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IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 8, 2917-2924 p.Article in journal (Refereed) Published
Abstract [en]

Context: GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (height(SDS)) was 1.3 (range 0-3), compared with 0.2 in the untreated group. Objective: The objective of the study was to analyze the relationship between IGF-1(SDS), IGF binding protein-3 SDS (IGFBP3(SDS)), and their ratio(SDS) with a gain in the height(SDS) until AH in non-GH-deficient short children. Design and Setting: This was a randomized, controlled, multicenter clinical trial. Intervention: The intervention included GH treatment: 33 or 67 mu g/kg.d plus untreated controls. Subjects: One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). Main Outcome Measures: Increments from baseline to on-treatment study mean IGF-1(SDS) (Delta IGF-1(SDS)), IGFBP3(SDS), and IGF-1 to IGFBP3 ratio(SDS) were assessed in relationship to the gain in height(SDS). Results: Sixty-two percent of the variance in the gain in height(SDS) in children on GH treatment could be explained by four variables: Delta IGF-1(SDS) (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1(SDS) was at baseline, the higher was its increment during treatment. For both the All(PP)- and the ISSPP-treated groups, the attained IGF-1(SDS) study level did not correlate with height gain. Conclusion: In short non-GH-deficient children, the GH dose-related increment in IGF-1(SDS) from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1(SDS), IGFBP3(SDS), and their ratio(SDS) were compared concurrently.

Place, publisher, year, edition, pages
Endocrine Society , 2014. Vol. 99, no 8, 2917-2924 p.
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:umu:diva-95293DOI: 10.1210/jc.2014-1101ISI: 000342341200066PubMedID: 24823461OAI: oai:DiVA.org:umu-95293DiVA: diva2:758624
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-05-10Bibliographically approved
In thesis
1. Growth hormone responsiveness in children: results from Swedish multicenter clinical trials of growth hormone treatment
Open this publication in new window or tab >>Growth hormone responsiveness in children: results from Swedish multicenter clinical trials of growth hormone treatment
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The general aims of the thesis were to study GH responsiveness by estimation of pharmacokinetics and bioavailability of injected recombinant human GH (rhGH), of growth response as gain in heightSDS during childhood and puberty, and IGF-I response as change in circulating IGF-ISDS and IGFBP3SDS. Methods Short children were recruited during 1988–1999 into two national randomized multicentre clinical trials on growth until adult height. A group of 117 GHD patients who had been treated from prepuberty with a single GH dose of 33μg/kg/day for at least 1 year were randomized at onset of puberty either to remain on this dose regimen or to an increased dose, GH67μg/kg/day, administered once daily or divided into two doses, GH33x2μg/kg/day. Data on IGF-ISDS and IGF binding protein 3 (IGFBP3)SDS were available from 111 patients and analysed as stated below. The 151 short prepubertal non-GHD patients were randomized into three groups: untreated controls, GH33 or GH67μg/kg/day. A subpopulation from both trials, 128 patients examined annually in Gothenburg, formed the study sample on GH uptake. They received sc GH injections to obtain 16–24 hour GH curves and the GH pharmacokinetics and bioavailability was calculated. Results: A dose-dependent effect on Cmax was found with great intra- and inter-individual variability. Of the Cmax variability, 43% was explained by the rhGH dose and proxies for injection depth. Median bioavailability of the injected dose was 71%, with great variation, mainly dependent on injection depth. In the IGHD group a dose-dependent difference in pubertal gain in heightSDS was found, with mean of 0.8 for the GH67 group and 0.4 for GH33, p<0.01. The mean total gain in heightSDS during treatment was 1.9 for GH67 and 1.4 for GH33, p<0.01. A dose-dependent pubertal ΔIGF-ISDS was 0.5 vs −0.1, p=0.007, correlating to pubertal gain in heightSDS, p=0.003; and was the most important variable to explain the variation in pubertal gain in heightSDS. In the non-GHD group the ΔIGF-ISDS from baseline to mean study level was dose-dependent 2.07 vs 1.20, p=0.001; and correlated negatively with baseline values of IGF-ISDS, rho= -0.56 for GH67, p=0.001, vs rho= -0.82 for GH33, p=0.0001, and correlated positively with gain in heightSDS in both GH-treated groups, rho= 0.42, p<0.001. In multivariable regression analyses, ΔIGF-ISDS was always an important explanatory variable for long-term growth response from the prepubertal period until adult height, while the IGF-ISDS study level per se was not. Conclusion: Growth response to GH treatment was dose dependent with great variability between patients. More pubertal growth was attained by an increased rhGH dose, mimicking the physiology of healthy children, in whom GH secretion rate increases during puberty. This resulted in a gain in IGF-ISDS closely correlating to pubertal gain in heightSDS in both IGHD and non-GHD patients. A broad range in GH responsiveness was found for both growth and IGF response in both diagnostic groups, but lower in the non-GHD group. Higher uptake of a given GH dose was observed after a deep injection and a higher GH concentration. These results are clinically applicable for individuals who remain short close to onset of puberty; by identifying and deeply injecting a rhGH dose that accounts for individual responsiveness, we can stimulate an increment in IGF-ISDS that correlates to gain in heightSDS during puberty.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2017. 106 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1879
Keyword
gain in height, puberty, IGHD, non-GHD, IGF-I, bioavailability
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-134569 (URN)978-91-7601-662-6 (ISBN)
Public defence
2017-06-02, Sal D, unod T9, byggnad 1D, plan 9, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
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Supervisors
Available from: 2017-05-11 Created: 2017-05-09 Last updated: 2017-05-11Bibliographically approved

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Kriström, BeritLundberg, Elena

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