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. 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) The influence of growth hormone (rhGH) therapy on tooth formation in idiopathic short statured children. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. Adult Height in Children with Idiopathic Short Stature Treated with Growth Hormone 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. Safety of Growth Hormone Treatment of Children with Idiopathic Short Stature: The US Experience Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study Quality of life and self-esteem in children treated for idiopathic short stature. A Randomised Study of the Effect of Two Doses of Biosynthetic Human Growth Hormone on Final Height of Children with Familial Short Stature Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. Once versus twice daily injections of growth hormone in children with idiopathic short stature Effect of Zinc Supplementation on Growth Hormone Secretion, IGF-I, IGFBP-3, Somatomedin Generation, Alkaline Phosphatase, Osteocalcin and Growth in Prepubertal Children with Idiopathic Short Stature Recombinant human growth hormone treatment in children with thalassemia major. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. Patient, Physician, and Consumer Drivers: Referrals for Short Stature and Access to Specialty Drugs Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty. Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years. Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation Normal Progression of Testicular Size in Boys with Idiopathic Short Stature and Isolated Growth Hormone Deficiency Treated with Growth Hormone: Experience from the KIGS
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 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 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 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 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 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 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 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 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 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 / Aims : The effects of biosynthetic human growth hormone ( r-hGH ) in children with familial short stature ( FSS ) are varied . We determined whether responsivity to r-hGH in FSS is dose-dependent . Method : R and omised trial of two doses ( 20 or 40 IU/m2 body surface area/week by daily subcutaneous injection ) of r-hGH in 29 ( 24 male , 5 female ) FSS children with assessment at adult height . Results : Age range at presentation was 5.1–10.5 years , height less than 1.5 st and ard deviation scores ( SDS ) below the mean , height velocity SDS greater than –1.5 and peak growth hormone response to provocative testing over 13.5 mU/l  . Adult height data ( SDS ) at 16.5 ± 2.1 years for the low-dose group and 16.1 ± 1.1 years for the high-dose group ( p = 0.62 ) were similar [ low dose –1.06 ( SD 0.75 ) , high dose –1.02 ( SD 0.83 ) ; p = 0.88 ] . The incremental effect of both doses on stature was minimal [ low-dose difference in height actual-predicted 0.79 ( SD 0.94 ) , high dose 1.27 ( SD 0.88 ) ; p = 0.12 ] . Conclusion : Using this r-hGH dosing schedule there were little short- or long-term effects on height in children with FSS 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 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 Controversy exists about the effect of zinc on growth and the GH-IGF system .  Zinc supplementation has been shown to stimulate linear growth in zinc-deficient children . However the mechanism of this effect has not been well characterized . Furthermore , the effect of zinc supplementation on non-zinc-deficient short children is unknown . We investigated the effect of zinc supplementation on endogenous GH secretion , serum IGF-I and IGFBP-3 concentrations , IGF-I and IGFBP-3 generation in response to exogenous GH , bone formation markers , and linear growth of non-zinc-deficient children with idiopathic short stature . We analyzed prospect ively serum zinc , IGF-I , IGFBP-3 , alkaline phosphatase , osteocalcin , and GH response to clonidine test  , and performed a somatomedin generation test before and 6 weeks after zinc supplementation in 22 ( 16 M , 6 F ) prepubertal children with idiopathic short stature .  Serum IGF-I increased from 67.4+/-70.6 to 98.2+/-77.3 ng/ml ( p < 0.001 ) , IGFBP-3 from 2326+/-770 to 2758+/-826 ng/ml ( p < 0.001 ) , alkaline phosphatase from 525+/-136 to 666+/-197 U/l ( p < 0.0001 ) , and osteocalcin from 16.8+/-10.6 to 25.8+/-12.8 ng/ml ( p < 0.05 ) after zinc supplementation despite there being no difference in GH response to clonidine after zinc supplementation ( peak GH 11.6+/-6.9 vs 13.4+/-7.8 ng/ml , GH area under the curve during clonidine test 689+/-395 vs 761+/-468 , NS ) . Percent change in IGF-I and IGFBP-3 during the somatomedin generation test was not significantly affected by zinc supplementation ( 118 % vs 136 % and 57 % vs 44 % , respectively ) . There was no significant correlation between percentage increase in zinc levels and percentage increase in parameters tested . Height SDS or weight SDS did not improve significantly in 17 patients who continued on zinc supplementation for at least 6 months ( 6 - 12 months ) ( -2.59 vs -2.53 SDS and -1.80 vs -1.67 SDS , respectively ) . Zinc supplementation increased basal IGF-I , IGFBP-3 , alkaline phosphatase and osteocalcin without changing GH response to clonidine . Zinc supplementation did not affect sensitivity to exogenous GH as tested by IGF-I and IGFBP-3 generation test . These results suggest a direct stimulatory effect of zinc on serum IGF-IGFBP-3 , alkaline phosphatase and osteocalcin . Despite improvements in the above parameters , zinc supplementation to children with idiopathic short stature with normal serum zinc levels did not significantly change height or weight SDS during 6 - 12 months follow-up BACKGROUND To evaluate the growth hormone reserve and the growth hormone response to recombinant human growth hormone ( GH ) in prepubertal thalassemic children with growth retardation . METHODS Twenty thalassemic patients with short stature and delayed bone age were studied . Patients were r and omized into GH-treated ( n = 10 ) and non-GH treated ( control ; n = 10 ) groups . The GH-treated group received recombinant human (rh)-GH ( Genotropin ) at the dose of 0.7 IU/kg per week for 12 months . RESULTS There was a significant discordance between GH response to pharmacologic stimuli and physiological secretion of GH/GHRH testing . Following the administration of rhGH , growth velocity increased from 2.47 + /- 0.48 cm/year to 6.27 + /- 0.76 cm/year ( P = 0.005 ) , whereas there was not a similar change in the non-GH-treated group . The height velocities of the two groups during the 1 year follow-up period were significantly different ( 6.27 + /- 0.76 vs 3.99 + /- 0.34 cm/year ; P = 0.025 ) . There were significant differences between the height velocity improvements and height velocity st and ard deviation scores of the two groups as well . CONCLUSION The present study has demonstrated that rhGH is a safe and efficacious mode of treatment in thalassemic children 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 : C and i date s for specialty drugs , the fastest growing and costliest pharmaceuticals , typically originate with primary care referrals . However , little is known about what drives such referrals — especially for large population s such as short , otherwise normal children ( idiopathic short stature ) . Recent exp and ed approval of growth hormone ( GH ) makes more than 585,000 US children eligible for such treatment , potentially costing over $ 11 billion/y . Methods : To quantify the relative impact of patient physiological indicators , physician characteristics , and consumer preferences on referrals to endocrinologists ( and potential access to GH ) for short children , a national study of 1268 r and omly selected US pediatricians was conducted , based on a full factorial experimental design in a structured survey . Results : While patient indicators ( height , growth pattern ) influenced referrals ( P < 0.001 ) , consumer drivers ( family concern ) and physician attitudes had almost as great an impact — especially for children with less severe growth impairment ( P < 0.001 ) . Physician belief that short stature impairs emotional well-being and physician characteristics ( female , older , shorter , beliefs about drug company information ) increased referrals ( P < 0.03–0.001)—independent of growth parameters . Conclusions : Referral recommendations that create the pool of c and i date s for the specialty drug GH are heavily swayed by physician characteristics and consumer preferences , particularly in the absence of compelling physiological evidence . This makes most of children with short stature strikingly susceptible to nonphysiological influences on referrals that render them c and i date s for this specialty drug . Only 1 additional referral per US pediatrician would likely increase GH costs by over $ 100 million/y OBJECTIVE Our objective was to assess final height ( FH ) and adverse effects of combined GH and GnRH agonist ( GnRHa ) treatment in short adolescents born small for gestational age or with normal birth size ( idiopathic short stature ) . DESIGN AND PATIENTS Thirty-two adolescents with Tanner stage 2 - 3 , age and bone age ( BA ) less than 12 yr for girls or less than 13 yr for boys , height sd score ( SDS ) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height ( PAH0 ) less than -2.0 SDS were r and omly allocated to receive  GH plus GnRHa  ( n=17 ) or no treatment ( n=15 ) for 3 yr . FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys . RESULTS FH was not different between treatment and control groups . Treated children had a larger height gain ( FH-PAH0 ) than controls : 4.4 ( 4.9 ) and -0.5 ( 6.4 ) cm , respectively ( P<0.05 ) . FH was higher than PAH0 in 76 and 60 % of treated and control subjects , respectively . During follow-up , 50 % of the predicted height gain at treatment withdrawal was lost , result ing in a mean gain of 4.9 cm ( range , -4.0 to 12.3 cm ) compared with controls . Treatment did not affect body mass index or hip bone mineral density . Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys , albeit statistically not significant . CONCLUSION Given the expensive and intensive treatment regimen , its modest height gain results , and the possible adverse effect on peak bone mineralization in males , GH plus GnRHa can not be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age Most children born small for gestational age ( SGA ) normalize their size through spontaneous catch-up growth within the first 2 yr after birth . Some SGA children fail to do so and maintain an abnormally short stature throughout childhood . We have previously reported that high dose GH treatment ( 66 or 100 microg/kg x day s.c . over 2 yr ; age at start , 2 - 8 yr ; n = 38 ) induces pronounced catch-up growth in short children born SGA , thereby normalizing their height and weight in childhood . Here , we report on the further prepubertal growth course of these children over the first 4 yr after withdrawal of early , high dose GH treatment . Of the 38 treated children , none developed precocious puberty , and 22 remained prepubertal . Mean age of the latter at start of GH was 4.4 yr , height was -3.7 SD score , and height after adjustment for midparental height was -2.9 SD score . Height increased by an average of 2.5 SD during the 2 yr of GH treatment and decreased by 0.4 and 0.3 SD , respectively , during the first and second year after GH withdrawal . Subsequently , when stature was not extremely short at the start ( mean adjusted height SD score , -2.7 ; n = 13 ) , no further GH treatment was given , and the adjusted height was stabilized around -1.0 SD score ; when stature was very short at the start ( mean adjusted height , -3.3 SD score ; n = 9 ) , a second course of GH treatment ( 66 microg/kg x day s.c . ) was initiated either 2 yr ( n = 5 ) or 3 yr ( n = 4 ) after initial GH withdrawal . This second course was associated with renewed catch-up growth and also result ed in a mean adjusted height of -1.0 SD score . In each subgroup , the pattern of the weight course paralleled that of the height course ; GH treatment was well tolerated . In conclusion , early , discontinuous , high dose GH treatment appears to be a safe and efficient option to normalize prepubertal height and weight in the majority of short SGA children . It remains to be examined whether the normalized stature will be maintained during pubertal development , either with or without further GH treatment 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 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
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 .