It is generally accepted in the sporting world that glucocorticoid (GC) use enhances maximum performance, and, as a consequence, this pharmacological class is banned by the World Anti-Doping Agency (WADA) after systemic administration. However, this claim has never been scientifically corroborated after acute administration. Indeed, although short-term therapeutic intake has recently been shown to significantly improve endurance performance,1 literature on the influence of ergogenic effects of acute GC intake appears very scarce; in fact, research is limited to three studies. Using an animal model, Gorostiaga et al2 showed that a single injection of GC (cortisol acetate, 100 mg/kg body weight) is capable of improving endurance in female rats. In contrast, Soetens et al3 did not find any significant increase of maximum performance with 1 mg adrenocorticotropic hormone (ACTH) injection in professional cyclists. Similarly, we showed in a previous study4 that acute therapeutic administration of oral prednisolone (20 mg) does not improve time of cycling until exhaustion (about 20 minutes) during intense submaximal exercise (80–85% VO_2max) in healthy moderately trained male volunteers. Several possible explanations could be offered, such as the relatively low dose (therapeutic) given or the mode of administration (acute). However, another explanation for the lack of ergogenic effects after GC intake obtained in our previous study is the relatively short exercise duration. Indeed, it may be suggested that the speculative mechanisms proposed to account for an eventual performance gain after GC intake, such as euphoria5 and increases in blood glucose and energy store mobilization,6 may require exercise for a longer duration.

This study was therefore designed to test the hypothesis that acute oral therapeutic administration of prednisolone 20 mg improves endurance performance during a less intense, submaximal exercise (70–75% VO_2max) in a group of non-asthmatic recreational athletes. Furthermore, given the well-known direct or indirect involvement of GC in several metabolic pathways, hormonal and/or metabolic effects resulting from prednisolone intake may be expected to have an influence on exercise endurance. Performance, hormonal (ACTH, dehydroepiandrosterone (DHEA), growth hormone (GH), prolactin, insulin) and metabolic parameters (blood glucose, lactate and interleukin (IL)-6) were therefore monitored in the present study.

METHODS

The protocol was approved by the ethics committee of Tours Hospital, and all subjects gave their informed consent after experimental procedures and possible risks had been explained both verbally and in writing.

Subjects

In total, 14 recreational male athletes (mean (SE) age 25.2 (2.8) years, weight 67.2 (2.1) kg), who had been actively cycling and/or running 2–3 times/week for at least 3 years, were chosen for this experiment. None was taking any medication or had a family history of any endocrine disorder.

Procedure

All the subjects had previously participated in physical exercise experiments in the laboratory. In the month before the study, an incremental test for maximum O₂ uptake (VO_2max) was conducted on a Monark cycle ergometer (model 918E; Monark-Crescent AB, Varberg, Sweden) to select a power output in watts eliciting 70–75% VO_2max (W_70–75), following a standard laboratory procedure. Mean VO_2max was 56.4 (1.0) ml/kg/min. To increase the reproducibility of time to exhaustion and to habituate themselves to the protocol, the subjects returned for one additional submaximal (W_70–75) trial ride in the 2 weeks before the actual experiment.

Subjects then reported to the laboratory on two separate days and cycled twice on the same ergometer at W_70–75 until exhaustion, once after taking a lactose placebo and once after GC (20 mg of prednisolone) treatment. Prednisolone was chosen for its relatively short pituitary inhibition and its preferential use by athletes. With regard to the kinetic studies,7 8 maximum pharmacological activity can be expected between 2 and 4 h after oral intake. The placebo and GC, packaged in identical capsules, were thus given to each subject according to a randomised double-blind procedure 3 h before the exercise to elicit maximum GC activity during the test. The two treatments were separated by 3 weeks of normal training, permitting the complete elimination of GC between the trials.7 8 Subjects were required to refrain from vigorous exercise and to abstain from alcohol and caffeine for a minimum of 24 h before their laboratory visit to avoid an interaction with GC. Before each test, they reported to the laboratory after fasting overnight and were tested at the same time of day (10:00– 11:00) for the two trials to account for diurnal variation in hormone responses.

Protocol

Between 07:00 and 08:00, each subject ingested either a GC or placebo capsule. Then, between 08:00 and 09:00, once the absorption period had ended, a standard breakfast (about 500 kcal), which was identical for each trial, was ingested. After insertion of a catheter into a superficial forearm vein (09:00–10:00), the subjects rested for 30 minutes before the pre-exercise resting blood sample was collected. From 10:00 to 11:00, the subjects cycled until exhaustion at their W_70–75. Blood samples were taken every 10 minutes during the first 30 minutes of exercise. No samples were taken between 30 minutes and exhaustion so that subjects could not count samples as a crude time device. No external clues regarding the duration of exercise were given to the subjects during the trials. Water was given ad libitum during exercise. Performance was assessed by the exercise time, stopping when the pedal cadence fell to <60 revolutions/min despite verbal encouragement. Results were disclosed only at the completion of the entire study.

Analysis

Blood samples (7 ml) were immediately transferred to different tubes. A 2 ml aliquot was placed in a chilled sodium heparinised tube for insulin and prolactin determination. The remaining 5 ml were placed in a chilled tube containing EDTA and aprotinin for blood glucose, lactate, ACTH, DHEA, growth hormone (GH) and IL-6 analysis. All tubes were promptly centrifuged at 4°C for 10 minutes at 2000 g, and stored at–72°C until assays.

ELISA tests were used for most of the analyses, using commercial kits (ACTH, Biomerica, USA; GH, DSL, Germany; IL-5, R&D Systems, USA; prolactin, DHEA and insulin, Bioadvance, France). Lactate and glucose were analyzed by classic enzymatic methods. All assays were performed in duplicate. Coefficients of variation (interassay and intra-assay) for all parameters were always <10%.

Statistical analysis

Data are presented as mean (SE). A specific test for crossover trials was used to determine whether significant differences existed between placebo and GC performance parameters.

Differences in blood parameters between the trials were analysed using a one-way analysis of variance (ANOVA) with repeated measurements. A post hoc Newman–Keuls test was performed to determine the location of the difference, in the event of an ANOVA revealing a significant main effect. Statistical significance was set at p<0.05.

RESULTS

Performance responses

No rank order was detected. Acute GC ingestion produced no significant change in performance during submaximal exercise (fig 1). No difference in cycling time was found after placebo (48.8 (2.9) minutes) and GC (55.9 (5.2) minutes). After GC, exercise exhaustion time was increased in eight subjects and decreased in six.

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Figure 1 Individual performance times of cycling to exhaustion after placebo (placebo) and prednisolone (GC) ingestion.

Hormonal and metabolic parameters

Adrenocorticotropic hormone, dehydroepiandrosterone, prolactin, growth hormone

Basal ACTH and DHEA values were both significantly decreased with GC treatment versus placebo (p<0.01). GC also induced significantly lower (p<0.01) (fig 2) ACTH and DHEA levels compared with placebo from the start of exercise to exhaustion, and ACTH and DHEA levels remained significantly lower with GC versus placebo throughout the recovery (p<0.01). With placebo but not with GC, exercise induced a significant increase in basal ACTH and DHEA levels (p<0.05) after 20 minutes of exercise and at exhaustion respectively.

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Figure 2 Mean (SE) ACTH, DHEA, prolactin (PRL) and growth hormone (GH) responses at rest (0), during cycling to exhaustion (10, 20, 30, exh) and recovery (r10, r20) after placebo and GC intake. *Significant difference between placebo and GC (p<0.05). †Start of significant difference between rest and exercise after placebo intake (p<0.05). ‡Start of significant difference between rest and exercise after GC intake (p<0.05).

Prolactin resting values were significantly increased with GC and placebo, after 30 minutes of exercise and at exhaustion (p<0.05) respectively. No change in prolactin values between the two treatments was found during the experiment.

Basal values of GH were identical after placebo and GC. Exercise induced a significant increase after 20 minutes of exercise after both treatments (p<0.05) with similar values after placebo and GC.

Insulin, glucose, lactate, interleukin-6

Exercise induced a significant decrease in insulin basal values after 10 minutes up until the end of the experiment with placebo and GC, without any significant change between the two treatments (fig 3).

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Figure 3 Mean (SE) blood glucose (GLU), insulin (INS), lactate (LAC) and IL-6 levels at rest, during cycling to exhaustion (10, 20, 30, exh) and recovery (r10, r20) after placebo and GC intake.*Significant difference between placebo and GC (p<0.05). †Start of significant difference between rest and exercise after placebo intake (p<0.05). ‡Start of significant difference between rest and exercise after GC intake (p<0.05).

Blood glucose level was significantly increased after GC versus placebo treatment, during rest, exercise and recovery (p<0.01). During exercise, glucose level remained constant after both placebo and GC treatments.

Basal lactate levels were quite similar in the placebo and GC trials. Exercise induced a significant increase after both treatments (p<0.05), without any significant treatment effect. Basal IL-6 values were not significantly different between GC and placebo. Exercise led to a significant increase in IL-6 levels (p<0.05) at exhaustion in both treatments, with significantly lower values under GC v placebo at exhaustion and during the passive recovery (p<0.05).

DISCUSSION

The major finding of this study is that acute therapeutic administration of GC induces some alterations in blood hormonal and metabolic parameters during submaximal exercise without having any significant repercussions on performance.

Physical exercise is a physiological challenge that induces threshold-dependent and intensity-dependent hypothalamic–pituitary–adrenal (HPA) activation, leading to increased production of ACTH. Consistent with these previous findings, we found a gradual increase in ACTH during exercise and recovery compared with rest values after placebo treatment in the present study, but, in agreement with previous studies,4 9^–11 this ACTH increase appears completely blunted by GC administration. Indeed, GCs are known to interact with the brain and pituitary gland and to inhibit the release of CRH and ACTH, forming a closed-loop feedback system. Deuster et al,11 12 however, showed that healthy men exhibit differential pituitary–adrenal responses to high-intensity exercise after pretreatment with 4 mg of dexamethasone, with about 30% of the subjects (designated as high responders) showing a persistence of pituitary–adrenal responsiveness to exercise, as shown by significant increases in plasma levels of ACTH and cortisol. In the present study, we did not find any persistence of HPA activation to exercise in our subjects after 20 mg of prednisolone intake, and, after ACTH inhibition, DHEA level appeared to be blunted under GC versus placebo in all of them. It may be that this discrepancy from the results of Deuster et al is due either to the dose and/or nature of the GC chosen or to the intensity of the exercise performed.

GCs are important neuromodulators of the somatotropic axis. Casanueva et al13 and Thakore et al14 found that acute administration of dexamethasone directly stimulated GH release in normal controls and they hypothesised that GCs act by inhibiting somatostatinergic neurons. Petrides et al investigated dexamethasone and hydrocortisone on GH responses after intermittent exercise.12 After dexamethasone, they found significantly greater exercise-induced GH response than with the placebo in the low responders (that is, with the abolishment of exercise-induced pituitary–adrenal responses after dexamethasone pretreatment), but not in high responders. Hydrocortisone treatment failed to augment the GH response to high-intensity exercise compared with placebo treatment in either low or high responders. In our previous study during intense submaximal exercise (80–85% VO_2max) we were unable to find any significant change in GH level, either at rest or during exercise with placebo or acute prednisolone 20 mg treatments. Similarly, in the present study, exercise induced a significant increase in plasma basal GH level regardless of the treatment given, without any significant change between placebo and GC. With regard to the results obtained by Petrides et al,12 the potential GH inhibiting effect may directly be linked to the nature of the GC and/or the dose given.

In parallel, in the present study, prolactin levels were measured to provide an index of the central 5-hydroxytryptamine receptor activity.15 To our knowledge, prolactin levels, used as a marker of “central fatigue”,16^–18 have never previously been investigated after acute GC administration during exercise but Rupprecht et al19 reported that acute (1 mg of dexamethasone) intake of GCs in normal controls and in patients with atopic dermatitis suppressed anterior pituitary prolactin levels, showing that the effect of GCs on the hormone system is not restricted to the HPA axis. Similarly, we found previously1 that short-term prednisolone administration (7 days) delivered orally at therapeutic dosage (60 mg/day) significantly decreases rest and exercise prolactin levels. Consistent with previous studies, prolactin levels increased during the later stages of exercise.17 18 However, our results indicate the inability of 20 mg acute prednisolone intake to alter prolactin secretion. These prolactin results provide limited support for the suggestion that acute GC intake may delay the onset of fatigue during endurance exercise.

GCs6 20 increase hepatic glucose production. They may do so directly by increasing the gluconeogenic and glycogenic capacity, or indirectly by increasing the gluconeogenic substrate availability. Glucocorticoids may also function in a permissive role by enabling other counterregulatory hormones to exert their effects on the liver. In accordance with the literature, we found a significant increase in basal blood glucose after GC treatment12 20 and this hyperglycaemia persists during exercise. Previous data during exercise, however, appear to be conflicting. Indeed, we did not find exercise hyperglycaemia after the same GC treatment (20 mg of prednisolone) during exercise of lower (60% VO_2max)9 or higher (80–85% VO_2max)4 intensity exercise. Petrides et al12 and Soetens et al,3 however, investigating dexamethasone (4 mg) and hydrocortisone (100 mg) intake and ACTH (1 mg) injection respectively, on exercise blood glucose responses, found a greater peak exercise-induced glucose response after both GC and ACTH than after placebo. However, these authors did not explore the repercussions of these drugs on insulin secretion, and surprisingly little work has been carried out determine whether acute GC intake has any effect on exercise insulinaemia. In fact, only our two aforementioned studies4 9 have investigated exercise insulin level, and both found no effect of acute GC on this parameter. Similarly, we found in the present work a significant decrease in insulin level during exercise compared with basal values, but with no difference between the two treatments despite the marked hyperglycaemia under GC. It may therefore be the case that acute prednisolone intake induces insulin resistance without hyperinsulinaemia21 both at rest and during this type of exercise, and that the persistence of hyperglycaemia during the submaximal exercise used with prednisolone treatment may reflect either a decrease in carbohydrate use9 or an increase in neoglycogenesis and glycogenolysis. Blood lactate levels do not appear to be altered by GC intake and further investigations are necessary to clarify the mechanisms implicated.

Lastly, we found a significant increase in basal levels of IL-6 during exercise, but this increase appeared significantly blunted at exhaustion and during recovery under GC v placebo. These findings are consistent with previous literature. Indeed, GCs inhibit endogenous IL-6 secretion whereas physical exercise stimulates it.22 23 Moreover, recent work indicates22 23 that exogenous GCs attenuate the IL-6-stimulating exercise effect and that this inhibition may be linked directly or indirectly to the decrease in carbohydrate oxidation after GC treatment.

CONCLUSION

Our results show that acute GC intake, in contrast to short-term administration,1 does not improve cycling performance during 70–75% VO_2max submaximal exercise. This lack of ergogenic effect of prednisolone is in agreement with the results of the few investigations conducted in humans during dynamic exercise after acute ACTH or GC administration.3 4 These results do not support the initial hypothesis that acute GC intake improves performance during endurance exercise. However, it is possible that ergogenic effects of acute GC administration may occur after higher doses, other types of GC or other routes of administration, and this will have to be verified in further work.