The antiinflammatory effect of corticosteroids is one of the main reasons for their wide use in medicine. This effect is thought to relate to the inhibition of phospholipid breakdown during and after cell injury. There are no studies available that determine the prevalence of corticosteroid use in athletes. Indeed, use of this class of drugs in athletes seems, at first view, to be largely restricted to the treatment of chronic, painful musculoskeletal injuries (6). Tennis elbow, rotator cuff, and Achilles tendon problems are among the most frequent musculoskeletal problems treated with corticosteroids if nonsteroidal antiinflammatory drugs have not been successful (1). However, it is now clear (17,23) that glucocorticoids are also employed as ergogenic agents, probably because of the potential impact of these drugs on central and/or peripheral level. For example, they have been shown to induce CNS excitation and euphoria at rest (24) and to increase blood glucose and energy-store mobilization (18), inducing the ban of this pharmacological class by the World Antidoping Agency (WADA) after systemic administration (WADA list of doping classes and methods, 2007). Limited data, however, are available on the direct effect of short-term corticosteroid administration on athletic performance in healthy athletes. Indeed, only one study (17) has focused on the ergogenic effects of short-term (4.5 d) corticosteroid intake (dexamethasone) delivered orally at low (0.5 mg) and high doses (1.5 mg) during maximal exercise. Briefly, blood levels of ACTH, beta-endorphin, cortisol, and cortisol-binding globulin were lowered by dexamethasone at rest and after exercise. Dexamethasone showed no significant effects after both doses on fitness, sleep, exhaustion during exercise, maximal O2 consumption, ventilatory threshold, or maximal blood lactate. Blood glucose at rest was higher after dexamethasone than after placebo; the opposite was found during exercise. However, no published information on endurance performance and on eventual hormone and/or metabolism corticosteroid interaction(s) is available for submaximal exercise after short-term systemic administration.
We tested the effects of short-term corticosteroid administration (7 d) delivered orally at a therapeutic dosage (60 mg·d−1) on performance during submaximal exercise (70-75% V˙O2max) in recreational, trained, healthy volunteers. Furthermore, to contribute to a wider knowledge of glucocorticoid-action mechanisms during exercise, hormonal (prolactin, growth hormone, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone (DHEA), insulin) and metabolic parameters (blood glucose and lactate) were monitored in the present study.
Ten male recreationally trained volunteers agreed to participate in the study after being informed of the nature of the experiments. They had been actively cycling and/or running three to five times per week for at least 3 yr. All subjects signed a consent form that outlined the details, discomforts, and possible risks associated with the experimental protocol, which had been approved by the ethics committee of the Tours Hospital. The subjects were screened with a medical history and physical examination to exclude those subjects with histories of bronchospasm or atopy. Exclusion criteria included respiratory tract infection during the previous month, regular use of tobacco, regular use of any medical drug, recognized asthma or allergy during the 5 yr before the study, or a restriction in forced expiratory volume during 1 s (FEV1) of more than 10% after incremental maximal exercise. The test subject sample size was determined on the basis of previous studies in our laboratory; we estimated that 10 subjects would be sufficient to detect a between-treatment difference of 15% in physical performance. Table 1 provides the descriptive characteristics of the subjects.
All the subjects had previously participated in physical exercise experiments in the laboratory. In the month before the first treatment, an incremental test for maximum oxygen uptake (V˙O2max) was conducted on a Monark cycle ergometer (model 918E, Monark-Crescent AB, Varberg, Sweden) to select a power output eliciting 70-75% V˙O2max (W70-75), following a standard laboratory procedure. To increase the reproducibility of time to exhaustion, and to habituate themselves to the protocol, they returned for one submaximal trial ride in the 2 wk before the actual experiment.
Subjects were asked to maintain similar exercise patterns and normal food intake throughout the duration of the experiments, and to abstain from intense exercise and any caffeine and alcohol for 24 h before each trial.
The double-blind, randomized crossover study consisted of two 1-wk treatments for each subject, separated by a 3-wk drug-free washout period: lactose (placebo, Pla), and prednisolone (Pred). Pla and Pred (trade name Hydrocortancyl, Aventis Laboratory, Paris; 5 mg, tablet) were packaged in identical capsules. Each day during the experimental periods (7 d), the subjects took either Pred (60 mg) or Pla (lactose) at home, at 7:00-8:00 A.M. Pred treatment was given without a taper. Indeed, during short-term use (< 2 wk), there were no untoward clinical effects of the abrupt withdrawal of the steroid, and using a tapering dose was, therefore, unnecessary (14,25). When questioned after the completion of the study regarding their knowledge of which treatment they had received first, three mentioned some overexcitement after Pred treatment, but the others were unable to report any difference. No significant changes in body weight were measured at the end of experiment.
Trials to exhaustion were performed on the seventh day of each treatment, 2 h after a final capsule ingestion of either Pla or Pred, with an additional trial to exhaustion performed after the drug-free washout period (WO).
The protocol for each trial was identical. Trials were held at the same time of day (10:00-11:00 A.M.) for each subject, to prevent diurnal variations in hormonal responses. On the actual testing days, subjects reported to the laboratory at 9:00-10:00 A.M., 2 h after ingesting capsules containing either Pla or Pred (60 mg) and 1 h after ingesting a small meal, which was identical for each trial. Dietary consistency (about 500 kcal) was confirmed through self-reported diet records and questioning before each trial. After insertion of a catheter into a superficial forearm vein (9:30-10:30 A.M.), subjects warmed up with light cycling. An accurate record was kept of the duration and intensity of the warm-up on the first trial (about 5 min), which was identical for all trials and was not considered to be part of the total exercise time.
The subjects then rested (30 min), and, at 10:00-11:00 A.M., after a resting blood sample had been taken, they exercised at W70-75 until exhaustion. Blood samples were taken every 10 min during the first 30 min of exercise and the first 20 min of recovery. No samples were taken between 30 min and exhaustion, so subjects could not count samples as a crude time device. Exhaustion was determined by the investigators when cadence could no longer be maintained at a rate of 90% of the subject's set rate (i.e., 80 rpm). Water was given ad libitum during exercise. Subjects did not have access to any indication of time after the initial 30-min sampling period during the exercise, and results were disclosed only on completion of the entire study.
Blood samples (7 mL) were immediately transferred to different tubes. Two milliliters were placed in a chilled sodium-heparinized tube for insulin (Ins) and prolactin (PRL) determination. The last 5 mL were placed in a chilled EDTA-aprotinin tube for blood glucose (Glu), blood lactate (Lac), ACTH, DHEA, and growth hormone (GH) analysis. All tubes were promptly centrifuged, 10 min at 4°C, 3000 rpm, and stored at −72°C until assays.
Enzyme-linked immunosorbent assay (ELISA) tests were used for most of the analyses: ACTH, GH, PRL, DHEA, and Ins (kits from Biomerica-USA for ACTH and DSL, from Biomerica-Germany for GH, and from Bioadvance-France for PRL, DHEA, and Ins). Lac and Glu were analyzed by classic enzymatic method.
All assays were made in duplicate. Coefficients of variation (inter- and intraassay) for all parameters were always < 10%.
Data are presented as mean values ± standard errors of the mean (SE).
A specific test for crossover trials was used to determine whether there were any significant differences 1) between Pla and Pred performance parameters, and 2) between the WO trial and the Pla trial, to verify the complete elimination of the Pred effect. Differences in all the measured hormonal and metabolic variables were statistically analyzed for time (0, 10, 20, 30, exhaustion, R10, R20) and treatment (Pred vs Pla) effects using a two-way ANOVA. When a significant F ratio was observed, a Newman-Keuls multiple-comparison test was performed to determine the location of the differences. The null hypothesis was rejected at P < 0.05.
No rank effect was detected. Time to exhaustion was significantly increased over Pla after the Pred treatment (Pred: 74.5 ± 9.5 min; Pla: 46.1 ± 3.3 min; P < 0.01). There was no significant difference in times to exhaustion between Pla and the additional trial to exhaustion performed after the drug-free washout period (WO: 43.0 ± 2.8 min) (Fig. 1).
Hormonal and Metabolic Data
ACTH and DHEA.
Basal ACTH (Pla: 28.4 ± 4.4; Pred: 11.7 ± 2.9 pg·mL−1) and DHEA values (Pla: 12.1 ± 1.5; Pred: 3.1 ± 0.4 ng·mL−1) were both significantly decreased with Pred treatment versus Pla (P < 0.01) (Figs. 2-4). Pred also induced significantly lower ACTH and DHEA concentrations (P < 0.01) compared with Pla from the start of exercise until exhaustion, and ACTH and DHEA concentrations remained significantly lower with Pred versus Pla throughout the recovery (P < 0.01).
With Pla, but not with Pred, exercise induced a significant increase in basal ACTH and DHEA concentrations (P < 0.05) after, respectively, 30 min (PlaACTH: 48.7 ± 7.0 pg·mL−1) and 20 min (PlaDHEA: 16 ± 2.1 ng·mL−1) of exercise.
PRL and GH.
PRL values were significantly decreased (P < 0.05) during the whole experiment by Pred intake (Fig. 3). Basal values were significantly increased at exhaustion with Pla and after 10 min of recovery with Pred (P < 0.05).
GH basal values were identical after Pla and Pred (Pla: 0.20 ± 0.06 ng·mL−1; Pred: 0.22 ± 0.06 ng·mL−1). Exercise induced a significant increase after 10 min of exercise after both treatments (P < 0.05), with significantly lower values under Pred from 30 min of exercise (Pla: 24.6 ± 6.2 ng·mL−1; Pred: 11.7 ± 2.7 ng·mL−1) until 20 min of recovery.
Ins, Glu, and Lac.
Basal Ins concentrations were significantly increased with Pred (Pla: 21.9 ± 4.7 mIU·L−1; Pred: 29.5 ± 5.8 mIU·L−1, P < 0.05) and remained higher than Pla concentrations until 30 min of exercise (Fig. 4). Exercise induced a significant decrease in basal values from 10 min (Pla: 9.8 ± 1.5 mIU·L−1; Pred: 19.7 ± 3.7 mIU·L−1, P < 0.05) until the end of the experiment with Pla and Pred.
Glu concentration was significantly increased after Pred treatment at rest and during exercise and recovery (P < 0.01). During exercise, Glu levels remain constant after both Pla and Pred treatments.
Basal Lac concentrations were quite similar in Pla and Pred trials. Exercise induced a significant increase after both treatments (P < 0.05), but Lac concentrations started to be significantly higher after Pred treatment versus Pla after 10 min of exercise (Pla: 6.4 ± 0.3 mM; Pred: 8.5 ± 0.8 mM, P < 0.05) until 10 min of recovery.
In this study, we examined the effects of short-term therapeutic oral administration of the glucocorticoid Pred on hormonal, metabolic, and endurance responses. Our major finding is the significant improvement in exercise performance after Pred intake, with concomitant changes in hormonal and metabolic parameters.
Because of the cross-reactivity between Pred and cortisol in most ELISA kits, it was not possible to measure the cortisol concentrations in the present study. However, plasma concentrations of ACTH and DHEA were measured at rest and during exercise and recovery, to provide an index of the inhibition in the function of the hypothalamic-pituitary-adrenal (HPA) axis by our short-term therapeutic Pred treatment. As expected, we found significantly lower basal ACTH and DHEA values after administration of Pred versus Pla. In parallel, according to exercise-induced HPA activation (8,9), we found a gradual increase in ACTH during exercise and recovery in this study compared with rest values after Pla treatment, but this increase seemed to be completely abolished by Pred treatment. This alteration by glucocorticoids in the HPA axis by negative feedback during exercise is in agreement with previous studies (2,9,17) performed after an acute intake. In view of our results, it seems that the HPA axis was completely depressed at the end of the short-term Pred treatment delivered orally at a therapeutic dosage (60 mg·d−1, for 7 d).
In contrast to anabolic steroids, glucocorticoids are considered to be catabolic; this includes bone, cartilage, and muscle proteins (15). The glucocorticoids interfere with the GH-IGF-1 axis at the hypothalamic, pituitary, and target organ levels, affecting hormone release, receptor abundance, signal transduction, gene transcription, pre-mRNA splicing, and mRNA translation (15). Stimulated GH secretion seems, therefore, to be generally suppressed by glucocorticoid chronic treatment (13,15), probably through a steroid-mediated increase in hypothalamic somatostatin tone (13). To our knowledge, this is the first study to investigate the repercussions of short-term glucocorticoid treatment on exercise GH concentrations. In this work, we did not find any significant differences at rest between our two treatments, but exercise GH secretion was significantly decreased by a short-term Pred intake. It seems, therefore, that the blunted exercise GH secretion with Pred failed to impair performance during this submaximal exercise.
In parallel, our results indicate the ability of short-term Pred intake to alter the exercise PRL secretion. This finding is in accordance with previous literature. Indeed, Rupprecht et al. (22) report that both acute (1 mg of dexamethasone) or prolonged (40 mg of methylprednisolone, for 6 d) intake of glucocorticoids in normal controls and in patients with atopic dermatitis suppressed anterior pituitary PRL levels, demonstrating that the effect of glucocorticoids on the hormone system is not restricted to the hypothalamic-pituitary-adrenal axis. PRL, measured in the peripheral blood circulation (16), reflects alterations in central-brain 5-hydroxytryptamine (serotonin) and dopaminergic activity and is used as a marker of central fatigue. Fatigue is a limiting factor of endurance exercise performance and is traditionally attributed to peripheral factors such as substrate depletion. More recently, an increase in serotonin concentration in the brain has been implicated in the onset of fatigue during endurance exercise (4,7,10,19). These fatiguing effects of an increase in brain serotonin concentration have been described in experimental animals, and an increase in serotonin levels has been shown to inhibit descending motoneurones in animals. We therefore hypothesize that short-term oral intake of Pred has a central ergogenic effect. Decreases in 5-HT release induced by short-term Pred administration, as reflected in decreased plasma PRL concentration (16), may delete the onset of fatigue and, thus, may be one of the contributors to the significant improvement in performance found in the present study. Further studies are necessary to verify this hypothesis and to clarify the direct or indirect impact of short-term glucocorticoid intake at a central level and on the hypothalamic-pituitary-adrenal axis.
Glucocorticoids are well known to induce hyperglycemia by stimulating hepatic glycogenolysis as well as neoglycogenesis (18). Several types of glucocorticoid influences result in an increased release of glyconeogenic substrate from peripheral tissues: amino acids by inhibiting protein synthesis and increasing proteolysis, glycerol by stimulating lipolysis, and Lac by stimulating the glycogenolytic actions of catecholamines. They also play a permissive role by increasing the liver's sensitivity to the glyconeogenic actions of glucagon and the catecholamines (18). Although acute glucocorticoid intake did not systematically induce an increase in Ins secretion, it is well known that chronic glucocorticoid excess at rest resulted in glucose-stimulated Ins levels (5,20). According to the literature, we found a significant increase in basal Glu and Ins after Pred treatment (11). These cases of hyperglycemia and hyperinsulinemia induced at rest by short-term Pred treatment were maintained, respectively, during the whole experiment and during the first 30 min of exercise. Previous data (2,17,21,23) of exercise Glu and Ins responses after acute intake of glucocorticoid seem conflicting, but to our knowledge there is no published work investigating the repercussions of chronic glucocorticoid on these parameters during submaximal exercise. In view of our results, it can be suggested that glucocorticoid-induced Ins resistance disappears at the end of this type of exercise. In parallel, the persistence of hyperglycemia during the submaximal exercise with Pred treatment may reflect either an increase in neoglycogenesis and glycogenolysis or a decrease in carbohydrate use, as with acute intake (3). The higher exercise Lac concentrations after Pred intake, however, are difficult to understand, and these need further verification. Because the exercise chosen did not induce any hypoglycemia with the Pla treatment, it seems doubtful that the increase in glycemia by glucocorticoid treatment may play a direct role in the improvement in performance.
Although effective, oral administration of corticosteroids also carries the risk of systemic adverse effects (1). As mentioned before, they have a distinct effect on the glucose metabolism. Development of diabetes mellitus is possible and, as part of the disturbance of the energy metabolism, corticosteroids tend to mobilize and redistribute fat stores, with "buffalo hump" and "moon face" characteristics in patients who use systemic steroids chronically. Fluid retention is also possible, as are disturbances in bone metabolism. Moreover, after chronic systemic corticosteroid use, the adrenal glands may be irreversibly suppressed, resulting in an inability to deal with the stress (1). To avoid these major adverse effects, we have chosen a short-term oral administration (1 wk) at a therapeutic dosage. With regard to the short duration of the treatment, there were no risks of development of either diabetes mellitus or osteoporosis, no changes in body weight or body composition were noted, and tapering of doses was unnecessary at the end of the treatment. The side effects were limited to some overexcitement under Pred treatment for three subjects, probably reflecting the central effect of the drug.
In conclusion, the results of this investigation reveal that 1 wk of therapeutic oral Pred intake did seem to improve performance significantly during submaximal exercise. To our knowledge, the present study is the first to clearly demonstrate an ergogenic effect of glucocorticoid during dynamic exercise. The concomitant alterations in exercise hormonal and metabolic parameters analyzed demonstrate that the drug had both central and peripheral effects. Indeed, decreases in PRL may reflect alterations in serotonin and/or dopaminergic activity. In parallel, ACTH, DHEA, and GH were lower under Pred, whereas Glu and Ins were significantly higher versus Pla. Further studies will be necessary to elucidate the mechanisms of these hormonal and metabolic changes, and to determine whether the changes may be associated with the marked performance improvement obtained. Moreover, new studies are needed to determine whether the results obtained in recreationally trained male subjects are applicable to elite male and female athletes.
This project has been carried out with the support of WADA (World Anti-Doping Agency). The authors wish to express their gratitude to the subjects for their dedicated performance. In addition, we also thank the CHR of Orléans, Nathalie Crépin, Patrick Guenon, Nicole Chevrier. and Dr M. Ferry for their assistance.
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