Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. Absence of growth hormone effects on cognitive function in girls with Turner syndrome. Methionyl human growth hormone and oxandrolone in Turner syndrome: preliminary results of a prospective randomized trial. Treatment with two growth hormone regimens in girls with Turner syndrome: final height results. Dutch Growth Hormone Working Group. Growth promotion and Turner-specific bone age after therapy with growth hormone and in combination with oxandrolone: when should therapy be started in Turner syndrome? Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. Acceleration of growth in Turner syndrome patients treated with growth hormone: summary of three-year results. Non-conventional growth hormone therapy in Turner syndrome: the United States experience. Psychological aspects of the Canadian randomized controlled trial of human growth hormone and low-dose ethinyl oestradiol in children with Turner syndrome. The Canadian Growth Hormone Advisory Group. Final Height of Growth Hormone-Treated GH-Deficient Children and Girls with Turner’s Syndrome: The Dutch Experience Final height outcome in girls with Turner syndrome treated with a combination of low dose oestrogen and oxandrolone Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone Growth hormone therapy in Turner's syndrome: an update on final height. Genentech National Cooperative Study Group. Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial Recombinant human growth hormone and oxandrolone in treatment of short stature in girls with Turner syndrome. Growth hormone therapy in Turner's syndrome. Impact of injection frequency and initial bone age. Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., 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) Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner's syndrome. Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis Yearly stepwise increments of the growth hormone dose results in a better growth response after four years in girls with Turner syndrome. Dutch Working Group on Growth Hormone.
A cardinal clinical feature of Turner syndrome ( TS ) is linear growth failure result ing in extreme short stature : the median adult height of untreated women with TS is 143 cm , 20 cm ( 8 in . ) below that of the general female population . In the largest multicenter , r and omized , long-term , dose-response study conducted in the United States , 232 subjects with TS received either 0.27 or 0.36 mg/kg.wk of recombinant human GH with either low dose ethinyl E2 or oral placebo . The study was placebo-controlled for both GH and estrogen for the first 18 months and remained placebo-controlled for estrogen for its duration . The near-final height  of the 99 subjects whose bone age was at least 14 yr was 148.7 + /- 6.1 cm after 5.5 + /- 1.8 yr of GH started at a mean age of 10.9 + /- 2.3 yr ; this represents an average increase of 1.3 + /- 0.6 SD scores from baseline ( TS st and ard ) . Height was greater than 152.4 cm ( 60 in . ) in 29 % of subjects compared with the expected 5 % of untreated patients . Mean near-final heights of subjects who received the lower GH dose , with or without estrogen , were 145.1 + /- 5.4 and 149.9 + /- 6.0 cm , respectively ; those who received the higher GH dose with or without estrogen achieved mean near-final heights of 149.1 + /- 6.0 and 150.4 + /- 6.0 cm , respectively . Factors that most impacted outcome were younger age , lower bone age/chronological age ratio , lower body weight , and greater height SD score at study entry . This study demonstrates significant  GH-induced improvement in height SD score , with correction of height to within the normal channels for a significant number of patients , and provides evidence of a GH dose-response effect . These data also indicate that early administration of estrogen , even at relatively low doses , does not improve gain in near-final height in patients with TS Turner syndrome ( TS ) is a genetic disorder characterized by short stature , gonadal dysgenesis , and a particular neurocognitive profile of normally developed language abilities ( particularly verbal IQ ) and impaired visual-spatial and /or visual-perceptual abilities . We have followed a large sample of girls with Turner syndrome who were enrolled in a long-term , double-blind , placebo-controlled trial of the effects of growth hormone ( GH ) treatment on final adult height . This study provides a unique opportunity to prospect ively evaluate the effects of GH treatment on neurocognitive function in this population of girls with Turner syndrome . The GH- and placebo-treated Turner syndrome subjects were well matched for age , treatment duration , race , karyotype , and socioeconomic status . Treatment ( GH or placebo ) duration s ranged from 1 - 7 yr . Whether GH deficiency and /or treatment in childhood and adolescence influences cognitive outcome in short children or GH-children is controversial . The major result of this study was the absence of GH treatment effects on cognitive function in girls with Turner syndrome . Our findings are in agreement with most of the previous studies that found no apparent growth hormone treatment effects on cognitive function in growth-hormone deficient children . We conclude that this study does not support a role for growth hormone in influencing childhood brain development in girls with Turner syndrome . Their characteristic nonverbal neurocognitive deficits were not altered with GH treatment into early adolescence Seventy girls with Turner syndrome , 4 to 12 years of age , were r and omly assigned to receive either no treatment ( control ) or methionyl human growth hormone ( 0.125 mg/kg three times per week ) , ox and rolone ( 0.125 mg/kg/day ) , or combination hGH plus ox and rolone therapy .  Baseline growth rates averaged 4.3 cm/yr , and all were within 2 SD of mean growth velocity for age in girls with Turner syndrome . Sixty-seven girls remained in the study for a minimum of 1 year . Growth rates and growth velocity ( in st and ard deviations for age in girls with Turner syndrome ) were control 3.8 cm/yr ( -0.1 SD ) , hGH 6.6 cm/yr ( + 2.3 SD ) , ox and rolone 7.9 cm/yr ( + 3.7 SD ) , and combination therapy 9.8 cm/yr ( + 5.4 SD ) . Mean bone ages advanced 1.0 years ( hGH ) , 1.3 years ( ox and rolone ) , and 1.6 years ( combination ) . However , median increments in height age/bone age ( delta HA/delta BA ) ratios ranged from 1.0 to 1.1 for treatment groups , compared with 0.8 for the controls . Predicted adult height by the method of Bayley-Pinneau increased 2.5 cm for hGH or ox and rolone alone , and 3.2 cm for combination treatment . These data indicate that both hGH and ox and rolone can significantly stimulate short-term skeletal growth in patients with Turner syndrome , and potentially increase final adult height In 1987 a multicentre trial of recombinant human growth hormone ( GH ) was started in girls with Turner syndrome . Fifty-four patients were r and omly assigned to receive GH , 8 IU/m2 3 times/week ( group 1 ) , or 4 IU/m2 6 times/week ( group 2 ) . In addition , the 35 patients older than 12 years received ethinyloestradiol , 100 ng/kg body weight/day , and after 2 years GH therapy was increased to 6 IU/m2 6 times/week . Recombinant human GH treatment was stopped when the height increment during the previous 6 months of treatment was less than 0.5 cm . Treatment has so far been stopped in 48 patients : treatment was stopped early in 2 patients due to lack of motivation , 1 patient died suddenly and the treatment protocol was completed in 45 patients . The last height measurement obtained , which was considered as ( near ) final height , was 152.3 + /- 5.3 cm ( mean + /- SD ) in these patients , which is higher ( p < 0.001 ) than the adult height of 147.0 + /- 6.3 cm reported in 63 untreated adult Dutch patients with Turner syndrome . No differences in outcome were found between the two dose regimens The aims of this comparative multicenter study of 67 girls with Turner syndrome ( TS ) on three different therapeutical regimens were , first , to evaluate the effect of either recombinant human growth hormone ( GH ) alone or in combination with the anabolic steroid ox and rolone ( Oxa ) on height velocity and on Turner-specific bone age ( BA'TS ) and , second , to estimate the gain in final height taking the age at the onset of treatment into account . The mean advancement of BA'TS in 2 years of treatment was 2.5 years/2 years in group 1 ( low dose GH : 16 IU/m2/week ) , 2.8 years/2 years in group 2 ( high dose GH : 28 IU/m2/week ) and 3.3 years/2 years in group 3 ( GH : 24 IU/m2/week + Oxa : 0.06 mg/kg/day ) instead of the expected 2 years/2 years advancement in untreated girls with TS . On all treatment regimens the advancement of BA'TS was more pronounced in the younger girls . In many girls with a BA'TS below 9 years at the onset of treatment the increase in height did not outweigh the advancement in BA'TS , suggesting that starting growth-promoting treatment before 9 years would not be the best way to improve final height . In our opinion , the optimal age for starting growth-promoting therapy is at 9 years . A start at a younger age might have no advantage in regard of an ultimate gain in final height . On the other h and , therapy should not be delayed much after the age of 9 years giving the girls with TS the possibility to catch up substantially before estrogen treatment is initiated Seventy girls with Turner syndrome , verified by karyotype , were r and omly assigned to observation or treatment with human growth hormone ( hGH ) , ox and rolone , or a combination of hGH plus ox and rolone for a period of 12 to 24 months , to assess the effect of treatment on growth velocity and adult height . Subsequently , all subjects received either hGH alone or hGH plus ox and rolone . Data are presented for 62 subjects treated for a period of 3 to 6 years . When compared with the anticipated growth rate in untreated patients , the growth rate after treatment with hGH , both alone and in combination with ox and rolone , showed a sustained increase for at least 6 years . Treatment is continuing in over half of the subjects ; at present , 14 ( 82 % ) of 17 girls receiving hGH alone and 41 ( 91 % ) of 45 girls receiving combination therapy exceeded their expected adult heights .  Thirty girls have completed treatment ; mean height for these 30 patients is 151.9 cm , compared with their mean original projected adult height of 143.8 cm . We conclude that therapy with hGH , alone and in combination with ox and rolone , can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome BACKGROUND Short stature and ovarian failure are characteristic features of Turner 's syndrome . Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome , a r and omized , placebo-controlled trial is needed to document whether such treatment increases adult height . Furthermore , it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit . We examined the independent and combined effects of growth hormone and early , ultra-low-dose estrogen on adult height in girls with Turner 's syndrome . METHODS In this double-blind , placebo-controlled trial , we r and omly assigned 149 girls , 5.0 to 12.5 years of age , to four groups : double placebo ( placebo injection plus childhood oral placebo , 39 patients ) , estrogen alone ( placebo injection plus childhood oral low-dose estrogen , 40 ) , growth hormone alone ( growth hormone injection plus childhood oral placebo , 35 ) , and growth hormone-estrogen ( growth hormone injection plus childhood oral low-dose estrogen , 35 ) . The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week . The doses of ethinyl estradiol ( or placebo ) were adjusted for chronologic age and pubertal status . At the first visit after the age of 12.0 years , patients in all treatment groups received escalating doses of ethinyl estradiol . Growth hormone injections were terminated when adult height was reached . RESULTS The mean st and ard-deviation scores for adult height , attained at an average age of 17.0±1.0 years , after an average study period of 7.2±2.5 years were -2.81±0.85 , -3.39±0.74 , -2.29±1.10 , and -2.10±1.02 for the double-placebo , estrogen-alone , growth hormone-alone , and growth hormone-estrogen groups , respectively ( P<0.001 ) . The overall effect of growth hormone treatment ( vs. placebo  ) on adult height was a 0.78±0.13 increase in the height st and ard-deviation score ( 5.0 cm ) ( P<0.001 ) ; adult height was greater in the growth hormone-estrogen group than in the growth hormone-alone group , by 0.32±0.17 st and ard-deviation score ( 2.1 cm ) ( P=0.059 ) , suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone . CONCLUSIONS Our study shows that growth hormone treatment increases adult height in patients with Turner 's syndrome . In addition , the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement . ( Funded by the National Institute of Child Health and Human Development and Eli Lilly ; Clinical Trials.gov number , NCT00001221 . ) In 1983 , a multicenter , collaborative , prospect i ve study was begun to investigate the efficacy of human growth hormone ( hGH ) , alone and in combination with ox and rolone , in girls with Turner syndrome . While subjects in the control group grew 3.8 cm/yr ( -0.1 SD for untreated Turner patients ) , subjects receiving hGH alone  grew 6.6 , 5.4 and 4.6 cm/yr in years 1 - 3 , respectively ( + 3.1 , + 2.0 , + 1.4 SD ) . Subjects in the combination therapy group grew 9.8 , 7.4 and 6.1 cm/yr ( + 6.6 , + 4.3 , + 3.0 SD ) . Turner subjects in both treatment groups showed increased in Bayley-Pinneau predicted adult heights and in Turner projected adult heights Beginning in 1983 , 71 girls with Turner syndrome were enrolled in a prospect i ve , r and omized study of human growth hormone ( hGH ) , alone and in combination with ox and rolone ; 4 - 5 patient-year data are currently available on 66 subjects . While the annual growth rate of the untreated control group ( expressed as a Z score for untreated Turner girls ) was -0.1 SD , the annual Turner growth rate Z scores for girls receiving hGH alone were + 3.1 , + 2.0 , + 1.5 and + 2.9 SD for years 1 - 4 , respectively ( hGH was given daily in year 4 ) . mean annual Turner growth rate Z scores for subjects on combination therapy with ox and rolone were + 6.6 , + 4.3 , + 3.0 and + 2.7 SD for years 1 - 4 , respectively . The mean height for the 20 subjects greater than or equal to 16 years of age is 150 cm Preliminary results are presented after 2 years of the Canadian long-term multicentre study on the impact of hormone therapy on the final height , sexual development and psychological status of girls with Turner syndrome . Girls entering the study were r and omized either to be treated with recombinant human growth hormone or to act as controls . Both groups received oestrogen replacement therapy in the same dose and format at the age of 13 years . However , for the purpose s of the psychological study at this time , children receiving oestrogen were excluded from analysis . Girls treated with GH for a period of 2 years showed a significant increase in growth rate , which declined with continued treatment , while the growth rate in the control group remained constant throughout . There was a correlation between the higher growth rate and the girls ' perceptions of themselves as more intelligent , more attractive , having more friends , greater popularity and experiencing less teasing than the untreated group . Growth rate was not correlated with family or school functioning In the Dutch growth hormone ( GH ) registration data base there are currently 552 GH-deficient children being treated , subcutaneously , with recombinant human GH six to seven times per week . Of those , 112 who have been treated for at least 2 years have reached final height . Mean age at start of therapy was 11.70 years . Mean GH dose was 15.5 IU/m2 body surface per week . Mean final height  was 173.2 cm ( boys ) and 159.7 cm ( girls ) and –1.36 SD of the population mean . Of the patients , 73.2 % and 63.4 % , respectively , reached a final height  above –2 SD of the population or within target limits . FH-SDS was higher compared with the results of earlier cohorts with different treatment regimens . Target height , GH peak value at diagnosis , age at start of GH therapy , height SDS ( HSDS ) at start of puberty , and duration of GH therapy were significantly correlated with final height . These results , combined with those of a prospect i ve GH dose-response study , suggest that better long-term results can be obtained with early and prolonged treatment and if the GH dose is individually adapted to the short-term growth response . In an ongoing dose-response study , 68 girls with Turner ’s syndrome , aged 2–11 years , were r and omized into three dosage groups with a daily GH dose of : ( group A ) 4 IU/m2 body surface ; ( group B ) 4 IU/m2 in the first year of therapy and 6 IU/m2 thereafter ; ( group C ) 4 IU/m2 in the first year , 6 IU/m2 in the second year , and 8 IU/m2 thereafter . After 4 years of GH therapy , girls aged 12 years or older started low-dose oestrogen therapy . After 7 years of GH  therapy , mean HSDS in all three groups had increased to values above the third percentile for healthy girls . Mean final height and final height gain of 25 girls was 159.1 and 12.5 cm , 161.8 and 14.6 cm , and 162.7 and 16.0 cm in groups A , B and C respectively . These long-term and final height results are more favourable than the results of earlier Dutch Turner ’s syndrome studies . Possible explanations are the higher GH doses and /or the younger age at start of GH therapy Abstract  Final stature in girls with Turner syndrome treated with combination of low dose oestrogen and ox and rolone .  Nineteen prepubertal girls with Turner syndrome ( mean age 10.9 years , range , 8.9–14.2 years ) were r and omly assigned to receive either ox and rolone ( 0.05 mg/kg/day ) or ethinyloestradiol ( 40 ng/kg/day ) for 1 year . Subsequently the alternate therapy was added and the combination given until attainment of final height . Ethinyloestradiol was gradually increased at the age of 12.5 years in order to induce secondary sexual characteristics . The duration of treatment was a mean of 5.2 years ( range , 3–7 years ) when the 1st year of monotherapy was included . Therapy produced a sustained acceleration in growth rate for a duration of 4 years and eventually has result ed in an increment of mean adult height of 3 cm relative to pre-treatment projected height with mean values of 146.5 cm versus 143.5 cm respectively . The moderate side-effects observed did not cause any of the girls to discontinue treatment . Nevertheless , amelioration of adult height appears to be modest , notably in comparison to published data of growth hormone treatment and 4 girls had a decrease in final height prediction . Conclusion Combination of low dose of ox and rolone and oestrogen may have a moderate but positive impact on final height  in girls with Turner syndrome . However , some girls do worse than predicted in term of final height using this regimen . Oestrogen therapy started at low dose around the age of 10 years and increased gradually at approximately 12.5 years to induce secondary sexual characteristics does not have a deleterious effect on adult height in Turner syndrome . In summary , low dose ox and rolone-oestrogen treatment was found to accelerate the tempo of growth in girls with Turner syndrome , but did not appear to have a consistent effect on final height Background There are limited long-term r and omized controlled trials of growth hormone ( GH ) supplementation to adult height and few published reports of the health-related quality of life ( HRQOL ) following treatment . The present follow-up study of young adults from a long-term controlled trial of GH treatment in patients with Turner syndrome ( TS ) yielded data to examine whether GH supplementation result ed in a higher HRQOL ( either due to taller stature or from the knowledge that active treatment and not placebo had been received ) or alternatively a lower HRQOL ( due to medicalization from years of injections ) . Methods The original trial r and omized 154 Canadian girls with TS aged 7 - 13 years from 13 centres to receive either long-term GH injections at the pharmacologic dose of 0.3 mg/kg/week or to receive no injections ; estrogen prescription for induction of puberty was st and ardized . Patients were eligible for the follow-up study if they were at least 16 years old at the time of follow-up . The instrument used to study HRQOL was the SF-36 , summarized into physical and mental component scales ( PCS and MCS ) ; higher scores indicate better HRQOL . Results Thirty-four of the 48 eligible participants ( 71 % ) consented to participate ; data were missing for one patient . Both groups ( GH and no treatment ) had normal HRQOL at this post-treatment assessment . The GH group had a ( mean ± SD ) PCS score of 56 ± 5 ; the untreated group 58 ± 4 ; mean score for 16 - 24 year old females in the general population 53.5 ± 6.9 . The GH group had a mean MCS score of 52 ± 6 ; the untreated group 49 ± 13 ; mean score for 16 - 24 year old females in the general population 49.6 ± 9.8 . Secondary analyses showed no relationship between HRQOL and height . Conclusions We found no benefit or adverse effect on HRQOL either from receiving or not receiving growth hormone injections in a long-term r and omized controlled trial , confirming larger observational studies . We suggest that it remains ethically acceptable as well as necessary to maintain a long-term untreated control group to estimate the effects of pharmacological agents to manipulate adult height . Young adult women with TS have normal HRQOL suggesting that they adjust well to their challenges in life . Trial Registration Clinical Trials.gov Identifier NCT00191113 The Genentech National Cooperative Study of growth hormone ( GH ) therapy in Turner 's syndrome was initiated in 1983 ; 70 girls with Turner 's syndrome were r and omly assigned to observation or to treatment with GH alone , ox and rolone alone , or a combination of GH plus ox and rolone for a period of 12 - 24 months . After completion of this phase , patients receiving GH alone were continued on GH , while all other patients received the combination of GH plus ox and rolone . Data are currently available on the 62 girls who were treated for a minimum of 3 - 6 years . When compared with the height velocities anticipated for girls of comparable ages with untreated Turner 's syndrome , both GH alone and a combination of GH plus ox and rolone result ed in an increase in height velocity , which was most prominent during the first 2 years of treatment and was sustained for at least 6 years . Although GH therapy is continuing at present in half of the patients , 14 of 17 girls ( 82 % ) receiving GH alone and 42 of 45 girls ( 93 % ) receiving combination therapy have exceeded their projected adult heights . For the 30 girls who have stopped therapy , the current mean height is 151.9 cm , compared with their original mean projected adult height of 143.8 cm . These results demonstrate that GH therapy can result in short-term ( 3 - 6 years ) acceleration of growth , as well as in improved adult height Objective To examine the effect of ox and rolone and the timing of pubertal induction on final height in girls with Turner ’s syndrome receiving a st and ard dose of growth hormone . Design R and omised , double blind , placebo controlled trial . Setting 36 paediatric endocrinology departments in UK hospitals . Participants Girls with Turner ’s syndrome aged 7 - 13 years at recruitment , receiving recombinant growth hormone therapy ( 10 mg/m2/week ) . Interventions Participants were r and omised to ox and rolone ( 0.05 mg/kg/day , maximum 2.5 mg/day ) or placebo from 9 years of age . Those with evidence of ovarian failure at 12 years were further r and omised to oral ethinylestradiol ( year 1 , 2 µg daily ; year 2 , 4 μg daily ; year 3 , 4 months each of 6 , 8 , and 10 μg daily ) or placebo ;  participants who received placebo  and those recruited after the age of 12.25 years  started ethinylestradiol at age 14 . Main outcome measure Final height . Results 106 participants were recruited , of whom 14 withdrew and 82/92 reached final height . Both ox and rolone and late pubertal induction increased final height : by 4.6 ( 95 % confidence interval 1.9 to 7.2 ) cm ( P=0.001 , n=82 ) for ox and rolone and 3.8 ( 0.0 to 7.5 ) cm ( P=0.05 , n=48 ) for late pubertal induction with ethinylestradiol . In the 48 children who were r and omised twice , the effects on final height ( compared with placebo and early induction of puberty ) of ox and rolone alone , late induction alone , and ox and rolone plus late induction were similar , averaging 7.1 ( 3.4 to 10.8 ) cm ( P<0.001 ) . No cases of virilisation were reported . Conclusion Ox and rolone had a positive effect on final height in girls with Turner ’s syndrome treated with growth hormone , as did late pubertal induction with ethinylestradiol at age 14 years . However , these effects were not additive , so using both had no advantage . Ox and rolone could , therefore , be offered as an alternative to late pubertal induction for increasing final height in Turner ’s syndrome . Trial registration Current Controlled Trials IS RCT N50343149 91 girls with Turner syndrome ( TS ) with a mean chronological age ( CA ) and bone age ( BA ) of 10.3 + /- 2.3 and 8.9 + /- 1.9 years , respectively , were r and omly assigned to subcutaneous treatment with recombinant human growth hormone ( rhGH ) alone ( n = 47 ) , 2.6 IU/m2 body surface area daily or combination treatment ( n = 44 ) with the same dose of rhGH and ox and rolone 0.1 mg/kg body weight orally , for the first 12 months of this study . During the 1st year of therapy , there was a striking increase in height velocity ( HV ) in both groups , from 4.0 + /- 0.8 to 6.3 + /- 1.3 cm/year [ HV st and ard ( st and ards of untreated Turner patients ) deviation score ( SDS ) for CA from 0.0 + /- 0.7 to 2.9 + /- 1.3 ] in the rhGH group and from 4.2 + /- 1.2 to 8.5 + 2- 1.7 cm/year ( HV SDS-CA from + 0.3 + /- 1.0 to 5.6 + /- 1.6 ) in the combination group . The difference between the groups was statistically significant ( p < 0.01 ) . During the 2nd year of treatment , the rhGH dose was increased to 3.4 IU/m2 daily for the rhGH-alone group , whereas in the combination treatment group the ox and rolone dose was reduced to 0.05 mg/kg daily . HV was maintained at significantly higher levels than those prior to treatment , at 5.3 + /- 1.1 cm/year ( HV SDS-CA : + 2.1 + /- 1.3 ) and 6.2 + /- 1.5 cm/year ( HV SDS-CA : + 3.6 + /- 1.4 ) in the rhGH-alone and the combination group , respectively ( p < 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVE To determine the influence of the injection frequency and the initial bone age on the efficacy of treatment with biosynthetic growth hormone in Turner 's syndrome . DESIGN R and omized study . SETTING Referral-based pediatric endocrinology departments of seven university medical centers . PATIENTS Fifty-two patients with Turner 's syndrome confirmed with chromosomal analysis . TREATMENT Somatotropin recombinant DNA ( 24 IU/m2 of body surface area ) subcutaneously administered in three or six injections per week for 2 years . Patients who were older than 12 years at the beginning of the study received low doses of estrogen . RESULTS The following statistically significant findings supported the use of six injections per week compared with three injections per week : the mean ( + /- SD ) increment in height during 2 years was 11.3 cm ( 3.8 cm ) with six injections vs 8.6 cm ( 3.4 cm ) with three injections ; the increment in height st and ard deviation score was 0.9 cm ( 0.5 cm ) vs 0.6 cm ( 0.3 cm ) ; the growth velocity was 6.6 cm/y ( 2.0 cm/y ) vs 5.2 cm/y ( 1.7 cm/y ) in year 1 and 4.7 cm/y ( 2.0 cm/y ) vs 3.4 cm/y ( 1.7 cm/y ) in year 2 ; and the increment in height st and ard deviation score for bone age was 0.8 cm ( 0.5 cm ) vs 0.4 cm ( 0.6 cm ) . For patients whose initial bone age was more than 13 years , growth velocity increased by 1 to 2 cm in year 1 ; in year 2 no increment was observed . We did not observe adverse effects . CONCLUSIONS Biosynthetic growth hormone in a higher-frequency regimen in Turner 's syndrome is more efficient in terms of increment in height , growth velocity , and height st and ard deviation score for bone age than treatment in a lower-frequency regimen . In patients with an initial bone age of more than 13 years , the response was poor . Longer follow-up is necessary to assess the effect on final height Clinical trials of recombinant human GH therapy in Turner syndrome that began more than a decade ago show that GH accelerates the linear growth rate . Several studies indicate that final height is also improved , although the magnitude of the increase has been debated . The age at which feminization is induced could be an important factor in determining the patient 's ultimate growth response . To test this , 60 patients from a large ( n = 117 ) , previously unreported , clinical trial of GH treatment were r and omly assigned to begin conjugated estrogens at either 12 or 15 yr of age . The 60 patients were all less than 11 yr of age at entry ( mean , 9.5 yr ) and received 0.375 mg/kg x week of GH for nearly 6 yr on a daily or three times weekly regimen . Height gain was calculated by comparing the study patients ' final or near final heights to their pretreatment projected heights as well as to those of a separate set of age-matched , historical control patients . Patients in whom estrogen treatment was delayed until age 15 yr gained an average of 8.4 + /- 4.3 cm over their projected height , whereas those starting estrogen at 12 yr gained only 5.1 + /- 3.6 cm , on the average ( P < 0.01 ) . Analysis of the interval data showed that growth was stimulated for approximately 2 yr after estrogen initiation , but then declined in association with bone age advancement . Patients who were older than 11 yr at entry ( n = 57 ) all initiated  estrogen  1 yr after beginning GH and showed a mean gain in adult height of 4.7 cm , similar to those given estrogen at age 12 yr . Multivariate analysis revealed that the number of years of GH therapy before estrogen  treatment was a strong factor in predicting height gained , indicating that the timing of estrogen introduction is an important determinant of final height in this cohort of GH-treated patients with Turner syndrome matched for baseline age and other characteristics 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 Forty patients with Turner 's syndrome , aged 5.0 - 16.6 yr , were r and omly allocated to receive daily sc injections of recombinant human GH ( hGH ) at a dose of 1 IU/kg.week alone ( group I ) or in combination with 25 ng/kg.day ethinyl estradiol ( E2 ; group II ) . The mean pretreatment height velocity was 3.8 cm/yr for both groups . During the first year of treatment height velocity increased significantly ( P less than 0.001 ) in both groups , to 7.5 + /- 1.3 and 8.1 + /- 1.6 cm/yr , respectively . The difference between the two groups was not significant . The mean ( + /- SD ) height velocity expressed as the SD score for chronological age ( Turner references ) was 0.0 + /- 1.2 for group I and 0.2 + /- 1.4 for group II and increased significantly ( P less than 0.001 ) during the first year of treatment to + 4.3 + /- 1.1 in group I and + 5.4 + /- 1.2 in group II . The difference between both groups was statistically significant ( P less than 0.01 ) . Height SD score for chronological age ( Turner references ) increased from -0.2 + /- 0.9 to + 0.6 + /- 1.0 in group I and from -0.2 + /- 1.0 to + 0.7 + /- 1.1 in group II . Mean bone age progressed similarly in both treatment groups ( 1.1 + /- 0.6 yr during 1 yr of treatment ) . However , bone age maturation accelerated more rapidly in younger patients . Twelve girls ( three in group I and nine in group II ) had minor breast development . No major adverse effects were reported . We conclude that daily sc therapy with hGH stimulates height velocity in Turner 's syndrome . The beneficial effect on height velocity increment of E2 addition was small . Furthermore , even very low doses of E2 may induce breast development at an early age and accelerate bone maturation . For these reasons , the addition of E2 to hGH is not warranted in young patients with Turner 's syndrome Short stature and ovarian failure are the main features in Turner syndrome ( TS ) . To optimize GH and estrogen treatment , we studied 68 previously untreated girls with TS , age 2 - 11 yr , who were r and omly assigned to one of three GH dosage groups : group A , 4 IU/m2 day ( approximately 0.045 mg/kg x day ) ; group B , first yr 4 , thereafter 6 IU/m2 x day ( approximately 0.0675 mg/kg/day ) ; group C , first yr 4 , second yr 6 , thereafter 8 IU/m2 x day ( approximately 0.090 mg/kg x day ) . In the first 4 yr of GH treatment , no estrogens for pubertal induction were given to the girls . Thereafter , girls started with 17beta-estradiol ( 5 microg/kg bw x day , orally ) when they had reached the age of 12 yr . Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved . Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood . After 7 yr , 85 % of the girls had reached a height within the normal range for healthy Dutch girls . The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition , we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr ( range , 5.0 - 8.75 ) . Mean ( SD ) height was 158.8 cm ( 7.1 ) , 161.0 cm ( 6.8 ) , and 162.3 cm ( 6.1 ) in groups A , B , and C , respectively . The mean ( SD ) difference between predicted adult height before treatment and achieved height was 12.5 cm ( 2.1 ) , 14.5 cm ( 4.0 ) , and 16.0 cm ( 4.1 ) for groups A , B , and C , respectively , being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups . In conclusion , GH treatment starting in relatively young girls with TS results in normalization of height during childhood , as well as of adult height , in most of the individuals . With this GH and estrogen treatment regimen , most girls with TS can grow and develop much more in conformity with their healthy peers BACKGROUND Turner syndrome accounts for 15–20 % of childhood usage of growth hormone ( GH ) in the UK but final height benefit remains uncertain . The most effective strategy for oestrogen replacement is also unclear . METHODS Fifty eight girls who , at start of treatment , were of mean age 9.1 years and projected final height 142.2 cm were r and omised to receive in year 1 , either low dose ethinyloestradiol 50–75 ng/kg/day , GH 28 IU/m2 surface area/week as a daily injection , or a combination of ethinyloestradiol and GH . After the first year , the ethinyloestradiol treated girls received combination treatment . After two years , girls aged over 12 years were given escalating ethinyloestradiol to promote pubertal development . RESULTS  Near final height was available for 49 girls at age 16.5 years , 146.8 cm , representing a gain of 4.6 cm , range −7.9 to + 11.7 cm . Twelve of the 49 girls gaining 7.5 cm or more were less than 13 years at the start and had received GH for at least four years . Height gain was correlated with greater initial height deficit . Fifteen girls ( 31 % ) reached 150 cm or more compared to a predicted 10 % . Early supplementation with ethinyloestradiol  provided no final height advantage . CONCLUSIONS Final height gain was modest at 4.6 cm . Younger , shorter girls gained greatest height advantage from GH . Low dosage ethinyloestradiol before planned induction of puberty was not beneficial To optimize the growth promoting effect of growth hormone ( GH ) , 65 previously untreated girls with Turner syndrome ( TS ) , chronological age ( CA ) 2 - 11 yr , were r and omized into 3 dosage regimen groups : A , B , and C , with a daily recombinant-human GH dose during 4 study years of 4 - 4 - 4 - 4 , 4 - 6 - 6 - 6 , and 4 - 6 - 8 - 8 IU/m2 b.s . The first GH dosage increase in groups B and C result ed in a significantly higher mean height velocity ( HV ) compared with constant dose group A. During the third year , when the dose was raised again only in group C , mean HV was significantly higher in groups B and C than in group A , and in group C compared with group B. In year 4 only group C mean HV remained significantly higher than group A. The pattern of change in HSDSCA ( Dutch-Swedish-Danish Turner references ) was identical ; however , in year 4 mean delta HSDSCA in group B also remained significantly higher than group A. After 4 yr GH treatment , the following was determined . 1 ) The mean delta HSDSCA was significantly higher for groups B and C compared with group A , but not significantly different between groups B and C. 2 ) Although significantly higher compared with estimated values for untreated Dutch girls with TS , bone maturation of the GH treated girls was not significantly different between groups . 3 ) It was positively related with the degree of bone age ( BA ) retardation at start of study and negatively with baseline CA . 4 ) Both the modified Index of Potential Height ( mIPHRUS ) and a recently developed Turner-specific final height ( FH ) prediction method ( PTSRUS ) , based on regression coefficients for H , CA , and bone age , showed significant increases in mean FH prediction , without significant differences between groups . PTSRUS values were markedly higher than the mIPHRUS values . Dose dependency could be shown for the area under the curve ( AUC ) for GH , but delta HSDSCA was not linearly related with AUC . Baseline GH binding protein ( BP ) levels were in 84 % of the cases within the normal age range ; the decrease in mean levels after 6 months GH was not significant . Mean insulin-like growth factor I ( IGF-I ) and IGFBP-3 plasma levels increased significantly , without significant differences between groups . delta HSDSCA during GH was dependent on IGF-I plasma levels at baseline and during the study period , beta-0.002 and beta-0.0004 . Thus , a stepwise GH-dosing approach reduced the " waning " effect of the growth response after 4 yr treatment without undue bone maturation . FH prediction was not significantly different between treatment groups . Irrespective of the GH dose used , initiation of GH treatment at a younger age was beneficial after 4 yr GH when expressed as actual cm gained or as gain in FH prediction , but was not statistically significant when expressed as delta HSDSCA over the study period
Skeletal maturity was not accelerated by treatment with recombinant growth hormone ( hGH ) .
Adverse effects were minimally reported .
There is little evidence of serious short-term adverse effects in these trials , but they are underpowered to detect rare adverse effects .
REVIEW ER 'S CONCLUSIONS Recombinant human growth hormone ( hGH ) doses between 0.3 - 0.375 mg/kg/wk increase short-term growth in girls with Turner Syndrome ( TS ) by approximately 3 cm in the first year of treatment and by approximately 2 cm per year after 2 years of treatment .
There is little evidence on the effects of hGH on final height .
BACKGROUND Turner syndrome ( TS ) affects about one in 1,500 to 2,500 live-born females .
One of the most prevalent and salient features of the syndrome is extremely short stature .
Untreated women are approximately 20 - 21 cm shorter than normal women within their respective population s. Recombinant human growth hormone ( hGH ) has been used to increase growth and final height in women who have Turner syndrome .
OBJECTIVES To assess the effects of recombinant growth hormone on short-term growth and final height in children and adolescents with Turner syndrome .