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) Final height gain by GH therapy in children with idiopathic short stature is dose dependent. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. 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. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. Normal Progression of Testicular Size in Boys with Idiopathic Short Stature and Isolated Growth Hormone Deficiency Treated with Growth Hormone: Experience from the KIGS Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study A longitudinal study of craniofacial growth in idiopathic short stature and growth hormone-deficient boys treated with growth hormone. The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. Genentech Collaborative Study Group. Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. Spontaneous adult height in idiopathic short stature. Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation Once versus twice daily injections of growth hormone in children with idiopathic short stature
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 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 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 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 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 Background : The aim of this retrospective analysis was to evaluate the effects of growth hormone ( GH ) treatment on testicular development in boys with idiopathic short stature ( ISS ) and isolated GH deficiency ( IGHD ) followed in the KIGS ( Pharmacia International Growth Data base ) . Methods : For inclusion in the study , the patients had to have received more than 1 year of prepubertal GH treatment , at least 4 consecutive years of GH treatment in total , and to have attained their final height , defined as a height velocity of less than 2 cm/year . Data on 107 boys in the KIGS data base have been analyzed . Results : No significant differences in duration of GH treatment and testicular volume at the start of treatment or at final height were found between the boys with ISS and those with IGHD . The progression of testicular volume in boys with ISS or IGHD during GH treatment did not differ from the reference population . Conclusions : This analysis shows that GH treatment does not alter testicular growth in boys with ISS or IGHD . However , prospect i ve controlled studies are needed to rule out moderate attenuating or stimulating effects 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 / 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 The aim of this prospect i ve , longitudinal , controlled study is to describe the long-term safety and efficacy of growth hormone ( GH ) administration on craniofacial morphology in boys with short stature . Forty-six boys , who started GH treatment at the Department of Paediatrics Göteborg Paediatric Growth Research Centre , were consecutively included in the study . Twenty-five boys were classified as growth hormone-deficient ( GHD ) and 21 as idiopathic short stature ( ISS ) . The patients were injected with 33 ( n=31 ) or 67 ( n=15 ) microg GH/kg body weight/day . The mean age at the start of treatment was 11.8 years [ st and ard deviation ( SD ) 1.7 ] . To assess craniofacial growth , st and ard lateral cephalometric radiographs were obtained at the start of GH treatment , annually during 4 years , and at the end of GH treatment or when growth was less than 1 cm/year . The mean follow-up period was 6.4 years ( SD 1.4 ) . Growth changes were compared with boys from a semi-longitudinal reference group of 130 healthy subjects , 7 - 21 years of age . t-tests for independent and paired sample s and multiple regression analysis were applied . Age- and gender-specific st and ard deviation scores for the cephalometric variables were calculated . Repeated measures analysis of variance was used to identify significant covariates over time , such as low/high GH dose and GHD/ISS and orthodontic treatment . During the study period , eight ( out of 40 ) boys were treated with fixed orthodontic appliances , three with functional appliances ( activators ) , and three with other appliances ( plates and lingual arches ) . During GH treatment period , an overall enhancement in growth of the facial skeleton was observed in boys with short stature . The changes induced by GH yielded a more prognathic growth pattern , a more anterior position of the jaws in relation to the cranial base , and increased anterior rotation of the m and ible . The m and ibular corpus length and anterior face height of the GH-treated boys were greater at the end of the study compared with the boys in the reference group . No differences in growth response were noted either between the GHD and ISS boys or between those treated with either 33 ( low dose ) or 67 ( high dose ) microg GH/kg body weight/day . The only change that remained significantly correlated with orthodontic treatment was the alteration in m and ibular ramus height , showing a larger change in the boys who had not undergone orthodontic therapy . The findings of this study demonstrate that GH treatment has a favourable influence on the craniofacial growth pattern of boys with short stature without acromegalic features 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 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 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 Two hundred and thirty-six patients with idiopathic short stature ( ISS ) ( 184 m , 52 f ) who presented at a mean age of 12.2 ( range 2.8 - 17.5 ) years , a mean height of -2.16 st and ard deviation score ( SDS ) , a mean target height ( THT ) of -0.27 SDS ( m = f ) , were reinvestigated at a mean age of 20.5 ( range 18 - 24 ) years . 182(142 m , 37 f ) ( 67 % ) had reached  normal adult height ( AHT ) while 54 ( 39 m , 15 f ) ( 23 % ) had not . However , only 23 ( 17 m , 6 f ) did not reach a height within their familial target . Patients were subdivided into 2 groups according to deviation from familial height target : 60(44 m , 16 f ) were considered adequate for their families ( group 1 ) , while 176 ( 140 m , 39 f ) were smaller ( group 2 ) . Children in group 1 were younger and bone age ( BA ) was less retarded . Patients in group 1 reached their THT , this was not the case in group 2 . Young age , low THT and low predicted adult height ( PAH ) at presentation were the factors associated with poor stratural outcome , but AHT could not be predicted in individuals . In boys , PAH ( Bayley-Pinneau ) ( 0.0 SDS ) exceeded AHT ( -0.7 SDS ) , in girls , both were almost identical ( -0.79 , -0.77 SDS ) . Since most children with ISS reach an AHT within the normal range , attempts to improve AHT by means of growth-promoting therapies appear to be justified only in a minority of selected patients with ISS . Methods to improve the accuracy of individual height prognoses are needed 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 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
GH therapy can increase short-term growth and improve ( near ) final height .
Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature .
BACKGROUND Idiopathic short stature ( ISS ) refers to children who are very short compared with their peers for unknown or hereditary reasons .
Recombinant human growth hormone ( GH ) has been used to increase growth and final height in children with ISS .
OBJECTIVES To assess the effects of recombinant human GH on short-term growth and final height in children with ISS .