The timing of administration of exogenous glucocorticoid affects 24 hour growth hormone secretion in children☆
Introduction
Exogenous glucocorticoids may suppress longitudinal growth in children [1], [2], [3], [4], [5], [6]. The pathophysiological mechanisms have not been properly established, but central endocrine as well as peripheral end-organ multifactorial mechanisms are likely to be involved [7]. During childhood, a sufficient pituitary secretion of growth hormone (GH) is required for normal longitudinal growth, which is the result of lengthening of the epiphyseal growth plates of the long bones. The primary growth promoting effects of GH are mediated by insulin-like-growth factor-I (IGF-I), and the six IGF binding proteins (IGFBP-1 to -6), which control IGF-I serum levels, tissue accessibility and ability to activate the IGF-I receptor [8].
Circulating IGF-I has an important role in the acquisition of bone and collagen, and exogenous glucocorticoid may reduce IGF-I receptor activity systemically and locally [9], [10], [11]. The integrity of the GH - IGF-I axis is, however, a prerequisite for resulting anabolic effects on bone formation, nitrogen retention and collagen formation [12], [13], [14]. The growth stimulating effect of GH depends on a specific diurnal secretory rhythm, with low levels of circulating GH during day time and high levels during night time [12], [15]. Administration of exogenous glucocorticoid may not affect the overall secretion of GH, but observational studies in adult individuals have suggested that the pulsatile secretion of GH is influenced [16]. Accordingly, a short-term growth study in children showed that whereas 400 μg of the inhaled glucocorticoid budesonide administered twice daily suppressed longitudinal growth, 800 μg budesonide administered only once daily in the morning had a sparing effect on growth rate [2]. The finding suggested that evening dosing of exogenous glucocorticoid may suppress nocturnal GH secretion to a greater extent than morning dosing. The hypothesis, however, has not been rigorously tested. Therefore, the aim of the present study was to assess whether the timing of administration of exogenous glucocorticoid affects 24-hour GH secretion in children.
Section snippets
Subjects
Inclusion criteria were age 8–15 years and a history of mild asthma not requiring other treatment than short acting β2-agonists during the year prior to enrollment in the study. Exclusion criteria were treatment with exogenous glucocorticoids during a year prior to enrollment, concurrent disease requiring pharmaceutical treatment of any kind, endocrine disease, other chronic disease, mental illness, hospital admission during the study, and surgery of any kind during the study.
A total of 8
Results
Two girls and 2 boys were randomized first to receive prednisolone in the evening, then prednisolone in the morning and the other half was randomized to receive treatment in the opposite order. During both prednisolone periods, compliance with treatment regimen was 100% in all children.
Mean diurnal secretory profiles of the primary outcome of the study, serum levels of GH, during run-in, and prednisolone in the evening and in the morning, respectively, are presented in Fig. 1. We observed a
Discussion
The principal outcome of the present study showed that short-term prednisolone 5 mg administered once in the evening, caused a suppression of 24 hour GH secretion as compared to short-term once daily in the morning administration. Previous observations have indicated that glucocorticoid induced effects on GH secretion may be stimulatory as well as inhibitory depending on the concentration and length of glucocorticoid exposure [24], [25], [26]. Acute administration of glucocorticoid may augment
Conclusions
Though the sample of patients in the present study was quite small, short-term once daily dosing of 5 mg of prednisolone administered in the morning was demonstrated to alleviate nocturnal GH suppression as compared to once daily prednisolone administered in the evening. The finding is consistent with observations that longitudinal growth rates in children may be less affected by once daily in the morning as compared to once daily in the evening administration of exogenous glucocorticoids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
Jan Frystyk, who is co-authoring this paper, also serves as Editor-in-Chief of Growth Hormone and IGF Research. However, this has not influenced on the handling of the paper, which has been subjected to the Journal’s usual procedures. Thus, the peer review process has been handled independently of Jan Frystyk, who has been blinded to the review process.
Acknowledgments
The authors would like to thank study participants and their families for participating in the study.
References (36)
- et al.
Adverse effects of inhaled budesonide 800 μg on growth and collagen turnover in asthmatic children: a double blind comparison of once versus twice daily administration
J. Pediatr.
(1998) Effects of inhaled steroids on growth, bone metabolism, and adrenal function
Adv. Pediatr.
(2006)Free insulin-like growth factors – measurements and relationships to growth hormone secretion and glucose homeostasis
Growth Hormon. IGF Res.
(2004)The robustness of diagnostic tests for GH deficiency in adults
Growth Hormon. IGF Res.
(2015)- et al.
The role of glucocorticoids in the regulation of Growth Hormone secretion: mechanisms and clinical significance
Trends Endocrinol. Metab.
(1992) - et al.
The hidden but positive role for glucocorticoids in the regulation of growth hormone-producing cells
Mol. Cell. Endocrinol.
(2012) - et al.
Long-term treatment with glucocortiosteroids/ACTH in asthmatic children. III. Effects on growth and adult height
Acta Paediatr. Scand.
(1990) Impact of inhaled and intranasal corticosteroids on the growth of children
BioDrugs
(2000)- et al.
A randomised trial of lower leg and height growth in children with asthma treated with inhaled budesonide from a new dry powder inhaler
Pediatr. Allergy Immunol.
(2010 Feb) - et al.
Effect of inhaled glucocorticoids in childhood on adult height
N. Engl. J. Med.
(2012)
Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total of free IGF1
Eur. J. Endocrinol.
The multi-functional role of insulin-like growth factor binding proteins in bone
Pediatr. Nephrol.
GH/IGF-I and bone resorption in vivo and in vitro
Eur. J. Endocrinol.
Circulating levels of IGF-I directly regulate bone growth and density
J. Clin. Investig.
Growth hormone axis overview-somatomedin hypothesis
Pediatr. Nephrol.
Endocrine regulation of the growth plate
Horm. Res.
Short and tall stature: a new paradigm emerges
Nat. Rev. Endocrinol.
Circadian variation of integrated concentration of growth hormone in children and adults
J. Clin. Endocrinol. Metab.
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The authors have no conflicts of interest.