Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease HRT and cardiovascular disease. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Postmenopausal Hormone Use and Secondary Prevention of Coronary Events in the Nurses' Health Study: A Prospective, Observational Study [Influence of hormone replacement therapy on the quality of life in postmenopausal women with hypertension]. Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies? Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. 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 Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Observational Studies Analyzed Like Randomized Experiments: An Application to Postmenopausal Hormone Therapy and Coronary Heart Disease Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups Effects of hormone therapy on brain structure The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants.
CONTEXT The timing of initiation of hormone therapy may influence its effect on  cardiovascular disease .  OBJECTIVE To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began . DESIGN , SETTING , AND PARTICIPANTS Secondary analysis of the Women 's Health Initiative ( WHI ) r and omized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were r and omized to conjugated equine estrogens ( CEE ) or placebo and  16,608 postmenopausal women who had not had a hysterectomy  were r and omized to CEE plus medroxyprogesterone acetate ( CEE + MPA ) or placebo .  Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998 . MAIN OUTCOME MEASURES Statistical test for trend of the effect of hormone therapy on coronary heart disease ( CHD ) and stroke across categories of age and years since menopause in the combined trials . RESULTS In the combined trials , there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [ corrected ] cases of CHD and 239 cases of stroke in the placebo group . For women with less than 10 years since menopause began , the hazard ratio ( HR ) for CHD was 0.76 ( 95 % confidence interval [ CI ] , 0.50 - 1.16 ) ; 10 to 19 years , 1.10 ( 95 % CI , 0.84 - 1.45 ) ; and 20 or more years , 1.28 ( 95 % CI , 1.03 - 1.58 ) ( P for trend = .02 ) . The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years ; for women 10 to 19 years since menopause began , 4 per 10,000 person-years ; and for women 20 or more years from menopause onset , 17 per 10,000 person-years . For the age group of 50 to 59 years , the HR for CHD was 0.93 ( 95 % CI , 0.65 - 1.33 ) and the absolute excess risk was -2 per 10,000 person-years ; 60 to 69 years , 0.98 ( 95 % CI , 0.79 - 1.21 ) and -1 per 10,000 person-years ; and 70 to 79 years , 1.26 ( 95 % CI , 1.00 - 1.59 ) and 19 per 10,000 person-years ( P for trend = .16 ) . Hormone therapy increased the risk of stroke ( HR , 1.32 ; 95 % CI , 1.12 - 1.56 ) . Risk did not vary significantly by age or time since menopause . There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women ( HR of 0.70 for 50 - 59 years ; 1.05 for 60 - 69 years , and 1.14 for 70 - 79 years ; P for trend = .06 ) . CONCLUSIONS Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause , but this trend test did not meet our criterion for statistical significance . A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause . These data should be considered in regard to the short-term treatment of menopausal symptoms . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women . Design Open label , r and omised controlled trial . Setting Denmark , 1990 - 93 . Participants 1006 healthy women aged 45 - 58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values . 502 women were r and omly allocated to receive hormone replacement therapy and 504 to receive no treatment ( control ) .  Women who had undergone hysterectomy were included if they were aged 45 - 52 and had recorded values for postmenopausal serum follicle stimulating hormone . Interventions In the treatment group , women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day . Intervention was stopped after about 11 years owing to adverse reports from other trials , but participants were followed for death , cardiovascular disease , and cancer for up to 16 years . Sensitivity analyses were carried out on women who took more than 80 % of the prescribed treatment for five years . Main outcome measure The primary endpoint was a composite of death , admission to hospital for heart failure , and myocardial infa rct ion . Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months . After 10 years of intervention , 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group ( hazard ratio 0.48 , 95 % confidence interval 0.26 to 0.87 ; P=0.015 ) and 15 died compared with 26 ( 0.57 , 0.30 to 1.08 ; P=0.084 ) . The reduction in cardiovascular events was not associated with an increase in any cancer ( 36 in treated group v 39 in control group , 0.92 , 0.58 to 1.45 ; P=0.71 ) or in breast cancer ( 10 in treated group v 17 in control group , 0.58 , 0.27 to 1.27 ; P=0.17 ) . The hazard ratio for deep vein thrombosis ( 2 in treated group v 1 in control group ) was 2.01 ( 0.18 to 22.16 ) and for stroke ( 11 in treated group v 14 in control group ) was 0.77 ( 0.35 to 1.70 ) . After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer . Conclusions After 10 years of r and omised treatment , women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality , heart failure , or myocardial infa rct ion , without any apparent increase in risk of cancer , venous thromboembolism , or stroke . Trial registration Clinical Trials.gov NCT00252408 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 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 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 The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of postmenopausal hormone  use in 2763 women ( 1 ) . Unlike previous observational studies , it included only women with previous coronary heart disease , and hormone therapy was exclusively oral conjugated estrogen plus progestin . In HERS , overall rates of recurrent coronary heart disease did not differ between the treated and nontreated groups . However , in additional , unplanned analyses , the results of HERS were not uniformly null . A marked and statistically significant trend toward decreasing risk was observed with increasing duration of hormone use ( 1 ) ; in the first year , the rate of major coronary events was 52 % higher in the treatment group . In the second year , rates were equal , but during the final fourth and fifth years , women assigned to hormone therapy had a 33 % lower risk for coronary events . The overall results of HERS and the apparent changes in risk over time were both unexpected . Since no previous investigations have examined the relation between duration of hormone use or combined hormone treatment to secondary prevention of coronary heart disease events , it remains unclear whether the time trend was authentic and whether the observations in HERS are limited to that hormone regimen ( 2 ) . In addition , we were interested in underst and ing how women 's use of hormone therapy before their initial coronary disease event might affect the outcome of their hormone use after that event . In HERS , duration of hormone therapy before trial entry was necessarily disregarded ( although 23 % of participants had previously taken hormones ) ; thus , it remains unknown how , or whether , to account for hormone use or duration of use before a patient 's initial coronary event . To further examine the effects of duration of hormone therapy and to explore the effect of different hormone regimens , we investigated the relation between  postmenopausal hormone use and secondary prevention of major coronary events in 2489 women with established coronary disease in the Nurses ' Health Study , a large observational cohort . 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  postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . Every 2 years , we mail follow-up question naires to the original participants to up date information on risk factors and to identify newly diagnosed cases of major illnesses . The total follow-up for the cohort to date exceeds 92 % . Sample for Analysis For this analysis , we limited the cohort to postmenopausal women who reported a previous myocardial infa rct ion or documented coronary atherosclerosis ( coronary artery bypass graft surgery , percutaneous coronary revascularization , or angiographic evidence of 70 % occlusion of one or more major coronary arteries ) . Such women were identified on the baseline question naire in 1976 ; postmenopausal women who reported one of these conditions on a subsequent follow-up question naire were added to the sample at that time . Women ranged in age from 34 to 73 years at entry into the sample for analysis ; 60 % of women had a natural menopause . These criteria closely parallel those used in HERS ( 1 ) ; however , in HERS , women with hysterectomy were excluded , occlusion was defined as at least 50 % , and participants ranged in age from 44 to 79 years . 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 ) ( 3 ) . The women 's reports of age at menopause and type of menopause were highly accurate ( 4 ) . In HERS , women with a history of breast or endometrial cancers were excluded . In the current study , we excluded women who reported stroke or cancer ( except nonmelanoma skin cancer ) on the 1976 baseline question naire at the outset and excluded women from further follow-up if they reported these diseases on a subsequent biennial question naire . This was done to avoid potential bias , in which major diseases such as stroke or cancer may have caused women to alter their hormone use and may be related to risk for coronary heart disease . This type of bias could not have occurred in a r and omized trial , such as HERS . Two hundred forty-eight postmenopausal women with coronary disease entered the analysis in 1976 , and 2241 postmenopausal women were added during follow-up as they reported heart disease ; thus , 17 239 person-years accrued during up to 20 years of follow-up from 1976 to 1996 . Ascertainment of Hormone Use In 1976 , women were asked about current and past use and duration of hormone therapy ;  this information was up date d on each biennial question naire . Beginning in 1978 and on each subsequent question naire , we collected information on type of hormone used . For the period 19761978 , we assigned women to the type of hormone reported on the 1978 question naire . If no data were available on hormone therapy for a given 2-year period , those women were assigned to a missing category for that period . In the HERS trial , women who had taken hormones in the 3 months before their screening visit were excluded ( although 23 % to 24 % of the enrolled participants had previously used hormones ) . Because this study is observational , we could not impose a 3-month washout period ; thus , we could not duplicate that aspect of the HERS protocol . We analyzed duration of hormone use in two different ways . In the main analysis , we performed a HERS replication and used a method similar to that in HERS to calculate duration of use . In HERS , duration of hormone therapy began to accrue at r and omization ( regardless of previous hormone use ) ; r and omization occurred sometime after the participant 's initial coronary disease event . Therefore , in our main analysis , we began accruing duration of hormone use for each participant immediately after her initial coronary disease event ( regardless of hormone use before this event ) . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 4 years . In an alternative analysis , we considered the women 's full experience with hormone therapy ( both before and after the initial coronary disease event ) . Thus , duration of hormone use accumulated continuously from start to termination of therapy . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 6 years . Similar to HERS participants , 29 % of the nurses had taken hormones before their first coronary disease event . Identification of Second Coronary Disease Events Similar to HERS , in our study the category of recurrent major coronary heart disease included nonfatal myocardial infa rct ion and fatal coronary disease that occurred between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met the World Health Organization criteria ( 5 ) ( symptoms , plus either elevated cardiac enzyme levels or diagnostic electrocardiograms ) . Infa rct ions requiring hospitalization and corroborated by interview or letter , but for which medical records were unobtainable , were included as probable . Most deaths were reported by the participants ' families . Every 2 years , we search the National Death Index ( 6 ) to identify deaths among nonrespondents ; follow-up for death remains more than 98 % complete to date . 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 due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . Cases in which coronary disease was listed on the death certificate as the underlying cause of death and another , more plausible cause could not be discerned were included as probable cases , since the nurse was known to have had coronary disease before death . The investigators conducted all interviews and medical record review s without knowledge of participants ' hormone use status . In separate analyses , results for probable cases of coronary disease ( 20 % ) were almost identical to those for confirmed cases ( 80 % ) ; thus , we present data from analyses in which confirmed and probable cases are combined . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the baseline data and were up date d every 2 years according to information received on follow-up question naires . Examination of type of hormone therapy was limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate , as this was the most common hormone regimen . If information on hormone use was missing during a follow-up period , then person-time was assigned to a missing category for that time period . So that the study would be prospect i ve , we established hormone status during each 2-year follow-up period from women 's reports at the start of the time period ; thus , we probably underestimate duration of use by an average of 1 year in both the main analysis and the alternate analysis . Follow-up for a participant ended with diagnosis of myocardial infa rct ion , death , or 1 June 1996 , whichever came first . The analysis is based on incidence rates , using person-months of follow-up as the denominator . We used relative risk as the measure of association , defined as the incidence of second major coronary events among women in various categories of hormone use divided by the rate among women who never used hormones 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 Over the last 40 years , there has been increasing epidemiological evidence that post-menopausal treatment with sex steroids in physiological doses may reduce the relative risk of cardiovascular disease ( CVD ) . These findings have been supported by biological studies showing favourable changes in cardiovascular risk factors with estrogen supplementation . The impact of the so-called ' healthy user ' bias has been eagerly debated , and the results of the first and only r and omized long-term clinical trial of HRT for primary prevention have therefore been long awaited . The dramatic decision to halt the Women 's Health Initiative ( WHI ) study before completion came unexpectedly as the consequence of not only an increased risk of breast cancer but also increased occurrence of cardiovascular events with HRT . Due to the superior design of the study , the results from the WHI study have had an enormous impact on the clinical recommendations of HRT to post-menopausal women , concurrent with a degradation of evidence from observational studies . It is not very likely that other long-term r and omized clinical trials ( RCTs ) will be completed and epidemiology has certainly been disreputed-so is this ' time out ' for HRT studies CONTEXT The Heart and Estrogen/progestin Replacement Study ( HERS ) found no overall reduction in risk of coronary heart disease ( CHD ) events among postmenopausal women with CHD . However , in the hormone group , findings did suggest a higher risk of CHD events during the first year , and a decreased risk during years 3 to 5 . OBJECTIVE To determine if the risk reduction observed in the later years of HERS persisted and result ed in an overall reduced risk of CHD events with additional years of follow-up . DESIGN AND SETTING R and omized , blinded , placebo-controlled trial of 4.1 years ' duration ( HERS ) and subsequent unblinded follow-up for 2.7 years ( HERS II ) conducted at outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS ; 2321 women ( 93 % of those surviving ) consented to follow-up in HERS II . INTERVENTION Participants were r and omly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate ( n = 1380 ) , or placebo ( n = 1383 ) during HERS ; open-label hormone therapy was prescribed at personal physicians ' discretion during HERS II . The proportions with at least 80 % adherence to hormones declined from 81 % ( year 1 ) to 45 % ( year 6 ) in the hormone group , and increased from 0 % ( year 1 ) to 8 % ( year 6 ) in the placebo group . MAIN OUTCOME MEASURES The primary outcome was nonfatal myocardial infa rct ion and CHD death . Secondary cardiovascular events were coronary revascularization , hospitalization for unstable angina or congestive heart failure , nonfatal ventricular arrhythmia , sudden death , stroke or transient ischemic attack , and peripheral arterial disease . RESULTS There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS , HERS II , or overall . The unadjusted relative hazard ( RH ) for CHD events in HERS was 0.99 ( 95 % confidence interval [ CI ] , 0.81 - 1.22 ) ; HERS II , 1.00 ( 95 % CI , 0.77 - 1.29 ) ; and overall , 0.99 ( 0.84 - 1.17 ) . The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups ( RH , 0.97 ; 95 % CI , 0.82 - 1.14 ) , and in analyses restricted to women who were adherent to r and omized treatment assignment ( RH , 0.96 ; 95 % CI , 0.77 - 1.19 ) . CONCLUSIONS Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up . After 6.8 years , hormone therapy did not reduce risk of cardiovascular events in women with CHD . Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD BACKGROUND Estrogen plus progestin therapy increases the risk for coronary heart disease ( CHD ) in postmenopausal women . However , this increased risk might be limited to the first years of use and to women who start therapy late in menopause . OBJECTIVE To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause . DESIGN Women 's Health Initiative r and omized , double-blinded , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00000611 ) SETTING 40 U.S. clinical centers . PATIENTS 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998 . INTERVENTION Conjugated equine estrogens , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , or placebo . MEASUREMENTS Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting . RESULTS Compared with no use of hormone therapy , the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 ( 95 % CI , 1.55 to 3.62 ) for the first 2 years and 1.69 ( CI , 0.98 to 2.89 ) for the first 8 years . For women within 10 years after menopause , the hazard ratios were 1.29 ( CI , 0.52 to 3.18 ) for the first 2 years and 0.64 ( CI , 0.21 to 1.99 ) for the first 8 years , and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years ( CI , 2 years to 10 years ) . LIMITATION The analysis may not have fully adjusted for joint determinants of adherence and CHD risk . Sample sizes for some subgroup analyses were small . CONCLUSION No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use , including in women who initiated therapy within 10 years after menopause . A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use . PRIMARY FUNDING SOURCE National Heart , Lung , and Blood Institute IMPORTANCE Postmenopausal hormone therapy with conjugated equine estrogens ( CEEs ) may adversely affect older women ’s cognitive function . It is not known whether this extends to younger women . OBJECTIVE To test whether prescribing CEE-based hormone therapy to postmenopausal women aged 50 to 55 years has longer-term effects on cognitive function . DESIGN Trained , masked staff assessed participants with an annual telephone-administered cognitive battery that included measures of global and domain-specific cognitive functions . Cognitive testing was conducted an average of 7.2 years after the trials ended , when women had a mean age of 67.2 years , and repeated 1 year later . Enrollment occurred from 1996 through 1999 . SETTING Forty academic research centers . PARTICIPANTS The study population comprised 1326 postmenopausal women , who had begun treatment in 2 r and omized placebo-controlled clinical trials of hormone therapy when aged 50 to 55 years . INTERVENTION The clinical trials in which the women had participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years . MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function . Secondary outcomes were verbal memory , attention , executive function , verbal fluency , and working memory . RESULTS Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo : mean ( 95 % CI ) intervention effect of 0.02 ( −0.08 to 0.12 ) st and ard deviation units ( P = .66 ) . Similarly , no overall differences were found for any individual cognitive domain ( all P > .15 ) . Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy : mean treatment effects of −0.17 ( −0.33 to −0.02 ) and −0.25 ( −0.42 to −0.08 ) , respectively ; however , this may be a chance finding . CONCLUSIONS AND RELEVANCE CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years . We are not able to address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function , either in the short or longer term . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01124773 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 CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue Background : The Women 's Health Initiative r and omized trial found greater coronary heart disease ( CHD ) risk in women assigned to estrogen/progestin therapy  than in those assigned to placebo . Observational studies had previously suggested reduced CHD risk in hormone users . Methods : Using data from the observational Nurses ’ Health Study , we emulated the design and intention-to-treat ( ITT ) analysis of the r and omized trial . The observational study was conceptualized as a sequence of “ trials , ” in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy . Results : The ITT hazard ratios ( HRs ) ( 95 % confidence intervals ) of CHD for initiators versus noninitiators were 1.42 ( 0.92–2.20 ) for the first 2 years , and 0.96 ( 0.78–1.18 ) for the entire follow-up . The ITT HRs were 0.84 ( 0.61–1.14 ) in women within 10 years of menopause , and 1.12 ( 0.84–1.48 ) in the others ( P value for interaction = 0.08 ) . These ITT estimates are similar to those from the Women 's Health Initiative . Because the ITT approach causes severe treatment misclassification , we also estimated adherence-adjusted effects by inverse probability weighting . The HRs were 1.61 ( 0.97–2.66 ) for the first 2 years , and 0.98 ( 0.66–1.49 ) for the entire follow-up . The HRs were 0.54 ( 0.19–1.51 ) in women within 10 years after menopause , and 1.20 ( 0.78–1.84 ) in others ( P value for interaction = 0.01 ) . We also present comparisons between these estimates and previously reported Nurses ’ Health Study estimates . Conclusions : Our findings suggest that the discrepancies between the Women 's Health Initiative and Nurses ’ Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up 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 Objective : To investigate the effects of hormone therapy on brain structure in a r and omized , double-blinded , placebo-controlled trial in recently postmenopausal women . Methods : Participants ( aged 42–56 years , within 5–36 months past menopause ) in the Kronos Early Estrogen Prevention Study were r and omized to ( 1 ) 0.45 mg/d oral conjugated equine estrogens ( CEE ) , ( 2 ) 50 μg/d transdermal 17β-estradiol , or ( 3 ) placebo pills and patch for 48 months . Oral progesterone ( 200 mg/d ) was given to active treatment groups for 12 days each month . MRI and cognitive testing were performed in a subset of participants at baseline , and at 18 , 36 , and 48 months of r and omization ( n = 95 ) . Changes in whole brain , ventricular , and white matter hyperintensity volumes , and in global cognitive function , were measured . Results : Higher rates of ventricular expansion were observed in both the CEE and the 17β-estradiol groups compared to placebo ; however , the difference was significant only in the CEE group ( p = 0.01 ) . Rates of ventricular expansion correlated with rates of decrease in brain volume ( r = −0.58 ; p ≤ 0.001 ) and with rates of increase in white matter hyperintensity volume ( r = 0.27 ; p = 0.01 ) after adjusting for age . The changes were not different between the CEE and 17β-estradiol groups for any of the MRI measures . The change in global cognitive function was not different across the groups . Conclusions : Ventricular volumes increased to a greater extent in recently menopausal women who received CEE compared to placebo but without changes in cognitive performance . Because the sample size was small and the follow-up limited to 4 years , the findings should be interpreted with caution and need confirmation . Classification of evidence : This study provides Class I evidence that brain ventricular volume increased to a greater extent in recently menopausal women who received oral CEE compared to placebo 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
We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality , cardiovascular death , non-fatal myocardial infa rct ion , angina , or revascularisation .
There was no strong evidence of effect on risk of stroke in this group .
Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall , for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events
BACKGROUND Evidence from systematic review s of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women , however the results of r and omised controlled trials ( RCTs ) have had mixed results .
This is an up date d version of a Cochrane review published in 2013 .
OBJECTIVES To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women , and whether there are differential effects between use in primary or secondary prevention .
Secondary aims were to undertake exploratory analyses to ( i ) assess the impact of time since menopause that treatment was commenced ( ≥ 10 years versus < 10 years ) , and where these data were not available , use age of trial participants at baseline as a proxy ( ≥ 60 years of age versus < 60 years of age ) ; and ( ii ) assess the effects of length of time on treatment .