Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome. Growth hormone therapy in Turner's syndrome: an update on final height. Genentech National Cooperative Study Group. Growth hormone therapy of Turner's syndrome: beneficial effect on adult height. Prospective Study Confirms Oxandrolone-Associated Improvement in Height in Growth Hormone-Treated Adolescent Girls with Turner Syndrome The effect of oxandrolone on voice frequency in growth hormone-treated girls with Turner syndrome. The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome 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? Three-year results of treatment with growth hormone, alone or associated with oxandrolone, in girls with Turner syndrome. The Kabi Collaborative Study Group. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome. Favorable Final Height Outcome in Girls with Ullrich-Turner Syndrome Treated with Low-Dose Growth Hormone Together with Oxandrolone Despite Starting Treatment After 10 Years of Age Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. Final height outcome in girls with Turner syndrome treated with a combination of low dose oestrogen and oxandrolone Methionyl human growth hormone and oxandrolone in Turner syndrome: preliminary results of a prospective randomized trial. Androgen-responsive aspects of cognition in girls with Turner syndrome. Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial Demography, auxology and response to recombinant human growth hormone treatment in girls with Turner's syndrome in the Kabi Pharmacia International Growth Study Non-conventional growth hormone therapy in Turner syndrome: the United States experience. Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. 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 Acceleration of growth in Turner syndrome patients treated with growth hormone: summary of three-year results. Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. Recombinant human growth hormone and oxandrolone in treatment of short stature in girls with Turner syndrome. Body proportions during long-term growth hormone treatment in girls with Turner syndrome participating in a randomized dose-response trial. Absence of growth hormone effects on cognitive function in girls with Turner syndrome. The effect of short-term growth hormone or low-dose oxandrolone treatment in boys with constitutional growth delay Results from the First 2 Years of a Clinical Trial with Recombinant DNA‐derived Human Growth Hormone (Somatrem) in Turner's Syndrome Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. 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. Oxandrolone in Girls with Turner's Syndrome 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 Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis Treatment with two growth hormone regimens in girls with Turner syndrome: final height results. Dutch Growth Hormone Working Group. Final height in girls with Turner’s syndrome treated with once or twice daily growth hormone injections Short-term growth hormone treatment in girls with Turner syndrome decreases fat mass and insulin sensitivity: a randomized, double-blind, placebo-controlled, crossover study. Final Height of Growth Hormone-Treated GH-Deficient Children and Girls with Turner’s Syndrome: The Dutch Experience Early treatment with GH alone in Turner syndrome: prepubertal catch-up growth and waning effect. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. Growth promoting treatment normalizes speech frequency in Turner syndrome. Effects of Growth Hormone on Growth, Insulin Resistance and Related Hormones (Ghrelin, Leptin and Adiponectin) in Turner Syndrome
CONTEXT AND OBJECTIVE GH therapy increases growth and adult height in Turner syndrome ( TS ) . The benefit to risk ratio of adding the weak and rogen ox and rolone ( Ox ) to GH is unclear . DESIGN AND PARTICIPANTS A r and omized , placebo-controlled , double-blind , dose-response study was performed in 10 centers in The Netherl and s. One hundred thirty-three patients with TS were included in age group 1 ( 2 - 7.99 yr ) , 2 ( 8 - 11.99 yr ) , or 3 ( 12 - 15.99 yr ) . Patients were treated with GH ( 1.33 mg/m(2 ) . d ) from baseline , combined with placebo ( Pl ) or Ox in low ( 0.03 mg/kg . d ) or conventional ( 0.06 mg/kg . d ) dose from the age of 8 yr and estrogens from the age of 12 yr . Adult height gain ( adult height minus predicted adult height ) and safety parameters were systematic ally assessed . RESULTS Compared with GH+Pl , GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis ( mean + /- sd , 9.5 + /- 4.7 vs. 7.2 + /- 4.0 cm , P = 0.02 ) and per- protocol analysis ( 9.8 + /- 4.9 vs. 6.8 + /- 4.4 cm , P = 0.02 ) . Partly due to accelerated bone maturation ( P < 0.001 ) , adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl ( 8.3 + /- 4.7 vs. 7.2 + /- 4.0 cm , P = 0.3 ) . Breast development was slower on GH+Ox ( GH+Ox 0.03 , P = 0.02 ; GH+Ox 0.06 , P = 0.05 ) , and more girls reported virilization on GH+Ox 0.06 than on GH+Pl ( P < 0.001 ) . CONCLUSIONS In GH-treated girls with TS , we discourage the use of the conventional Ox dosage ( 0.06 mg/kg . d ) because of its low benefit to risk ratio . The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile , except for some deceleration of breast development 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 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 Background / Aims : Untreated girls with Turner syndrome ( TS ) have growth failure , and adult height is , on average , 20 cm less than predicted height . Treatment with growth hormone ( GH ) is now st and ard of care . The objective of this study was to investigate the benefit of adding ox and rolone ( Ox ) to GH in a long-term , r and omized , placebo (Pl)-controlled prospect i ve trial to near adult height in TS . Methods : Prospect i ve , r and omized , Pl-controlled study : 76 girls with TS ( ages 10–14.9 years ) were r and omized to receive Ox ( 0.06 mg/kg/day ) or Pl in combination with GH ( 0.35 mg/kg/week , daily ) over 2 years . Auxologic data , breast and pubic hair Tanner stages , and hormone and lipid levels were measured . Subjects who chose to continue were followed in a 2-year double-blind extension , also received estrogen therapy ( years 3 , 4 ) , and had dual-energy X-ray absorptiometry evaluation of bone density ( years 3 , 4 ) . Results : At year 4 , the change in absolute height and height SDS was greater in the GH/Ox versus GH/Pl group [ 26.2 ± 6.7 vs. 22.2 ± 5.1 cm , analysis of covariance ( ANCOVA ) p < 0.001 ; 1.8 ± 0.9 vs. 1.2 ± 0.7 st and ard deviation scores , ANCOVA p < 0.001 ] . Bone mineral density ( BMD ) of the wrist ( 0.51 ± 0.17 vs. 0.54 ± 0.05 g/cm2 ) and spine ( 0.91 ± 0.34 vs. 0.96 ± 0.13 g/cm2 ) in the GH/Ox versus GH/Pl groups was similar after 4 years . Breast development was slower in the GH/Ox versus GH/Pl group [ year 4 : Tanner stage 2.9 ±1.3 ( Ox ) vs. 4.1 ± 1.3 ( Pl ) , p = 0.003 ] , and menarche was approximately 1 year later . Conclusions : The addition of Ox to GH at mean age 12.0 ± 1.7 year augmented height gain after 4 years of treatment , slowed breast development and did not affect BMD in girls with TS . Whether initiation of Ox prior to initiation of pubertal development would optimize height gain without impeding breast development will require further study OBJECTIVES /HYPOTHESIS Ox and rolone ( Ox ) increases height gain but may also cause voice deepening in growth hormone (GH)-treated girls with Turner syndrome ( TS ) . We assessed the effect of Ox on objective and subjective speaking voice frequency in GH-treated girls with TS . STUDY DESIGN A multicenter , r and omized , placebo (Pl)-controlled , double-blind study was conducted . METHODS One hundred thirty-three patients were included and treated with GH ( 1.33 mg/m2/d ) from baseline ,  combined with Pl or Ox  in a low ( 0.03 mg/kg/d ) or conventional ( 0.06 mg/kg/d ) dose from the age of 8 years and estrogens from the age of 12 years . Yearly from starting Ox/Pl until 6 months after discontinuing GH+Ox/Pl , voices were recorded and question naires were completed . RESULTS At start , mean ( ±st and ard deviation [ SD ] ) voice frequency SD score ( SDS ) was high for age ( 1.0±1.2 , P<0.001 ) but normal for height . Compared with GH+Pl , voices tended to lower on GH+Ox 0.03 ( P=0.09 ) and significantly lowered on GH+Ox 0.06 ( P=0.007 ) . At the last measurement , voice frequency SDS was still relatively high in GH+Pl group ( 0.6±0.7 , P=0.002 ) but similar to healthy girls in both GH+Ox groups . Voice frequency became lower than -2 SDS in one patient ( 3 % ) on GH+Ox 0.03 and three patients ( 11 % ) on GH+Ox 0.06 . The percentage of patients reporting subjective voice deepening was similar between the dosage groups . CONCLUSIONS Untreated girls with TS have relatively high-pitched voices . The addition of Ox to GH  decreases voice frequency in a dose-dependent way . Although most voice frequencies remain within the normal range , they may occasionally become lower than -2 SDS , especially on GH+Ox 0.06 mg/kg/d The weak and rogen ox and rolone ( Ox ) increases height gain in growth-hormone ( GH ) treated girls with Turner syndrome ( TS ) , but may also give rise to virilizing side effects . To assess the effect of Ox , at a conventional and low dosage , on behavior , aggression , romantic and sexual interest , mood , and gender role in GH-treated girls with TS , a r and omized , placebo-controlled , double-blind study was conducted . 133 patients were treated with GH ( 1.33 mg/m(2)/d ) from baseline , combined with placebo ( Pl ) , Ox 0.03 mg/kg/d , or Ox 0.06 mg/kg/d from the age of eight , and with estrogens from the age of 12 . The child behavior checklist ( CBCL ) , Junior Dutch Personality Question naire ( DPQ-J ) , State-subscale of the Spielberger 's State-Trait Anger Scale , Romantic and Sexual Interest Question naire , Mood Question naire , and Gender Role Question naire were filled out before , during , and after discontinuing Ox/Pl . The changes during Ox/Pl therapy were not significantly different between the dosage groups . In untreated patients , the mean CBCL total ( P=0.002 ) and internalizing ( P=0.003 ) T scores , as well as the mean DPQ-J social inadequacy SD score ( SDS ) ( P=0.004 ) were higher than in reference girls , but decreased during GH+Ox/Pl therapy ( P<0.001 , P=0.05 , P<0.001 , respectively ) . Whereas the mean total ( P=0.01 ) and internalizing ( P<0.001 ) T score remained relatively high , the mean social inadequacy SDS became comparable with reference values . We conclude that in GH-treated girls with TS , Ox 0.03 mg/kg/d or 0.06 mg/kg/d does not cause evident psychological virilizing side effects . Problem behavior , frequently present in untreated girls with TS , decreases during therapy , but total and internalizing problem behavior remain increased 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 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 OBJECTIVE Short stature is a prominent feature of Turner syndrome ( TS ) , which is partially overcome by GH treatment . We have previously reported the results of a trial on the effect of ox and rolone ( Ox ) in girls with TS . Ox in a dose of 0.03 mg/kg per day ( Ox 0.03 ) significantly increased adult height gain , whereas Ox mg/kg per day ( 0.06 ) did not , at the cost of deceleration of breast development and mild virilization . The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment . DESIGN AND METHODS During the previous r and omized controlled trial , 133 girls were treated with GH combined with placebo ( Pl ) , Ox 0.03 , or Ox 0.06  from 8 years of age and estrogen from 12 years . Sixty-eight women ( Pl , n=23 ; Ox 0.03 , n=27 ; and Ox 0.06 , n=18 ) participated in the double-blind follow-up study ( mean age , 24.0 years ; mean time since stopping GH , 8.7 years ; and mean time of Ox/Pl use , 4.9 years ) . We assessed height , body proportions , breast size , virilization , and body composition . RESULTS Height gain ( final minus predicted adult height ) was maintained at follow-up ( Ox 0.03 10.2±4.9 cm , Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm ) . Breast size , Tanner breast stage , and body composition were not different between groups . Ox-treated women reported more subjective virilization and had a lower voice frequency . CONCLUSION Ox 0.03 mg/kg per day has a beneficial effect on  adult height gain in TS patients . Despite previously reported deceleration of breast development during Ox 0.03 treatment , adult breast size is not affected . Mild virilization persists in only a small minority of patients . The long-term evaluation indicates that Ox 0.03 treatment is effective and safe The objective of this study was to find out whether moderate doses of growth hormone ( GH ) in combination with ox and rolone ( Ox ) and late initiation of puberty could improve adult height even in relatively old patients with Ullrich-Turner syndrome ( UTS ) . Ninety-one patients with UTS were r and omly assigned to receive either GH alone ( Saizen , Ares-Serono , Geneva ) 18 IU/m2/week ( 0.2 mg/kg/week ) by daily s.c . injections ( group GH ) or a combination of GH and Ox 0.1 mg/kg/day p.o . ( group GH + Ox ) . Prior to treatment mean age was 10.2 years ( GH ) and 10.5 years ( GH + Ox ) , mean projected adult height ( PAH ) was 146.4 cm ( GH ) and 146.7 cm ( GH + Ox ) . During year 2 the GH dose was increased in the GH group to 24 and later to 28 IU/m2/week ( 0.27 mg and later 0.31 mg/kg/week ) . In group GH + Ox , the Ox dose was reduced to 0.05 mg/kg/day after the first 12 months of therapy , and during the last treatment years the GH dose was raised to 24 - 28 IU/m2/week ( 0.27 - 0.31 mg/kg/week ) due to declining growth promotion . Some of the patients of group GH were later given Ox in addition to GH because of waning growth velocity , whereas some of the patients of group GH + Ox were taken off Ox due to virilizing side-effects of the high Ox dose , thus making up a third group of patients : group GH + transient Ox . Puberty was induced at a mean age of 14.9 years . In group GH + Ox , cumulative growth during 5 years of therapy was twice the growth anticipated from st and ards of untreated patients with UTS . Forty-seven patients are now near or at final height : in group GH ( n = 7 ) , mean final height was 151.7 cm ( PAH 148.1 cm , gain 3.6 cm ) ; in group GH + Ox ( n = 15 ) , 155.1 cm ( PAH 147.2 cm , gain 7.9 cm ) ; and in group GH + transient Ox ( n = 25 ) , 152.8 cm ( PAH 146.4 cm , gain 6.4 cm ) . These results should be regarded as an underestimate of true final height since some the patients are still growing . Moderate doses of GH plus Ox and late induction of puberty definitely improved final height even in patients with UTS treated relatively late 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 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 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 Turner syndrome ( TS ) represents a unique , sex hormone-deficient model in which to study the biological effects of and rogen treatment ( replacement ) on cognition in females because TS girls have gonadal dysgenesis and absent ovarian and rogen and estrogen production . We investigated the effects of and rogen replacement therapy in TS girls , ages 10 - 14 yr , on cognitive function . A total of 64 TS girls were r and omized to receive ox and rolone or placebo  for 2 yr . They had a cognitive evaluation of four domains ( verbal abilities , spatial cognition , executive function , and working memory ) at baseline , 1 , and 2 yr of the study . In addition , all subjects were examined for study safety every 6 months . Three of the four domains studied did not change significantly in response to ox and rolone treatment ( verbal abilities , spatial cognition , and executive function ) . In contrast , the working memory summary score had a significant group by time interaction . The ox and rolone-treated group demonstrated improved performance after 2 yr , compared with the placebo group ( P < 0.03 ) . Minimal or no side effects were observed . In conclusion , ox and rolone treatment for 2 yr improves working memory in adolescent girls with TS . What this degree of improvement will mean in real life terms for TS girls remains to be determined 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 Demographic and auxological data were analysed from 818 girls with Turner 's syndrome treated with recombinant human growth hormone ( GH ) and entered into the Kabi Pharmacia International Growth Study . Size at birth was low and correlated with the heights of both parents . The median age at start of GH  treatment was 11.4 years and the parents had a median height SDS of ‐2.9 . Height SDS at the start of treatment correlated with parental heights . Height velocities conformed to Turner‐specific st and ards . The weight‐for‐height index increased sharply above 9 years of age . The frequency of spontaneous appearance of Tanner breast stage 2 was high ( 34.1 % of girls > 10 years of age ) . Bone age ( Greulich and Pyle ) data were described by the equation : bone age = 1.61 ( chronological age ) ‐0.04(chronological age)2 ‐ 3.61 . This equation was used to correct adult height predictions . The median initial dose of GH  was 0.8 IUkglweek and was maintained during the first 3 years of treatment . The median frequency of injections was six/week . Height velocity increased from 4.1 to 6.8 cm/year in the first year , and height velocity SDS for chronological age remained positive for 4 years . The height prediction corrected for bone age increased over the first 2 years only . Differences in demography and auxology were described according to karyotype and country of origin . A greater height velocity SDS was observed at higher GH doses and when ox and rolone was used concomitantly 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 Seventy girls with Turner syndrome , 4 to 12 years of age , participated in a prospect i ve , r and omized study to determine the effects on growth of methionyl human growth hormone ( met-hGH ) or ox and rolone . Subjects were r and omly assigned to receive either no treatment ( control ) or met-hGH ( 0.125 mg/kg three times per week ) , ox and rolone ( 0.125 mg/kg/day ) , or combination met-hGH plus ox and rolone . At the end of an initial period of 12 to 20 months , patients in the original control and ox and rolone groups were given combination met-hGH plus ox and rolone . At that time the dosage of ox and rolone was lowered to 0.0625 mg/kg/day . Sixty-five subjects have now completed the first 3 years of the study . Compared with the control growth rate for year 1 ( 3.8 cm/yr ) , significant increases in growth rate were seen in all 3 years of combination therapy ( 9.8 , 7.4 , and 6.1 cm/yr , respectively ) and in the first 2 years of treatment with met-hGH alone ( 6.6 , 5.4 , and 4.6 cm/yr ) . When growth velocity was expressed as st and ard deviation for age in girls with Turner syndrome , significant increases relative to the control group for year 1 ( -0.1 SD ) were seen in all three years of both combination therapy and met-hGH alone ( combination , + 6.6 , + 4.3 , + 3.0 SD ; met-hGH , + 3.1 , + 2.0 , + 1.4 SD ) . After 3 years of treatment , predicted adult height by the method of Bayley-Pinneau increased 4.5 cm in the met-hGH group and 8.2 cm in the combination group 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 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 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 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 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 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 We evaluated the effect of six-month treatment with growth hormone ( GH ) or low-dose ox and rolone in a group of boys with constitutional growth delay ( CGD ) . Sixteen boys were r and omly assigned to two treatment groups . Group 1 received GH ( 0.6 U/kg/week sc 5–6 times/week ) and Group 2 received ox and rolone ( 0.07 mg/kg po ) . The boys of the two groups were closely matched for age ( 13.7 ± 0.5 and 12.8 ± 0.4 years ) ( mean ± SE ) , chronologic age/bone age ratio ( 1.15 ± 0.04 and 1.16 ± 0.02 ) , height st and ard deviation score ( SDS ; −2.7 ± 0.4 and −2.5 ± 0.3 ) and pretreatment height velocity ( HV ) ( 3.7 ± 0.8 and 4.0 ± 0.4 cm/year ) . Other known causes of short stature were excluded in all subjects , and none had taken long-term medication prior to the study . After 6 months of treatment HV increased to 7.5 ± 0.4 and to 8.1 ± 0.5 cm/year in group 1 and 2 , respectively . Plasma IGF-I concentrations rose significantly after treatment in both groups . Predicted adult height was not significantly affected by either GH or ox and rolone treatment . We conclude that a short-term course of low-dose ox and rolone is as effective as GH to accelerate growth in boys with CGD . Low-dose ox and rolone represents an effective , cheap , and convenient therapeutic approach in boys with CGD A total of 70 subjects with Turner 's syndrome from 11 centres were enrolled in a study of somatrem . After an initial observation period , they were r and omly assigned to one of four groups , receiving no treatment ( Group 1 , control ) ; ox and rolone , 0.125 mg/kg/day ( Group 2 ) ; somatrem , 0.125 mg/kg 3 times/week ( Group 3 ) ; or a combination of somatrem and ox and rolone on the above dose regimens ( Group 4 ) . After 12–20 months , Groups 1 ( control ) , 2 ( ox and rolone ) and 4 ( combination ) were treated with somatrem , 0.125 mg/kg 3 times/week , and ox and rolone , 0.0625 mg/kg/day ; Group 3 remained on somatrem , 0.125 mg/kg 3 times/week . All three treatment groups showed a statistically significant increase during year 1 in growth velocity over both their pretreatment growth rates and the control group growth rate . These increases were slightly less in year 2 for the somatrem and combination therapy groups , but remained significantly higher than the year 1 control group growth rate . Plasma IGF‐1 levels were elevated in years 1 and 2 in the somatrem and combination groups . Adverse events were few with the somatrem group , though mild virilization occurred with ox and rolone , alone or in combination . Bone age advancement was observed with all treatments but was greater with combination therapy ; it was accompanied by height age advancement . The effect of this therapy on predicted adult height was also evaluated 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 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 Twenty‐six one‐year treatment periods on ox and rolone ( 0.1 mg/kg/day ) were studied in 20 patients with Turner 's syndrome . Control patients with Turner 's syndrome were matched by using the following criteria : difference in bone age being not greater than 0.S years and difference in the Bayley‐Pinneau height prediction not greater than 3 cm . Height and height velocity were compared with st and ards of girls with Turner 's syndrome ( 10 ) and expressed in st and ard deviation scores ( SDS ) . On ox and rolone  height velocity increased significantly from −0.3 SDS to + 3.0 SDS . The increase in height velocity was negatively correlated to the bone age at onset of treatment ( r= 0.62 , p<0.01 ) . Height SDS improved by 0.45 SDS in the treated patients whereas it did not change in the control patients . The bone age velocity during the treatment period ( including a six‐month period after treatment ) was 0.75 year/year in the treated , compared to 0.66 year/year in the control patients ( NS ) . 15 of the 20 patients have reached final height . The difference in final height minus predicted height ( Bayley‐Pinneau ) at onset of treatment was taken as a measure of “ gain in final height ” . Seven of those ( mean bone age 12.1 years at onset of treatment ) were treated for one year only and had – compared to the matched controls – a mean net gain in final height of 2.5 cm ( NS ) . Eight patients ( mean bone age 10.1 years at onset of treatment ) were treated for two one‐year periods and had a significant mean net gain in final height of 5.2 cm . Height predictions calculated by the method of Lenko ( 14 ) gave an identical mean net gain in final height ( 5.1 cm GH is known to improve height velocity in girls with Turner syndrome ( TS ) but the optimal dosage regimen has yet to be defined 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 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 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 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 BACKGROUND Most girls with Turner syndrome ( TS ) receive growth hormone ( GH ) treatment during childhood and adolescence , but controlled data on the effects on body composition and glucose metabolism are lacking . OBJECTIVE To study the effects of GH treatment on insulin sensitivity , glucose metabolism , bone turnover , and body composition . METHODS A r and omized , placebo-controlled , crossover study was conducted with girls with TS . All girls with TS were treated with GH 0.1 IU/kg/d subcutaneously at bedtime or with placebo for 2 months and studied at the end of each period . Control subjects were studied once without treatment . Twelve girls with TS , aged 9.5 to 14.8 years ( median : 12.9 years ) and 16 age-matched control subjects ( 10.3 - 16.0 years ; median : 12.1 years ) were studied . Twenty-four-hour sampling of blood was performed ; GH , insulin-like growth factor I ( IGF-I ) , IGF binding proteins ( IGFBPs ) , insulin , glucose , and lipolytic and gluconeogenic precursors were assayed , followed by an oral glucose tolerance test . Body composition was evaluated by dual-energy x-ray absorptiometry scanning and body mass index ( BMI ) . Fasting bone markers were measured . RESULTS Height was reduced in TS as compared with control subjects . In the placebo situation , 24-hour integrated GH as well as IGF-I was significantly reduced in girls with TS compared with control subjects . Controlling for differences in lean body mass ( LBM ; or fat mass [ FM ] ) and sexual development did not explain the difference in 24-hour integrated GH . Differences in sexual development , BMI , FM , insulin sensitivity , and IGFBP-3 could explain the difference in IGF-I between TS and control subjects . Carbohydrate metabolism in TS was comparable with control subjects . GH treatment induced insulin resistance , with increments in fasting glucose and insulin , as well as 24-hour insulin . Circulating levels of lipid and gluconeogenic substrates were comparable in TS and control subjects and unchanged in response to treatment . Bone markers increased in response to GH . Total FM was increased in girls with TS , accounted for by an increased FM in the arms and trunk , whereas LBM was decreased . Especially LBM in the legs was decreased . Overall , bone mineral content was diminished . Treatment with GH reduced FM in TS , especially in the arms and legs , and likewise increased total LBM , primarily in the trunk . CONCLUSION This study documented evidence of impaired GH secretion and action , disproportionate body composition , but a normal carbohydrate metabolism in girls with TS . Short-term GH administration was associated with favorable changes in body composition but also with relative impairment of glucose tolerance and insulin sensitivity . We recommend that glucose metabolism be monitored carefully during long-term GH treatment in these patients 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 OBJECTIVE In order to ascertain the advantages of early GH treatment in Turner syndrome ( TS ) , we started a prospect i ve study aim ed at evaluating prepubertal height gain in a cohort of 29 girls who were treated with the same pro-kilo GH dose ( 1.0 IU/kg per week ) since they were less than 6 years old and for at least 5 years before entering puberty . PATIENTS AND DESIGN Following a minimum of 6 months of baseline observations , 29 girls with TS were enrolled for this prospect i ve study provided that they ( a ) were less than 6 years old , ( b ) were below -1.0 st and ard deviation score ( SDS ) for height , ( c ) had a projected adult height ( PAH ) lower than the respective target height ( TH ) and ( d ) had a height velocity ( HV ) lower than -1.0 SDS . All the selected girls underwent a 5-year treatment with biosynthetic GH at a stable dose of 1.0 IU/kg per week and were periodically measured during the treatment period in order to evaluate height , HV and PAH . RESULTS After a dramatic acceleration during the 1st year , HV was attenuated during the subsequent years , reaching its nadir at the 5th year . Height deficiency under therapy progressively decreased from entry onwards , shifting from -2.4+/-0.7 to -1.0+/-1.2 SDS . In the same period , mean PAH progressively increased , although after 5 years it remained lower than the average TH . CONCLUSIONS ( a ) An effective growth-promoting strategy in TS should be based on early GH treatment , as suggested by our results . ( b ) This strategy could result in a prepubertal normalization of height , thus allowing the appropriate timing for the induction of puberty . ( c ) An initial GH dose of 1.0 IU/kg per week may be suitable during the first years of therapy , as shown by our data documenting an important waning effect of GH therapy only after the 4th year of treatment . ( d ) No acceleration of bone maturation was observed under this treatment regimen CONTEXT Typically , growth failure in Turner syndrome ( TS ) begins prenatally , and height sd score ( SDS ) declines progressively from birth . OBJECTIVE This study aim ed to determine whether GH treatment initiated before 4 yr of age in girls with TS could prevent subsequent growth failure . Secondary objectives were to identify factors associated with treatment response , to determine whether outcome could be predicted by a regression model using these factors , and to assess the safety of GH treatment in this young cohort . DESIGN This study was a prospect i ve , r and omized , controlled , open-label , multicenter clinical trial ( Toddler Turner Study , August 1999 to August 2003 ) . SETTING The study was conducted at 11 U.S. pediatric endocrine centers . SUBJECTS Eighty-eight girls with TS , aged 9 months to 4 yr , were enrolled . INTERVENTIONS Interventions comprised recombinant GH ( 50 mug/kg.d ; n = 45 ) or no treatment ( n = 43 ) for 2 yr . MAIN OUTCOME MEASURE The main outcome measure was baseline-to-2-yr change in height SDS . RESULTS Short stature was evident at baseline ( mean length/height SDS = -1.6 + /- 1.0 at mean age 24.0 + /- 12.1 months ) . Mean height SDS increased in the GH group from -1.4 + /- 1.0 to -0.3 + /- 1.1 ( 1.1 SDS gain ) , whereas it decreased in the control group from -1.8 + /- 1.1 to -2.2 + /- 1.2 ( 0.5 SDS decline ) , result ing in a 2-yr between-group difference of 1.6 + /- 0.6 SDS ( P < 0.0001 ) . The baseline variable that correlated most strongly with 2-yr height gain was the difference between mid-parental height SDS and subjects ' height SDS ( r = 0.32 ; P = 0.04 ) . Although attained height SDS at 2 yr could be predicted with good accuracy using baseline variables alone ( R(2 ) = 0.81 ; P < 0.0001 ) , prediction of 2-yr change in height SDS required inclusion of initial treatment response data ( 4-month or 1-yr height velocity ) in the model ( R(2 ) = 0.54 ; P < 0.0001 ) . No new or unexpected safety signals associated with GH treatment were detected . CONCLUSION Early GH treatment can correct growth failure and normalize height in infants and toddlers with TS OBJECTIVE To assess objective and subjective voice parameters among Turner syndrome ( TS ) women in relation to genotype , hearing , growth , and previous treatment with growth hormone ( GH ) and and rogen given that lowering of speaking fundamental frequency ( SFF ) during treatment is regarded as a negative side effect . STUDY DESIGN Cross-sectional , controlled for karyotype and age . METHODS Voice function was studied objective ly ( SFF ) and subjectively ( question naire ) in 117 women with TS . RESULTS SFF did not differ between treated and nontreated participants or between patients with a spontaneous versus induced puberty . SFF was dependent on karyotype but not age . Subjective voice change was reported four times more often among treated compared with nontreated TS women ( odds ratio [ OR ] = 4.4 ; 95 % confidence interval [ CI ] : 0.9 - 20.10 ) , whereas voice and articulation problems were reported three times more often among untreated compared with treated cases ( OR = 2.9 ; 95 % CI : 1.0 - 8.3 ) . Voice symptoms were over-represented among patients having micrognathia ( OR = 6.0 ; 95 % CI : 1.6 - 22.3 ) , hearing loss ( OR = 8.6 ; 95 % CI : 1.7 - 43.1 ) , and monosomy ( OR = 6.2 ; 95 % CI : 0.8 - 36.2 ) but not among those with an arched palate . CONCLUSIONS When given to TS girls , GH ( 33 - 66 microg/kg/d ) and and rogen ( 0.05 mg/kg/d ) normalized SFF and reduced voice and articulation problems in adulthood . The TS phenotype includes important voice and speech problems , which in turn are associated with hearing problems , although genotypic , monosomic , and isochromosome patients have more voice problems and also more high-pitched voices than mosaic patients . Most TS women , despite their karyotype or age , exhibit a higher frequency of pitched voice than non-TS women Background : Concomitant evaluation of the metabolic and growth-promoting effects of growth hormone ( GH ) therapy in Turner syndrome ( TS ) may be used in the prediction of the growth response to GH therapy . Aim : To evaluate the metabolic effects of GH therapy  in TS and correlation with the short-term growth response . Patients : 24 prepubertal children with TS , aged 9.4 ± 2.6 years were followed for auxology and IGF-I , IGFBP-3 , leptin , ghrelin , adiponectin , lipids and OGTT results in a prospect i ve multicenter study . Intervention : GH ( Genotropin ® ) in a dose of 50 µg/kg/day for 1 year . Results : Height st and ard deviation score ( SDS ) increased from –3.9 ± 1.5 to –3.5 ± 1.4 ( p = 0.000 ) on therapy . BMI did not change . IGF-I SDS increased from –2.3 ± 0.4 to –1.6 ± 1.1 at 3 and 6 months ( p = 0.001 ) and decreased thereafter . Serum leptin decreased significantly from 2.3 ± 3.9 to 1.7 ± 5.3 ng/ml ( p = 0.022 ) at 3 months and increased afterwards . Serum ghrelin decreased from 1.2 ± 0.8 to 0.9 ± 0.4 ng/ml ( p = 0.005 ) with no change in adiponectin . Basal and stimulated insulin levels also increased significantly . Δ height SDS over 1 year showed a significant correlation with Δ IGF-I0–3 months ( r = 0.450 , p = 0.027 ) . Conclusion : IGF-I may be considered as a marker of growth response in TS at short term . Leptin shows a decrease at short term but does not have a correlation with growth response . The decrease in ghrelin in face of unchanged weight seems to be associated with increase in IGF-I and insulin levels . The unchanged adiponectin levels in spite of an increase in insulin levels indicates that adiponectin is mainly affected by weight , not insulin
AUTHORS ' CONCLUSIONS Addition of ox and rolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS .
BACKGROUND The final adult height of untreated girls aged up to 18 years with Turner syndrome ( TS ) is approximately 20 cm shorter compared with healthy females .
Treatment with growth hormone ( GH ) increases the adult height of people with TS .
The effects of adding the and rogen , ox and rolone , in addition to GH are unclear .
Therefore , we conducted this systematic review to investigate the benefits and harms of ox and rolone as an adjuvant therapy for people with TS treated with GH .
OBJECTIVES To assess the effects of ox and rolone on growth hormone-treated girls aged up to 18 years with Turner syndrome .