title: Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. Final height of short normal children treated with growth hormone Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. Comparison of final heights of growth hormone-treated vs. untreated children with idiopathic growth failure. Final height after growth hormone therapy in non-growth-hormone-deficient children with short stature. Adult Height in Children with Idiopathic Short Stature Treated with Growth Hormone Final height gain by GH therapy in children with idiopathic short stature is dose dependent. Randomised trial of growth hormone in short normal girls
abstract: GH is often used to treat children with idiopathic short stature despite the lack of definitive , long-term studies of efficacy . We performed a r and omized , double-blind , placebo-controlled trial to determine the effect of GH on adult height in peripubertal children . Subjects ( n = 68 ; 53 males and 15 females ) , 9 - 16 yr old , with marked , idiopathic short stature [ height or predicted height < or = -2.5 sd score ( SDS ) ] received either GH ( 0.074 mg/kg ) or placebo sc three times per week until they were near adult height . At study termination , adult height measurements were available for 33 patients after mean treatment duration of 4.4 yr . Adult height was greater in the GH-treated group ( -1.81 + /- 0.11 SDS , least squares mean + /- sem ) than in the placebo-treated group ( -2.32 + /- 0.17 SDS ) by 0.51 SDS ( 3.7 cm ; P < 0.02 ; 95 % confidence interval , 0.10 - 0.92 SDS ) . A similar GH effect was demonstrated in terms of adult height SDS minus baseline height SDS and adult height SDS minus baseline predicted height SDS . Modified intent-to-treat analysis in 62 patients treated for at least 6 months indicated a similar GH effect on last observed height SDS ( 0.52 SDS ; 3.8 cm ; P < 0.001 ; 95 % confidence interval , 0.22 - 0.82 SDS ) and no important dropout bias . In conclusion , GH treatment increases adult height in peripubertal children with marked idiopathic short stature BACKGROUND Short-term studies have demonstrated acceleration of growth rate following administration of biosynthetic human growth hormone ( r-hGH ) to short normal children . We describe the effect of such treatment on final height . METHODS This was an open study of consecutive referrals to a growth disorder clinic from which 16 short children ( height st and ard deviation score [ SDS ] -2.17 [ range -1.8 to -3.3 ] ; height velocity SDS -0.44 [ 0.33 ] ; peak serum GH response to stimulation 27.9 mU/L [ 9.2 ] were treated with r-hGH , and 7 short children who declined treatment ( height SDS -2.34 [ 0.61 ] ; height velocity SDS -0.36 [ 0.28 ] ; peak serum GH response 28.2 mU/L [ 6.8 ] ) acted as an observation group .  Subcutaneous r-hGH dose ranged between 12.2 and 21.0 U/m2 per week ( 0.02 - 0.04 mg/kg per day ) for the first 2 years of treatment and 20 U/m2 per week thereafter , 3 untreated children were lost to long-term follow-up . FINDINGS r-hGH significantly increased the difference in final height compared with pretreatment predicted height ( + 0.42 SDS [ 0.79 ] , p = 0.03 ) but this change was not significantly greater than that of the observation group ( + 0.16 SDS [ 0.20 ] ) . Treatment had no effect on the timing of puberty . Boys progressed slightly faster through puberty , associated with an acceleration in bone-age maturation . No untoward effects on glucose metabolism were observed . Long-term therapy did not alter body-fat distribution or blood pressure . INTERPRETATION Long-term therapy in this group of children appears safe but the small increment in final height , approximately 2.8 cm in boys and 2.5 cm in girls , does not justify the widespread use of r-hGH for short normal children OBJECTIVES To investigate in an open-label r and omized study , the effect of two doses of growth hormone ( GH ) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature ( mean baseline height st and ard deviation score [ SDS ] -3.2 ) . STUDY DESIGN Patients were treated with GH at 0.24 mg/kg/week , 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter ( 0.24 - ->0.37 ) , or 0.37 mg/kg/week . Final height was evaluated in 50 patients at study completion ( mean treatment duration , 6.5 years ) . RESULTS Patients who received 0.37 mg/kg/week ( n = 72 ) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week ( n = 70 ) ( treatment difference = 0.8 cm/year ; P = .003 ) or 0.24 - ->0.37 mg/kg/week ( n = 67 ) ( treatment difference = 0.9 cm/year ; P = .001 ) . For the 50 patients for whom final height measurements were available , mean height SDS increased by 1.55 , 1.52 , and 1.85 SDS , respectively , for the three dose groups . For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups , the mean treatment difference ( adjusted for differences in baseline predicted height SDS ) was 0.57 SDS ( 3.6 cm ; P = .025 ) . Mean overall height gains ( final height minus baseline predicted height ) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups , respectively , without dose effects on safety parameters . Final height measurements were within the normal adult height range for 94 % of patients r and omized to 0.37 mg/kg/week who continued to final height . CONCLUSION GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature CONTEXT The effect of GH therapy in short non-GH-deficient children , especially those with idiopathic short stature ( ISS ) , has not been clearly established owing to the lack of controlled trials continuing until final height ( FH ) . OBJECTIVE The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children , mainly with ISS , compared with untreated controls . DESIGN AND SETTING A r and omized , controlled , long-term multicenter trial was conducted in Sweden . INTERVENTION Two doses of GH ( Genotropin ) were administered , 33 or 67 microg/kg.d ; control subjects were untreated . SUBJECTS A total of 177 subjects with short stature were enrolled . Of these , 151 were included in the intent to treat ( AllITT ) population , and 108 in the per protocol ( AllPP ) population . Analysis of ISS subjects included 126 children in the ITT ( ISSITT ) population and 68 subjects in the PP ( ISSPP ) population . MAIN OUTCOME MEASURES We measured FH sd score ( SDS ) , difference in SDS to midparenteral height ( diff MPHSDS ) , and gain in heightSDS . RESULTS After 5.9+/-1.1 yr on GH therapy , the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 ( 33 microg/kg.d , -1.7+/-0.70 ; and 67 microg/kg.d , -1.4+/-0.86 ; P<0.032 ) , vs. -2.4+/-0.85 ( P<0.001 ) ; the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 ( P<0.001 ) ; and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 ( P<0.001 ) . GH therapy was safe and had no impact on time to onset of puberty . A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four population s. CONCLUSION GH treatment significantly increased FH in ISS children in a dose-dependent manner , with a mean gain of 1.3 SDS ( 8 cm ) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls We measured adult heights ( Ht ) of 94 healthy GH-sufficient children ( peak GH > 10 ng/mL , polyclonal RIA ) whose Ht at presentation were more than 2 SD below the mean for chronological age , with normal weight-to-Ht ratios , normal body proportions , and pathologic growth velocity for chronological age . Group 1 ( n 36 , 6 females ) received st and ardized doses ( 0.3 mg/kg x week ) of GH ( mean duration = 41 months ) , while group 2 ( n = 58 , 17 females )  received no treatment . Our conclusion was that the mean final Ht SD score in the GH-treated group ( -1.5 ) was significantly greater than in the untreated group ( -2.1 ) ; P < .001 . Genetic predisposition to short stature was evident in both groups : the midparental Ht SD score was -1.1 in the treated and -1.0 in the untreated group . Midparental Ht was met or exceeded by 42 % of the GH-treated group but only 15 % of the untreated group . Final Ht was not significantly different from predicted Ht , except from GH-treated girls , who exceeded their predicted Ht . Although the mean Ht gains ( 6.8 cm in girls and 3 cm in boys ) were modest and variable , GH treatment provided significantly better Ht outcomes for the majority of children with idiopathic growth failure We report the effect of growth hormone ( GH ) treatment for 4 to 10 years in 15 prepubertal non-GH-deficient short children ( 10 boys , 5 girls , aged 7.4 to 13.2 years ) . In 7 patients , GH was administered at a dosage of 0.5 U/kg per week ( group 1 : 4 boys , 3 girls ) and in 8 patients ( group 2 : 6 boys , 2 girls ) at a dosage of 1.0 U/kg per week . After the first year , mean linear growth velocity had significantly increased in both groups . The increase in growth velocity was sustained during the first 4 years and then declined to pretreatment values in the majority of subjects . Treatment with GH did not induce an earlier onset of puberty , but there was a tendency toward faster skeletal maturation . The mean final height st and ard deviation score ( SDS ) was similar in the two groups and was significantly higher than the height SDS for chronologic age before treatment , but it did not differ from mean pretreatment predicted adult height SDS nor from mean target height SDS in both groups . Final height was significantly correlated with target height in both groups . These preliminary observations indicate that GH treatment does not generally increase final height over target height in short non-GH-deficient children Idiopathic short stature ( ISS ) includes a heterogeneous group of patients with common characteristics to those of familial short stature and constitutional delay . Some authors state that these children can often respond to GH treatment , thus increasing their adult height . The aims of this study were to determine the effect of GH treatment ( 0.5 - 0.7 IU/kg/week ) and the influence of some initial variables on adult height in patients with ISS . It was a non-r and omized , observational study of 30 boys with ISS and a historical control group of 42 patients . The patients were followed until achieving their adult height . The mean height gain of the treated group attributable to GH was 4.5 cm . A stepwise regression model considering predicted adult height and target height as independent variables and final height as dependent variable gave an R2 coefficient of 0.38 . We conclude that GH significantly increases final height in boys with ISS Recombinant human GH therapy to children with idiopathic short stature ( ISS ) increases growth velocity , but its effect on final height ( FH ) is still uncertain . The aim of this study was to investigate the effect of recombinant human GH on FH of patients with ISS who were treated according to two protocol s in comparison to untreated historical controls . In study 1 ( n = 24 ) , all patients were treated with 14 IU ( 4.6 mg)/m(2 ) body surface x wk in the first year ; thereafter the dosage was doubled if the growth response was insufficient . In study 2 ( n = 34 ) , patients were r and omized into three arms : 18 IU ( 6 mg)/m(2 ) x wk ; 27 IU ( 9 mg)/m(2 ) x wk ; and 18 IU/m(2 ) x wk in the first year , followed by 27 IU/m(2 ) x wk thereafter .  Observed or estimated FH was available for 53 patients . Thirty-four untreated controls from the same centers were available for comparison . Mean FH SD score in GH-treated children was -2.1 , vs. -2.4 in controls ( -2.4 ) ( NS ) , but height SD score gain ( 1.3 vs. 0.7 ) and the difference between FH and predicted adult height ( 4.0 vs. 0.8 cm ) were significantly greater . The growth response on an initial dosage of 27 IU/m(2 ) x wk ( 6.9 cm ) was significantly better than on other regimens ( 2.8 cm ) . We conclude that a GH dosage of 27 IU ( 9 mg)/m(2 ) x wk to prepubertal children with ISS leads to a mean FH gain of approximately 7 cm , whereas regimens starting on lower dosages are less efficacious BACKGROUND There are few data on the long-term outcome of growth-hormone treatment in short normal children . We assessed the impact of growth-hormone treatment on pubertal development and near-final height in girls . METHODS In a r and omised controlled trial , we studied ten girls , with a mean age of 8.07 years and height 2 SDs or more below the mean for their age , and eight short untreated controls matched for age , and 20 short untreated girls who did not give consent for r and omisation . The girls received either 30 IU/m2 somatropin per week as daily subcutaneous injections or no treatment . We assessed pubertal staging and height gain every 6 months . FINDINGS Eight treated girls completed a mean of 6.2 years ' therapy . By a mean age of 16.4 years , their mean height SD score had changed significantly from -2.42 to -1.14 ( p=0.008 ) and they were , on average , 7.5 cm taller than the girls in the control group ( height SD scores did not change significantly from -2.55 ) and 6.0 cm taller than the non-consent group . The timing of each pubertal stage , and the age and amplitude of peak height velocity were similar for all groups . INTERPRETATION Growth-hormone therapy effectively increased height SD score among short normal girls started on treatment in early to mid childhood , with no untoward effect on pubertal progression
target: CONCLUSIONS Growth hormone therapy in children with idiopathic short stature seems to be effective in partially reducing the deficit in height as adults , although the magnitude of effectiveness is on average less than that achieved in other conditions for which growth hormone is licensed .
background: OBJECTIVE To systematic ally determine the impact of growth hormone therapy on adult height of children with idiopathic short stature .