title: Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. Non-conventional growth hormone therapy in Turner syndrome: the United States experience. 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? Impact of spin in the abstracts of articles reporting results of randomized controlled trials in the field of cancer: the SPIIN randomized controlled trial. Methods for evidence synthesis in the case of very few studies Prospective Study Confirms Oxandrolone-Associated Improvement in Height in Growth Hormone-Treated Adolescent Girls with Turner Syndrome Designing psycho-oncology randomised trials and cluster randomised trials: variance components and intra-cluster correlation of commonly used psychosocial measures. Acceleration of growth in Turner syndrome patients treated with growth hormone: summary of three-year results. Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Århus, Denmark The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Short-term growth hormone treatment in girls with Turner syndrome decreases fat mass and insulin sensitivity: a randomized, double-blind, placebo-controlled, crossover study. Oxandrolone in Girls with Turner's Syndrome Comparison of registered and published primary outcomes in randomized controlled trials. A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation Recombinant human growth hormone and oxandrolone in treatment of short stature in girls with Turner syndrome. Growth promoting treatment normalizes speech frequency in Turner syndrome. Growth hormone therapy of Turner's syndrome: beneficial effect on adult height. Results from the First 2 Years of a Clinical Trial with Recombinant DNA‐derived Human Growth Hormone (Somatrem) in Turner's Syndrome Self-esteem and social adjustment in young women with Turner syndrome--influence of pubertal management and sexuality: population-based cohort study. Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. The effect of oxandrolone on voice frequency in growth hormone-treated girls with Turner syndrome. Methionyl human growth hormone and oxandrolone in Turner syndrome: preliminary results of a prospective randomized trial. Assessing baseline imbalance in randomised trials: implications for the Cochrane risk of bias tool. Anabolic Effects of Oxandrolone After Severe Burn Final height outcome in girls with Turner syndrome treated with a combination of low dose oestrogen and oxandrolone Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial 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 Growth hormone therapy in Turner's syndrome: an update on final height. Genentech National Cooperative Study Group. Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with 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. Androgen-responsive aspects of cognition in girls with Turner syndrome. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome.
abstract: Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries , which GH dosage to use and which age to start puberty induction are issues of debate . This study shows  final height ( FH ) in 60 girls with Turner syndrome treated in a r and omized dose-response trial , combining GH treatment with low dose estrogens at a relatively young age . Girls were r and omly assigned to group A ( 4 IU/m(2).d ; approximately 0.045 mg/kg/d ) , group B ( first year , 4 IU/m(2).d ; thereafter 6 IU/m(2).d ) , or group C ( first year , 4 IU/m(2).d ; second year , 6 IU/m(2).d ; thereafter , 8 IU/m(2).d ) . After a minimum of 4 yr of GH treatment , at a mean age of 12.7 + /- 0.7 yr , low dose micronized 17beta-estradiol was given orally . After a mean duration of  GH treatment  of 8.6 + /- 1.9 yr , FH was reached at a mean age of 15.8 + /- 0.9 yr . FH , expressed in centimeters or SD score , was 157.6 + /- 6.5 or -1.6 + /- 1.0 in group A , 162.9 + /- 6.1 or -0.7 + /- 1.0 in group B , and 163.6 + /- 6.0 or -0.6 + /- 1.0 in group C. The difference in FH in centimeters , corrected for height SD score and age at start of treatment , was significant between groups A and B [ regression coefficient , 4.1 ; 95 % confidence interval ( CI ) , 1.4 , 6.9 ; P < 0.01 ] , and groups A and C ( coefficient , 5.0 ; 95 % CI , 2.3 , 7.7 ; P < 0.001 ) , but not between groups B and C ( coefficient , 0.9 ; 95 % CI , -1.8 , 3.6 ) . Fifty of the 60 girls ( 83 % ) had reached a normal FH ( FH SD score , more than -2 ) . After starting estrogen treatment , the decrease in height velocity ( HV ) changed significantly to a stable HV , without affecting bone maturation ( change in bone age/change in chronological age ) . The following variables contributed significantly to predicting FH SD score : GH dose , height SD score ( ref . normal girls ) , chronological age at start of treatment , and HV in the first year of GH treatment . GH treatment was well tolerated . In conclusion , GH treatment leads to a normalization of FH in most girls , even when puberty is induced at a normal pubertal age . The optimal GH dosage depends on height and age at the start of treatment and first year HV Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged 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 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 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 PURPOSE We aim ed to assess the impact of spin ( ie , reporting to convince readers that the beneficial effect of the experimental treatment is greater than shown by the results ) on the interpretation of results of abstract s of r and omized controlled trials ( RCTs ) in the field of cancer . METHODS We performed a two-arm , parallel-group RCT . We selected a sample of published RCTs with statistically nonsignificant primary outcome and with spin in the abstract conclusion . Two versions of these abstract s were used-the original with spin and a rewritten version without spin . Participants were clinician corresponding authors of articles reporting RCTs , investigators of trials , and review ers of French national grants . The primary outcome was clinicians ' interpretation of the beneficial effect of the experimental treatment ( 0 to 10 scale ) . Participants were blinded to study hypothesis . RESULTS Three hundred clinicians were r and omly assigned using a Web-based system ; 150 clinicians assessed an abstract with spin and 150 assessed an abstract without spin . For abstract s with spin , the experimental treatment was rated as being more beneficial ( mean difference , 0.71 ; 95 % CI , 0.07 to 1.35 ; P = .030 ) , the trial was rated as being less rigorous ( mean difference , -0.59 ; 95 % CI , -1.13 to 0.05 ; P = .034 ) , and clinicians were more interested in reading the full-text article ( mean difference , 0.77 ; 95 % CI , 0.08 to 1.47 ; P = .029 ) . There was no statistically significant difference in the clinicians ' rating of the importance of the study or the need to run another trial . CONCLUSION Spin in abstract s can have an impact on clinicians ' interpretation of the trial results In systematic review s , meta‐analyses are routinely applied to summarize the results of the relevant studies for a specific research question . If one can assume that in all studies the same true effect is estimated , the application of a meta‐ analysis with common effect ( commonly referred to as fixed‐effect meta‐ analysis ) is adequate . If between‐ study heterogeneity is expected to be present , the method of choice is a meta‐ analysis with r and om effects . The widely used DerSimonian and Laird method for meta‐analyses with r and om effects has been criticized due to its unfavorable statistical properties , especially in the case of very few studies . A working group of the Cochrane Collaboration recommended the use of the Knapp‐Hartung method for meta‐analyses with r and om effects . However , as heterogeneity can not be reliably estimated if only very few studies are available , the Knapp‐Hartung method , while correctly accounting for the corresponding uncertainty , has very low power . Our aim is to summarize possible methods to perform meaningful evidence syntheses in the situation with only very few ( ie , 2‐4 ) studies . Some general recommendations are provided on which method should be used when . Our recommendations are based on the existing literature on methods for meta‐ analysis with very few studies and consensus of the authors . The recommendations are illustrated by 2 examples coming from dossier assessment s of the Institute for Quality and Efficiency in Health Care 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 OBJECTIVE The study aims to provide information about variance components of psychosocial outcomes : within and between-participant variance , within-participant correlation and for cluster r and omised trials , the intra-cluster correlation ( ICC ) and , also , to demonstrate how estimates of these variance components and ICCs can be used to design r and omised trials and cluster r and omised trials . METHOD Data from 15 longitudinal multi-centre psycho-oncology studies were analysed , and variance components including ICCs were estimated . Studies with psychosocial outcomes that had at least one measurement post-baseline including individual r and omised controlled trials , cluster r and omised trials and observational studies were included . RESULTS Variance components and ICCs from 87 outcome measures were estimated . The unadjusted , single timepoint ( first post-baseline ) ICCs ranged from 0 to 0.16 , with a median value of 0.022 and inter-quartile range 0 to 0.0605 . The longitudinal ICCs ranged from 0 to 0.09 with a median value of 0.0007 and inter-quartile range 0 to 0.018 . CONCLUSIONS Although the magnitude of variance components and ICCs used for sample -size calculation can not be known in advance of the study , published estimates can help reduce the uncertainty in sample -size calculations . Psycho-oncology research ers should be conservative in their sample -size calculations and use approaches that improve efficiency in their design and analysis 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 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 Summary As part of a larger prospect i ve study of the influence of environmental factors on pregnancy , birth and the fetus , chromosome examinations have been made in 34910 newborn children in Århus over a 13-year period . Klinefelter 's syndrome was found in 1 per 576 boys , XYY in 1 per 851 boys , triple-X in 1 per 947 girls and Turner 's syndrome in 1 per 1893 girls . Other sex chromosome aberrations were found in 1 per 11637 children . The total incidence of sex chromosome abnormalities was 1 per 426 children or 2.34 per 1000 . The most frequent autosomal abnormalities were that of Down 's syndrome with 1 per 592 children , and reciprocal translocations with 1 per 712 children . The total incidence of autosomal abnormalities was 1 per 164 children . Chromosome abnormalities were found in 276 liveborn children and in 19 fetuses , who were aborted after prenatal chromosome examination . The combined incidence of sex chromosomal and autosomal abnormalities was 1 per 118 children or 8.45 per 1000 children Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more 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 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 CONTEXT As of 2005 , the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial 's findings in member journals . OBJECTIVE To assess the proportion of registered trials with results recently published in journals with high impact factors ; to compare the primary outcomes specified in trial registries with those reported in the published articles ; and to determine whether primary outcome reporting bias favored significant outcomes . DATA SOURCES AND STUDY SELECTION MEDLINE via PubMed was search ed for reports of r and omized controlled trials ( RCTs ) in 3 medical areas ( cardiology , rheumatology , and gastroenterology ) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors . DATA EXTRACTION For each included article , we obtained the trial registration information using a st and ardized data extraction form . RESULTS Of the 323 included trials , 147 ( 45.5 % ) were adequately registered ( ie , registered before the end of the trial , with the primary outcome clearly specified ) . Trial registration was lacking for 89 published reports ( 27.6 % ) , 45 trials ( 13.9 % ) were registered after the completion of the study , 39 ( 12 % ) were registered with no or an unclear description of the primary outcome , and 3 ( 0.9 % ) were registered after the completion of the study and had an unclear description of the primary outcome . Among articles with trials adequately registered , 31 % ( 46 of 147 ) showed some evidence of discrepancies between the outcomes registered and the outcomes published . The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6 % ( 19 of 23 ) . CONCLUSION Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently 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 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 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 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 CONTEXT Pediatric management of patients with Turner syndrome focuses on height , frequently result ing in a delay of pubertal induction . The influence of pubertal management on psychosocial adjustment and sex life has not been evaluated in Turner syndrome patients . OBJECTIVE The objective of the study was to identify the determinants of self-esteem , social adjustment , and initiation of sex life in patients with Turner syndrome , particularly those related to pubertal management . DESIGN This was a prospect i ve evaluation , the StaTur study . SETTING The study was conducted with a population -based registry of GH-treated patients . PARTICIPANTS Participants included 566 young adult women with Turner syndrome , aged 22.6 + /- 2.6 yr ( range , 18.3 - 31.2 ) . MAIN OUTCOME MEASURES Measures used in the study were Coopersmith 's Self-Esteem Inventory , Social Adjustment Scale Self-Report , questions on sexual experience , and extensive data on pediatric management . RESULTS Low self-esteem was associated with otological involvement and limited sexual experience . Low social adjustment was associated with lower paternal socioeconomic class and an absence of sexual experience . Late age at first kiss or date was associated with cardiac involvement and a lack of spontaneous pubertal development . Age at first sexual intercourse was related to age at puberty and paternal socioeconomic class . Delayed induction of puberty had a long-lasting effect on sex life . Height and height gain due to GH treatment had no effect on outcomes . CONCLUSIONS Puberty should be induced at a physiologically appropriate age in patients with Turner syndrome to optimize self-esteem , social adjustment , and initiation of the patient 's sex life . Therapeutic interventions altering normal pubertal development in other groups of patients should be reconsidered in light of these findings 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 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 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 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 A key component of the Cochrane Collaboration 's risk of bias tool for critically evaluating r and omised trials is the consideration of whether baseline characteristics of the treatment groups being compared are systematic ally different . Considered under the domain of ' selection bias ' , this is currently evaluated by looking at the methods of r and omisation and specifically at the generation of the r and omised allocation sequence and the concealment of this sequence during the process of r and omisation . Assessment of the actual similarity of baseline variables across groups in demographic and clinical characteristics is seldom performed . Even when performed , the link with selection bias is sometimes not considered . Methods of r and omisation and allocation concealment are often poorly reported in published trials , yet baseline data tables are presented in a large majority of trial reports . In this article , we propose that assessment of trial baseline data should form a key and prominent part of selection bias judgements when using the risk of bias tool . We outline the possible benefits from using this approach , including reduced uncertainty in systematic review conclusions , reduced risk of chance findings being ascribed to treatment effects and better use of available evidence by a more considered approach to evaluating studies using imperfect r and omisation and allocation methods Objective To explore the hypothesis that ox and rolone may reverse muscle catabolism in cachectic , critically ill pediatric burn patients . Summary Background Data Severe burn causes exaggerated muscle protein catabolism , contributing to weakness and delayed healing .  Ox and rolone is an anabolic steroid that has been used in cachectic hepatitis and AIDS patients . Methods Fourteen severely burned children were enrolled during a 5-month period in a prospect i ve cohort analytic study . There was a prolonged delay in the arrival of these patients to the burn unit for definitive care . This neglect of skin grafting and nutritional support result ed in critically ill children with significant malnutrition . On arrival , all patients underwent excision and skin grafting and received similar clinical care . Subjects were studied 5 to 7 days after admission , and again after 1 week of ox and rolone treatment at 0.1 mg/kg by mouth twice daily or no pharmacologic treatment .  Muscle protein kinetics were derived from femoral arterial and venous blood sample s and vastus lateralis muscle biopsies during a stable isotope infusion . Results Control and ox and rolone subjects were similar in age , weight , and percentage of body surface area burned . Muscle protein net balance decreased in controls and improved in the ox and rolone group . The improvement in the ox and rolone group was associated with increased protein synthesis efficiency . Muscle protein breakdown was unchanged . Conclusions In burn victims , ox and rolone improves muscle protein metabolism through enhanced protein synthesis efficiency . These findings suggest the efficacy of ox and rolone in impeding muscle protein catabolism in cachectic , critically injured children 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 OBJECTIVE The ability to accurately identify articles about therapy in large bibliographic data bases such as EMBASE is important for research ers and clinicians . Our study aim ed to develop optimal search strategies for detecting sound treatment studies in EMBASE in the year 2000 . METHODS H and search es of journals were compared with retrievals from EMBASE for c and i date search strategies . Six trained research assistants review ed fifty-five journals indexed in EMBASE and rated articles using purpose and quality indicators . C and i date search strategies were developed for identifying treatment articles and then tested , and the retrievals were compared with the h and - search data . The operating characteristics of the strategies were calculated . RESULTS Three thous and eight hundred fifty articles were original studies on treatment , of which 1,256 ( 32.6 % ) were method ologically sound . Combining search terms revealed a top performing strategy ( r and om:.tw . OR clinical trial:.mp . OR exp health care quality ) with sensitivity of 98.9 % and specificity of 72.0 % . Maximizing specificity , a top performing strategy ( double-blind:.mp . OR placebo:.tw . OR blind : .tw . ) achieved a value over 96.0 % , but with compromised sensitivity at 51.7 % . A 3-term strategy achieved the best optimization of sensitivity and specificity ( r and om:.tw . OR placebo:.mp . OR double-blind:.tw . ) , with both these values over 92.0 % . CONCLUSION Search strategies can achieve high performance for retrieving sound treatment studies in EMBASE 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 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 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 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 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 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 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 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 BACKGROUND Short stature and ovarian failure are characteristic features of Turner 's syndrome . Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome , a r and omized , placebo-controlled trial is needed to document whether such treatment increases adult height . Furthermore , it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit . We examined the independent and combined effects of growth hormone and early , ultra-low-dose estrogen on adult height in girls with Turner 's syndrome . METHODS In this double-blind , placebo-controlled trial , we r and omly assigned 149 girls , 5.0 to 12.5 years of age , to four groups : double placebo ( placebo injection plus childhood oral placebo , 39 patients ) , estrogen alone ( placebo injection plus childhood oral low-dose estrogen , 40 ) , growth hormone alone ( growth hormone injection plus childhood oral placebo , 35 ) , and growth hormone-estrogen ( growth hormone injection plus childhood oral low-dose estrogen , 35 ) . The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week . The doses of ethinyl estradiol ( or placebo ) were adjusted for chronologic age and pubertal status . At the first visit after the age of 12.0 years , patients in all treatment groups received escalating doses of ethinyl estradiol . Growth hormone injections were terminated when adult height was reached . RESULTS The mean st and ard-deviation scores for adult height , attained at an average age of 17.0±1.0 years , after an average study period of 7.2±2.5 years were -2.81±0.85 , -3.39±0.74 , -2.29±1.10 , and -2.10±1.02 for the double-placebo , estrogen-alone , growth hormone-alone , and growth hormone-estrogen groups , respectively ( P<0.001 ) . The overall effect of growth hormone treatment ( vs. placebo  ) on adult height was a 0.78±0.13 increase in the height st and ard-deviation score ( 5.0 cm ) ( P<0.001 ) ; adult height was greater in the growth hormone-estrogen group than in the growth hormone-alone group , by 0.32±0.17 st and ard-deviation score ( 2.1 cm ) ( P=0.059 ) , suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone . CONCLUSIONS Our study shows that growth hormone treatment increases adult height in patients with Turner 's syndrome . In addition , the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement . ( Funded by the National Institute of Child Health and Human Development and Eli Lilly ; Clinical Trials.gov number , NCT00001221 . ) 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
target: 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: 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 .