Androgen replacement therapy in Turner syndrome: a pilot study. A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner's syndrome. Choosing an oestrogen replacement therapy in young adult women with Turner syndrome* Androgen-responsive aspects of cognition in girls with Turner syndrome. Decreased bone mass despite long-term estrogen replacement therapy in young women with Turner's syndrome and previously normal bone density. Growth hormone therapy in Turner's syndrome. Impact of injection frequency and initial bone age. Comparison of Transdermal and Oral Estrogen Therapy in Girls with Turner's Syndrome [The effect of primary lack of estrogens and the influence of the age at the beginning of estrogen therapy on bone mineral density in patients with Turner's syndrome]. Absence of growth hormone effects on cognitive function in girls with Turner syndrome. Estrogen Deficiency in Adolescents and Young Adults: Impact on Bone Mineral Content and Effects of Estrogen Replacement Therapy 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? Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner's syndrome. Calcium Supplementation with and without Hormone Replacement Therapy To Prevent Postmenopausal Bone Loss Hormone replacement therapy and the prevention of postmenopausal osteoporosis The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone Methionyl human growth hormone and oxandrolone in Turner syndrome: preliminary results of a prospective randomized trial.
CONTEXT Women with Turner syndrome ( TS ) have reduced levels of and rogens due to ovarian failure . HYPOTHESES Morbidity associated with TS , such as bone fragility , metabolic changes , obesity , neurocognitive profile , and sexual problems may partly relate to and rogen insufficiency and improve on and rogen replacement therapy ( ART ) . OBJECTIVES The objective of the study was to determine the effect of and rogens on morbidity in TS . DESIGN Fourteen TS women ( aged 17 - 27 yr ) participated in a r and omized , double-blind , placebo-controlled crossover pilot . The study was conducted in a hospital outpatient clinic between December 2001 and July 2004 . INTERVENTION TS patients were on estrogen/progestin replacement therapy .  Subjects received oral 1.5 mg methyl testosterone ( ART ) or placebo for 1 yr and the alternative for another year . MAIN OUTCOME MEASURES The study compared body composition as a primary outcome , and physiology , biochemistry , visceral fat , cognition , and quality of life ( QOL ) as secondary outcomes . RESULTS ART as compared with placebo reduced total cholesterol , triglycerides , and high-density lipoprotein cholesterol . It improved bone mineral density , increased lean body mass , and decreased fat mass .  ART improved attention , reaction time , and verbal memory and had no effect on executive functions and spatial cognition . Patients reported improved QOL , including general health , coping with stress , and sexual desire . CONCLUSIONS And rogen insufficiency plays a role in TS-impaired body composition , neurocognition , and QOL , and these aspects improve with ART , which was safe and effective when given for 1 yr It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis , and that there are management strategies to replace bone that is already lost . While estrogen ( E2 ) is generally considered to prevent bone loss by suppressing bone resorption , it is now recognized that estrogen also exerts an anabolic effect on the human skeleton . In this study , we tested whether estrogen could increase bone mass in women with primary ovarian failure . We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement .  Twenty-one women with Turner 's syndrome , aged 20 - 40 years , were studied . The T scores of bone mineral density at lumbar spine and proximal femur at baseline were -1.4 and -1.1 , respectively . Hormone replacement was given as subcutaneous E2 implants ( 50 mg every 6 months ) with oral medroxy progesterone .  Serum E2 levels increased incrementally from 87.5 pM at baseline to 323 , 506 , 647 , and 713 pM after 6 months and 1 , 2 , and 3 years of hormone replacement therapy ( HRT ) , respectively . The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of -0.2 and -0.4 , respectively . The cancellous bone volume increased significantly from 13.4 % to 18.8 % . There was a decrease in activation frequency , but the active formation period was increased by HRT . There was a significant increase in the wall thickness from 33.4 microm at baseline to 40.9 microm after 3 years of HRT , reflecting an increase in bone formed at individual remodeling units . Although there was an early increase in biochemical markers of bone formation , these declined thereafter . Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turner 's syndrome and low bone mass OBJECTIVE Hormone replacement therapy ( HRT ) is prescribed to most patients with Turner syndrome ( TS ) although its use in adult TS patients has not been scientifically evaluated . The present study was performed to compare the short‐term effects in adult women with Turner syndrome of  low‐dose oral conjugated oestrogen (  0·625  mg , CE ) with relatively high dose ethinyl oestradiol ( 30 µg , EE2 ) ; both combined with an oral progestin 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 determine whether young women with Turner 's syndrome who had normal bone mineral density ( BMD ) before the induction of puberty maintain normal BMD in young adulthood . DESIGN Controlled clinical study . SETTING A private hospital clinical research setting . PATIENTS Young women with Turner 's syndrome in Tanner stage V of puberty with previously normal BMD . INTERVENTIONS Oral conjugated estrogens and progesterone acetate were administered continuously for a mean ( + /-SD ) of 4.1+/-1.0 years . Bone mineral densities and blood sample s were evaluated . MAIN OUTCOME MEASURE(S ) The BMD of the lumbar spine and the femoral neck was determined during young adulthood . The change in BMD over the previous 6 years also was evaluated . Serum concentrations of the carboxy-terminal propeptide of type 1 collagen and of the carboxy-terminal cross-linked telopeptide of type 1 collagen were measured . RESULT ( S ) The BMD of the lumbar spine was reduced significantly in our patients . There was no change in the BMD of the femoral neck or lumbar spine over a period of 6.1 years . Concentrations of the carboxy-terminal propeptide of type 1 collagen were decreased , whereas concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen were increased . CONCLUSION ( S ) Young women with Turner 's syndrome do not attain normal peak bone mass even when estrogen replacement therapy is begun in adolescence . Their low BMD seems to be due to decreased bone formation and increased bone resorption STUDY OBJECTIVE To determine the influence of the injection frequency and the initial bone age on the efficacy of treatment with biosynthetic growth hormone in Turner 's syndrome . DESIGN R and omized study . SETTING Referral-based pediatric endocrinology departments of seven university medical centers . PATIENTS Fifty-two patients with Turner 's syndrome confirmed with chromosomal analysis . TREATMENT Somatotropin recombinant DNA ( 24 IU/m2 of body surface area ) subcutaneously administered in three or six injections per week for 2 years . Patients who were older than 12 years at the beginning of the study received low doses of estrogen . RESULTS The following statistically significant findings supported the use of six injections per week compared with three injections per week : the mean ( + /- SD ) increment in height during 2 years was 11.3 cm ( 3.8 cm ) with six injections vs 8.6 cm ( 3.4 cm ) with three injections ; the increment in height st and ard deviation score was 0.9 cm ( 0.5 cm ) vs 0.6 cm ( 0.3 cm ) ; the growth velocity was 6.6 cm/y ( 2.0 cm/y ) vs 5.2 cm/y ( 1.7 cm/y ) in year 1 and 4.7 cm/y ( 2.0 cm/y ) vs 3.4 cm/y ( 1.7 cm/y ) in year 2 ; and the increment in height st and ard deviation score for bone age was 0.8 cm ( 0.5 cm ) vs 0.4 cm ( 0.6 cm ) . For patients whose initial bone age was more than 13 years , growth velocity increased by 1 to 2 cm in year 1 ; in year 2 no increment was observed . We did not observe adverse effects . CONCLUSIONS Biosynthetic growth hormone in a higher-frequency regimen in Turner 's syndrome is more efficient in terms of increment in height , growth velocity , and height st and ard deviation score for bone age than treatment in a lower-frequency regimen . In patients with an initial bone age of more than 13 years , the response was poor . Longer follow-up is necessary to assess the effect on final height Eight girls with Turner 's syndrome were given low dose oral ethinyl estradiol or transdermal 17 beta-estradiol in order to compare the effect of the route of administration on selected markers of hepatic metabolism , and various hormonal concentrations . Oral estrogen was given at a dose of 100 ng/kg/day and transdermal estrogen via adhesive skin patch at 0.0125 mg/kg/day . The subjects received one form of estradiol for one month , and after a one month washout period , received the other form . Both oral and transdermal estradiol caused a significant decrease in FSH while only transdermal result ed in a significant decrease in LH . Oral estradiol , though not transdermal estradiol , increased serum high density lipoprotein , thyroxine binding protein and growth hormone binding protein . Urinary growth hormone excretion increased after both forms of therapy , while insulin-like growth factor-I and insulin-like growth factor binding protein-3 remained unchanged . Thus , in girls with Turner 's syndrome , estrogen replacement by the transdermal route may have less deleterious effect on hepatic metabolism than oral estrogen Lumbar spine bone mineral density ( BMD ) values were measured in women with Turner 's syndrome ( TS ) and the influence of primary ovarian failure as well as the age at the start of estroprogestins ( EP ) therapy were considered . EP treatment with 2 mg of estradiol ( E2 ) and BMD monitoring were started in 72 and finally continued for 5 years in 34 patients with TS , aged 12 - 38 years , previously not treated with growth hormone or anabolic steroids .  The mean total BMD gain ( deltaBMD ) was 20 % and the most significant increase was observed after the first ( 7.5 % ) and the second ( 6.6 % ) year of the therapy . Before the start and during EP treatment E2 levels were evaluated : they increased from 9.2pg/ml to the values observed in the controls ( C ) but positive correlation with BMD was not observed . Analysis of TS patients in age brackets ( < 15 years , 15 - 20 years , 21 - 25 years , > 25 years ) showed that only in the group that started EP treatment before the age of 15 every year significant deltaBMD was observed . The group that started EP therapy after the age of 20 did n't achieve significant deltaBMD . Patients wit TS had significantly higher levels of bone metabolism markers ( Ntx and BALP ) than the controls and in both groups negative correlation with age was found . On the basis of the results the conclusion was made that in hypoestrogenic women , not exclusively TS , the age when estrogen therapy is started may determine the effects in relation to bone mass . The administered E2 doses may also be important 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 Because the long-term effects of estrogen replacement in adolescents with ovarian failure and hypothalamic amenorrhea have not been previously studied , we conducted a 2-year study of 35 patients to determine factors contributing to baseline bone density measures ( bone density , bone mineral content , and bone width ) and the response to estrogen therapy . Estrogen-deficient patients were often profoundly osteopenic by single-photon absorptiometry of the radius and dual-photon absorptiometry of the spine , despite estrogen replacement . Variables that were significant predictors of better initial single-photon absorptiometry measurements included increased age , increased body mass index , spontaneous pubertal development , lack of radiation therapy , and lower serum osteocalcin . Patients treated with estrogen/progestin had stable cortical bone mineral content and bone density at the distal one-third of the radius , a slight improvement in bone density at the distal one-tenth of the radius , and an encouraging , but marginal , improvement in the z score ( st and ard deviation from the mean ) of bone mineral content at the distal onetenth . The z scores for cortical bone width and bone density decreased , suggesting a possible relative worsening over time . In untreated estrogen-deficient girls , bone mineral content and bone density decreased ( but not significantly ) ; the z score of cortical bone width showed a significant decrease . Using dual-photon absorptiometry , a history of radiation therapy was found to be a predictor of lower bone density compared with age-matched controls . Estrogen/ progestin therapy did not result in changes in serum levels of lipids and antithrombin HI , weight , or blood pressure . This study suggests that because most adolescent/young adult patients with estrogen deficiency may not achieve normal bone density with current therapy , earlier and more aggressive intervention may be necessary 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 Forty patients with Turner 's syndrome , aged 5.0 - 16.6 yr , were r and omly allocated to receive daily sc injections of recombinant human GH ( hGH ) at a dose of 1 IU/kg.week alone ( group I ) or in combination with 25 ng/kg.day ethinyl estradiol ( E2 ; group II ) . The mean pretreatment height velocity was 3.8 cm/yr for both groups . During the first year of treatment height velocity increased significantly ( P less than 0.001 ) in both groups , to 7.5 + /- 1.3 and 8.1 + /- 1.6 cm/yr , respectively . The difference between the two groups was not significant . The mean ( + /- SD ) height velocity expressed as the SD score for chronological age ( Turner references ) was 0.0 + /- 1.2 for group I and 0.2 + /- 1.4 for group II and increased significantly ( P less than 0.001 ) during the first year of treatment to + 4.3 + /- 1.1 in group I and + 5.4 + /- 1.2 in group II . The difference between both groups was statistically significant ( P less than 0.01 ) . Height SD score for chronological age ( Turner references ) increased from -0.2 + /- 0.9 to + 0.6 + /- 1.0 in group I and from -0.2 + /- 1.0 to + 0.7 + /- 1.1 in group II . Mean bone age progressed similarly in both treatment groups ( 1.1 + /- 0.6 yr during 1 yr of treatment ) . However , bone age maturation accelerated more rapidly in younger patients . Twelve girls ( three in group I and nine in group II ) had minor breast development . No major adverse effects were reported . We conclude that daily sc therapy with hGH stimulates height velocity in Turner 's syndrome . The beneficial effect on height velocity increment of E2 addition was small . Furthermore , even very low doses of E2 may induce breast development at an early age and accelerate bone maturation . For these reasons , the addition of E2 to hGH is not warranted in young patients with Turner 's syndrome Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures . Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [ 1 - 4 ] . However , only about 10 % of American women elect to receive replacement therapy because of attitudes of physicians and patients , the undesirability of menstrual bleeding , and unresolved questions about the relation of the use of estrogen to breast cancer [ 5 ] . Moreover , the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued , yet the incidence of some adverse effects increases with the duration of estrogen use . Safer alternatives to estrogen use have been sought . Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss , and prospect i ve studies have yielded conflicting results [ 6 - 17 ] . Moreover , some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [ 18 ] . We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo . The study had a three-arm , r and omized , parallel design . The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians , whereas the placebo and calcium groups were double blinded . Methods Healthy , white women between 6 months and 6 years after a natural menopause were recruited to participate in the study . The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory ; written informed consent was obtained from each participant . Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign . All participants had a history and physical examination . Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use , gastrointestinal disease , or any chronic illness . Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements . Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm ( breast or uterus ) , undiagnosed vaginal bleeding , thrombophlebitis or thromboembolism , and acute liver disease .  Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded : gallbladder disease , history of liver disease , first-degree relatives with breast cancer , and hypertension . Calcium urolithiasis was also an exclusion factor . Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study . One hundred eighteen women entered the study . The women were r and omly assigned to three groups : 1 ) hormonal replacement [ estrogen-progesterone-calcium carbonate ] , 2 ) calcium carbonate , or 3 ) placebo . Assignment to the groups was based on computer-generated r and om numbers provided by the statistician , with stratification for years postmenopause . The women in the hormonal replacement group took conjugated equine estrogens ( Premarin , Wyeth-Ayerst Laboratories , Inc. ; Philadelphia , Pennsylvania ) , 0.625 mg daily for 25 days of the month along with medroxyprogesterone ( Provera , Upjohn ; Kalamazoo , Michigan ) , 10 mg from days 16 to 25 . All women received 400 IU of vitamin D daily in the form of a multivitamin , and calcium supplementation ( as Caltrate , Lederle ; Clifton , New Jersey ) was provided to the two treatment groups . The duration of the study was 2.9 1.1 years ( mean SD ) . A 7-day dietary history was review ed with a nutritionist every 2 months ; calcium was provided as calcium carbonate , 600 mg ( Caltrate ) , and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium ( the mean + 2 SD found by Heaney and colleagues [ 7 ] to result in zero calcium balance in estrogen-deprived women ) . The calcium supplements were taken with meals in divided doses . The placebo appeared identical to the calcium carbonate tablets . No patients took antacids or histamine-2 blockers . All women had a baseline mammogram . Measurements Routine laboratory studies included a complete blood count , urinalysis , and serum fasting calcium , phosphorus , urea nitrogen , creatinine , alkaline phosphatase , cholesterol , and aminotransferase measurements [ 19 , 20 ] . In addition , follicle-stimulating hormone , estradiol , parathyroid hormone , osteocalcin , free thyroxine , and bone alkaline phosphatase were measured , and a urine specimen was collected after an overnight fast for hydroxyproline , calcium , and creatinine determinations , following a 3-day low-hydroxyproline diet [ 21 - 23 ] . Total body calcium was measured annually in the participants , using the delayed neutron activation method at Brookhaven National Laboratory [ 24 , 25 ] . This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 ( natural abundance of 0.187 % ) in the body . The Brookhaven National Laboratory whole-body counter was up grade d in 1987 to use 32 NaI ( T1 ) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [ 25 ] . The activated isotope , Calcium-49 , decays with a half-life of 8.72 minutes , emitting a 3.08 MeV characteristic line . More than 99.5 % of the body calcium is contained in the bone [ 26 ] . The method provides total body calcium with a coefficient of variation of about 1.5 % when no substantial change in the body weight occurs during the period of repeated studies . The measurements were made annually . The bone mineral density of the distal radius site was measured using a Lunar Radiation ( Madison , Wisconsin ) single-photon absorptiometer ( SP2 ) .  Bone mineral density of the spine ( L2-L4 ) and femur ( neck , trochanter , and Ward triangle ) was measured using a Lunar Radiation DP4 dual-photon absorptiometer . The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1 . All scans were analyzed using the same software version , which corrects for source decay . Instruments were calibrated daily , and the radioactive source was changed annually . Each measurement was done every 6 months . The coefficient of variation of these measurements was 2 % , except for the Ward triangle ( 2.5 % ) . Activity was measured using  activity monitors  ( large-scale integrated monitors ) , which were worn about the waist [ 27 ] . The average of 2 weekdays and 1 weekend day was used as an activity score . Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise . Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons : It measures mass rather than density per unit area ; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique ; it is more precise than the other measurements ; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton . The rate of change in bone mineral was calculated for each woman at each of the sites used in the study . St and ard linear regression procedures were used to estimate the rate of bone mineral change for each woman , and the regression intercept was used as the best estimate of the baseline value . Because some women terminated their participation in the study before others , the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [ 28 ] . Analyses of covariance were done using body mass index , activity scores , cigarette smoking , calcium intake , age , and years postmenopause as covariates . The data reported in this article are based on all women who provided at least three observations for a particular skeletal site . We considered other criteria , such as using data only from women who had participated in the study for at least 2 years , and all data analyses were done for this subgroup as well . The results of these analyses were invariably similar to those reported here and therefore are not presented separately . The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages ; separate analyses were carried out for each . The two indices were similar . Evidence from recent research is substantial that estrogen replacement therapy is effective , whereas the efficacy of calcium supplements is question able . Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy , and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown . A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions . We used two a priori contrasts : the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo . All P values reported are two-tailed . Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1 . Analysis of variance showed no significant differences in the baseline variables . The initial and final activity scores did not differ significantly . Table 1 . Baseline Values for Patient Characteristics , Bone Mineral Measurements , and Chemical Variables The range of initial daily calcium intake in the overall study group was 150 to 1263 mg ; in the calcium augmentation group , it was 222 to Fracture prevention is one of the public health priorities worldwide . Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis , the most common metabolic bone disease . Different effective treatments for osteoporosis are available . Hormone replacement therapy ( HRT ) at different doses rapidly normalizes turnover , preserves bone mineral density ( BMD ) at all skeletal sites , leading to a significant , reduction in vertebral and non-vertebral fractures .  Tibolone , a selective tissue estrogenic activity regulator ( STEAR ) , is effective in the treatment of vasomotor symptoms , vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT . Selective estrogen receptor modulators ( SERMs ) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures . The combination of bazedoxifene and conjugated estrogens , defined as tissue selective estrogen complex ( TSEC ) , is able to reduce climacteric symptoms , reduce bone turnover and preserve BMD . In conclusion , osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms . The use of a st and ard dose of HRT for osteoporosis prevention is based on biology , epidemiology , animal and pre clinical data , observational studies and r and omized , clinical trials . The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover , with compelling scientific evidence To study the effects of prolonged anorexia nervosa on bone density ( BD ) and to determine whether estrogen administration prevents bone loss in women with this disorder , 48 amenorrheic women with anorexia nervosa ( mean age , 23.7 yr ) were r and omized to receive estrogen and progestin replacement ( n = 22 ) or no replacement ( n = 26 ) . Clinical variables , biochemical indices , and spinal trabecular BD were measured every 6 months for a mean of 1.5 yr . Initial mean BD ( 130 + /- 27 mg K2HPO4/cm3 , + /- 1 SD ) was significantly ( P < 0.001 ) less than normal ( 176 + /- 26 mg K2HPO4/cm3 ) and less than 2 SD below normal in 21 of the 48 women . Forty-four women completed the study ( 19 in the estrogen group and 25 in the control group ) . The mean duration of follow-up was comparable in the estrogen-treated ( 1.57 + /- 0.89 yr ) vs. the control group ( 1.41 + /- 0.69 yr ) . The estrogen-treated group had no significant change in BD compared with the control group ; however , there was a 4.0 % increase in mean BD in patients with an initial ideal body weight of less than 70 % who were treated with estrogen . In contrast , control patients with comparably low initial weight had a 20.1 % decrease in BD . Women in the control group with spontaneous resumption of menses , all of whom had an initial percent ideal body weight of greater than 70 % , had a 19.3 % increase in bone mass . It is concluded that : 1 ) estrogen replacement can not prevent progressive osteopenia in young women with anorexia nervosa ; 2 ) a subset of patients may have improved BD with estrogen and progestin administration depending on initial body weight ; and 3 ) recovery from anorexia nervosa is associated with significantly improved BD 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 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
Using r and om-effects models , estrogen replacement therapy showed an increase in bone mineral density [ weighted mean change from baseline 0.09 g/cm2 ( 0.04–0.14 ) ] that differed by type of estrogen but not route of administration .
Oral estrogen replacement therapy showed a higher increase in high density lipoprotein cholesterol levels when compared to transdermal [ weighted mean difference 9.33 mg/dl ( 4.82–13.85 ) ] with no significant effect on other lipid fractions .
The current evidence suggests possible benefit of estrogen replacement therapy  on bone mineral density and high density lipoprotein cholesterol .
Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency .
Hence , long-term estrogen replacement therapy is the cornerstone treatment .
The estimates of its effect and optimal use , however , remain uncertain .
We aim ed to summarize the benefits and harms of estrogen replacement therapy on bone , cardiovascular , vasomotor and quality of life outcomes in patients with Turner syndrome .