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DOI: 10.1055/s-0043-1778678
A Systematic Review of the Impact of Growth Hormone Therapy on Final Adult Height of Children with Idiopathic Short Stature
Funding and Sponsorship None.![](https://www.thieme-connect.de/media/10.1055-s-00053246/202401/lookinside/thumbnails/10-1055-s-0043-1778678_23120002-1.jpg)
Abstract
Introduction This review aims to systematically determine the effect of growth hormone (GH) therapy on adult height of children and adolescents with idiopathic short stature (ISS).
Methods A systematic review was conducted to assess the effectiveness of GH therapy in children with ISS. Databases like ProQuest Central, journal @ Ovoid, EBSCOhost Medline Complete, Oxford University Press Journals, KB + JISC Collections Elsevier Science Direct Freedo, and BMJ, and cross-referencing of bibliographies were searched electronically. The randomized trials from 1989 to January 2023 were retrieved. Randomized trials with final adult height measurements and fit the inclusion criteria (height >2 standard deviation [SD] score below the mean with no comorbid conditions that would impair growth, peak growth hormone responses >10 μg/L, no previous history of GH therapy) were included in this review. The exclusion criteria are nonrandomized trials; trials include causes of short stature other than ISS, and studies include interventions other than GH and gonadotropin-releasing hormone analog (GnRH-a). A structured approach to the critical appraisal program by Oxford was used to analyze and extract the data.
Results The study reviewed 14 eligible randomized trials, which recruited 2,206 assessable children for analysis. Seven trials compared different GH doses, four trials compared GH therapy with controls, and three trials compared a combination of GH and GnRH therapy with GH alone. Apart from one study, the overall dropout rate was not high. The high percentage of boys was a potential source of heterogeneity between trials. The change in height (HT)-SD score was 1.06 ± 0.30 and 0.18 ± 0.27 with treatment and control children, respectively, and the difference is statistically significant (p < 0.001). The overall mean height gain was 5 cm (0.84 SD score) more in treated children. The height velocity was found to be decreased significantly (p < 0.001) in the second and third years of treatment in the GH + GnRH-a treated group from 7 cm/year during the first year of treatment to 5.4 cm during the second year and 4.9 cm/year during the third year. They also found that using a higher dose of GH at 9 mg/m2/week leads to approximately 7 cm mean final height gain; however, lower dose regimens are less effective.
Conclusion Although the magnitude of the effectiveness of GH therapy is, on average, less than that achieved in other conditions for which GH is licensed, GH therapy seems to be effective in children with idiopathic short stature, and it reduces the deficit in height as adults. Moreover, the effect seems to be dose-dependent, with better results at high GH doses, and the response variability is seen in different individuals. The use of combined GH with GnRH therapy needs to be balanced with their side effects.
Keywords
short stature - idiopathic short stature - GH therapy - r-hGH therapy - combined GH with GnRH-a - systematic reviewCompliance with Ethical Principles
This study is a systematic review, and the data of individual patients will not be included. Therefore, approval was optional. To ensure transparency and accuracy of the review, it was conducted under the guidance of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Standards[21]
Authors' Contribution
All the authors have contributed equally.
Publikationsverlauf
Artikel online veröffentlicht:
19. Februar 2024
© 2024. Gulf Association of Endocrinology and Diabetes (GAED). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Ho KK. 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol 2007; 157 (06) 695-700
- 2 Growth Hormone Research Society, GH Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 2000; 85 (11) 3990-3993
- 3 WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. . Acta Paediatr Suppl 2006; 95. (S 450) : 76-85
- 4 Bang P. Statement 3: a low serum IGF-I Level in idiopathic short stature patients indicates partial GH insensitivity. Pediatr Endocrinol Rev 2008; 5 (Suppl. 03) 841-846
- 5 Wit JM, Clayton PE, Rogol AD, Savage MO, Saenger PH, Cohen P. Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008; 18 (02) 89-110
- 6 Rosenfeld RG. Molecular mechanisms of IGF-I deficiency. Horm Res 2006; 65 (Suppl. 01) 15-20
- 7 Bonert VS, Melmed S. Growth hormone. The Pituitary. 4th ed.. Academic Press; 2017: 85-127
- 8 Pedicelli S, Peschiaroli E, Violi E, Cianfarani S. Controversies in the definition and treatment of idiopathic short stature (ISS). J Clin Res Pediatr Endocrinol 2009; 1 (03) 105-115
- 9 Luo ZC, Albertsson-Wikland K, Karlberg J. Target height as predicted by parental heights in a population-based study. Pediatr Res 1998; 44 (04) 563-571
- 10 Zlotkin D, Varma SK. Psychosocial effects of short stature. Indian J Pediatr 2006; 73 (01) 79-80
- 11 Backeljauw P, Cappa M, Kiess W. et al. Impact of short stature on quality of life: a systematic literature review. Growth Horm IGF Res 2021; 57-58: 101392
- 12 Grimberg A, Kanter GP. US growth hormone use in the idiopathic short stature era: trends in insurer payments and patient financial burden. J Endocr Soc 2019; 3 (11) 2023-2031
- 13 Grimberg A, Allen DB. Growth hormone treatment for growth hormone deficiency and idiopathic short stature: new guidelines shaped by the presence and absence of evidence. Curr Opin Pediatr 2017; 29 (04) 466-471
- 14 Ariza-Jimenez AB, Leiva Gea I, Martinez-Aedo Ollero MJ, Lopez-Siguero JP. Isolated growth hormone deficiency and idiopathic short stature: Comparative efficiency after growth hormone treatment up to adult height. J Clin Med 2021; 10 (21) 4988
- 15 Grimberg A, DiVall SA, Polychronakos C. et al; Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr 2016; 86 (06) 361-397
- 16 Huh K, Park MJ. Questionnaire-based analysis of growth-promoting attempts among children visiting a university growth clinic. Clin Exp Pediatr 2009; 52 (05) 576-580
- 17 Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review. BMJ 2011; 342: c7157
- 18 Allen DB. Growth promotion ethics and the challenge to resist cosmetic endocrinology. Horm Res Paediatr 2017; 87 (03) 145-152
- 19 Bolin K, Sandin R, Koltowska-Häggström M, Loftus J, Prütz C, Jonsson B. The cost-effectiveness of growth hormone replacement therapy (Genotropin®) in hypopituitary adults in Sweden. Cost Eff Resour Alloc 2013; 11 (01) 24
- 20 Geisler A, Lass N, Reinsch N. et al. Quality of life in children and adolescents with growth hormone deficiency: association with growth hormone treatment. Horm Res Paediatr 2012; 78 (02) 94-99
- 21 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151 (04) 264-269 , W64
- 22 Whiting LS. Systematic review protocols: an introduction. Nurse Res 2009; 17 (01) 34-43
- 23 Hughes IP, Harris M, Choong CS. et al; Australasian Paediatric Endocrine Group (APEG). Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature. Clin Endocrinol (Oxf) 2012; 77 (01) 62-71
- 24 Schena L, Meazza C, Pagani S. et al. Efficacy of long-term growth hormone therapy in short non-growth hormone-deficient children. J Pediatr Endocrinol Metab 2017; 30 (02) 197-201
- 25 Hou L, Liang Y, Wu W, Lin HH, Luo XP, Ying YQ. Comparison of the efficacy and safety of recombinant human growth hormone in treating idiopathic short stature and growth hormone deficiency in children. Growth Horm IGF Res 2020; 53-54: 101331
- 26 Wu D, Chen RM, Chen SK. et al. Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty. BMC Pediatr 2020; 20 (01) 138
- 27 Hindmarsh PC, Brook CG. Final height of short normal children treated with growth hormone. Lancet 1996; 348 (9019): 13-16
- 28 Reiter EO. A brief review of the addition of gonadotropin-releasing hormone agonists (GnRH-Ag) to growth hormone (GH) treatment of children with idiopathic growth hormone deficiency: previously published studies from America. Mol Cell Endocrinol 2006; 254-255: 221-225
- 29 Pasquino AM, Pucarelli I, Roggini M, Segni M. Adult height in short normal girls treated with gonadotropin-releasing hormone analogs and growth hormone. J Clin Endocrinol Metab 2000; 85 (02) 619-622
- 30 Lazar L, Levy S, Oron T. et al. The beneficial effect of combined GH/GnRHa therapy in increasing adult height outcome in children with ISS. J Clin Endocrinol Metab 2019; 104 (08) 3287-3295
- 31 Shea BJ, Reeves BC, Wells G. et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358: j4008
- 32 Swiglo BA, Murad MH, Schünemann HJ. et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 2008; 93 (03) 666-673
- 33 Mohsina S, Gurushankari B, Niranjan R, Sureshkumar S, Sreenath GS, Kate V. Assessment of the quality of randomized controlled trials in surgery using Jadad score: where do we stand?. J Postgrad Med 2022; 68 (04) 207-212
- 34 Leschek EW, Rose SR, Yanovski JA. et al; National Institute of Child Health and Human Development-Eli Lilly & Co. Growth Hormone Collaborative Group. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004; 89 (07) 3140-3148
- 35 McCaughey ES, Mulligan J, Voss LD, Betts PR. Randomised trial of growth hormone in short normal girls. Lancet 1998; 351 (9107): 940-944
- 36 van Gool SA, Kamp GA, Visser-van Balen H. et al. Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty. J Clin Endocrinol Metab 2007; 92 (04) 1402-1408
- 37 Yuan J, Fu J, Wei H. et al. A randomized controlled phase 3 study on the efficacy and safety of recombinant human growth hormone in children with idiopathic short stature. Front Endocrinol (Lausanne) 2022; 13: 864908
- 38 Benabbad I, Rosilio M, Tauber M. et al; Phoenix Study Group. Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature. Endocr Connect 2018; 7 (05) 708-718
- 39 Barton JS, Gardineri HM, Cullen S, Hindmarsh PC, Brook CGD, Preece MA. The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature. Clin Endocrinol (Oxf) 1995; 42 (06) 619-626
- 40 Wit JM, Rekers-Mombarg LT, Cutler Jr GB. et al. Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. J Pediatr 2005; 146 (01) 45-53
- 41 Albertsson-Wikland K, Aronson AS, Gustafsson J. et al. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. J Clin Endocrinol Metab 2008; 93 (11) 4342-4350
- 42 Wit JM, Rekers-Mombarg LTM. Dutch Growth Hormone Advisory Group. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. J Clin Endocrinol Metab 2002; 87 (02) 604-611
- 43 Counts DR, Silverman LA, Rajicic N. et al. A 4-year, open-label, multicenter, randomized trial of Genotropin® growth hormone in patients with idiopathic short stature: analysis of 4-year data comparing efficacy, efficiency, and safety between an individualized, target-driven regimen and standard dosing. Horm Res Paediatr 2015; 84 (02) 79-87
- 44 Guaraldi F, Beccuti G, Gori D, Ghizzoni L. Management of endocrine disease: Long-term outcomes of the treatment of central precocious puberty. Eur J Endocrinol 2016; 174 (03) R79-R87
- 45 Rekers-Mombarg LTM, Massa GG, Wit JM. et al; European Study Group Participating Investigators. Growth hormone therapy with three dosage regimens in children with idiopathic short stature. J Pediatr 1998; 132 (3 Pt 1): 455-460
- 46 Maiorana A, Cianfarani S. Impact of growth hormone therapy on adult height of children born small for gestational age. Pediatrics 2009; 124 (03) e519-e531
- 47 Baxter L, Bryant J, Cave CB, Milne R. and Cochrane Metabolic and Endocrine Disorders Group. Recombinant growth hormone for children and adolescents with Turner syndrome. Cochrane Database Syst Rev 2007; 2010 (01) CD003887
- 48 Allen DB. Growth hormone post-marketing surveillance: safety, sales, and the unfinished task ahead. J Clin Endocrinol Metab 2010; 95 (01) 52-55
- 49 Dahlgren J. Growth outcomes in individuals with idiopathic short stature treated with growth hormone therapy. Horm Res Paediatr 2011; 76 (Suppl. 03) 42-45
- 50 Genentech Collaborative Study Group. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. J Pediatr 1989; 115 (5 Pt 1): 713-719
- 51 Hintz RL, Attie KM, Baptista J, Roche A. Genentech Collaborative Group. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999; 340 (07) 502-507
- 52 Kamp GA, Mul D, Waelkens JJJ, Jansen M, Delemarre-Van De Waal HA. et al A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001; 86 (07) 2969-2975
- 53 McCaughey ES, Mulligan J, Voss LD, Betts PR. Growth and metabolic consequences of growth hormone treatment in prepubertal short normal children. Archives of disease in childhood 1994; 71 (03) 201-206