Recombinant human growth hormone has revolutionized the management of children and adolescents with growth hormone deficiency and other growth disorders, but clinical and ethical controversies remain regarding diagnostic approach, optimal recombinant human growth hormone dose and duration, and expected outcomes. Management of pubertal and transitioning patients with growth hormone deficiency has also commanded increased attention. Recent clinical studies that demonstrate the positive health benefits of recombinant human growth hormone in children with cystic fibrosis, inflammatory bowel disease, and juvenile rheumatoid arthritis have not yet clarified issues about patient selection and appropriate long-term use. An understanding of current recombinant human growth hormone indications and controversies can facilitate patient evaluation and expedite referral for potential treatment. This review summarizes current indications for recombinant human growth hormone use, discusses clinical challenges, and provides recommendations for pediatricians caring for children who may be appropriate candidates for recombinant human growth hormone therapy.
Allen DBGrowth hormone treatment. In: Lifshitz F, ed. Pediatric Endocrinology. New York: Marcel Dekker, Inc; 2003:87-111.
2.
Lindsay R., Feldkamp M., Harris D., Robertson J., Rallison M.Utah Growth Study: growth standards and the prevalence of growth hormone deficiency . J Pediatr.1994; 125:29-35.
3.
Levy RA, Connelly K.Diagnostic growth hormone deficiency testing practices among patients in the NCGS/ NCSS databases. J Pediatr Endocrinol Metab. 2003; 16(suppl 3):619-624.
4.
GrowthHormone 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;85:3990-3993.
5.
Wilson TA, Rose SR, Cohen P., et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee . J Pediatr.2003;143: 415-421.
6.
Centers for Disease Control and Prevention (CDC).Use and interpretation of the CDC growth charts. An instructional guide. Available at: http://www.cdc.gov/nccdphp/dnpa/growthcharts/00binaries/growthchart.pdf . Accessed Aug 28, 2006.
7.
Blethen SL, Baptista J., Kuntze J., Foley T., LaFranchi S., Johanson A.Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group. J Clin Endocrinol Metab.1997;82:418-420.
8.
MacGillivray MH, Baptista J., Johanson A.Outcome of a four-year randomized study of daily versus three times weekly somatropin treatment in prepubertal naive growth hormone-deficient children. Genentech Study Group. J Clin Endocrinol Metab.1996;81:1806-1809.
9.
MacGillivray MH, Blethen SL, Buchlis JG, Clopper RR, Sandberg DE, Conboy TACurrent dosing of growth hormone in children with growth hormone deficiency: how physiologic? Pediatrics.1998;102:527-530.
10.
Lipman TH, Hench KD, Benyi T., et al. A multicentre randomised controlled trial of an intervention to improve the accuracy of linear growth measurement. Arch Dis Child.2004;89:342-346.
11.
Mauras N., Attie KM, Reiter EO, Saenger P., Baptista J., Genentech, Inc., Cooperative Study Group. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. J Clin Endocrinol Metab.2000;85:3653-3660.
12.
Codner E., Mericq V., Cassorla F.Optimizing growth hormone therapy during puberty. Horm Res . 1997; 48(suppl 5):16-20.
13.
Saenger P.Dose effects of growth hormone during puberty. Horm Res. 2003;60:52-57.
14.
Allen DB, Fost N.hGH for short stature: ethical issues raised by expanded access. J Pediatr.2004;144:648-652.
15.
Park P., Cohen P.The role of insulin-like growth factor I monitoring in growth hormone-treated children. Horm Res. 2004;62(suppl 1):59-65.
16.
Saggese G., Baroncelli GI, Bertelloni S., Barsanti S.The effect of long-term growth hormone (GH) treatment on bone mineral density in children with GH deficiency. Role of GH in the attainment of peak bone mass. J Clin Endocrinol Metab.1996;81:3077-3083.
17.
Underwood LE , Attie KM, Baptista J., Genentech Collaborative Study Group. Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study. J Clin Endocrinol Metab.2003;88:5273-5280.
18.
Boguszewski CL, Meister LH, Zaninelli DC, Radominski RBOne year of GH replacement therapy with a fixed low-dose regimen improves body composition, bone mineral density and lipid profile of GH-deficient adults. Eur J Endocrinol.2005;152:67-75.
19.
Lanes R., Paoli M., Carrillo E., Villaroel O., Palacios A.Cardiovascular risk of young growth-hormone-deficient adolescents. Differences in growth-hormone-treated and untreated patients. Horm Res . 2003;60:291-296.
20.
Colao A., Di Somma C., Pivonello R., et al. The cardiovascular risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: a 12-month prospective study. J Clin Endocrinol Metab.2002;87:1088-1093.
21.
Clayton PE, Cuneo RC, Juul A., Monson JP, Shalet SM, Tauber M.Consensus statement on the management of the GH-treated adolescent in the transition to adult care. Eur J Endocrinol.2005;152:165-170.
22.
Allen DB, Fost NCGrowth hormone therapy for short stature: panacea or Pandora's box? J Pediatr.1990;117: 16-21.
23.
Hintz RL, Attie KM, Baptista J., Roche A.Effect of growth hormone treatment on adult height of children with idiopathic short stature. Genentech Collaborative Group. N Engl J Med.1999;340:502-507.
24.
Finkelstein BS, Imperiale TF, Speroff T., Marrero U., Radcliffe DJ, Cuttler L.Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med.2002; 156: 230-240.
25.
Leschek EW, Rose SR, Yanovski JA, et al. 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;89:3140-3148.
26.
Kemp SF, Kuntze J., Attie KM, et al. Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab.2005;90: 5247-5253.
27.
Saenger P.Turner's syndrome. N Engl J Med.1996;335: 1749-1754.
28.
Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J., Genentech, Inc., Collaborative Study Group. Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. J Clin Endocrinol Metab.2000;85:2439-2445.
29.
Sas TC, De Muinck Keizer-Schrama SM, Stijnen T., et al. Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. J Clin Endocrinol Metab.1999;84:4607-4612.
30.
Reiter EO, Blethen SL, Baptista J., Price L.Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner's syndrome. J Clin Endocrinol Metab.2001;86:1936-1941.
31.
Rosenfeld RG, Attie KM, Frane J., et al. Growth hormone therapy of Turner's syndrome: beneficial effect on adult height. J Pediatr.1998;132:319-324.
32.
Savendahl L., Davenport MLDelayed diagnoses of Turner's syndrome: proposed guidelines for change. J Pediatr.2000;137:455-459.
33.
Gunay-Aygun M. , Schwartz S., Heeger S., O'Riordan MA, Cassidy SBThe changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics.2001;108:E92.
34.
Carrel AL, Myers SE, Whitman BY, Allen DBSustained benefits of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome are dose-dependent . J Pediatr Endocrinol Metab. 2001;14:1097-1105.
35.
Carrel AL, Myers SE, Whitman BY, Allen DBBenefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study . J Clin Endocrinol Metab.2002;87:1581-1585.
36.
Carrel AL, Myers SE, Whitman BY, Allen DBGrowth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study. J Pediatr.1999;134:215-221.
37.
Lindgren AC , Hellstrom LG, Ritzen EM, Milerad J.Growth hormone treatment increases CO(2) response, ventilation and central inspiratory drive in children with Prader-Willi syndrome . Eur J Pediatr.1999; 158: 936-940.
38.
Haqq AM, Stadler DD, Jackson RH, Rosenfeld RG, Purnell JQ, LaFranchi SHEffects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. J Clin Endocrinol Metab.2003;88:2206-2212.
39.
Eiholzer U.Deaths in children with Prader-Willi syndrome. A contribution to the debate about the safety of growth hormone treatment in children with PWS. Horm Res. 2005;63:33-39.
40.
van Vliet G. , Deal CL, Crock PA, Robitaille Y., Oligny LLSudden death in growth hormone-treated children with Prader-Willi syndrome. J Pediatr.2004 ;144:129-131.
41.
Allen DB, Carrel ALGrowth hormone therapy for Prader-Willi syndrome: a critical appraisal. J Pediatr Endocrinol Metab.2004;17(suppl 4):1297-1306.
42.
Kuizon BD, Salusky IBGrowth retardation in children with chronic renal failure. J Bone Miner Res.1999;14: 1680-1690.
43.
Roelfsema V. , Clark RGThe growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol.2001;12:1297-1306.
44.
Fine RN, Kohaut EC, Brown D., Perlman AJGrowth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized double-blind placebo-controlled study. Genentech Cooperative Study Group. J Pediatr.1994; 124:374-382.
45.
Hokken-Koelega A., De Mulder P.,Jong R., Lilien M., Donckerwolcke R., Groothof J.Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency. Pediatr Nephrol.2000;14:701-706.
46.
Haffner D., Schaefer F., Nissel R., Wuhl E., Tonshoff B., Mehls O.Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. N Engl J Med.2000;343:923-930.
47.
Van Dyck M. , Gyssels A., Proesmans W., Nijs J., Eeckels R.Growth hormone treatment enhances bone mineralisation in children with chronic renal failure. Eur J Pediatr.2001;160:359-363.
48.
Fine RN, Yadin O., Moulton L., Nelson PA, Boechat MI, Lippe BMFive years experience with recombinant human growth hormone treatment of children with chronic renal failure. J PediatrEndocrinol.1994;7:1-12.
49.
Tonshoff B. , Tonshoff C., Mehls O., et al. Growth hormone treatment in children with preterminal chronic renal failure: no adverse effect on glomerular filtration rate. Eur J Pediatr.1992;151:601-607.
50.
North American Pediatric Renal Transplant Cooperative Study. 2005 Annual Report. Available at: http://spit-fire.emmes.com/study/ped/resources/annlrept2005.pdf . Accessed: Aug 28, 2006.
51.
Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P.International Small for Gestational Age Advisory Board. 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; 111:1253-1261.
52.
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;57:216-222.
53.
van Pareren Y., Mulder P., Houdijk M., Jansen M., Reeser M., Hokken-Koelega A.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;88:3584-3590.
54.
Arends NJ, Boonstra VH, Mulder PG, et al. GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol ( Oxf). 2003;59:779-787.
55.
de Zegher F. , Ong K., van Helvoirt M., Mohn A., Woods K., Dunger D.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: 148-151.
56.
Hintz RLThe prismatic case of Creutzfeldt-Jakob disease associated with pituitary growth hormone treatment. J Clin Endocrinol Metab.1995;80:2298-2301.
57.
Blethen SL, Allen DB, Graves D., August G., Moshang T., Rosenfeld R.Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab.1996;81:1704-1710.
58.
Maneatis T., Baptista J., Connelly K., Blethen S.Growth hormone safety update from the National Cooperative Growth Study. J Pediatr Endocrinol Metab.2000; 13(suppl 2):1035-1044.
59.
Bell JJ, Bolar K., Swinford RD, Hoffman AR, Maneatis T., Lippe B.Long-term safety of recombinant human growth hormone: the National Cooperative Growth Study Experience. Poster presented at: 87th Annual Meeting of the Endocrine Society; June 4-7, 2005; San Diego, Ca. P2-450.
60.
Mills JL, Schonberger LB, Wysowski DK, et al. Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients. J Pediatr.2004 ;144: 430-436.
61.
GrowthHormone Research Society. Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J Clin Endocrinol Metab.2001;86: 1868-1870.
62.
Hardin DS, Woo J., Butsch R., Huett B.Current prescribing practices and opinions about growth hormone therapy: results of a nationwide survey of paediatric endocrinologists. Clin Endocrinol (Oxf). 2007;66:85-94.
63.
Cuttler L., Silvers JB, Singh J., Tsai AC, Radcliffe D.Physician decisions to discontinue long-term medications using a two-stage framework: the case of growth hormone therapy. Med Care.2005;43:1185-1193.
Hardin DS, Stratton R., Kramer JC, Reyes de la Rocha S., Govaerts K., Wilson DPGrowth hormone improves weight velocity and height velocity in prepubertal children with cystic fibrosis. Horm Metab Res.1998;30:636-641.
66.
Hardin DS, Ellis KJ, Dyson M., Rice J., McConnell R., Seilheimer DKGrowth hormone improves clinical status in prepubertal children with cystic fibrosis: results of a randomized controlled trial. J Pediatr.2001;139:636-642.
67.
Alemzadeh R. , Upchurch L., McCarthy V.Anabolic effects of growth hormone treatment in young children with cystic fibrosis. J Am Coll Nutr. 1998;17:419-424.
68.
Hardin DS, Rice J., Ahn C., et al. Growth hormone treatment enhances nutrition and growth in children with cystic fibrosis receiving enteral nutrition. J Pediatr.2005;146:324-328.
69.
Bechtold S. , Ripperger P., Bonfig W., Pozza RD, Haefner R., Schwarz HPGrowth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography . J Clin Endocrinol Metab.2005;90:3168-3173.
70.
Allen DB, Julius JR, Breen TJ, Attie KMTreatment of glucocorticoid-induced growth suppression with growth hormone . National Cooperative Growth Study. J Clin Endocrinol Metab.1998;83:2824-2829.
71.
Saavedra JM , Henderson RA, Perman JA, Hutton N., Livingston RA, Yolken RHLongitudinal assessment of growth in children born to mothers with human immunodeficiency virus infection. Arch Pediatr Adolesc Med.1995;149:497-502.
72.
Johann-Liang R., O'Neill L., Cervia J., et al. Energy balance, viral burden, insulin-like growth factor-1, interleukin-6 and growth impairment in children infected with human immunodeficiency virus. AIDS.2000 ;14:683-690.
73.
Arpadi SM, Cuff PA, Kotler DP, et al. Growth velocity, fat-free mass and energy intake are inversely related to viral load in HIV-infected children. J Nutr.2000; 130: 2498-2502.
74.
Hardin DS, Rice J., Doyle ME, Pavia A.Growth hormone improves protein catabolism and growth in prepubertal children with HIV infection. Clin Endocrinol ( Oxf). 2005; 63:259-262.
75.
Seguy D., Vahedi K., Kapel N., Souberbielle JC, Messing B.Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study. Gastroenterology . 2003;124:293-302.
76.
Mauras N., George D., Evans J., et al. Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study. Metabolism.2002;51:127-135.
