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      Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models

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          Abstract

          The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.

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          Most cited references60

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          A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone.

          Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this variation are entirely unknown. In two cohorts of short children treated with growth hormone, we found that an isoform of the growth hormone receptor gene that lacks exon 3 (d3-GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (P < 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001). One-half of Europeans are hetero- or homozygous with respect to the allele encoding the d3-GHR isoform, which is dominant over the full-length isoform. These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics.
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            Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables.

            Information about the expected growth response of children to GH therapy is currently inadequate. The aim of the study was to compare observed and expected growth in response to GH in prepubertal children and to propose how these parameters can be used to optimize GH therapy. Indices considered were observed growth, observed growth relative to reference data [height sd score (Ht SDS), change in (Delta) Ht SDS, height velocity (HV)], and observed growth relative to growth predicted from prediction models [Studentized residual (SR)]. Design/Setting/Patients/Intervention: Growth data from KIGS-Pfizer International Growth Database-on prepubertal children aged 1-13 yr with severe GH deficiency (GHD; maxGH <5 microg/liter; n = 2129), with less-severe GHD (maxGH of 5-10 microg/liter; n = 3075), and with Turner syndrome (n = 2350), and short children born small for gestational age (n = 993) were analyzed before and during 2 yr of GH treatment. For each patient group, growth responses during the first 2 yr of GH treatment were established. The relationships of HV and DeltaHt SDS with SR were determined. Reference data were generated for assessing adequate individual responses. Responses to GH in terms of HV and DeltaHt SDS were greatest in children with severe GHD. HV and DeltaHt SDS were highly correlated with SR during only the first year of GH treatment (R approximately 0.7; P < 0.001). Decisions on GH therapy regimens should be made using both traditional (HV or DeltaHt SDS) and prediction model-derived (SR) indices of growth response.
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              Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database.

              Treatment with GH has been used to correct the growth deficit in children with GH deficiency (GHD). Although successful in increasing height velocity, such treatment often falls short of helping patients achieve full genetic height potential. This study set out to analyze near-final height (FH) data from a cohort of GH-treated children with idiopathic GHD. Of 1258 evaluable patients in the Pfizer International Growth Database (KIGS) with GHD, 980 were of Caucasian origin, and 278 were of Japanese origin; 747 had isolated GHD (IGHD), and 511 had multiple pituitary hormone deficiencies (MPHD). Near-FH, relation to midparental height, and factors predictive of growth outcomes were the main outcome measures. Median height sd scores (SDS) at the start of treatment were -2.4 (IGHD) and -2.9 (MPHD) for Caucasian males and -2.6 (IGHD) and -3.4 (MPHD) for females, respectively; comparable starting heights were -2.9 (IGHD) and -3.6 (MPHD) for Japanese males and -3.3 (IGHD) and -4.0 (MPHD) for females, respectively. Corresponding near-adult height SDS after GH treatment were -0.8 (IGHD) and -0.7 (MPHD) for Caucasian males and -1.0 (IGHD) and -1.1 (MPHD) for females, respectively; and -1.6 (IGHD) and -1.9 (MPHD) for Japanese males and -2.1 (IGHD) and -1.8 (MPHD) for females, respectively. Differences between near-adult height and midparental height ranged between -0.6 and +0.2 SDS for the various groups, with the closest approximation to MPH occurring in Japanese males with MPHD. The first-year increase in height SDS and prepubertal height gain was highly correlated with total height gain, confirming the importance of treatment before pubertal onset. It is possible to achieve FH within the midparental height range in patients with idiopathic GHD treated from an early age with GH, but absolute height outcomes remain in the lower part of the normal range. Patients with MPHD generally had a slightly better long-term height outcome.
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                Author and article information

                Journal
                HRP
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2013
                June 2013
                27 May 2013
                : 79
                : 5
                : 257-270
                Affiliations
                aDepartment of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; bPaediatric Endocrinology Section, Children's Hospital, University of Tübingen, Tübingen, Germany; cGöteborg Pediatric Growth Research Center (GP-GRC), Department of Pediatrics, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; dDepartments of Paediatrics and Paediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Autonomous University of Barcelona, CIBERER (Centre for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain; eDepartment of Pediatrics, Oregon Health and Science University, Portland, Oreg., USA; fTNO Quality of Life, Leiden, and gDepartment of Biostatistics, Utrecht University, Utrecht, The Netherlands; hDepartment of Pediatrics, Institute of Clinical Science, Umeå University, Umeå, Sweden; iDepartment of Pediatrics, University of Cologne, Cologne, Germany; jDepartment of Pediatric Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands; kDivision of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; lLilly Research Laboratories, Bad Homburg, Germany; mGoryeb Children's Hospital, Atlantic Health System, Morristown, N.J., nEthel Percy Andrus Gerontology Center, USC Davis School of Gerontology, University of Southern California, Los Angeles, Calif., USA; oMolecular Endocrinology Unit, ‘Bambino Gesù' Children's Hospital, Rome, Italy; pDepartment of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; qEndocrine Service, Hôpital Sainte-Justine, Université de Montréal, Montréal, Qué., Canada; rPaediatric Endocrinology, Royal Manchester Children's Hospital, and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK; sDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; tQuintiles Consulting, Hawthorne, N.Y., USA; uDepartment of Anthropogenetics, Vrije Universiteit Brussel, Brussels, Belgium
                Author notes
                *Dr. J.M. Wit, Department of Pediatrics, Leiden University Medical Center, NL-2300 Leiden (The Netherlands), E-Mail J.M.Wit@lumc.nl
                Article
                351025 Horm Res Paediatr 2013;79:257-270
                10.1159/000351025
                23735882
                c5e73190-8ad6-4000-8416-8f6008738093
                © 2013 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 20 December 2012
                : 02 April 2013
                Page count
                Figures: 5, Tables: 3, Pages: 14
                Categories
                Mini Review

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Insulin-like growth factor I,Growth hormone deficiency,Idiopathic short stature,Growth hormone receptor ,Small for gestational age

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