turner syndrome is characterized by short stature , hypogonadism and minor anomalies ( 1 ) . it has been reported that approximately one third of 
 turner girls develop spontaneous puberty and one fifth experience menarche ( 2 , 3 ) . however , 
 pubertal development in turner syndrome sometimes does not reach maturity completely and 
 8090 percent of turner girls receive estrogen therapy during and/or after the adolescent 
 period . saenger et al . ( 4 ) recommended that estrogen 
 replacement therapy should be started before 15 yr of age , but should not be started before 
 12 yr when adult height is taken into consideration . they also recommended that estrogen 
 replacement should begin at one fourth to one sixth of the adult dose , and increase at 3 to 
 6 mo interval , to achieve full pubertal maturation in 2 to 3 yr , mimicing the slow natural 
 pubertal development . recently , bondy ( 5 ) more 
 strongly recommended starting low dose estrogen as early as 12 yr of age . however , there is 
 no recommendation of timing of the start of estrogen therapy in relation to height or adult 
 height prediction . pediatric endocrinologists of the turner syndrome research collaboration ( trc ) in japan in 
 answer to a questionnaire regarding the timing of the start of estrogen therapy , responded 
 that chronological age is the most reliable factor , bone age the second , and height comes 
 the third . their ideal timing for the start of estrogen replacement was 12 yr to 14 yr of 
 chronological age , 12 yr of bone age and 140 to 145 cm of height . in this study , we analyzed the relation between timing of the start of estrogen therapy and 
 height gain until adult height in turner girls and propose recommending the timing of the 
 start of estrogen therapy in consideration of adult height . among fifty - seven turner girls who were born between 1971 and 1989 and had visited the 
 division of endocrinology and metabolism , national children s hospital / national center for 
 child health and development , the patients who passed the following inclusion criteria were 
 investigated : 1 ) no spontaneous puberty throughout the whole observation period ; 2 ) received 
 gh and estrogen therapy ; and 3 ) reached their adult height . adult height is defined as 
 tallest height after height velocity less than 1 cm / yr . twenty - seven patients who passed the 
 inclusion criteria were divided into two groups according to their birth years : group i 
 consisted of 16 patients born between 1980 and 1989 , and group ii consisted of 11 patients 
 born before 1980 . the clinical characteristics of gh therapy in groups i and ii are shown in 
 table 1table 1 . ages at the start and stop of gh therapy were significantly younger in group 
 i than in group ii , but height or height sds at the start and stop of gh therapy was not 
 significantly different between the two groups . their mean age and height 
 at the start of anabolic steroid treatment were 12.1 yr and 128.8 cm ( 2.82 sd for japanese 
 female standard 1990 ) , respectively . for eight of them , anabolic steroid was stopped before 
 estrogen therapy and the remaining five had combined use of anabolic steroid and estrogen . 
 all patients started estrogen therapy with conjugated equine estrogens ( premalin ) at various 
 doses : 1 tablet ( 0.625 mg ) in two patients , 1/2 tablet in three patients , 1/3 tablet in four 
 patients , 1/4 tablet in four patients and 1/10 , 1/5 and 2/5 tablets respectively for the 
 remaining three patiens . growth hormone was started at 0.5 u / kg / wk ( 0.167 mg / kg / wk ) for 12 
 patients and 1.0 u / kg / wk ( 0.33 mg / kg / wk ) for four patients . in group ii , estrogen therapy 
 was started at 1 tablet with or without medroxyprogesterone ( provera ) . using the data from group i , the pearson s correlation coefficient between pubertal growth 
 ( height difference from the start of estrogen therapy until adult height ) and clinical 
 characteristics ( chronological age , bone age and height ) at start of estrogen therapy were 
 calculated . the projected adult height is calculated by converting height sds of 
 turner syndrome at the start of gh therapy to adult height data of turner syndrome without 
 any treatment ( 6 ) . bone age was estimated by one trained doctor using the tw2 rus method standardized for 
 japanese children . the prediction formula obtained for group table 1 shows the clinical characteristics of 
 estrogen replacement therapy and cyclic estrogen - progesterone therapy ( hrt ) . ages at the 
 start of estrogen therapy and hrt were significantly younger in the patients of group i than 
 in the patients of group ii . however height and height sds at the start of estrogen therapy 
 and hrt were not significantly different between the two groups . pubertal growth , projected adult height , clinical characteristics at adult 
 height and the effect of therapy shows pubertal growth , projected adult height ( pah ) , and clinical 
 characteristics at adult height of the two groups . pubertal growth was significantly greater 
 in group i than in group ii , while projected adult height , adult height and the effect of 
 therapy were not significantly different . the difference of adult height minus projected 
 adult height , which is considered as the effect of the growth promoting therapy including 
 gh , anabolic steroid and estrogen did not differ , either . correlation between pubertal growth and clinical characteristics at start of 
 estrogen therapy shows the correlation co - efficient between pubertal growth and clinical 
 characteristics at the start of estrogen ( e ) therapy . using stepwise multiple regression analysis taking pubertal growth as an independent 
 factor , and chronological age , bone age , and height as dependent factors , we determined the 
 following formula ( p<0.001 , r2=0.737):(pubertal growth ) = 1.01  
 ( chronological age at start of e )  0.326  ( height at start of e ) 1.779  ( bone age at 
 start of e ) + 90.997 although height did not correlate with pubertal growth by itself , stepwise multiple 
 regression analysis showed it was a significant factor . since bone age was missing for one 
 patient in group i , the formula above was drawn from data of 15 patients in group i. 
 predicted adult height is calculated as follows:(predicted adult height ) = 
 ( height at start of e ) + ( predicted pubertal growth ) =  1.01  ( chronological age at 
 start of e ) + 0.674  ( height at start of e ) 1.779  ( bone age at start of e ) + 
 90.997 figures 1 ( a ) and ( b)fig . 1 . pubertal growth and predicted pubertal growth ( a ) , and adult height and predicted 
 adult height ( b ) in group i. show the correlation between real pubertal height and predicted pubertal height and 
 between real adult height and predicted adult height in group i. the mean absolute 
 difference between real adult height and predicted adult height was 1.6  0.9 cm ( 0.32.8 
 cm ) . pubertal growth and predicted pubertal growth ( a ) , and adult height and predicted 
 adult height ( b ) in group i. the formula for the prediction of adult height was applied to the patients in group ii . since bone age was missing for two patients in group ii , the predicted pubertal growth and 
 predicted adult height of nine patients in group ii were compared with real pubertal growth 
 and real adult height ( fig . pubertal growth and predicted pubertal growth ( a ) , and adult height and predicted 
 adult height ( b ) in group ii . ) . the mean absolute difference between real adult height and predicted adult 
 height was 1.0  0.7 cm ( 0.12.0 cm ) . pubertal growth and predicted pubertal growth ( a ) , and adult height and predicted 
 adult height ( b ) in group ii . gh therapy was approved for turner syndrome in 1991 in japan , but approval was limited to 
 turner girls with gh deficiency ( ghd ) and the dose was low at 0.5 iu / kg / wk ( 0.167 mg / kg / wk ) . 
 in 1999 , the limitation of ghd was removed and the widely accepted dose for turner syndrome , 
 1.0 iu / kg / wk ( 0.33 mg / kg / wk ) , was approved . the adult height of turner syndrome was reported 
 as 139.1  5.6 cm without any treatment ( 6 ) and 142.4 
  3.9 cm with anabolic steroid hormone treatment ( 7 ) 
 in japan . after innovation of gh therapy , the adult height of turner syndrome was increased 
 to 144.5  5.2 cm at 0.5 iu / kg / wk and 147.0 cm at 1.0 iu / kg / wk of gh therapy ( 8) . although adult height of turner girls was improved 
 with gh therapy , gh is not as effective in turner syndrome as in ghd . the mean growth 
 velocity in the first year of therapy is 8.5 cm / yr at 0.5 iu / kg / wk in ghd ( 9 ) and 6.37.2 cm / yr at 1.0 iu / kg / wk in turner syndrome 
 ( 10 ) . the adult height of ghd girls has been 
 reported as 147.8  5.4 cm ( 11 ) , which is not so 
 different from that of the turner girls of groups i and ii . in turner syndrome , although response to gh therapy is poor , improved adult height is 
 obtained by delaying estrogen replacement therapy . because of hypogonadism , bone age 
 decelerates at around 10.5 yr ( 12 ) and taller adult 
 height can be obtained if estrogen replacement is started at an older age ( 13 ) . in this study , the mean adult height was not 
 significantly different between groups i and ii , although age at the start of gh therapy was 
 older and height sd score was lower in group ii than in group i. the same adult height was 
 achieved by starting estrogen replacement therapy later , by approximately three years , in 
 group ii than in group i. the most recent guideline on the management for turner syndrome recommends inducing 
 pubertal development at 1213 yr of age to avoid psychological problems and reduced bone 
 mineral density caused by delayed start of estrogen replacement therapy ( 5 ) . however , patients and their parents desired adult 
 height can not be ignored in clinical practice . puberty is the period in which sexual 
 characteristics mature , during which growth velocity accelerates , decelerates and finally 
 stops . it is necessary to predict adult height if a patient s desired adult height is to be 
 taken into account . a formula to predict pubertal growth at the start of estrogen therapy 
 was derived from age , height and bone age using stepwise multiple regression analysis . adult 
 height can be predicted by adding predicted pubertal growth to height at the start of 
 estrogen therapy . since the patient with the 
 lowest dose ( 1/10 conjugated equine estrogens ) had no bone age data , her data was not used 
 to derive the prediction formula . very low dose estrogen therapy is recommended and it may 
 induce greater pubertal growth . since there was no significant correlation between initial 
 estrogen dose and pubertal growth ( data not shown ) in group ii , it seems that pubertal 
 growth is not influenced by an initial estrogen dose greater than 0.2 tablets of conjugated 
 equine estrogens . the prediction model was applied to group i and pubertal growth was 
 predicted very well with a maximum difference of 2.0 cm . however , it should be noted that 
 the prediction was established and tested in subjects with estrogen therapy initiated at 
 considerably advanced ages . recently , it has been recommended that very low dose estrogen therapy such as transdermal 
 estradiol 6.25 g daily or micronized estradiol 0.25 mg daily oral administration is started 
 at a young age to mimic the process of normal puberty ( 5 ) . in japan , conjugated equine estrogens ( premalin ) 0.0625 mg daily oral 
 administration , transdermal estradiol 0.09 mg every two days or estradiol 1 ng daily oral 
 administration ( 14 ) have been used as very low dose 
 estrogen therapy . although we do nt have enough data on very low dose estrogen therapy , the 
 present prediction model may imply that the therapy will not shorten pubertal growth but 
 rather increase pubertal growth . in our experience , patient s or parents desired adult height is at least 150 cm . various 
 situations were tested with this prediction model . in the case of a turner girl of 140 cm 
 height at 12 yr of age , pubertal growth is predicted as 14.3 cm and adult height is 
 predicted as 154.3 cm , provided the prediction can be adequately extrapolated to an earlier 
 start of estrogen therapy . as shown in table 
 4table 4 . predicted adult height at 140 cm of height , a height at 140 cm seems to be a critical point for starting estrogen therapy 
 in consideration of adult height . however , it is sometimes difficult to treat turner girls 
 of 140 cm until 14 yr of age , early diagnosis and early initiation of gh treatment is very 
 important . from the consensus statements and the present study , the following therapy can be 
 recommended in consideration of favorable adult height for turner girls during childhood : 1 ) 
 start gh therapy at 0.35 mg / kg / wk as early as 8 yr with greater than 2.5 sd of height sds ; 
 2 ) start very low dose estrogen therapy at 1214 yr at approximately 140 cm of height ; 3 ) 
 dose of estrogen is gradually increased every 36 mo ; 4 ) start cyclic estrogen - progesterone 
 therapy approximately 2 yr after start of low dose estrogen therapy . further studies related 
 to early gh treatment , anabolic steroid treatment and low dose estrogen treatment are 
 necessary . in summary , a prediction model for pubertal growth at the start of estrogen therapy in 
 turner syndrome was derived . using this prediction model , timing the start of estrogen 
 therapy
abstractin estrogen replacement therapy in turner syndrome , there is no report which 
 recommends the timing of the start of estrogen therapy in relation to height or adult 
 height prediction . 
 we have established a prediction model for pubertal growth ( height 
 difference from the start of estrogen therapy until adult height ) at the start of estrogen 
 replacement therapy . 
 twenty - seven turner girls without spontaneous puberty were divided 
 into two groups according to birth years ; group i consisted of 16 patients born from 
 19801989 and group ii consisted of 11 patients born before 1980 . using clinical 
 characteristics from group i , stepwise multiple regression analysis taking pubertal growth 
 as an independent factor , and chronological age , bone age ( tw2 rus method standardized for 
 japanese children ) , height and height sds as dependent factors revealed following formula 
 ( p<0.001 , r2=0.737 ) : ( pubertal growth ) =  1.01x ( chronological age at start of e )  
 0.326x ( height at start of e )  1.779x ( bone age at start of e ) + 90.997 . 
 predicted adult 
 height was obtained by adding predicted pubertal growth to height at the start of estrogen 
 therapy . 
 the mean absolute difference between real adult height ( tallest height after 
 height velocity less than 1 cm / yr ) and predicted adult height was 1.6  0.9 cm ( 0.32.8 
 cm ) in group i. when this prediction model was applied to group ii , the mean absolute 
 difference between real adult height and predicted adult height was 1.0  0.7 cm ( 0.12.0 
 cm ) . a prediction model for pubertal growth at start of estrogen therapy in turner 
 syndrome was obtained . using this prediction model , 
 the timing of the start of estrogen 
 therapy can be decided in consideration of the patient s desired adult height .