Final Height in Patients with Turner Syndrome after

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1 Clin Pediatr Endocrinol 1997; 6(Suppl 10), Copyright (C) 1997 by The Japanese Society for Pediatric Endocrinology Final Height in Patients with Turner Syndrome after Treatment with GH Kazue Takano, Masamichi Ogawa, Toshiaki Tanaka, Katsuhiko Tachibana, Keinosuke Fujita, Naomi Hizuka and The Members of The Committee for the Treatment of Turner Syndrome Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College (KT, NH), Tokyo and The Foundation for Growth Science in Japan (KT, MO, TT, KT, KF, NH), Tokyo, Japan Abstract Clinical trials of human GH therapy for Turner syndrome were started in The number of patients enrolled from 1986 to 1989 was 375. The age at the start of treatment ranged from 5 to 18 with a mean of 10 years. About half of the enrolled patients stopped receiving the therapy within 3 years. A total of 115 patients were treated for more than six years with recombinant hgh. Fifty-one patients received hgh at a weekly dosage of 0.5 IU/kg and 64 received 1.0 IU/kg by daily sc injection. Both treatment groups showed a statistically significant growth increase during the initial 4 years of treatment. The high dose increased height velocity to a significantly greater degree for the initial 2 years as compared with the low dose so that the increase in height over the 6 year treatment with 0.5 IU/kg/W and 1.0 IU/kg/W, as expressed by the SD score ( SDS) for chronological age, was 1.5 and 1.8, respectively. Ninety percent of the patients above the age of 14 exceeded their projected adult height. During the 6 years of treatment, 260 patients stopped or ceased GH therapy. In 31 percent of the patients, the height was above - 2SD for normal girls. In 27% of the patients, the growth rate was not sufficient when they stopped treatment. The final height (FH) of Turner patients was tentatively designated to be the height when the growth rate became <1 cm/year. FH was greater in patients who were treated with GH for more than 6 years. The mean FH of the patients above 17 years who were treated for more than 6 years was } 3.0 cm (N=6) with hgh 0.5 IU/kg/W, and } 2.8 cm (N=12) with hgh 1.0 IU/kg/W. Although FH did not differ statistically for the two treatments, adult height was improved 6-8 cm by GH treatment. No remarkable adverse event occurred during the treatment. These results indicate that hgh treatment improve the final height in patients with Turner syndrome. Key words: Turner patient, Turner syndrome, hgh treatment, final height Introduction Correspondence: Dr. Kazue Takano, Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1 Kawada-cho, Shinjukuku, Tokyo 162, Japan Human GH therapy for Turner syndrome was started systematically about 10 years ago in clinical trials. Although GH could obviously induce a substantial increase in height velocity,

2 52 Takano et al. Vol.6 / Suppl 10 the long-term outcome in terms of final height is still unclear. Final height data are now being requested by the regulatory authority to validate the benefits of GH therapy for Turner syndrome. The Japanese multicentre trial of GH therapy for Turner syndrome was started in 1986, and interim results have already been reported (1-5). In 1991, the Japanese Ministry of Health and Welfare approved GH treatment only for Turner patients who had GH deficiency with a dose of 0.5 IU/kg/week which was the same dose as approved for patients with GH deficiency (pituitary dwarfism). Some of the patients who Fig. 1 Age distribution at the start of hgh treatment in patients with Turner syndrome. : 1.0 IU/ kg/w, : 0.5 IU/kg/w. fulfilled these criteria changed at that time to the GH preparations which were commercially available. Here we report the results of clinical trials held from 1986 to 1990 in Japan. jected adult height were calculated on the basis of the cross-sectional growth study of Japanese Turner girls described previously (6). Projected adult height (PAH) at 17 years was calculated Patients and Methods by assuming that each subject would remain on the same Turner growth curve observed at the start of treatment. For the entire group of Japanese Turner patients, the mean PAH was 137 cm. For statistical analysis parametric tests were used because the data fit normal distribution Within each treatment group the paired t -test was used to compare treatment results with the baseline. Results are expressed as the mean } SD. Intergroup comparisons were performed with the unpaired t-test. The correlations between various measurements were calculated by linear regression analysis (Person's correlation coefficient). Differences with p<0.05 were considered significant. Results Periods of GH treatment. The number of patients enrolled in clinical trials of GH treatment during these 5 years was 341. The age distribution is shown in Fig. 1. The chronological age ranged from 4 to 18 with a mean of 10 years. About 90 percent of the patients showed hgh response to two kinds of classical GH provocative tests with a peak level above 10ƒÊg/l. None of the patients had been treated with other growth-accelerating medications before the treatment. The patients were divided into two groups and treated with either 0.5 IU/kg/week (0.5 IU group) or 1.0 IU/kg/week hgh (1.0 IU group). There were no differences between the groups in chronological age, bone age, height, degree of overweight or growth rate at the start of the treatment. The growth hormone preparations used in this study were recombinant hgh kindly provided by Sumitomo Pharmaceutical Co., Ltd. (Osaka Japan), Novo Nordisk Pharmaceuticals, Ltd. (Tokyo, Japan), and Eli Lilly Japan K.K. (Kobe,, The numbers of patients treated with GH are shown in Fig. 2. During the first 3 years, the clinical trials were under the control of the re - Japan). Height (SD), growth rate (SD) and pro- spective pharmaceutical companies. Thereafter

3 Final Height in Patients with Turner Syndrome after Treatment with GH 53 Fig. 2 Percent of the patients treated for 1-3 years (left) and more than 3 years (right) with hgh. the clinical trials were transferred to the control of the foundation for Growth Science in Japan. During the 1st, 2nd and 3rd years of treatment, the treatment was stopped or ceased in 14%, 20% and 16% of the patients, respectively. Thus during 3 years of clinical trials, 50% of the patients had stopped GH treatment and the number of the patients did not differ statistically between the 2 dosage groups. Thereafter, around 5-6% patients stopped treatment per year in both groups of patients. Growth acceleration during GH treatment A total of 115 patients were treated for more than 6 years (51 in the 0.5 IU group and 64 in the 1.0 IU group). Both treatment groups showed. a statistically significant increase in height during the initial 4 years of treatment. The high dose increased height velocity to a significantly greater degree for the initial 2 years (p<0.05) as compared with the low dose. The height increase (ASDS) during the 6-8 years of GH treatment is shown in Fig. 3. The increase in height during the 6 year treatment with 0.5 and 1.0 IU/kg/w, as expressed by the SD score (ASDS) was 1.5 and 1.8, respectively. Ninety percent of the patients above the age of 14 exceeded their projected adult height. Height of the patients who stopped GH treatment One hundred and thirty-nine patients and 121 patients treated with 0.5 and 1.0 IU/kg/w, respectively, stopped and/or ceased GH within 6 years. Their heights at the termination of GH treatment are analysed according to the age and

4 54 Takano et al. Vol.6 / Suppl 10 Fig. 3 Growth rate before and during 6 years of 0.5 IU/kg/w ( ) and 1.0 IU/kg/w ( ) hgh treatment (upper; cm/year, middle: SD, lower: SDS). Fig. 4 Height and growth rate at the termination of GH treatment (upper: 0.5 IU/kg/w, lower: 1.0 IU/kg/w). _??_ -2SD, _??_ - 2SD for normal girls. growth rate when they stopped treatment (Fig. 4). Among the patients below 15 years old treated with 0.5 IU/kg/w and 1.0 IU/kg/w, 52 patients (68%) and 41 (73%) stopped treatment in spite of having a growth rate above 4 cm/year. About one-fourth of these patients reached a height above - 2SD for normal girls. In patients above 15 years of age, half of the patients stopped treatment in spite of having a growth rate above 2 cm/year. About one-third of these patients reached a height above - 2SD for normal girls. Of all the patients treated with GH, about 30% were estimated to have stopped GH therapy because of a poor growth rate. Final height of the patients treated with GH Among the patients treated with GH, we analysed the height of the patients whose growth rate was less than 1 cm/year and who had reached final height. Thirty five patients were fulfilled this criterion. The height and (CH-PAH) are shown in Figs. 5 and 6. The height gain was greater in patients treated for more than 6 years. The final height of the patients treated for more than 6 years and their chronological age above 17 years are shown in Table 1. With 0.5 IU/kg/w GH treatment, final height ranged from to cm with a mean of } 3.0 cm. CH-PAH ranged from 4.6 to 10.8 with a mean of 7.53 } 2.53 cm. The height increase ( SDS) ranged from 0.95 to 2.26 with a mean of 1.56 }0.53. With 1.0

5 Final Height in Patients with Turner Syndrome after Treatment with GH 55 Fig. 6 (CH-PAH) of Turner patients treated with hgh who reached nearly final height (GR<1 cm/year). œ puberty (-), puberty (+), E2 treatment. Discussion Fig. 5 Final height (GR<1 cm/year) in patients with Turner syndrome treated with hgh (upper: 0.5 IU/kg/w, lower: 1.0 IU/kg/w). hgh 3 years, 3<_??_6 years, œ>6 _??_ years of treatment. IU/kg/w GH treatment these mean values were } 2.77 cm, 6.96 } 3.24 cm and 1.44 } 0.67, respectively. The mean values did not differ statistically for the 2 GH treatment doses. Growth hormone treatment for patients with Turner syndrome has become widespread since adequate amounts of r-hgh have become available but the reports dealing with final adult height after long-term treatment are yet few (7-10). We report here on the effects of two hgh treatment doses (including final adult height). Growth acceleration was observed with both doses: the effect, which was greatest during the 1st year, decreased gradually with the duration of treatment. These results were similar to those of other studies (11-16). The decrease in the effectiveness of GH treatment with the duration of Table 1 Final height (GR< 1 cm/y) of the patients above 17 years old treated for 6-8 years The average height of Japanese Turner patients at age of 17 is 138 cm. CH: Current Height, PAH: Projected Adult Height.

6 56 Takano et al. Vol.6 / Suppl 10 treatment might be due to resistance of the tissue to GH and/or IGF-I but the mechanism of this phenomenon is not yet clear and further study will be required to clarify it. Comparing the two doses, the larger dose increased the growth rate by a significantly greater degree only during the initial 2 years of treatment. The current height of the patients over the age of 17 showed a large variation in each group of patients and the mean final height in the two dose groups did not differ statistically. But this did no prove that the effects of the two doses on final height were similar, because these patients started GH treatment above the age of 11. We need further study to obtain the final height of patients who started GH treatment at younger ages. During the 6 years of treatment no serious adverse events occurred. Glucose intolerance was not observed in any patients. No patient had an antibody to hgh after 6 years of treatment. Without GH treatment the mean final height of Japanese Turner girls is 137 cm so that the final height improved by 6-8 cm with GH treatment. These results were similar to those reported by others (7-10). At this point we could conclude that GH therapy in Turner patients is capable of both accelerating growth and increasing adult height. In this study we observed that the effect of treatment was of the same magnitude in both groups of Turner patients with or without GH deficiency. In Japan the government only permits GH treatment for Turner patients with GH deficiency. We are very anxious to be able to treat all Turner patients with hgh to improve final adult height. In future we could normalize the adult height of Turner patients by further studying the optimal time to start GH treatment, ideal dosage, frequency of injections, and the use of anabolic steroids, etc. Acknowledgements The authors are very grateful to Sumitomo Pharmaceutical Co., Ltd. (Osaka, Japan), Novo Nordisk Pharmaceuticals, Ltd. (Tokyo, Japan) and Eli Lilly Japan K.K. (Kobe, Japan) for supplying the recombinant human growth hormone used in this study. We also thank Novo Nordisk Pharmaceuticals, Ltd. (Tokyo, Japan) for helping with statistical analyses. The authors wish to thank all the investigators who participated in these studies. References 1. Takano K, Shizume K, Hibi I, Members of the committee for the Treatment of Turner Syndrome. Treatment of 203 patients with Turner syndrome with recombinant human growth hormone for one year: results of a multicentric study in Japan. Acta Endocrinol 1989; 120: Takano K, Shizume K, Hibi I, Members of the Committee for the Treatment of Turner Syndrome. Treatment of 94 patients with Turner syndrome with recombinant human growth hormone (SM 9500) for two years: results of a multicentric study in Japan. Endocrinol Japon 1989; 36: Takano K, Shizume K, Hibi I, Members of the committee for the Treatment of Turner Syndrome. GH treatment in Turner syndrome: the result of a multicentre study in Japan. In: Ranke MB, Rosenfeld RG, editors, Turner syndrome: Growth-promoting therapies. Frankfurt: Elsevier, 1991: Takano K, Shizume K, Hibi I, Members of the committee for the Treatment of Turner Syndrome. Treatment of 46 patients with Turner syndrome with recombinant human growth hormone (YM 17798) for three years: a multicentric study. Acta Endocrinol 1992; 126: Takano K, Ogawa M, Okada Y, Tanaka T, Tachibana K, Hizuka N, the members of the Committee for the Treatment of Turner syndrome. Final height and long-term effects after growth hormone therapy in Turner syndrome: results of a 6-year multicentre study in Japan. In: Albertsson-Wikland K, Ranke K, editors, Proceedings of the 4th International Symposium on Turner syndrome. Elsevier, 1995:

7 Final Height in Patients with Turner Syndrome after Treatment with GH Takano K, Shizume K, Hibi I, Suwa S, Okada Y. Cross-sectional growth study of patients with Turner syndrome. Endocrinol Japon 1988; 35: Rosenfeld RG, on behalf of the Genentech National Cooperative Study Group. Long-term results of GH therapy in Turner syndrome. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elsevier, 1993: Massa G, Otten BJ, de Muinck Keizer-Schramac SMPF, Delemarre-van de Waal HA, Jansen M, Vulsma T, et al. Treatment with two growth hormone regimens in girls with Turner syndrome: final height results. Horm Res 1995; 43: Attanasio A, James D, Reinhardt R, Rekers-Mombarg L. Final height and long-term outcome after growth hormone therapy in Turner syndrome: results of a German multicentre trial. Horm Res 1995; 43: Van den Broeck J, Massa GG, Attanasio A, Matranga A, Chaussain JL, Price DA, et al. Final height after long-term growth hormone treatment in Turner syndrome. J Pediatricus (USA) 1995; 127: Chaussain JL, Gendrel C, Job YC, Ducret JP. Optimization of the dose of growth hormone in girls with Turner syndrome. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elsevier, 1993: Westerlaken CR, Nienhuis HE, Wit JM, Otten BJ, de Muinck Keizer Schrama SMPF, Drayer NM, et al. The effect of four years of growth hormone therapy on body stature and proportions in patients with Turner syndrome. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elseivier, 1993: Nilsson KO, Albertsson-Wikland K, Aronson 5, Gustafsson J, Hagenas L, Hager A, et al. Longterm results of combination treatment with growth hormone, oxandrolone and ethinyl estradiol in girls with Turner syndrome. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elsevier, 1993: Stahnke N, Stubbe P, Attanasio A, Reinhardt D, Partsch CJ, Sippell WG. GH therapy alone or together with oxandrolone in 212 patients with Turner syndrome (TS): the German experience. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elsevier, 1993: Spoudeas HA, Motta RM, Stanhope R, Hindmarsh PC, Brook CGD. Therapeutic options for promoting growth in the Turner syndrome. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elsevier, 1993: Massa G, Vanderschueren-Lodeweyckx M, on behalf of the Belgian Study Group for Pediatric Endocrinology. In: Hibi I, Takano K, editors, Basic and clinical approach to Turner syndrome. Amsterdam: Elsevier, 1993;