Growth hormone treatment for children born small for gestational age
- Alan D Rogol, MD, PhD
Alan D Rogol, MD, PhD
- Professor Emeritus
- University of Virginia
Growth hormone (GH) affects many of the metabolic processes carried out by somatic cells, the best known of which is the effect of increasing body mass. Although generalized growth is stimulated, it is not evenly distributed among the protein, lipid, and carbohydrate compartments. Body protein content increases, total body fat content falls, and an increase in plasma and liver lipid content occurs because of mobilization of free fatty acids (FFA) from peripheral fat stores. The ability of insulin to promote fatty acid synthesis is antagonized by growth hormone.
Most children who were born small for gestational age (SGA) have adequate catch-up growth without pharmacologic intervention. However, for a minority, growth hormone can augment growth parameters.
The indications for and efficacy of exogenous growth hormone treatment in children with intrauterine growth restriction are reviewed here. The causes of and diagnostic approach to the child with short stature are discussed separately. (See "Causes of short stature" and "Diagnostic approach to children and adolescents with short stature".)
The use of growth hormone for children with other conditions is addressed in separate topic reviews:
- Hokken-Koelega AC, De Ridder MA, Lemmen RJ, et al. Children born small for gestational age: do they catch up? Pediatr Res 1995; 38:267.
- Hediger ML, Overpeck MD, Maurer KR, et al. Growth of infants and young children born small or large for gestational age: findings from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 1998; 152:1225.
- Karlberg JP, Albertsson-Wikland K, Kwan EY, et al. The timing of early postnatal catch-up growth in normal, full-term infants born short for gestational age. Horm Res 1997; 48 Suppl 1:17.
- Karlberg J, Albertsson-Wikland K. Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 1995; 38:733.
- Paz I, Seidman DS, Danon YL, et al. Are children born small for gestational age at increased risk of short stature? Am J Dis Child 1993; 147:337.
- Lee PA, Chernausek SD, Hokken-Koelega AC, et al. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics 2003; 111:1253.
- Wit JM, Finken MJ, Rijken M, de Zegher F. Preterm growth restraint: a paradigm that unifies intrauterine growth retardation and preterm extrauterine growth retardation and has implications for the small-for-gestational-age indication in growth hormone therapy. Pediatrics 2006; 117:e793.
- Persson I, Ahlsson F, Ewald U, et al. Influence of perinatal factors on the onset of puberty in boys and girls: implications for interpretation of link with risk of long term diseases. Am J Epidemiol 1999; 150:747.
- Proos L, Gustafsson J. Is early puberty triggered by catch-up growth following undernutrition? Int J Environ Res Public Health 2012; 9:1791.
- Papadimitriou A, Nicolaidou P, Fretzayas A, Chrousos GP. Clinical review: Constitutional advancement of growth, a.k.a. early growth acceleration, predicts early puberty and childhood obesity. J Clin Endocrinol Metab 2010; 95:4535.
- Hindmarsh P, Brook C, Rodeck C, Nicolaides K. Hormonal levels in the human fetus between 14 and 22 weeks gestation. Early Hum Dev 1987; 15:253.
- Giudice LC, de Zegher F, Gargosky SE, et al. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 1995; 80:1548.
- de Zegher F, Bettendorf M, Kaplan SL, Grumbach MM. Hormone ontogeny in the ovine fetus: XXI. The effect of insulin-like growth factor-I on plasma fetal growth hormone, insulin and glucose concentrations. Endocrinology 1988; 123:658.
- Leger J, Noel M, Limal JM, Czernichow P. Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR. Pediatr Res 1996; 40:101.
- Deiber M, Chatelain P, Naville D, et al. Functional hypersomatotropism in small for gestational age (SGA) newborn infants. J Clin Endocrinol Metab 1989; 68:232.
- van Dijk M, Mulder P, Houdijk M, et al. High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age. J Clin Endocrinol Metab 2006; 91:1390.
- Iñiguez G, Ong K, Bazaes R, et al. Longitudinal changes in insulin-like growth factor-I, insulin sensitivity, and secretion from birth to age three years in small-for-gestational-age children. J Clin Endocrinol Metab 2006; 91:4645.
- Van den Berghe G, de Zegher F, Lauwers P, Veldhuis JD. Growth hormone secretion in critical illness: effect of dopamine. J Clin Endocrinol Metab 1994; 79:1141.
- Gluckman PD, Cutfield W, Harding JE, et al. Metabolic consequences of intrauterine growth retardation. Acta Paediatr Suppl 1996; 417:3.
- Dennison E, Fall C, Cooper C, Barker D. Prenatal factors influencing long-term outcome. Horm Res 1997; 48 Suppl 1:25.
- de Zegher F, Du Caju MV, Heinrichs C, et al. Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years. J Clin Endocrinol Metab 1999; 84:1558.
- Azzi S, Salem J, Thibaud N, et al. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet 2015; 52:446.
- Clayton PE, Cianfarani S, Czernichow P, et al. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007; 92:804.
- Hokken-Koelega AC, van Pareren Y, Sas T, Arends N. Final height data, body composition and glucose metabolism in growth hormone-treated short children born small for gestational age. Horm Res 2003; 60 Suppl 3:113.
- de Zegher F, Hokken-Koelega A. Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term. Pediatrics 2005; 115:e458.
- Johnston LB, Savage MO. Should recombinant human growth hormone therapy be used in short small for gestational age children? Arch Dis Child 2004; 89:740.
- Chernausek SD. Treatment of short children born small for gestational age: US perspective, 2005. Horm Res 2005; 64 Suppl 2:63.
- de Zegher F, Albertsson-Wikland K, Wilton P, et al. Growth hormone treatment of short children born small for gestational age: metanalysis of four independent, randomized, controlled, multicentre studies. Acta Paediatr Suppl 1996; 417:27.
- Albanese A, Stanhope R. GH treatment induces sustained catch-up growth in children with intrauterine growth retardation: 7-year results. Horm Res 1997; 48:173.
- Boguszewski M, Albertsson-Wikland K, Aronsson S, et al. Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial. Acta Paediatr 1998; 87:257.
- Ranke MB, Lindberg A, Cowell CT, et al. Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 2003; 88:125.
- Van Pareren Y, Mulder P, Houdijk M, et al. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 2003; 88:3584.
- Dahlgren J, Wikland KA, Swedish Study Group for Growth Hormone Treatment. Final height in short children born small for gestational age treated with growth hormone. Pediatr Res 2005; 57:216.
- Lem AJ, van der Kaay DC, de Ridder MA, et al. Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial. J Clin Endocrinol Metab 2012; 97:4096.
- Renes JS, Willemsen RH, Mulder JC, et al. New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial. Clin Endocrinol (Oxf) 2015; 82:854.
- Dos Santos C, Essioux L, Teinturier C, et al. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 2004; 36:720.
- De Zegher F, Chatelain PG. Growth hormone treatment of short children born small for gestational age: Epianaylsis of controlled studies and clinical experience. In: Progress in Growth Hormone Therapy-10 Years of KIGS, Ranke M, Wilton P (Eds), J and J Verlag, Mannheim 1998.
- de Zegher F, Butenandt O, Chatelain P, et al. Growth hormone treatment of short children born small for gestational age: reappraisal of the rate of bone maturation over 2 years and metanalysis of height gain over 4 years. Acta Paediatr Suppl 1997; 423:207.
- Simon D, Leger J, Fjellestad-Paulsen A, et al. Intermittent recombinant growth hormone treatment in short children born small for gestational age: four-year results of a randomized trial of two different treatment regimens. Horm Res 2006; 66:118.
- Preece MA. Puberty in children with intrauterine growth retardation. Horm Res 1997; 48 Suppl 1:30.
- Kamp GA, Mul D, Waelkens JJ, 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; 86:2969.
- 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; 92:1402.
- Reiter EO, Lindberg A, Ranke MB, et al. The KIGS experience with the addition of gonadotropin-releasing hormone agonists to growth hormone (GH) treatment of children with idiopathic GH deficiency. Horm Res 2003; 60:68.
- Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol 2006; 254-255:226.
- Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009; 123:e752.
- Woods KA, van Helvoirt M, Ong KK, et al. The somatotropic axis in short children born small for gestational age: relation to insulin resistance. Pediatr Res 2002; 51:76.
- Cutfield WS, Jackson WE, Jefferies C, et al. Reduced insulin sensitivity during growth hormone therapy for short children born small for gestational age. J Pediatr 2003; 142:113.
- de Zegher F, Ong K, van Helvoirt M, et al. High-dose growth hormone (GH) treatment in non-GH-deficient children born small for gestational age induces growth responses related to pretreatment GH secretion and associated with a reversible decrease in insulin sensitivity. J Clin Endocrinol Metab 2002; 87:148.
- Cutfield WS, Lindberg A, Rapaport R, et al. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res 2006; 65 Suppl 3:153.
- Tanaka T, Fujieda K, Yokoya S, et al. Efficacy and safety of growth hormone treatment in children born small for gestational age in Japan. J Pediatr Endocrinol Metab 2008; 21:423.
- Bachmann S, Bechtold S, Bonfig W, et al. Insulin sensitivity decreases in short children born small for gestational age treated with growth hormone. J Pediatr 2009; 154:509.
- Sas T, Mulder P, Hokken-Koelega A. Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency. J Clin Endocrinol Metab 2000; 85:3786.
- van Dijk, M. J Clin Endocrinol Metab 2006; Rapid Electronic Publication first published on Oct 24, 2006 as doi:doi:10.1210/jc.2006-1073.