Objective: Subnormal hypothalamic-pituitary-adrenal (HPA) function and rare cases of adrenal crisis have been reported in asthmatic children treated with inhaled corticosteroids. We investigated subnormal HPA activity and followed up affected patients until recovery of normal HPA functions. Study Design: 100 children with persistent asthma underwent low-dose corticotropin testing, with the administration of 1 µg of 1–24 ACTH intravenously. Treatments were beclomethasone dipropionate as a metered-dose inhaler, n = 14, budesonide as a dry-powder inhaler, n = 16, fluticasone propionate as a metered-dose inhaler n = 31 or a dry-powder inhaler n = 39. The mean commercially labelled dose was 520 ± 29 µg/day (mean ± SEM, range: 160–1,000) and the equipotent dose (which compares the efficiency of these drugs for treating asthma and their responsibility for systemic effects) was 890 ± 55 µg/day (range: 200–2,000). Results: The mean stimulated cortisol level ± SEM (and range) of the patient was 482 ± 12 (148–801), and that of 40 age-matched controls was 580 ± 12.5 (439–726), (SD = 79). The result was subnormal (more than 2 SD below the mean of the controls) in28 of the 100 patients. One–four stepwise decreases of 10–100% in the daily equipotent doses received by the patients with abnormal low-dose corticotropin testing results led to normal results in subsequent low-dose corticotropin testing in 27 retested patients. The mean time interval between two tests was 5 months (range: 2–6 months) and the mean period required for normalization of the test was 13 months (range: 2–21). Only one case of asthma exacerbation and no adrenal crisis were observed over these periods. Conclusions: Decreasing daily equipotent doses led to recovery of normal HPA function without asthma exacerbation. Thus, a revision of the doses of inhaled corticosteroids used in asthmatic children with a progressive decrease to the consensus-recommended doses should decrease the systemic effects of inhaled corticosteroids, while minimizing the risk of asthma exacerbation.

Keywords:
Inhaled corticosteroids, Low-dose corticotropin stimulation test, Hypothalamic-pituitary-adrenal axis, Fluticasone propionate, Beclomethasone dipropionate, Budesonide
1.
Rao R, Gregson RK, Jones AC, Miles EA, Campbell MJ, Warner JO: Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone. Eur Respir J 1999;13:87–94.
2.
Agertoft L, Pedersen S: Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;12:1064–1069.
3.
Patel L, Wales JK, Kibirige MS, Massarano AA, Couriel JM, Clayton PE: Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child 2001;85:330–334.
4.
Sizonenko PC: Effects of inhaled or nasal glucocorticosteroids on adrenal function and growth. J Pediatr Endocrinol Metab 2002;15:5–26.
5.
Schlienger RG, Jick SS, Meier CR: Inhaled corticosteroids and the risk of fractures in children and adolescents. Pediatrics 2004;114:469–473.
6.
Broide J, Soferman R, Kivity S, Golander A, Dickstein G, Spirer Z, Weisman Y: Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995;80:1243–1246.
7.
Fitzgerald D, Van Asperen P, Mellis C, Honner M, Smith L, Ambler G: Fluticasone propionate 750 μg/day versus beclomethasone dipropionate 1500 μg/day: comparison of efficacy and adrenal function in paediatric asthma. Thorax 1998;53:656–661.
8.
Lipworth BJ: Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159:941–955.
9.
Kannisto S, Korppi M, Remes K, Voutilainen R: Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab 2000;85:652–657.
10.
Martin RJ, Szefler SJ, Chinchilli VM, Kraft M, Dolovich M, Boushey HA, Cherniack RM, Craig TJ, Drazen JM, Fagan JK, Fahy JV, Fish JE, Ford JG, Israel E, Kunselman SJ, Lazarus SC, Lemanske RF Jr, Peters SP, Sorkness CA: Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;165:1377–1383.
11.
Eid N, Morton R, Olds B, Clark P, Sheikh S, Looney S: Decreased morning serum cortisol levels in children with asthma treated with inhaled fluticasone propionate. Pediatrics 2002;109:217–221.
12.
Sim D, Griffiths A, Armstrong D, Clarke C, Rodda C, Freezer N: Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma. Eur Respir J 2003;21:633–636.
13.
Kelly HW, Nelson HS: Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol 2003;112:469–478.
14.
Drake AJ, Howells RJ, Shield JP, Prendiville A, Ward PS, Crowne EC: Symptomatic adrenal insufficiency presenting with hypoglycaemia in children with asthma receiving high dose inhaled fluticasone propionate. BMJ 2002;324:1081–1083.
15.
Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D: Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002;87:457–461.
16.
World Health Organisation: Fluticasone and adrenal crisis. Aust Adverse Drug React Bull 2003;22:6.
17.
Adams N, Bestall JM, Jones PW: Inhaled beclomethasone versus inhaled budesonide for chronic asthma. Cochrane Database Syst Rev 2002; CD002310.
18.
Adams N, Bestall JM, Lasserson TJ, Jones PW: Inhaled fluticasone versus inhaled beclomethasone or inhaled budesonide for chronic asthma. Cochrane Database Syst Rev 2004; CD002310.
19.
Masoli M, Weatherall M, Holt S, Beasley R: Systematic review of the dose-response relation of inhaled fluticasone propionate. Arch Dis Child 2004;89:902–907.
20.
Sempé M: Auxologie. Méthodes et séquences. Paris, Théraplix, 1979.
21.
Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W: Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998;83:1558–1562.
22.
Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M: Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773–778.
23.
Hurel SJ, Thompson CJ, Watson MJ, Harris MM, Baylis PH, Kendall-Taylor P: The short Synacthen and insulin stress tests in the assessment of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 1996 ;44:141–146.
24.
Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Jackson RV: Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1–24) infusion tests. J Clin Endocrinol Metab 1999;84:3648–3655.
25.
Rose SR, Lustig RH, Burstein S, Pitukcheewanont P, Broome DC, Burghen GA: Diagnosis of ACTH deficiency. Comparison of overnight metyrapone test to either low-dose or high-dose ACTH test. Horm Res 1999;52:73–79.
26.
Gonzalbez J, Villabona C, Ramon J, Navarro MA, Gimenez O, Ricart W, Soler J: Establishment of reference values for standard dose short synacthen test (250 μg), low dose short synacthen test (1 μg) and insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in normal subjects. Clin Endocrinol. 2000;53:199–204.
27.
Tordjman K, Jaffe A, Trostanetsky Y, Greenman Y, Limor R, Stern N: Low-dose (1 μg) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary-adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 μg) test. Clin Endocrinol 2000;52:633–640.
28.
Thorsson L, Edsbacker S, Kallen A, Lofdahl CG: Pharmacokinetics and systemic activity of fluticasone via Diskus and pMDI, and of budesonide via Turbuhaler. Br J Clin Pharmacol 2001;52:529–538.
29.
Daley-Yates PT, Price AC, Sisson JR, Pereira A, Dallow N: Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol 2001;5:400–409.
30.
Bisgaard H, Klug B, Sumby BS, Burnell PK: Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma. Eur Respir J 1998;11:1111–1115.
31.
Agertoft L, Pedersen S: Lung deposition and systemic availability of fluticasone Diskus and budesonide Turbuhaler in children. Am J Respir Crit Care Med 2003;168:779–782.
32.
Onhoj J, Thorsson L, Bisgaard H: Lung deposition of inhaled drugs increases with age. Am J Respir Crit Care Med 2000;162:1819–1822.
33.
Lipworth BJ, Clark DJ, McFarlane LC: Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to asthmatic school children. Thorax 1997;52:686–689.
34.
Dempsey OJ, Wilson AM, Coutie WJ, Lipworth BJ: Evaluation of the effect of a large volume spacer on the systemic bioactivity of fluticasone propionate metered-dose inhaler. Chest 1999;116:935–940.
35.
Goldberg S, Einot T, Algur N, Schwartz S, Greenberg AC, Picard E, Virgilis D, Kerem E: Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: comparison between dry powder inhaler and pressurized metered-dose inhaler attached to a spacer. Ann Allergy Asthma Immunol 2002;89:566–571.
36.
Vermeer H, Hendriks-Stegeman BI, van den Brink CE, van der Saag PT, van der Burg B, van Buul-Offers SC, Jansen M: A novel specific bioassay for the determination of glucocorticoid bioavailability in human serum. Clin Endocrinol 2003;59:49–55.
37.
Grahnen A, Jansson B, Brundin RM, Ling-Andersson A, Lonnebo A, Johansson M, Eckernas SA: A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbuhaler. Eur J Clin Pharmacol1997;52:261–267.
38.
Toogood JH, White FA, Baskerville JC, Fraher LJ, Jennings B: Comparison of the antiasthmatic, oropharyngeal, and systemic glucocorticoid effects of budesonide administered through a pressurized aerosol plus spacer or the Turbuhaler dry powder inhaler. J Allergy Clin Immunol 1997;99:186–193.
39.
Donnelly R, Williams KM, Baker AB, Badcock CA, Day RO, Seale JP: Effects of budesonide and fluticasone on 24-hour plasma cortisol. A dose-response study. Am J Respir Crit Care Med 1997;156:1746–1751.
40.
Mager DE, Moledina N, Jusko WJ: Relative immunosuppressive potency of therapeutic corticosteroids measured by whole blood lymphocyte proliferation. J Pharm Sci 2003;92:1521–1525.
41.
Roca-Ferrer J, Mullol J, Lopez E, Xaubet A, Pujols L, Fernandez JC, Picado C: Effect of topical anti-inflammatory drugs on epithelial cell-induced eosinophil survival and GM-CSF secretion. Eur Respir J 1997;10:1489–1495.
42.
Stellato C, Atsuta J, Bickel CA, Schleimer RP: An in vitrocomparison of commonly used topical glucocorticoid preparations. J Allergy Clin Immunol 1999;104:623–629.
43.
Hogger P, Rohdewald P: Binding kinetics of fluticasone propionate to the human steroids 1994;59:597–602.
44.
DeRijk RH, Schaaf M, de Kloet ER: Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol 2002;81:103–122.
45.
Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention/NHLB/WHO Workshop Report. Bethesda, National Institutes of Health, National Heart, Lung, and Blood Institute, 2004.
46.
Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Fagan JK, Fahy JV, Fish JE, Ford JG, Israel E, Kiley J, Kraft M, Lazarus SC, Lemanske RF Jr, Mauger E, Peters SP, Sorkness CA: Asthma Clinical Research Network of the National Heart Lung, and Blood Institute. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410–418.
47.
Everden P, Campbell M, Harnden C, McGoldrick H, Bodalia B, Manion V, Reynia S; FACT Study Group: Eformoterol Turbohaler compared with salmeterol by dry powder inhaler in asthmatic children not controlled on inhaled corticosteroids. Pediatr Allergy Immunol 2004;15:40–47.
48.
Aalbers R, Backer V, Kava TT, Omenaas ER, Sandstrom T, Jorup C, Welte T: Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma. Curr Med Res Opin 2004;20:225–240.
49.
Kankaanranta H, Lahdensuo A, Moilanen E, Barnes PJ: Add-on therapy options in asthma not adequately controlled by inhaled corticosteroids: a comprehensive review. Respir Res 2004;27:17.
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2006
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