title: Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Postmenopausal hormone use and the risk of nephrolithiasis: results from the Women's Health Initiative hormone therapy trials. Long-term effects of conjugated equine estrogen therapies on domain-specific cognitive function: results from the Women's Health Initiative study of cognitive aging extension. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS) Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women's Health Initiative randomized controlled trial Remnant-like lipoproteins, hormone therapy, and angiographic and clinical outcomes: the Women's Angiographic Vitamin & Estrogen Trial. Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study: A Randomized, Double-Blind, Placebo-Controlled Trial Postmenopausal hormone therapy and change in mammographic density. A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial Women's angiographic vitamin and estrogen trial: design and methods. Estrogen plus progestin and the risk of coronary heart disease. Pulsed estrogen therapy improves postmenopausal quality of life: a 2-year placebo-controlled study. Heart and Estrogen/progestin Replacement Study (HERS): design, methods, and baseline characteristics. Effect of estrogen therapy on gallbladder disease. Colorectal Cancer in Relation to Postmenopausal Estrogen and Estrogen Plus Progestin in the Women's Health Initiative Clinical Trial and Observational Study Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Hormone replacement therapy: discrepancies between evidence and recommendations Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies? Menopausal Symptoms and Treatment-Related Effects of Estrogen and Progestin in the Women's Health Initiative Venous thrombosis and conjugated equine estrogen in women without a uterus. Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. Effect of postmenopausal hormone therapy on coronary heart disease events after percutaneous transluminal coronary angioplasty. Hot flushes during the menopause transition: a longitudinal study in Australian-born women The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. Estrogen after ischemic stroke: clinical basis and design of the Women's Estrogen for Stroke Trial. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin.
abstract: Background — The Women ’s Health Initiative ( WHI ) Estrogen Alone trial assessed the balance of benefits and risks of hormone use in healthy postmenopausal women . The trial was stopped prematurely because there was no benefit for coronary heart disease and an increased risk of stroke . This report provides a thorough analysis of the stroke finding using the final results from the completed trial data base . Methods and Results — The WHI Estrogen Alone hormone trial is a multicenter , double-blind , placebo-controlled , r and omized clinical trial in 10 739 women aged 50 to 79 years who were given daily conjugated equine estrogen ( CEE ; 0.625 mg ; n=5310 ) or placebo ( n=5429 ) . During an average follow-up of 7.1 years , there were 168 strokes in the CEE group and 127 in the placebo group ; 80.3 % of strokes were ischemic . For all stroke the intention-to-treat hazard ratio [ HR ] ( 95 % CI ) for CEE versus placebo was 1.37 ( 1.09 to 1.73 ) . The HR ( 95 % CI ) was 1.55 ( 1.19 to 2.01 ) for ischemic stroke and 0.64 ( 0.35 , 1.18 ) for hemorrhagic stroke . The HRs indicate excess risk of ischemic stroke was apparent in all categories of baseline stroke risk , including younger and more recently menopausal women and in women with prior or current use of statins or aspirin . Conclusions — CEE increases the risk of ischemic stroke in generally healthy postmenopausal women . The excess risk appeared to be present in all subgroups of women examined , including younger and more recently menopausal women . There was no convincing evidence to suggest that CEE had an effect on the risk of hemorrhagic stroke CONTEXT The Women 's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks , including invasive breast cancer , exceeded benefits . Outst and ing issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography . OBJECTIVE To determine the relationship among estrogen plus progestin use , breast cancer characteristics , and mammography recommendations . DESIGN , SETTING , AND PARTICIPANTS Following a comprehensive breast cancer risk assessment , 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were r and omly assigned to receive combined conjugated equine estrogens ( 0.625 mg/d ) plus medroxyprogesterone acetate ( 2.5 mg/d ) or placebo from 1993 to 1998 at 40 clinical centers . Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter . MAIN OUTCOME MEASURES Breast cancer number and characteristics , and frequency of abnormal mammograms by estrogen plus progestin exposure . RESULTS In intent-to-treat analyses , estrogen plus progestin increased total ( 245 vs 185 cases ; hazard ratio [ HR ] , 1.24 ; weighted P<.001 ) and invasive ( 199 vs 150 cases ; HR , 1.24 ; weighted P = .003 ) breast cancers compared with placebo . The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger ( mean [ SD ] , 1.7 cm [ 1.1 ] vs 1.5 cm [ 0.9 ] , respectively ; P = .04 ) and were at more advanced stage ( regional/metastatic 25.4 % vs 16.0 % , respectively ; P = .04 ) compared with those diagnosed in the placebo group . After 1 year , the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group ( 716 [ 9.4 % ] of 7656 ) compared with placebo group ( 398 [ 5.4 % ] of 7310 ; P<.001 ) , a pattern which continued for the study duration . CONCLUSIONS Relatively short-term combined estrogen plus progestin use increases incident breast cancers , which are diagnosed at a more advanced stage compared with placebo use , and also substantially increases the percentage of women with abnormal mammograms . These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis Background Although breast cancer risk is greater in users of estrogen – progestin than estrogen-only formulations of menopausal hormonal therapy  , reports on their effects have been somewhat inconsistent . We investigated whether the timing of these therapies affected breast cancer incidence . Methods A total of 1 129 025 postmenopausal UK women provided prospect i ve information on hormonal therapy use and other factors relevant for breast cancer risk . We used Cox regression to estimate adjusted relative risks ( RRs ) of breast cancer in hormonal therapy  users vs never users and calculated st and ardized incidence rates . All statistical tests were two-sided . Results During 4.05 million woman-years of follow-up , 15 759 incident breast cancers occurred , with 7107 in current users of hormonal therapy .  Breast cancer incidence was increased in current users of hormonal therapy , returning to that of never users a few years after use had ceased . The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap ( Pheterogeneity < .001 , for both estrogen-only and estrogen-progestin formulations ) . Among current users of estrogen-only formulations , there was little or no increase in risk if use began 5 years or more after menopause ( RR = 1.05 , 95 % confidence interval [ CI ] = 0.89 to 1.24 ) , but risk was statistically significantly increased if use began before or less than 5 years after menopause ( RR = 1.43 , 95 % CI = 1.35 to 1.51 ) . A similar pattern was observed among current users of estrogen – progestin formulations ( RR = 1.53 , 95 % CI = 1.38 to 1.70 , and RR = 2.04 , 95 % CI = 1.95 to 2.14 , respectively ) . At 50–59 years of age , annual st and ardized incidence rates for breast cancer were 0.30 % ( 95 % CI = 0.29 % to 0.31 % ) among never users of hormone therapy and 0.43 % ( 95 % CI = 0.42 % to 0.45 % ) and 0.61 % ( 95 % CI = 0.59 % to 0.64 % ) , respectively , among current users of estrogen-only and estrogen – progestin formulations who began use less than 5 years after menopause . Conclusions There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy . Risks were greater among users of estrogen – progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later CONTEXT The Women 's Health Initiative Estrogen-Aone trial comparing conjugated equine estrogens ( CEE ) with placebo was stopped early because of an increased stroke incidence and no reduction in risk of coronary heart disease . Preliminary results suggesting possible reduction in breast cancers warranted more detailed analysis . OBJECTIVE To determine the effects of CEE on breast cancers and mammographic findings . DESIGN , SETTING , AND PARTICIPANTS Following breast cancer risk assessment , 10,739 postmenopausal women aged 50 to 79 years with prior hysterectomy were r and omized to CEE or placebo at 40 US clinical centers from 1993 through 1998 . Mammography screenings and clinical breast examinations were performed at baseline and annually . All breast cancers diagnosed through February 29 , 2004 , are included . INTERVENTION A dose of 0.625 mg/d of CEE or an identical-appearing placebo . MAIN OUTCOME MEASURES Breast cancer incidence , tumor characteristics , and mammogram findings . RESULTS After a mean ( SD ) follow-up of 7.1 ( 1.6 ) years , the invasive breast cancer hazard ratio ( HR ) for women assigned to CEE vs placebo was 0.80 ( 95 % confidence interval [ CI ] , 0.62 - 1.04 ; P = .09 ) with annualized rates of 0.28 % ( 104 cases in the CEE group ) and 0.34 % ( 133 cases in the placebo group ) . In exploratory analyses , ductal carcinomas ( HR , 0.71 ; 95 % CI , 0.52 - 0.99 ) were reduced in the CEE group vs placebo group ; however , the test for interaction by tumor type was not significant ( P = .054 ) . At 1 year , 9.2 % of women in the CEE group had mammograms with abnormalities requiring follow-up vs 5.5 % in the placebo group ( P<.001 ) , a pattern that continued through the trial to reach a cumulative percentage of 36.2 % vs 28.1 % , respectively ( P<.001 ) ; however , this difference was primarily in assessment s requiring short interval follow-up . CONCLUSIONS Treatment with CEE alone for 7.1 years does not increase breast cancer incidence in postmenopausal women with prior hysterectomy . However , treatment with CEE increases the frequency of mammography screening requiring short interval follow-up . Initiation of CEE should be based on consideration of the individual woman 's potential risks and benefits . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered BACKGROUND Observational studies examining the role of estrogen in the risk of kidney stone formation have shown conflicting results . However , r and omized trial evidence on nephrolithiasis risk with  estrogen therapy in postmenopausal women is lacking . METHODS We review ed the incidence of nephrolithiasis in the Women 's Health Initiative estrogen-alone and estrogen plus progestin trials conducted at 40 US clinical centers . A total of 10 739 postmenopausal women with hysterectomy were r and omized to receive 0.625 mg/d of conjugated equine estrogens ( CEE ) or placebo , and 16 608 postmenopausal women without hysterectomy were r and omized to receive placebo or estrogen plus progestin given as CEE plus medroxyprogesterone acetate ( 2.5 mg/d ) . The incidence of nephrolithiasis was determined for an average follow-up of 7.1 years for the CEE trial and 5.6 years for the estrogen plus progestin trial . RESULTS Baseline demographic characteristics and risk factors for nephrolithiasis were similar in the placebo and treatment arms . Estrogen therapy was associated with a significant increase in nephrolithiasis risk from 34 to 39 cases per 10 000 person-years ( hazard ratio , 1.21 ; 95 % confidence interval , 1.03 - 1.44 ) . Censoring data from women when they ceased to adhere to study medication increased the hazard ratio to 1.39 ( 95 % confidence interval , 1.08 - 1.78 ) . The increased nephrolithiasis risk was independent of progestin coadministration , and effects did not vary significantly according to prer and omization history of nephrolithiasis . CONCLUSIONS These data suggest that estrogen therapy increases the risk of nephrolithiasis  in healthy postmenopausal women . These findings should be considered in decision making regarding postmenopausal estrogen use . The mechanisms underlying this higher susceptibility remain to be determined . Trial Registration clinical trials.gov Identifier : NCT0000611 OBJECTIVES To determine whether small decrements in global cognitive function that conjugated equine estrogen ( CEE ) therapies have been shown to produce in older women persist after cessation and extend to specific cognitive domains . DESIGN R and omized controlled clinical trial . SETTING Fourteen clinical centers of the Women 's Health Initiative . PARTICIPANTS Two thous and three hundred four women aged 65 to 80 free of probable dementia at enrollment . INTERVENTION CEE 0.625 mg/d with or without medroxyprogesterone acetate ( MPA , 10 mg/d ) and matching placebos . MEASUREMENTS Annual administrations of a battery of cognitive tests during and after the trial . RESULTS Assignment to CEE-based therapies was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the trial , which largely persisted through up to 4 years after the trial . The strongest statistical evidence was for global cognitive function ( 0.07-st and ard deviation decrements during ( P=.007 ) and after ( P=.01 ) the trial . For domain-specific scores , the mean decrements were slightly smaller , were less significant , and tended to be larger for CEE-alone therapy . CONCLUSION CEE-based therapies , when initiated after the age of 65 , produce a small broad-based decrement in cognitive function that persists after their use is stopped , but the differences in cognitive function are small and would not be detectable or have clinical significance for an individual woman . Differences in effects between cognitive domains suggest that more than one mechanism may be involved UNLABELLED Further analyses from the Women 's Health Initiative estrogen trial shows that CEE reduced fracture risk . The fracture reduction at the hip did not differ appreciably among risk strata . These data do not support overall benefit over risk , even in women at highest risk for fracture . INTRODUCTION The Women 's Health Initiative provided evidence that conjugated equine estrogen ( CEE ) can significantly reduce fracture risk in postmenopausal women . Additional analysis of the effects of CEE on BMD and fracture are presented . MATERIAL S AND METHODS Postmenopausal women 50 - 79 years of age with hysterectomy were r and omized to  CEE 0.625 mg daily ( n = 5310 ) or placebo ( n = 5429 ) and followed for an average 7.1 years . Fracture incidence was assessed by semiannual question naire and verified by adjudication of radiology reports . BMD was measured in a subset of women ( N = 938 ) at baseline and years 1 , 3 , and 6 . A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk . RESULTS CEE reduced the risk of hip ( hazard ratio [ HR ] , 0.65 ; 95 % CI , 0.45 - 0.94 ) , clinical vertebral ( HR , 0.64 ; 95 % CI , 0.44 - 0.93 ) , wrist/lower arm ( HR , 0.58 ; 95 % CI , 0.47 - 0.72 ) , and total fracture ( HR , 0.71 ; 95 % CI , 0.64 - 0.80 ) . This effect did not differ among strata according to age , oophorectomy status , past hormone use , race/ethnicity , fall frequency , physical activity , or fracture history . Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms ( HR , 0.86 ; 95 % CI , 0.68 - 1.08 ) . CEE also provided modest but consistent positive effects on BMD . The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk ( lowest risk : HR , 0.81 ; 95 % CI , 0.62 - 1.05 ; mid risk : HR , 1.09 ; 95 % CI , 0.92 - 1.30 ; highest risk : HR , 1.04 ; 95 % CI , 0.88 - 1.23 ; interaction , p = 0.42 ) . CONCLUSIONS CEE reduces the risk of fracture and increases BMD  in hysterectomized postmenopausal women . Even among the women with the highest risk for fractures , when considering the effects of estrogen on other important health outcomes , a summary of the burden of monitored effects does not indicate a significant net benefit 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 —Although effects of statins on cardiovascular outcomes are well established in men , fewer data exist for women . Furthermore , the effects of statins plus hormone replacement therapy ( HRT ) on cardiovascular outcomes are uncertain . Methods and Results —We examined statin use , cardiovascular events , and total mortality in the Heart and Estrogen/progestin Replacement Study ( HERS ) , a r and omized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease ( n=2763 ) . A nonr and omized comparison of statin users and nonusers revealed lower rates of the primary outcome , nonfatal myocardial infa rct ion or coronary heart disease death ( relative hazard [RH]=0.79 , 95 % confidence intervals [ CI ] 0.63 to 0.99 , P = 0.04 ) , and total mortality ( RH=0.67 , 95 % CI 0.51 to 0.87 , P = 0.003 ) . Rates of venous thromboembolic events were also lower among statin users ( RH=0.45 , 95 % CI 0.23 to 0.88 , P = 0.02 ) . HRT result ed in a significant increase in early risk for primary events in women who did not use statins ( RH=1.75 , 95 % CI 1.02 to 3.03 , P = 0.04 ) but not in statin users ( RH=1.34 , 95 % CI 0.63 to 2.86 , P = 0.45 ) . Adjustment for postr and omization statin use showed no effect of HRT on risk for the primary outcome ( RH=0.96 , 95 % CI 0.77 to 1.29;P = 0.72 ) . Conclusions —In HERS , statin use was associated with lower rates of cardiovascular events , venous thromboembolic events , and total mortality . These data provide strong support for statin use in eligible women with coronary disease Context : The Women 's Health Initiative ( WHI ) r and omized controlled trial that compared estrogen plus progestin versus placebo was stopped because of a significantly increased risk of breast cancer in the active treatment group ( reason 1 ) , and because a global index supported a finding of overall harm ( reason 2 ) . The possibility that the findings could have been accounted for by bias was not considered . Objective : The present analysis was undertaken to determine whether detection bias is a plausible alternative to causality as an explanation for those findings that contributed to the reasons for discontinuing the study . Design , setting and participants : This work took the form of a sensitivity analysis of the published WHI data to determine the magnitude of the detection bias required to account for those findings that contributed to the two reasons for stopping the study . Main outcome measures : These were differences in incidence rates of breast cancer ( reason 1 ) , and breast cancer , coronary heart disease , stroke and pulmonary embolism ( reason 2 ) , among  estrogen plus progestin and placebo recipients . Results In the WHI study , 44.4 % of the women on active treatment , as against 6.8 % of the  placebo recipients , had their treatments unblinded ( mainly because of vaginal bleeding ) . Among them , detection bias could not be excluded . For the three cardiovascular outcomes , bias became a strong likelihood after the women were twice caution ed about possible increased risks observed in the interim data among estrogen plus progestin recipients . On the null hypothesis , bias could have accounted for the observed associations if , on average , it augmented the detection of disease that would otherwise have gone undiagnosed by 0.7 - 0.8/1000 per year . Conclusions : For differences in incidence of the order of 0.7 - 0.8/1000 per year , it is not possible to discriminate between causation and detection bias as alternative explanations for the findings BACKGROUND Little is known about the impact of post-menopausal hormone therapy on remnant-like particle ( RLP ) concentrations and about the relationship between RLP concentration and angiographic progression of coronary artery disease and clinical events in women . METHODS RLP cholesterol and triglyceride levels were measured at baseline and 3 months after r and omization in 397 post-menopausal women enrolled in The Women 's Angiographic Vitamin & Estrogen ( WAVE ) trial . Correlates of baseline RLP levels and changes in levels with post-menopausal hormone therapy were determined with multiple linear regression . Coronary angiography was performed at baseline and after a mean of 2.9 years . Changes in minimal and average luminal diameter were modeled with multivariate linear regression , clinical outcomes ( non-fatal myocardial infa rct ion , stroke , or cardiovascular death ) with multiple logistic regression . RESULTS The mean subject age was 65 years , 66 % of subjects were white , 18 % of subjects smoked , most subjects were overweight or obese , and 35 % of subjects had diabetes mellitus .  RLP cholesterol ( 0.277 + /- 0.254 mmol/L ) and triglyceride ( 0.386 + /- 0.552 mmol/L ) levels corresponded approximately to the 90th percentile in women in the Framingham study . RLP levels did not change significantly with hormone therapy . RLP levels at baseline , changes in RLP levels , and on treatment RLP levels did not relate to angiographic changes or clinical outcomes ( non-fatal myocardial infa rct ion , stroke , or cardiovascular death ) . CONCLUSIONS RLP levels were high among post-menopausal women enrolled in the WAVE study , were not affected by hormone therapy , and did not relate to angiographic progression of coronary artery disease or clinical outcomes Context In observational studies , postmenopausal hormone therapy has been associated with lower fasting glucose levels . No prospect i ve , controlled trial has evaluated the effect of postmenopausal hormone therapy on the development of diabetes mellitus . Contribution Among the 2029 women in the Heart and Estrogen/progestin Replacement Study who had coronary disease but no diabetes at baseline , 6.2 % of those receiving 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate  and 9.5 % of those receiving placebo developed diabetes . Implication s Recommendations about combination postmenopausal hormone therapy should consider that for every 30 women treated for 4 years , therapy might prevent one case of diabetes . The Editors Several clinical studies have evaluated the effect of postmenopausal hormone therapy on glucose metabolism and have had disparate results . Results from r and omized , controlled trials performed primarily in women without diabetes have found decreased mean fasting glucose or insulin levels among those assigned to hormone therapy ( 1 - 5 ) or no difference between those assigned to hormones and those assigned to placebo ( 6 - 10 ) . Fewer clinical trials have evaluated the effect of postmenopausal hormones on fasting glucose and insulin levels among women with type 2 diabetes mellitus , but again , the results have been mixed ( 11 - 16 ) . Observational studies have more consistently found that postmenopausal women taking hormone therapy have lower fasting glucose or hemoglobin A1c levels than those not taking hormones ( 17 - 24 ) . In addition , some ( 25 , 26 ) but not all ( 24 , 27 ) observational studies have noted a decreased incidence of diabetes among users of postmenopausal hormone therapy . No r and omized , controlled trial has evaluated the long-term effect of hormone therapy on diabetes incidence . To determine the effect of hormone therapy on subsequent diabetes , we analyzed data from the Heart and Estrogen/progestin Replacement Study ( HERS ) , in which 2763 postmenopausal women with documented coronary heart disease ( CHD ) were r and omly assigned to daily estrogen plus progestin therapy or to placebo . We evaluated the effect of hormone therapy on fasting glucose levels and incident diabetes over 4 years of follow-up . Methods Study Setting , Participants , and Design The design , methods , baseline characteristics ( 28 ) , and main findings ( 29 ) of HERS have been published elsewhere . Briefly , HERS was a r and omized , double-blind , placebo-controlled trial performed to evaluate daily doses of 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate for the prevention of coronary events in postmenopausal women with established CHD . The trial enrolled 2763 women at 20 clinical centers in the United States between January 1993 and September 1994 and followed participants for a mean of 4.1 years . To be included in the trial , women had to be younger than 80 years of age and have CHD , as evidence d by previous myocardial infa rct ion , coronary artery bypass graft surgery , mechanical revascularization , or angiographic evidence of coronary stenosis . Women who reported a CHD event within 6 months of r and omization or who had used postmenopausal hormone therapy within 3 months of the initial screening were excluded . Those with serum triglyceride levels of 3.39 mmol/L or greater ( 300 mg/dL ) , fasting blood glucose levels of 16.5 mmol/L or greater ( 300 mg/dL ) , or uncontrolled hypertension ( systolic blood pres sure 200 mg Hg or diastolic blood pressure 105 mm Hg ) were also excluded . Computer-generated r and om numbers were used to specify the allocation sequence . Women were r and omly assigned to the two treatment groups by use of a tamper-proof blocked r and omization stratified by clinical center . Participants , investigators , and staff at the clinical centers ; Wyeth-Ayerst Research ; and those adjudicating study outcomes were blinded to medication assignment . Additional details about sample size calculations , r and omization , and blinding procedures have been published elsewhere ( 29 ) . For our analysis , women were classified as having diabetes at the baseline visit if they reported a physician diagnosis of diabetes , were taking diabetes medication , or had a fasting plasma glucose level of 6.9 mmol/L or greater ( 126 mg/dL ) . Women were classified as having impaired fasting glucose if they had a fasting glucose level of 6.0 to 6.9 mmol/L ( 110 to 125 mg/dL ) at baseline . The remaining women were considered to have normal glucose metabolism . Data Collection At baseline , participants completed a question naire to ascertain age , race or ethnicity , education , smoking habits ( current , former , or never ) , alcohol consumption ( drinks per week ) , and exercise or walking activity . Physical examination variables measured at baseline were body weight , height , waist and hip circumference , and systolic and diastolic blood pressure . At baseline , at year 1 , and at the end-of-trial visit , participants had fasting blood tests for levels of total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , and lipoprotein(a ) measured by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital , Baltimore , Maryl and . Fasting serum glucose level was measured at baseline , at year 1 , and at the end-of-trial visit . Venous blood was obtained in the morning after a 12-hour fast , and SmithKline Beecham Clinical Laboratory , Van Nuys , California , analyzed the sample s using the hexokinase enzymatic method . We determined coefficients of variation by using ChemTrac ( Medical Analysis Systems , Inc. , Camarillo , California ) control . The coefficient of variation for serum glucose level was 1.6 % at a mean value ( SD ) of 4.2 0.05 mmol/L ( 77 1.0 mg/dL ) and 1.1 % at a mean value ( SD ) of 14.6 0.16 mmol/L ( 266 3.0 mg/dL ) .  Adherence to study medication was reassessed every 4 months , at each visit . Ascertainment of Outcomes Diabetes incidence was not a secondary end point of the main HERS trial , but blood glucose level was prespecified as a variable that may mediate the effects of hormone therapy on CHD outcomes . We defined incident cases of diabetes by the presence of a  fasting glucose level of 6.9 mmol/L or greater ( 126 mg/dL ) at year 1 or at the end-of-trial visit , self-report of new diabetes or a complication directly related to diabetes , or initiation of hypoglycemic medication at any point during follow-up . Self-reported complications included diabetic neuropathy , diabetic retinopathy , diabetic foot ulcer , and diabetic renal disease . Hypoglycemia was considered a complication of diabetes if a participant taking an antidiabetic medication reported it to the study staff as an adverse event . Statistical Analysis To compare fasting glucose levels by treatment assignment at baseline , at year 1 , and at the end-of-trial visit , t-tests were used . In addition , mixed linear models for repeated measures were used to assess treatment effects on fasting glucose level measured at year 1 and at the end-of-trial visit . Since mean values changed little after the year 1 visit , treatment effects were modeled by using the interaction between treatment assignment and an indicator for follow-up compared with baseline . These analyses were repeated after stratification by baseline diabetes status ( diabetes , impaired fasting glucose , or normal glucose metabolism ) . We calculated the number needed to treat for benefit by taking the inverse of the absolute risk reduction of incident diabetes between the treatment groups . The effect of treatment assignment on incident diabetes was assessed by using Cox proportional-hazards models . Primary analyses used unadjusted intention-to-treat models ; in supplementary analyses , we adjusted first for age and then for a range of potential confounders selected a priori , including age ; ethnicity ; education ; current smoking ; alcohol use ; exercise ; body mass index ; waist circumference ; and baseline use of diuretics , -blockers , angiotensin-converting enzyme inhibitors , and statins . In addition to intention-to-treat analyses , we also performed as treated analyses to determine whether the observed effect of hormone therapy on glucose levels and incident diabetes was also seen among women who adhered to the study medication . In these analyses , follow-up was censored at the beginning of the first 2-week period in which participants did not adhere to medication . To minimize potential confounding , these analyses were adjusted for baseline variables that differed between adherent and nonadherent women . We hypothesized that certain characteristics ( body mass index , waist circumference , weight change , smoking , triglyceride level , high-density lipoprotein cholesterol level , hypertension , and certain cardiac medications ) may mediate the effect of hormone therapy on fasting glucose level and diabetes incidence . To test this theory , we added postr and omization values of one or more hypothesized mediators as covariates to Cox regression models for incident diabetes . All analyses were conducted by using SAS software , version 8.02 ( SAS Institute , Inc. , Cary , North Carolina ) . A P value less than 0.05 was considered statistically significant . Role of the Funding Sources The funding sources had no role in the design or conduct of this analysis or in the decision to su bmi t the paper for publication . Results Characteristics of women enrolled in HERS did not differ substantially between the hormone therapy group and the  placebo group ( Table 1 ) . At the baseline examination , 734 women ( 26.6 % ) were classified as diabetic based on self-report of diagnosis or medication use ( n = 640 [ 87.2 % ] ) or by a fasting serum glucose level of 6.9 mmol/L or greater ( 126 mg/dL ) ( n = 101 [ 13.8 % ] ) . Impaired fasting glucose ( fasting serum glucose level , 6.0 to 6.9 mmol/L [ 110 to 125 mg/dL ] ) was noted in 218 women ( 7.9 % ) , and 1811 women ( 65.5 % ) were classified as nondiabetic ( Table 2 ) . Women with diabetes had higher body mass index , waist circumference , BACKGROUND Mammographic density is an independent risk factor for breast cancer . Postmenopausal hormone use is associated with an increase in mammographic density , but the magnitude of the density increase is unknown . METHODS Baseline and 12-month mammograms were obtained for 571 ( 65 % ) of the 875 women , aged 45 - 64 years , who were enrolled in the Postmenopausal Estrogen/Progestin Interventions Trial and r and omly assigned to receive placebo , daily conjugated equine estrogens at 0.625 mg/day ( CEE ) , daily CEE and medroxyprogesterone acetate ( MPA ) at 10 mg/day on days 1 - 12 ( CEE+MPA-cyclic ) , daily CEE and MPA at 2.5 mg/day ( CEE+MPA-continuous ) , or daily CEE and micronized progesterone ( MP ) at 200 mg/day on days 1 - 12 ( CEE+MP ) . We analyzed digitized mammograms to determine the percentage of the left breast that was composed of dense tissue ( i.e. , mammographic percent density ) . Linear regression analysis was used to examine the effects of treatments on the change in mammographic percent density between baseline and 12 months , before and after adjustment for possible confounders . All statistical tests were two-sided . RESULTS The adjusted absolute mean changes in mammographic percent density over 12 months were 4.76 % ( 95 % confidence interval [ CI ] = 3.29 % to 6.23 % ) , 4.58 % ( 95 % CI = 3.19 % to 5.97 % ) , and 3.08 % ( 95 % CI = 1.65 % to 4.51 % ) for women in the CEE+MPA-cyclic , CEE+MPA-continuous , and CEE-MP groups , respectively . Each of those absolute mean changes was statistically significantly different from the adjusted absolute mean change in mammographic percent density for women in the placebo group , which was -0.07 % ( 95 % CI = -1.50 % to 1.38 % ) . CONCLUSION Greater mammographic density was associated with the use of estrogen/progestin combination therapy , regardless of how the progestin was given , but not with the use of estrogen only We examined whether estradiol and norethindrone hormone therapy ( HT ) prevented decline in delayed verbal recall in older women with normal to mildly impaired memory functioning . This was a 2-year , r and omized , double-blind , placebo-controlled trial of 142 women aged 61 - 87 , r and omly assigned to receive 1 mg 17-beta estradiol daily and 0.35 mg norethindrone 3 days/week or daily placebo for 2 years . The primary outcome was short-delay verbal recall of the California Verbal Learning Test ( CVLT ) . To look for differences in response to HT by baseline short-delay recall , we examined the primary outcome in participants grouped according to whether their baseline scores were below average for the age group or greater than or equal to this score and according to whether they met criteria for Mild Cognitive Impairment ( MCI ) or not . 133 women completed 1 year of the trial and 128 completed 2 years . Prespecified covariates in all repeated measures analyses of covariance ( RANCOVA ) included age , education , APOE epsilon4 , and prior HT use . RANCOVA showed no overall significant treatment effects at year 1 or year 2 . After testing for an interaction , which was significant ( p=0.02 ) , we found that women in the HT group who scored at or above the average showed significantly less decline than the placebo group in short-delay verbal recall after 1 year , p=0.007 and 2 years , p=0.01 . No treatment effects were found in women below the average in either year . When grouped according to whether the participant met criteria for MCI , the interaction between treatment group and MCI subgroup was not significant . These results suggest that benefits of estrogen exposure may be limited to those with average to above average scores on the delayed verbal recall .  HT dose and formulation may have contributed to these beneficial outcomes . Replication is warranted before recommendations can be made in the clinical setting BACKGROUND In the post-intervention period of the Women 's Health Initiative ( WHI ) trial , women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo . Results also suggested that the combined hormone therapy might increase mortality from lung cancer . To assess whether such an association exists , we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period . METHODS The WHI study was a r and omised , double-blind , placebo-controlled trial undertaken in 40 centres in the USA . 16 608 postmenopausal women aged 50 - 79 years with an intact uterus were r and omly assigned by a computerised , stratified , permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate ( n=8506 ) or matching placebo ( n=8102 ) . We assessed incidence and mortality rates for all lung cancer , small-cell lung cancer , and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00000611 . FINDINGS After a mean of 5.6 years ( SD 1.3 ) of treatment and 2.4 years ( 0.4 ) of additional follow-up , 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group ( incidence per year 0.16%vs 0.13 % ; hazard ratio [ HR ] 1.23 , 95 % CI 0.92 - 1.63 , p=0.16 ) . 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo ( 0.14%vs 0.11 % ; HR 1.28 , 0.94 - 1.73 , p=0.12 ) . More women died from lung cancer in the combined hormone therapy group than in the placebo group ( 73 vs 40 deaths ; 0.11%vs 0.06 % ; HR 1.71 , 1.16 - 2.52 , p=0.01 ) , mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group ( 62 vs 31 deaths ; 0.09%vs 0.05 % ; HR 1.87 , 1.22 - 2.88 , p=0.004 ) . Incidence and mortality rates of small-cell lung cancer were similar between groups . INTERPRETATION Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer , it increased the number of deaths from lung cancer , in particular deaths from non-small-cell lung cancer . These findings should be incorporated into risk-benefit discussion s with women considering combined hormone therapy , especially those with a high risk of lung cancer . FUNDING National Heart , Lung and Blood Institute , National Institutes of Health The Women 's Angiographic Vitamin and Estrogen trial was a r and omized , double-blind , placebo-controlled study design ed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease .  Postmenopausal women with one or more angiographically documented coronary stenoses of 15 - 75 % at baseline were assigned in a 2 x 2 factorial r and omization to active hormone replacement therapy ( conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri ) or placebo and to active vitamins E and C or their placebos .  Seven clinical centers , five in the United States and two in Canada , r and omized 423 women between July 1997 and July 1999 . Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years BACKGROUND Recent r and omized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease ( CHD ) . In this report , we provide the final results with regard to estrogen plus progestin and CHD from the Women 's Health Initiative ( WHI ) . METHODS The WHI included a r and omized primary -prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line . Participants were r and omly assigned to receive conjugated equine estrogens ( 0.625 mg per day ) plus medroxyprogesterone acetate ( 2.5 mg per day ) or placebo . The primary efficacy outcome of the trial was CHD ( nonfatal myocardial infa rct ion or death due to CHD ) . RESULTS After a mean follow-up of 5.2 years ( planned duration , 8.5 years ) , the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits . Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 ( nominal 95 percent confidence interval , 1.00 to 1.54 ; 95 percent confidence interval after adjustment for sequential monitoring , 0.97 to 1.60 ) . The elevation in risk was most apparent at one year ( hazard ratio , 1.81 [ 95 percent confidence interval , 1.09 to 3.01 ] ) . Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy , higher base-line levels of C-reactive protein , other biomarkers , and other clinical characteristics did not significantly modify the treatment-related risk of CHD . CONCLUSIONS Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women , especially during the first year after the initiation of hormone use . This treatment should not be prescribed for the prevention of cardiovascular disease OBJECTIVE To investigate the effect of pulsed estrogen therapy S21400 ( intranasal 17 beta-estradiol ) on different quality of life ( QoL ) dimensions in early postmenopausal women treated with S21400 150 microg per day , S21400 300 microg per day , or placebo in a double blind , r and omized , controlled 2-year study . STUDY DESIGN QoL was assessed based on the vali date d Women 's Health Question naire design ed for peri- and post-menopausal women . Three hundred and thirty-five healthy , early postmenopausal Danish women , 53 years of age in average , who completed one question naire at baseline and one under study treatment were included in the analysis set . All analyses were performed on an intention-to-treat basis . RESULTS QoL improved significantly in both S21400 groups compared to placebo in the dimensions ' memory/concentration ' , ' vasomotor symptoms ' , ' sleep problems ' and ' sexual behavior ' ( difference in mean change scores being respectively + 7.9 , + 28.3 , + 9.9 and + 10.8 % , p < 0.001 , between the S21400 300 microg and placebo group ) . There were no significant differences between actively treated groups and placebo in the dimensions ' anxiety/depressed mood ' and ' well-being ' . CONCLUSION Pulsed estradiol therapy had a pronounced effect not only on vasomotor symptoms but also a significant and clinical ly relevant improvement in several other QoL dimensions The Heart and Estrogen/progestin Replacement Study ( HERS ) is a r and omized , double-blind , placebo-controlled trial design ed to test the efficacy and safety of estrogen plus progestin therapy for prevention of recurrent coronary heart disease ( CHD ) events in women . The participants are postmenopausal women with a uterus and with CHD as evidence d by prior myocardial infa rct ion , coronary artery bypass graft surgery , percutaneous transluminal coronary angioplasty , or other mechanical revascularization or at least 50 % occlusion of a major coronary artery . Between February 1993 and September 1994 , 20 HERS centers recruited and r and omized 2763 women . Participants ranged in age from 44 to 79 years , with a mean age of 66.7 ( SD 6.7 ) years . Most participants were white ( 89 % ) , married ( 57 % ) , and had completed high school or some college ( 80 % ) . As expected , the prevalence of coronary risk factors was high : 62 % were past or current smokers , 59 % had hypertension , 90 % had serum LDL-cholesterol of 100 mg/dL or higher , and 23 % had diabetes . Each woman was r and omly assigned to receive one tablet containing 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate daily or an identical placebo . Participants will be evaluated every 4 months for an average of 4.2 years for the occurrence of CHD events ( CHD death and nonfatal myocardial infa rct ion ) . We will also assess other major CHD endpoints , including revascularization and hospitalization for unstable angina . The primary analysis will compare the rate of CHD events in women assigned to active treatment with the rate in those assigned to placebo . The trial was design ed to have power greater than 90 % to detect a 35 % reduction in the incidence of CHD events , assuming a 50 % lag in effect for 2 years and a 5 % annual event rate in the placebo group . The design , analysis , and conduct of the study are controlled by the Steering Committee of Principal Investigators and coordinated at the University of California , San Francisco . HERS is the largest trial of any intervention to reduce the risk of recurrent CHD events in women with heart disease and is the first controlled trial to seek evidence of the efficacy and safety of postmenopausal hormone therapy to prevent recurrent CHD events CONTEXT Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than r and omized trials . OBJECTIVE To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes . DESIGN , SETTING , AND PARTICIPANTS Two r and omized , double-blind , placebo-controlled trials conducted at 40 US clinical centers . The volunteer sample was 22,579 community-dwelling women aged 50 to 79 years without prior cholecystectomy . INTERVENTION Women with hysterectomy were r and omized to 0.625 mg/d of conjugated equine estrogens ( CEE ) or placebo ( n = 8376 ) . Women without hysterectomy were r and omized to estrogen plus progestin ( E + P ) , given as CEE plus 2.5 mg/d of medroxyprogesterone acetate ( n = 14,203 ) . MAIN OUTCOME MEASURES Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures , with events ascertained through medical record review . Cox proportional hazards regression was used to assess hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) using intention-to-treat and time-to-event methods . RESULTS The CEE and the E + P groups were similar to their respective placebo groups at baseline . The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials , respectively . The annual incidence rate for any gallbladder event was 78 events per 10,000 person-years for the CEE group ( vs 47/10,000 person-years for placebo ) and 55 per 10,000 person-years for E + P ( vs 35/10,000 person-years for placebo ) . Both trials showed greater risk of any gallbladder disease or surgery with estrogen ( CEE : HR , 1.67 ; 95 % CI , 1.35 - 2.06 ; E + P : HR , 1.59 ; 95 % CI , 1.28 - 1.97 ) . Both trials indicated a higher risk for cholecystitis ( CEE : HR , 1.80 ; 95 % CI , 1.42 - 2.28 ; E + P : HR , 1.54 ; 95 % CI 1.22 - 1.94 ) ; and for cholelithiasis ( CEE : HR , 1.86 ; 95 % CI , 1.48 - 2.35 ; E + P : HR , 1.68 ; 95 % CI , 1.34 - 2.11 ) for estrogen users . Also , women undergoing estrogen therapy were more likely to receive cholecystectomy ( CEE : HR , 1.93 ; 95 % CI , 1.52 - 2.44 ; E + P : HR , 1.67 ; 95 % CI , 1.32 - 2.11 ) , but not other biliary tract surgery ( CEE : HR , 1.18 ; 95 % CI , 0.68 - 2.04 ; E + P : HR , 1.49 ; 95 % CI , 0.78 - 2.84 ) . CONCLUSIONS These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy .  The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy Background : Colorectal cancer incidence was reduced among women assigned to active treatment in the Women 's Health Initiative ( WHI ) estrogen plus progestin-r and omized trial , but the interpretation was obscured by an associated later stage of diagnosis . In contrast , the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis . Here , data from the WHI observational study are considered , in conjunction with colorectal cancer mortality data from the hormone therapy trials , in an attempt to clarify postmenopausal hormone therapy effects . Participants and Methods : Postmenopausal women ages 50 to 79 years at WHI enrollment .  Estrogen-alone  analyses include 21,552 and 10,739 women who were posthysterectomy from the observational study and clinical trial , respectively .  Estrogen plus progestin analyses include 32,084 and 16,608 observational study and clinical trial women with uterus . Colorectal cancers were verified by central medical and pathology report review . Results : Hazard ratios ( 95 % confidence intervals ) from the WHI observational study were 0.80 ( 0.53 - 1.20 ) for estrogen and 1.15 ( 0.74 - 1.79 ) for estrogen plus progestin , with , respectively , 168 and 175 women diagnosed with colorectal cancer . Delayed diagnosis with estrogen plus progestin is not evident in the observational study . No protective effect on colorectal cancer mortality in the estrogen plus progestin trial is seen over an 8-year intervention and follow-up period . Conclusion : Hazard ratio patterns in the WHI clinical trial and observational study do not provide strong evidence of a clinical ly important colorectal cancer benefit with either estrogen-alone or estrogen plus progestin over 7 to 8 years of treatment and follow-up . ( Cancer Epidemiol Biomarkers Prev 2009;18(5):1531–7 OBJECTIVE This study was undertaken to assess whether estrogen therapy ( ET ) reduces the risk of cognitive decline in women with cerebrovascular disease . STUDY DESIGN We conducted a r and omized , double-blind trial of estradiol 17beta versus placebo for secondary stroke prevention in 664 postmenopausal women with a recent stroke or transient ischemic attack . The Mini-Mental State Examination ( MMSE ) and 5 domain measures were obtained at baseline and exit . RESULTS Among 461 women withdrawn alive without stroke , ET did not have a significant effect on cognitive measures after an average of 3 years ( relative risk of MMSE decline : 0.74 , 95 % CI , 0.49 - 1.13 ) . In women with normal MMSE at entry , estrogen was associated with less decline ( relative risk , 0.46 , 95 % CI , 0.24 - 0.87 ) . CONCLUSION In this study , estradiol did not have significant effects on cognitive measures . However , in women with normal function at baseline , there may be a benefit for ET in reducing the risk for cognitive decline Postmenopausal hormone therapy is widely used to prevent diseases . This is not , however , based on the kind of evidence that is normally required of a preventive drug therapy : it is based on intermediary outcomes of trials and non-experimental studies . Many reasons can be postulated for the fact that we know little of this old and widely used therapy . To remedy the current situation , we should encourage r and omised controlled trials , reveal the insufficiency of the current evidence , and challenge the drug industry 's biased influence 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 OBJECTIVE : To estimate the effects of estrogen plus progestin ( E+P ) therapy on  menopausal symptoms , vaginal bleeding , gynecologic surgery rates , and treatment-related adverse effects  in postmenopausal women . METHODS : R and omized , double-blind , placebo-controlled trial of 16,608 postmenopausal women , ages 50–79 ( mean ± st and ard deviation 63.3 ± 7.1 ) years , with intact uterus , r and omized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate ( n = 8,506 ) or placebo ( n = 8,102 ) , and followed for a mean of 5.6 years . Change in symptoms and treatment-related effects were analyzed at year 1 in all participants . Bleeding and gynecologic surgery rates were analyzed through study close-out . RESULTS : Baseline symptoms did not differ between the treatment groups . More women assigned to E+P than placebo reported relief of hot flushes ( 85.7 % versus 57.7 % , respectively ; odds ratio 4.40 ; 95 % confidence interval 3.40–5.71 ) , night sweats ( 77.6 % versus 57.4 % ; 2.58 ; 2.04–3.26 ) , vaginal or genital dryness ( 74.1 % versus 54.6 % ; 2.40 ; 1.90–3.02 ) , joint pain or stiffness ( 47.1 % versus 38.4 % ; 1.43 ; 1.24–1.64 ) , and general aches or pains ( 49.3 % versus 43.7 % ; 1.25 ; 1.08–1.44 ) . Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness ( 9.3 % versus 2.4 % , respectively ; 4.26 ; 3.59–5.04 ) , vaginal or genital discharge ( 4.1 % versus 1.0 % ; 4.47 ; 3.44–5.81 ) , vaginal or genital irritation ( 4.2 % versus 2.8 % ; 1.52 ; 1.27–1.81 ) , and headaches ( 5.8 % versus 4.7 % ; 1.26 ; 1.08–1.46 ) than women on placebo . Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms . Vaginal bleeding was reported by 51 % of women on E+P and 5 % of women on placebo at 6 months ; most bleeding was reported as spotting . Gynecologic surgeries ( hysterectomy and dilation and curettage ) were performed more frequently in women assigned to E+P ( 3.1 % versus 2.5 % for hysterectomy , hazard ratio = 1.23 , P = .026 ; 5.4 % versus 2.4 % for dilation and curettage , hazard ratio = 2.23 , P < .001 ) . CONCLUSION : Estrogen plus progestin relieved some menopausal symptoms , such as vasomotor symptoms and vaginal or genital dryness , but contributed to treatment-related effects , such as bleeding , breast tenderness , and an increased likelihood of gynecologic surgery . LEVEL OF EVIDENCE : BACKGROUND Postmenopausal hormone therapy has been associated with a 2- to 3-fold increased risk of  venous thromboembolism ( VT ) ( including deep vein thrombosis and pulmonary embolism ) in observational studies and secondary prevention clinical trials . Clinical trial data on the effects of estrogen alone on VT are limited . METHODS The Women 's Health Initiative estrogen trial enrolled 10 739 women aged 50 to 79 years without a uterus . Participants were r and omly assigned to receive conjugated equine estrogen ( 0.625 mg/d ) or placebo . RESULTS During a mean of 7.1 years , VT occurred in 111 women r and omly assigned to receive estrogen ( 3.0 per 1000 person-years ) and 86 r and omly assigned to receive placebo ( 2.2 per 1000 person-years ; hazard ratio , 1.32 ; 95 % confidence interval , 0.99 - 1.75 ) . Deep venous thrombosis was reported in 85 women r and omly assigned to receive estrogen ( 2.3 per 1000 person-years ) and 59 r and omly assigned to receive placebo ( 1.5 per 1000 person-years ; hazard ratio , 1.47 ; 95 % confidence interval , 1.06 - 2.06 ) . The VT risk was highest in the first 2 years . There were no significant interactions between estrogen use and age , body mass index , or most other VT risk factors . Comparison of Women 's Health Initiative VT findings for estrogen and previous Women 's Health Initiative findings for estrogen plus progestin showed that the hazard ratios for estrogen plus progestin were significantly higher than those for estrogen alone ( P = .03 ) , even after adjusting for VT risk factors . CONCLUSION An early increased VT risk is associated with use of estrogen , especially within the first 2 years , but this risk increase is less than that for estrogen plus progestin BACKGROUND In the Women 's Health Initiative ( WHI ) r and omized controlled trial , use of estrogen plus progestin increased  lung cancer mortality . We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer . METHODS The WHI study is a r and omized , double-blind , placebo-controlled trial conducted in 40 centers in the United States . A total of 10 739 postmenopausal women aged 50 - 79 years who had a previous hysterectomy were r and omly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen ( n = 5310 ) or matching placebo ( n = 5429 ) . Incidence and mortality rates for all lung cancers , small cell lung cancers , and non-small cell lung cancers in the two r and omization groups were compared by use of hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) that were estimated from Cox proportional hazards regression analyses . Analyses were by intention to treat , and all statistical tests were two-sided . RESULTS After a mean of 7.9 years ( st and ard deviation = 1.8 years ) of follow-up , 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group ( incidence of lung cancer per year = 0.15 % vs 0.13 % , respectively ; HR of incidence = 1.17 , 95 % CI = 0.81 to 1.69 , P = .39 ) . Non-small cell lung cancers were of comparable number , stage , and grade in both groups . Deaths from lung cancer did not differ between the two groups ( 34 vs 33 deaths in estrogen and placebo groups , respectively ; HR of death = 1.07 , 95 % CI = 0.66 to 1.72 , P = .79 ) . CONCLUSION Unlike use of estrogen plus progestin , which increased deaths from lung cancer , use of conjugated equine estrogen alone did not increase incidence or death from lung cancer Despite several observational studies , 1–3 no clinical trial has evaluated the effect of hormone therapy on percutaneous transluminal coronary angioplasty ( PTCA ) outcomes in matched population s r and omized to hormones or placebo . We compared the incidence of  coronary heart disease ( CHD ) events after PTCA among women who previously had been r and omly assigned to hormone therapy and placebo in the Heart and Estrogen/progestin Replacement Study ( HERS ) .  The design , methods , and primary results of HERS have been previously published . 4,5 Briefl y , HERS participants were postmenopausal women aged 80 years with established CHD who had not had a hysterectomy . Inclusion criteria were prior myocardial infa rct ion , coronary artery bypass graft surgery ( CABG ) , PTCA , or angiographic evidence of a 50 % diameter narrowing of 1 major coronary artery . Exclusion criteria were a recent CHD event , New York Heart Association class IV or severe class III congestive heart failure , serum triglyceride levels 300 mg/ dl , recent use of any hormone therapy , uncontrolled hypertension or diabetes , a disease ( other than CHD ) judged likely to be fatal within 4 years , or prior intolerance to hormone therapy . At the initiation of the HERS , participants were r and omly assigned to receive a single identical tablet containing either conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg or placebo . During the HERS , 357 patients underwent PCTA and constituted the study population . These patients were followed subsequently to ascertain their rate for subsequent CHD events . Demographic characteristics , health history , CHD risk factors , medication use , educational level , and quality of life were assessed at baseline . Baseline levels of fasting total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , and lipoprotein ( a ) were determined by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital ( Baltimore , Maryl and ) . Follow-up time for this analysis began at the time of the initial PTCA and concluded at the closeout of the HERS . All suspected outcome events were classifi ed independently by 2 physician review ers who were unaware of treatment assignment . Discordant classifi cations were resolved in discussion s between the review ers Objective : To investigate factors associated with the presence , severity , and frequency of hot flushes . Design : A 9-year prospect i ve study of 438 Australian-born women , aged 45 to 55 years and menstruating at baseline .  Annual fasting blood collection , physical measurements , and interviews including questions about bothersome hot flushes in previous 2 weeks were performed . A “ hot flush index ” score was calculated from the product of the severity and frequency data . Data were analyzed using r and om-effects time-series regression models . Results : A total of 381 women supplied complete data over the follow-up years . A total of 350 women experienced the menopause transition , of whom 60 ( 17 % ) never reported bothersome hot flushes . At baseline , women who reported hot flushes were significantly more likely to have higher negative moods , not be in full- or part-time paid work , smoke , and not report exercising every day . Over the 9-year period of the study , variables significantly associated with reporting bothersome hot flushes were relatively young age ( P < 0.001 ) , low exercise levels ( P < 0.05 ) , low estradiol levels ( P < 0.001 ) , high follicle-stimulating hormone ( FSH ) levels ( P < 0.001 ) , smoking ( P < 0.01 ) , being in the late menopause transition ( P < 0.001 ) , or being postmenopausal ( P < 0.001 ) . In women reporting hot flushes , the hot flush index score increased as their FSH levels increased ( P < 0.01 ) , as they entered the late stage of the menopause transition ( P < 0.001 ) , and as they became postmenopausal ( P < 0.05 ) , and decreased with as their age ( P < 0.001 ) and exercise level ( P < 0.05 ) increased . Between-women analyses found that the hot flush index score was greater in women with higher average FSH levels over time ( P < 0.05 ) . Conclusion : Menopause status , FSH and estradiol levels , age , exercise level , and smoking status all contributed to the experience of bothersome hot flushes OBJECTIVE To assess the efficacy of unopposed estrogen , and three estrogen/progestin regimens on selected heart disease risk factors among adherent women and to contrast those results with efficacy among all women in the PEPI study . DESIGN A 3-year , multicenter , r and omized , double-blinded , placebo-controlled clinical trial . PARTICIPANTS A total of 847 healthy postmenopausal women aged 45 to 64 years of age with no known contraindication to hormone therapy , who attended their 36 month clinical visit . INTERVENTION Participants were r and omized in equal numbers to one of the following treatments : ( 1 ) placebo ; ( 2 ) conjugated equine estrogen ( CEE ) 0.625 mg daily ; ( 3 ) CEE 0.625 daily plus medroxyprogesterone acetate ( MPA ) 10 mg , days 1 - 12 ; ( 4 ) CEE 0.625 daily plus MPA 2.5 mg daily ; or ( 5 ) CEE 0.625 daily plus micronized progesterone ( MP ) 200 mg , days 1 - 12 . ANALYSIS Analyses are based on adherent women , where adherence is defined as taking at least 80 % of pills at each 6-month visit . RESULTS Adherence rates were high in all groups except women with a uterus assigned to unopposed CEE . The difference in HDL-C levels result ing from the CEE vs. CEE+MP was approximately three times larger than in the intent-to-treat analyses , reaching statistical significance ( P < 0.05 ) . In each active treatment , LDL-C decreased 10 - 15 % . Triglycerides increased 15 - 20 % in each opposed CEE arm and over 25 % in the CEE only arm ; this difference was not statistically significant . Fibrinogen increased by 7 % among placebo adherers , but decreased or remained fairly stable among the active arm adherers . Systolic blood pressure increased 3 - 5 % in all treatment arms . Women adherent to the CEE+MPA arms had twice the increase of 2 h glucose levels as women adherent to CEE only , or CEE+MP ( 8 - 9 % vs. 3 - 4 % ) . Two-hour insulin levels decreased 3 - 12 % for all arms . The patterns of change for fibrinogen , SBP , 2 h glucose and insulin were similar to those from the intent-to-treat analyses . CONCLUSIONS In analyses limited to adherent women , all active treatments , compared to placebo , continued to have similar and favorable effects on LDL-cholesterol and fibrinogen and no significant effects on blood pressure or insulin levels . Given the overall high adherence rates in PEPI , the results are similar to the intent-to-treat analyses , as expected . Only the trend of HDL-C to have a larger increase in the CEE only arm ( in the intent-to-treat analyses ) gained statistical significance in analyses restricted to adherers BACKGROUND AND PURPOSE Observational studies have found that women who take estrogen after menopause are less likely to have a stroke than women who do not take estrogen .  Although these findings indicate that estrogen may prevent stroke , an alternative explanation for the improved outcome of  estrogen users is that they are healthier before starting therapy than nonusers . To test the therapeutic effect of estrogen with research methods that avoid this selection bias , we design ed a r and omized controlled trial . TRIAL DESIGN The  Women 's Estrogen For Stroke  Trial ( WEST ) is a double-blind , r and omized trial with a primary goal of determining whether 1 mg 17beta-estradiol daily , when compared with placebo , reduces the risk of recurrent stroke or death among postmenopausal women who have experienced a transient ischemic attack or nondisabling ischemic stroke . Exclusion criteria include use of estrogen at the time of stroke , breast or uterine cancer , inability to speak English , and estimated survival less than 5 years . Once r and omized , women remain under the care of their personal physicians for management of stroke risk factors . For early detection of endometrial hyperplasia and cancer , asymptomatic women receive medroxyprogesterone yearly ( 5 mg for 12 days ) and vaginal ultrasonography or biopsy at the end of the trial . Unscheduled uterine bleeding is evaluated with biopsy . A total of 652 women are sought at 20 hospitals in Connecticut and one in Massachusetts . CONCLUSIONS The WEST promises to provide critical guidance to women and their physicians regarding the effectiveness of estrogen in secondary stroke prevention CONTEXT Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function , but data from r and omized clinical trials have been sparse and inconclusive . The Women 's Health Initiative Memory Study ( WHIMS ) is an ancillary study of the Women 's Health Initiative ( WHI ) hormone therapy trials . On July 8 , 2002 , the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women . OBJECTIVE To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled clinical trial , WHIMS is an ancillary study of geographically diverse , community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995 . Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline , 4532 ( 92.6 % ) were enrolled in the estrogen plus progestin component of WHIMS . A total of 4381 participants ( 96.7 % ) provided at least 1 valid cognitive function score between June 1995 and July 8 , 2002 . INTERVENTIONS Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate ( n = 2145 ) or matching placebo ( n = 2236 ) . MAIN OUTCOME MEASURE Global cognitive function measured annually with the Modified Mini-Mental State Examination . RESULTS The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time ( mean follow-up of 4.2 years ) . Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo ( P = .03 ) , but these differences were not clinical ly important . Removing women by censoring them after adjudicated dementia , mild cognitive impairment , or stroke , and nonadherence to study protocol , did not alter the findings . Prior hormone therapy use and duration of prior use did not affect the interpretation of the results , nor did timing of prior hormone therapy initiation with respect to the final menstrual period . More women in the estrogen plus progestin group had a substantial and clinical ly important decline ( > or = 2 SDs ) in Modified Mini-Mental State Examination total score ( 6.7 % ) compared with the placebo group ( 4.8 % ) ( P = .008 ) . CONCLUSIONS Among postmenopausal women aged 65 years or older , estrogen plus progestin did not improve cognitive function when compared with placebo . While most women receiving estrogen plus progestin did not experience clinical ly relevant adverse effects on cognition compared with placebo , a small increased risk of clinical ly meaningful cognitive decline occurred in the estrogen plus progestin group PURPOSE To determine if hormone therapy results in better cognitive function in older postmenopausal women . SUBJECTS AND METHODS The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized , placebo-controlled trial involving 2763 women with coronary disease . Women were assigned r and omly to conjugated estrogen ( 0.625 mg ) plus medroxyprogesterone acetate ( 2.5 mg ) in one tablet daily or identical placebo ; they were followed for a mean ( + /- SD ) of 4.2 + /- 0.4 years . Participants at 10 of the 20 HERS centers were invited to enroll in the cognitive function sub study . At the end of the trial , we measured cognitive function in 517 women in the hormone group and 546 in the placebo group using six st and ard tests : the modified Mini-Mental Status Examination , Verbal Fluency , Boston Naming , Word List Memory , Word List Recall , and Trails B. Cognitive function was not measured at baseline . RESULTS The mean age of participants at the time of cognitive function testing was 71 + /- 6 years . There were no differences in age-adjusted cognitive function test scores between the two treatment groups , except that women assigned to hormones scored worse on the Verbal Fluency test than women assigned to placebo ( 15.9 + /- 4.8 vs. 16.6 + /- 4.8 , P = 0.02 ) . Adjustment for other potential confounders and restriction of the analyses to women who had been adherent to study medication did not change the results . CONCLUSION Among older postmenopausal women with coronary disease , 4 years of treatment with postmenopausal hormone therapy did not result in better cognitive function as measured on six st and ardized tests . Whether these results also apply to elderly women without coronary disease can not be determined from this study OBJECTIVES To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin ( E+P ) in the Women 's Health Initiative ( WHI ) r and omized trial . METHODS Subgroup analyses of prior hormone use on  invasive breast cancer incidence in 16,608 postmenopausal women in the WHI r and omized trial of E+P over an average 5.6 years of follow-up . RESULTS Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar . Duration of E+P use within the trial ( mean 4.4 years , S.D. 2.0 ) did not vary by prior use . Among 4311 prior users , the adjusted hazard ratio ( HR ) for E+P versus placebo was 1.96 ( 95 % confidence interval [ CI ] : 1.17 - 3.27 ) , significantly different ( p=0.03 ) from that among 12,297 never users ( HR 1.02 ; 95 % CI : 0.77 - 1.36 ) . The interaction between study arm and follow-up time was significant overall ( p=0.01 ) and among never users ( p=0.02 ) but not among prior users ( p=0.10 ) . The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users , and after about 5 years in women with no prior use . No interaction was found with duration ( p=0.08 ) or recency of prior use ( p=0.17 ) . Prior hormone use significantly increased the E+P hazard ratio for larger , more advanced tumors . CONCLUSION A safe interval for combined hormone use could not be reliably defined with these data . However , the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up , initially concentrated in women with prior hormone exposure , but with increasing risk over time in women without prior exposure , suggests that duration s only slightly longer than those in the WHI trial are associated with increased risk of breast cancer . Longer-term exposure and follow-up data are needed
target: 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: 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 .