High Risk of Adrenal Insufficiency after a Single Articular Steroid Injection in Athletes : Medicine & Science in Sports & Exercise

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High Risk of Adrenal Insufficiency after a Single Articular Steroid Injection in Athletes

DUCLOS, MARTINE1,2,3; GUINOT, MICHEL4; COLSY, MARINA1; MERLE, FRANCIS5; BAUDOT, CHRISTOPHE5; CORCUFF, JEAN BENOIT6; LEBOUC, YVES7,8,9,10

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Medicine & Science in Sports & Exercise: July 2007 - Volume 39 - Issue 7 - p 1036-1043
doi: 10.1249/mss.0b013e31805468d6
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Abstract

Cortisol and its synthetic derivatives exert potent antiinflammatory pharmacologic effects. However, corticosteroids have pleiotropic effects, causing adverse effects that limit their clinical use. Among the many side effects of oral corticosteroid treatment (weight gain, fluid retention, infections, osteoporosis), the suppression of adrenal response is a major, life-threatening complication. Local forms of corticosteroids (inhaled, dermal, intraarticular) were developed to reduce the possibility of side effects associated with oral corticosteroids. However, numerous studies have reported that corticosteroids have a systemic effect regardless of the route of administration, and possible occurrence of these complications is not prevented with local forms of these molecules: inhaled corticosteroids (27), topical corticosteroids (21), or after intraarticular corticosteroids (2,16,17,19,28).

Local corticosteroids injections initially were used to treat chronic inflammatory forms of rheumatism, to avoid the deleterious effects of systemic administration (13). Certain studies (29,30) have supported the passage of steroid infiltrations into the bloodstream and have suggested that corticosteroid infiltrations were actually a form of general corticosteroid treatment administered locally. Young et al. (30) report that 21% (31/148) of patients with rheumatoid polyarthritis treated by infiltration presented an attenuation of inflammatory signs at joints other than those treated. Several studies (2,23,24) have since demonstrated the presence in the plasma of the corticosteroid injected into the joint, for various molecules. However, all of these studies were carried out in subjects older than age 40 yr who were suffering from chronic inflammatory rheumatic diseases.

Given these reports of the passage of injected intraarticular corticosteroids into the bloodstream in subjects suffering from chronic inflammatory rheumatic diseases, and the widespread use of this treatment in healthy subjects with posttraumatic or microtraumatic articular injuries, we investigated whether this treatment could also cause biologically significant hypothalamo-pituitary-adrenal suppression in healthy young subjects.

SUBJECTS AND METHODS

Ten healthy young male volunteers (mean ± SEM age 28.8 ± 8.1 yr) with posttraumatic or microtraumatic articular injuries underwent intra- or periarticular corticosteroid infiltration (Table 1). Such injuries have been established as an indication for this treatment by a sports medicine physician. None of the subjects were taking any medication, nor had any of them undergone previous general or intra-/periarticular corticosteroid therapy. Participants were excluded from the study if they had been treated with local corticosteroids (inhaled, transdermal, articular) in the previous 6 months. None of the subjects smoked or consumed alcohol excessively. The study was approved by the hospital's ethics committee, and informed written consent was obtained from all subjects. Anthropometric data for the athletes and the indications for corticosteroid infiltration are described in Table 1.

T1-2
TABLE 1:
Clinical data for the 10 participants and abnormal fasting and ACTH-stimulated cortisol levels after intra- or periarticular cortivazol or betamethasone injection.

Subjects were given a single intra- or periarticular infiltration by a trained physician, in the absence of x-ray or ultrasound control (Table 1). None of the subjects complained of feeling unwell at the time of the infiltration. During the 14 d of follow-up, no symptoms (asthenia, vomiting, nausea, sweating, or feelings of hunger) suggesting adrenal insufficiency were noted. Exercise or physical activity was contraindicated for the next 14 d after injection. No other intervention was prescribed during the follow-up period (ice, heat, local or systemic antiinflammatory medication).

The synthetic corticosteroids used were cortivazol and betamethasone, both of which are frequently used for intra- and periarticular injection (see characteristics in Table 2). These molecules are frequently used in combination with prednisolone in posttraumatic conditions in athletes (11). The antibody against cortisol used to measure endogenous plasma cortisol levels cross-reacts with exogenous prednisolone from 10% (present study) to 70% (other kits used to measure plasma cortisol levels). Therefore, because most of the kits used to determine plasma cortisol concentration cross-react with prednisolone, leading to the overestimation of plasma cortisol concentration, we decided not to include prednisolone in the treatments investigated in this study. Typical doses were adapted according to the weight of the subject and the site of the injection (Table 1).

T2-2
TABLE 2:
Characteristics of the glucocorticoids used.

Subjects came to the laboratory for testing on four occasions, at the same time (from 0715 to 0730 h) on each occasion, after an overnight fast: the day of steroid injection (D0) and 2 d (D2), 7 d (D7), and 14 d (D14) later. The duration of follow-up (14 d) of this preliminary study is justified by the previous works of Henzen et al. (12) and Mader et al. (19). From 0715 to 0730 h, all subjects were allowed to rest in a sitting position. At 0730 h, we drew a 6-mL blood sample to determine plasma cortisol and ACTH concentrations. The infiltration took place on D0, 30 min after blood sampling.

ACTH test.

During the second visit (D2), a short ACTH test was carried out in all subjects (16). A venous catheter was inserted at 0715 h, and the subject was allowed to rest in a sitting position for 15 min. At 0730 h, a venous blood sample was taken immediately before the intravenous injection of 1 μg of ACTH (D2 T0) and 30 min after the injection (D2 T30).

Laboratory assays.

Blood was collected in dry tubes for cortisol (3 mL) and in EDTA tubes for ACTH (3 mL) determinations. Blood samples were centrifuged at 4°C, and serum/plasma aliquots were stored at −20°C until assay. All samples were run in duplicate. Serum cortisol concentrations were determined by solid-phase RIA (Cortisol RIA Immunotech SMN, Immunotech, Marseille, France). This procedure has an intraassay coefficient of variation (CV) of 4, 6, and 8% for serum cortisol concentrations of 940, 355, and 76 nM, respectively. The interassay CV were 3, 7, and 14% for plasma cortisol concentrations of 903, 369, and 97 nM, respectively. The detection limit of the assay was 16 nM, and normal fasting values at this time in the morning ranged between 260 and 720 nM. No cross-reactivity was observed with betamethasone or cortivazol. Plasma ACTH concentrations were determined by solid-phase IRMA (ACTH IRMA Immunotech SMN, Immunotech, Marseille, France). This procedure has an intraassay CV of 43% and an interassay CV of 11%, for a plasma ACTH concentration of 39 pM. The detection limit of this assay was 1.5 pM, and the normal fasting values at this time in the morning ranged between 2.0 and 11.5 pM.

On day 2, subjects were considered to have cortisol suppression if 1) fasting cortisol concentrations were below 100 nM (18), and/or if 2) plasma cortisol concentration 30 min after ACTH stimulation (D2 T30) was below 550 nM (12,22), and/or if 3) the difference between plasma cortisol concentrations at D2 T0 and D2 T30 was less than 200 nM (3). On D7 and D14, a subject could be considered to have normal adrenal function if fasting cortisol concentrations exceeded the lower limit of the normal reference range for the kit used (260 nM). However, this cutoff point does not give a reliable assessment of the adequacy of the adrenal response to stress; many studies have reported adrenal insufficiency with pharmacological stimulation tests in patients treated with corticosteroids with plasma cortisol concentrations of up to 500 nM-that is, in the normal range of the kit (7,18). Because we did not carry out ACTH tests on D7 and D14, to interpret adrenal function in subjects with cortisol levels above 260 nM and to evaluate the risk of adrenal insufficiency in our subjects, we used the comparison with baseline cortisol levels (percentage) on D7 and D14. Subjects with plasma cortisol levels above 260 nM but lower than their baseline cortisol levels (D0) could not be considered abnormal by the reference range, but because their cortisol levels did not return to basal values, there were considered to have potentially abnormal adrenal function.

Statistics.

Data are presented as means ± SEM. Wilcoxon's test was used to compare paired items. Associations between two variables were quantified using Pearson's product-moment correlation coefficient or a nonparametric test (Spearman's rank correlation coefficient) for nonnormally distributed variables. P < 0.05 was considered statistically significant.

RESULTS

All subjects had normal pretreatment (D0) fasting cortisol (mean ± SEM: 486.8 ± 27.9 nM) and ACTH (5.3 ± 0.5 pM) levels. Two days after corticosteroid infiltration, fasting cortisol levels were below preinjection levels in all 10 subjects (D2 vs D0: P = 0.005) and averaged 18.8 ± 6.5% of D0 levels (Table 3). Six of the 10 subjects had plasma cortisol concentrations below 100 nM and were diagnosed as having adrenal insufficiency. Thirty minutes after the injection of 1 μg of ACTH, three of the four subjects with initial plasma cortisol concentrations exceeding 100 nM (on D2 T0) failed the short ACTH test (peak cortisol concentration below 550 nM and increase in cortisol concentration of less than 200 nM). None of the six subjects with cortisol levels below 100 nM met these two criteria after the injection of ACTH. Adrenal insufficiency occurred in 9 of 10 subjects after a single intra- or periarticular injection of cortivazol or betamethasone (Table 4). Interestingly, before the ACTH test, ACTH was detectable in the plasma of only one of the subjects (Table 5), and only this subject (subject 3) passed the short ACTH test (this is also the subject with the higher basal cortisol levels on D2 T0, before ACTH stimulation).

T3-2
TABLE 3:
Plasma cortisol levels (C) before (D0), 2 d (D2), 7 d (D7), and 14 d (D14) after a single betamethasone or cortivazol intra- or periarticular injection in healthy young subjects.
T4-2
TABLE 4:
Analysis of the cortisol response to stimulation with 1 μg of ACTH 2 d (D2) after single intra- or periarticular injection of cortivazol or betamethasone in 10 healthy subjects.
T5-2
TABLE 5:
Plasma ACTH levels before (D0), 2 d (D2), 7 d (D7), and 14 d (D14) after a single betamethasone or cortivazol intra- or periarticular injection in healthy young subjects.

Seven days after corticosteroid injection, fasting plasma cortisol concentrations remained significantly lower than preinjection levels (P = 0.005) in all 10 subjects, at a mean of 48.2 ± 7.3% of D0 levels (Table 3). Two of the 10 subjects still had cortisol levels below 100 nM, which represented continued adrenal insufficiency. Three subjects had plasma cortisol concentrations below the lower limit of normal range on D0 (260 nM), and the other five subjects had cortisol levels above 260 nM but below the percentage of baseline cortisol levels (including subject 3, who had a normal response in the ACTH-stimulation test). Concerning basal ACTH levels, only subject 3 had a higher basal plasma ACTH level than on D0 (291% of the D0 value) (Table 5), confirming the recommencement of hypothalamo-pituitary axis activity. Thus, on D7, five subjects fell below the 260 nM range and, therefore, would be considered abnormal. Although the remaining five with cortisol levels above 260 nM could not be considered abnormal by reference range, these five athletes exhibited cortisol levels at an average of 65.0 ± 1.5% of D0 levels (Table 3) with undetectable or lower ACTH levels than D0, suggesting the possibility that their adrenal function might still have been impaired.

Fourteen days after infiltration, fasting plasma cortisol concentrations remained significantly lower than preinjection levels (P = 0.02), averaging 77.3 ± 8.3% of D0 levels (Table 3). None of the subjects had cortisol concentrations below 100 nM, but three subjects had cortisol concentrations below the reference range of the kit (260 nM). Thus, on D14, three subjects fell below the 260 nM range and, therefore, would be considered to have abnormal adrenal function. Although the remaining seven could not be considered abnormal by the reference range, five of these seven athletes exhibited cortisol levels at an average of 87.4 ± 4.1% of D0 levels, suggesting that their adrenal function may still have been impaired (subject 3 was excluded because his ACTH test on D2 showed normal adrenal function).

An analysis of ACTH levels showed that only four subjects had detectable levels of ACTH (Table 5): subject 3, and the other three subjects with cortisol concentrations close to their cortisol levels on D0 (73%: subject 2; 94%: subject 9; 95%: subject 10).

Factors influencing the decrease in plasma cortisol concentration after infiltration.

The likelihood of adrenal insufficiency did not depend on the route of administration (intra- or periarticular) or the molecule administered (cortivazol or betamethasone) (Table 1). Two days after corticosteroid administration, basal cortisol concentration was positively correlated with initial plasma cortisol concentration before infiltration (D0) (r = 0.68, P = 0.03), negatively correlated with the age of the subject (r = −0.73, P = 0.01), and tended to be negatively correlated with the dose of corticosteroid (in prednisone equivalents) administered per unit of body weight (r = −0.58, P = 0.07). The cortisol response to ACTH stimulation (D2 T30) was negatively correlated with the dose of corticosteroid (in prednisone equivalents) administered per unit of body weight (r = −0.70, P = 0.02) and positively correlated with plasma cortisol concentration before ACTH stimulation (D2 T0) (r = 0.79, P = 0.006).

On D7, plasma cortisol concentration tended to decrease with the dose (in prednisone equivalents) administered per unit of body weight (r = −0.61, P = 0.05), with a significant threshold reached on D14 (r = −0.68, P = 0.02).

DISCUSSION

In this study, a single intra- or periarticular injection of cortivazol or betamethasone in healthy, young, leisure athletes, who had no history of prior corticosteroid injection and/or intake, induced biological adrenal insufficiency in 9 of the 10 subjects studied after 2 d. This adrenal suppression was associated with a lack of response of the adrenal glands to stimulation with ACTH (1 μg). This suggests that these athletes are at high risk of adrenal crisis in cases of trauma, infection, or surgery (5,27). Cortisol levels remained low (< 260 nM) 7 d after the intra- or periarticular administration of cortivazol or betamethasone administration in five of the nine subjects with adrenal insufficiency on D2, three of whom still had not recovered normal cortisol levels 2 wk later (three of nine subjects with adrenal insufficiency on D14). On D7 and D14, although five other athletes with cortisol levels above 260 nM could not be considered abnormal by the reference range, they exhibited cortisol levels at an average of 65.0 ± 1.5% (D7) and 87.4 ± 4.1% (D14) of D0 levels, suggesting that their adrenal function may still have been impaired, but in the absence of ACTH test, no definitive conclusion could be made.

Although we did not measure the plasma or urine concentrations of cortivazol or betamethasone, these results clearly reflect the passage into the bloodstream of these corticosteroids, as demonstrated in previous studies after the intraarticular administration of hydrocortisone (23), prednisolone acetate (24), or methylprednisolone (2). No previous study has investigated serum cortivazol or betamethasone levels after intra- or periarticular injection. Several factors are likely to influence the passage into the bloodstream of corticosteroids administered via the intraarticular route. There seems to be a dose-dependence relationship, because it has been shown that the peak plasma concentration of the corticosteroids administered is proportional to the dose administered (2,23,24). Our results confirm these previous findings; we found a negative correlation between the dose of corticosteroids administered, in prednisolone equivalents and per unit of body weight, and cortisol concentration 2 d later, before and after an ACTH test. Furthermore, the only subject with no significant hypothalamo-pituitary-adrenal suppression (subject 3) received the lowest dose. The bioavailability of corticosteroids also depends on the area over which synovial/bloodstream exchanges take place; it has been shown that the plasma concentration of the corticosteroids administered is proportional to the number of joints treated (2). Unlike all the patients in previous studies, who had chronic rheumatoid arthritis, and although the joints/tendons were not evaluated by ultrasound or MRI, the athletes in our study suffered from a condition of mechanical origin, with no underlying joint diseases comparable with the hypertrophy and hypervascularization observed in rheumatoid arthritis. The surface available for exchanges between the joint cavity and the plasma was, therefore, presumably smaller in our subjects. Finally, as shown in Table 1, the athletes suffered from chronic posttraumatic or microtraumatic injuries, where the inflammatory response is usually weak. Most of these (except cases 1 and 2) were cartilaginous lesions and/or impingement syndromes without joint effusion (not shown in Table 1), meaning that there was probably no or very mild synovitis. Surprisingly, the frequency of adrenal insufficiency in our study was at least equivalent to, if not higher than, that reported for subjects with rheumatoid polyarthritis, 24-48 h after intraarticular corticosteroid administration (90% in this study vs 83% for Koehler and Urowitz (16), 64-81% for Armstrong et al. (2), and 48% for Mader et al. (19)). This difference may be attributable to some of these infiltrations not being truly intraarticular. Indeed, in the present study, the seven intraarticular infiltrations were carried out without x-ray control. It has been shown that only about one third of infiltrations carried out without x-ray control are truly intraarticular (9). Moreover, even if carried out by an experienced doctor, periarticular infiltration may lead to the product being delivered to or diffusing into neighboring tissues (subcutaneous tissues, muscles, or vessels). As suggested by Young et al. (30), these observations suggest that all or some of the antiinflammatory and analgesic effects of corticosteroid infiltrations are mediated by the systemic action of these drugs.

The type of corticosteroid administered may also account for differences between this and other studies. Duration of local effects of corticosteroids is inversely proportional to their solubility and increases with higher half-life of corticosteroids. During the last 20 yr, efforts have focused on decreasing the solubility of corticosteroids to render them less soluble and, thereby, increase their retention time in the articular cavity. We used a soluble product with a long half-life (betamethasone) and a microcrystalline suspension (cortivazol), which also has a long half-life in the body. These features allow prolonged duration of activity of corticosteroids. Most previous studies have investigated the systemic effects of local administration of corticosteroids in soluble gallenic forms and with shorter half-lives (methylprednisolone) (2,16,19).

The major consequence of the passage of corticosteroids into the bloodstream is the occurrence of crude adrenal insufficiency. Acute adrenal crisis may occur when there is marked suppression of endogenous cortisol production caused by administration of exogenous corticosteroids (the injected corticosteroids exert a negative feedback effect on the hypothalamo-pituitary axis, decreasing adrenal cortisol secretion) and adrenal reserve is insufficient to respond to stressful stimuli such as respiratory infection, traumatism, surgical intervention, dehydration, etc. Such situations frequently occur in certain sporting disciplines with a high risk of infection and trauma and in sports in which conditions may be extreme (e.g., in terms of temperature and hypoxia) (5,27,28). It is recommended that an athlete rest for a period of time, from a couple of days up to 2 wk, after a corticosteroid injection. These recommendations are sometimes not respected at high competition levels, where corticosteroid injections are used to allow athletes to continue sporting activity. This tendency not to respect activity restriction postinjection may submit an athlete to the trauma risks of his or her sport; it may also increase blood flow to the injected area and, therefore, the amount of steroid that enters into the bloodstream.

This inhibition of the hypothalamo-pituitary-adrenal axis after the injection of corticosteroids into joints has been reported in some studies in patients suffering from rheumatoid arthritis (17,24). Most studies have looked only at a decrease in basal cortisol concentration. Plasma cortisol concentration is not sufficient for evaluation of the risk of adrenal insufficiency in conditions of major stress, with the exception of very low concentrations, the threshold for which depends on the study considered: from 100 nM (7,18) to 185 nM (12). Indeed, several studies using pharmacological stimulation tests have demonstrated adrenal insufficiency in patients previously treated with corticosteroids, even if those patients had plasma cortisol concentrations in the normal range for the kit used (7,14), right up to basal concentrations of 500 nM (7,18). For this reason, to minimize the risk of missing an adrenal insufficiency in our subjects, and considering that we have not realized ACTH tests on D7 and D14, for subjects with plasma cortisol levels < 260 nM (reference values), the cortisol levels reached on D7 and D14 were compared with their basal levels on D0. Therefore, 14 d after corticosteroid injection, three of the nine subjects initially presenting adrenal insufficiency had not recovered normal cortisol levels, one had returned to his basal cortisol levels (D0), and the remaining five were "indeterminate"-that is, they had cortisol levels above 260 nM but lower than their respective basal (D0) cortisol levels.

Few studies have used adrenal function stimulation tests after local infiltrations of corticosteroids. Koehler et al. (16) have demonstrated an absence of adrenal response in an insulin-induced hypoglycemia test in five of six patients who had received intraarticular infiltrations of methylprednisolone 48 h earlier. Kay et al. (15) report that 5 of 14 patients did not respond to 150 μg of ACTH 48 h after an epidural infiltration of corticosteroids. Only Esselinckx et al. (8) have reported no difference in ACTH response between eight patients receiving intraarticular injections of triamcinolone or hydrocortisone acetate and control subjects receiving oral dexamethasone. However, the ACTH test carried out involved an 8-h intravenous infusion of ACTH, corresponding to nonstandardized, supraphysiological stimulation of the adrenal glands. The different screening tests for adrenal insufficiency used in previous studies may, to some extent, account for discrepancies between studies. The insulin-induced hypoglycemia test has been considered the gold standard for diagnosis of adrenal insufficiency, but this test is expensive, uncomfortable, and potentially dangerous (4,6). By contrast, the low-dose (1 μg) ACTH test is well tolerated, its results are closely correlated with those of the insulin-induced hypoglycemia test, and its performance is better than that of the standard (250 μg) short ACTH test (1,20,26). Indeed, during the supraphysiological, 250-μg ACTH test, the adrenal glands are exposed to at least 1000 times the dose required for maximal adrenal stimulation, whereas 1 μg of ACTH is sufficient to cause ACTH stimulation and to give cortisol levels similar to those achieved in insulin-induced hypoglycemia (10). Lastly, Dickstein et al. (6) have demonstrated that 1 μg of ACTH causes a cortisol response similar to that obtained with 250 μg of ACTH at 30 min. We therefore used the 1-μg ACTH test to investigate adrenal insufficiency in our subjects. Only Mader et al. (19) have previously used this 1-μg ACTH test, after intraarticular methylprednisolone injection in patients with rheumatic diseases. Low fasting cortisol levels (< 147 nM) and/or a blunted peak cortisol response to ACTH were detected in 12 of 25 patients (48%) after 1 d, in 3 of 25 patients (12%) after 1 wk, and in 2 of 25 patients (8%) 2 wk after intraarticular methylprednisolone injection.

The duration of post-corticosteroid treatment adrenal insufficiency is a major concern in athletes, in whom the adrenal glands may be subjected to much stronger constraints during competition and training than occur in sedentary individuals (if resting recommendations after injection have not been respected), who may suffer at any time from a decompensation of this latent adrenal insufficiency. Henzen et al. (12) have shown that adrenal insufficiency generally resolved within 2 wk of short-term, high-dose glucocorticoid treatment (at least 25 mg of prednisone per day, for 5-30 d). However, in their series, two patients continued to present adrenal insufficiency 30 d after the end of corticosteroid treatment. Reid et al. (25) have shown, in stimulation tests with 250 μg of ACTH and in insulin-induced hypoglycemia tests, that this adrenal insufficiency could persist for up to 7 wk after the last infiltration. In our study, 14 d after infiltration, three of the nine subjects who presented with adrenal insufficiency had not recovered normal cortisol levels, and five still had potentially abnormal adrenal function (7,18).

Limited data are available on the effect of biological adrenal insufficiency on athletic performance. The most current signs of adrenal insufficiency in subjects taking inhaled corticosteroids are mainly lethargy and nausea (27). Other subjects (mainly children, although cases in adults have been reported) have presented with acute hypoglycemia and decreased levels of consciousness, coma, or coma and convulsions (5,27). Therefore, it is plausible that atypical forms of adrenal crisis (hypoglycemia, feeling of faintness) could explain some apparently unexplained decreases in performance observed in some athletes. Whereas the majority of adults have presented with insidious onset of symptoms, the potential severity of the decompensation of subclinical adrenal insufficiency induced by corticosteroids has been reported in sedentary subjects (5,22,27) and requires evaluation in a population exposed to stresses other than those that sedentary subjects experience. Indeed, competitive and/or intensive exercising may require intense, prolonged physical effort, sometimes in extreme conditions that can change suddenly (heat, cold, hypoxia). Moreover, some athletes (e.g., cyclists, rugbymen, soccer players) are at risk of severe injuries that may require surgery, and they have a high risk of infections, particularly those affecting the upper respiratory tract. Although biological insufficiency did not seem to be always associated with clinical symptoms, in view of the severity of cases of adrenal crisis described in subjects taking corticosteroids (5,27), we recommend that athletes receiving intra- or periarticular corticosteroids should be considered for adrenal investigation, at least with determination of morning plasma cortisol levels.

CONCLUSION

These results demonstrate that recreational athletes have a high risk of adrenal insufficiency after a single corticosteroid infiltration. This occurs even in the absence of diseases that blunt the response of the corticotropic axis, such as inflammatory rheumatism, which tends to affect older individuals, and of joint conditions similar to those observed in patients with inflammatory rheumatism (hypertrophy and hypervascularization). Although we are dealing here with biological forms of adrenal insufficiency, the risk of acute adrenal insufficiency is probably underestimated, given the difficulties involved in the clinical detection of crude forms of acute adrenal insufficiency in active subjects (27). This risk is likely to increase as the practice of corticosteroid injection increases among athletes. It should be stressed that this risk of adrenal crisis in healthy subjects is disproportionate with respect to the expected, but not yet demonstrated, benefit of this type of treatment. Further studies are necessary to demonstrate the efficacy of corticosteroids in periarticular and articular conditions without synovial involvement, and to determine more precisely the dose-effect relationship. Moreover, future studies will have to rigorously examine, in a larger cohort of subjects, the duration of the adrenal insufficiency using repeated ACTH tests (until 4-6 wk after injection) and to test other corticosteroids with shorter half-lives (such as prednisolone) than those of the synthetic molecules used in the present study.

Although biological insufficiency did not seem to be always associated with clinical symptoms, in view of the severity of cases of adrenal crisis described in subjects taking corticosteroids (5,27), we recommend that athletes receiving intra- or periarticular corticosteroids should be considered for adrenal investigation. Finally, we feel that all subjects undergoing corticosteroid infiltrations should be informed of the risks of adrenal insufficiency, and they should report any symptoms to their physician. It would be prudent to prohibit patients from all sporting or professional activities with a high risk of trauma or infection for a period of 2 wk after treatment, corresponding to the period in which adrenal function is most disturbed (12).

We would like to thank Beckman Coulter Laboratories for generously supplying kits for hormone assays: Cortisol RIA (#2030) and ACTH IRMA (#1841) (Immunotech Marseille, France). This work was supported by INRA-UMR 1243, INSERM U515, and University Pierre and Marie Curie Paris VI. We would like to thank the French Committee for the Prevention of Doping (CPLD)/French Agency Against Doping (AFLD) (Pr M. Rieu) for their advice.

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Keywords:

HYPOTHALAMO-PITUITARY-ADRENAL AXIS; INTRAARTICULAR CORTICOSTEROIDS; PERIARTICULAR CORTICOSTEROIDS; SPORT

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