title: Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. Body proportions during long-term growth hormone treatment in girls with Turner syndrome participating in a randomized dose-response trial. Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. 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. Acceleration of growth in Turner syndrome patients treated with growth hormone: summary of three-year results. 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. Growth hormone therapy in Turner's syndrome. Impact of injection frequency and initial bone age. Final height in girls with Turner’s syndrome treated with once or twice daily growth hormone injections Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner's syndrome. Recombinant human growth hormone and oxandrolone in treatment of short stature in girls with Turner syndrome. Growth hormone therapy of Turner's syndrome: beneficial effect on adult height. Treatment with two growth hormone regimens in girls with Turner syndrome: final height results. Dutch Growth Hormone Working Group. Three years of GH treatment in Turner's syndrome: complex effect of GH dosage on growth parameters Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., Collaborative Study Group. A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis Growth response and levels of growth factors after two years growth hormone treatment are similar for a once and twice daily injection regimen in girls with Turner syndrome Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. Growth hormone therapy in Turner's syndrome: one versus two daily injections. Treatment of patients with Ullrich-Turner syndrome with conventional doses of growth hormone and the combination with testosterone or oxandrolone: Effect on growth, IGF-I and IGFBP-3 concentrations Absence of growth hormone effects on cognitive function in girls with Turner syndrome. Growth hormone therapy in Turner's syndrome: an update on final height. Genentech National Cooperative Study Group. Final Height of Growth Hormone-Treated GH-Deficient Children and Girls with Turner’s Syndrome: The Dutch Experience Three-year results of treatment with growth hormone, alone or associated with oxandrolone, in girls with Turner syndrome. The Kabi Collaborative Study Group.
abstract: 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 To assess body proportions in girls with Turner syndrome ( TS ) during long term GH treatment , height , sitting height ( SH ) , h and ( H and ) and foot ( Foot ) lengths , and biacromial ( Biac ) and biiliacal ( Biil ) diameters were measured in 68 girls with TS participating in a GH dose-response trial . These previously untreated girls with TS , aged 2 - 11 yr , were r and omly assigned to 1 of 3 GH dosage groups : group A , 4 IU/m2 x day ; group B , first year 4 and thereafter 6 IU/m2 x day ; group C , first year 4 , second year 6 , and thereafter 8 IU/m2 x day . Seven-year data were evaluated to assess the effect of GH treatment on body proportions during childhood . In addition , data from all girls who had reached adult height were evaluated to determine the effect on the adult body proportions . All results were adjusted for age and sex and expressed as SD scores using reference values of healthy Dutch girls . To describe the proportions of SH , H and , Foot , Biac , and Biil to height , these values were adjusted for the SD score of height and were expressed as shape values , using the formula , e.g. for SH : shape SH = ( SH SD score - height SD score)/square root(2 - 2 x correlation coefficient between SH and height in the reference population ) . Furthermore , SD scores using references of untreated girls with TS were calculated for height and SH . Values less than -2 or more than + 2 were considered outside the normal range . At baseline , the shape values of all measurements were significantly higher than zero , but most mean shape values were still within the normal range . Seven-year data of 64 girls and adult height data of 32 girls showed that an increase in height was accompanied by an even higher increase in Foot , result ing in mean SD scores above zero and shape values of + 2 and higher . The increase in the shape value of Foot was significantly higher in groups B and C compared to that in group A after 7 yr of GH treatment , but there were no significant differences between the GH dosage groups in the girls who had reached adult height . The shape values of SH had decreased to values closer to zero after reaching adult height , especially in group A. A similar pattern in the relationship of SH to height was seen using references of girls with TS . No significant changes in the other proportions were found after reaching adult height . In conclusion , on the average , untreated girls with TS have relatively large trunk , h and s , and feet , and broad shoulders and pelvis compared to height . The increase in height after long term GH treatment is accompanied by an even higher increase in Foot and a moderate improvement of the disproportion between height and SH . Recently published reference data from untreated adults with TS and the results of a different patient group receiving a comparable GH dosage suggest that the disproportionate growth of feet has to be considered a part of the natural development in TS , but might be influenced by higher GH dosages . The development of large feet can play a role in the decision of the girl to discontinue GH treatment in the last phase of growth 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 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 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 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 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 OBJECTIVES To study final height in girls with Turner ’s syndrome treated with once or twice daily injections of growth hormone ( GH ) in combination with low dose ethinyl oestradiol . DESIGN Until final height was reached , the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day . Twice daily injections were given as one third in the morning and two thirds at bedtime . All girls concurrently received low dose oestradiol ( 0.05 μg ethinyl oestradiol/kg/day , increased to 0.10 μg/kg/day after 2.25 years ) . PATIENTS Nineteen girls with Turner ’s syndrome aged ⩾ 11 years ( mean ( SD ) 13.6 ( 1.7 ) years ) . MEASUREMENTS To determine final height gain , we assessed the difference between the attained final height and the final height predictions at the start of treatment . These final height predictions were calculated using the Bayley-Pinneau ( BP ) prediction method , the modified projected adult height ( mPAH ) , the modified index of potential height ( mIPHRUS ) , and the Turner ’s specific prediction method ( PTSRUS ) . RESULTS The gain in final height ( mean ( SD ) ) was not significantly different between the once daily and the twice daily regimens ( 7.6 ( 2.3 ) v 5.1 ( 3.2 ) cm ) . All girls exceeded their adult height prediction ( range , 1.6–12.3 cm ) . Thirteen of the 19 girls  had a final height gain > 5.0 cm . Mean ( SD ) attained final height was 155.5 ( 5.4 ) cm . A “ younger bone age ” at baseline and a higher increase in height st and ard deviation score for chronological age ( Dutch – Swedish – Danish references ) in the first year of GH treatment predicted a higher final height gain  after GH treatment . CONCLUSIONS Division of the total daily GH dose ( 6 IU/m2/day ) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain . Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner ’s syndrome , even if they start GH treatment at a relatively late age 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 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 OBJECTIVE To carry out a multicenter , prospect i ve , r and omized trial of human growth hormone ( GH ) , alone or in combination with ox and rolone ( OX ) , in patients with Turner 's syndrome ( TS ) . METHODS In an initial phase lasting 12 to 24 months , 70 girls with TS , verified by karyotype , were r and omly assigned to one of four groups : ( 1 ) observation , ( 2 ) OX , ( 3 ) GH , or ( 4 ) GH plus OX . After completion of the first phase , group 3 subjects continued to receive GH only . All other subjects were treated with GH plus OX . Subjects were followed up until attainment of adult height and /or cessation of treatment . Data from this trial were compared with growth characteristics of 25 American historical subjects with TS ( matched for age , height , parental target height , and karyotype ) who never received either GH or and rogens .  RESULTS Of the 70 subjects enrolled , 60 completed the clinical trial . The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm ( mean + /- SD ) , 8.4+/-4.5 cm taller than their mean projected adult height at enrollment ( 95 % confidence interval [ CI ] : 6.3 to 10.6 cm ) . The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm , 10.3+/-4.7 cm taller than their mean projected adult height ( 95 % CI : 8.9 to 11.7 cm ) . The historical control subjects had a mean adult height of 144.2+/-6.0 cm , precisely matching their original projected adult height of 144.2+/-6.1 cm . CONCLUSIONS GH , either alone or in combination with OX , is capable of stimulating short-term growth and augmenting adult height in girls with TS . With early diagnosis and initiation of treatment , an adult height of more than 150 cm is a reasonable goal for most girls with TS 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 OBJECTIVE There have been few studies of GH dose responses in Turner 's syndrome . We have therefore compared the growth effect of two doses of subcutaneous rGH : 0.45 ( D1 ) or 0.90 ( D2 ) IU/kg/week 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 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 GH is known to improve height velocity in girls with Turner syndrome ( TS ) but the optimal dosage regimen has yet to be defined 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 In 44 girls with Turner 's syndrome , aged 4.0 - 15.3 yr , the effects of biosynthetic GH ( 25 U/m2.week ) given as once daily or twice daily injections were compared . During 1 yr of treatment , the growth rate increased similarly by 3.5 + /- 1.3 cm/yr in the once daily group and 2.7 + /- 1.8 cm/yr in the twice daily group . Although pretreatment height velocity was negatively related to age , the increase in height velocity during therapy was not . The mean progression in bone age ( TW2-RUS method ) , during therapy was 1.3 yr in both groups . No significant change in the median insulin secretory response to an oral glucose tolerance test was found . Serum cholesterol and triglyceride concentrations did not change significantly throughout the study in either treatment group . Thyroid hormone concentrations remained within normal limits . Normal increments in left ventricular wall thickness and left ventricular mass for age and body surface were observed after 1 yr of GH treatment . We conclude that division of the daily GH dose given to Turner 's syndrome patients into two injections does not result in either a significantly different growth response or different side-effects from once daily treatment during the first year of therapy Thirty-nine girls with Ullrich-Turner syndrome ( UTS ) ( median age 9.5 years ) were treated with growth hormone ( GH ) with either 12 or 18 IU/m2 per week for 12 months followed by combination therapy with either ox and rolone ( Ox ) ( 0.0625 mg/kg/day po ) or low-dose testosterone ( T ) ( 5 mg i m every 2 weeks ) . Growth velocity improved significantly after 12 IU/m2 per week ( 6.4±1.7 cm/year vs 4.0±1.3 cm/year , x±SD , P<0.001 ) and 18 IU/m2 per week of GH ( 6.5±1.3 cm/year vs 4.5±1.4 cm/year , P<0.001 ) . Ox , but not T was effective in maintaining growth velocity during the 2nd year of therapy ( 6.9±1.3 vs 5.3±1.5 cm/year ) . Basal insulin-like growth factor-I ( IGF-I ) concentrations were in the lower normal range and increased significantly in patients treated with 18 IU/m2 per week ( 357±180 ng/ml vs 160±84 ng/ml ) and 12 IU/m2 per week ( 273±121 ng/ml vs 140±77 ng/ml ) . IGF-I concentrations increased further after addition of Ox ( 533±124 ng/ml , P<0.001 ) or T ( 458±158,P<0.05 ) . IGFBP-3 concentrations were in the upper normal range before therapy and increased only moderately in both GH dosage groups . However , IGF binding protein-3 ( IGFBP-3 ) concentrations were not affected by additional Ox or T treatment . Conclusions 1 . Conventional GH doses are effective in increasing growth velocity in UTS , especially , when combined with Ox . This additive effect is not evident when GH is combined with low dose T. 2 . Changes in growth velocity are accompanied by an increase of the IGF-I/IGFBP-3 ratio . 3 . Ox obviously acts by increasing IGF-I levels independent of the GH status 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 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 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 22 girls with Turner syndrome aged 10.8 + /- 2.4 years with bone age 8.58 + /- 1.32 years , r and omized in two groups , were treated for 3 years with either growth hormone ( GH ) , 0.1 U/kg daily ( group A ) , or GH , 0.1 U/kg , plus ox and rolone , 0.06 mg/kg ( group B ) . This result ed in a sharp increase in growth rate for the first year of treatment , followed in the second and third years by a growth rate near to the normal mean for age . The growth velocity was better in group B , the difference being significant during the first year only . After 3 years , the predicted adult height had increased by 2.1 cm as a mean in group A and by 4.5 cm in group B , with important individual variations , result ing in a gain of at least 3 cm in 3/10 patients of group A and 9/12 of group B. No metabolic or other side effects occurred . These 3-year data confirm that GH improves the predictable height in Turner girls . They suggest that it may be useful for at least 3 years and that adding a small dose of ox and rolone for 2 years in girls aged more than 8 years could be of good practice . However , earlier and more protracted treatment with GH has to be studied with the hope to better improve the predictable adult height
target: Skeletal maturity was not accelerated by treatment with recombinant growth hormone ( hGH ) .
background: BACKGROUND Turner syndrome ( TS ) affects about one in 1500 to 2500 live-born females .
  One of the most prevalent and salient features of the syndrome is extremely short stature .
  Untreated women are approximately 20 to 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 girls who have Turner syndrome .
  OBJECTIVES To assess the effects of recombinant growth hormone in children and adolescents with TS .