Acid
Patdiair Scand [Suppl] 366: 29-30. 1990
Effects of Growth Hormone in Short, Slowiy Growing Children without Growth Hormone Deficiency C.T. COWELL in collaboration with the AUSTRALASIAN PAEDIATRIC ENDOCRINE GROUP From the Row1 Alexandra Hospital for Children Sydnqv. Ausrraliu ABSTRACT. Cowell, C.T. in collaboration with the Australasian Paediatric Study Group. (Royal Alexandra Hospital for Children, Sydney, Australia). Effects o f growth hormone in short, slowly growing children without growth hormone deficiency. Acta Faediatr Scand [Suppl] 366: 29, 1W. The aim o f the study was to measure the real effect o f growth hormone (GH) treatment compared to the effect o f placebo, since a placebo effect has been shown in other studieh involving interventional growth therapy. Changes in height velocity and insulin-like growth factor I (IGF-1). relative to pretreatment variables, were examined during o 12-month, double-blind study.
PATIENTS AN11 METHODS Eight paediatric growth centres in Australia and New Zealand participated in the study. The study involved 104 short, slowly growing children (86 boys, 18 girls) with normal provncative growth hormone (GH) secretion (peak GH > 20 mU/I) and without recognizable dysmorphic o r skeletal disorders. The mean chronological age was 9.7 years (range 3.2-15.5 years). Bone age was less than 10 years in girls and less than 12 years in boys, with a mean bone age delay o f 2.3 years (range 0 . 5 4 . 5 years). Thirty-four per cent o f the children were small in stature and 18% were premature at birth. The mean mid-parental height SDS was low (-1.1: range -3.7 to +1.0), but showed only a weak relation to the child's height SDS at study commencement 1.r = 0.26, p = 0.006). A t entry into the study, the mean height SDS was -3 (range -5.0 to -1.91), mean weight SDS -2.08 (range -3.72 to -0.08), mean height velocity 4.19 cm/year (range 2.24-8.63 cmlyear) and mean height velocity SDS (BA) -2.41 (range -4.72 to -0.16). There were no differences between the randomized groups for pretreatment variables. Randomization to the different treatment groups was stratified for patient numbers at each centre and was carried oul aRer 12 months o f observation. For the firs1 6 months, the children received GH (Genotropin'). 0.6 JU/kg/week ( l o r - d m GH) o r 1.2 IU/kg/weeh (highdose GH). o r placebo. For the following 6 months, all the children received G H at either dose, after which the code was broken. During the study, height imean of three stretched heights) and other auxolqical variables were measured every 3 months. Serum ICF-I levels were measured by radioimmunoassay in one laboratory (R Baxter. Sydney) at 0 , I, 3 and 6 months and &monthly IhereaRer. Bone age (Greulich and Pyle (1)) was measured every 6 months and potential side-effects were monitored every 3-6 month%. RESULTS A total of 102 children completed the first 6 months o f the study: 27 children received placebo, 37 received low-dose G H and 40 received highdose therapy. There was a significanl difference in height velocity between the three treatment groups during the first 6 months: placebo, 5.3 f 1.0 cm/year (mean k SD); low-dose GH, 8.7 f 1.8 cm/year; high-dose GH. 10.8 f 1.8 cmiyear. I n the placebo group, there was a significant increase in height velocit.! (and in height velocity SDS (BA)). but only five children showed catch-up growth 0.e. height velocity SDS (BA) > 0). By contrast, 31 out of 35 children who received lowdose G H and all o f those who received high-dose G H showed catch-up growth. Of the 68 children who completed I2 months o f GH treatment. only two (one from each GH dose group) failed 11) show catch-up growth. There was a strong relationship between the change in height velocity during the first 3 months and that during the first 6 months ( r = 0.81, p < 0.001). with approximately 90% o f height velocity changes during the first 3 months being predictive o f the subsequent growth
ICienotropin. trademark KabiVitrum AB. Sweden. for recombinant somatropin; Cienoronorm in Belgium. France and Spaiii
30
C.T. Cowell et al.
Acta Paediatr Scand [SupplJ 366
response. There was a significant correlation between height velocity response and GH t mtme n t at both doses, and a n inverse correlation between height velocity response and age. There were significant dose-dependent increases in serum IGF-I levels during the first 6 months, with values of 21.9 f 8.9 nmolll in the placebo group, 30.7 f 14.8 nmolll in the iow-dose GH group and 42.9 f 13.7 nmolll in the highdose GH group. When IGF-I levels were expressed as SDS for chronological age, the percentage of children with an SDS greater than +2 after 6 months was 4% in the placebo group, 36% in the lowdose GH group and 56% in the highdose GH group. A strong relationship was seen between height velocity and change in IGF-I levels during the first 6 months ( r = 0.67, p c 0.001). No significant side-effects were observed. There was a significant decrease in free thyroxine index (n = 63) at 6 months !kom a mean of 104 to 98 ( p = 0.002), but there was no significant change in thyroid-stimulating hormone VSH). No child developed biochemical evidence of hypothyroidism.
CONCLUSIONS There was a placebo effect on height velocity, but significant catch-up growth in short, slowly growing children was seen only with GH treatment. The height velocity and IGF-I response to GH was dose-dependent. The best predictor of growth response over 6-12 months was the short-term height velocity response measured at 3 months. Key words: Growth hormone, shod sfature, placebo effect, non-growth hormone-deficient children, insulin-like growth factor 1.
ACKNOWLEDGEMENT This study was supported by Kabi Peptide Hormones. Stockholm, Sweden.
REFERENCE SI. Radiographic atlas of skeletal development of the hand and wrist. California: Stanford University Press, 1959.
1. Greulich WW. Pyle
(C.T.C.) Royal Alexandra Hospital for Children Camperdown 2050 Sydney New South Wales Australia
Patdiair Scand [Suppl] 366: 29-30. 1990
Effects of Growth Hormone in Short, Slowiy Growing Children without Growth Hormone Deficiency C.T. COWELL in collaboration with the AUSTRALASIAN PAEDIATRIC ENDOCRINE GROUP From the Row1 Alexandra Hospital for Children Sydnqv. Ausrraliu ABSTRACT. Cowell, C.T. in collaboration with the Australasian Paediatric Study Group. (Royal Alexandra Hospital for Children, Sydney, Australia). Effects o f growth hormone in short, slowly growing children without growth hormone deficiency. Acta Faediatr Scand [Suppl] 366: 29, 1W. The aim o f the study was to measure the real effect o f growth hormone (GH) treatment compared to the effect o f placebo, since a placebo effect has been shown in other studieh involving interventional growth therapy. Changes in height velocity and insulin-like growth factor I (IGF-1). relative to pretreatment variables, were examined during o 12-month, double-blind study.
PATIENTS AN11 METHODS Eight paediatric growth centres in Australia and New Zealand participated in the study. The study involved 104 short, slowly growing children (86 boys, 18 girls) with normal provncative growth hormone (GH) secretion (peak GH > 20 mU/I) and without recognizable dysmorphic o r skeletal disorders. The mean chronological age was 9.7 years (range 3.2-15.5 years). Bone age was less than 10 years in girls and less than 12 years in boys, with a mean bone age delay o f 2.3 years (range 0 . 5 4 . 5 years). Thirty-four per cent o f the children were small in stature and 18% were premature at birth. The mean mid-parental height SDS was low (-1.1: range -3.7 to +1.0), but showed only a weak relation to the child's height SDS at study commencement 1.r = 0.26, p = 0.006). A t entry into the study, the mean height SDS was -3 (range -5.0 to -1.91), mean weight SDS -2.08 (range -3.72 to -0.08), mean height velocity 4.19 cm/year (range 2.24-8.63 cmlyear) and mean height velocity SDS (BA) -2.41 (range -4.72 to -0.16). There were no differences between the randomized groups for pretreatment variables. Randomization to the different treatment groups was stratified for patient numbers at each centre and was carried oul aRer 12 months o f observation. For the firs1 6 months, the children received GH (Genotropin'). 0.6 JU/kg/week ( l o r - d m GH) o r 1.2 IU/kg/weeh (highdose GH). o r placebo. For the following 6 months, all the children received G H at either dose, after which the code was broken. During the study, height imean of three stretched heights) and other auxolqical variables were measured every 3 months. Serum ICF-I levels were measured by radioimmunoassay in one laboratory (R Baxter. Sydney) at 0 , I, 3 and 6 months and &monthly IhereaRer. Bone age (Greulich and Pyle (1)) was measured every 6 months and potential side-effects were monitored every 3-6 month%. RESULTS A total of 102 children completed the first 6 months o f the study: 27 children received placebo, 37 received low-dose G H and 40 received highdose therapy. There was a significanl difference in height velocity between the three treatment groups during the first 6 months: placebo, 5.3 f 1.0 cm/year (mean k SD); low-dose GH, 8.7 f 1.8 cm/year; high-dose GH. 10.8 f 1.8 cmiyear. I n the placebo group, there was a significant increase in height velocit.! (and in height velocity SDS (BA)). but only five children showed catch-up growth 0.e. height velocity SDS (BA) > 0). By contrast, 31 out of 35 children who received lowdose G H and all o f those who received high-dose G H showed catch-up growth. Of the 68 children who completed I2 months o f GH treatment. only two (one from each GH dose group) failed 11) show catch-up growth. There was a strong relationship between the change in height velocity during the first 3 months and that during the first 6 months ( r = 0.81, p < 0.001). with approximately 90% o f height velocity changes during the first 3 months being predictive o f the subsequent growth
ICienotropin. trademark KabiVitrum AB. Sweden. for recombinant somatropin; Cienoronorm in Belgium. France and Spaiii
30
C.T. Cowell et al.
Acta Paediatr Scand [SupplJ 366
response. There was a significant correlation between height velocity response and GH t mtme n t at both doses, and a n inverse correlation between height velocity response and age. There were significant dose-dependent increases in serum IGF-I levels during the first 6 months, with values of 21.9 f 8.9 nmolll in the placebo group, 30.7 f 14.8 nmolll in the iow-dose GH group and 42.9 f 13.7 nmolll in the highdose GH group. When IGF-I levels were expressed as SDS for chronological age, the percentage of children with an SDS greater than +2 after 6 months was 4% in the placebo group, 36% in the lowdose GH group and 56% in the highdose GH group. A strong relationship was seen between height velocity and change in IGF-I levels during the first 6 months ( r = 0.67, p c 0.001). No significant side-effects were observed. There was a significant decrease in free thyroxine index (n = 63) at 6 months !kom a mean of 104 to 98 ( p = 0.002), but there was no significant change in thyroid-stimulating hormone VSH). No child developed biochemical evidence of hypothyroidism.
CONCLUSIONS There was a placebo effect on height velocity, but significant catch-up growth in short, slowly growing children was seen only with GH treatment. The height velocity and IGF-I response to GH was dose-dependent. The best predictor of growth response over 6-12 months was the short-term height velocity response measured at 3 months. Key words: Growth hormone, shod sfature, placebo effect, non-growth hormone-deficient children, insulin-like growth factor 1.
ACKNOWLEDGEMENT This study was supported by Kabi Peptide Hormones. Stockholm, Sweden.
REFERENCE SI. Radiographic atlas of skeletal development of the hand and wrist. California: Stanford University Press, 1959.
1. Greulich WW. Pyle
(C.T.C.) Royal Alexandra Hospital for Children Camperdown 2050 Sydney New South Wales Australia
