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(Chest. 2005;128:902-905.)
© 2005 American College of Chest Physicians

Inhaled Beclomethasone Dipropionate Acutely Stimulates Dose-Dependent Growth Hormone Secretion in Healthy Subjects*

Francesco Bertoldo, MD; Mario Olivieri, MD; Giorgia Franchina, MD; Francesco De Blasio, MD, FCCP and Vincenzo Lo Cascio, MD

* From the Department of Biomedical and Surgical Science (Drs. Bertoldo, Franchina, and Lo Cascio), Institute of Internal Medicine, University of Verona, Verona; Department of Medicine and Public Health (Dr. Olivieri), Unit of Occupational Medicine, University of Verona, Verona; and Respiratory Medicine and Pulmonary Rehabilitation Section (Dr. De Blasio), Clinic Center Private Hospital Naples, Italy.

Correspondence to: Bertoldo Francesco, MD, Dipartimento di Scienze Biomediche e Chirurgiche, Medicina D–Policliclinico "G. Rossi," 37134 Verona, Italy; e-mail: francesco.bertoldo{at}univr.it


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: It is well known that systemic administration of corticosteroids has a dual effect on growth hormone (GH) secretion in man: acute systemic administration stimulates GH release, whereas chronic administration consistently blocks it. In this study, we evaluate whether administration of inhaled corticosteroids could acutely stimulate GH secretion, and whether this effect could be dose related.

Design: Double-blind, placebo-controlled, crossover study.

Participants: Eight normal male volunteers all recruited at our institution.

Interventions: Administration of increasing doses of inhaled beclomethasone dipropionate (BDP; range, 50 to 1,500 µg) or placebo.

Measurements and results: Blood samples for GH determinations were collected at – 15, 0, 60, 120, 180, 240, 300, and 360 min in relation to BDP or placebo administration. The results of this study show a peak GH secretion at 240 min after the administration of BDP at doses > 100 µg. The comparisons among the peaks obtained with increasing doses showed a dose-response effect on GH secretion, starting from 100 to 1,000 µg. BDP 1,500 µg did not induce a peak significantly different from that obtained with 1,000 µg. When we calculated the GH response to BDP as an area under the curve (micrograms per liter x 6 h), the data confirmed that GH secretion was elicited in a dose-related manner.

Conclusions: Our data show that inhaled BDP at dose > 100 µg acutely stimulates GH secretion in a strictly dose-dependent manner. We propose this test as a surrogate for systemic absorption and as a valuable test to compare systemic effects among different inhaled steroids.

Key Words: beclomethasone dipropionate • growth hormone • systemic effects of inhaled steroids


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids are the most effective and widely used anti-inflammatory drugs for the treatment of bronchial asthma, and to such an extent they have been incorporated into national as well as international guidelines.1 It is well accepted that low doses of inhaled steroids do not have serious systemic adverse effects.234 However, to achieve greater control over the inflammatory disease and improve asthma symptoms, these pharmaceutical agents are currently administered at higher dosages and for longer periods of time than ever before. High-dose or long-period inhaled steroids regimens are accompanied by concern about possible systemic adverse effects such as pituitary-adrenal axis suppression and a negative impact on bone metabolism and on childhood growth.5

Systemic administration of corticosteroids has a dual effect on growth hormone (GH) secretion in man: long-term administration consistently blocks GH release,6 leading to a possible growth delay in childhood,7 whereas acute systemic administration stimulates GH release.8 To our knowledge, there is no evidence that inhaled steroids exert any effect on GH secretion. Therefore, in this study we evaluated the possible effect of inhaled corticosteroid administration on GH secretion and whether this effect is dose related.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Eight healthy nonsmoker male volunteers, all working at our institution, were studied in a double-blind, placebo-controlled, crossover design comparing the acute effect of increasing doses of inhaled beclomethasone dipropionate (BDP) on GH secretion. The mean age (± SD) was 32.1 ± 5.3 years; the mean body mass index was 22.6 ± 1.7. All subjects provided informed consent. The study was approved by the local Ethical Committee, and the procedures used were in accordance with the recommendations of Helsinki Declaration. None of the subjects had previous respiratory diseases, and all had normal spirometry results.

Subjects were randomly assigned to receive active drug or placebo. Placebo was administered via a metered-dose inhaler that contained the same propellants without the active drug, using the same time schedule. A 1-week wash-out period after each treatment was provided.

Tests started at 8 AM after an overnight fast. An indwelling catheter was placed in a forearm vein, and blood samples for GH were collected twice before drug/placebo inhalation (– 15 min and 0 min). The catheter was kept patent with a slow sterile saline solution infusion. BDP or placebo was inhaled at time 0 through a 750-mL spacer device, and the inhalation was followed by a 10-s breath hold and mouth rinsing. This standard procedure was used to minimize intersubject and intrasubject drug/placebo delivery variability and its subsequent systemic absorption. After BDP inhalation, blood samples for GH determinations were collected at 60, 120, 180, 240, 300, and 360 min. Determinations of serum GH were carried out with a commercial kit (Sorin Biomedica; Italy) with a 5% intra-assay coefficient of variation and sensitivity of 0.15 µg/L. All samples from each subject were analyzed with the same assay.

Statistical Analysis
Data are expressed as mean ± SD. The areas under the curve (AUC) of GH secretion (micrograms per liter x 6 h) were calculated using the trapezoidal method. Comparison of mean GH peaks and AUCs were performed by the nonparametric Mann-Whitney U test. The statistical level of significance was set at p < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
As compared to baseline values, inhaled placebo did not induce any significant change in GH levels. The curve of GH secretion after BDP 50 µg was not different from the placebo curve. On the contrary, BDP inhalation at doses within 100 µg and 1,500 µg stimulated a significant GH production. Independent of the BDP dose used, a significant increase in GH serum level was found at 120 min from the beginning of the test, with a peak at 240 min. GH levels returned at basal levels within 360 min. Mean peak GH serum levels were 1.58 ± 0.57 µg/L (p = 0.0001 vs baseline) with a dose of 100 µg, 3.52 ± 0.94 µg/L (p = 0.0001 vs baseline) with a dose of 250 µg, 5.38 ± 1.07 µg/L (p = 0.0012 vs baseline) with a dose of 500 µg, 8.68 ± 2.18 µg/L (p = 0.0005 vs baseline) with a dose of 1,000 µg, and 8.84 ± 2.11 (p = 0.0003 vs baseline) with a dose of 1,500 µg. The curves obtained with the increasing doses of BDP were well synchronized.

The comparison between the peaks obtained with increasing doses showed a dose-response effect on GH secretion, starting from 100 µg. The mean GH peak with BDP 100 µg was significantly higher than that obtained after BDP 50 µg (p = 0.0001). The mean GH peak with BDP 100 µg was significantly lower than that obtained with BDP 250 µg (p = 0.0027), the latter being significantly lower than the 500-µg peak (p = 0.0028). The mean GH peak elicited with BDP 500 µg was lower than that with 1,000 µg (p = 0.0018). There was no significant difference between peaks obtained with 1,000 µg and 1,500 µg (p = 0.88). When the GH response to BDP as an AUC (micrograms per liter x 6 h) was calculated, the data confirmed that GH secretion was elicited in a dose-related manner (mean AUC at 100 µg, 207.3 ± 51; AUC at 250 µg, 380.2 ± 80.0; AUC at 500 µg, 570.2 ± 112.7; AUC at 1,000 µg, 777.5 ± 81.9; AUC at 1,500 µg, 792.2 ± 72.3) [Fig 1, 2 ].



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  		Figure 1.. Mean GH peaks at 240 min after administration of 50, 100, 250, 500, 1,000, and 1,500 µg of BDP inhalation; 100 µg vs 50 µg, p = 0.0018; 250 µg vs 100 µg, p = 0.0028; 500 µg vs 250 µg, p = 0.0027; 1,000 µg vs 500 µg, p = 0.0001 (Mann-Whitney U test).

 


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  		Figure 2.. AUC of GH secretions after administration of 50, 100, 250, 500, 1,000, and 1,500 µg of BDP; bars represent SDs; *100 µg vs 50 µg, p = 0.012; **250 µg vs 100 µg, p = 0.0023; ***500 µg vs 250 µg, p = 0.001; ****1,000 µg vs 500 µg, p = 0.008 (Mann-Whitney U test).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our data show an acute systemic effect induced by a single dose of inhaled steroid. Many systemic side effects (skin bruising, hypophysis-adrenal axis suppression, osteoporosis, impaired growth in asthmatic children) are reported in adults as well as in children due to systemic absorption when the drug is administered long term and in high doses.5791011

There is considerable debate about the effects of inhaled steroids on pituitary function. There is some evidence of a dose-response relationship between inhaled steroid doses and hypophysis-adrenal axis function, even with low doses,1213 but a suppressive effect on growth hormone secretion was excluded in asthmatic children.1314 In fact, mean doses of 200 to 400 µg/d of BDP have no demonstrable adverse effects on first morning urinary GH excretion (which is the integrated measure of GH secreted during sleep) and on overnight serum GH profiles in asthmatic children receiving inhaled corticosteroids from 2 weeks to 2 months. The results of this study show that a single dose of BDP, even as low as 100 µg, elicits an acute and potent stimulus on GH secretion.

Corticosteroids appear to be the most potent releasers of GH, with the exception of GH-releasing hormone. A consistent and reproducible GH-releasing activity of corticosteroids was demonstrated within 3 to 4 h after acute IV or oral drug administration in normal adults and children.1516 This stimulus acted at the hypothalamic level, probably through somatostatinergic reduction.815 However the acute stimulatory action of inhaled BDP on GH secretion reveals some intriguing issues.

We observed that doses of 500 µg or 1,000 µg of inhaled BDP induced a marked increase from 15- to 22-fold of GH levels. Even if it is difficult to compare the systemic bioequivalent potencies of inhaled steroids with different systemic corticosteroids, our findings apparently are similar to those elicited by oral administration of 1 to 4 mg of dexamethasone or 60 mg of deflazacort and IV administration of 100 mg of hydrocortisone.816 Furthermore, our data demonstrate, for the first time, that the GH release induced by corticosteroid is not an on/off phenomenon but is dose dependent, as demonstrated for the hypothalamo-pituitary-adrenal (HPA) axis.1712 We argue that the higher pharmacological doses of steroids administered by other authors816 would have elicited an effect that could have been on the plateau of the dose-response curve, hence determining a maximal stimulation on GH and masking the dose-effect phenomenon.

Another interesting aspect is that the timing of GH discharge was similar between the different dosages of inhaled BDP and those observed after systemic administration of hydrocortisone, dexamethasone, and deflazacort. This suggests that the stimulatory action of corticosteroids on GH is time dependent and related neither to the route of administration and nor to the type of corticosteroid employed.

It is likely that inhaled BDP activates GH secretion by acting at the hypothalamic level. The most obvious explanation is the systemic absorption of BDP by the gut or by the lung. In this study, all subjects used a spacer device (Volumatic; Glaxo) that reduces the amount of drug absorbed by the stomach increasing that deposited in the lung.18 Brown et al192021 suggested that the use of a large-volume spacer in asthmatic patients receiving high-dose BDP reduced significantly the suppression of the HPA. Our data provide the evidence of a significant effect on the HPA in normal subjects also by using a spacer device, suggesting that very low doses of steroid are a potent stimulus for GH release. Unlikely budesonide and fluticasone, BDP is partially biotransformed in the lung by enzymatic hydrolysis to a more topically active beclomethasone 17-monopropionate, which also has glucocorticoid activity.20 This major metabolite is bioactive and is more slowly metabolized than budesonide or fluticasone propionate after absorption, ie, 900 min for the second phase. The systemic bioavailability of the inhaled fraction that enters the systemic circulation after absorption from the lung is dependent on the pharmacokinetic parameters of the corticosteroid molecule, such as elimination half-life and volume of distribution. Therefore, caution should be taken in extrapolating our results with BDP to budesonide and fluticasone propionate.21

Our observation of an acute systemic effect induced with a single dose of inhaled steroid could have some practical implications, eg, to utilize the dose-dependent stimulated GH response as a suitable acute test to assess the systemic bioavailability of various inhaled corticosteroids (with or without a high first-pass liver metabolism) or to study the degree of GH deficit in pituitary diseases. In conclusion, our data demonstrate that inhaled BDP is able to acutely stimulate a significant GH release in a dose-dependent manner. The clinical implication of this effect awaits further studies.


   Footnotes
 
Abbreviations: AUC = area under the curve; BDP = beclomethasone dipropionate; GH = growth hormone; HPA = hypothalamo-pituitary-adrenal

The study was carried out at the Department of Biomedical and Surgical Science, Institute of Internal Medicine, University of Verona Medical School, Verona, Italy.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: www.chestjournal.org/misc/reprints.shtml).

Received for publication November 18, 2004. Accepted for publication January 31, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  4. Halpern, MT, Schmier, JK, Van Kerkhove, MD, et al Impact of long-term inhaled corticosteroid therapy on bone mineral density: results of a meta-analysis. Ann Allergy Asthma Immunol 2004;92,201-207[Medline]
  5. Lipworth, BJ Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159,941-955[Abstract/Free Full Text]
  6. Burguera, B, Muruais, C, Penalva, A, et al Dual and selective action of glucocorticoids upon basal and stimulated growth hormone release in man. Neuroendocrinology 1990;51,51-58[CrossRef][ISI][Medline]
  7. Littlewood, JM, Johnson, AW, Edwards, PA, et al Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. Lancet 1988;1,115-116[Medline]
  8. Casanueva, FF, Burguera, B, Muruais, C, et al Acute administration of corticoids: a new and peculiar stimulus of growth hormone secretion in man. J Clin Endocrinol Metab 1990;70,234-237[Abstract]
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