Metabolic differences between short children with GH peak levels in the lower normal range and healthy children of normal height

Highlights

• The metabolic profile of short children with GH peaks of 7-14 µg/l was analysed and compared to children of normal height.

• Few significant metabolic differences were found between the groups.

• Subgroup analysis demonstrated lower fasting insulin levels and HOMA-IR in the children with the GH peak levels < 10 μg/L.

Abstract

Objective

Severe growth hormone deficiency (GHD) leads to several metabolic effects in the body ranging from abnormal body composition to biochemical disturbances. However, less is known regarding these parameters in short children with GH peak levels in the lower normal range during provocation tests. Our aim was to study the metabolic profile of this group and compare it with that of healthy children of normal height.

Design

Thirty-five pre-pubertal short children (<− 2.5 SDS) aged between 7 and 10 years, with peak levels of GH between 7 and 14 μg/L in an arginine insulin tolerance test (AITT), were compared with twelve age- and sex-matched children of normal height. The metabolic profile of the subjects was analysed by blood samples, DEXA, frequently sampled intravenous glucose tolerance test, microdialysis and stable isotope examinations of rates of glucose production and lipolysis.

Results

There were no overall significant metabolic differences between the groups. However, in the subgroup analysis, the short children with GH peaks < 10 μg/L had significantly lower fasting insulin levels which also correlated to other metabolic parameters.

Conclusion

The short pre-pubertal children with GH peak levels between 7 and 14 μg/L did not differ significantly from healthy children of normal height but subpopulations within this group show significant metabolic differences.

Introduction

Severe growth hormone deficiency (GHD) is associated with several metabolic features, such as deranged body composition due to reduced lipolysis [1], [2], [3] and impaired protein anabolism [4] as well as decreased hepatic glucose production [5] and increased peripheral glucose uptake due to increased insulin sensitivity [6]. However, severe GHD is a rare condition and the majority of pediatric patients referred to endocrinologists due to short stature do not present with this phenotype. The difficulty in determining if these patients have an adequate GH secretion has led to the development of different clinical algorithms and GH stimulation tests. However, defining an adequate peak GH cut-off level for GHD in such tests has been difficult due to large inter-assay variability, different standardisations over time and considerable intrapersonal variability [7], [8], [9].

In the 1960′s, GHD was defined as stimulated GH concentrations below 3 μg/L but over time the cut-off levels gradually increased to 7 μg/L and later 10 μg/L [9]. Today, a stimulated GH peak < 7 μg/L is frequently used for defining GHD but a cut-off level of 10 μg/L is also often used when GHD is distinguished from non-GHD forms of short stature, i.e. idiopathic short stature (ISS) or familial short stature (FSS) [10], [11]. The use of different standards for GH assay calibration has further complicated the issue. The introduction of recombinant calibration standards produced lower GH concentration values compared with older pituitary-derived standards [12], [13], [14] and the conversion from mU/L to μg/L have added an additional source of error where a large variation has been shown [15], [16]. In this study, we have chosen GH peak limits of 7–14 μg/L in our inclusion criteria to study short children in the lower normal range of GH peak levels and used the classical GHD-ISS cut-off level of 10 μg/L for our subgroup analyses.

Several studies address the metabolic effects of recombinant human GH (rhGH) therapy in different patient groups [17], [18], [19], [20], [21] but few have examined metabolic characteristics of short children with GH peak levels in the lower normal range prior to treatment, even if this group traditionally has been treated under the indications “partial GHD” or ISS. If there, in fact, are individuals in this group of short children with a deficiency of GH as a cause of their reduced stature, one would also expect signs of GH deficiency in their metabolic profile. Our aim is to analyse if such signs exist by thoroughly characterising the metabolic profile of this patient group and compare it with that of healthy age- and sex-matched controls of normal height.