Managing menopause. Raloxifene reduces risk of vertebral fractures [corrected] in postmenopausal women regardless of prior hormone therapy. Characteristics of hormone therapy, cognitive function, and dementia Hormone therapy in menopausal women with cognitive complaints Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. The effect of hormone therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone Therapy trial Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women Reproductive hormone exposure timing and ischemic heart disease: Complicated answers to a simple question. Health-related quality of life during hormone therapy after breast cancer: a randomized trial Hormone therapy and Alzheimer disease dementia Fragility fractures and the osteoporosis care gap in women: the Canadian Multicentre Osteoporosis Study The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study. Long-Term Prevention with Hormone-Replacement Therapy after the Menopause: Which Women should be Targeted? NIH asks participants in Women's Health Initiative estrogen-alone study to stop study pills, begin follow-up phase. Efficacy and safety of DT56a compared to hormone therapy in Greek post-menopausal women Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Healthy women with a family history of breast cancer: impact of a tailored genetic counseling intervention on risk perception, knowledge, and menopausal therapy decision making.
OBJECTIVE To provide up date d guidelines for health care providers on the management of menopause in asymptomatic healthy women as well as in women presenting with vasomotor or urogenital symptoms and on considerations related to cardiovascular disease , breast cancer , urogynaecology , and sexuality . OUTCOMES Lifestyle interventions , prescription medications , and complementary and alternative therapies are presented according to their efficacy in the treatment of menopausal symptoms . Counselling and therapeutic strategies for sexuality concerns in the peri- and postmenopausal years are review ed . Approaches to the identification and evaluation of women at high risk of osteoporosis , along with options for prevention and treatment , are presented in the companion osteoporosis guideline . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library in August and September 2012 with the use of appropriate controlled vocabulary ( e.g. , hormone therapy , menopause , cardiovascular diseases , and sexual function ) and key words ( e.g. , hormone therapy , perimenopause , heart disease , and sexuality ) . Results were restricted to clinical practice guidelines , systematic review s , r and omized control trials/controlled clinical trials , and observational studies . Results were limited to publication date s of 2009 onwards and to material in English or French . Search es were up date d on a regular basis and incorporated in the guideline until January 5 , 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , national and international medical specialty societies , and clinical practice guideline collection OBJECTIVE We examined whether past use of hormone therapy influences the effects of raloxifene on the risk of new vertebral fracture , cardiovascular events , or breast cancer . STUDY DESIGN The Multiple Outcomes of Raloxifene Evaluation ( MORE ) trial examined vertebral fracture incidence as the primary endpoint , breast cancer incidence as a secondary endpoint . Cardiovascular events were collected as secondary safety endpoints . POPULATION The MORE trial enrolled 7705 postmenopausal women . Of the 7682 women who reported their previous HT use status , 29 % used HT before screening . OUTCOMES MEASURED Separate logistic regression models analyzed the relationships between prior HT use and the risk of vertebral fracture , cardiovascular events , or breast cancer . Interaction terms with P<.10 were considered to be statistically significant . Confidence intervals for relative risks ( RR ) were calculated using the Mantel-Haenszel method . RESULTS Raloxifene 60 mg/d , the clinical ly approved dose for osteoporosis prevention and treatment , reduced the risk of vertebral fractures by 54 % ( RR=0.46 ) and 29 % ( RR=0.71 ) in women with and without prior HT use , respectively ( interaction P=.05 ) . A lower incidence of invasive breast cancer in women with prior HT use ( RR=0.23 ) and in women without prior HT use [ RR=0.31 ; interaction P=.60 ] was observed in women receiving raloxifene ( pooled doses ) . Irrespective of prior HT use , women treated with raloxifene ( pooled doses ) had no change in incidence of cardiovascular events ( interaction P=.56 ) . CONCLUSIONS The risk of vertebral fractures was lower in women treated with raloxifene , regardless of prior HT use , but there was a suggestion that the effect was greater in women who had used HT . Women r and omized to receive raloxifene exhibited a decreased incidence of invasive breast cancer , compared with women receiving placebo . No change occurred in the incidence of cardiovascular events , regardless of prior HT use Objectives : To examine the association between hormone therapy ( HT ) and cognitive performance or dementia , focusing on the duration and type of treatment used , as well as the timing of initiation of HT in relation to the menopause . Methods : Women 65 years and older were recruited in France as part of the Three City Study . At baseline and 2- and 4-year follow-up , women were administered a short cognitive test battery and a clinical diagnosis of dementia was made . Detailed information was also gathered relating to current and past HT use . Analysis was adjusted for a number of sociodemographic , behavioral , physical , and mental health variables , as well as APOE ε4 . Results : Among 3,130 naturally postmenopausal women , current HT users performed significantly better than never users  on verbal fluency , working memory , and psychomotor speed . These associations varied according to the type of treatment and a longer duration of HT appeared to be more beneficial . However , initiation of HT close to the menopause was not associated with better cognition . HT did not significantly reduce dementia risk over 4 years but current treatment diminished the negative effect associated with APOE ε4 . Conclusions : Current hormone therapy ( HT ) was associated with better performance in certain cognitive domains but these associations are dependent on the duration and type of treatment used . We found no evidence that HT needs to be initiated close to the menopause to have a beneficial effect on cognitive function in later life . Current HT may decrease the risk of dementia associated with the APOE ε4 allele Objective : To evaluate the effects of hormone therapy ( HT ) on cognition and subjective quality of life ( QoL ) in recently postmenopausal women with cognitive complaints . Methods : Cognitive Complaints in Early Menopause Trial ( COGENT ) was a r and omized , double-blind , placebo-controlled , multicenter , pilot study of 180 healthy postmenopausal women aged 45 to 55 years , r and omly assigned to receive either placebo or conjugated equine estrogen 0.625 mg/medroxyprogesterone acetate 2.5 mg for 4 months . Outcome measures included memory , subjective cognition , QoL , sexuality , and sleep , which were assessed at baseline and month 4 . Results : The study was terminated before the expected final sample size of 275 due to a decrease in enrollment coinciding with the publication of findings from the Women ’s Health Initiative . There were no differences between groups on any cognitive or QoL measures , except for an increase in sexual interest and thoughts with HT . Modest negative effects on short- and long-term verbal memory approached significance ( p < 0.10 ) . Women with baseline vasomotor symptoms ( VMS ) showed a decrease in VMS and an improvement in general QoL , but no cognitive benefit vs placebo . Conclusions : With the power to detect an effect size of ≥0.45 , this study suggests potential modest negative effects on verbal memory that are consistent with previous hormone therapy trials in older women . GLOSSARY : BTA = Brief Test of Attention ; BVRT = Benton Visual Retention Test ; COGENT = Cognitive Complaints in Early Menopause Trial ; CRT = Educational Testing Service Card Rotation Test ; CVLT = California Verbal Learning ; FAS = Letter Fluency Test ; HERS = Heart and Estrogen/progestin Replacement Study ; HT = hormone therapy ; MFSQ = McCoy Female Sexuality Scale Question naire ; MFQ = The Memory Functioning Question naire ; PANAS = Positive and Negative Affect Scale ; PSQI = The Pittsburgh Sleep Quality Index ; QoL = subjective quality of life ; SWAN = Study of Women ’s Health Across the Nation ; UQoL = Utian Quality of Life ; VMS = vasomotor symptoms Test ; WHI = Women ’s Health Initiative ; WHISCA = WHI Study of Cognitive Aging ; WMS-R/DGT-F , MS-R/DGT-B = Digit Span Forward and Backward Subtests of the Wechsler Memory Scale – Revised Description This guideline up date s the 2008 American College of Physicians ( ACP ) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women . This guideline is endorsed by the American Academy of Family Physicians . Methods The ACP Clinical Guidelines Committee based these recommendations on a systematic review of r and omized controlled trials ; systematic review s ; large observational studies ( for adverse events ) ; and case reports ( for rare events ) that were published between 2 January 2005 and 3 June 2011 . The review was up date d to July 2016 by using a machine-learning method , and a limited up date to October 2016 was done . Clinical outcomes evaluated were fractures and adverse events . This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density , including pharmaceutical prescriptions , calcium , vitamin D , and estrogen . Evidence was grade d according to the GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) system . Target Audience and Patient Population The target audience for this guideline includes all clinicians . The target patient population includes men and women with low bone density and osteoporosis . Recommendation 1 ACP recommends that clinicians offer pharmacologic treatment with alendronate , risedronate , zoledronic acid , or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis . ( Grade : strong recommendation ; high- quality evidence ) . Recommendation 2 ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 3 ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinical ly recognized osteoporosis . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 4 ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 5 ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women . ( Grade : strong recommendation ; moderate- quality evidence ) . Recommendation 6 ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences , fracture risk profile , and benefits , harms , and costs of medications . ( Grade : weak recommendation ; low- quality evidence ) Background For postmenopausal women , the main reason to start hormone therapy ( HT ) is to reduce menopausal symptoms and to improve quality of life ( QOL ) . The aim of this study was to analyse the impact of HT on different aspects of symptom experience and QOL during a r and omised trial . A total of 1823 postmenopausal women were recruited into the Estonian Postmenopausal Hormone Therapy ( EPHT ) trial in 1999–2001 . Women were r and omised to blind HT , open-label HT , placebo or non-treatment arm . After one year in the trial , a question naire was mailed and 1359 women ( 75 % ) responded , 686 in the HT arms and 673 in the non-HT arms . Mean age at filling in the question naire was 59.8years . The question naire included Women 's Health Question naire ( WHQ ) to assess menopause specific QOL of middle-aged women together with a 17-item question naire on symptoms related to menopause , a question about painful intercourse , and a question about women 's self-rated health . Results After one year in the trial , fewer women in the HT arms reported hot flashes , trouble sleeping , and sweating on the symptom question naire . According to WHQ , women in the HT arms had fewer vasomotor symptoms , sleep problems , and problems with sexual behaviour , but more menstrual symptoms ;  HT had no effect on depression , somatic symptoms , memory , attractiveness , or anxiety . A smaller proportion of women reported painful intercourse in the HT arms . There were no significant differences between the trial arms in women ’s self-rated subjective health . Conclusions The results from the EPHT trial confirm that HT is not justified for treating symptoms , other than vasomotor symptoms , among postmenopausal women . WHQ proved to be a useful and sensitive tool to assess QOL in this age group of women OBJECTIVE Use of estrogen-based hormone therapy ( HT ) as a protection from cognitive decline and Alzheimer disease ( AD ) is controversial , although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17β-estradiol preferable to conjugated equine estrogen formulations . Little is known regarding specific population s of women who may derive benefit from HT . METHODS Women with heightened risk for AD ( aged 49 - 69 ) , all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset , underwent  cognitive assessment  followed by r and omization to continue or discontinue HT . Assessment s were repeated at 2 years after r and omization . RESULTS Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention , working memory , and processing speed measures . Women who used 17β-estradiol versus conjugated equine estrogen , whether r and omized to continue or discontinue HT , showed better verbal memory performance at the 2-year follow-up assessment . An interaction was also found with HT r and omization and family history of AD in a first-degree relative . All female offspring of patients with AD declined in verbal memory ; however , women who continued HT declined less than women who discontinued HT . Women without a first-degree relative with AD showed verbal memory improvement ( likely because of practice effects ) with continuance and declined with discontinuance of HT . CONCLUSION Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset Objective To assess the long term risks and benefits of hormone replacement therapy ( combined hormone therapy versus placebo , and oestrogen alone versus combined hormone therapy ) . Design Multicentre , r and omised , placebo controlled , double blind trial . Setting General practice s in UK ( 384 ) , Australia ( 91 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 years at r and omisation . At early closure of the trial , 56 583 had been screened , 8980 entered run-in , and 5692 ( 26 % of target of 22 300 ) started treatment . Interventions Oestrogen only therapy ( conjugated equine oestrogens 0.625 mg orally daily ) or combined hormone therapy ( conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ) . Ten years of treatment planned . Main outcome measures Primary outcomes : major cardiovascular disease , osteoporotic fractures , and breast cancer . Secondary outcomes : other cancers , death from all causes , venous thromboembolism , cerebrovascular disease , dementia , and quality of life . Results The trial was prematurely closed during recruitment , after a median follow-up of 11.9 months ( interquartile range 7.1 - 19.6 , total 6498 women years ) in those enrolled , after the publication of early results from the women 's health initiative study . The mean age of r and omised women was 62.8 ( SD 4.8 ) years . When combined hormone therapy ( n=2196 ) was compared with placebo ( n=2189 ) , there was a significant increase in the number of major cardiovascular events ( 7 v 0 , P=0.016 ) and venous thromboembolisms ( 22 v 3 , hazard ratio 7.36 ( 95 % CI 2.20 to 24.60 ) ) . There were no statistically significant differences in numbers of breast or other cancers ( 22 v 25 , hazard ratio 0.88 ( 0.49 to 1.56 ) ) , cerebrovascular events ( 14 v 19 , 0.73 ( 0.37 to 1.46 ) ) , fractures ( 40 v 58 , 0.69 ( 0.46 to 1.03 ) ) , and overall deaths ( 8 v 5 , 1.60 ( 0.52 to 4.89 ) ) . Comparison of combined hormone therapy ( n=815 ) versus oestrogen therapy ( n=826 ) outcomes revealed no significant differences . Conclusions Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause . The results are consistent with the findings of the women 's health initiative study and secondary prevention studies . Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause , when the effect may be different . Trial registration Current Controlled Trials IS RCT N Premenopausal women have a relatively lower risk of ischemic heart disease ( IHD )  compared to age matched men and this gender gap narrows after menopause . The observation that the onset of IHD occurs 10 years later in women than it does in men is said to suggest that endogenous reproductive hormones play a protective role . Indeed , animal models and human epidemiological studies suggest that oophorectomy is a risk factor for accelerated IHD . In animal models , hormone therapy ( HT ) has anti-atherosclerotic effects after oophorectomy , HT in the form of oral contraceptives ( OCs ) prevents atherosclerosis in anovulatory cycling women , and large numbers of premenopausal women taking OCs have relative safety from an IHD st and point ( 1 ) . Further , observational epidemiological studies in humans have consistently demonstrated protective effects for IHD among HT users . Such studies are typically performed on relatively younger women where  HT  is prescribed for  vasomotor symptoms during menopausal transition or shortly following menopause . In contrast , clinical trials in older , postmenopausal and often asymptomatic women have demonstrated no overall benefit and early adverse effects when r and omized to a variety of forms of HT ( 1 ) . These data discrepancies have called into question the validity of the reproductive hormone estrogen protection hypothesis , and raise the alternative possibility that  HT efficacy may differ according to the timing of exposure . Stated as a simple question , is the effect of HT on the risk of IHD in relatively young pre- or early menopausal women with vasomotor symptoms , different than it is in older , fully menopausal women ? Data from the Women ’s Ischemia Syndrome Evaluation ( WISE ) , a prospect i ve multi-center NHLBI-sponsored study design ed to explore female-specific pathophysiology in a large sample of women undergoing coronary angiography for suspected IHD ( 2 ) , may shed light on this controversy . These new data , prospect ively obtained using novel methods , including detailed reproductive health question naires , menopausal adjudication algorithms , and quantitative coronary angiography as a measure of atherosclerosis , allow a more precise inspection of this question . However , to answer this simple question we need to first answer others . Specifically , how can we integrate and underst and the findings from the available observational , animal and clinical trial data ? And to interpret these data other questions become relevant : 1 ) How accurately was menopause assessed in prior observational HT studies ? 2 ) Does HT in premenopausal women in the form of OC therapy confirm atherosclerosis benefit ? and 3 ) Does HT in early menopausal women confer reduced atherosclerosis and benefit on the risk of IHD Aim To study the effects of menopausal hormone therapy ( HT ) on health-related quality of life in women after breast cancer . Patients and methods In the Stockholm trial , breast cancer survivors were r and omized to HT ( estradiol and progestogen ) or to a control group ( no treatment ) .  A subgroup of 75 women was studied ( 38 with HT , 37 controls ) . Fifty patients were on concomitant tamoxifen .  Patients completed three question naires ( EORTC QLQ C-30 , EORTC QLQ-BR 23 and the Hospital Anxiety and Depression Scale ( HADS ) ) during 1 year of treatment . Results A significant group-by-time interaction was found for improvement of insomnia in the HT group ( p < 0.001 ) . Within the HT group , but not in the control group , there was significant improvement for HADS anxiety , HADS depression , emotional , cognitive , and social functions and global quality of life . When HT was added to tamoxifen , the increase in global quality of life was significant ( p < 0.01 ) . Conclusion The effects of HT on quality of life in breast cancer survivors have not previously been reported . The present data suggest that this controversial treatment may improve quality of life after breast cancer Objectives : Observational studies suggest reduced risk of Alzheimer disease ( AD ) in users of hormone therapy ( HT )  , but trials show higher risk . We examined whether the association of HT with AD varies with timing or type of HT use . Methods : Between 1995 and 2006 , the population -based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT .  During this interval , 176 women developed incident AD . Cox proportional hazard models evaluated the association of HT use with AD , overall and in relation to timing , duration of use , and type ( opposed vs unopposed ) of HT . Results : Women who used any type of HT within 5 years of menopause had 30 % less risk of AD ( 95 % confidence interval 0.49–0.99 ) , especially if use was for 10 or more years . By contrast , AD risk was not reduced among those who had initiated HT 5 or more years after menopause . Instead , rates were increased among those who began “ opposed ” estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline ( adjusted hazard ratio 1.93 ; 95 % confidence interval 0.94–3.96 ) . This last hazard ratio was similar to the ratio of 2.05 reported in r and omized trial participants assigned to opposed HT . Conclusions : Association of HT use and risk of AD may depend on timing of use . Although possibly beneficial if taken during a critical window near menopause , HT ( especially opposed compounds ) initiated in later life may be associated with increased risk . The relation of AD risk to timing and type of HT deserves further study Summary Canadian women over 50 years old were studied over a 10-year period to see if those who sustained a fracture ( caused by minimal trauma ) were receiving the recommended osteoporosis therapy . We found that approximately half of these women were not being treated , indicating a significant care gap in osteoporosis treatment . Introduction Prevalent fragility fracture strongly predicts future fracture . Previous studies have indicated that women with fragility fractures are not receiving the indicated treatment . We aim ed to describe post fracture care in Canadian women using a large , population -based prospect i ve cohort that began in 1995–1997 . Methods We followed 5,566 women over 50 years of age from across Canada over a period of 10 years in the Canadian Multicentre Osteoporosis Study . Information on medication use and incident clinical fragility fractures was obtained during a yearly question naire or interview and fractures were confirmed by radiographic/medical reports . Results Over the 10-year study period , 42–56 % of women with yearly incident clinical fragility fractures were not treated with an osteoporosis medication . During year 1 of the study , 22 % of the women who had experienced a fragility fracture were on treatment with a bisphosphonate and 26 % were on hormone therapy ( HT ) . We were not able to differentiate HT use for menopause symptoms vs osteoporosis . Use of bisphosphonate therapy  increased over time ; odds ratio ( OR ) for use at year 10 compared to use at year 1 was 3.65 ( 95 % confidence interval ( CI ) 1.83–7.26 ) . In contrast , HT use declined , with an OR of 0.07 ( 95%CI 0.02–0.24 ) at year 10 compared to year 1 of the study . Conclusion In a large population -based cohort study , we found a therapeutic care gap in women with osteoporosis and fragility fractures . Although bisphosphonate therapy usage improved over time , a substantial gap remains AIMS At the time of the design of the Osteoporosis Prevention and Arterial effects of tiboLone ( OPAL ) study in 1996 , oral hormone therapy ( HT ) was assumed to reduce cardiovascular risk . The evidence mainly came from the effects of combined conjugated equine oestrogens plus medroxyprogesterone acetate ( CEE/MPA ) therapy . Other HT regimes had not been studied widely . Tibolone , a selective tissue oestrogenic activity regulator , has several effects on cardiovascular risk factors , one of which is HDL lowering . Because the overall effect of tibolone on cardiovascular risk was unknown , the OPAL study was design ed . METHODS AND RESULTS The OPAL study was a three-arm , r and omized , placebo-controlled , double-blind study to determine the effect of tibolone ( 2.5 mg daily ) and of CEE/MPA ( 0.625/2.5 mg daily ) over 3 years on progression of carotid intima-media thickness ( CIMT ) in 866 healthy post-menopausal women . The women were recruited from six US and five European centres . The primary outcome was change in mean common CIMT . Annual common CIMT progression rates in the tibolone and CEE/MPA groups were higher than in the placebo group : 0.0077 mm [ 95 % confidence interval ( CI ) 0.0051 - 0.0103 ] in the tibolone group , 0.0074 mm ( 0.0048 - 0.0099 ) in the CEE/MPA group , and 0.0035 mm ( 0.009 - 0.0061 ) in the placebo group . The differences with placebo ( 0.0042 mm/year for tibolone and 0.0039 mm/year for CEE/MPA ) were statistically significant . HDL cholesterol increased in CEE/MPA group and was lowered in the tibolone group . CONCLUSION Both tibolone and CEE/MPA showed increased progression of common CIMT . Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the Women 's Health Initiative study . This suggests that the net effect of tibolone and CEE/MPA on cardiovascular events may depend on the combined effects on the arterial wall , clotting factors , and possibly inflammation 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 The National Institutes of Health ( NIH ) has instructed participants in the estrogen-alone study of the Women ’s Health Initiative ( WHI ) , a large multi-center trial , to stop taking their study pills and to begin the follow-up phase of the study . Letters have been sent to all participants in the estrogenalone study , 11,000 healthy postmenopausal women who have had a hysterectomy , informing them of a recent NIH review of the study data . After careful consideration of the data , NIH has concluded that with an average of nearly 7 years of follow-up completed , estrogen alone does not appear to affect ( either increase or decrease ) heart disease , a key question of the study . At the same time , estrogen alone appears to increase the risk of stroke and decrease the risk of hip fracture . It has not increased the risk of breast cancer during the time period of the study . The increased risk of stroke in the estrogen-alone study is similar to what was found in the WHI study of estrogen plus progestin when that trial was stopped in July 2002 . In that study , women taking estrogen plus progestin had 8 more strokes per year for every 10,000 women than those taking the placebo . The NIH believes that an increased risk of stroke is not acceptable in healthy women in a research study . This is especially true if estrogen alone does not affect ( either increase or decrease ) heart disease , as appears to be the case in the current study . The NIH has determined that the results would not likely change if the estrogen trial continued to its planned completion in 2005 . Furthermore , enough data have been obtained to assess the overall risks and benefits of the use of estrogen in this trial . WHI research ers have begun a detailed analysis of the data from the estrogen-alone study and expect to report full results in the next two months . The report , to be published in a peer- review ed journal , will include additional data collected through the end of February 2004 . A separate report will contain information on  probable dementia or mild cognitive impairment in the women age 65 and older who participated in the estrogen-alone WHI-Memory Study ( WHIMS ) , an ancillary study of the WHI Hormone Trials . Preliminary data suggest that for the WHIMS participants who were on estrogen  alone when compared to the women who were taking the placebo , there was a trend toward increased risk of probable dementia and /or mild cognitive impairment . The WHI estrogen study was design ed to assess the effect of long-term use of hormone therapy in healthy postmenopausal women on the prevention of heart disease and hip fractures , and any associated change in risk for breast cancer . It was not design ed to evaluate the short-term risks and benefits of hormones for the treatment of moderate to severe menopausal symptoms . The estrogen-alone study involved women ages 50 to 79 years . Study participants were r and omly assigned to a daily dose of estrogen—0.625 mg/day of conjugated equine estrogen — or a placebo . The NIH decision to stop the estrogen-alone trial was made on February 2 , 2004 . In November and December 2003 , the WHI Data and Safety Monitoring Board ( DSMB ) , an independent advisory committee which regularly review s study data and oversees the safety of study participants , review ed the latest data from the estrogen-alone study . The DSMB was split as to whether the study pills should be stopped or whether the pills should be continued , provided that a letter would be sent to the participants clearly informing them of the stroke risks and other findings . After careful review , the NIH decided that women in the estrogen-alone study should stop taking their study pills . From the National Heart , Lung , and Blood Institute of the National Institutes of Health Background : Hormone therapy ( HT ) is the treatment of choice for the alleviation of menopausal symptoms ; concerns , however , about its concomitant long-term health risks have limited its use . DT56a is a unique enzymatic isolate of soybeans . The purpose of our study was to evaluate the efficacy and safety of DT56a , compared to HT , in symptomatic post-menopausal women . Subjects and methods : Eighty-nine post-menopausal women were studied prospect ively . Women with climacteric symptoms were r and omly assigned to receive eitherDT56a ( no.=27 ) or oral low dose continuous combined HT ( no.=26 ) . Symptomatic women not wishing to receive any treatment served as controls ( no.=36 ) . Menopausal symptoms as assessed through the Kupperman index , serum lipids and lipoproteins , calcium , as well as bone mineral density ( BMD ) , endometrial thickness , and mammography were assessed at baseline and at 12 months . Results : Patients receiving HT and DT56a showed a significant and independent decrease in menopausal symptoms ( mean difference in Kupperman score , DT56a group : −3.98 , HT group −5.601 , no treatment group + 1.76 , p-value < 0.001 ) . Lumbar spine BMD T-score was significantly lower in women receiving no treatment , as opposed to the two treatment arms which showed no significant change ( No treatment , baseline : −0.60 , final : −0.85 , p=0.001 ; HT , baseline : −84 , final −0.99 , p=0.79 ; DT56a , baseline −0.51 , final : −0.76 , p=0.75 ) . No differences in femoral bone density , ET or mammography classification were detected in any of the treatment arms . Likewise , serum lipids or lipoproteins did not differ between the three groups . Conclusions : DT56a decreased menopausal symptoms significantly and in the same degree as HT Objective This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol ( ELITE ) , the only clinical trial design ed to specifically test the timing hypothesis of postmenopausal hormone therapy ( HT ) . The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause . Methods ELITE is a r and omized , double-blind , placebo-controlled trial with a 2 × 2 factorial design . Six hundred forty-three healthy postmenopausal women without cardiovascular disease were r and omized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause ( < 6 or ≥10 y ) . Carotid artery intima-media thickness ( CIMT ) and cardiac computed tomography  were conducted to determine HT effects on sub clinical atherosclerosis across menopause strata . Results Participants in the early and late postmenopausal strata were well-separated by mean age ( 55.4 vs 65.4 y ) and median time since menopause ( 3.5 vs 14.3 y ) . Expected risk factors ( age , blood pressure , and body mass index ) were associated with CIMT at baseline in both strata . In the early postmenopausal group , but not in the late postmenopausal group , we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation . These include low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , sex hormone – binding globulin , and serum total estradiol . Conclusions The ELITE r and omized controlled trial is timely and unique . Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease Background At the time of feasibility work and final design of the trial there was no r and omised control trial evidence for the long-term risks and benefits of hormone replacement therapy . Observational studies had suggested that long term use of estrogen was likely to be associated , amongst other things , with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer . Concomitant use of progestogens had been shown to protect against endometrial cancer , but there were few data showing how progestogen might affect estrogen actions on other conditions . Disease specific risks from observational studies suggested that , overall , long-term HRT was likely to be beneficial . Several studies showed that mortality from all causes was lower in HRT users than in non-users . Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women . The WISDOM trial was design ed to compare combined estrogen and progestogen versus placebo , and estrogen alone versus combined estrogen and progestogen . During the development of WISDOM the Women 's Health Initiative trial was design ed , funded and started in the US . Design R and omised , placebo , controlled , trial . Methods The trial was set in general practice s in the UK ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . In these practice s 284175 women aged 50–69 years were registered with 226282 potentially eligible . We sought to r and omise 22300 postmenopausal women aged 50 – 69 and treat for ten years . The interventions were : conjugated equine estrogens , 0.625 mg orally daily ; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ; matched placebo . Primary outcome measures were : major cardiovascular disease , osteoporotic fractures , breast cancer and dementia . Secondary outcomes were : other cancers , all cause death , venous thromboembolism and cerebro-vascular disease . Results The trial was prematurely closed during recruitment following publication of early results from the Women 's Health Initiative . At the time of closure , 56583 had been screened , 8980 entered run-in , and 5694 ( 26 % of target of 22,300 ) r and omised . Those women r and omised had received a mean of one year of therapy , mean age was 62.8 years and total follow-up time was 6491 person years . Discussion The WISDOM experience leads to some simple messages . The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery . When a trial is very costly and beyond the re sources of one country , funders and investigators should make every effort to develop international collaboration with joint funding Introduction Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy ( HT ) . We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes . Methods Healthy , non-smoking freshly postmenopausal women ( n = 150 ) with no previous HT use were studied . Seventy-two women reported intolerable hot flushes ( ≥7 moderate/severe episodes/day ) and 78 women tolerable hot flushes ( ≤3 mild episodes/day ) . The participants were treated in r and omized order with either transdermal estradiol gel ( 1 mg ) , oral estradiol valerate ( 2 mg ) with or without medroxyprogesterone acetate ( 5 mg ) , or placebo for 6 months . Treatment-induced changes in lipids , lipoproteins , apolipoproteins , sex hormone binding globulin ( SHBG ) and high-sensitivity C-reactive protein were compared . The trial is registered in the US National Institutes of Health Clinical Research Registry ( no. NCT00668603 ) . Results Pretreatment hot flush status was not related to the responses of these markers to different forms of HT . However , when all active regimens were evaluated together as a post-hoc analysis , 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes . Furthermore , in women with intolerable hot flushes and with HT use , the increases in SHBG ( Spearman 's rho = − 0.570 , p < 0.001 ) were related to the reductions in hot flushes during the use of HT . Conclusions Hot flushes appear to be no significant determinant for the responses of vascular  markers to HT use Menopause impacts 25 million women world wide each year , and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030 . Menopause has been associated with symptoms of hot flashes , night sweats , dysphoric mood , sleep disturbance , and conditions of cardiovascular disease , depression , osteoporosis , osteoarthritis , depression , dementia , and frailty . Conventional hormone replacement therapy results in increased thrombotic events , and an increased risk of breast cancer and dementia as evidence d in large prospect i ve clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women 's Health Initiative . A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors . Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile , yet long-term studies of this treatment model are lacking . The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol , estradiol , progesterone , DHEA , and testosterone on cardiovascular biomarkers , hemostatic , inflammatory , immune signaling factors ; quality -of-life measures ; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care . A prospect i ve , cohort , closed-label study received approval from the Human Subjects Committee . Recruitment from outpatient clinics at an academic medical center and the community at large result ed in three hundred women giving signed consent . Seventy-five women who met strict inclusion /exclusion criteria were enrolled .  Baseline hormone evaluation was performed along with baseline experimental measures . Following this , women received compounded transdermal bioidentical hormone therapy of BiEst ( 80%Estriol/20%Estradiol ) , and /or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women . The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic , ischemic , or neuronal injury . Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of and rogens of DHEA and Testosterone if indicated . Experimental subjects were monitored for 36 months . Baseline , 2-month , and annual values were obtained for : blood pressure , body mass index , fasting glucose , Homeostasis Metabolic Assessment of Insulin Resistance ( HOMA-IR ) , fasting triglycerides , total Factor VII , Factor VIII , fibrinogen , Antithrombin III , Plasminogen Activator Inhibitor1(PAL-1 ) , C-reactive protein ( CRP ) , Interleukin-6 ( IL-6 ) , Matrix Metalloproteinase-9 ( MMP-9 ) , Tumor Necrosis Factor-alpha ( TNF ) , Insulin-like Growth Factor ( IGF-1 ) , and sex steroid levels . Psychosocial measures included : Greene Climacteric Scale , Visual Analog Pain Scale , Hamilton Anxiety Scale , Hamilton Depression Scale , Holmes Rahe Stress Scale , Job Strain , and Home Strain . Health outcome measures included the number of prescribed medications used , number of co-morbidities , and endometrial thickness in postmenopausal women with intact uteri . Subjects receiving  compounded transdermal bioidentical hormone therapy showed significant favorable changes in : Greene Climacteric Scale scores , Hamilton Anxiety Scale , Hamilton Depression Scale , Visual Analog Pain Scale , fasting glucose , fasting triglycerides , MMP-9 , C-reactive Protein , fibrinogen , Factor VII , Factor VIII , Insulin-Like Growth Factor 1 , and health outcomes of co-morbidities and a number of prescribed medications . Antithrombin III levels were significantly decreased at 36 months . All other measures did not exhibit significant effects . Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women . Cardiovascular biomarkers , inflammatory factors , immune signaling factors , and health outcomes were favorably impacted , despite very high life stress , and home and work strain in study subjects . The therapy did not adversely alter the net prothrombotic potential , and there were no associated adverse events . This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in population s with high perceived stress and a history of stressful life events prior to , or during the menopausal transition OBJECTIVE To eluci date the effects of low-dose 17beta-estradiol and norethisterone ( hormone therapy [ HT ] ) versus placebo in women with Alzheimer Disease ( AD ) on cognition , depressive symptoms , and activities of daily living . DESIGN A 12-month r and omized , double-blind , placebo-controlled study , stratified by apolipoprotein E ( ApoE ) genotype ( with versus without the epsilon4 allele ) , duration of education ( < or = 9 versus > 9 years ) , and age ( < or = 75 versus > 75 years ) performed during 2000 - 2004 . SETTING Ambulatory memory clinic in a general hospital . PARTICIPANTS Sixty-five female out patients aged 65 - 89 years who met criteria for probable AD according to Diagnostic and Statistical Manual of Mental Disorders , fourth edition and International Classification of Diseases , tenth edition . Ten patients were excluded , result ing in 55 participants who had at least one posttreatment efficacy evaluation . INTERVENTION R and omly assigned to receive either 1-mg estradiol and 0.5-mg norethisterone or placebo once daily . MEASUREMENTS Cognitive variables were the Dementia Rating Scale , tests from Consortium to Establish a Registry for AD , Global Deterioration Scale ( GDS ) and Barthel Index . RESULTS When only treatment effects were compared by analysis of variance , there were nonsignificant differences between treatment groups for all efficacy variables . A linear model analysis , including stratifying factors in addition to treatment in the model , revealed a significant main effect on mood . The depressive symptoms were lower in the HT group than in the placebo group . Those treated with HT without the ApoE epsilon4 allele had better mood , Word Learning Memory score , and GDS score . Those in the HT group with a higher level of education obtained a better GDS score . Adverse events did not differ between the groups . CONCLUSION HT interacts with ApoE genotype in women with AD . Women without an ApoE epsilon4 allele may get better mood and cognition with HT . HT may reduce depressive mood and give less cognitive decline BACKGROUND Apparently discrepant findings have been reported by the Women 's Health Initiative ( WHI ) trial compared with observational studies of postmenopausal hormone therapy ( HT ) and coronary heart disease ( CHD ) . METHODS We prospect ively examined the relation of HT to CHD , according to timing of hormone initiation relative to age and time since menopause . Participants were postmenopausal women in the Nurses ' Health Study , with follow-up from 1976 to 2000 . Information on hormone use was ascertained in biennial , mailed question naires . We used proportional hazards models to calculate multivariable adjusted relative risks ( RR ) and 95 % confidence intervals ( CI ) . We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT . RESULTS Women beginning HT near menopause had a significantly reduced risk of CHD ( RR = 0.66 , 95 % CI 0.54 - 0.80 for estrogen alone ; RR = 0.72 , 95 % CI 0.56 - 0.92 for estrogen with progestin ) . In the subgroup of women demographically similar to those in the WHI , we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause ( RR = 0.87 , 95 % CI 0.69 - 1.10 for estrogen alone ; RR = 0.90 , 95 % CI 0.62 - 1.29 for estrogen with progestin ) . Among women who began taking hormones at older ages , we also found no relation between current use of estrogen alone and CHD ( for women aged 60 + years , RR = 1.07 , 95 % CI 0.65 - 1.78 ) , although there was a suggestion of possible reduced risk for combined HT ( RR = 0.65 , 95 % CI 0.31 - 1.38 ) . In sensitivity analyses , we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT . CONCLUSIONS These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk BACKGROUND Women with a family history of breast cancer have several menopausal therapy options , including tamoxifen , hormone therapy ( HT ) , alternative medications , or no treatment . This complex decision should be based on each woman 's risk to develop breast cancer , menopausal symptoms , preferences , and risks for other conditions . The authors determined the effects of a personalized risk assessment and genetic counseling intervention on knowledge , risk perception , and decision making in a group of healthy women who had a first-degree relative with breast cancer . METHODS Forty-eight cancer-free menopausal women age > or = 40 years who had at least one first-degree relative with breast cancer were r and omized to a genetic counseling intervention or control .  Intervention participants were given a personalized risk assessment for breast cancer , heart disease , osteoporosis , and uterine cancer based on family history and personal health data . Knowledge , risk perception , and medication usage were measured at baseline , 1 month , and 6 months . RESULTS Knowledge was higher in the intervention group at both follow-up time points postintervention . Perceived risk for developing breast cancer was significantly lower and more accurate in the intervention group at 1 and 6 months postintervention than at baseline , as was perceived risk of developing heart disease . Although the counseling intervention did affect both knowledge and risk perception , overall , both groups were reluctant to take any form of menopausal therapy . CONCLUSIONS A personalized risk assessment and genetic counseling intervention improves patient knowledge and risk perception ; however , it is unclear that the intervention influenced menopausal treatment decisions
In relatively healthy women , combined continuous HT significantly increased the risk of venous thrombo-embolism or coronary event ( after one year 's use ) , stroke ( after three years ) , breast cancer and gallbladder disease .
Long-term oestrogen-only HT significantly increased the risk of venous thrombo-embolism , stroke and gallbladder disease ( after one to two years , three years and seven years ' use respectively ) , but did not significantly increase the risk of breast cancer .
The only statistically significant benefits of HT were a decreased incidence of fractures and ( for combined HT ) colon cancer , with long-term use .
Among women aged over 65 who were relatively healthy ( i.e. generally fit , without overt disease ) and taking continuous combined HT , there was a statistically significant increase in the incidence of dementia .
Among women with cardiovascular disease , long-term use of combined continuous HT significantly increased the risk of venous thrombo-embolism .
AUTHORS ' CONCLUSIONS HT is not indicated for the routine management of chronic disease .
We need more evidence on the safety of HT for menopausal symptom control , though short-term use appears to be relatively safe for healthy younger women
BACKGROUND Hormone therapy ( HT ) is widely used for controlling menopausal symptoms and has also been used for the management and prevention of cardiovascular disease , osteoporosis and dementia in older women .
This is an up date d version of the original Cochrane review first published in 2005 .
OBJECTIVES To assess the effect of long-term HT on mortality , cardiovascular outcomes , cancer , gallbladder disease , cognition , fractures and quality of life .