title: Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. 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 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 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: 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 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 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 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 ) .
  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: 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 .