Growth hormone (GH) dose-dependent IGF-I response relates to pubertal height gain

Abstract

BackgroundResponsiveness to GH treatment can be estimated by both growth and ∆IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height.MethodsA multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 μg/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6–10.7). At onset of puberty, children were randomized into three groups, to receive 67 μg/kg/day (GH67) given once (GH67x1; n = 30) or divided into two daily injection (GH33x2; n = 36), or to remain on a single 33 μg/kg/day dose (GH33x1; n = 38). The outcome measures were change and obtained mean on-treatment IGF-ISDS, IGFBP3SDS and IGF-I/IGFBP3 ratioSDS during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in heightSDS.ResultsMean prepubertal increases 1 year after GH start were: 2.1 IGF-ISDS, 0.6 IGFBP3SDS and 1.5 IGF-I/IGFBP3ratioSDS. A significant positive correlation was found between prepubertal ∆IGFs and both prepubertal and total gain in heightSDS. During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-ISDS was higher in GH67 vs GH33 (p = 0.031). First year pubertal ∆IGF-ISDS was significantly higher in the GH67vs GH33 group (0.5 vs −0.1, respectively, p = 0.007), as well as ∆IGF-ISDS to the pubertal mean level (0.2 vs −0.2, p = 0.028). In multivariate analyses, the prepubertal increase in ‘∆IGF-ISDS from GH start’ and the ‘GH dose-dependent pubertal ∆IGF-ISDS’ were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in heightSDS.Trial registrationTRN 88–177, not applicable 1988.ConclusionThe dose-dependent change in IGFs was related to a dose-dependent pubertal gain in heightSDS. The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in heightSDS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-015-0080-8) contains supplementary material, which is available to authorized users.

Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children

“…The patients with acquired GHD were also taller and had a higher BMI SDS at diagnosis than those with non-acquired GHD. Serum IGF-I SDS increased after treatment initiation in all groups, but, consistent with other reports (10,14,23), was found to be independent of treatment duration, with median values remaining stable from six months after the start of treatment until the final evaluation, although most reports, with the exception of three studies concerning patients with a treatment duration of three to five years (15,16,17), described findings for the first one to two years of treatment only (9,10,11,12,13,14).…”

“…To date, only a few studies have assessed the value of serum IGF-I SDS monitoring for exploring the variability of serum IGF-I SDS during GH treatment in children with GH deficiency (9,10,11,12,13,14,15,17). Previous studies have reported considerable individual biological variation of serum IGF-I SDS, as also found in this study, for all ages and treatment durations.…”

“…The determination of IGF-I and its standardization present their own difficulties, and studies on IGF-I SDS during the treatment of children with GH deficiency are therefore scarce (9,10,11,12,13,14,15,16). Most studies to date have concerned small series of patients and many did not involve the systematic evaluation of serum IGF-I levels with the same assay, or evaluated the relationship between GH dose, serum IGF-I SDS and growth responses mostly during the first two years of GH treatment, resulting in a lack of relationship (9,10,12,13,15) or only an apparently poor (14,17) relationship being identified between these two factors, probably due to the high degree of individual variability in IGF-I concentration and growth responsiveness and the narrow range of GH doses used in children with GH deficiency. At higher doses of GH, corresponding to about twice the usual dose, the dose-dependent change in IGF-I SDS concentration has been shown to be related to the prepubertal (11) and pubertal (17) gain in height SDS.…”

Serum relaxin-3 hormone relationship to male delayed puberty

“…GH is derived from the somatotrophs in the anterior pituitary that induces the liver to produce insulin growth factor 1 which, together with sex hormones, induces the growth of bone and muscle mass during puberty (Devesa, Almengló, & Devesa, ). Also, GH accelerates cartilage growth, intramembranous bone growth, including the suture as well as cartilage development (Lundberg, Kriström, Jonsson, & Albertsson‐Wikland, ).…”

Using a spontaneous profile rather than stimulation test makes the KIGS idiopathic growth hormone deficiency model more accessible for clinicians

“…Depending on the severity of the IGHD, some time may be needed for dose escalation. Basically, a dose that is high enough and within label to give a substantial short‐time IGF‐I increment and catch‐up growth should be used, as the greatest growth response in relation to the dose is seen during the first year on GH treatment.…”