title: Growth of short normal children in puberty treated for 3 years with growth hormone alone or in association with gonadotropin-releasing hormone agonist. Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. Growth Hormone Treatment in Non‐Growth Hormone‐Deficient Children: Effects of Stopping Treatment Once versus twice daily injections of growth hormone in children with idiopathic short stature Growth parameters and predictors of growth in short children with and without growth hormone (GH) deficiency treated with human GH: a randomized controlled study. Spontaneous adult height in idiopathic short stature. The effect of short-term growth hormone or low-dose oxandrolone treatment in boys with constitutional growth delay The influence of growth hormone (rhGH) therapy on tooth formation in idiopathic short statured children. High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature 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. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. Genentech Collaborative Study Group. Quality of life and self-esteem in children treated for idiopathic short stature. Randomised trial of growth hormone in short normal girls Combined treatment with growth hormone and luteinizing hormone releasing hormone-analogue (LHRHa) of pubertal children with familial short stature
abstract: GH , 0.1 IU/kg/day 6 days/week , was given to 30 early pubertal short patients for 3 years . There were 16 males , aged 14.4 + /- 0.8 years , and 14 females , aged 12.2 + /- 1.2 years , at pubertal stage 2 or 3 with slow growth ( 4.2 + /- 1.2 cm/year ) and no detected GH insufficiency or other cause for short stature . They were r and omized in 2 groups : group A with GH alone , and group B with GH and a gonadotropin-releasing hormone agonist during the first 2 years . 28 of the 30 patients completed 3 years of treatment . The annual growth rate increased during the 1st year in both groups and sexes , the increase being significant ( p < 0.01 ) in group A only . Patients of group A kept an improved growth velocity in the 2nd year , then returned to pretreatment growth rate in the 3rd year , while completing their sexual development and bone maturation . Their height , expressed as st and ard deviation score ( SDS ) for bone age , improved in the first 2 years , but decreased thereafter . Group B patients returned to pretreatment growth velocity in the 2nd year , and had no significant improvement in growth rate in the 3rd year with GH alone . Their bone maturation , slow when on the GnRH agonist , accelerated when sexual development resumed . At the end of the 3 years , height , expressed as SDS for age , improved in group A from -2.5 + /- 0.6 to -1.5 + /- 0.4 in males ( p < 0.05 ) and from -2.8 + /- 0.5 to -2.1 + /- 0.9 in females ( NS ) . ( ABSTRACT TRUNCATED AT 250 WORDS 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 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 ABSTRACT . Overnight physiological  growth hormone ( GH ) secretion was evaluated in 95 short , prepubertal children ( 73 boys , 22 girls ) . All the children were below the 3rd centile for height and achieved CH levels greater than 15 mU/1 following pharmacological stimulation . The mean average GH level was 7.1 mU/l and the mean sum of pulse amplitudes 80.4 mU/l . No relationship was found between age , height or height velocity and any of the parameters of GH secretion . The group was r and omized to receive placebo , GH or remain under observation for the first 6 months and then all patients received GH treatment for a further 6 months . Those treated with GH , 0.27 IU/kg ( 0.1 mg/kg ) three times weekly , in the first phase . demonstrated a mean increase in height velocity SDS of 3.24 . There was no difference in growth response between the placebo or observation groups . In the second 6‐month period . all children received GH according to the same dose regimen : they were then observed for a further 6 months following its discontinuation . In the 6 months following withdrawal of GH , all groups showed a significant fall in height velocity SDS , which returned to pretreatment levels , without demonstrating‘catch‐down’growth . Repeat sampling of overnight GH secretion within 3 days of discontinuing GH showed normal secretory patterns with a small reduction in mean peak amplitude . These results suggest that short children without classic GH insufficiency respond well to exogenous GH in the short term and return to pretreatment height velocities afterwards . Consequently , it may be possible to increase final adult height in such children by GH treatment 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 Seventy-seven prepubertal short children with heights below the third centile for age and gender were divided into three groups according to their peak GH response to clonidine and insulin provocation .  Group ( I ) included 30 children with peak GH response < 7 micrograms/l , group ( II ) included 19 children , with GH peak response between 7 and 10 micrograms/l , and group ( III ) included 24 children with GH peak > 10 micrograms/l . Each group was divided into two subgroups , a and b. Subgroups (I)b , (II)a and (III)b were treated daily for 1 year with subcutaneous recombinant human growth hormone ( GH ) 15 U/m2/week , and group (I)a was treated with GH ( 30 U/m2/week ) . Before initiation of treatment , the chronological age , the height st and ard deviation score ( HtSDS ) , and the bone age delay did not differ among the study subgroups . The height growth velocity ( GV ) and insulin-like growth factor-I concentrations were significantly higher in group ( III ) , with normal GH response to provocation , compared to those for group ( I ) with GH deficiency . All the children had normal thyroid function and normal glucose tolerance . CT examination of the hypothalamic-pituitary area revealed a picture of empty sella ( either partial or complete ) in 35 per cent of the children in group ( I ) and 21 per cent of children in group ( II ) . After 1 year of GH therapy , the HtSDS , GV , and IGF-I concentrations increased significantly in the four subgroups treated with GH compared to their pretreatment values and to their controls . All the children in group ( I ) were responders ( increment in GV of 2 cm2/year above the pretreatment GV ) , of the nine subjects treated in group (II)a , one child was a non-responder and of the 12 children in group (III)a three children were non-responders . GV was non-significantly higher in group (I)a ( 30 U/m2/week ) v. group (I)b ( 15 U/m2/week ) . GV of children in groups (I)b , with abnormal GH response to provocation , was significantly higher than GV of children in group (III)a . Bone age advanced by less than 1 year in the treated groups ( 0.84 + /- 0.14 years ) v. the untreated groups ( 0.73 + /- 0.3 years ) . None of the children had impaired glucose tolerance or abnormal thyroid function after 1 year of GH therapy . In all the treated children , GV after 1 year of GH treatment was correlated significantly with the pretreatment GV ( r = -0.63 , P < 0.01 ) , peak GH response to provocation ( r = -0.59 , P < 0.01 ) , IGF-I concentration ( r = -0.54 , P < 0.01 ) , and positively with the GH dose ( r = 0.589 , P < 0.01 ) . In group ( III ) children , with normal GH reserve , GV correlated significantly with the pretreatment GV ( r = -0.48 , P < 0.01 ) and negatively with the GH peak response to provocation ( r = -0.25 , P < 0.05 ) . In conclusion , GH therapy improved GV of children growing along or parallel to the 3rd centile , irrespective of their GH response to provocation , without untoward effect on skeletal maturation , thyroid function or glucose tolerance 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 We evaluated the effect of six-month treatment with growth hormone ( GH ) or low-dose ox and rolone in a group of boys with constitutional growth delay ( CGD ) . Sixteen boys were r and omly assigned to two treatment groups . Group 1 received GH ( 0.6 U/kg/week sc 5–6 times/week ) and Group 2 received ox and rolone ( 0.07 mg/kg po ) . The boys of the two groups were closely matched for age ( 13.7 ± 0.5 and 12.8 ± 0.4 years ) ( mean ± SE ) , chronologic age/bone age ratio ( 1.15 ± 0.04 and 1.16 ± 0.02 ) , height st and ard deviation score ( SDS ; −2.7 ± 0.4 and −2.5 ± 0.3 ) and pretreatment height velocity ( HV ) ( 3.7 ± 0.8 and 4.0 ± 0.4 cm/year ) . Other known causes of short stature were excluded in all subjects , and none had taken long-term medication prior to the study . After 6 months of treatment HV increased to 7.5 ± 0.4 and to 8.1 ± 0.5 cm/year in group 1 and 2 , respectively . Plasma IGF-I concentrations rose significantly after treatment in both groups . Predicted adult height was not significantly affected by either GH or ox and rolone treatment . We conclude that a short-term course of low-dose ox and rolone is as effective as GH to accelerate growth in boys with CGD . Low-dose ox and rolone represents an effective , cheap , and convenient therapeutic approach in boys with CGD The purpose of this preliminary study was to evaluate tooth formation in children with idiopathic short stature , before and during treatment with recombinant growth hormone ( rhGH ) . Twenty-nine short-statured children ages 6 to 13 years were assigned into two treatment groups , an " experimental " group ( n = 18 ) , which received rhGH , and a " control " group ( n = 11 ) , which was observed for 1 year before commencing rhGH  treatment . Clinical and radiographic records were obtained at the initial , year 1 , and year 2 visits . Tooth formation and stature were assessed by calculating Z-scores , appropriate for the age and gender of each child . Delta-Z scores , which measure the change in Z-score over time , were also calculated between annual visits . Height was measured and recorded every 3 months , and Z-score statural norms for age and gender were derived from the 1977 National Center for Health Services national probability sampling . Tooth formation st and ards were derived from Moorrees et al. A matched control sample for tooth development was derived from untreated children . Tooth formation was initially delayed although the degree of reduction in stature exceeded the initial degree of delay in tooth formation . During this 2-year study , rhGH therapy had a significant influence on acceleration or gain in stature , but did not have a significant influence on tooth formation Background : Long term growth hormone ( GH ) treatment in children with idiopathic short stature ( ISS ) results in a relatively small mean gain in final height of 3–9 cm , which may not justify the cost of treatment . As it is unknown whether GH treatment during puberty adds to final height gain , we sought to improve the cost – benefit ratio , employing a study design with high dose GH treatment restricted to the prepubertal period . Aims : To assess the effect of short term , high dose GH treatment before puberty on growth , bone maturation , and pubertal onset . Methods : Five year results of a r and omised controlled study are reported . Twenty six boys and nine girls were r and omly assigned to a GH treatment group ( n = 17 ) or a control group ( n = 18 ) . Inclusion criteria were : no signs of puberty , height less than −2 SDS , age 4–8 years for girls or 4–10 years for boys , GH concentration > 10 μg/l after provocation , and normal body proportions . To assess GH responsiveness , children assigned to the GH treatment group received GH treatment for two periods of three months ( 1.5 IU/m2/day and 3.0 IU/m2/day ) , separated by three month washout periods , during the first year of study . High dose GH treatment ( 6.0 IU/m2/day ) was then started and continued for at least two full years . When puberty occurred , GH treatment was discontinued at the end of a complete year ’s treatment ( for example , three or four years of GH treatment ) . Results : In response to at least two years on high dose GH treatment , mean ( SD ) height SDS for chronological age increased significantly in GH treated children from −2.6 ( 0.5 ) to −1.3 ( 0.5 ) after two years and −1.4 ( 0.5 ) SDS after five years of study . No changes in height SDS were observed in controls . A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment . Height SDS for bone age was not significantly different between groups during the study period . GH treated children entered into puberty at a significantly earlier age compared to controls . Conclusions : High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty . This may limit the potential therapeutic benefit of this regimen in ISS 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 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 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 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 We evaluated the 12 month growth of 18 pubertal children with familial short stature r and omly assigned to clinical follow-up ( group A ) , GH treatment alone ( group B ) and GH+LHRH analogue ( LHRHa ) treatment ( group C ) . Height velocity increased significantly compared to baseline in groups A and B ( 4.7±0.4 vs 6.6±0.6 and 4.4±0.3 vs 8±1 respectively ) , but not in C ( 5±0.5 vs 6.5±0.4 ) . Moreover in group B height and height prognosis st and ard deviation score SDS ) also were higher ( −2.2±0.2 vs−1.7±0.2 and 1.8±0.3 vs −1±0.2 , respectively ) . Comparisons among the groups showed a significant increase in group B vs the other groups of height velocity SDS ( 3.9±1.3 vs 0.4 + 1 and 0.3±0.7 ) and of height prognosis SDS ( −1±0.2 vs −2.4±0.3 and −2.4±0.3 ) . In conclusion , after one-year treatment , GH seems to be more effective in stimulating growth  than GH±LHRHa , even if studies of longer duration and /or follow-up are needed
target: 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: 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 .