Effects of Growth Hormone Therapy in Children with Idiopathic Short Stature

특발성 저신장증 소아에서 성장호르몬의 치료효과

  • Lee, Kyong A (Department of Pediatrics, College of Medicine and Medical Research Instituter, Chungbuk National University) ;
  • Han, Heon Seok (Department of Pediatrics, College of Medicine and Medical Research Instituter, Chungbuk National University)
  • 이경아 (충북대학교 의과대학 소아과학교실, 의학연구소) ;
  • 한현석 (충북대학교 의과대학 소아과학교실, 의학연구소)
  • Received : 2005.03.22
  • Accepted : 2005.05.10
  • Published : 2005.08.15

Abstract

Purpose : The use of growth hormone(GH) to promote growth in normal short children without classical GH deficiency is controversial. Numerous foreign studies have shown the effects of GH therapy in children with idiopathic short stature(ISS) whereas few has been interested in Korea. Therefore, this study is designed to investigate the effects of GH therapy on ISS by observing correlations and changes among various growth parameters such as, insulin-like growth factor-I(IGF-I) and insulin-like growth factor binding protein-3(IGFBP-3). Methods : This study was conducted retrospectively with 15 children with ISS in Chungbuk National University Hospital in Korea. Mean age was $11.44{\pm}2.81$ and the children were treated with 0.66 IU/kg/wk dosage of GH for 1 or 2 years. Also, the growth parameters before and after the GH therapy were observed. Results : Height standard deviation score(HT-SDS) was increased from $-1.85{\pm}0.70$ to $-1.58{\pm}0.56$ at 1 year and to $-1.21{\pm}0.37$ at 2 years after GH therapy. Predicted adult height standard deviation score(PAH-SDS) was also increased from $-2.10{\pm}0.52$ to $-1.67{\pm}0.59$ at 1 year, and to $-0.96{\pm}0.60$ at 2 years. Serum IGF-I and IGFBP-3 levels were significantly increased after 1 year and marginally increased after 2 years of GH therapy. Conclusion : It is concluded that GH therapy has growth promoting effect. The significant increase in IGF-I and IGFBP-3 levels during the GH therapy suggests that IGF-I and IGFBP-3 are useful predictors of response to the use of GH therapy. It is expected that larger patient samples would provide more reliable information about the effect of GH therapy.

목 적 : 최근까지 성장호르몬 결핍증으로 진단 받은 소아에서의 성장호르몬 치료는 그 효과를 인정받아 왔으나 성장호르몬 자극 유발 검사에서 유의한 결과를 보이지 않는 특발성 저신장증은 그 원인이 성장호르몬의 부분적 결핍 또는 감수성의 부족 때문이므로 성장호르몬의 치료 효과가 기대되나 성장호르몬 투여가 인정되어 오지 못한 현실이다. 특발성 저신장 소아에서의 성장호르몬의 효과에 대하여 몇몇 국외 연구 논문들이 발표되어 왔으나 국내에서는 거의 없는 실정으로 이에 저자들은 국내 소아를 대상으로 국내에서 생산된 성장호르몬을 투여하기 전과 후의 여러 성장 관련인자들 및 신장을 비교 분석하여 특발성 저신장증에서의 성장호르몬 치료효과에 대하여 검증하고자 하였다. 방 법 : 충북대학교병원에서 최소 1년 이상 성장호르몬 투여를 받은 특발성 저신장증 환아 15명을 대상으로 하여 1년 치료군과 2년 치료군으로 나누어 투여 전 및 후의 여러 성장 관련변수들 및 신장의 변화를 검토하여 성장호르몬의 효과를 비교 분석하였다. 결 과 : 15명의 소아 중 남아가 7명, 여아가 8명이었고 평균 연령은 $11.44{\pm}2.81$세(4.6-12.73세)이었다. 성장호르몬을 사용하기 전에 1년 치료군과 2년 치료군 사이의 역 연령, 골 연령, 신장 표준 편차치, 예측 성인 신장의 표준 편차치, 표적 신장의 표준 편차치, IGF-I, 그리고 IGFBP-3의 차이는 없었다. 또한 성장호르몬 투여 1년 후의 각종 성장 관련변수들의 비교 결과 1년 치료군과 2년 치료군 사이의 유의한 차이는 없었다. 그러나 성장호르몬 투여 전후의 신장의 변화를 비교하였을 때 1년 치료군과 2년 치료군 모두에서 의미 있는 증가를 보였다. 또한 각종 성장 관련 변수들도 두 군 모두에서 증가를 보였으나 2년 치료군에서는 IGF-I과 IGFBP-3가 통계학적으로 관련성이 미미한 것처럼 보였는데 이는 환아의 수가 적기 때문으로 보인다. 결 론 : 통상적으로 최대 자극 성장호르몬 치를 성장호르몬 치료의 기준으로 사용하여 왔다. 그러나 이 연구에서는 성장호르몬 자극 검사상 성장호르몬 결핍증의 범위에서 벗어나는 특발성 저신장의 치료에도 성장호르몬이 효과가 있으며 또한 치료의 지표로서 IGF-I과 IGFBP-3를 사용할 수 있다는 것을 보여주고 있다.

Keywords

Acknowledgement

Supported by : 충북대학교

References

  1. 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;340:502-7 https://doi.org/10.1056/NEJM199902183400702
  2. Van Vliet G, Styne DM, Kaplan SL, Grumbach MM. Growth hormone treatment for short stature. N Engl J Med 1983;309:1016-22 https://doi.org/10.1056/NEJM198310273091703
  3. Plotnick LP, Van Meter QL, Kowarski AA. Human growth hormone treatment of children with growth failure and normal growth hormone levels by immunoassay : lack of correlation with somatomedine generation. Pediatrics 1983;71: 324-7
  4. Gertner JM, Genel M, Gianfredi SP, Hintz RL, Rosenfeld RG, Tamborlane WV, et al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J Pediatr 1984;104:172-6 https://doi.org/10.1016/S0022-3476(84)80987-7
  5. Hindmarsh PC, Pringle PJ, Di Silvio L, Brook CG. Effects of 3 years of growth hormone therapy in short normal children. Acta Paediatr Scand Suppl 1990;366:6-12
  6. Takano K, Hizuka N, Asakawa K, Sukegawa I, Horikawa R, Shizume K. Effects of short-term growth hormone therapy in short children without growth hormone deficiency. Acta Paediatr Scand Suppl 1990;366:14-22
  7. The Korean Pediatric Society. Tables for age structure and growth pattern of Korean children and adolescence in 1998. Seoul; Kwangmoon Co, 1999:52-3
  8. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age : revised for use with the Greulich-Pyle hand standards. J Pediatr 1952;40:423-41 https://doi.org/10.1016/S0022-3476(52)80205-7
  9. Tanner JM, Whitehouse RH, Marshall WA, Carter BS. Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16 with allowance for midparent height. Arch Dis Child 1975;50:14-26 https://doi.org/10.1136/adc.50.1.14
  10. Tanner JM, Whitehouse RH, Marshall WA, Hearly MJR, Goldstein H. Assessment of skeletal maturity and prediction of adult height. London : Academic Press, 1975
  11. Tanner JM, Landt KW, Cameron N, Carter BS, Patel J. Prediction of adult height from height and bone age in childhood : a new system of equations(TW Mark II) based on a sample including very tall and very short children. Arch Dis Child 1983;58:767-76 https://doi.org/10.1136/adc.58.10.767
  12. Roche AF, Johnson JM. A comparison between methods of calculating skeletal age(Greulich-Pyle). Am J Phys Anthropol 1969;30:221-9 https://doi.org/10.1002/ajpa.1330300209
  13. Raben MS. Treatment of a pituitary dwarf with human growth hormone. J Clin Endocrinol Metab 1958;18:901-3 https://doi.org/10.1210/jcem-18-8-901
  14. Geffner ME. Growth hormone : uses and abuses. Serono Symposia International, a Current Review of Pediatric Endocrinology; 2003 Apr 29-May 2; Seattle. Seattle : Serono Symposia International, Inc. and The Lawson Wilkins Pediatric Endocrine Society, 2003:97-106
  15. Blair JC, Camacho-Hubner C, Miraki Moud F, Rosberg S, Burren C, Lim S, et al. Standard and low dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature. Clin Endocrinol 2004; 60:163-8 https://doi.org/10.1046/j.1365-2265.2004.01957.x
  16. Marchini A, Marttila T, Winter A, Caldeira S, Malanchi I, Blaschke RJ, et al. The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes. J Biol Chem 2004;279:37103-14 https://doi.org/10.1074/jbc.M307006200
  17. Rose SR, Municchi G, Barnes KM, Cutler GB Jr. Overnight growth hormone concentrations are usually normal in pubertal children with idiopathic short stature : a clinical research center study. J Clin Endocrinol Metab 1996;81: 1063-8 https://doi.org/10.1210/jc.81.3.1063
  18. Saenger P. Growth hormone and idiopathic short stature - it is too soon to call it a mistrial. Eur J Endocrinol 1998; 138:258-61 https://doi.org/10.1530/eje.0.1380258
  19. Frindik JP, Kemp SF, Hunold JJ. Near adult heights after growth hormone treatment in patients with idiopathic short stature or idiopathic growth hormone deficiency. J Pediatr Endocrinol Metab 2003;16:607-12
  20. Rogol AD, Blethen SL, Sy JP, Veldhuis JD. Do growth hormone(GH) serial sampling, insulin-like growth factor-I (IGF-I) or auxological measurements have an advantage over GH stimulation testing in predicting the linear growth response to GH therapy? Clin Endocrinol 2003;58:229-37 https://doi.org/10.1046/j.1365-2265.2003.01701.x
  21. Blair JC, Savage MO. The GH-IGF-I axis in children with idiopathic short stature. Trends Endocrinol Metab 2002;13: 325-30 https://doi.org/10.1016/S1043-2760(02)00631-8
  22. 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;130:205-9 https://doi.org/10.1016/S0022-3476(97)70344-5
  23. Loche S, Cambiaso P, Setzu S, Carta D, Marini R, Borrelli P, et al. Final height after growth hormone therapy in non-growth-hormone-deficient children with short stature. J Pediatr 1994;125:196-200 https://doi.org/10.1016/S0022-3476(94)70192-X
  24. Hindmarsh PC, Brook CG. Final height of short normal children treated with growth hormone. Lancet 1996;348:13- 6 https://doi.org/10.1016/S0140-6736(96)01038-0
  25. Kamp GA, Wit JM. High-dose growth hormone therapy in idiopathic short stature. Horm Res 1998;49 Suppl 2:67-72 https://doi.org/10.1159/000053090
  26. Hintz RL. Growth hormone treatment of idiopathic short stature. Horm Res 1996;46:208-14 https://doi.org/10.1159/000185025
  27. Zadik Z, Chalew S, Zung A, Landau H, Leiberman E, Koren R, et al. Effect of long-term growth hormone therapy on bone age and pubertal maturation boys with and without classic growth hormone deficiency. J Pediatr 1994;125: 189-95
  28. 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 metaanalysis. Arch Pediatr Adolesc Med 2002;156:230-40
  29. Wit JM, Rekers-Mombarg LT. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. J Clin Endocrinol Metab 2002;87:604-11 https://doi.org/10.1210/jc.87.2.604
  30. Bryant J, Cave C, Milne R. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database Syst Rev 2003;(4):CD004440
  31. Rekers-Mombarg LT, Massa GG, Wit JM, Matranga AM, Buckler JM, Butenandt O, et al. Growth hormone therapy with three dosage regimens in children with idiopathic short stature. J Pediatr 1998;132:455-60 https://doi.org/10.1016/S0022-3476(98)70020-4
  32. Wilson TA, Rose SR, Cohen P, Rogol AD, Backeljauw P, Brown R, 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;143:415-21 https://doi.org/10.1067/S0022-3476(03)00246-4