Elsevier

Growth Hormone & IGF Research

Volume 35, August 2017, Pages 40-44
Growth Hormone & IGF Research

The timing of administration of exogenous glucocorticoid affects 24 hour growth hormone secretion in children

https://doi.org/10.1016/j.ghir.2017.06.004Get rights and content

Highlights

  • Ten children in an open randomized 2-periods cross-over trial were given 5 mg prednisolone in the morning or in the evening.

  • At run-in and on the last day of each treatment period blood was collected every 20 min for 24 hours for assessment of GH.

  • Evening prednisolone suppressed 24 hours GH secretion, whereas morning administration did not.

  • Prednisolone administered in the morning may alleviate nocturnal GH suppression as compared to evening administration in children.

Abstract

Exogenous glucocorticoids may suppress linear growth by affecting the diurnal secretory rhythm of GH.

Objective

To assess whether the timing of exogenous glucocorticoid administration affects GH secretion in children.

Design

Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I–IV were studied in an open randomized 2-period cross-over trial, with a 1-day un-in, and two 4-day periods of 5 mg prednisolone in the morning or in the evening, respectively, separated by a 3-week washout period. At run-in and on the last day of each treatment period serum was collected every 20 min for 24 h for assessment of GH. Secondary analyses were serum levels of IGF-I and IGFBP-3 (measured every 8 h), and IGFBP-1, insulin, and collagen markers PICP, PINP, ICTP and PIIINP (measured every 2 h).

Results

Evening prednisolone suppressed 24 hour GH secretion (P = 0.016), overnight GH secretion (P = 0.023) and IGF-I (P = 0.024) when compared to morning prednisolone, but not when compared to run-in. Evening prednisolone also increased nocturnal insulin levels as compared to run-in (P = 0.010). Irrespective of time of day, prednisolone increased serum collagen markers PICP, PIINP, ICTP and PINP (all P < 0.05).

Conclusions

Short-term prednisolone 5 mg administered in the morning may alleviate nocturnal GH suppression as compared to evening administration. In analogy, growth rates are less affected by morning as compared to evening administration of exogenous glucocorticoids. In contrast, collagen markers and metabolic indices were not affected by the timing of prednisolone administration.

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.

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