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      Mechanisms of Steroid Impairment of Growth

      Hormone Research in Paediatrics

      S. Karger AG

      Steroids, Growth, Chronic disease

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          Abstract

          With child growth being multifactorial and the glucocorticoids (GC) having many target physiological and biochemical mechanisms, growth and the GC collide in several meeting points. Indirectly, GC have a general anti-anabolic and catabolic influences that include bone, cartilage and muscle proteins. The GC interfere with the GH–IGF-1 axis at the hypothalamic, pituitary and target organ levels, affecting hormone release, receptor abundance, signal transduction, gene transcription, pre-mRNA splicing and mRNA translation. GC disturb normal calcium balance at the intestine and kidney. Direct effects at the growth plate include the suppression of multiple gene expression, chondrocyte proliferation and matrix proteoglycan synthesis, sulfation, release and mineralization as well as the augmentation of hypertrophic cell apoptosis. At the tissues adjacent to the growth plate, GC enhance osteoclast and suppress osteoblast recruitment and function, they reduce muscle strength and disrupt the normal control of vascular invasion at the cartilage–bone interface. Growth damage from GC is maximal during the initial months of treatment and prevention is more effective than post-factual therapy. To reduce these growth-retarding effects, the following measures, which are partly experimental, may be effective in a decreasing order: minimize GC dose and use an alternate-day treatment; utilize the oxazoline analog of prednisolone deflazacort, normalize calcium balance; employ hGH or IGF-1.

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          Most cited references 11

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          Suppressed spontaneous and stimulated growth hormone secretion in patients with Cushing's disease before and after surgical cure

           M A Magiakou (1994)
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            Cortisol inhibits the synthesis of insulin-like growth factor-binding protein-5 in bone cell cultures by transcriptional mechanisms.

            Glucocorticoids inhibit the synthesis of insulin-like growth factor-binding protein-5 (IGFBP-5) in osteoblasts, but the mechanisms involved are unknown. IGFBP-5 stimulates bone cell growth, and its inhibition by glucocorticoids may be relevant to the action of this binding protein on bone formation. We tested the effects of cortisol on IGFBP-5 expression in cultures of osteoblast-enriched cells from fetal rat calvariae (Ob cells). Cortisol decreased IGFBP-5 polypeptide levels in the extracellular matrix and caused a time- and dose-dependent decrease in IGFBP-5 mRNA. IGFBP-5 transcripts were markedly decreased by cycloheximide, and further suppressive effects of cortisol could not be determined. Cortisol did not modify the decay of IGFBP-5 mRNA in transcriptionally arrested Ob cells. Cortisol decreased IGFBP-5 hnRNA, the rate of IGFBP-5 transcription, and the activity of the murine IGFBP-5 promoter by 35% in transient transfection experiments. Deletion analysis showed that the region responsive to cortisol is from base pairs -70 to +22, and E-box-binding proteins or c-Myb-related nuclear factors may be involved in its regulation. In conclusion, cortisol inhibits IGFBP-5 transcription in Ob cells through the Myb-binding domain. This effect may be partly responsible for the effect of glucocorticoids on bone formation.
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              Dexamethasone inhibits both growth hormone (GH)-induction of insulin-like growth factor-I (IGF-I) mRNA and GH receptor (GHR) mRNA levels in rat primary cultured hepatocytes.

              Glucocorticoids are potent inhibitors of growth. In this work, we investigated whether glucocorticoids inhibit the stimulatory action of GH on IGF-I gene expression in rat hepatocytes. GH increased IGF-I mRNA levels 11-fold after 24 h, whereas high doses of DXM (10(-6)M) caused a slight (2.6-fold) increase of IGF-I mRNA levels. However, high doses of DXM (10(-6)M) inhibited the induction of IGF-I mRNA by GH. To assess the role of GHR in this inhibition, we investigated the regulation of GHR expression. High doses of DXM decreased GHR mRNA levels. This effect was already detectable 6 h after addition of 10(-6)M DXM and was dose-dependent, with a maximal inhibition observed at a concentration of 10(-6)M. In conclusion, our results show that high doses of DXM inhibits the GH-induced IGF-I gene expression and the GHR gene expression. The parallel decrease of GHR and GH-induced IGF-I mRNA suggests that the GH resistance caused by DXM is mediated by diminished GH receptor synthesis. Copyright 1999 Harcourt Publishers Ltd.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                978-3-8055-7475-4
                978-3-318-00893-7
                1663-2818
                1663-2826
                2002
                September 2002
                17 November 2004
                : 58
                : Suppl 1
                : 33-38
                Affiliations
                Pediatric Endocrinology, Meyer Children’s Hospital, Haifa, Israel
                Article
                64764 Horm Res 2002;58(suppl 1):33–38
                10.1159/000064764
                12373012
                © 2002 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.

                Page count
                Figures: 1, Tables: 4, References: 38, Pages: 6
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