|Year : 2012 | Volume
| Issue : 3 | Page : 314-318
The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis
Keivan Gohari Moghaddam1, Negin Rashidi1, Hamidreza Aghaei Meybodi2, Nader Rezaie1, Mahdi Montazeri1, Ramin Heshmat2, Zohreh Annabestani2
1 Department of Pulmonology, Tehran University of Medical Science (TUMS), Tehran, Iran
2 Department of Endocrinology and Metabolism Research Center (EMRC), Tehran University of Medical Science (TUMS), Tehran, Iran
|Date of Submission||19-Jun-2011|
|Date of Decision||11-Dec-2011|
|Date of Acceptance||28-Feb-2012|
|Date of Web Publication||17-May-2012|
Department of Pulmonology, Tehran University of Medical Science (TUMS), Tehran
Objectives: The aim of this study was to compare systemic effects of high-dose fluticasone propionate (FP) and beclomethasone dipropionate (BDP) via pressurized metered dose inhaler on adrenal and pulmonary function tests.
Materials and Methods: A total of 66 patients with newly diagnosed moderate persistent asthma without previous use of asthma medications participated in this single blind, randomized, parallel design study. FP or BDP increased to 1 500 μg/d in 62 patients who had not received oral or IV corticosteroids in the previous six months. Possible effects of BDP and FP on adrenal function were evaluated by free cortisol level at baseline and after Synacthen test (250 μg). Fasting plasma glucose and pulmonary function tests were also assessed. Similar tests were repeated 3 weeks after increasing dose of inhaled corticosteroids to 1 500 μg/d.
Results: No statistically significant suppression was found in geometric means of cortisol level post treatment in both groups. After treatment in FP group, mean forced expiratory volume in one second (FEV1) and mean forced vital capacity (FVC) values improved by 0.17 l (5.66% ± 13.91, P=0.031) and 0.18 l (5.09% ± 10.29, P=0.010), respectively. Although FEV1 and FVC improved in BDP group but was not statistically significant. Oral candidiasis and hoarseness were observed in 6.5% patients receiving BDP, but hoarseness was found in 3.2% patients in FP group (P=0.288).
Conclusions: The results indicate that safety profiles of high doses of BDP and FP with respect to adrenal function are similar, but FP is more efficacious than that of BDP in improving pulmonary function test.
Keywords: Adrenal cortex function tests, adrenal insufficiency, asthma, beclomethasone dipropionate, fluticasone
|How to cite this article:|
Moghaddam KG, Rashidi N, Meybodi HA, Rezaie N, Montazeri M, Heshmat R, Annabestani Z. The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis. Indian J Pharmacol 2012;44:314-8
|How to cite this URL:|
Moghaddam KG, Rashidi N, Meybodi HA, Rezaie N, Montazeri M, Heshmat R, Annabestani Z. The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis. Indian J Pharmacol [serial online] 2012 [cited 2013 May 24];44:314-8. Available from: http://www.ijp-online.com/text.asp?2012/44/3/314/96300
| » Introduction|| |
According to Global Initiative for Asthma, inhaled glucocorticoids have emerged the cornerstone for asthma treatment due to inflammatory nature of the disease. It has been recommended in all steps of management approach of asthma except step 1. In the newly diagnosed symptomatic asthmatic patients, high doses of inhaled corticosteroid can be used in the absence of long-acting beta agonist instead of low doses of inhaled corticosteroids and a long-acting beta agonist. 
In decreasing airway inflammation and relieving symptoms in moderate asthma, it seems that effects of high-dose inhaled corticosteroid are comparable with oral prednisolone.  Nevertheless, there are some concerns about possible systemic adverse effects of inhaled corticosteroids, this may include Hypothalamic-Pituitary-adrenal (HPA) axis suppression, and adverse effects on growth and bone metabolism. In a number of studies, adrenal insufficiency has been reported after three weeks of treatment with corticosteroids. ,
The severity of HPA-Axis suppression is associated with duration, route, dose, and time of drug administration.  Low- and high-dose ACTH suppression tests are the standard tests which are mainly used to assess HPA-Axis suppression. , In order to decrease circadian rhythm effect on the test results, high-dose ACTH test is recommended. 
Fluticasone propionate (FP) and Beclomethasone dipropionate (BDP) are the two most commonly used inhaled corticosteroids in our society. FP appears to be more potent than BDP and Budesonide. ,, High topical potency, decreased systemic bioavailability, and rapid elimination are the favorable features of an inhaled corticosteroid and FP has the minimum oral bioavailability, which is ideal for an inhaled corticosteroid. 
In a meta-analysis, maximum clinical benefit for asthma treatment was obtained in a dose of 500 μg/d, but there are some concerns about adrenal suppression with FP in a dose of 1.5 mg/d.  It has been shown that FP can suppress serum cortisol and overnight urinary cortisol when used in medium and high doses. 
According to another trial, high dose of FP with a dose of 1 760 μg/d could result in decreased amount of mean serum cortisol compared with placebo but low-dose Synacthen test did not confirm the same results. ,
To address some of these issues, the present study compared the systemic and pulmonary effects of high dose of 3 weeks of therapy with FP and BDP in symptomatic moderate asthma patients by means of high-dose synacthen test and spirometry.
| » Materials and Methods|| |
A sample of 66 moderate asthmatic patients volunteered to participate in the study [Figure 1]. They were followed at Shariati hospital clinic, referral tertiary center, university hospital, Tehran University of Medical Sciences. All newly diagnosed stable patients with moderate persistent asthma according to NAEPP  (step3 GINA) criteria  were examined preliminarily and their clinical history were recorded. Patients who needed hospitalization were excluded.
|Figure 1: Effect of inhaled corticosteroids on HPA - axis - A randomized clinical study|
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Inclusion criteria: All newly diagnosed asthmatic patients with symptomatic moderate persistent asthma according to NAEPP criteria;  in all the eligible patients, normal adrenal function was demonstrated by peak cortisol level ≥600 nmol/l after 250 μg ACTH test at baseline. 
Exclusion criteria were asthma exacerbations during the study, corticosteroid use (Intramuscular, Intravenous, Oral) in the previous six months, smoking, respiratory tract infections during treatment, those unable to use pressurized metered dose inhaler (pMDI) correctly, those who refused to complete the study, or had poor compliance, and currently users of medications such as oral contraceptive pills, ketoconazole, phenytoin, carbamazepine, Phenobarbital, and rifampin in the previous six months.
This was a single blind (investigator blind), randomized, parallel group clinical trial to investigate both the effects of FP (250 μg, GSK; France) and BDP (250 μg, chiesi; Italy) with the same dosage (1 500 μg/d) on adrenal function tests, pulmonary function tests, and fasting plasma glucose (FPG) of asthmatic outpatient adults meeting all criteria. By using high doses of inhaled corticosteroid as an alternative approach, according to GINA guidelines,  the effect of confounding factors was attenuated; therefore, there was no need to use a long-acting beta agonist. All eligible patients were randomized by Permuted Balanced Block Randomization to treatment with BDP or FP and were trained to use a pMDI with spacer and rinse their mouth after using inhaler. Of 66 patients, four patients were excluded: two patients because of non-compliance and two due to incomplete follow-up. Eventually, 62 patients were assigned to receive 1 500 μg FP or 1 500 μg BDP according to randomization, via a metered dose inhaler in two divided doses. After 3 weeks of treatment, the tests were repeated. Three weeks is the earliest time required for the complications to occur and the aim of this project was to assess the prevalence of complications occurring after consuming high doses of inhaled corticosteroids. Compliance was assessed based on taking empty canister at the end of the expected time, and thereafter the full canister was given to the patients. FPG, spirometry, and high-dose ACTH test were performed at baseline and at the end of 3 weeks of increased high-dose ICS.
The study protocol was approved by the Ethics Committee of Endocrinology and Metabolism Research Institute (EMRI), (e-0026 April 2009). Written informed consent was obtained from all participants and verbal explanations were given to them all. The study is registered at IRCT.
After an overnight fast, a cannula was inserted in antecubital fossa and 5 cc venous blood sample was taken from the patients pretreatment. At baseline, serum cortisol level on 0, 30, 60 minutes after intravenous, 250 μg ACTH (Synacthen: Alliance Pharmaceuticals Ltd; England) and FPG and spirometric values were measured. All samples were taken between 8:00 am to 9:00 am. Plasma cortisol levels were measured using an automated micro plate-based enzyme immunoassay (Micro plate Reader 4 plus, Hiperion Rev: 1.6 e Medizintechnik GmbH and CO.kg; Germany) and the specific kit (kit: Monobind; USA; intra assay coefficient of variation=7.5%). After 3 weeks of trial treatment, all the tests were repeated.
We used supraphysiologic ACTH doses of 250 μg, which could result in higher peak cortisol levels after 60 minutes and higher false-negative results could occur; in order to decrease the false-negative results, the cut-off level in this study was selected to be 600 nmol/l. , The highest of the two measured levels after ACTH test was determined to be the peak cortisol level.
Pulmonary function tests using (masterscope version 4.6 Jaegers Viasys Healthcare GmbH: Germany) before and after intervention for each patient was recorded.
According to the results of previous trials and difference between high-dose inhaled corticosteroids in the amounts of decreased cortisol level, the sample size in each group was determined to be 31 patients.  Statistical analysis was performed using the Statistical Package for Social Sciences 18.0 (SPSS, Chicago, Illinois, USA). Mean ± SD described continuous parameters. The data were analyzed with student T-Test, Paired T-Test as appropriate for comparison between and within the groups. Cortisol levels were normalized by logarithmic transformation and were presented as geometric Mean. Parametric statistical analysis (ANOVA) was used in analysis for multiple comparisons of geometric means of cortisol. Categorical data are described as percentage. The P value of <0.05 and confidence interval of 95% were considered statistically significant.
| » Results|| |
Of the mentioned 66 patients who were enrolled in the study, two patients were excluded because of refusal to complete the test, two other patients were dropped out due to non-compliance of the intervention and eventually 62 patients aged 21 to 65 years with mean age 44.23 years (SD=10.90) completed the study. Thirty-one patients received 1 500 μg/d FDP and the same numbers of patients were treated with the same dose of BDP and were followed after 3 weeks of trial period. BDP group comprised of 18 (58.1%) women and 13 (41/9%) men and in FP group, 19 (61.3%) patients were women and 12 (38.7%) patients were men. Demographic characteristics of both groups are summarized in [Table 1], and were comparable for sex, age, body mass index, and race, forced expiratory volume in one second (FEV1), forced vital capacity (FVC). Mean of pretreatment FPG and geometric means of fasting cortisol and cortisol after 30 and 60 minutes after ACTH were comparable in both groups [Table 2].
|Table 1: Comparison of demographic characteristics of patients among two treatment groups|
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|Table 2: Comparison of baseline pulmonary and adrenal test and fasting plasma glucose variables between two treatment groups|
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Early morning serum cortisol level samples were collected from all patients who were enrolled in the study. Before treatment, the geometric mean of baseline cortisol level in BDP group was 366.05 nmol/l (SD=44.26) and in FP group was 321.09 nmol/l (SD=45.09) and no statistically significant difference was detected (P=0.279). Before treatment, there were no significant differences in geometric means of cortisol after 30 and 60 minutes high-dose ACTH test in both groups (P=0.914 and P=0.930, respectively).
After treatment, high-dose Synacthen test did not show significant adrenal suppression in both groups. Adrenal suppression demonstrated by 250 μg ACTH test, considering the cut-off level of 600 nmol/l, was observed in seven subjects (22.6%) treated with FP and in five subjects (16.1%) in BDP group (P=0.520), although there was no statistically significant difference between two groups. The calculated risk ratio was about 1.4 (CI95%:0.34-6.21) in FP group comparing with BDP group.
The comparison of pulmonary variables within each group demonstrated significant improvement in the mean of percentage of FEV1 (5.66 ± 13.91, P=0.031) and FVC in FP group (5.09±10.29, P=0.01). FEV1 and FVC improved in BDP group but were not statistically significant. The other variables did not improve significantly [Table 3].
|Table 3: Comparison of pulmonary variables before and after treatment between two treatment groups|
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The comparison of mean changes of pulmonary variables between 2 groups at baseline and after treatment showed significant improvement in the percentage of FVC (5.09 ± 10.30, P=0.010) in FP compared with BDP group [Table 3].
After treatment, mean level of FPG in BDP group was 111.48 ± 16.49 mg/dl and in FP group was 108.03 ± 13.124 mg/dl. Statistically no significant differences were observed in FP (P=0.788) and BDP (P=0.209) groups before and after treatment.
In BDP group, oral candidiasis was observed in two patients (6.5%) but in FP group nothing was detected in any of the patients. Hoarseness was observed in two patients (6.5%) in BDP group and in one patient (3.2%) in FP group. None of the patients required serious treatment for resolving symptoms.
| » Discussion|| |
This study was designed to investigate whether increased dose of FP or BDP to 1 500 μg/d have any adverse effects on HPA axis, i.e., prescriptions of 1 500 μg/d of BDP and FP in asthmatic patients are safe. In our knowledge, this study is the first study in Iran in which high dose of ACTH test has been used to compare systemic effects of BDP and FP.
We found that neither BDP nor FP in this study has suppressive effect on adrenal function tests. Adrenal suppression demonstrated by 250 μg ACTH test, considering the cut-off level of 600 nmol/l, was observed in FP group (22.6%) and in BDP group (16.1%), although it was not statistically significant in either groups, the calculated risk ratio was about 1.4 (CI 95%:0.34-6.21) that implies 40% increased risk of adrenal suppression in FP group, which however was not statistically significant.
Our results substantiates the results of study by Gagnon et al. in which 1 000 μg BDP and ACTH test was used to determine adrenal suppression and is in accordance with the other study that used 1 500-2 000 μg of BDP and FP by measuring plasma cortisol.  But our results contradict adrenal suppression, which was shown in another study which compared 750 μg FP with 1 500 μg BDP.  These differences may be due to our provision not to use other systemic steroids and different dose and spacer use. In a range of 1 000-2 000 μg per day use of FP adrenal suppression has been shown in some studies. , This discrepancy may be attributed to various laboratory tests used in these studies, different cut-off level for adrenal suppression, previous use of systemic corticosteroids, different population groups, and different number of cases in the study. In addition, the results of this study may be due to the use of spacer, since spacers can reduce systemic effects of inhaled corticosteroids. 
Three patients (4.8%) in FP group and one patient (1.6%) in BDP who had baseline cortisol level ≤3 μg/dl after treatment showed suppressed cortisol levels of 30, 60 minutes after dose increment, which implies that performing ACTH test may not be necessary in this group of patients in order to determine adrenal suppression, as showed by Hagge et al.'s study results. 
The study demonstrated significant difference in FEV1 and FVC which was produced in FP group, and indicates that high dose of FP is more efficient than that of equivalent dose of BDP in moderate asthma control. The results are concordant with the findings of the other studies that FP is more efficacious than BDP but is in contrast to another study that did not show the higher efficacy of FP. ,
In our study, the incidences of adverse events were similar in both groups. Adverse effects were detected in a small number of patients that point out efficacy and safety of spacer use and also desirable hygiene of the patients since a spacer will decrease deposition of drug in oropharyngeal area.
One of the limitations of this study was the short period of intervention and it is possible that with longer period of treatment, adrenal suppression may occur. In addition, higher doses of inhaled corticosteroids rather than 1 500 μg/d may suppress HPA axis. Other studies are needed to investigate these effects when using higher doses and for longer courses.
We found that BDP and FP in a dose of 1 500 μg/d did not suppress pituitary adrenal axis, resulted in no effect on FPG, nevertheless FP improved FEV1 and FVC significantly.
| » Acknowledgment|| |
This study was financially supported by Endocrinology and Metabolism Research Center (EMRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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[Table 1], [Table 2], [Table 3]