Decreased bone mass despite long-term estrogen replacement therapy in young women with Turner's syndrome and previously normal bone density. A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner's syndrome. Comparison of Transdermal and Oral Estrogen Therapy in Girls with Turner's Syndrome Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., Collaborative Study Group. Androgen replacement therapy in Turner syndrome: a pilot study. Androgen-responsive aspects of cognition in girls with Turner syndrome. Design and baseline characteristics of the soy phytoestrogens as replacement estrogen (SPARE) study--a clinical trial of the effects of soy isoflavones in menopausal women. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. Randomized prospective trial of estrogen-replacement therapy in women with a history of breast cancer. 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? [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]. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. Insulin resistance and body composition in Turner syndrome: Effect of sequential change in the route of estrogen administration Long-Term Prevention with Hormone-Replacement Therapy after the Menopause: Which Women should be Targeted? Estrogen Deficiency in Adolescents and Young Adults: Impact on Bone Mineral Content and Effects of Estrogen Replacement Therapy
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 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 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 Clinical trials of recombinant human GH therapy in Turner syndrome that began more than a decade ago show that GH accelerates the linear growth rate . Several studies indicate that final height is also improved , although the magnitude of the increase has been debated . The age at which feminization is induced could be an important factor in determining the patient 's ultimate growth response . To test this , 60 patients from a large ( n = 117 ) , previously unreported , clinical trial of GH treatment were r and omly assigned to begin conjugated estrogens at either 12 or 15 yr of age . The 60 patients were all less than 11 yr of age at entry ( mean , 9.5 yr ) and received 0.375 mg/kg x week of GH for nearly 6 yr on a daily or three times weekly regimen . Height gain was calculated by comparing the study patients ' final or near final heights to their pretreatment projected heights as well as to those of a separate set of age-matched , historical control patients . Patients in whom estrogen treatment was delayed until age 15 yr gained an average of 8.4 + /- 4.3 cm over their projected height , whereas those starting estrogen at 12 yr gained only 5.1 + /- 3.6 cm , on the average ( P < 0.01 ) . Analysis of the interval data showed that growth was stimulated for approximately 2 yr after estrogen initiation , but then declined in association with bone age advancement . Patients who were older than 11 yr at entry ( n = 57 ) all initiated  estrogen  1 yr after beginning GH and showed a mean gain in adult height of 4.7 cm , similar to those given estrogen at age 12 yr . Multivariate analysis revealed that the number of years of GH therapy before estrogen  treatment was a strong factor in predicting height gained , indicating that the timing of estrogen introduction is an important determinant of final height in this cohort of GH-treated patients with Turner syndrome matched for baseline age and other characteristics 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 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 Following the results of the Women 's Health Initiative , many women now decline estrogen replacement at the time of menopause and seek natural remedies that would treat menopausal symptoms and prevent bone loss and other long-term consequences of estrogen deficiency , but without adverse effects on the breast , uterus , and cardiovascular system . The results of most soy studies in this population have had limitations because of poor design , small sample size , or short duration . This report describes the study rationale , design , and procedures of the Soy Phytoestrogens As Replacement Estrogen ( SPARE ) study , which was design ed to determine the efficacy of soy isoflavones in preventing spinal bone loss and menopausal symptoms in the initial years of menopause . Women ages 45 to 60 without osteoporosis and within 5 years from menopause were r and omized to receive soy isoflavones 200 mg daily or placebo for 2 years . Participants have yearly measurements of spine and hip bone density , urinary phytoestrogens , and serum lipids , thyroid stimulating hormone , and estradiol . Menopausal symptoms , mood changes , depression , and quality of life are assessed annually . The SPARE study recruited 283 women , 66.1 % were Hispanic white . With a large cohort , long duration , and large isoflavone dose , this trial will provide important , relevant , and currently unavailable information on the benefits of purified soy isoflavones in the prevention of bone loss and menopausal symptoms in the first 5 years of menopause . Given the high proportion of Hispanics participating in the study , the results of this trial will also be applicable to this minority group 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 . ) With the onset of menopause , women develop increased risk for heart disease , vasomotor instability , and osteoporosis , which is related to estrogen deficiency , and can be corrected with estrogen-replacement therapy ( ERT ) .  Menopausal women with a history of breast cancer are advised against estrogen therapy because of concerns that ERT may adversely affect the course of the disease . There have been no prospect i ve studies that address the issue of risk versus benefit for ERT in women with a history of breast cancer . We have initiated a r and omized , prospect i ve clinical study to define the influence , if any , of ERT on the clinical course of breast cancer ( measure of potential risk ) and the efficacy of ERT in the treatment of metabolic bone derangements ( measure of benefit ) . Changes in serum lipids , cardiovascular events , and indices of psychological well-being are compared but do not constitute statistical end points . Eligible women must have had stage I or stage II breast cancer and must have had no evidence of disease for at least 2 years since therapy if estrogen-receptor-negative disease or for at least 10 years if the estrogen-receptor status is unknown . They were r and omized to receive ERT ( Premarin at 0.625 mg , days 1 - 25 ) versus no intervention ( study control ) . Parameters of benefit and risk will be measured to detect a 10 % change in disease-free rate for up to 5 years , with interim analyses at 20 , 30 , and 36 months of patient accrual . This study will allow us to begin the development of safe and effective strategies for the management of estrogen deficiency in patients with breast cancer . ( ABSTRACT TRUNCATED AT 250 WORDS 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 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 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 The aim of the present study was to examine the impact of sequential change in the route of estrogen administration on body composition and insulin resistance in patients with Turner syndrome ( TS ) using  cyclical hormone replacement therapy ( HRT ) with conjugated equine estrogens ( CEE ) plus medroxyprogesterone acetate ( MPA ) . We carried out a self-controlled study of nine non-obese patients with TS , with an average age of 23 ± 4.9 years .  Body mass index ( BMI ) , waist-to-hip ratio ( WHR ) , fasting glycemia , insulin tolerance ( glucose disappearance constant during an insulin tolerance test , kITT ) and body composition ( dual-energy X-ray absorptiometry ) were studied after 1 year 's use of CEE plus MPA and repeated after 1 year 's use of 17β-estradiol gel with the same schedule of MPA administration . We did not observe any difference between the oral and percutaneous HRT with regard to BMI , WHR and insulin tolerance ( kITT : 4.9 ± 1.5 vs. 5.3 ± 1.5%/min , p = 0.8 ) . During administration of the 17β-estradiol gel a tendency to increased total lean mass ( p = 0.054 ) was observed . We conclude that sequential change in the route of estrogen administration in TS patients using cyclical HRT with CEE and MPA does not affect insulin resistance , although use of percutaneous 17β-estradiol gel seems to exert favorable changes in body composition For decades , hormone-replacement therapy ( HRT ) was considered safe and was the first choice in prevention of postmenopausal osteoporosis induced by estrogen deficiency . Numerous experimental and epidemiological studies further supported a protective effect of exogenous female sex hormones on atherogenesis and coronary heart disease ( CHD ) in women after the menopause . However , the fact that these promising results were not translated into lower incidences of CHD events in hormone-treated women compared with placebo in subsequent , large , r and omized studies of healthy subjects as well as women with known CHD raised a very intense debate concerning the safety of HRT in terms of cardiovascular risk . A critical mass of data points toward a protective influence of HRT on cardiovascular disease end points in early postmenopausal women , but increased harm in elderly women , especially those with abdominal adiposity or metabolic syndrome . Once the quasi-hysterical reaction to the largest of the r and omized studies ( the Women 's Health Initiative ) has abated , a future strategy should be to concentrate on identifying those relatively few individuals who are not suitable for HRT , as HRT still remains the most thoroughly investigated pharmacological prevention strategy of osteoporosis 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
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 .