진성 성조숙증으로 진단 받은 여아에서 gonadotropin-releasing hormone agonist 단독치료 및 growth hormone의 병합치료 시 예측 성인키의 변화 및 성장 획득의 비교

The comparison of predicted adult height change and height gain after gonadotropin-releasing hormone agonist and combined growth hormone treatment in girls with idiopathic central precocious puberty

  • 서지영 (서울대학교 의과대학 소아과학교실) ;
  • 윤인석 (서울대학교 의과대학 소아과학교실) ;
  • 신충호 (서울대학교 의과대학 소아과학교실) ;
  • 양세원 (서울대학교 의과대학 소아과학교실)
  • Seo, Ji-Young (Department of Pediatrics, College of Medicine, Seoul National University) ;
  • Yoon, In-Suk (Department of Pediatrics, College of Medicine, Seoul National University) ;
  • Shin, Choong-Ho (Department of Pediatrics, College of Medicine, Seoul National University) ;
  • Yang, Sei-Won (Department of Pediatrics, College of Medicine, Seoul National University)
  • 투고 : 2005.09.15
  • 심사 : 2005.10.25
  • 발행 : 2006.03.15

초록

목 적 : 성조숙증은 사춘기가 일찍 발생함으로써 최종성인키의 저하가 초래되는 질환으로 사춘기 발현을 억제하여 최종성인키를 향상시키기 위하여 사용되는 성선자극호르몬방출호르몬유도체(gonadotropin releasing hormone agonist, GnRHa)와 일부환자에서 병합치료로 이용되는 성장호르몬(GH)의 치료 효과를 알아보고자 하였다. 방 법 : 1989-2003년까지 서울대학교병원 소아과에서 특발성진성 성조숙증으로 진단 받고 2년 이상 GnRHa를 투여한 21명과 성장호르몬의 병합치료를 시행한 9명에 대하여 2년간의 성장 속도, 예측성인키(predicted adult height, PAH)를 조사하였으며, GnRHa만 투여받은 15명과 성장호르몬을 병합투여받은 6명에서 최종성인키 차이를 후향적으로 비교 분석하였다. 모든 분석은 GnRHa 치료 전 예측성인키가 중간부모키-5 cm(성인여성의 키 1 표준편차)보다 작은 군(PAH_L)과 큰 군(PAH_H), 성장호르몬 병합치료군(GnRHa+GH)으로 구분하여 시행하였다. 결 과 : GnRHa 치료에 따른 PAH의 증가는 PAH_L군에서 첫 1년 동안에 관찰되어, PAH(키 SDS)는 치료 시작 시 $149.7{\pm}6.4cm(-2.1{\pm}1.3)$에서 1년 후에는 $153.5{\pm}6.5cm(-1.4{\pm}1.3)$로 유의하게 증가하고(P=0.004), 2년째에는 $155.8{\pm}8.0cm(-0.9{\pm}1.6)$이었다. 이 시기 동안에 성장속도는 $6.2{\pm}0.7cm$/년이였으며, 골연령 증가(골연령-역연령) 정도는 변화가 없었다. PAH_H군에서는 치료 전 PAH(키 SDS) $160.0{\pm}4.4cm(-0.1{\pm}0.9)$에서 변화가 없어 2년째 $159.5{\pm}6.0cm(-0.2{\pm}1.2)$였다. GnRHa+GH군은 첫 GnRHa 치료시의 PAH는 $149.4{\pm}7.8cm$로 PAH_L군과 비슷하며, 평균 2.3년 동안 GnRHa로 치료받은 후 PAH(키 SDS)는 $154.0{\pm}5. cm(-1.7{\pm}0.9)$로 증가하였으나(P=0.065), GnRHa 투여군들과는 차이가 없었다. 성장호르몬을 병합 투여한 후에 첫 1년 동안 성장속도가 $8.0{\pm}2.8cm/yr$로 치료 전 성장속도 $4.7{\pm}1.2cm/yr$에 비하여 유의하게 증가하여(P=0.013), 결국 1년째 PAH(키 SDS)가 $159.6{\pm}4.4cm(-0.4{\pm}0.6)$로 병합치료 전에 비하여 유의하게 증가하였으며, 2년째는 증가보다는 유지되는 정도였다. PAH_L군(N=8)의 최종성인키(키 SDS)는 $159.8{\pm}5.2cm(-0.1{\pm}1)$로 치료 전에 비하여 $8.5{\pm}2.2cm$ 커졌으며(P<0.001), PAH_H군(N=7)의 최종성인키(키 SDS)는 $156.5{\pm}5.1cm(-0.8{\pm}1)$로 치료 전 예측성인키(SDS) $158.6{\pm}3.8cm(-0.4{\pm}0.8)$, 중간부모키 $157.9{\pm}5.1cm(-0.4{\pm}0.9)$와 차이가 없었다. GnRHa+GH군(N=6)의 최종성인키(키 SDS)는 $158.7{\pm}3.7cm(-0.3{\pm}0.7)$로 GnRHa 치료 전 및 성장호르몬 병합치료 전 예측성인키(키 SDS)에 비하여 각각 평균 11.8 cm, 6.2 cm 증가하였으며(P<0.05), 중간부모키와 비슷하였다. 결 론 : GnRHa 투여의 효과는 첫 1년째에 중간부모키에 비하여 치료 전 예측성인키가 작은 환자에서 뚜렷하게 나타나며, GnRHa 투여 중 성장속도가 저하되면서 예측성인키와 중간부모 키가 작은 환자에서 성장호르몬을 병합 투여하면 중간부모키와 비슷한 최종성인키를 얻을 수 있을 것으로 사료된다.

Purpose : GnRH analogues(GnRHa) are used to treat central precocious puberty(CPP). However, in some patients, the GV decrease is so remarkable that it impairs predicted adult height(PAH); and there fore, the addition of growth hormone(GH) is suggested. We analysed the growth changes during two years and final adult height(FAH) in girls with idiopathic CPP treated with combined therapy, compared with those of girls treated with GnRHa alone. Methods : For the analysis, we classified the patients, who was treated for longer than two years, into three groups depending on the initial PAH and combination of GH; PAH_L, treated with GnRHa and PAH less than midparental height(MPH) - 5 cm. PAH_H, treated with GnRHa and PAH greater than MPH - 5 cm. GnRHa+GH, combined GH treatment, regardless of PAH before treatment. We analysed the GV and PAH change during the first two years and FAH. Results : In PAH_L, the PAH(SDS) at first year of therapy was significantly increased to $153.5{\pm}6.5cm(-1.4{\pm}1.3)$ from $149.7{\pm}6.4cm(-2.1{\pm}1.3)$ before treatment(P=0.004). In PAH_H, there was no significant increase in PAH during the two years of treatment. During the first year of combination of GH and GnRHa, GV and PAH increased significantly. We observed significant increases in FAH, comparing to the initial PAH in the PAH_L and GnRHa+GH groups. The height gains(FAH - initial PAH) were significantly higher in the PAH_L and GnRHa+GH groups than that in the PAH_H group. Conclusion : This study suggests the FAH and height gains are improved in patients, whose predicted adult height before treatment was shorter than those with higher predicted adult height, with the treatment of GnRHa alone or in combination with GH. GH could not improve the final adult height, but compensated the growth in patients whose growth velocity was decelerated by GnRHa alone.

키워드

참고문헌

  1. Grumbach M, Styne D. Puberty : ontogeny, neuroendocrinology, physiology, and disorders. In : Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinololgy. 10th ed. Philadelphia : WB Saunders Co, 2003:1202-40
  2. Rice A, Rivkees SA. Receptor transduction of hormone action. In : Sperling MA, editor. Pediatric endocrinology. 2nd ed. Philadelphia : WB Saunders Co, 2002:33-63
  3. Bertelloni S, Baroncelli GI, Sorrentino MC, Perri G, Saggese G. Effect of central precocious puberty and gonadotropin-releasing hormone analogue treatment on peak bone mass and final height in females. Eur J Pediatr 1998;157:363-7 https://doi.org/10.1007/s004310050831
  4. Shankar RR, Pescovitz OH. Precocious puberty. Adv Endocrinol Metab 1995;6:55-89
  5. Oostdijk W, Rikken B, Schreuder S, Otten B, Odink R, Rouwe C, et al. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child 1996;75:292-7 https://doi.org/10.1136/adc.75.4.292
  6. Oerter KE, Manasco PK, Barnes KM, Jones J, Hill S, Cutler GB Jr. Effects of luteinizing hormone-releasing hormone agonists on final height in luteinizing hormone-releasing hormone-dependent precocious puberty. Acta Paediatr Suppl 1993;388:62-8
  7. Paul D, Conte FA, Grumbach MM, Kaplan SL. Long term effect of gonadotropin-releasing hormone agonist therapy on final and nearfinal height in 26 children with true precocious puberty treated at a median age of less then 5 years. J Clin Endocrinol Metab 1995;80:546-51 https://doi.org/10.1210/jc.80.2.546
  8. Pasquino AM, Pucarelli I, Segni M, Matrunola M, Cerroni F. Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone. J Clin Endocrinol Metab 1999;84:449-52 https://doi.org/10.1210/jc.84.2.449
  9. Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler GB Jr. Increased final height in precocious puberty after longterm treatment with LHRH agonists : the National Institutes of Health experience. J Clin Endocrinol Metab 2000;86: 4711-6 https://doi.org/10.1210/jc.86.10.4711
  10. Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty : final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab 1999;84:4583-90 https://doi.org/10.1210/jc.84.12.4583
  11. Antoniazzi F, Arrigo T, Cisternino M, Galluzzi F, Bertelloni S, Pasquino AM, et al. End results in central precocious puberty with GnRH analog treatment : the data of the Italian Study Group for Physiopathology of Puberty. J Pediatr Endocrinol Metab 2000;13 Suppl 1:773-80
  12. Mul D, Oostdijk W, Otten BJ, Rouwe C, Jansen M, Delemarre-van de Waal HA, et al. Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty : the Dutch experience. J Pediatr Endocrinol Metab 2000;13 Suppl 1:765-72 https://doi.org/10.1515/JPEM.2000.13.S1.765
  13. DiMartino-Nardi J, Wu R, Varner R, Wong WL, Saenger P. The effect of luteinizing hormone-releasing hormone analog for central precocious puberty on growth hormone (GH) and GH-binding protein. J Clin Endocrinol Metab 1994;78:664-8 https://doi.org/10.1210/jc.78.3.664
  14. Harris DA, Van Vliet G, Egli CA, Grumbach MM, Kaplan SL, Styne DM, et al. Somatomedin-C in normal puberty and in true precocious puberty before and after treatment with a potent luteinizing hormone-releasing hormone agonist. J Clin Endocrinol Metab 1985;61:152-9. https://doi.org/10.1210/jcem-61-1-152
  15. Kamp GA, Manasco PK, Barnes KM, Jones J, Rose SR, Hill SC, et al. Low growth hormone levels are related to increased body mass index and do not reflect impaired growth in luteinizing hormone-releasing hormone agonisttreated children with precocious puberty. J Clin Endocrinol Metab 1991;72:301-7 https://doi.org/10.1210/jcem-72-2-301
  16. Juul A, Scheike T, Nielsen CT, Krabbe S, Muller J, Skakkebaek NE. Serum insulin-like growth factor I(IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty : effects of two different treatment regimens with gonadotropin-releasing hormone agonists, without or in combination with an antiandrogen(cyproterone acetate). J Clin Endocrinol Metab 1995;80:3059-67 https://doi.org/10.1210/jc.80.10.3059
  17. Sklar CA, Rothenberg S, Blumberg D, Oberfield SE, Levine LS, David R. Suppression of the pituitary-gonadal axis in children with central precocious puberty : effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion. J Clin Endocrinol Metab 1991;73:734-8 https://doi.org/10.1210/jcem-73-4-734
  18. Oostdijk W, Drop SL, Odink RJ, Hummelink R, Partsch CJ, Sippell WG. Long-term results with a slow-release gonadotrophin-releasing hormone agonist in central precocious puberty. Acta Paediatr Scand Suppl 1991;372:39-45
  19. Saggese G, Pasquino AM, Bertelloni S, Baroncelli GI, Battini R, Pucarelli I, et al. Effect of combined treatment with gonadotropin releasing hormone analogue and growth hormone in patients with central precocious puberty who had subnormal growth velocity and impaired height prognosis. Acta Paediatr 1995;84:299-304 https://doi.org/10.1111/j.1651-2227.1995.tb13632.x
  20. Tato L, Saggese G, Cavallo L, Antoniazzi F, Corrias A, Pasquino AM, et al. Use of combined Gn-RH agonist and hGH therapy for better attining the goals in precocious puberty treatment. Horm Res 1995;44 Suppl 3:49-54 https://doi.org/10.1159/000184674
  21. Brauner R, Adan L, Malandry F, Zantleifer D. Adult height in girls with idiopathic true precocious puberty. J Clin Endocrinol Metab 1994;79:415-20 https://doi.org/10.1210/jc.79.2.415
  22. Bassi F, Bartolini O, Neri AS, Gheri RG, Bucciantini S, Cheli D, et al. Precocious puberty : auxological criteria discriminating different forms. J Endocrinol Invest 1994;17:793-7 https://doi.org/10.1007/BF03347778