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(Chest. 2005;127:515-521.)
© 2005 American College of Chest Physicians

Growth Hormone Response to Growth Hormone-Releasing Hormone Is Reduced in Adult Asthmatic Patients Receiving Long-term Inhaled Corticosteroid Treatment*

Mario Malerba, MD; Simonetta Bossoni, MD; Alessandro Radaeli, MD; Erica Mori, MD; Stefania Bonadonna, MD; Andrea Giustina, MD and Claudio Tantucci, MD

* From the Department of Internal Medicine, University of Brescia, Brescia, Italy.

Correspondence to: Mario Malerba, MD, Department of Internal Medicine, University of Brescia, 1° Divisione di Medicina, Spedali Civili, Piazza Spedali Civili 1, 25100 Brescia, Italy; e-mail: malerba{at}master.cci.unibs.it


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Some studies have demonstrated that the function of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is significantly impaired in patients with oral corticosteroid (CS)-induced osteoporosis. The aim of study was to investigate the effects of long-term therapy with inhaled CSs (ICSs) on the hypothalamic-pituitary-GH axis by the GH response to GH-releasing hormone (GHRH), as well as bone turnover, in adult asthmatic patients.

Design: Cross-sectional study.

Patients: Twenty-seven adult subjects with mild-to-moderate persistent asthma (long-term ICS therapy [ie, > 1 year], 20 patients; naive to ICS treatment, 7 patients) and 10 control subjects.

Measurements: Each subject underwent testing with an IV bolus (1 µg/kg) injection of human GHRH, and samples of GH were taken 15 min before the GHRH injection, at 0 min (ie, at the time of GHRH injection), and at 15, 30, 45, 60, and 90 min after injection to obtain values for peak GH and {Delta}GH. At baseline, samples of serum IGF-1 and blood-urine were collected for bone turnover markers.

Results: The GH response to GHRH was significantly reduced in asthmatic patients receiving ICSs (peak GH, p < 0.05; and {Delta}GH, p < 0.01) in comparison with control subjects and asthmatic patients who were naive to ICS therapy (peak GH and {Delta}GH, p < 0.01). Baseline IGF-1 levels were similar in the three groups. Serum osteocalcin, a marker of bone formation, was significantly reduced (p < 0.01) and correlated with GH peak (r2 = 0.34; p = 0.007) in asthmatic patients who were treated with ICSs.

Conclusions: We conclude that GH secretion in response to GHRH is significantly reduced in adult asthmatic patients receiving therapy with ICS and that such inhibition could play a negative role in bone metabolism.

Key Words: adult asthmatic patients • bone metabolism • growth hormone • inhaled corticosteroids


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids (ICSs) are recommended as the first-line choice for antiinflammatory drugs in the management of asthma, and, currently, their use is widespread.1 Although ICS treatment is associated with fewer side effects compared to that with oral corticosteroids (CSs),2 ICSs may cause dose-related systemic effects2 affecting the adrenal-growth hormone (GH) axis and bone metabolism,3 and causing cataracts4 and skin bruising.5 These long-term adverse effects of ICS therapy have been only partially assessed.67 Osteoporosis is a common side effect of long-term treatment with CSs, however, the mechanism by which they lead to a reduction in bone mass is complex, involving direct and indirect effects on the remodeling cycle.8 Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and resorption.9 The reduction of GH secretion seems to play a relevant role in the osteoporosis induced by CSs.101112 The inhibitory effect of CSs on GH secretion is likely due to an increase in hypothalamic somatostatin tone, which blocks GH pituitary secretion.13 After a single dose of systemic CSs, the GH response to GH-releasing hormone (GHRH) is reduced compared to that after a dose of placebo.13 In patients who have received long-term treatment with systemic CSs, it has been shown that the GH response to GHRH is suppressed.13 Finally, some studies10 have demonstrated that the GH-insulin-like growth factor (IGF)-1 axis function is significantly impaired in the presence of oral CS-induced osteoporosis, indicating that subclinical hyposomatotropism might represent an important pathogenetic mechanism. To our knowledge, there are no controlled studies showing the effects of long-term ICS treatment on GH secretion in response to GHRH in asthma patients. Therefore, the aim of study was to investigate the hypothalamic-pituitary-GH axis by the GH response to GHRH, as well as bone turnover, in adult asthmatic patients during long-term (ie, > 1 year) ICS treatment, compared to healthy subjects and asthmatic patients who never used ICSs, to check the real impact of either ICS therapy or asthma on GH secretion and bone metabolism.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
In a cross-sectional study, we enrolled 27 consecutive adult patients with mild-to-moderate persistent asthma that had been diagnosed according to National Institutes of Health criteria,1 of whom 20 were receiving long-term (ie, > 1 year) ICS therapy (12 women and 8 men; mean [± SD] age, 50.2 ± 7.3 years; mean body mass index [BMI], 26.6 ± 4.3 kg/m2) and 7 were naive to ICS treatment (4 women and 3 men; mean age, 46.7 ± 6.3 years; mean BMI, 23.9 ± 3.4 kg/m2). Patients had been referred to our Pulmonary Function Laboratory in the Department of Internal Medicine (Brescia, Italy). We enrolled 10 healthy control subjects (6 women and 4 men; mean age, 44.6 ± 15.6 years; mean BMI, 25.9 ± 4.4 kg/m2).

Exclusion criteria were as follows: age < 18 years and > 65 years; BMI, > 30 and < 20 kg/m2; diseases potentially interfering with the study (ie, endocrine disease, hepatic or renal failure, and premature or surgical menopause without replacement hormonal therapy); and treatment with other drugs known to influence either GH secretion or bone metabolism. Moreover, asthmatic patients with a sedentary lifestyle, with excessive alcohol intake, with a history of undergoing a course of systemic CS therapy in the past 6 months or undergoing more than two courses ever and having used > 10 inhalers of a nasal CS or 10 prescriptions of dermal CS ever were excluded. At the time of study inclusion, all asthmatic patients were in a stable condition and were free from respiratory exacerbations. The study protocol was approved by the local ethics board, and all subjects gave their written informed consent to participate to the study, which was conducted in accordance with the principles of the Helsinki Declaration. The demographic and functional characteristics of the asthmatic patients and control subjects are reported in Table 1 .


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  		Table 1. Demographic and Functional Characteristics of the Population Studied*

 
Criteria Used for the Diagnosis of Asthma
For each patient, the presence of any two of the following criteria was considered diagnostic of asthma: (1) a history of attacks of wheezing associated with shortness of breath; (2) the presence of airway obstruction with spirometric evidence of a bronchodilator response; and (3) the presence of bronchial hyperresponsiveness (performed when basal spirometry findings were normal). The severity of asthma was classified into groups, which were studied by clinical features and pulmonary function test results before treatment.1

Study Protocol
Clinical Assessment:
At the beginning of the study, each subject completed a questionnaire and performed pulmonary function tests. The questionnaire asked about current and previous drug treatment, history of asthma, smoking and alcohol intake, and physical activity. Exercise tolerance was not specifically assessed; however, no difference was found in the questionnaire concerning physical activity between asthmatic patients receiving therapy with ICSs and asthmatic patients who were ICS naive. Women were asked about menstrual history or premature or surgical menopause. All ICS-treated patients were receiving the lowest possible maintenance dose as a result of previous attempts to step down the dose. The asthmatic patients taking ICSs who were included in the study used a standard dosage of either budesonide or fluticasone propionate. The mean daily dose of budesonide administered with a turbohaler was 790 ± 258 µg in 12 patients, while the mean daily dose of fluticasone propionate administered with a metered-dose inhaler was 687 ± 427 µg in 8 patients. Given the relatively small number of asthmatic patients who were treated with ICS and the almost equipotent mean dose of budesonide and fluticasone propionate that they used, these patients were analyzed as a single group.

Lung Function Measurements:
Dynamic lung volumes were measured using a spirometer (CAD/Net system 1070; MCG; St. Paul, MN) in accordance with the American Thoracic Society standard procedure.14 An FVC test was also performed starting with a full inspiration to total lung capacity, followed by a rapid, maximal expiration to residual volume, and then the loop was completed by inspiring back to total lung capacity. Predicted values were used in accordance with the standards of the European Community for Coal and Steel.15 In subjects with FEV1 ≤ 70% of FVC, two puffs from the bronchodilator (albuterol, 200 µg) were administered with a metered-dose inhaler, and the FVC test was repeated after 20 min. A significant bronchodilator response was defined as an increase of 12% and 200 mL with respect to the baseline FEV1.

Hormonal and Biochemical Measurements:
During the second visit, all subjects spent one morning in the clinical research unit. After an overnight fast, all subjects rested in a recumbent position and had an antecubital vein catheter inserted percutaneously. After a 30-min stabilization period, all subjects received an IV bolus of human GHRH-(1–29)NH2 (Geref; Serono, Italy) in a dose of 1 µg/kg. Blood samples for GH (immunoradiometric assay and Allegro hGH; Nichols Institute; San Juan Capistrano, CA; interassay coefficient of variation, ± 5.4%; intraassay coefficient of variation, ± 2.3%; sensitivity limit of the assay, 0.02 µg/L) were taken 15 min before administration of the GHRH bolus (baseline), at time 0 (ie, immediately before administration of the GHRH bolus), and at 15, 30, 45, 60, and 90 min after GHRH administration. We have considered the following for analysis: GH values at different times; peak GH (ie, the highest GH value observed after stimulus with GHRH); and {Delta}GH (ie, peak GH – [baseline GH + GH at time 0]/2).

At baseline (–15 min), both blood and urine samples were obtained to measure levels of serum IGF-1 (immunoradiometric assay [after acid-ethanol extraction]), serum calcium, serum phosphorus, serum cortisol, and urinary calcium. A 24-h urinary sample was obtained for urinary cortisol measurement. Serum osteocalcin as a marker of bone formation was assessed by radioimmunoassay (Nichols Institute), and urinary deoxypyridinoline as marker of bone resorption was assessed by enzyme-linked immunosorbent assay (corrected for urinary creatinine concentration).

Statistical Analysis
Data are expressed as the mean ± SD or 95% confidence intervals. Significant differences among groups were performed by one-way analysis of variance. Whenever the F ratio indicated significance, an unpaired t test or nonparametric test was used, when appropriate, to identify individual differences. A linear regression model was used to study the relationship between the considered variables. {chi}2 analysis was used to test categoric variables. A p value of < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographic and functional data of subjects and patients are reported in Table 1. No significant differences were observed among the three groups studied. The values for the biochemical markers of bone metabolism and hormones are presented in Table 2 . The median duration of treatment in the asthmatic patients receiving ICSs was 36.7 months (range, 18 to 54 months). Values for levels of serum GH sampled at baseline and at different times after patients received the GHRH IV bolus are shown for the three groups in Figure 1 .


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  		Table 2. Biochemical Characteristics of the Population Studied*

 


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  		Figure 1. Values (mean ± SE) of GH before and after administration of the GHRH IV bolus (arrow) in the three groups. *p < 0.01 vs control subjects and asthmatic patients who were ICS naive.

 
The mean GH peak in asthmatic patients treated with ICSs was lower (4.3 ± 3.1 ng/mL) compared to those in both control subjects (16.7 ± 14.5 ng/mL; p = 0.025) and asthmatic patients who had never received ICSs (17.7 ± 13.1 ng/mL; p = 0.036) [Fig 2 ]. The mean {Delta}GH was also significantly lower in asthmatic patients treated with ICSs (2.1 ± 3.0 ng/mL) compared to those in control subjects (11.4 ± 9.4 ng/mL; p = 0.01) and asthmatic patients who were naive to ICSs (11.4 ± 9.7 ng/mL; p = 0.043) [Fig 2].



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  		Figure 2. Individual values of {Delta}GH and GH peak in the three groups. *p < 0.05 vs control subjects and asthmatic patients who were ICS naive.

 
Baseline IGF-1 values were similar in all groups. However, asthmatic patients who had received ICSs had a tendency toward lower levels compared to the other groups (Table 2). No significant correlation was observed between the duration of ICS treatment and GH peak or {Delta}GH. ICS treatment had no effect on levels of serum calcium, serum phosphorus, and urinary calcium, whereas mean serum osteocalcin levels were significantly reduced in the group of asthmatic patients receiving long-term ICS treatment (5.6 ± 2.1 ng/mL) compared with those in control subjects (14.7 ± 7.5 ng/mL; p = 0.004) and asthmatic patients who had never received ICS treatment (15.2 ng/mL; p = 0.033) [Table 2]. The urinary levels of deoxypyridinoline were similar among the groups considered. Urinary and serum levels of cortisol were not significantly different among the three groups. Osteocalcin serum levels in the group of asthmatic patients receiving ICSs showed a significant correlation with values of GH peak (r2 = 0.34; p = 0.007) [Fig 3 ]. No statistical difference in any variable considered was found between asthmatic patients who were naive to ICSs and the control group.



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  		Figure 3. Correlation between osteocalcin serum levels and GH peak after administration of the GHRH IV bolus in asthmatic patients who were receiving ICS treatment.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates that in asthmatic patients receiving long-term treatment with ICSs, GH secretion in response to GHRH is significantly reduced in comparison with control subjects and asthmatic patients who had never been treated with ICSs. Moreover, such inhibition is associated with a decrease in the level of osteocalcin, a marker of the bone formation, which is known to be decreased in the presence of CS-induced osteoporosis.16 The pathogenesis of CS-induced osteoporosis is due to several factors, including the reduction of GH secretion observed during CS administration. It has been shown previously that GH secretion is important in the regulation of bone growth, mainly favoring the increase of bone formation by direct interaction with GH receptors on osteoblasts and the induction of IGF-1.17 Moreover, it has been observed that low circulating levels of GH may induce a reduction of bone mass.18 In this respect, several studies192021 have documented that in humans glucocorticoids cause the suppression of GH secretion by promoting an enhanced hypothalamic somatostatin tone. Interestingly, Berneis et al12 found that in healthy subjects after 6 days of oral methylprednisolone treatment, the administration of GH and IGF-1 was able to counteract the bone loss and the decrease in bone synthesis associated with osteocalcin reduction. In addition, it has been previously shown that 1 week of GH treatment is able to partially reverse the suppression of bone turnover observed in patients receiving long-term treatment with systemic CSs,22 underlining the potential role of GH secretion in the pathogenesis of CS-induced osteoporosis. Our study shows that long-term therapy with ICSs decreases GH secretion after stimulus with GHRH in asthmatic patients and that such inhibition is related to a decrease in bone formation, as reflected by osteocalcin levels. This observation supports the idea that the reduction in GH secretion induced by ICSs may negatively affect the bone metabolism in asthmatic patients. Previous studies2324 have suggested that, with administration by inhalation, budesonide may have relatively less impact on bone formation than other CSs. However, in this respect, it must be underlined that our observation of serum osteocalcin reduction, after > 36 months of treatment with ICSs, is in line with a recently published systematic review24 claiming that ICSs, even at low dosage, lead to an alteration of bone metabolism markers lasting for several years, acting predominantly as inhibitors of bone formation. In fact, bone markers as osteocalcin can be used to assess bone metabolism to predict the risk for the development of osteoporosis.24

Abnormalities in GH secretion and/or osteocalcin should lead clinicians to carefully confirm a suspicion of an increased risk of fracture with bone densitometry in order to initiate, when indicated, antiosteoporosis treatment or to modify antiasthmatic therapy (eg, a decrease in dosage or a change in the type of treatment).25 In the present study, we were unable to find any significant difference in serum and urinary cortisol levels among the groups studied. This finding is in line with previously reported data324 showing that treatment with ICSs has modest effects on the hypothalamic-pituitary-adrenal axis. Moreover, our group has previously demonstrated26 that, even in a condition of subclinical hypercortisolism caused by an adrenal incidentaloma that was not biochemically detectable, a significant suppression of GH response to GHRH occurs, suggesting that this finding may be, as in our ICS patients, among the earliest features of even subtle glucocorticoid excess. A retrospective cohort study27 found an increased risk of fracture among patients who used ICSs, as well as inhaled bronchodilators, when compared with control subjects who had never used antiasthmatic drugs, suggesting a hypothetical negative effect of the asthma itself on bone metabolism. Therefore, a group of asthmatic patients who were matched for the severity of disease who were naive to ICS treatment were introduced in our study. In these asthmatic patients, similar to control subjects, neither a significant reduction in osteocalcin levels nor a diminished GH response to GHRH was found. These data suggest that the bone loss observed in asthmatic patients during long-term ICS treatment was more likely related to the CS systemic absorption than to a direct effect of the underlying chronic inflammatory airway disease on bone. Finally, other theoretical possibilities to explain at least in part our findings may include the hypothesis of potential little differences in exercise tolerance between patients treated with ICSs in comparison with those who were naive to ICSs and the increased bioavailability of budesonide in patients with asthma that was not severe. In this case, a greater deposition of ICSs is expected in the peripheral airways, along with increased systemic absorption and a potentially higher risk of related side effects.2829

In conclusion, the results of our study suggest that the long-term administration of ICSs significantly inhibits GH secretion in response to GHRH in adult asthmatic patients and that such inhibition may be associated with lower levels of osteocalcin. Therefore, the presence of subclinical hyposomatotropism can represent an early pathogenetic mechanism of ICS-induced osteoporosis. These data have practical implications in the long-term management of asthma, suggesting that the evaluation of both the hypothalamic-pituitary-GH axis and markers of bone formation may be useful in the follow-up of asthmatic patients who are re-ceiving long-term treatment with ICSs. Long-term prospective studies are needed to confirm these data, and also to assess whether in selected patients who are at higher risk to develop osteoporosis it might be useful to prescribe antiosteoporosis drugs and eventually to discontinue treatment with ICSs.


   Acknowledgements
 
The authors thank Professor Vittorio Grassi for his constructive advice.


   Footnotes
 
Abbreviations: BMI = body mass index; CS = corticosteroid; GH = growth hormone; GHRH = growth hormone-releasing hormone; ICS = inhaled corticosteroid; IGF = insulin-like growth factor

Received for publication April 6, 2004. Accepted for publication August 10, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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