Skip to main content
NCBI home page
Archives of Disease in Childhood logoLink to Archives of Disease in Childhood
. 2002 Sep;87(3):215–220. doi: 10.1136/adc.87.3.215

High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature

G Kamp 1, J Waelkens 1, Keizer- S M P F de Muinck 1, de Delemarre-Van 1, L Verhoeven-Wind 1, A Zwinderman 1, J Wit 1, P Clayton 1
PMCID: PMC1719235  PMID: 12193430

Abstract

Background: Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3–9 cm, which may not justify the cost of treatment. As it is unknown whether GH treatment during puberty adds to final height gain, we sought to improve the cost–benefit ratio, employing a study design with high dose GH treatment restricted to the prepubertal period.

Aims: To assess the effect of short term, high dose GH treatment before puberty on growth, bone maturation, and pubertal onset.

Methods: Five year results of a randomised controlled study are reported. Twenty six boys and nine girls were randomly assigned to a GH treatment group (n = 17) or a control group (n = 18). Inclusion criteria were: no signs of puberty, height less than -2 SDS, age 4–8 years for girls or 4–10 years for boys, GH concentration >10 µg/l after provocation, and normal body proportions. To assess GH responsiveness, children assigned to the GH treatment group received GH treatment for two periods of three months (1.5 IU/m2/day and 3.0 IU/m2/day), separated by three month washout periods, during the first year of study. High dose GH treatment (6.0 IU/m2/day) was then started and continued for at least two full years. When puberty occurred, GH treatment was discontinued at the end of a complete year's treatment (for example, three or four years of GH treatment).

Results: In response to at least two years on high dose GH treatment, mean (SD) height SDS for chronological age increased significantly in GH treated children from -2.6 (0.5) to -1.3 (0.5) after two years and -1.4 (0.5) SDS after five years of study. No changes in height SDS were observed in controls. A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment. Height SDS for bone age was not significantly different between groups during the study period. GH treated children entered into puberty at a significantly earlier age compared to controls.

Conclusions: High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty. This may limit the potential therapeutic benefit of this regimen in ISS.

Full Text

The Full Text of this article is available as a PDF (150.2 KB).

Figure 1 .

Figure 1

Open in a new tab

Height SDS for chronological age during five years of study in GH treated children compared to controls. Bars represent the 95% confidence intervals of the means.

Figure 2 .

Figure 2

Open in a new tab

Bone age during five years of study in GH treated children compared to controls. Bars represent the 95% confidence intervals of the means.

Figure 3 .

Figure 3

Open in a new tab

Cumulative proportion of GH treated and control children in puberty since start of study, adjusted for age at randomisation and sex.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albertsson-Wikland K., Bischofberger E., Brook C. G., Dahlström G., Edén S., Hall K., Kaplan S., Preece M., Ranke M. B., Rappaport R. Growth hormone treatment of short stature. State-of-the-art 1989. Acta Paediatr Scand Suppl. 1989;362:9–13. doi: 10.1111/j.1651-2227.1989.tb11300.x. [DOI] [PubMed] [Google Scholar]
  2. Bierich J. R., Nolte K., Drews K., Brügmann G. Constitutional delay of growth and adolescence. Results of short-term and long-term treatment with GH. Acta Endocrinol (Copenh) 1992 Nov;127(5):392–396. doi: 10.1530/acta.0.1270392. [DOI] [PubMed] [Google Scholar]
  3. Bourguignon J. P. Linear growth as a function of age at onset of puberty and sex steroid dosage: therapeutic implications. Endocr Rev. 1988 Nov;9(4):467–488. doi: 10.1210/edrv-9-4-467. [DOI] [PubMed] [Google Scholar]
  4. Bourguignon J. P., Vandeweghe M., Vanderschueren-Lodeweyckx M., Malvaux P., Wolter R., Du Caju M., Ernould C. Pubertal growth and final height in hypopituitary boys: a minor role of bone age at onset of puberty. J Clin Endocrinol Metab. 1986 Aug;63(2):376–382. doi: 10.1210/jcem-63-2-376. [DOI] [PubMed] [Google Scholar]
  5. Buchlis J. G., Irizarry L., Crotzer B. C., Shine B. J., Allen L., MacGillivray M. H. Comparison of final heights of growth hormone-treated vs. untreated children with idiopathic growth failure. J Clin Endocrinol Metab. 1998 Apr;83(4):1075–1079. doi: 10.1210/jcem.83.4.4703. [DOI] [PubMed] [Google Scholar]
  6. Burns E. C., Tanner J. M., Preece M. A., Cameron N. Final height and pubertal development in 55 children with idiopathic growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr. 1981 Oct;137(2):155–164. doi: 10.1007/BF00441309. [DOI] [PubMed] [Google Scholar]
  7. Cole T. J., Roede M. J. Centiles of body mass index for Dutch children aged 0-20 years in 1980--a baseline to assess recent trends in obesity. Ann Hum Biol. 1999 Jul-Aug;26(4):303–308. [PubMed] [Google Scholar]
  8. Franks S. Growth hormone and ovarian function. Baillieres Clin Endocrinol Metab. 1998 Jul;12(2):331–340. doi: 10.1016/s0950-351x(98)80026-8. [DOI] [PubMed] [Google Scholar]
  9. Guyda H. J. Four decades of growth hormone therapy for short children: what have we achieved? J Clin Endocrinol Metab. 1999 Dec;84(12):4307–4316. doi: 10.1210/jcem.84.12.6189. [DOI] [PubMed] [Google Scholar]
  10. Hindmarsh P. C., Brook C. G. Final height of short normal children treated with growth hormone. Lancet. 1996 Jul 6;348(9019):13–16. doi: 10.1016/s0140-6736(96)01038-0. [DOI] [PubMed] [Google Scholar]
  11. Hintz R. L., Attie K. M., 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 Feb 18;340(7):502–507. doi: 10.1056/NEJM199902183400702. [DOI] [PubMed] [Google Scholar]
  12. Hopwood N. J., Hintz R. L., Gertner J. M., Attie K. M., Johanson A. J., Baptista J., Kuntze J., Blizzard R. M., Cara J. F., Chernausek S. D. Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy. J Pediatr. 1993 Aug;123(2):215–222. doi: 10.1016/s0022-3476(05)81691-9. [DOI] [PubMed] [Google Scholar]
  13. Kamp G. A., Wit J. M. High-dose growth hormone therapy in idiopathic short stature. Horm Res. 1998;49 (Suppl 2):67–72. doi: 10.1159/000053090. [DOI] [PubMed] [Google Scholar]
  14. Kawai M., Momoi T., Yorifuji T., Yamanaka C., Sasaki H., Furusho K. Unfavorable effects of growth hormone therapy on the final height of boys with short stature not caused by growth hormone deficiency. J Pediatr. 1997 Feb;130(2):205–209. doi: 10.1016/s0022-3476(97)70344-5. [DOI] [PubMed] [Google Scholar]
  15. Lesage C., Walker J., Landier F., Chatelain P., Chaussain J. L., Bougnères P. F. Near normalization of adolescent height with growth hormone therapy in very short children without growth hormone deficiency. J Pediatr. 1991 Jul;119(1 Pt 1):29–34. doi: 10.1016/s0022-3476(05)81034-0. [DOI] [PubMed] [Google Scholar]
  16. Loche S., Cambiaso P., Setzu S., Carta D., Marini R., Borrelli P., Cappa M. Final height after growth hormone therapy in non-growth-hormone-deficient children with short stature. J Pediatr. 1994 Aug;125(2):196–200. doi: 10.1016/s0022-3476(94)70192-x. [DOI] [PubMed] [Google Scholar]
  17. McCaughey E. S., Mulligan J., Voss L. D., Betts P. R. Randomised trial of growth hormone in short normal girls. Lancet. 1998 Mar 28;351(9107):940–944. doi: 10.1016/S0140-6736(05)60604-6. [DOI] [PubMed] [Google Scholar]
  18. Ranke M. B., Lindberg A. Growth hormone treatment of idiopathic short stature: analysis of the database from KIGS, the Kabi Pharmacia International Growth Study. Acta Paediatr Suppl. 1994 Dec;406:18–24. doi: 10.1111/j.1651-2227.1994.tb13415.x. [DOI] [PubMed] [Google Scholar]
  19. Rekers-Mombarg L. T., Cole T. J., Massa G. G., Wit J. M. Longitudinal analysis of growth in children with idiopathic short stature. Ann Hum Biol. 1997 Nov-Dec;24(6):569–583. doi: 10.1080/03014469700005332. [DOI] [PubMed] [Google Scholar]
  20. Rekers-Mombarg L. T., Kamp G. A., Massa G. G., Wit J. M. Influence of growth hormone treatment on pubertal timing and pubertal growth in children with idiopathic short stature. Dutch Growth Hormone Working Group. J Pediatr Endocrinol Metab. 1999 Sep-Oct;12(5):611–622. doi: 10.1515/jpem.1999.12.5.611. [DOI] [PubMed] [Google Scholar]
  21. Rikken B., Massa G. G., Wit J. M. Final height in a large cohort of Dutch patients with growth hormone deficiency treated with growth hormone. Dutch Growth Hormone Working Group. Horm Res. 1995;43(4):135–137. doi: 10.1159/000184259. [DOI] [PubMed] [Google Scholar]
  22. Sas T., de Waal W., Mulder P., Houdijk M., Jansen M., Reeser M., Hokken-Koelega A. Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. J Clin Endocrinol Metab. 1999 Sep;84(9):3064–3070. doi: 10.1210/jcem.84.9.5942. [DOI] [PubMed] [Google Scholar]
  23. Stanhope R., Albanese A., Hindmarsh P., Brook C. G. The effects of growth hormone therapy on spontaneous sexual development. Horm Res. 1992;38 (Suppl 1):9–13. doi: 10.1159/000182563. [DOI] [PubMed] [Google Scholar]
  24. Tanner J. M. Normal growth and techniques of growth assessment. Clin Endocrinol Metab. 1986 Aug;15(3):411–451. doi: 10.1016/s0300-595x(86)80005-6. [DOI] [PubMed] [Google Scholar]
  25. Usher R., McLean F. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr. 1969 Jun;74(6):901–910. doi: 10.1016/s0022-3476(69)80224-6. [DOI] [PubMed] [Google Scholar]
  26. Van Vliet G., Styne D. M., Kaplan S. L., Grumbach M. M. Growth hormone treatment for short stature. N Engl J Med. 1983 Oct 27;309(17):1016–1022. doi: 10.1056/NEJM198310273091703. [DOI] [PubMed] [Google Scholar]
  27. Wang E., Wang J., Chin E., Zhou J., Bondy C. A. Cellular patterns of insulin-like growth factor system gene expression in murine chondrogenesis and osteogenesis. Endocrinology. 1995 Jun;136(6):2741–2751. doi: 10.1210/endo.136.6.7750499. [DOI] [PubMed] [Google Scholar]
  28. Werther G. A., Haynes K. M., Barnard R., Waters M. J. Visual demonstration of growth hormone receptors on human growth plate chondrocytes. J Clin Endocrinol Metab. 1990 Jun;70(6):1725–1731. doi: 10.1210/jcem-70-6-1725. [DOI] [PubMed] [Google Scholar]
  29. Wilson M. E., Gordon T. P., Rudman C. G., Tanner J. M. Effects of growth hormone on the tempo of sexual maturation in female rhesus monkeys. J Clin Endocrinol Metab. 1989 Jan;68(1):29–38. doi: 10.1210/jcem-68-1-29. [DOI] [PubMed] [Google Scholar]
  30. Wit J. M., Boersma B., de Muinck Keizer-Schrama S. M., Nienhuis H. E., Oostdijk W., Otten B. J., Delemarre-Van de Waal H. A., Reeser M., Waelkens J. J., Rikken B. Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group. Clin Endocrinol (Oxf) 1995 Apr;42(4):365–372. doi: 10.1111/j.1365-2265.1995.tb02644.x. [DOI] [PubMed] [Google Scholar]
  31. Wit J. M., Fokker M. H., de Muinck Keizer-Schrama S. M., Oostdijk W., Gons M., Otten B. J., Delemarre-Van de Waal H. A., Reeser M., Waelkens J. J. Effects of two years of methionyl growth hormone therapy in two dosage regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues. (Dutch Growth Hormone Working Group). J Pediatr. 1989 Nov;115(5 Pt 1):720–725. doi: 10.1016/s0022-3476(89)80648-1. [DOI] [PubMed] [Google Scholar]
  32. Wit J. M., Kamp G. A., Rikken B. Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature. Pediatr Res. 1996 Feb;39(2):295–302. doi: 10.1203/00006450-199602000-00018. [DOI] [PubMed] [Google Scholar]
  33. Wit J. M., Rietveld D. H., Drop S. L., Oostdijk W., Gons M., Otten B. J., Delemarre-van de Waal H. A., Reeser M., Waelkens J. J., Bot A. A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group. Acta Paediatr Scand. 1989 May;78(3):426–435. doi: 10.1111/j.1651-2227.1989.tb11103.x. [DOI] [PubMed] [Google Scholar]
  34. Zadik Z., Chalew S., Zung A., Landau H., Leiberman E., Koren R., Voet H., Hochberg Z., Kowarski A. A. Effect of long-term growth hormone therapy on bone age and pubertal maturation in boys with and without classic growth hormone deficiency. J Pediatr. 1994 Aug;125(2):189–195. [PubMed] [Google Scholar]
  35. Zadik Z., Mira U., Landau H. Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone. Horm Res. 1992;37(4-5):150–155. doi: 10.1159/000182300. [DOI] [PubMed] [Google Scholar]
  36. de Zegher F., Albertsson-Wikland K., Wollmann H. A., Chatelain P., Chaussain J. L., Löfström A., Jonsson B., Rosenfeld R. G. Growth hormone treatment of short children born small for gestational age: growth responses with continuous and discontinuous regimens over 6 years. J Clin Endocrinol Metab. 2000 Aug;85(8):2816–2821. doi: 10.1210/jcem.85.8.6719. [DOI] [PubMed] [Google Scholar]

Articles from Archives of Disease in Childhood are provided here courtesy of BMJ Publishing Group

RESOURCES