title: Outcome of a four-year randomized study of daily versus three times weekly somatropin treatment in prepubertal naive growth hormone-deficient children. Genentech Study Group. Laboratory Values for Children With Newly Diagnosed Inflammatory Bowel Disease Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty. Final height of short normal children treated with growth hormone Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. A Randomised Study of the Effect of Two Doses of Biosynthetic Human Growth Hormone on Final Height of Children with Familial Short Stature Comparison of final heights of growth hormone-treated vs. untreated children with idiopathic growth failure. Adult Height in Children with Idiopathic Short Stature Treated with Growth Hormone Safety of Growth Hormone Treatment of Children with Idiopathic Short Stature: The US Experience 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. Randomised trial of growth hormone in short normal girls Patient, Physician, and Consumer Drivers: Referrals for Short Stature and Access to Specialty Drugs
abstract: A comparison was made of the growth responses of prepubertal naive GH-deficient children who were r and omly assigned to receive 0.3 mg/kg.week  recombinant human GH administered either daily ( QD ) or three times weekly ( TIW ) over 4 yr . The effects of the two regimens on annual growth velocity , change in height SD score , bone maturation , and age at onset of puberty are presented as the mean + /- SD . During each of the 4 yr , the annual growth velocity was significantly greater in the QD vs. TIW group . At 48 months , the mean total gain in height was 9.7 cm greater in the QD group ( 38.4 + /- 5.5 ) than that in the TIW group 28.7 + /- 3.2 ; P = 0.0002 ) . The mean height SD score at the end of each year was significantly greater in the QD group . After 4 yr , the total gain in height SD score was 3.2 + /- 1.2 in the QD group compared to 1.5 + /- 0.5 in the TIW group ( P = 0.0003 ) . The height SD score at 4 yr was 0.2 in the QD group ( pretreatment , -2.9 ) compared to -1.4 in the TIW group ( pretreatment , -2.9 ) . After 4 yr of rhGH treatment , the increment in bone age was similar in the QD ( 4.9 + /- 1.0 yr ) and TIW ( 4.8 + /- 1.1 yr ) groups . The change in height age minus the change in bone age was more favorable in the QD ( 1.2 + /- 0.8 yr ) than in the TIW ( 0.0 + /- 0.9 yr ) group ( P = 0.003 ) . The mean age at onset of puberty in boys was the same in the QD ( 13.2 yr ) and TIW ( 13.0 yr ) groups ( P = 0.71 ) , and the mean bone age at the start of puberty was also similar ( 11.5 in QD and 11.3 in TIW groups ; P = 0.66 ) . The advantages of QD rhGH treatment in prepubertal GH-deficient children after 4 yr were additional gains of 1.7 height SD score and 9.7 cm in height over those treated with the TIW regimen ( P = 0.0002 ) OBJECTIVE . The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease . METHODS . Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospect ively in 18 US/Canadian centers . Laboratory values investigated included hemoglobin level , platelet count , albumin level , and erythrocyte sedimentation rate . Disease severity was categorized by physician global assessment . RESULTS . A total of 526 children ( mean age : 11.6 years ; 58 % male ; 392 with Crohn disease and 134 with ulcerative colitis ) were studied . All 4 values were normal for 21 % of patients with mild Crohn disease and 54 % with mild ulcerative colitis . In contrast , only 3.8 % of children with moderate/severe Crohn disease and 4.3 % with moderate/severe ulcerative colitis had normal results for all 4 tests . The erythrocyte sedimentation rate was least likely to be normal ; overall , 26 % of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate , including 18 % with moderate/severe disease . Hemoglobin levels were normal for 32 % , platelet counts for 50 % , and albumin levels for 60 % . There was no clear association between Crohn disease location and either severity or number of normal laboratory values . In contrast , there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests . CONCLUSION . The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease 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 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 BACKGROUND Short-term studies have demonstrated acceleration of growth rate following administration of biosynthetic human growth hormone ( r-hGH ) to short normal children . We describe the effect of such treatment on final height . METHODS This was an open study of consecutive referrals to a growth disorder clinic from which 16 short children ( height st and ard deviation score [ SDS ] -2.17 [ range -1.8 to -3.3 ] ; height velocity SDS -0.44 [ 0.33 ] ; peak serum GH response to stimulation 27.9 mU/L [ 9.2 ] were treated with r-hGH , and 7 short children who declined treatment ( height SDS -2.34 [ 0.61 ] ; height velocity SDS -0.36 [ 0.28 ] ; peak serum GH response 28.2 mU/L [ 6.8 ] ) acted as an observation group .  Subcutaneous r-hGH dose ranged between 12.2 and 21.0 U/m2 per week ( 0.02 - 0.04 mg/kg per day ) for the first 2 years of treatment and 20 U/m2 per week thereafter , 3 untreated children were lost to long-term follow-up . FINDINGS r-hGH significantly increased the difference in final height compared with pretreatment predicted height ( + 0.42 SDS [ 0.79 ] , p = 0.03 ) but this change was not significantly greater than that of the observation group ( + 0.16 SDS [ 0.20 ] ) . Treatment had no effect on the timing of puberty . Boys progressed slightly faster through puberty , associated with an acceleration in bone-age maturation . No untoward effects on glucose metabolism were observed . Long-term therapy did not alter body-fat distribution or blood pressure . INTERPRETATION Long-term therapy in this group of children appears safe but the small increment in final height , approximately 2.8 cm in boys and 2.5 cm in girls , does not justify the widespread use of r-hGH for short normal children OBJECTIVES To investigate in an open-label r and omized study , the effect of two doses of growth hormone ( GH ) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature ( mean baseline height st and ard deviation score [ SDS ] -3.2 ) . STUDY DESIGN Patients were treated with GH at 0.24 mg/kg/week , 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter ( 0.24 - ->0.37 ) , or 0.37 mg/kg/week . Final height was evaluated in 50 patients at study completion ( mean treatment duration , 6.5 years ) . RESULTS Patients who received 0.37 mg/kg/week ( n = 72 ) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week ( n = 70 ) ( treatment difference = 0.8 cm/year ; P = .003 ) or 0.24 - ->0.37 mg/kg/week ( n = 67 ) ( treatment difference = 0.9 cm/year ; P = .001 ) . For the 50 patients for whom final height measurements were available , mean height SDS increased by 1.55 , 1.52 , and 1.85 SDS , respectively , for the three dose groups . For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups , the mean treatment difference ( adjusted for differences in baseline predicted height SDS ) was 0.57 SDS ( 3.6 cm ; P = .025 ) . Mean overall height gains ( final height minus baseline predicted height ) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups , respectively , without dose effects on safety parameters . Final height measurements were within the normal adult height range for 94 % of patients r and omized to 0.37 mg/kg/week who continued to final height . CONCLUSION GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature CONTEXT The effect of GH therapy in short non-GH-deficient children , especially those with idiopathic short stature ( ISS ) , has not been clearly established owing to the lack of controlled trials continuing until final height ( FH ) . OBJECTIVE The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children , mainly with ISS , compared with untreated controls . DESIGN AND SETTING A r and omized , controlled , long-term multicenter trial was conducted in Sweden . INTERVENTION Two doses of GH ( Genotropin ) were administered , 33 or 67 microg/kg.d ; control subjects were untreated . SUBJECTS A total of 177 subjects with short stature were enrolled . Of these , 151 were included in the intent to treat ( AllITT ) population , and 108 in the per protocol ( AllPP ) population . Analysis of ISS subjects included 126 children in the ITT ( ISSITT ) population and 68 subjects in the PP ( ISSPP ) population . MAIN OUTCOME MEASURES We measured FH sd score ( SDS ) , difference in SDS to midparenteral height ( diff MPHSDS ) , and gain in heightSDS . RESULTS After 5.9+/-1.1 yr on GH therapy , the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 ( 33 microg/kg.d , -1.7+/-0.70 ; and 67 microg/kg.d , -1.4+/-0.86 ; P<0.032 ) , vs. -2.4+/-0.85 ( P<0.001 ) ; the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 ( P<0.001 ) ; and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 ( P<0.001 ) . GH therapy was safe and had no impact on time to onset of puberty . A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four population s. CONCLUSION GH treatment significantly increased FH in ISS children in a dose-dependent manner , with a mean gain of 1.3 SDS ( 8 cm ) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls 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 We measured adult heights ( Ht ) of 94 healthy GH-sufficient children ( peak GH > 10 ng/mL , polyclonal RIA ) whose Ht at presentation were more than 2 SD below the mean for chronological age , with normal weight-to-Ht ratios , normal body proportions , and pathologic growth velocity for chronological age . Group 1 ( n 36 , 6 females ) received st and ardized doses ( 0.3 mg/kg x week ) of GH ( mean duration = 41 months ) , while group 2 ( n = 58 , 17 females )  received no treatment . Our conclusion was that the mean final Ht SD score in the GH-treated group ( -1.5 ) was significantly greater than in the untreated group ( -2.1 ) ; P < .001 . Genetic predisposition to short stature was evident in both groups : the midparental Ht SD score was -1.1 in the treated and -1.0 in the untreated group . Midparental Ht was met or exceeded by 42 % of the GH-treated group but only 15 % of the untreated group . Final Ht was not significantly different from predicted Ht , except from GH-treated girls , who exceeded their predicted Ht . Although the mean Ht gains ( 6.8 cm in girls and 3 cm in boys ) were modest and variable , GH treatment provided significantly better Ht outcomes for the majority of children with idiopathic growth failure Idiopathic short stature ( ISS ) includes a heterogeneous group of patients with common characteristics to those of familial short stature and constitutional delay . Some authors state that these children can often respond to GH treatment , thus increasing their adult height . The aims of this study were to determine the effect of GH treatment ( 0.5 - 0.7 IU/kg/week ) and the influence of some initial variables on adult height in patients with ISS . It was a non-r and omized , observational study of 30 boys with ISS and a historical control group of 42 patients . The patients were followed until achieving their adult height . The mean height gain of the treated group attributable to GH was 4.5 cm . A stepwise regression model considering predicted adult height and target height as independent variables and final height as dependent variable gave an R2 coefficient of 0.38 . We conclude that GH significantly increases final height in boys with ISS Recombinant human 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 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 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 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
target: 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
background: 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 .