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      Possible effects of an early diagnosis and treatment in patients with growth hormone deficiency: the state of art

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          Abstract

          Growth hormone deficiency (GHD) is a relatively uncommon and heterogeneous endocrine disorder presenting in childhood with short stature. However, during the neonatal period, the metabolic effects of GHD may to require prompt replacement therapy to avoid possible life-threatening complications. An increasing amount of data suggests the importance of an early diagnosis and treatment of GHD because of its auxological, metabolic, and neurodevelopmental features with respect to the patients diagnosed and treated later in life.

          The available results show favourable auxological outcomes for patients with GHD diagnosed and treated with r-hGH early in life compared with those from patients with GHD who do not receive this early diagnosis and treatment. Because delayed referral for GHD diagnosis and treatment is still frequent, these results highlight the need for more attention in the diagnosis and treatment of GHD.

          Despite these very encouraging data regarding metabolic and neurodevelopmental features, further studies are needed to better characterize these findings. Overall, the importance of early diagnosis and treatment of GHD needs to be addressed.

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          VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation.

          H P Gerber, T. H. Vu, A. Ryan … (1999)
          Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through the systemic administration of a soluble receptor chimeric protein (Flt-(1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.
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            Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.

            Gwenan Knight, Eric Johnson, S Didrickson … (2001)
            Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.
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              Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society.

              Peter Clayton (2000)
              Article 0 comments Cited 139 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Stefano Stagi:
                ORCID: http://orcid.org/0000-0002-2259-4685
                +39-055-5662585 , stefano.stagi@yahoo.it
                Perla Scalini: perla.scalini@gmail.com
                Giovanni Farello: giovanni.farello@cc.univaq.it
                Alberto Verrotti: alberto.verrottidipianella@univaq.it
                Journal
                Journal ID (nlm-ta): Ital J Pediatr
                Journal ID (iso-abbrev): Ital J Pediatr
                Title: Italian Journal of Pediatrics
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1824-7288
                Publication date (Electronic): 16 September 2017
                Publication date PMC-release: 16 September 2017
                Publication date Collection: 2017
                Volume: 43
                Electronic Location Identifier: 81
                Affiliations
                [1 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Health Sciences Department, , University of Florence, Anna Meyer Children’s University Hospital, ; viale Pieraccini 24, Florence, Italy
                [2 ]ISNI 0000 0004 1757 2611, GRID grid.158820.6, Department of Paediatrics, , University of L’Aquila, ; L’Aquila, Italy
                Author information
                http://orcid.org/0000-0002-2259-4685
                Article
                Publisher ID: 402
                DOI: 10.1186/s13052-017-0402-8
                PMC ID: 5603037
                PubMed ID: 28915901
                SO-VID: e64c5479-91b8-4890-9d2e-c8f0b1ae5572
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 30 May 2017
                Date accepted : 11 September 2017
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Pediatrics
                Keywords: growth hormone,growth hormone deficiency,early treatment,height,adult height,brain,metabolism,dwarfism,early diagnosis,hormone replacement therapy
                Data availability:
                ScienceOpen disciplines: Pediatrics
                Keywords: growth hormone, growth hormone deficiency, early treatment, height, adult height, brain, metabolism, dwarfism, early diagnosis, hormone replacement therapy

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