Original. Tsuyoshi Isojima 1), 2), 3), Tomonobu Hasegawa 1), 4), Susumu Yokoya 1), 5) 1), 6) and Toshiaki Tanaka

Transcription

1 2017, 64 (9), Original The response to growth hormone treatment in prepubertal children with growth hormone deficiency in Japan: Comparing three consecutive years of treatment data of The Foundation for Growth Science in Japan between the 1990s and 2000s Tsuyoshi Isojima 1), 2), 3), Tomonobu Hasegawa 1), 4), Susumu Yokoya 1), 5) 1), 6) and Toshiaki Tanaka 1) Growth Hormone (GH) and its related Factors Study Committee and GH Treatment Study Committee, The Foundation for Growth Science in Japan, Tokyo, Japan 2) Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 3) Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan 4) Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan 5) Department of Medical Subspecialties, National Center for Child Health and Development, Tokyo, Japan 6) Tanaka Growth Clinic, Tokyo, Japan Abstract. Growth hormone (GH) treatment for children with GH deficiency (GHD) is effective in improving adult height. To achieve favorable effects, GH treatment before puberty is very important, because prepubertal height gain is highly correlated with total height gain. However, no report has studied the effects by analyzing a nationwide data from recent GHD patients in Japan. We investigated the response to GH treatment using data compiled in the Foundation for Growth Science in Japan, and compared the effects between the 1990s and 2000s using analysis of covariance. We analyzed 534 prepubertal GHD subjects treated in the 2000s with three consecutive years of data from the start and investigated predictive factors for the effects. The cumulative height standard deviation score (SDS) change over three years of GH treatment was 0.91 ± 0.57 and 1.20 ± 0.62 in the 1990s and 2000s, respectively. Subjects in the 2000s were divided into three groups by severity, and the cumulative height SDS was 1.60 ± 0.93, 1.20 ± 0.54, and 1.00 ± 0.40 indicating severe, moderate, and mild GHD, respectively. Age and height SDS at the start and severity were identified as independent predictive factors. We also found a significant difference in the effects between the two cohorts after adjusting for the different factors (regression coefficient: 0.069, 95% confidence interval: 0.11 to 0.030, p = ), which might be due to the GH dose effect. We conclude that the effects of GH treatment in the 2000s had improved compared with those in the 1990s. Key words: Growth hormone, Growth hormone deficiency, Prepubertal children, Nationwide cohort GROWTH HORMONE (GH) treatment for children with GH deficiency (GHD) is effective in improving adult height (AH) [1-7]. The mean AH standard deviation score (SDS) of patients with GHD was reported to be approximately 1.0 according to the GH treatment guideline from the Pediatric Endocrine Society, which collected data from more than 4,250 patients [2], whereas the mean AH SDS of untreated patients with idiopathic GHD was reported to be 4.7, ranging Submitted Feb. 10, 2017; Accepted May 8, 2017 as EJ Released online in J-STAGE as advance publication Jul. 4, 2017 Correspondence to: Tsuyoshi Isojima, M.D., Ph.D., Department of Pediatrics, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo , Japan. isojimat-tky@umin.ac.jp The Japan Endocrine Society from 3.9 to 6 [8]. In contrast, an analysis from the Pfizer International Growth Study (KIGS) on 374 patients with idiopathic GHD showed that the AH of Japanese patients with GHD after GH treatment was cm ( 1.8 SD) in males and cm ( 2.2 SD) in females [5]. Similarly, from the database compiled in the Foundation for Growth Science in Japan (FGS), the mean AH of individuals with GHD after GH treatment was cm ( 1.8 SD) in males and cm Abbreviations: GH, Growth hormone; GHD, Growth hormone deficiency; AH, Adult height; SDS, Standard deviation score; KIGS, Pfizer International Growth Study; FGS, Foundation of Growth Science in Japan; TS, Turner syndrome; IGF-1, Insulinlike growth factor 1; BMI, Body mass index; GV, Growth velocity; ANCOVA, Analysis of covariance.

2 852 Isojima et al. ( 1.9 SD) in females [9]. The reported AH SDS of individuals with GHD after GH treatment in Japan is insufficient compared to those in foreign countries. To achieve favorable effects from GH treatment in patients with GHD, treatment before pubertal onset is very important, because prepubertal height gain is highly correlated with total height gain [4]. Tanaka et al. reported that the treatment effect was greater in younger rather than older groups in Japan by analyzing the data of prepubertal children with GHD treated in the 1990s from the FGS database [10]. They also showed that the accumulated gain of height SDS in the first three years was approximately 0.85 [10]. However, after the year 2000, there have been no reports about the effects of GH treatment using a large number of nationwide data. Therefore, clarifying the effects of GH treatment should be vital for recent prepubertal patients with GHD in Japan. In addition, a standardized unit for GH preparation was introduced in Japan by the year 2000 in accordance with the recommendation of international standards for GH [11]. In the recommendation, 3 IU was defined to be equivalent to 1 mg. Thereafter, the GH dose for GHD treatment in Japan was modified from 0.5 IU/kg/week (approximately mg/kg/week) to mg/kg/week. Thus, there may be a difference in the effects of GH treatment between the 1990s and 2000s. In this study, we first investigated the effects of GH treatment on prepubertal Japanese children with GHD in the 2000s and clarified the pretreatment factors that affect the effects of GH treatment using the data compiled in the FGS. Then, we compared these results to those in the 1990s [10] to elucidate the different effects of GH treatment during the two decades ( ) in Japan. Methods Subjects The subjects were obtained from a retrospective cohort. The FGS has been monitoring the use of GH through its registration system and determines the candidates eligibility for GH treatment according to the diagnostic criteria for GHD, Turner syndrome (TS), and other pertinent disorders [12]. Physicians are encouraged to register each candidate for GH treatment at the FGS using an application form that includes the following information: the candidates pre-treatment anthropometric measurements, parents heights, results of GH stimulation tests, serum concentrations of insulin-like growth factor 1 (IGF-1), thyroid function, bone age, complications, history of the neonatal period, karyotypes (in the case of TS), presence or absence of puberty, and evidence of informed consent from each subject regarding the use of the data for scientific purposes. After the FGS recommends GH treatment, they are also encouraged to report the response to GH treatment, including anthropometric measurements, GH treatment doses, presence or absence of puberty, adverse events, and evidence of informed consent from each subject regarding the use of the data for scientific purposes. Between 2001 and 2010, 9,426 subjects were registered to have GHD in this cohort, while 9,350 subjects were determined to be eligible for GH treatment. The subjects diagnosis was confirmed by reviewing application forms according to the criteria established by the Study Group of Hypothalamo-Pituitary Disorder of the Ministry of Health, Labour and Welfare [13]. Subjects with a history of preceding treatment that affects their growth were excluded. After excluding 117 patients because of their use of anabolic steroids (28 subjects), gonadotropin releasing hormone analogues (82 subjects), both anabolic steroid and gonadotropin releasing hormone analogues (3 subjects) and oral steroids (4 subjects), 9,233 subjects were enrolled in this study. These subjects constituted approximately 30% 40% of all patients with GHD treated with GH in Japan, according to data compiled in the Medical Aid Program for Chronic Pediatric Diseases of Specified Categories in Japan [14]. These inclusion criteria were identical to the previous study [10]. From these subjects, we determined those with three consecutive years of data from the start of GH treatment, which were measured at less than 9 years of age in accordance with a previous method [10]. This was done to investigate the effects of GH treatment in prepubertal children and compare these effects to those in the 1990s. Data for 1 year of treatment were defined as those measured between 0.5 and 1.5 years after the start of GH treatment. Similarly, data for 2 and 3 years of treatment were defined as those measured between 1.5 and 2.5 years and 2.5 and 3.5 years, respectively. Finally, we could analyze all three consecutive years of data in 534 subjects (329 males and 205 females). According to the GHD criteria established by the Study Group of Hypothalamo-Pituitary Disorder of the Ministry of Health, Labour and Welfare [13], patients

3 Effect of GH treatment on GHD in Japan 853 with GHD are classified into three groups depending on the results of their GH provocation tests. Those with maximum peak GH levels equal to or less than 3 μg/l are classified into severe GHD. Those with maximum peak GH levels equal to or less than 6 μg/l, except for those with severe GHD, are classified into moderate GHD. Those with maximum peak GH levels more than 6 μg/l but have at least two peak GH levels equal to or less than 6 μg/l are classified into mild GHD. We then classified our subjects into three groups by these criteria (i.e., severe GHD: 80, moderate GHD: 351, and mild GHD: 103). Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Growth velocity (GV) was calculated as the annual height difference between two longitudinal measurements. Target height was calculated using a formula tailored for the Japanese [15]. Methods We calculated height, weight, and BMI SDSs using Japanese standards for normal children by sex and age [16-18]. We also calculated IGF-1 SDSs using Japanese standards [19]. Using these data, we analyzed the responses to GH treatment by calculating cumulative changes in height SDS from baseline and GV in each year and compared these data to those in the 1990s, which had been analyzed in the same way and compiled in the FGS cohort [10]. Analyses were also performed according to the severity of GHD. In addition, we performed a multiple linear regression analysis to investigate factors that affect cumulative changes in height SDS following three years of treatment. We conducted this analysis for detecting predicting factors for the effects. A similar multiple linear regression analysis was also performed on patients with moderate and mild GHD, because they received the most number of treatments from Japanese clinics. In addition, the absence of differences in clinical factors, such as pretreatment GV and growth response to GH treatment, between moderate and mild GHD had been reported [20]. Finally, to elucidate the difference in the effects of GH treatment during the two decades, we compared cumulative changes in height SDS between the two cohorts (i.e., 1990s and 2000s) using analysis of covariance (ANCOVA). This study was performed with approval from the Ethics Committee of the University of Tokyo (approval number: ). Statistical analyses The results are expressed as means ± SD or frequencies and percentages. A univariate comparison was made using Student s t-test for continuous variables and chi-square test or Fisher s exact test for discrete variables. Then, factors affecting changes in height SDS over three years of treatment were investigated using multiple linear regression analyses, with changes in height SDS as the dependent variable and potential pretherapeutic predictors as independent variables. The effects of GH treatment between the two cohorts (i.e., 1990s and 2000s) were compared for changes in height SDS over three years of treatment using ANCOVA, with covariates that included age at the start of GH treatment, height SDS at the start of GH treatment, severity of GHD, target height SDS, and interaction between these factors and each cohort. All analyses were performed using JMP 12 (SAS Institute Inc., Cary, NC, USA), and p values <0.05 were considered statistically significant. Results Table 1 shows the baseline demographic data of the subjects in the 1990s [10] and 2000s. Age, height, and height SDS were significantly smaller in the 2000s than in the 1990s, whereas the proportion of severe GHD was larger in the 2000s than in the 1990s. These results may be mainly due to the revision of the criteria for Japanese Medical Aid Program for GHD. The cut-off values of height SDS for medical aid in GHD had been changed from 2 SDS to 2.5 SDS in Therefore, mild GHD with a height SDS of 2 to 2.5 had to pay 30% of medical charges, which led to a reduction in the number of patients with mild GHD receiving GH treatment [21]. In fact, the numbers of patients with severe and moderate GHD were similar in the two cohorts (Table 1). Table 2 shows the cumulative height SDS changes and GVs after GH treatment. Both cumulative height SDS changes and GVs were higher in the 2000s than in the 1990s in all three years. Cumulative height SDS changes over three years of GH treatment were 0.91 ± 0.57 and 1.20 ± 0.62 in the 1990s and 2000s, respectively (p < ). Table 3 shows the GH treatment effects according to the severity of GHD. We note that none of the effects of GH treatment for patients with severe GHD were significantly different between the 1990s and 2000s, except for GV after the first year of

4 854 Isojima et al. Table 1 Baseline demographic data of the subjects in the 1990s and 2000s analyzed in this study 1990s 2000s p value Number of subjects Male (%) 663 (66.4%) 329 (61.6%) Father s height (cm) ± ± 5.6 (n = 488) 0.22 Mother s height (cm) ± ± 5.1 (n = 492) Target height SDS 0.81 ± 0.73 (n = 976) 0.72 ± 0.69 (n = 488) Age* 4.8 ± ± 1.07 < Height* (cm) 93.6 ± ± 7.55 < Height SDS* 2.62 ± ± 0.75 < Weight* (kg) 13.4 ± ± 2.2 < BMI* (kg/m 2 ) 15.3 ± ± BMI SDS* ND ± 1.1 Initial GH dose* 0.43 ± 0.14 IU/kg/week (0.14 ± mg/kg/week**) (n = 796) 0.17 ± mg/kg/week (n = 436) <0.0001** IGF-1* (ng/ml) 68.2 ± ± 38.8 (n = 489) 0.40 IGF-1SDS* ND 1.01 ± 1.09 (n = 489) Severity of GHD (severe, moderate, mild) (%) 54/327/526 (6.0%/36.0%/58.0%) 80/351/103 (15.0%/65.7%/19.3%) < Idiopathic GHD /Organic GHD ND 493/41 Growth velocity* (cm/year) 5.3 ± ± The data from the 1990s were extracted and added to those analyzed in a previous study [10]. ND indicates not described. *: These data indicate those at the start of GH treatment. **: The data were compared after converting IU to mg based on the definition that 3 IU was equivalent to1 mg. Table 2 Cumulative height SDS changes and growth velocity during the first three years of GH treatment Cumulative height SDS changes from the start of treatment Growth velocity (cm/year) Years of treatment 1990s 2000s p value 1 year 0.51 ± ± 0.50 < years 0.76 ± ± 0.57 < years 0.91 ± ± 0.62 < year 8.6 ± ± 2.0 < years 6.9 ± ± years 6.2 ± ± Table 3 Cumulative height SDS changes and growth velocity during the first three years of GH treatment according to the severity of GHD Years of treatment Severity 1990s 2000s p value Severe 1.00 ± ± year Moderate 0.52 ± ± 0.44 < Cumulative height SDS changes from the start of treatment Growth velocity (cm/year) 2 years 3 years 1 year 2 years 3 years Mild 0.44 ± ± 0.34 < Severe 1.30 ± ± Moderate 0.75 ± ± 0.51 < Mild 0.69 ± ± Severe 1.50 ± ± Moderate 0.89 ± ± 0.54 < Mild 0.82 ± ± 0.40 < Severe 9.6 ± ± Moderate 8.3 ± ± 1.8 < Mild 8.7 ± ± Severe 7.2 ± ± Moderate 6.7 ± ± Mild 6.9 ± ± Severe 6.3 ± ± Moderate 6.1 ± ± Mild 6.1 ± ±

5 Effect of GH treatment on GHD in Japan 855 treatment. Cumulative height SDS changes over three years from the start of treatment in the 2000s were 1.60 ± 0.93, 1.20 ± 0.54, and 1.00 ± 0.40 in severe, moderate, and mild GHD, respectively. Table 4 summarizes the multiple regression analysis for the cumulative height SDS changes over three years using data from all patients with GHD. We extracted nine factors (age at the start of GH treatment, height SDS at the start of GH treatment, severity of GHD, IGF-1 SDS at the start of GH treatment, dose at the start of GH treatment, target height SDS, ratio of bone age over chronological age, gestational week, and birth length) after conducting univariate analyses and considering multi-colinearities among factors. Among these factors, age at the start of GH treatment, height SDS at the start of GH treatment, and severe GHD were identified as independent predictive factors for the cumulative height SDS changes following three years of GH treatment. Next, we performed a similar analysis using subjects with moderate and mild GHD, because they received the most number of treatments (Table 5). In this analysis, age at the start of GH treatment, height SDS at the start of GH treatment, and target height SDS were identified as independent predictive factors for the cumulative height SDS changes after three years of GH treatment. When the same analysis was performed using subjects with moderate GHD, similar results were found. Finally, we compared the cumulative height SDS changes over three years of GH treatment in the 2000s to those in the 1990s after adjusting for all different and predictive factors in the demographic data between the two cohorts (Tables 1 and 4). We found that there was a significant difference in the GH treatment effects between the 1990s and 2000s (regression coefficient: 0.069, 95% confidence interval (CI): 0.11 to 0.030, p = ). Table 4 Multiple regression analysis of the cumulative height SDS changes in three years for all patients with GHD on prognostic factors n=343 Estimated coefficient Standard error β T value p value VIF Intercept Age at the start of GH treatment < Height SDS at the start of GH treatment Severe GHD IGF-1 SDS at the start of GH treatment Dose at the start of GH treatment (mg/kg/week) Target height SDS Ratio of bone age over chronological age at the start of treatment (%) Gestational week Birth length Table 5 Multiple regression analysis of the cumulative height SDS changes in three years for patients with moderate and mild GHD on prognostic factors n=297 Estimated coefficient Standard error β T value p value VIF Intercept Age at the start of GH treatment < Height SDS at the start of GH treatment IGF-1 SDS at the start of GH treatment Dose at the start of GH treatment (mg/kg/week) Target height SDS Ratio of bone age over chronological age at the start of treatment (%) Gestational week Birth length

6 856 Isojima et al. Discussion In this study, we found a small but statistically significant difference in the effects of GH treatment between the 1990s and 2000s after adjusting for all predictive factors including severity of GHD in the demographic data between the two decades properly (regression coefficient: 0.069, 95% CI: 0.11 to 0.030, p = ). Although the reason for this difference is unclear, we were able to speculate two reasons. The first one is the effect of GH unit standardization in the year 2000 [11]. In Japan, GH dose for GHD treatment was modified from 0.5 IU/kg/week (approximately mg/ kg/week) to mg/kg/week in the year 2000, which means that the prescribed dose was virtually a little higher than that in the 1990s. In addition, the actual average activity of GH was reported to be 3.40 IU/mg in an international consensus [22], which implies the possibility that less GH doses had been administered in the 1990s. Moreover, the reported average GH dose in the 1990s was 0.43 ± 0.14 IU/kg/week. Therefore, the difference in GH treatment effects between the two cohorts might be due to the GH dose effect. The second one is that treatment adherence may have been improved over these periods. Treatment adherence is very important for an optimal growth response [23-25]. Over the years, several new user-friendly injection devices for GH treatment have been introduced. Although we could not confirm the effect of treatment adherence because the FGS does not include data on such, favorable progress in medical devices might have contributed to the improvement in the effects of GH treatment. We clarified the actual response to GH treatment in prepubertal children with GHD treated in Japan in the 2000s and found that the effects had improved compared with those in the 1990s using nationwide data compiled in the FGS (Tables 2 and 3). By analyzing the growth data from the KIGS on prepubertal children, Ranke et al. [26] reported that mean (SD) changes in height SDS during the first and the second years of treatment for children with severe GHD were 1.11 (0.69) and 0.54 (0.39), respectively, when GH treatment was started at the mean (SD) age of 6.44 (3.12). They also reported that mean (SD) changes in height SDS during the first and the second years of treatment for those with moderate GHD were 0.74 (0.43) and 0.39 (0.27), respectively, when GH treatment was started at the mean (SD) age of 6.86 (2.54). From the Belgian Register for the Study of Growth and Puberty Problems [27], Straetemans et al. reported that the observed mean (SD) height SDS change after the first year of treatment was 0.91 (0.59) when GH treatment was started at the mean (SD) age of 6.6 (3.0). Although it is difficult to compare our results with those in foreign countries precisely because of the difference in GH treatment doses and/or methodology for collecting prepubertal children s data, our data suggested that the effects of GH treatment for prepubertal children with GHD in the 2000s may catch up with those in foreign countries. We also found that age at the start of GH treatment, height SDS at the start of GH treatment, and severe GHD were predictive factors for accumulated height SDS after three years of GH treatment (Table 4). These factors were also reported as predictive factors for early growth response to GH [27]. This result indicated that the treatment of patients with severe GHD who have lower height SDS should start as early as possible for better three-year prepubertal growth responses. When we performed the analysis on subjects with moderate and mild GHD after excluding those with severe GHD, target height SDS was also determined as a predictive factor in addition to age and height SDS at the start of GH treatment. This result suggested that we should also look out for a difference between height SDS and parental height for better short-term growth outcome in typical clinical practices. In contrast, an initial GH dose was not selected in these analyses, although several studies showed a significant positive effect of an initial GH dose on short-term growth response [28-30]. In Japan, the dose for GH treatment has been fixed at mg/ kg/day since the year Therefore, we speculated that an initial GH dose with minimal difference among subjects might not affect the growth response. It is difficult to show the relationship between short-term growth response and an initial GH dose in this retrospective cohort. We think that a prospective randomized controlled trial should be vital in cases where the influence of an initial GH dose on the GH treatment effect needs to be clarified. This study has several limitations. First, there is a certain selection bias in this study. Given that it is not compulsory for physicians to register their patients in the FGS, subjects analyzed in this study might not be exactly representative of Japanese patients with GHD. However, the FGS contains approximately 30% 40%

7 Effect of GH treatment on GHD in Japan 857 of all patients with GHD who were treated with GH and is the biggest cohort in Japan, including data on patients with GH treatment. Moreover, we were able to elucidate the secular trend of the effects of GH treatment between the 1990s and 2000s, because we analyzed the data from the same FGS cohort using the same method for selecting patients. Secondly, the precise dose for patients treated in the 1990s was not available in this study. Although we found a significant difference in the response to GH treatment between the two cohorts while adjusting for other predictive factors, the reason for this difference was not clear. Other factors may have caused this difference aside from the GH dose effect and improved treatment adherence speculated. Finally, our method for selecting prepubertal patients was not based on physical examination but on age. In the application form of the FGS, there is a portion that allows for the description of the presence of puberty, but some of these portions had been left out. Thus, we selected prepubertal subjects based on age after three years of GH treatment in accordance with a previous method [10]. Therefore, the average age at the start of GH treatment was lower than that in other studies investigating the effect of GH treatment on prepubertal children [26, 27]. This means that our results might overestimate the recent effects of GH treatment on prepubertal children. However, this study provides evidence that the effects of GH treatment had improved after standardization of the GH unit. In conclusion, the effects of GH treatment in the 2000s had improved compared with those in the 1990s. In addition, we elucidated the effects of GH treatment on prepubertal children with GHD in the 2000s. Acknowledgments We wish to thank all the patients and physicians for the registration into this retrospective cohort. Conflict of Interest Statement The authors declare that there are no conflicts of interest. References 1. Murray PG, Dattani MT, Clayton PE (2016) Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence. Arch Dis Child 101: Grimberg A, Divall SA, Polychronakos C, Allen DB, Cohen LE, et al. (2016) Guidelines for growth hormone and insulin-like growth factor-i treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-i deficiency. Horm Res Paediatr 86: Alatzoglou KS, Webb EA, Le Tissier P, Dattani MT (2014) Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances. Endocr Rev 35: Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB (2006) Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab 91: Fujieda K, Tanaka T, Takano K, Chihara K, Seino Y, et al. (2011) Adult height after growth hormone treatment in Japanese children with idiopathic growth hormone deficiency: analysis from the KIGS Japan database. J Pediatr Endocrinol Metab 24: Rachmiel M, Rota V, Atenafu E, Daneman D, Hamilton J (2007) Final height in children with idiopathic growth hormone deficiency treated with a fixed dose of recombinant growth hormone. Horm Res 68: Blethen SL, Baptista J, Kuntze J, Foley T, LaFranchi S, et al. (1997) Adult height in growth hormone (GH)- deficient children treated with biosynthetic GH. The Genentech Growth Study Group. J Clin Endocrinol Metab 82: Wit JM, Kamp GA, Rikken B (1996) Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature. Pediatr Res 39: Tanaka T, Fujieda K, Hanew K, Nishi Y, Tachibana K, et al. (2001) Normalization of final height after recombinant human growth hormone (GH) treatment in GH-treated short children. Jpn J Pediatr Soc 105: (In Japanese). 10. Tanaka T, Ito J, Kanzaki S, Shimatsu A, Tanaka H, et al. (2010) The effect of growth hormone (GH) therapy in prepubertal short children with GH deficiency. J Jpn Ass Hum Auxo 16: (In Japanese). 11. Bristow AF (1999) International standards for growth hormone. Horm Res 51 Suppl 1: Tanaka T, Takano K, Hanew K, Nishi Y, Igarashi Y, et al. (1998) Registration system for growth hormone

8 858 Isojima et al. (GH) treatment with standardized immunoreactive GH values in Japan. Endocr J 45: Research Study Group on the Hypothalamo-Pituitary Dysfunction, the Ministry of Health, Labor and Welfare, Japan. Guidelines for the diagnosis and treatment of growth hormone deficient short stature. Available at: Accessed April 20, 2017 (In Japanese). 14. Information center for specific pediatric chronic diseases in Japan. Accessed Feb 9, 2017 (In Japanese). 15. Ogata T, Tanaka T, Kagami M (2007) Target height and target range for the Japanese children: revisited. Clin Pediatr Endocrinol 16: Tanaka T, Yokoya S, Kato N, Ito Y, Tachibana K, et al. (2011) Fundamental policies on evaluating auxological data for Japanese children. J Jpn Ass Hum Auxo 17: (In Japanese). 17. Isojima T, Kato N, Ito Y, Kanzaki S, Murata M (2016) Growth standard charts for Japanese children with mean and standard deviation (SD) values based on the year 2000 national survey. Clin Pediatr Endocrinol 25: Kato N, Takimoto H, Sudo N (2011) The cubic functions for spline smoothed L, S and M values for BMI reference data of Japanese children. Clin Pediatr Endocrinol 20: Isojima T, Shimatsu A, Yokoya S, Chihara K, Tanaka T, et al. (2012) Standardized centile curves and reference intervals of serum insulin-like growth factor-i (IGF-I) levels in a normal Japanese population using the LMS method. Endocr J 59: Tanaka T (1991) Growth hormone secretion and the therapeutic effects of human growth hormone: first Japanese results of the Kabi Pharmacia International Growth Study/International Cooperative Growth Study. Acta Paediatr Scand Suppl 379: Yokoya S, Tanaka T (2017) The history of growth hormone treatment for GHD in Japan. Ped Endocrinol Rev 14 Suppl 1: Bristow AF, Gaines-Das R, Jeffcoate SL, Schulster D (1995) The first international standard for Somatropin: report of an international collaborative study. Growth Regul 5: Kapoor RR, Burke SA, Sparrow SE, Hughes IA, Dunger DB, et al. (2008) Monitoring of concordance in growth hormone therapy. Arch Dis Child 93: Cutfield WS, Derraik JG, Gunn AJ, Reid K, Delany T, et al. (2011) Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One 6: e Hartmann K, Ittner J, Müller-Rossberg E, Schönau E, Stephan R, et al. (2013) Growth hormone treatment adherence in prepubertal and pubertal children with different growth disorders. Horm Res Paediatr 80: Ranke MB, Lindberg A (2010) Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metab 95: Straetemans S, Roelants M, Thomas M, Rooman R, De Schepper J (2014) Reference curve for the firstyear growth response to growth hormone treatment in prepubertal children with idiopathic growth hormone deficiency: validation of the KIGS first-year growth response curve using the Belgian Register for the Study of Growth and Puberty Problems. Horm Res Paediatr 81: Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, et al. (1999) Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study. J Clin Endocrinol Metab 84: Cohen P, Bright GM, Rogol AD, Kappelgaard AM, Rosenfeld RG, et al. (2002) Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab 87: De Muinck Keizer-Schrama S, Rikken B, Hokken- Koelega A, Wit JM, Drop S (1994) Comparative effect of two doses of growth hormone for growth hormone deficiency. The Dutch Growth Hormone Working Group. Arch Dis Child 71: