Adult Height in Children with Idiopathic Short Stature Treated with Growth Hormone The Basis for Optimising Growth with Growth Hormone Usage in Children with Idiopathic Short Stature: Analysis of Data from KIGS (Pfizer International Growth Study Database) Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. Genentech Collaborative Study Group. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. Safety of Growth Hormone Treatment of Children with Idiopathic Short Stature: The US Experience Quality of life and self-esteem in children treated for idiopathic short stature. Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy. Once versus twice daily injections of growth hormone in children with idiopathic short stature Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. High‐dose growth hormone therapy for short children born small for gestational age Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. Recombinant human growth hormone in short children born small for gestational age. German Study Group.
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 Many children with idiopathic short stature ( ISS ) remain short as adults . Height can be improved permanently by growth hormone ( GH ) treatment , as in children with Turner syndrome or born small for gestational age . Although GH treatment for ISS is an approved indication in the United States , there is ongoing controversy in Europe about approving GH treatment for this indication as well as determining the optimal mode of treatment . In addition to data from r and omized controlled trials , data from pharmacoepidemiological surveys such as the Pfizer International Growth Study Data base ( KIGS ) have provided substantial information about the short-term and long-term effects of GH on growth and adult height in children with ISS . Based on published articles and a recent survey from KIGS on 454 patients who have reached adult height , we attempted to categorize those children with ISS who have the greatest chances of achieving a normal adult height , or at least gain the most height following GH treatment . This analysis provides a rational basis for discussion about the most efficacious and cost-effective uses of GH treatment in children with ISS A multicenter r and omized trial of human growth hormone treatment was carried out in 121 children with short stature who did not meet the classic criteria for growth hormone deficiency . Patients treated for 1 year with recombinant somatropin , 0.1 mg/kg three times a week , had a significant increase in mean growth rate from 4.6 + /- 1.1 to 7.5 + /- 1.2 cm/yr , whereas untreated children 's growth rate did not change significantly ( 4.2 + /- 1.3 vs 5.0 + /- 1.4 cm/yr ) . There was a 1-year advance in bone age for each group ; thus there was a significant increase in the predicted height of the treated but not the control group . Among the treated children , the growth response did not differ among those classified on the basis of parental height and bone age as having familial short stature or constitutional delay of growth and development . Pre study anthropomorphic features were not related to subsequent growth in either the treated or control groups . The baseline plasma insulin-like growth factor I concentration was inversely related to the growth response to growth hormone treatment ( r = -0.50 , p = 0.0003 ) . By contrast , the serum growth hormone concentration measured in sample s obtained at 20-minute intervals for 12 or 24 hours or after clonidine administration did not predict the future growth rate . There were no side effects of growth hormone treatment . The results suggest that children who have significant short stature and slow growth may benefit from a trial of growth hormone therapy 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 A total of 130 short children were included in a French multicentre study and r and omized between a control group ( group A ) and two groups treated with daily subcutaneous injections of GH at doses of 0.7 IU/kg/week ( group B ) and 1.4 IU/kg/week ( group C ) for 2 years . Height velocity was significantly increased ( p<0.0005 ) in groups B and C , with a greater increase in group C than in group B ( p < 0.001 ) . The benefit after 2 years compared with controls was 4.3 cm in group B and 5.9 cm in group C. The rate of bone maturation was not affected by GH therapy . These results led to the conclusion that 2 years of treatment with GH improves final height prognosis in children with short stature secondary to IUGR , and that this effect is dose dependent . The effect on final height has still to be demonstrated 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 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 Recombinant human growth hormone ( rhGH ) is approved in the United States for treatment of idiopathic short stature ( ISS ) . The occurrence of adverse events ( AEs ) and the long-term safety of rhGH treatment in this patient population are review ed . Data were analyzed from postmarketing surveillance studies that included ISS patients , prospect i ve ISS treatment trials and studies of specific AEs in smaller groups of rhGH-treated children . Frequency rates of targeted AEs ( i.e. , scoliosis , slipped capital femoral epiphysis , intracranial hypertension , pancreatitis ) in patients with ISS are similar to or lower than the rates observed in other rhGH-treated conditions . At dosages of 0.24–0.37 mg/kg/week , rhGH treatment in children with ISS does not adversely affect blood glucose levels . At dosages ≧0.3 mg/kg/week , a dose-dependent increase in mean fasting and stimulated insulin levels is observed . Current evidence derived from ‘ on-treatment ’ surveillance studies suggests that rhGH does not increase the risk for new malignancies in children with ISS.The  safety profile  of rhGH at doses ≤0.37 mg/kg/week for the treatment of children with ISS is similar to or better than the profile seen in other rhGH-treated conditions and is not associated with any predictable AEs . Due to a continuing trend toward dose escalation to achieve greater height-promoting effects and the possibility of delayed post-treatment effects of hyperinsulinemia and /or heightened GH and insulin-like growth factor I exposure on cancer risk , caution and ongoing scrutiny of risks versus benefits are warranted OBJECTIVE Changes in health-related quality of life ( HRQOL ) and self-esteem were studied in children with idiopathic short stature ( ISS ) participating in a study on the effect of growth hormone treatment .  STUDY DESIGN Prepubertal children ( n = 36 ) with ISS were r and omly assigned to a treatment or control group .  Children with ISS , their parents , and the pediatrician completed  HRQOL and self-esteem question naires 3 times in 2 years . RESULTS At the start , children with ISS did not have lower scores than the norm population , except for social functioning HRQOL . The pediatrician reported an improvement of HRQOL in the treatment group , the parents reported no change , and the children in the treatment group reported the same , or sometimes even worse , HRQOL or self-esteem than the control group . Changes related to the child 's satisfaction with height and hardly to growth itself . CONCLUSION The assumption that growth hormone treatment improves HRQOL in children with ISS could not be supported in this study Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height . It is yet unknown whether therapy would alter pubertal development or affect final height . Three-year treatment results in a group of children with idiopathic short stature are reported . For year 1 of the study , 121 prepubertal children were r and omly selected to receive somatotropin , 0.3 mg/kg per week , administered subcutaneously three times weekly ( n = 63 ) , or to be nontreatment control subjects ( n = 58 ) . After 1 year , all subjects were again r and omly selected to receive either three-times-weekly or daily dosing at the same total dose . For the 92 subjects who completed 36 months of treatment , mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment . Daily dosing result ed in a significantly faster mean growth rate ( 9.0 cm/yr ) than three-times-weekly dosing ( 7.8 cm/yr ) ( p = 0.0005 ) . Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3 , respectively , and did not differ by dosing group . Mean st and ardized height for all subjects improved from -2.7 to -1.6 after 3 years . When the growth rate was st and ardized for bone age , however , subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period ( p < 0.02 ) . Mean st and ardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset , but for individuals this score was more variable . Year-1 growth response , expressed as growth rate or change in height SD score , was the best predictor of growth in subsequent years . Responses to therapy could not be reliably predicted from baseline anthropometric variables , plasma insulin-like growth factor I SD score , growth hormone levels . Final height assessment will be needed to determine the ultimate benefit of therapy The aim of this study was to compare the growth response of 22 short pre‐pubertal children without growth hormone deficiency , treated with a single daily growth hormone injection ( group A ) , to the growth response of 27 similar children , treated with the same daily dose divided into 2 subcutaneous injections per day ( group B ) , for 1 y , in a r and omized study . GH treatment significantly promoted growth parameters , height st and ard deviation score and height velocity st and ard deviation score in both groups . Serum insulin‐like growth factor I was also increased . There were no significant differences in growth response , serum IGF‐I levels , or the advance in bone age between the two study groups after 1 y of GH therapy . We conclude that twice daily s.c . growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency Background / Aims : To determine the optimal dose of LB03002 , a sustained-release , once-weekly formulation of recombinant human growth hormone ( rhGH ) , and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature ( ISS ) . Methods : This multicenter , r and omized , open-label , phase II study included GH-naïve , prepubertal children with ISS , r and omized to receive daily rhGH 0.37 mg/kg/week ( control , n = 16 ) , LB03002 0.5 mg/kg/week ( n = 14 ) , or LB03002 0.7 mg/kg/week ( n = 16 ) . The primary endpoint was height velocity ( HV ) change at week 26 . Results : At week 26 , the least square ( LS ) means for HV change ( cm/year ) with control , LB03002 0.5 mg/kg/week , and LB03002 0.7 mg/kg/week were 5.08 , 3.65 , and 4.38 , and the LS means for the change in height st and ard deviation score were 0.65 , 0.49 , and 0.58 , respectively . The lower bound of the 90 % confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change ( –1.72 ) satisfied the noninferiority margin ( –1.75 ) . Adverse events were generally mild and short-lived . Conclusion : A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments . LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH OBJECTIVE It Is possible that high dose GH treatment may have beneficial effects on growth but important adverse effects on cardiac function . We have therefore Investigated the efficacy and cardiovascular effects of high dose biosynthetic human GH ( r‐hGH ) treatment in children with idiopathic short stature and a normal pretreatment height velocity The influence of short stature on psychological adaptation in childhood and adolescence is controversial . GH is currently used to treat children with idiopathic short stature ( ISS , also known as non-GH-deficient short stature ) . This study represents the first double-blind , placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS , treated with GH until adult height was attained . Sixty-eight children ( 53 males , 15 females ) , 9 - 16 yr old , with marked ISS ( measured height or predicted adult height -2.5 sd or less ) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr . Parents completed the  Child Behavior Checklist ( CBCL ) and children the Self-Perception Profile ( SPP ) and Silhouette Apperception Technique at baseline and annually thereafter . Baseline behavioral/emotional adjustment ( CBCL ) and self-concept ( SPP ) scores for children with ISS were within the normative range . The two study groups exhibited similar behavioral and self-concept profiles ( CBCL ) during the first 2 yr of the study . However , CBCL behavior problems ( internalizing , externalizing , and total problems ) appeared to decline , in yr 3 and 4 , in the GH-treated group relative to the placebo-treated group . Group differences in CBCL competency domains and the SPP were not observed at any point during the study . Short stature among children with ISS enrolled in this long-term , placebo-controlled study was not associated with problems in psychological adaptation or self-concept with the psychological instruments employed . GH treatment was associated with a trend toward improvement in problem behaviors , as measured by question naires ( CBCL ) completed by study participants ' parents . It remains to be determined whether GH treatment significantly impacts adaptation , psychosocial function , or quality of life in children with ISS The growth-promoting effect of recombinant human growth hormone ( GH ; Genotropin ' ) therapy in short children born small for gestational age was evaluated in a r and omized , open-labelled , multicentre trial . Three parallel groups were recruited : group 1 was an untreated control group ; group 2 received  recombinant human GH , 0.2 IU/kg/day s.c . , and group 3 received recombinant human GH , 0.3 IU/kg/day S.C. Treatment was continued for 24 months . The inclusion criteria were : weight and /or length at birth below -2 SD for gestational age ; chronological age 2 - 8 years ; height/chronological age below -2.5 SD ; height velocity below + 1 SD ; and a serum G H concentration of at least 10 & I after exercise , glucagon administration or insulin-induced hypoglycaemia . The dose of G H was adjusted for body weight every 6 months . Preliminary 18-month data from 46 of the 51 children followed are reported here . This cohort consists of short children who suffered from idiopathic or non-syndromic intrauterine growth retardation ( n = 31 ) and children with either Silver-Russell syndrome ( n = 9 ) , Dubowitz syndrome ( n = 3 ) or fetal alcohol syndrome ( n = 3 ) .  Weight at birth was 1.99 k 0.08 kg ( mean i SEM ) , length at birth was 42.4 k 0.6 cm and gestational age was 37.9 f 4 weeks . At the start of the study , chronological age was 5.1 k 0.3 years , bone age ( Tanner-Whitehouse 2 method ) 3.9 k 0.3 years , height velocity 6.9 k 0.3 cdyears , height velocity for chronological age -0.7 i 0.1 SD , height for chronological age -3.5 k 0.1 SD , and height for bone age -1.5 k 0.3 SD . At the start , groups 1 , 2 and 3 did not differ significantly for any of the variables assessed . Salient 18-month growth data are summarized in Table 1 . The recombinant human GH therapy did not appear to be associated with any clinical adverse events . All children remained prepubertal during the study period . The fasting serum insulin concentrations were measured after 12 months and were found to be twice as high in children treated with G H ( approximately 20 mU/l ) compared with pretreatment levels or with those of untreated 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 The effects of recombinant human growth hormone ( rhGH ) treatment in 69 prepubertal , non-GH deficient children born small for gestational age ( SGA ) were evaluated over 2 years . At start of the study mean age was 5.1 years , mean bone age was 3.8 years and mean height SDS was -4.0 . The children were r and omly allocated to 3 groups receiving no treatment or daily subcutaneous injections of rhGH at a dose of 0.1 IU/kg body weight ( group 0.1 IU ) or 0.2 IU/kg body weight ( group 0.2 IU ) . At start of the study mean height velocity SDS was -1.4 in the control group , -0.7 in group 0.1 IU and -1.4 in group 0.2 IU . After 2 years there was a significant increase in height velocity SDS in children treated with rhGH as compared to untreated children . Mean height velocity SDS after the first year of treatment was -1.2 in the control group , 2.8 in group 0.1 IU and 5.5 in group 0.2 IU . Corresponding values during the second year were -0.9 , 1.6 and 2.9 . A statistically significant difference was observed between the groups receiving 0.1 IU/kg/day and 0.2 IU/kg/day during the first year of treatment , whereas no difference between the treatment groups was found during the second year . Catch-up growth , i.e. a height velocity 1 SD above the mean , was achieved for 86 % of group 0.1 IU and 95 % of group 0.2 IU during the first year of treatment and was maintained for 65 % and 79 % of the patients in group 0.1 IU and 0.2 IU respectively in the second year . GH treatment was associated with a distinct acceleration of bone age . Tolerance of treatment was good . No clear trends were seen in any of the laboratory variables . In conclusion , this study shows that daily rhGH given at a dose of 0.1 - 0.2 IU/kg/day for 24 months is an effective and safe therapy to increase linear growth and induce catch-up growth in short SGA children
For height outcome , articles were limited to studies reporting adult height and to systematic review s. FINDINGS Recombinant human growth hormone therapy of children with idiopathic short stature increases height in some children .
The cost-benefit ratio is controversial .
AND RELEVANCE Growth hormone treatment may be considered in some children with idiopathic short stature
IMPORTANCE Approximately 2 % of children are defined as having short stature .
Deciding when to pursue recombinant human growth hormone therapy to increase adult height is controversial .
OBJECTIVE To review the management of children with idiopathic short stature , including diagnostic evaluation and therapeutic options .