Glucocorticosteroids are used for the treatment of a large variety of common medical conditions where an inflammatory response is involved, such as skin rash, topical allergy, or inflammatory airway disease, and are therefore also widely used by athletes. Corticosteroids are included on the list of prohibited substances issued by the World Anti Doping Agency (WADA; http://www.wada-ama.org). Although inclusion on the doping list does not require performance-enhancing properties, for athletes possible ergogenic properties are relevant. Except for one recent study,1 all available data on the effects of corticosteroids in healthy athletes do not suggest any performance enhancement.2^–4 Concerning possible ergogenic effects, it has been suggested that the use of glucocorticosteroids may increase carbohydrate availability during exercise by elevating plasma glucose concentration, which might indirectly enhance performance. In addition, it has also been suggested that the performance enhancement could be mediated by corticosteroid-induced euphoria. Informal reports from athletes and support personnel suggest that there may be some abuse of corticosteroids for performance enhancement, although it is impossible to quantify the efficacy of these individual actions. Only a few controlled studies of corticosteroid administration on physical performance capacity have been conducted.1^–4 The first published double-blind, placebo-controlled study in professional cyclists was conducted by Soetens et al,2 who administered adrenocorticotropic hormone (ACTH) by injection, to enhance endogenous cortisol production. No evidence was found for an enhancement or reduction of cycling performance under standard laboratory conditions.2 Marquet et al3 studied the effects of 4 to 5 days of oral dexamethasone administration on ventilatory threshold, lactate parameters, maximal oxygen uptake and exhaustion during exercise. There was no effect on any of these performance parameters. A remarkable finding, however, was that, compared with placebo, the administration of both low and high doses of dexamethasone produced decreased plasma glucose levels during exercise.3 A third, double-blind, placebo-controlled study by Arlettaz et al4 showed that the administration of a single oral dose of 20 mg prednisolone, alone or in combination with salbutamol, did not enhance endurance performance in healthy, moderately trained men. Arlettaz et al1 studied the effect of short-term prednisolone intake (60 mg/day) in recreational athletes also, and found an increase in endurance time at 70–75% of peak VO₂. However, the effects of short-term glucocorticoid administration may differ from daily administration over a longer period of time.

Therefore, the aim of this study was to add to previous data on short-term administration and to investigate the effect of 4 weeks of corticosteroid (budesonide) inhalation in therapeutic dosage, on maximal power output in well-trained athletes, measured on a cycle ergometer under standard laboratory conditions. In addition, the effect of corticosteroid inhalation on mood state was assessed.

MATERIALS AND METHODS

Subjects and experimental design

Twenty-eight well-trained, male endurance athletes involved in cycling and rowing were recruited via advertisements. Subjects could only enrol when they met the following criteria: a) they had trained at a constant level during the 3 months prior to the study, b) they had trained regularly on a bicycle at least three to four times per week, including exercise at maximal intensity, c) they did not use corticosteroids and were not in possession of an (abbreviated) therapeutic use exemption (TUE or an aTUE) for corticosteroids, and d) to avoid possible doping violations, at the time of the intervention they did not compete in events where doping control tests might be involved.

Before entering the study, all subjects received oral and written information about the study; the design, purpose, possible risks and inconveniences (such as light throat irritation because of the forced inhalation). In addition, instructions about inhalation of the drug were provided. Before participation the subjects signed an informed consent form and were informed that they could withdraw their participation at any time. The local medical ethics committee approved the study. A double-blind, placebo-controlled design was used with parallel groups without cross-over.

Procedure

Subjects visited the lab on three occasions. During the first visit they received more detailed information about the study and underwent a baseline graded exercise test. After the first exercise test they received the medication for the next 4 weeks and were instructed how to use the inhaler properly. Using a placebo inhaler, the subjects practised inhalation in the presence of the researcher until a proper inhalation technique had been acquired. Before subjects mounted the cycle ergometer the saddle height and position of handle bar were adjusted.

Because maximal power output is a valid and easy measurable parameter for aerobic exercise performance in cyclists,5^–7 and is strongly related to time trial performance,8^–10 in the present study maximal power output (W_max) was the outcome parameter for exercise performance. Therefore all subjects performed three graded exercise tests on a cycle ergometer (Lode Excalibur, Lode, The Netherlands). The first exercise test was done before the start of the intervention, whereas the two consecutive tests were done after 2 and 4 weeks of intervention, respectively. Heart rate was measured with a heart rate monitor (Sport Tester PE3000, Polar, Kempele, Finland).

The cycle ergometer tests started with a 5 minute warm-up at 150 W, after which the power output was increased by 50 W every 2.5 minutes. From a heart rate between 155 and 160 beats/min onwards the load was increased by 25 W every 2.5 minutes, until the subject was unable to continue exercise. The subjects did not receive any feedback about the workload and were encouraged to push as far as possible.

Maximal power output (W_max) was calculated with the following equation:

W_max = W_previous+t/150*25 W

W_previous is the workload that could be completed for the full 2.5 minutes before the last, not fully completed workload, and t the number of seconds that the last workload could be sustained.11

To avoid diurnal variations in exercise performance all three measurements in each subject were done at approximately the same time of the day. Consequently also the time between the last inhalation and the exercise test were constant in every subject, and varied between subjects from 2 to 8 h. In every subject the protocol and increments in the second and third tests were identical to the first test.

To study possible effects on mood the participants filled out a questionnaire once a week, in which the profile of mood state (POMS) was scored. For this purpose the shortened, adjusted version translated into Dutch was used, as described by Albani et al.12

Drug intervention

Medication and placebo were manufactured by the hospital pharmacy, while the responsible pharmacist kept the key of the blinding protocol until the study was completed. The inhalers (Turbuhaler, AstraZeneca) filled with placebo or budesonide were identical, apart from the number written on the package (from 1 to 28). The testers and subjects could not tell the difference between the actual and the placebo inhalers.

During the 28 days the subjects took two puffs twice daily (in the morning and evening) of either budesonide (Pulmicort; each puff contained 200 μg budesonide) or placebo.

The subjects were advised to rinse their mouths after each drug administration to prevent possible local side effects. At every laboratory visit the subjects were asked about any health problems and/or potential side effects.

Data collection and data handling

The obtained data were stored in a data base (Excel) and analysed with ANOVA using the SPSS package. Analyses for sequence and treatment effects were conducted. In the case of any significant effect, a Tukey post hoc test was used for locating any differences. Statistical significance was set at p<0.05.

RESULTS

Subjects’ characteristics are presented in table 1. All subjects were able to complete the study and all reported full compliance.

Ten subjects reported during the first weeks of the study mild throat irritation and/or a strange aftertaste after inhalation (seven subjects in the steroid group and three in the placebo group). No other side effects were reported.

Blinding was successful, and 46% from the placebo group and 54% from the corticosteroid group guessed correctly about the intervention.

Table 2 presents the data from the three graded exercise tests. The mean maximal power output in the baseline graded cycle ergometer test was 376 (SD 25) W in the placebo group and 375 (36) W in the corticosteroid group. Maximal heart rate between the two groups was not significantly different, and within each group no differences in maximal heart rate were found between the three tests.

No significant differences in maximal power output were found between the budesonide and the placebo groups, in any of the three exercise tests. When the maximal power output of the three tests was compared within each group, no differences were found at any time.

During the 4 weeks of intervention no changes were found in body weight in either of the two groups.

The questionnaire reflecting the profile of mood state (POMS) did not show any consistent pattern. Especially, the items that might reflect euphoria did not change in either of the two groups.

Blinding was successful, and approximately 50% of both the placebo and the corticosteroid group were correct about the treatment.

DISCUSSION

The aim of the present study was to assess the effects of 4 weeks of therapeutic corticosteroid inhalation on physical performance capacity and mood state in well-trained endurance athletes. No effect on performance capacity or profile of mood state was found. In the present study maximal power output was used as a performance measure because it has been shown that maximal power output is a good indicator of performance in cyclists6 7 and is also strongly related to time trial performance.8^–10

Three previous studies where possible ergogenic effects of short-term corticosteroid administration were investigated also failed to demonstrate ergogenic benefits of corticosteroid administration.2^–4 Arlettaz et al4 showed that addition of salbutamol to prednisolone failed to enhance performance in healthy humans. One study in racehorses also failed to observe an ergogenic effect of dexamethasone administration.13 The only study showing an increase in endurance time1 may be explained by the exercise intensity. Arlettaz et al1 used endurance time at 70–75% of peak VO₂, while other studies used a higher, or maximal, exercise intensity, which is more related to sport performance.5

A novel and significant aspect of the present study is that, in addition to acute corticosteroid administration, also after 2 and 4 weeks’ inhalation of a corticosteroid no positive effect on exercise performance could be demonstrated.

Although all the performed studies were unable to find any direct performance enhancement, it has been suggested that corticosteroid administration may indirectly affect sport performance by stimulating gluconeogenesis or changes in mood state. Concerning the suggested possible (corticosteroid-induced) stimulatory effect on gluconeogenesis, the administration of corticosteroids could theoretically increase gluconeogenesis to its maximal capacity of 0.1 g per minute, which can maintain normal blood glucose levels in the resting state during periods of inadequate glucose intake such as starvation.14 However, the maximal capacity of gluconeogenesis is far below the carbohydrate requirement during exercise, which may vary from 1 to 3 g per minute.15 Although it can be argued that even small contributions to carbohydrate availability may help sport performance, Marquet et al3 failed to show any increase in carbohydrate availability during exercise. In fact they observed that, after administration of high and low doses of dexamethasone, plasma glucose levels decreased during exercise. Therefore the contribution of gluconeogenesis to meeting carbohydrate requirements during strenuous exercise is negligible. It has also been shown that corticosteroid administration decreases insulin sensitivity16 and glycogen synthesis,17 18 both of which are crucial factors for optimal, high-intensity endurance performance. Therefore, it appears that administration of corticosteroids to athletes may have negative rather than positive effects on high-intensity endurance performance.

Another suggested mechanism of performance enhancement is the euphoria-inducing effect of corticosteroids. For that reason the profile of mood state was measured. The data failed to reveal any change in mood state during the study in either group. It is possible that higher dosages are required to obtain a significant effect on mood state, or that the period of euphoria is transient and is not measured by a weekly assessment of the profile of mood state. However, it has also to be realised that, although corticosteroid administration may induce euphoria, in some individuals depression and psychosis may occur,19 which may also have a negative impact on sport performance.

While no positive effects on sports performance could be detected in any of the studies performed, it is quite possible that corticosteroids may exert a negative impact on sport performance, and jeopardise the athlete’s health. Löfberg et al20 showed that 3 days of oral administration of a therapeutic dosage of 60 mg of prednisolone does have a catabolic effect on muscle protein synthesis, which is likely to have a negative effect on physiological training and exercise adaptations.21 It has to be emphasised that even low doses of inhaled corticosteroids like budesonide, as used in the present study, may have an adrenal-suppressive effect, as shown by Kaliner.22 Also a single periarticular injection of corticosteroids may induce adrenal insufficiency.23 Adrenal insufficiency may affect both physiological training adaptations and physiological responses to various types of stress.21 Another potential negative effect of long-term corticosteroid administration, in particular with higher doses, is a decrease of bone mineral density.24 Therefore, corticosteroids should only be prescribed based upon a sound medical indication.

Considering the requirements for including a substance on the list of banned substances, the presence of corticosteroids and ACTH on the WADA list of prohibited substances in sport can be questioned as far as performance enhancement is concerned. An often ignored aspect of a list of prohibited substances and methods, as used in the international sporting arena, is that many people, including those involved in sport, assume that everything on the list is ergogenic. The mere fact that corticosteroids and ACTH are on the doping list strengthens this belief, which in turn may stimulate their use and misuse.25 The fact that such a widely prescribed medication is included on the list of banned substances also carries a great risk for unintentional doping violation, when no valid TUE is available at the time of testing, because of administrative procedures.

In conclusion, 4 weeks of corticosteroid or placebo inhalation in healthy, well-trained athletes did not affect maximal power output or mood state. Hence no ergogenic properties of corticosteroid administration with high-intensity exercise could be demonstrated, which corroborates previous studies of short-term corticosteroid administration.