Characteristics of hormone therapy, cognitive function, and dementia Hormone therapy in menopausal women with cognitive complaints Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease. Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia Long-Term Prevention with Hormone-Replacement Therapy after the Menopause: Which Women should be Targeted? The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. HRT and cardiovascular disease. The Effects of Hormone Therapy Decision Support for Women With Mobility Impairments Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups [Influence of hormone replacement therapy on the quality of life in postmenopausal women with hypertension]. Effects of hormone replacement therapy on cognitive performance in elderly women. Health-related quality of life during hormone therapy after breast cancer: a randomized trial Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Hormone therapy and Alzheimer disease dementia Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women The effect of hormone therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone Therapy trial A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease
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 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 The objective of this study was to examine the effects of estrogen-based hormone therapy ( HT ) on regional cerebral metabolism in postmenopausal women ( mean age = 58 , SD = 5 ) at risk for development of dementia . The prospect i ve clinical trial design included pre- and post-intervention neuroimaging of women r and omized to continue ( HT+ ) or discontinue ( HT− ) therapy following an average of 10 years of use . The primary outcome measure was change in brain metabolism during the subsequent two years , as assessed with  fluorodeoxyglucose-18 positron emission tomography ( FDG-PET ) . Longitudinal FDG-PET data were available for 45 study completers . Results showed that women r and omized to continue HT experienced relative preservation of frontal and parietal cortical metabolism , compared with women r and omized to discontinue HT . Women who discontinued 17-β estradiol (17βE)-based HT , as well as women who continued conjugated equine estrogen (CEE)-based HT , exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical ( PCC ) area . Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins ( with either 17βE or CEE ) . Together , these findings suggest that among postmenopausal subjects at risk for developing dementia , regional cerebral cortical metabolism is relatively preserved for at least two years in women r and omized to continue HT , compared with women r and omized to discontinue HT . In addition , continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC , known to undergo the most significant decline in the earliest stages of Alzheimer 's disease . Trial Registration Clinical Trials.gov 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 postmenopausal hormone therapy ( PHT ) component of the Women ’s Health Initiative ( WHI ) is composed of two r and omized , placebo-controlled , double-blind trials in postmenopausal women aged 50 to 79 years at initial screening , testing the effects of estrogen alone ( E-alone ) and estrogen plus progestin ( E P ) on coronary heart disease ( CHD ) as the primary outcome , hip and other fractures and colorectal cancer as secondary outcomes , and pulmonary embolism , breast and endometrial cancers as potential risks . The design and rationale of the PHT trials , including general eligibility and exclusion criteria and considerations regarding sample size and statistical power , have been described previously ( 1 ) . Postmenopausal hormones have been initiated in menopausal women for the treatment of vasomotor symptoms , mood disturbances , vaginal dryness , and prevention of rapid bone loss for several decades . Despite a paucity of data on effects of initiating hormone use in older women , postmenopausal hormones have also been promoted for the prevention of CHD , osteoporotic fractures , and other diseases that occur years after menopause ( 2 ) . It is generally recommended ( 2 ) that women with a uterus be prescribed a combination of estrogen and progestin to prevent Hormone replacement therapy ( HRT ) has profound effects on the cardiovascular system , with plausible biological mechanisms explaining both the benefits and harm . Benefits may result from oestrogen action on metabolic risk factors , such as lipids , glucose and insulin metabolism , as well as direct arterial effects , reducing atherogenesis . Harm may arise from inappropriately high starting doses causing transient increases in coagulation activation and adverse vascular remodelling . Observational studies of HRT suggest that there is a beneficial effect on the incidence of coronary heart disease ( CHD ) . Any benefit of HRT seen in r and omized clinical trials appears to be confined to those women within several years of their menopause , and it is clear from the r and omized trials that age at initiation is a crucially important consideration . Women initiating HRT within 10 years of menopause onset may achieve cardiovascular benefit , particularly in terms of primary CHD prevention , whilst avoiding risks of stroke and venous thrombo-embolism Deciding about hormone therapy ( HT ) use is particularly complex for women with mobility impairments . While HT controls menopausal symptoms , the potential increased risk of blood clots result ing from physical inactivity can contraindicate HT use . These women , therefore , may benefit from interventions to help them tailor st and ard information about HT . We r and omly assigned women to receive either a tailored decision support intervention or st and ard menopausal information . Both groups ( n = 176 ) significantly decreased their decisional conflict and uncertainty and increased knowledge after receiving the treatment material s. We interpret the findings in the context of limited medical information about HT for women with disabilities Background Postmenopausal hormone therapy may have long-term effects on cognitive function depending on women 's age . Methods Postintervention follow-up was conducted with annual cognitive assessment s of two r and omized controlled clinical trial cohorts , beginning an average of 6 - 7 years after study medications were terminated : 1,376 women who had enrolled in the Women 's Health Initiative when aged 50 - 54 years and 2,880 who had enrolled when aged 65 - 79 years . Women had been r and omly assigned to 0.625mg/d conjugated equine estrogens ( CEE ) for those with prior hysterectomy ( mean 7.1 years ) , CEE with 2.5mg/d medroxyprogesterone acetate for those without prior hysterectomy ( mean 5.4 years ) , or matching placebos . Results Hormone therapy , when prescribed to women aged 50 - 54 years , had no significant long-term posttreatment effects on cognitive function and on changes in cognitive function . When prescribed to older women , it was associated with long-term mean ( SE ) relative decrements ( st and ard deviation units ) in global cognitive function of 0.081 ( 0.029 ) , working memory of 0.070 ( 0.025 ) , and executive function of 0.054 ( 0.023 ) , all p < .05 . These decrements were relatively stable over time . Findings did not vary depending on the hormone therapy regimen , prior use , or years from last menstrual period . Mean intervention effects were small ; however , the largest were comparable in magnitude to those seen during the trial 's active intervention phase . Conclusions CEE-based hormone therapy delivered near the time of menopause provides neither cognitive benefit nor detriment . If administered in older women , it results in small decrements in several cognitive domains that remain for many years AIM The effect of hormone replacement therapy ( HRT ) on the quality of life in women with hypertension is still not clear . Thus , the aim of the study was to assess the effect of hormone replacement therapy on quality of life in postmenopausal women with essential hypertension by using a battery of st and ardized question naires . MATERIAL AND METHODS The study population consisted of 53 women ( mean age 50.9 + /- 6.3 years ) with mild and moderate essential hypertension ( mean duration 6.4 + /- 6.4 years ) . The postmenopausal status was defined as the absence of menstrual blood loss during > 6 months and blood estradiol concentration < 50 pg/ml , accompanied by follicle-stimulating hormone ( FSH ) levels > 21 U/I. Twenty seven women were blindly r and omised to transdermal hormone replacement therapy ( HRT ) and received 17-beta-estradiol and noretisterone acetate , TTS .  Twenty six women were r and omly selected as controls . The subjects were evaluated at baseline ( after 2 weeks ' wash-out from hypotensive drug period ) and after three months of HRT using self-administered st and ardized quality of life question naires : the Psychological General Well-being Index ( PGWB ) and the Subjective Symptoms Assessment Profile ( SSA-P ) . RESULTS No differences were found in blood pressure values , heart rate , body mass index and distribution of body fat tissue between women receiving HRT and controls at baseline and after 3 months of follow-up . There were no significant differences in the baseline total PGWB score as well as in its subscale between two groups . Similarly , the frequency and intensity of subjective symptoms assessed by SSA-profile were the same in both groups at baseline . After 3 months , a significant improvement in PGWB total score was observed in women receiving HRT . This effect was due to improvement in anxiety , positive well-being and vitality . Moreover , emotional distress , symptoms of flushing , sweating and trembling h and s also diminished and sexual capacity improved in women treated with HRT . CONCLUSION A three-month hormone replacement therapy in hypertensive postmenopausal women slightly improves the general well-being , seems to decrease emotional tension , increase sexual capacity and markedly relieves some vasomotor symptoms OBJECTIVE To determine the effects of 9 months of hormone replacement therapy ( HRT ) on cognitive performance in women aged 75 years and older . METHODS A 9-month r and omized , double-blinded , placebo-controlled parallel trial . Fifty-two elderly postmenopausal women ( age range 75 - 91 years ) without known contraindications to HRT or evidence of dementia or depression were enrolled . Participants were r and omly assigned in a 1:2 ratio to placebo or conjugated estrogens at 0.625 mg/d plus trimonthly medroxyprogesterone acetate at 5 mg/d for 13 days ( HRT ) . Main outcome measures were change from baseline and rate of change from baseline for the following psychometric tests : Verbal Fluency Test , Weschler Paired Associate Learning and 20 min Delayed Recall , Trailmaking A and B Tests , Cancellation R and om Letter and R and om Form Tests . RESULTS At baseline , women in the HRT group reported a younger age of onset of menopause and a higher prevalence of hysterectomy , but otherwise did not differ from women in the placebo group . After 9 months of treatment , there were no significant group differences for any of the cognitive performance measures . The lack of an observed group-by-time difference for all cognitive tests remained after controlling for age of onset of menopause , education , and previous hysterectomy . CONCLUSIONS Although conclusions are limited by small sample size and the relatively short duration of treatment , results suggest that 9 months of estrogen replacement in combination with trimonthly progestin does not improve cognitive performance in women over 75 years who do not have dementia or depression 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 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 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 Background : A r and omized trial of postmenopausal women over age 65 reported increased risks of cognitive decline with 4 years of combined estrogen and progestin treatment . However , questions remain , including the effect of longer duration or of hormone therapy initiated at younger ages . Methods : The Nurses ’ Health Study is a prospect i ve cohort begun in 1976 , comprising 121,700 female nurses who report health information via biennial mailed question naires . This sub study includes 13,807 participants age 70 to 81 who completed two telephone cognitive assessment s , 2 years apart , between 1995 and 2003 .  General cognition , verbal memory , category fluency , and attention were tested . Multiple linear regression was used to estimate adjusted mean declines and logistic regression to estimate adjusted risks of substantial decline in cognition ( ≥2 SD of baseline performance ) across hormone groups . APOE genotype was available in a subset of 3,667 participants . Results : Overall , little difference was found in mean cognitive decline between current hormone users and never users . However , for long-term users of estrogen alone or combined with progestin , increased risk of substantial decline was observed on most cognitive tests ( relative risk [ RR ] = 1.25 to 1.72 ) . Decline was particularly high among women initiating hormones at older ages compared with never users : for example , on our test of general cognition , RR of substantial decline was 1.74 ( 95 % CI 1.08 , 2.81 ) and mean difference in decline was −0.43 ( 95 % CI −0.73 , −0.12 ) . No significant interactions between hormone use and APOE ε4 allele were observed . Conclusion : Postmenopausal hormone therapy provides no appreciable cognitive benefits in older women 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 Whether to take hormone therapy is one of the most difficult medical decisions that healthy postmenopausal women face . The apparent coronary benefits ( 1 ) of hormone use are an important part of that decision . Although the data appear consistent in suggesting long-term coronary benefits , the Heart and Estrogen/progestin Replacement Study ( 2 ) showed an increased risk for coronary events during the first year of therapy in women with existing heart disease ; we also found such an elevated risk in an examination of secondary prevention in the Nurses ' Health Study ( 3 ) . More recently , a report from the Women 's Health Initiative , an ongoing r and omized clinical trial of hormone therapy for primary prevention of cardiovascular disease , suggested similar findings in healthy women ( National Institutes of Health . Press release ) . However , additional data on short-term effects of hormone use in women without previous cardiovascular disease are sparse . Many further questions also remain . Among them is the cardiovascular effect of daily doses lower than the st and ard 0.625 mg of oral conjugated estrogen . Recent studies suggest that lower doses of hormone therapy provide bone benefits ( 4 ) and , compared with higher doses , might decrease the risk for thromboembolism ( 5 ) and reduce endometrial hyperplasia ( 4 ) . However , few data are currently available on the relation between low-dose estrogen and primary prevention of heart disease and stroke . In an earlier report , we examined the relation between postmenopausal hormone therapy and primary prevention of cardiovascular disease based on 16 years of follow-up from the Nurses ' Health Study ( 6 ) . In the current analysis , we have almost 50 % more follow-up time among women taking daily doses less than 0.625 mg and more than 800 additional cases of cardiovascular disease , allowing more precise assessment of specific associations . Thus , we now report on the relation among  low-dose estrogen , short-term hormone use , and cardiovascular events in 70 533 postmenopausal women with no previous cardiovascular disease who were followed for up to 20 years . We also provide additional information on the effects of estrogen combined with progestin . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about their postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . We up date information with biennial follow-up question naires . Dietary and physical activity question naires were added in 1980 . Cohort follow-up is greater than 90 % . Ascertainment of Hormone Use In 1976 , women were asked about use and duration of hormone therapy after menopause . Beginning in 1978 , we collected information on type of hormones taken , and starting in 1980 , we asked about the dose of oral conjugated estrogen . All information is up date d biennially . Identification of Cardiovascular Disease We identified first occurrences of nonfatal myocardial infa rct ion , fatal coronary disease , and fatal and nonfatal stroke between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion or stroke were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met World Health Organization criteria ( 7 ) ( symptoms plus either elevated levels of cardiac enzymes or diagnostic electrocardiograms ) . Infa rct ions that required hospitalization and were corroborated by interview or letter but for which medical records were unobtainable were included as probable . Infa rct ions of indeterminate age discovered on routine examination were excluded . Nonfatal strokes were confirmed by review of medical records if they were characterized by a typical neurologic deficit , were rapid in onset , lasted at least 24 hours , and met the criteria of the National Survey of Stroke ( 8) . We classified strokes as ischemic ( thrombotic or embolic occlusion of a cerebral artery ) , subarachnoid hemorrhage , or intraparenchymal hemorrhage . We excluded subdural hematomas and strokes caused by infection or neoplasia . Strokes that required hospitalization and were corroborated by letter or interview but for which medical records were unavailable were included as probable . Most deaths were reported by the participants ' families . We search ed the National Death Index to identify deaths among nonrespondents to each 2-year question naire ; mortality follow-up was more than 98 % complete ( 9 ) . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered to be due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . We also included coronary disease listed on the death certificate as the underlying cause without another , more plausible cause , if the nurse was known ( from hospital records , family , or other sources ) to have had coronary disease before death . In no case was the cause listed on the death certificate used as the sole criterion for coronary death . Sudden death within 1 hour of the onset of symptoms in participants with no other plausible cause of death besides coronary disease was also included . Fatal strokes were documented by autopsy or hospital records or if stroke was listed as the underlying cause on the death certificate . The category of major coronary heart disease combines nonfatal myocardial infa rct ion and coronary death ; similarly , total stroke includes nonfatal and fatal cases . The category of combined cardiovascular disease includes major coronary heart disease and stroke . Confirmed and probable cases in each category were analyzed together ( 80 % of major coronary events and 73 % of strokes were confirmed ) . In this and previous analyses ( 6 ) , results for probable cases were similar to those for confirmed cases . The investigators conducted all interviews and record review s without knowledge of participants ' hormone use status . Population for Analysis Women who reported stroke , myocardial infa rct ion , angina , coronary revascularization , or cancer ( except nonmelanoma skin cancer ) on the 1976 question naire were excluded because their disease may have caused them to alter their hormone use . Similarly , women who reported such diagnoses on a subsequent question naire were excluded from further analysis . Thus , at the start of each 2-year interval , the base population included no women reporting these diagnoses . Our own studies ( 6 , 10 ) and other studies ( 11 ) have suggested that hormone therapy may differentially affect incident and fatal strokes ; thus , we separately examined deaths due to stroke . In these analyses , we excluded women with cancer and cardiovascular disease at baseline but did not up date the exclusions because the women who develop cardiovascular disease during follow-up are those most likely to die of stroke . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy  were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) . In this cohort , the women 's reports of age at menopause ( 12 ) and type of menopause ( 13 ) were highly accurate . In 1976 , 21 947 postmenopausal women entered the analysis , and 48 586 women were added during follow-up as they became postmenopausal , for a total of 70 533 participants ; 808 825 person-years of follow-up were accrued from 1976 to 1996 . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the 1976 data and were up date d every 2 years ( for estrogen dose , follow-up began in 1980 ) . For analyses of type of hormone therapy , we assigned the regimen reported on the 1978 question naire to women who reported hormone use in 1976 . Analyses of type of hormone therapy were limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate  , since these were the most common hormone regimens . If no data were available on hormones in a given time period , women were assigned to a missing category for that time period . To maintain the prospect i ve nature of the study , hormone use ( including duration ) during each 2-year period was established from women 's reports at the start of the period ; thus , we probably underestimate duration of use by an average of 1 year . Follow-up for a participant ended at the first diagnosis of cardiovascular disease , death , or 1 June 1996 , whichever came first . The primary analysis is based on incidence rates for which person-months of follow-up were used as the denominator . We used relative risk as the measure of association , defined as the incidence of cardiovascular events among women in various categories of hormone use divided by the incidence among women who never used hormones . We computed age-specific rates by using 5-year categories ( 14 ) and age-adjusted relative risks by using MantelHaenszel rate ratios ( 15 ) with 95 % CIs ( 16 ) . We used pooled logistic regression  across the ten 2-year time periods to adjust simultaneously for potential confounding factors ( 17 ) . In this approach , independent blocks of person-time are pooled for regression analysis , and time-varying covariates are readily accommo date d by assigning successive blocks of person-time to the covariate values at the start of each follow-up cycle . The dependence of the incidence rates on time is modeled nonparametrically with indicator variables . Simulation studies have established the asymptotic equivalence of pooled logistic regression to Cox regression with time-dependent covariates ( 18 ) . The necessary conditions for this equivalence include relatively short time intervals and small probability of the outcome during each interval , both
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 .