compares TUEs for all substances with glucocorticoids only. ADAMS, Anti-Doping Administration and Management System; TUEs, Therapeutic Use Exemptions.

A prospective TUE application is preferred both for control and to provide permission certainty for athletes. However, GC TUE applications are often requested retroactively (~40%). This is consistent with clinical practices in the management of acute situations where elite athletes face challenges of travel and demanding training schedules. An athlete will tend to follow their doctor’s advice and accept immediate medical treatment rather than waiting and applying for a TUE. A retroactive TUE application scenario can lead to significant anxiety and uncertainty for clean athletes and their doctors who know that rejection of a retroactive TUE application may result in an anti-doping rule violation and significant consequences for the athlete. Promoting clean sport requires both careful clinical decision-making and diligent medical documentation. Consistent with indications typical for athlete populations and responsible treatment decisions, most GC TUEs registered in the ADAMS are for a duration of 1 week or less (see figure 2). TUEs granted for longer durations are more often prospective and are typically granted for inflammatory arthritis, IBD and other chronic autoimmune conditions.

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Figure 2

The duration of granted GC TUEs from the ADAMS database for the period 2012–2016. ADAMS, Anti-Doping Administration and Management System; GC, glucocorticoid; TUEs, Therapeutic Use Exemptions.

TUECs evaluate applications based on the ISTUE and WADA’s TUE Physician Guidelines. These guidelines, regularly updated by sport and specialist physicians, address various health conditions, including a number where systemic GCs are considered an important element of treatment (eg, musculoskeletal conditions, IBD, adrenal insufficiency and asthma).