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A prospective randomized placebo controlled study Prevention of bone loss following oophorectomy in premenopausal women: a retrospective assessment of the effects of oophorectomy and a prospective controlled trial of the effects of mestranol therapy. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. The effect of hormone replacement on physical performance in community-dwelling elderly women. Colorectal Cancer in Relation to Postmenopausal Estrogen and Estrogen Plus Progestin in the Women's Health Initiative Clinical Trial and Observational Study Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative Randomized Clinical Trial. 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The ERA trial: findings and implications for the future Effect of Estrone Sulfate on Postmenopausal Bone Loss 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. 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. Reproductive hormone exposure timing and ischemic heart disease: Complicated answers to a simple question. Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease. EFFECTS OF NATURAL ESTROGEN/GESTAGEN AND THIAZIDE ON CORONARY RISK FACTORS IN NORMAL POSTMENOPAUSAL WOMEN A prospective, randomized, placebo-controlled study of the dose effect of oral oestradiol on menopausal symptoms, psychological well being, and quality of life in postmenopausal Chinese women. Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes Estrogen plus progestin and colorectal cancer in postmenopausal women. The Effect of Ultralow-Dose Transdermal Estradiol on Urinary Incontinence in Postmenopausal Women The effect of 3-year treatment with 0.25 mg/day of micronized 17beta-estradiol on cognitive function in older postmenopausal women. Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study Neither long-term treatment with raloxifene nor hormone replacement therapy modulate cardiac function in healthy postmenopausal women: two randomized, placebo-controlled, 2-year studies. Estrogen plus progestin and colorectal cancer incidence and mortality. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study The rationale, design, and baseline characteristics of the Women's Health Initiative Memory Study of Younger Women (WHIMS-Y) Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. Treatment of postmenopausal osteoporosis with transdermal estrogen. Dose effects of oral estradiol on bone mineral density in Japanese women with osteoporosis Estrogen replacement therapy for ovarian carcinoma survivors Effect of postmenopausal hormone therapy on coronary heart disease events after percutaneous transluminal coronary angioplasty. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. Hot flushes during the menopause transition: a longitudinal study in Australian-born women Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Effect of 10 years' hormone replacement therapy on bone mineral content in postmenopausal women. Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: A two-year study Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. Estrogen after ischemic stroke: clinical basis and design of the Women's Estrogen for Stroke Trial. The effects of oophorectomy and long-term mestranol therapy on the serum lipids of middle-aged women. Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women's health initiative randomized controlled trials. LONG-TERM PREVENTION OF POSTMENOPAUSAL OSTEOPOROSIS BY ŒSTROGEN: EVIDENCE FOR AN INCREASED BONE MASS AFTER DELAYED ONSET OF ŒSTROGEN TREATMENT Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? Effect of hormone replacement therapy on self-reported cognitive symptoms: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial Unopposed Estradiol Therapy in Postmenopausal Women: Results From Two Randomized Trials Effects of long-term transdermal administration of estradiol on serum lipids. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Combined versus Sequential Hormonal Replacement Therapy: A Double-Blind, Placebo-Controlled Study on Quality of Life-Related Outcome Measures Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study Effects of hormone therapy on brain structure Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. Conjugated equine estrogen and risk of benign proliferative breast disease: a randomized controlled trial. Estrogen and colorectal cancer incidence and mortality Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Effects of different hormone therapies on breast pain in recently postmenopausal women: findings from the Mayo Clinic KEEPS breast pain ancillary study. Adjuvant Hormone Therapy May Improve Survival in Epithelial Ovarian Cancer: Results of the AHT Randomized Trial.
abstract: Currently raloxifene , a selective estrogen receptor modulator , is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease . We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens ( CEEs ) . Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54 . 8+/-3.5 ( mean+/-SD ) years who entered this double-blind study and who were r and omly assigned to raloxifene hydrochloride 60 mg/d ( n=15 ) or 150 mg/d ( n=13 ) , placebo ( n=13 ) , or CEEs 0.625 mg/d ( n=15 ) . At baseline and after 6 , 12 , and 24 months of treatment , we assessed serum lipids , blood pressure , glucose metabolism , C-reactive protein , and various hemostatic parameters . Compared with placebo , both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L ( all P<0.04 ) and lowered , at 24 months , the level of fibrinogen by 0.71 to 0.86 g/L ( all P<0.05 ) . The effects of raloxifene and CEEs did not differ significantly . In contrast to raloxifene , from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL ( all P<0.02 versus both placebo and raloxifene ) . CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months ( P<0.05 versus placebo ) and prothrombin-derived fragment F1 + 2 by 0 . 79 nmol/L at 12 months ( P<0.001 versus placebo ) . Finally , from 12 months on , CEEs increased triglycerides by 0.33 to 0.56 mmol/L ( all P<0.05 versus both placebo and raloxifene ) . Our findings suggest that in healthy postmenopausal women , raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels . These treatments differ , however , in their effects on high density lipoprotein cholesterol , triglycerides , and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1 + 2 and C-reactive protein CONTEXT The effects of continuous combined hormone therapy on gynecologic cancers have not been investigated previously in a r and omized trial setting . OBJECTIVE To determine the possible associations of estrogen plus progestin on gynecologic cancers and related diagnostic procedures . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial of 16 608 postmenopausal women , who had not had a hysterectomy at baseline and who had been recruited from 40 US clinical centers between September 1993 and October 1998 ( average follow-up , 5.6 years ) . INTERVENTION One tablet per day containing 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate ( n = 8506 ) or placebo ( n = 8102 ) . MAIN OUTCOME MEASURE Incident invasive cancer of the ovary and endometrium . RESULTS In 5.6 years of follow-up , there were 32 cases of invasive ovarian cancer , 58 cases of endometrial cancer , 1 case of nonendometrial uterine cancer , 13 cases of cervical cancer , and 7 cases of other gynecologic cancers . The hazard ratio ( HR ) for invasive ovarian cancer in women assigned to estrogen plus progestin compared with placebo was 1.58 ( 95 % confidence interval [ CI ] , 0.77 - 3.24 ) . The HR for endometrial cancer was 0.81 ( 95 % CI , 0.48 - 1.36 ) . No appreciable differences were found in the distributions of tumor histology , stage , or grade for either cancer site . The incidence of other gynecologic cancers was low and did not differ by r and omization assignment . More women taking estrogen plus progestin required endometrial biopsies ( 33 % vs 6 % ; P<.001 ) . CONCLUSIONS This r and omized trial suggests that continuous combined estrogen plus progestin therapy may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo . The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen . These data provide additional support for caution in the use of continuous combined hormones 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 Background Menopausal hormone therapy ( MHT ) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women , and whether MHT affects mood in younger women . The ancillary Cognitive and Affective Study ( KEEPS-Cog ) of the Kronos Early Estrogen Prevention Study ( KEEPS ) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women . Methods and Findings KEEPS , a r and omized , double-blinded , placebo-controlled clinical trial , was conducted at nine US academic centers . Of the 727 women enrolled in KEEPS , 693 ( 95.3 % ) participated in the ancillary KEEPS-Cog , with 220 women r and omized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens ( o-CEE ) plus 200 mg/d micronized progesterone ( m-P ) for the first 12 d of each month , 211 women r and omized to receive 50 μg/d transdermal estradiol ( t-E2 ) plus 200 mg/d m-P for the first 12 d of each month , and 262 women r and omized to receive placebo pills and patches . Primary outcomes included the Modified Mini-Mental State examination ; four cognitive factors : verbal learning/memory , auditory attention/working memory , visual attention/executive function , and speeded language /mental flexibility ; and a mood measure , the Profile of Mood States ( POMS )  . MHT effects were analyzed using linear mixed-effects ( LME ) models , which make full use of all available data from each participant , including those with missing data . Data from those with and without full data were compared to assess for potential biases result ing from missing observations . For statistically significant results , we calculated effect sizes ( ESs ) to evaluate the magnitude of changes . On average , participants were 52.6 y old , and 1.4 y past their last menstrual period . By month 48 , 169 ( 24.4 % ) and 158 ( 22.8 % ) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment ( 3MS and cognitive factors ) and mood evaluations ( POMS ) , respectively . However , because LME models make full use all available data , including data from women with missing data , 95.5 % of participants were included in the final analysis ( n = 662 in cognitive analyses , and n = 661 in mood analyses ) . To be included in analyses , women must have provided baseline data , and data from at least one post-baseline visit . The mean length of follow-up was 2.85 y ( st and ard deviation [ SD ] = 0.49 ) for cognitive outcomes and 2.76 ( SD = 0.57 ) for mood outcomes . No treatment-related benefits were found on cognitive outcomes . For mood , model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment , compared to women on placebo . The model estimate for the depression subscale was −5.36 × 10−2 ( 95 % CI , −8.27 × 10−2 to −2.44 × 10−2 ; ES = 0.49 , p < 0.001 ) and for the anxiety subscale was −3.01 × 10−2 ( 95 % CI , −5.09 × 10−2 to −9.34 × 10−3 ; ES = 0.26 , p < 0.001 ) . Mood outcomes for women r and omized to t-E2 were similar to those for women on placebo . Importantly , the KEEPS-Cog results can not be extrapolated to treatment longer than 4 y. Conclusions The KEEPS-Cog findings suggest that for recently postmenopausal women , MHT did not alter cognition as hypothesized . However , beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE , but not with 4 y of t-E2 . The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles . Trial Registration Clinical Trials.gov NCT00154180 and OBJECTIVES To evaluate the effects of hormone replacement therapy ( HRT ) on lipids and lipoproteins in postmenopausal women with coronary artery disease . SETTING In this single-centre , controlled and r and omized study taking place in a tertiary referral clinic , patients were examined at baseline , and after 3 and 12 months . All analyses were performed examiner-blind . SUBJECTS Postmenopausal women ( n = 118 ) with angiographically verified coronary artery disease were recruited consecutively from patients referred for investigational procedures due to coronary artery disease . INTERVENTIONS The women were r and omized to HRT , i.e. transdermal application of continuous 17-beta oestradiol with cyclic medroxyprogesterone actetate tablets every 3rd month for 14 days , or to a control group . MAIN OUTCOMES Effects on lipids and lipoproteins . RESULTS After 3 months of unopposed oestradiol , triglycerides decreased significantly compared to the control group ( P = 0.006 ) . Sequential administration of medroxyprogesterone caused a decrease in HDL cholesterol ( P = 0.01 ) , concomitantly with a decrease in ApoA1 lipoproteins ( P = 0.007 ) . No other changes in lipids or lipoproteins were observed . After 12 months of therapy , no significant differences were observed between the two groups in lipid or lipoprotein levels . Concomitant statin treatment did not alter the main findings . CONCLUSIONS In postmenopausal women with established coronary artery disease in whom the majority is treated with statins , no additional effect of HRT on lipids or lipoproteins could be observed except for a transient decrease in triglycerides in the initial unopposed oestradiol phase . No deleterious effect could be observed during medroxyprogesterone administration except for a small transient decrease in HDL cholesterol and ApoA1 lipoproteins Abstract —Postmenopausal hormone replacement therapy ( HRT ) is associated with low cardiovascular morbidity and mortality in epidemiological studies . Yet , no r and omized trial has examined whether HRT is effective for prevention of coronary heart disease ( CHD ) in women with increased risk . The objective of this study was to determine whether HRT can slow progression of atherosclerosis , measured as intima-media thickness ( IMT ) in carotid arteries . Carotid IMT is an appropriate intermediate end point to investigate clinical ly relevant effects on atherogenesis . This r and omized , controlled , observer-blind , clinical , single-center trial enrolled 321 healthy postmenopausal women with increased IMT in ≥1 segment of the carotid arteries . For a period of 48 weeks , subjects received either 1 mg/d 17&bgr;-estradiol continuously plus 0.025 mg gestodene for 12 days every month ( st and ard-progestin group ) , or 1 mg 17&bgr;-estradiol plus 0.025 mg gestodene for 12 days every third month ( low-progestin group ) , or no HRT . Maximum IMT in 6 carotid artery segments ( common , bifurcation , and internal , both sides ) was measured by B-mode ultrasound before and after intervention . HRT  did not slow IMT progression in carotid arteries . Mean maximum IMT in the carotid arteries increased by 0.02±0.05 mm in the no HRT group and by 0.03±0.05 and 0.03±0.05 mm , respectively , in the HRT groups ( P > 0.2 ) . HRT  significantly decreased LDL cholesterol , fibrinogen , and follicle-stimulating hormone . In conclusion , 1 year of HRT was not effective in slowing progression of sub clinical atherosclerosis in postmenopausal women at increased risk In a recent r and omized , double-blind , placebo-controlled trial of women with a history of venous thromboembolism ( VTE ) , we found that hormone replacement therapy ( HRT ) was associated with an early excess risk of recurrent thrombosis . The aims of the present study were to characterize the effects of HRT on coagulation in these women to eluci date the mechanism(s ) by which HRT increases the risk of thrombosis . The study comprised 140 women who were r and omized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate  ( n = 71 ) or placebo ( n = 69 ) . HRT caused significant increases in prothrombin fragments 1 + 2 , thrombin-antithrombin complex , and D-Dimer after 3 months , but these changes were less pronounced on prolonged treatment . The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis , but was similar in carriers and non-carriers of the factor V Leiden mutation . HRT had no effects on fibrinogen and factor VIII . Activated factor VII , but not factor VII antigen , decreased significantly on HRT as compared with placebo . The coagulation inhibitors antithrombin , protein C , and TFPI , but not protein S , all showed significant sustained decreases in the HRT group as compared with placebo . Antithrombin and protein C decreased by 8 - 12 % on HRT , whereas TFPI activity decreased by 12 - 17 % and TFPI free antigen by 29 - 30 % . In multivariate analysis , only TFPI activity was a significant predictor for the increased activation of coagulation . We conclude that HRT was associated with early activation of coagulation , which corroborates the finding of an early risk of recurrent VTE . This activation may in part be explained by reduction in circulating anticoagulants 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 Objective To assess the effect of  combined hormone replacement therapy ( HRT )  on health related quality of life . Design R and omised placebo controlled double blind trial . Setting General practice s in United Kingdom ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 at r and omisation ; 3721 women with a uterus were r and omised to combined oestrogen and progestogen  ( n=1862 ) or placebo  ( n=1859 ) . Data on health related quality of life at one year were available from 1043 and 1087 women , respectively . Interventions Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year . Main outcome measures Health related quality of life and psychological wellbeing as measured by the women ’s health question naire . Changes in emotional and physical menopausal symptoms as measured by a symptoms question naire and depression by the Centre for Epidemiological Studies depression scale ( CES-D ) . Overall health related quality of life and overall quality of life as measured by the European quality of life instrument ( EuroQol ) and visual analogue scale , respectively . Results After one year small but significant improvements were observed in three of nine components of the women ’s health question naire for those taking combined HRT compared with those taking placebo :  vasomotor symptoms ( P<0.001 ) , sexual functioning ( P<0.001 ) , and sleep problems ( P<0.001 ) . Significantly fewer women in the combined HRT group reported hot flushes ( P<0.001 ) , night sweats ( P<0.001 ) , aching joints and muscles ( P=0.001 ) , insomnia ( P<0.001 ) , and vaginal dryness ( P<0.001 ) than in the placebo group , but greater proportions reported breast tenderness ( P<0.001 ) or vaginal discharge ( P<0.001 ) . Hot flushes were experienced in the combined HRT and placebo groups by 30 % and 29 % at trial entry and 9 % and 25 % at one year , respectively . No significant differences in other menopausal symptoms , depression , or overall quality of life were observed at one year . Conclusions Combined HRT started many years after the menopause can improve health related quality of life . Trial registration IS RCT N 63718836 Abstract Objective Endothelial dysfunction occurs early in the atherosclerotic disease process , often preceding clinical symptoms . Use of menopausal hormone treatment ( MHT ) to reduce cardiovascular risk is controversial . This study evaluated effects of 4 years of MHT on endothelial function in healthy , recently menopausal women .  Methods Endothelial function was determined by pulse volume digital tonometry providing a reactive hyperemia index ( RHI ) in a subset of women enrolled in the Kronos Early Estrogen Prevention Study .  RHI was measured before and annually after r and omization to daily oral conjugated equine estrogen ( oCEE , 0.45 mg ) , weekly transdermal 17β-estradiol ( tE2 , 50 μg ) each with intermittent progesterone ( 200 mg daily 12 days of the month ) or placebo pills and patch . Results At baseline , RHI averaged 2.39 ± 0.69 ( mean ± st and ard deviation ; n = 83 ) , and over follow-up did not differ significantly among groups : oCEE , 2.26 ± 0.48 ( n = 26 ) ; tE2 , 2.26 ± 0.45 ( n = 24 ) ; and placebo , 2.37 ± 0.37 ( n = 33 ) . Changes in RHI did not correlate with changes in traditional cardiovascular risk factors , but may inversely correlate with carotid intima medial thickness ( Spearman correlation coefficient ρ = −0.268 , p = 0.012 ) . Conclusion In this 4-year prospect i ve assessment of recently menopausal women  , MHT did not significantly alter RHI when compared to placebo 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 Objective To assess the effectiveness of enhanced communication therapy in the first four months after stroke compared with an attention control ( unstructured social contact ) . Design Externally r and omised , pragmatic , parallel , superiority trial with blinded outcome assessment . Setting Twelve UK hospital and community stroke services . Participants 170 adults ( mean age 70 years ) r and omised within two weeks of admission to hospital with stroke ( December 2006 to January 2010 ) whom speech and language therapists deemed eligible , and 135 carers . Interventions Enhanced , agreed best practice , communication therapy specific to aphasia or dysarthria , offered by speech and language therapists according to participants ’ needs for up to four months , with continuity from hospital to community . Comparison was with similarly re source d social contact ( without communication therapy ) from employed visitors . Outcome measures Primary outcome was blinded , functional communicative ability at six months on the Therapy Outcome Measure ( TOM ) activity subscale . Secondary outcomes ( unblinded , six months ) : participants ’ perceptions on the Communication Outcomes After Stroke scale ( COAST ) ; carers ’ perceptions of participants from part of the Carer COAST ; carers ’ wellbeing on Carers of Older People in Europe Index and quality of life items from Carer COAST ; and serious adverse events . Results Therapist and visitor contact both had good uptake from service users . An average 22 contacts ( intervention or control ) over 13 weeks were accepted by users . Impairment focused therapy was the approach most often used by the speech and language therapists . Visitors most often provided general conversation . In total , 81/85 of the intervention group and 72/85 of the control group completed the primary outcome measure . Both groups improved on the TOM activity subscale . The estimated six months group difference was not statistically significant , with 0.25 ( 95 % CI –0.19 to 0.69 ) points in favour of therapy . Sensitivity analyses that adjusted for chance baseline imbalance further reduced this difference . Per protocol analyses rejected a possible dilution of treatment effect from controls declining their allocation and receiving usual care . There was no added benefit of therapy on secondary outcome measures , subgroup analyses ( such as aphasia ) , or serious adverse events , although the latter were less common after intervention ( odds ratio 0.42 ( 95 % CI 0.16 to 1.1 ) ) . Conclusions Communication therapy had no added benefit beyond that from everyday communication in the first four months after stroke . Future research should evaluate reorganised services that support functional communication practice early in the stroke pathway . This project was funded by the NIHR Health Technology Assessment programme ( project No 02/11/04 ) and is published in full in Health Technology Assessment 2012;16(26):1 - 160 . Trial registration IS RCT In the 1990s , two r and omised clinical trials started in Sc and inavia addressing whether hormone replacement therapy ( HRT ) is safe for women with previous breast cancer . We report the findings of the safety analysis in HABITS ( hormonal replacement therapy after breast cancer -- is it safe ? ) , an open r and omised clinical trial with allocation to either HRT or best treatment without hormones . The main endpoint was any new breast cancer event . All analyses were done according to intention-to-treat . Until September , 2003 , 434 women were r and omised ; 345 had at least one follow-up report . After a median follow-up of 2.1 years , 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event . All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment . We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial , and the trial was terminated on Dec 17 , 2003 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 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 Recent observational studies suggest a 2 - 4 fold increased risk of venous thromboembolism ( VTE ) in women taking hormone replacement therapy ( HRT ) .  The present study was started before publication of these studies , and the aim was to determine if HRT alters the risk of VTE in high risk women . The study was a r and omized . double-blind , and placebo-controlled clinical trial with a double-triangular sequential design . Females with previously verified VTE were r and omized to 2 mg estradiol plus 1 mg norethisterone acetate , 1 tablet daily ( n = 71 ) or placebo ( n = 69 ) . The primary outcome was recurrent deep venous thrombosis ( DVT ) or pulmonary embolism ( PE ) .  Between 1996 and 1998 a total of 140 women were included . The study was terminated prematurely based on the results of circumstantial evidence emerging during the trial . Eight women in the HRT group and one woman in the placebo group developed VTE . The incidence of VTE was 10.7 % in the HRT group and 2.3 % in the placebo group . In the HRT group , all events happened within 261 days after inclusion . The sequential design did not stop the study , but strongly indicated a difference between the two groups . Our data strongly suggests that women who have previously suffered a VTE have an increased risk of recurrence on HRT . This treatment should therefore be avoided in this patient group if possible . The results also support those of recent epidemiological studies , which also indicate increased risk of VTE in non-selected female population s during HRT IMPORTANCE The use of menopausal hormone therapy ( HT ) continues in clinical practice , but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use . OBJECTIVE To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women 's Health Initiative ( WHI ) r and omized clinical trials . DESIGN , SETTING , AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010 . INTERVENTIONS A total of 16,608 women with a uterus were r and omized to conjugated equine estrogens ( 0.625 mg/d [ estrogen ] ) plus medroxyprogesterone acetate ( 2.5 mg/d [ progestin ] ) ( E + P ) or placebo with a median intervention duration of 5.6 years , and 10,739 women with prior hysterectomy were r and omized to conjugated equine estrogens alone ( 0.625 mg/d ) or placebo with a median intervention duration of 7.2 years . MAIN OUTCOMES AND MEASURES Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials . RESULTS In the E + P trial , hazard ratios ( HRs ) for the influence of  combined HT  on breast cancer were lower than 1 for 2 years ( HR , 0.71 ; 95 % CI , 0.47 - 1.08 ) and steadily increased throughout intervention , becoming significantly increased for the entire intervention phase ( HR , 1.24 ; 95 % CI , 1.01 - 1.53 ) . In the early postintervention phase ( within 2.75 years from intervention ) , there was a sharp decrease in breast cancer incidence in the combined HT group , though the HR remained higher than 1 ( HR , 1.23 ; 95 % CI , 0.90 - 1.70 ) . During the late postintervention phase ( requiring patient re-consent ) , the HR for breast cancer risk remained higher than 1 through 5.5 years ( median ) of additional follow-up ( HR , 1.37 ; 95 % CI , 1.06 - 1.77 ) . In the estrogen alone trial , the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase ( HR , 0.79 ; 95 % CI , 0.61 - 1.02 ) and remained lower than 1 in the early postintervention phase ( HR , 0.55 ; 95 % CI , 0.34 - 0.89 ) , but risk reduction was not observed during the late postintervention follow-up ( HR , 1.17 ; 95 % CI , 0.73 - 1.87 ) . Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials . CONCLUSIONS AND RELEVANCE In the E + P trial , the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase , but a higher breast cancer risk remained during the late postintervention follow-up . In the estrogen alone trial , the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up BACKGROUND Following the release of the 2002 report of the Women 's Health Initiative ( WHI ) trial of estrogen plus progestin , the use of menopausal hormone therapy in the United States decreased substantially . Subsequently , the incidence of breast cancer also dropped , suggesting a cause- and -effect relation between hormone treatment and breast cancer . However , the cause of this decrease remains controversial . METHODS We analyzed the results of the WHI r and omized clinical trial -- in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily and another group received placebo--  and examined temporal trends in breast-cancer diagnoses in the WHI observational- study cohort .  Risk factors for breast cancer , frequency of mammography , and time-specific incidence of breast cancer were assessed in relation to combined hormone use . RESULTS In the clinical trial , there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study , but the number of diagnoses increased over the course of the 5.6-year intervention period . The elevated risk decreased rapidly after both groups stopped taking the study pills , despite a similar frequency of mammography . In the observational study , the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group , but this difference in incidence decreased rapidly in about 2 years , coinciding with year-to-year reductions in combined hormone use . During this period , differences in the frequency of mammography between the two groups were unchanged . CONCLUSIONS The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography BACKGROUND While progestin addition to estrogen mitigates endometrial cancer risk , the magnitude of the effect on incidence , specific endometrial cancer histologies , and endometrial cancer mortality remains unsettled . These issues were assessed by analyses after extended follow-up of the Women 's Health Initiative ( WHI ) r and omized clinical trial evaluating continuous combined estrogen plus progestin use . METHODS The WHI enrolled 16 608 postmenopausal women into a r and omly assigned , double-blind , placebo-controlled trial . Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were r and omly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate ( n = 8506 ) as a single pill or matching placebo ( n = 8102 ) . Follow-up beyond the original trial completion date required reconsent , obtained from 12 788 ( 83 % ) of surviving participants . Analyses were by intent-to-treat . All statistical tests were two-sided . RESULTS After 5.6 years ' median intervention and 13 years ' median cumulative follow-up , there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group ( 66 vs 95 case patients , yearly incidence , 0.06 % vs 0.10 % ; hazard ratio [ HR ] = 0.65 , 95 % confidence interval [ CI ] = 0.48 to 0.89 , P = .007 ) . While there were somewhat fewer endometrial cancers during intervention ( 25 vs 30 , respectively ; HR = 0.77 , 95 % CI = 0.45 to 1.31 ) , the difference became statistically significant postintervention ( 41 vs 65 , respectively ; HR = 0.59 , 95 % CI = 0.40 to 0.88 , P = .008 ) , but hazard ratios did not differ between phases ( P difference = .46 ) . There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group ( 5 vs 11 deaths , HR = 0.42 , 95 % CI = 0.15 to 1.22 ) . CONCLUSION In postmenopausal women , continuous combined estrogen plus progestin decreases endometrial cancer incidence Background : In separate Women 's Health Initiative r and omized trials , combined hormone therapy with estrogen plus progestin reduced colorectal cancer incidence but estrogen alone in women with hysterectomy did not . We now analyze features of the colorectal cancers that developed and examine the survival of women following colorectal cancer diagnosis in the latter trial . Participants and Methods : 10,739 postmenopausal women who were 50 to 79 years of age and had undergone hysterectomy were r and omized to conjugated equine estrogens ( 0.625 mg/d ) or matching placebo .  Colorectal cancer incidence was a component of the monitoring global index of the study but was not a primary study endpoint . Colorectal cancers were verified by central medical record and pathology report review . Bowel exam frequency was not protocol defined , but information on their use was collected . Results : After a median 7.1 years , there were 58 invasive colorectal cancers in the hormone group and 53 in the placebo group [ hazard ratio , 1.12 ; 95 % confidence interval ( 95 % CI ) , 0.77 - 1.63 ] . Tumor size , stage , and grade were comparable in the two r and omization groups . Bowel exam frequency was also comparable in the two groups . The cumulative mortality following colorectal cancer diagnosis among women in the conjugated equine estrogen group was 34 % compared with 30 % in the placebo group ( hazard ratio , 1.34 ; 95 % CI , 0.58 - 3.19 ) . Conclusions : In contrast to the preponderance of observational studies , conjugated equine estrogens in a r and omized clinical trial did not reduce colorectal cancer incidence nor improve survival after diagnosis . ( Cancer Epidemiol Biomarkers Prev 2008;17(10):2609–18 Recent studies suggest that low‐dose oral contraceptives may cause acquired resistance to activated protein C ( APC ) . The aims of this study were to determine whether hormone replacement therapy ( HRT ) may also induce acquired APC resistance and to study the effects of APC resistance on the risk of recurrent thrombosis . The patients comprised 140 females with at least one previous venous thromboembolism ( VTE ) , who were r and omized to receive continuous treatment with 2 mg 17‐β‐oestradiol and 1 mg norethisterone acetate  ( n = 71 ) or placebo ( n = 69 ) . Normalized APC sensitivity ratios ( nAPCsr ) were calculated by measurement of the effect of APC on thrombin generation in plasma collected at baseline and after 3 months of treatment . Of the 140 women , 121 had plasma sample s collected both at baseline and after 3 months . The nAPCsr increased significantly ( P < 0·001 ) on HRT ( n = 62 ) , both in females not carrying the factor VLeiden mutation [ mean change 0·57 ( 95 % CI 0·45–0·70 ) , n = 50 ] and in females heterozygous for the factor VLeiden mutation [ mean change 1·10 ( 0·71–1·49 ) , n = 12 ] , but remained unchanged on placebo ( n = 59 ) . The baseline nAPCsr as well as the increase in nAPCsr associated with HRT use was not higher in the five women who subsequently developed recurrent VTE . Free protein S and free TFPI were both important parameters for the acquired APC resistant phenotype . We conclude that HRT diminishes the efficacy by which APC downregulates in‐vitro thrombin formation in a similar fashion to that observed with low‐dose oral contraceptives , but the increase in nAPCsr alone is not sufficient to explain the increased risk of VTE associated with use of HRT The Women 's Health Initiative ( WHI ) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women , including cancer , cardiovascular disease , and osteoporotic fractures . The WHI was initiated in 1992 , with a planned completion date of 2007 . Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial ( CT ) that will include about 64,500 women or an observational study ( OS ) that will include about 100,000 women . The CT is design ed to allow r and omized controlled evaluation of three distinct interventions : a low-fat eating pattern , hypothesized to prevent breast cancer and colorectal cancer and , secondarily , coronary heart disease ; hormone replacement therapy , hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and , secondarily , to reduce the risk of hip and other fractures , with increased breast cancer risk as a possible adverse outcome ; and calcium and vitamin D supplementation , hypothesized to prevent hip fractures and , secondarily , other fractures and colorectal cancer . Overall benefit-versus-risk assessment is a central focus in each of the three CT components . Women are screened for participation in one or both of the components -- dietary modification ( DM ) or hormone replacement therapy (HRT)--of the CT , which will r and omize 48,000 and 27,500 women , respectively . Women who prove to be ineligible for , or who are unwilling to enroll in , these CT components are invited to enroll in the OS . At their 1-year anniversary of r and omization , CT women are invited to be further r and omized into the calcium and vitamin D ( CaD ) trial component , which is projected to include 45,000 women . The average follow-up for women in either CT or OS is approximately 9 years . Concerted efforts are made to enroll women of racial and ethnic minority groups , with a target of 20 % of overall enrollment in both the CT and OS . This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component . Some detail is provided on specific study design choices , including eligibility criteria , recruitment strategy , and sample size , with attention to the partial factorial design of the CT . Some aspects of the CT monitoring approach are also outlined . The scientific and logistic complexity of the WHI implies particular leadership and management challenges . The WHI organization and committee structure employed to respond to these challenges is also briefly described 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 OBJECTIVE To evaluate the effect of a 17beta-estradiol(E2)/norgestimate ( NGM ) HRT regimen , which provides constant estrogen in combination with pulsed progestin administration , on endometrial histology in healthy postmenopausal women 40 to 65 years of age who had experienced natural menopause at least 12 months before the start of the study . METHODS A total of 1,253 postmenopausal women were r and omized to receive either continuous 1 mg E2 , or constant estrogen , pulsed progestin regimens of 1 mg E2/30 microg NGM , 1 mg E2/90 microg NGM , or 1 mg E2/180 microg NGM ( 3 days on , 3 days off ) in a 12-month , multicenter , double-blind study . Endometrial biopsies were obtained pre- and post-treatment , and were evaluated by at least 2 ( if required , by 3 ) pathologists who were blinded with respect to treatment and to each other 's diagnosis . RESULTS At the end of the study , no cases of endometrial hyperplasia were diagnosed in subjects who received E2 1 mg/NGM 90 microg or E21 mg/NGM 180 microg , whereas 74 ( 28 % ) and 16 ( 6 % ) cases of endometrial hyperplasia were diagnosed in subjects who received continuous E2 1 mg and E2 1 mg/NGM 30 microg , respectively . A dose-related endometrial response to  NGM  was apparent ( P < .001 ) . The percentage of patients with inactive/atrophic endometrium increased with NGM dose . CONCLUSION The results of this study support the safety and efficacy of this unique HRT regimen and suggest that the minimal NGM dose required to protect the endometrium from hyperplasia in a pulsed progestin regimen consisting of continuous E2 1 mg is 90 microg PURPOSE As the influence of estrogen alone on breast cancer detection is not established , we examined this issue in the Women 's Health Initiative trial , which r and omly assigned 10,739 postmenopausal women with prior hysterectomy to conjugated equine estrogen ( CEE ; 0.625 mg/d ) or placebo . METHODS Screening mammography and breast exams were performed at baseline and annually . Breast biopsies were based on clinical findings . Effects of CEE alone on breast cancer detection were determined by using receiver operating characteristic ( ROC ) analyses of mammogram performance . RESULTS After a 7.1-year mean follow-up , fewer invasive breast cancers were diagnosed in the CEE than in the placebo group , but the difference was not statistically significant . Use of CEE alone increased mammograms with short-interval follow-up recommendations ( cumulative , 39.2 % v 29.6.3 % ; P < .001 ) but not abnormal mammograms ( ie , those suggestive of or highly suggestive of malignancy ; cumulative , 7.3 % v 7.0 % ; P = .41 ) . Breast biopsies were more frequent in the CEE group ( cumulative , 12.5 % v 10.7 % ; P = .004 ) and less commonly diagnosed as cancer ( 8.9 % v 15.8 % , respectively , with positive biopsies ; P = .04 ) . Mammographic breast cancer detection in the CEE group was significantly compromised only in the early years of use . CONCLUSION CEE alone use for 5 years results in approximately one in 11 and one in 50 women having otherwise avoidable mammograms with short-interval follow-up recommendations or breast biopsies , respectively . Although the breast biopsies on CEE were less commonly diagnosed as cancer , breast cancer detection was not substantially compromised . These findings differ from estrogen-plus-progestin use , for which significantly increased abnormal mammograms and a compromise in breast cancer detection are seen BACKGROUND The effect of combined hormone therapy on breast cancer detection is not established . METHODS We examined the effect of combined hormone therapy on breast cancer detection in the Women 's Health Initiative trial , which r and omized 16,608 postmenopausal women to receive conjugated equine estrogens ( 0.625 mg/d ) plus medroxyprogesterone acetate ( 2.5 mg/d ) or placebo . Mammography and breast examinations were performed at baseline and annually per protocol , with breast biopsies based on clinical findings . The effects of conjugated equine estrogens plus medroxyprogesterone acetate on breast cancer detection was determined throughout 5.6 years of intervention using receiver operating characteristic analyses to evaluate mammography results . RESULTS Conjugated equine estrogens plus medroxyprogesterone acetate increased the cumulative frequency of mammograms with abnormalities vs placebo ( 35.0 % vs 23.0 % ; P < .001 ) , which had less sensitivity for cancer detection and increased cumulative breast biopsy frequency ( 10.0 % vs 6.1 % ; P < .001 ) . Although breast cancers were significantly increased and were diagnosed at higher stages in the combined hormone group , biopsies in that group less frequently diagnosed cancer ( 14.8 % vs 19.6 % ; P = .006 ) . After discontinuation of combined hormone therapy , its adverse effect on mammograms modulated but remained significantly different from that of placebo for at least 12 months ( P < .001 ) . CONCLUSIONS Use of conjugated equine estrogens plus medroxyprogesterone acetate for approximately 5 years result ed in more than 1 in 10 and 1 in 25 women having otherwise avoidable mammogram abnormalities and breast biopsies , respectively , and compromised the diagnostic performance of both . This adverse effect on breast cancer detection should be incorporated into risk-benefit discussion s with women considering even short-term combined hormone therapy . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 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 OBJECTIVE In older women , higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes . We examined whether the effect of postmenopausal hormone therapy ( HT ) on cognitive impairment incidence differs depending on type 2 diabetes . RESEARCH DESIGN AND METHODS The Women ’s Health Initiative ( WHI ) r and omized clinical trials assigned women to HT ( 0.625 mg/day conjugated equine estrogens with or without [ i.e. , unopposed ] 2.5 mg/day medroxyprogesterone acetate ) or matching placebo for an average of 4.7–5.9 years . A total of 7,233 women , aged 65–80 years , were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment ( mild cognitive impairment or dementia ) . RESULTS Through a maximum of 18 years of follow-up , women with diabetes had increased risk of probable dementia ( hazard ratio [ HR ] 1.54 [ 95 % CI 1.16–2.06 ] ) and cognitive impairment ( HR 1.83 [ 1.50–2.23 ] ) . The combination of diabetes and r and om assignment to HT increased their risk of dementia ( HR 2.12 [ 1.47–3.06 ] ) and cognitive impairment ( HR 2.20 [ 1.70–2.87 ] ) compared with women without these conditions , interaction P = 0.09 and P = 0.08 . These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens . CONCLUSIONS These analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women . The role estrogen plays in suppressing non – glucose-based energy sources in the brain may explain this interaction BACKGROUND Case-control studies have reported that exogenous estrogen use is associated with increased  risk of skin cancer .  The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma  were evaluated in post hoc analyses of the Women 's Health Initiative r and omized placebo-controlled hormone therapy trials of combined estrogen plus progestin ( E + P ) and estrogen only ( E-alone ) . METHODS Postmenopausal women aged 50 - 79 years were r and omly assigned to conjugated equine estrogen ( 0.625 mg/d ) plus medroxyprogesterone acetate ( 2.5 mg/d ) or placebo in the E + P trial if they had an intact uterus ( N = 16,608 ) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy ( N = 10,739 ) ; the mean follow-up was 5.6 and 7.1 years , respectively . Incident nonmelanoma skin cancers ( n = 980 [ E + P trial ] ; n = 820 [ E-alone trial ] ) and melanomas ( n = 57 [ E + P trial ] ; n = 38 [ E-alone trial ] ) were ascertained by self-report . Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records . Incidences of nonmelanoma skin cancer and melanoma were compared between the two r and omization groups within each trial using hazard ratios ( HRs ) , with corresponding 95 % confidence intervals ( CIs ) and Wald statistic P values from Cox proportional hazards models . All statistical tests were two-sided . RESULTS Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone ( combined analysis of E + P and E-alone ) and placebo groups ( nonmelanoma skin cancer : HR = 0.98 , 95 % CI = 0.89 to 1.07 ; melanoma : HR = 0.92 , 95 % CI = 0.61 to 1.37 ) . Results were similar for the E + P and E-alone trials when analyzed individually . CONCLUSIONS Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma . These findings do not support a role of menopausal estrogen , with or without progestin , in the development of skin cancer in postmenopausal women Evidence from animal , human cross-sectional , case-control , and prospect i ve studies indicate that hormone replacement therapy ( HRT ) is a promising treatment to delay the onset of symptoms of dementia . The Women 's Health Initiative Memory Study ( WHIMS ) is the first double-masked , r and omized , placebo-controlled , long-term clinical trial design ed to test the hypothesis that HRT reduces the incidence of all-cause dementia in women aged 65 and older . WHIMS , an ancillary study to the Women 's Health Initiative ( WHI ) funded by the National Institutes of Health , will recruit a subgroup of women aged 65 and older from among those enrolling in the HRT trial of the WHI . The WHI clinical centers and 10 affiliated satellites plan to enroll approximately 8300 women into WHIMS over a 2-year period . Participants will be followed annually for 6 years , receiving cognitive assessment s via the Modified Mini-Mental State ( 3MS ) Examination . Women who screen positively for cognitive impairment on the basis of an educational and age-adjusted 3MS cutpoint proceed to more extensive neuropsychological testing and neurologic evaluation . Each woman suspected to have dementia then undergoes a series of laboratory tests that confirm the clinical diagnosis and classify the type of dementia . WHIMS is design ed to provide more than 80 % statistical power to detect a 40 % reduction in the rate of all-cause dementia , an effect that could have profound public health implication s for older women 's health and functioning Introduction Paradoxically , a breast cancer risk reduction with conjugated equine estrogens ( CEE ) and a risk elevation with CEE plus medroxyprogesterone acetate ( CEE + MPA ) were observed in the Women ’s Health Initiative ( WHI ) r and omized controlled trials . The effects of hormone therapy on serum sex hormone levels , and on the association between baseline sex hormones and disease risk , may help explain these divergent breast cancer findings . Methods Serum sex hormone concentrations were measured for 348 breast cancer cases in the CEE + MPA trial and for 235 cases in the CEE trial along with corresponding pair-matched controls , nested within the WHI trials of healthy postmenopausal women . Association and mediation analyses , to examine the extent to which sex hormone levels and changes can explain the breast cancer findings , were conducted using logistic regression . Results Following CEE treatment , breast cancer risk was associated with higher concentrations of baseline serum estrogens , and with lower concentrations of sex hormone binding globulin . However , following CEE + MPA , there was no association of breast cancer risk with baseline sex hormone levels . The sex hormone changes from baseline to year 1 provided an explanation for much of the reduced breast cancer risk with CEE . Specifically , the treatment odds ratio ( 95 % confidence interval ) increased from 0.71 ( 0.43 , 1.15 ) to 0.92 ( 0.41 , 2.09 ) when the year 1 measures were included in the logistic regression analysis . In comparison , the CEE + MPA odds ratio was essentially unchanged when these year 1 measures were included . Conclusions Breast cancer risk remains low following CEE use among women having favorable baseline sex hormone profiles , but CEE + MPA evidently produces a breast cancer risk for all women similar to that for women having an unfavorable baseline sex hormone profile . These patterns could reflect breast ductal epithelial cell stimulation by CEE + MPA that is substantially avoided with CEE , in conjunction with relatively more favorable effects of either regimen following a sustained period of estrogen deprivation . These findings may have implication s for other hormone therapy formulations and routes of delivery . Trial registration clinical trials.gov identifier : NCT00000611 BACKGROUND Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events . In contrast , in a recent clinical trial of women with coronary disease , a subgroup analysis demonstrated increased risk during the early months of therapy . Because higher levels of inflammation factors predict vascular disease outcomes , the effect of hormones on these factors is of interest . METHODS AND RESULTS Four inflammation-sensitive factors , C-reactive protein , soluble E-selectin , von Willebr and factor antigen , and coagulation factor VIIIc were measured at baseline , 12 , and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions ( PEPI ) Trial , a r and omized , placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors . Compared with placebo , all 4 active preparations result ed in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin ( P=0.0001 ) . There were no effects of treatment on concentrations of von Willebr and factor or factor VIIIc . There were no differences in effects among treatment arms . Relative to placebo , when combining active treatment arms , final concentrations of C-reactive protein were 85 % higher whereas E-selectin was 18 % lower compared with baseline . CONCLUSIONS Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein . Such an effect may be related to adverse early effects of estrogen therapy . In contrast , hormones reduced the concentration of soluble E-selectin , and this might be considered an anti-inflammatory effect . Because PEPI was not design ed to assess clinical endpoints , studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed CONTEXT In the Women 's Health Initiative r and omized , placebo-controlled trial of estrogen plus progestin , after a mean intervention time of 5.6 ( SD , 1.3 ) years ( range , 3.7 - 8.6 years ) and a mean follow-up of 7.9 ( SD , 1.4 ) years , breast cancer incidence was increased among women who received combined hormone therapy . Breast cancer mortality among participants in the trial has not been previously reported . OBJECTIVE To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 ( SD , 2.7 ) years , through August 14 , 2009 . DESIGN , SETTING , AND PARTICIPANTS A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were r and omly assigned to receive combined conjugated equine estrogens , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , or placebo pill . After the original trial completion date ( March 31 , 2005 ) , reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 ( 83 % ) of the surviving participants . MAIN OUTCOME MEASURES Invasive breast cancer incidence and breast cancer mortality . RESULTS In intention-to-treat analyses including all r and omized participants and censoring those not consenting to additional follow-up on March 31 , 2005 , estrogen plus progestin was associated with more invasive breast cancers compared with placebo ( 385 cases [ 0.42 % per year ] vs 293 cases [ 0.34 % per year ] ; hazard ratio [ HR ] , 1.25 ; 95 % confidence interval [ CI ] , 1.07 - 1.46 ; P = .004 ) . Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive ( 81 [ 23.7 % ] vs 43 [ 16.2 % ] , respectively ; HR , 1.78 ; 95 % CI , 1.23 - 2.58 ; P = .03 ) . There were more deaths directly attributed to breast cancer ( 25 deaths [ 0.03 % per year ] vs 12 deaths [ 0.01 % per year ] ; HR , 1.96 ; 95 % CI , 1.00 - 4.04 ; P = .049 ) as well as more deaths from all causes occurring after a breast cancer diagnosis ( 51 deaths [ 0.05 % per year ] vs 31 deaths [ 0.03 % per year ] ; HR , 1.57 ; 95 % CI , 1.01 - 2.48 ; P = .045 ) among women who received estrogen plus progestin compared with women in the placebo group . CONCLUSIONS Estrogen plus progestin was associated with greater breast cancer incidence , and the cancers are more commonly node-positive . Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 Objective To study whether oestrongen replacement therapy has an effect on autonomic haemodynamic control in postmenopausal women PURPOSE To determine the effect of estrogen replacement therapy ( ERT ) on recurrence rate and survival in women who have undergone surgery for stage I or II endometrial cancer . PATIENTS AND METHODS After surgery , eligible patients were allocated to therapy with ERT or placebo after undergoing hysterectomy with or without pelvic and aortic nodal sampling . Planned duration of hormonal versus placebo treatment was 3 years , with an additional 2 years of follow-up . RESULTS The median follow-up time for all 1,236 eligible and assessable patients was 35.7 months . Stage , grade , histologic subtype , and percentage of patients receiving adjuvant therapy were similarly distributed between the groups . The median age at diagnosis for the 618 patients r and omly assigned to ERT was 57 years ( range , 26 to 91 years ) . Two hundred fifty-one patients ( 41.1 % ) were compliant with ERT for the entire treatment period . Disease recurrence was experienced in 14 patients ( 2.3 % ) . Eight patients ( 1.3 % ) developed a new malignancy . There were 26 deaths ( 4.2 % ) , and five deaths ( 0.8 % ) were a result of endometrial cancer . The  median age at diagnosis for the 618 patients in the placebo group was 57 years ( range , 30 to 88 years ) . Twelve patients ( 1.9 % ) experienced disease recurrence . Ten patients ( 1.6 % ) developed a new malignancy . There were 9 deaths ( 3.1 % ) in the placebo group , and four deaths ( 0.6 % ) were a result of endometrial cancer . CONCLUSION Although this incomplete study can not conclusively refute or support the safety of exogenous estrogen with regard to risk of endometrial recurrence , it is noteworthy that the absolute recurrence rate ( 2.1 % ) and the incidence of new malignancy were low BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later . However , the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation ( the hormone-timing hypothesis ) has not been tested . METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause ( < 6 years [ early postmenopause ] or ≥10 years [ late postmenopause ] ) and were r and omly assigned to receive either oral 17β-estradiol ( 1 mg per day , plus progesterone [ 45 mg ] vaginal gel administered sequentially [ i.e. , once daily for 10 days of each 30-day cycle ] for women with a uterus ) or placebo ( plus sequential placebo vaginal gel for women with a uterus ) . The primary outcome was the rate of change in carotid-artery intima-media thickness ( CIMT ) , which was measured every 6 months . Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography ( CT ) , which was performed when participants completed the r and omly assigned regimen . RESULTS After a median of 5 years , the effect of estradiol , with or without progesterone , on CIMT progression differed between the early and late postmenopause strata ( P=0.007 for the interaction ) . Among women who were less than 6 years past menopause at the time of r and omization , the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group ( P=0.008 ) . Among women who were 10 or more years past menopause at the time of r and omization , the rates of CIMT progression in the placebo and estradiol groups were similar ( 0.0088 and 0.0100 mm per year , respectively ; P=0.29 ) . CT measures of coronary-artery calcium , total stenosis , and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum . CONCLUSIONS Oral estradiol therapy was associated with less progression of sub clinical atherosclerosis ( measured as CIMT ) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause . Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum . ( Funded by the National Institute on Aging , National Institutes of Health ; ELITE Clinical Trials.gov number , NCT00114517 . ) 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 OBJECTIVE To evaluate the effects of menopause hormonal therapy on disease activity in women with systemic lupus erythematosus ( SLE ) . METHODS We conducted a double-blind , r and omized clinical trial involving 106 women with SLE who were in the menopausal transition or in early or late postmenopause . Patients received a continuous-sequential estrogen-progestogen regimen ( n = 52 ) or placebo ( n = 54 ) . Disease activity was assessed at baseline and at 1 , 2 , 3 , 6 , 9 , 12 , 15 , 18 , 21 , and 24 months , according to the SLE Disease Activity Index ( SLEDAI ) . The primary outcome measure was global disease activity , estimated by measuring the area under the SLEDAI curve . Secondary outcome measures included maximum SLEDAI score , change in SLEDAI score , incidence of lupus flares , median time to flare , medication use , and adverse events . Results were studied using intent-to-treat analysis . RESULTS At baseline , demographic and disease characteristics were similar in both groups . Mean + /- SD SLEDAI scores were 3.5 + /- 3.3 and 3.1 + /- 3.4 in the menopause hormonal therapy and placebo groups , respectively ( P = 0.57 ) . Disease activity remained mild and stable in both groups throughout the trial . There were no significant differences between the groups in global or maximum disease activity , incidence or probability of flares , or medication use . Median time to flare was 3 months in both groups . Thromboses occurred in 3 patients who received menopause hormonal therapy and in 1 patient who received placebo . One patient in each group died during the trial due to sepsis . CONCLUSION Menopause hormonal therapy did not alter disease activity during 2 years of treatment . However , an apparently increased risk of thrombosis seems to be a real threat in women with SLE who receive menopausal hormone therapy 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 The endothelium is thought to play an important role in the genesis of atherosclerosis , and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events . Estrogen has direct effects on the blood vessel wall , indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy ( HRT ) . Raloxifene relaxes coronary arteries in vitro by an estrogen receptor – dependent and NO-dependent mechanism , thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function . This study compared the effects of HRT and raloxifene on NO products , endothelin-1 plasma levels , and endothelium-dependent vasodilatation in postmenopausal women . Healthy postmenopausal women ( n=90 ) were enrolled in a double-blind , r and omized , placebo-controlled , 6-month trial . Women were r and omly assigned to receive continuous HRT ( 1 mg 17&bgr;-estradiol combined with 0.5 mg norethisterone acetate ) , raloxifene ( 60 mg/d ) , or placebo for 6 months . Flow-mediated endothelium-dependent vasodilation of the brachial artery , plasma NO concentrations , and endothelin levels were measured at baseline and after 6 months of therapy . The mean baseline level of NO breakdown products was 26.5±10.7 & mgr;mol/L and increased to 36.3±11.4 & mgr;mol/L after 6 months of treatment with raloxifene . The mean baseline plasma endothelin level was 17.3±8.9 pg/mL and decreased to 11.5±2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator . The mean baseline ratio of NO ( breakdown products ) to endothelin was also significantly increased at the end of treatment with raloxifene . Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin . In contrast , these markers of endothelial function did not change in the placebo-treated women  . Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3±2.1 % at baseline and increased to 12.3±2.1 % after 6 months of treatment with raloxifene . HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation . No change in flow-mediated vasodilation was observed in the participants treated with placebo . We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period . However , further investigation is warranted to enhance our underst and ing of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality Background At the time of feasibility work and final design of the trial there was no r and omised control trial evidence for the long-term risks and benefits of hormone replacement therapy . Observational studies had suggested that long term use of estrogen was likely to be associated , amongst other things , with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer . Concomitant use of progestogens had been shown to protect against endometrial cancer , but there were few data showing how progestogen might affect estrogen actions on other conditions . Disease specific risks from observational studies suggested that , overall , long-term HRT was likely to be beneficial . Several studies showed that mortality from all causes was lower in HRT users than in non-users . Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women . The WISDOM trial was design ed to compare combined estrogen and progestogen versus placebo , and estrogen alone versus combined estrogen and progestogen . During the development of WISDOM the Women 's Health Initiative trial was design ed , funded and started in the US . Design R and omised , placebo , controlled , trial . Methods The trial was set in general practice s in the UK ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . In these practice s 284175 women aged 50–69 years were registered with 226282 potentially eligible . We sought to r and omise 22300 postmenopausal women aged 50 – 69 and treat for ten years . The interventions were : conjugated equine estrogens , 0.625 mg orally daily ; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ; matched placebo . Primary outcome measures were : major cardiovascular disease , osteoporotic fractures , breast cancer and dementia . Secondary outcomes were : other cancers , all cause death , venous thromboembolism and cerebro-vascular disease . Results The trial was prematurely closed during recruitment following publication of early results from the Women 's Health Initiative . At the time of closure , 56583 had been screened , 8980 entered run-in , and 5694 ( 26 % of target of 22,300 ) r and omised . Those women r and omised had received a mean of one year of therapy , mean age was 62.8 years and total follow-up time was 6491 person years . Discussion The WISDOM experience leads to some simple messages . The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery . When a trial is very costly and beyond the re sources of one country , funders and investigators should make every effort to develop international collaboration with joint funding BACKGROUND Observational studies have suggested that estrogen-replacement therapy may reduce a woman 's risk of stroke and death . METHODS We conducted a r and omized , double-blind , placebo-controlled trial of estrogen therapy ( 1 mg of estradiol-17beta per day ) in 664 postmenopausal women ( mean age , 71 years ) who had recently had an ischemic stroke or transient ischemic attack . Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death . RESULTS During a mean follow-up period of 2.8 years , there were 99 strokes or deaths among the women in the estradiol group , and 93 among those in the placebo group ( relative risk in the estradiol group , 1.1 ; 95 percent confidence interval , 0.8 to 1.4 ) . Estrogen therapy did not reduce the risk of death alone ( relative risk , 1.2 ; 95 percent confidence interval , 0.8 to 1.8 ) or the risk of nonfatal stroke ( relative risk , 1.0 ; 95 percent confidence interval , 0.7 to 1.4 ) . The women who were r and omly assigned to receive estrogen therapy had a higher risk of fatal stroke ( relative risk , 2.9 ; 95 percent confidence interval , 0.9 to 9.0 ) , and their nonfatal strokes were associated with slightly worse neurologic and functional deficits . CONCLUSIONS Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease . This therapy should not be prescribed for the secondary prevention of cerebrovascular disease 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 OBJECTIVE To investigate treatment adherence and factors related to non-adherence in the Estonian postmenopausal hormone therapy ( EPHT ) trial . METHODS A total of 1823 postmenopausal women aged 50 - 64 years were recruited into the EPHT trial from 1999 to 2001 . They were r and omised into the blind group receiving continuous orally administered postmenopausal hormone therapy ( PHT ) or a placebo and to a non-blind group receiving open-label PHT or no drugs . A woman was classified as non-adherent , if she had stopped treatment for at least 6-month period in treatment arms or used PHT for at least 6-month period in the control group . Adherence was calculated by the Kaplan-Meier method , and factors affecting adherence were studied with Cox proportional hazard modelling . RESULTS The rate of adherent women declined approximately 50 % during the first year in all treatment arms . Less than 10 % of the control group women started taking prescribed PHT . Older women , with lower education , with only one birth , never used oral contraceptives ( OC ) , with lower physical activity or who were dissatisfied with the information received from the trial staff , were more likely to discontinue . In treatment arms , the two most often cited reasons for non-adherence were side-effects and woman 's loss of interest in participation . Control group women started PHT due to the menopausal symptoms or on doctor 's recommendation . CONCLUSIONS The adherence was similar to that found for PHT use in everyday life . Higher adherence was related to younger age , higher education , previous OC use , physical activity and satisfaction with received information 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 Whether menopausal hormone therapy ( MHT ) protects against cardiovascular disease ( CVD )  remains unclear . OBJECTIVE To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause . DESIGN R and omized , controlled trial . ( Clinical Trials.gov : NCT00154180 ) . SETTING Nine U.S. academic centers . PARTICIPANTS Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium ( CAC ) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days . INTERVENTION Oral conjugated equine estrogens ( o-CEE ) , 0.45 mg/d , or transdermal 17β-estradiol ( t-E2 ) , 50 mcg/d , each with 200 mg of oral progesterone for 12 days per month , or placebo for 48 months . MEASUREMENTS Primary end point was annual change in carotid artery intima-media thickness ( CIMT ) . Secondary end points included changes in markers of CVD risk . RESULTS Of 727 r and omly assigned women , 89.3 % had at least 1 follow-up CIMT and 79.8 % had CIMT at 48 months . Mean CIMT increases of 0.007 mm/y were similar across groups . The percentages of participants in whom CAC score increased did not differ significantly across groups . No changes in blood pressure were observed with o-CEE or t-E2 . Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone-binding globulin but not interleukin-6 increased with o-CEE . Insulin resistance decreased with t-E2 . Serious adverse events did not differ by treatment . LIMITATION Power to compare clinical events was insufficient . CONCLUSION Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk . PRIMARY FUNDING SOURCE Aurora Foundation Background The aim of the study was to determine the effect of postmenopausal hormone therapy on women 's symptom reporting and quality of life in a r and omized trial . Methods 1823 women participated in the Estonian Postmenopausal Hormone Therapy ( EPHT ) Trial between 1999 and 2004 . Women were r and omized to open-label continuous combined hormone therapy or no treatment , or to blind hormone therapy or placebo . The average follow-up period was 3.6 years . Prevalence of symptoms and quality of life according to EQ-5D were assessed by annually mailed question naires . Results In the hormone therapy arms , less women reported hot flushes ( OR 0.20 ; 95 % CI : 0.14–0.28 ) , sweating ( OR 0.56 ; 95 % CI : 0.44–0.72 ) , and sleeping problems ( OR 0.66 ; 95 % CI : 0.52–0.84 ) , but more women reported episodes of vaginal bleeding ( OR 19.65 ; 95 % CI : 12.15–31.79 ) . There was no difference between the trial arms in the prevalence of other symptoms over time . Quality of life did not depend on hormone therapy use . Conclusion Postmenopausal hormone therapy decreased vasomotor symptoms and sleeping problems , but increased episodes of vaginal bleeding , and had no effect on quality of life . Trial registration numberIS RCT 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 CONTEXT Different menopausal hormone therapies may have varied effects on specific cognitive functions . We previously reported that conjugated equine estrogens ( CEE ) with medroxyprogesterone acetate had a negative impact on verbal memory but tended to impact figural memory positively over time in older postmenopausal women . OBJECTIVE The objective of the study was to determine the effects of unopposed CEE on changes in domain-specific cognitive function and affect in older postmenopausal women with prior hysterectomy . DESIGN This was a r and omized , double blind , placebo-controlled clinical trial . SETTING The study was conducted at 14 of 40 Women 's Health Initiative ( WHI ) clinical centers . PARTICIPANTS Participants were 886 postmenopausal women with prior hysterectomy , aged 65 yr and older ( mean 74 yr ) , free of probable dementia , and enrolled in the WHI and WHI Memory Study ( WHIMS ) CEE-Alone trial for a mean of 3 yr and followed up for a mean of 2.70 yr . INTERVENTION Intervention was 0.625 mg of CEE daily or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS Compared with placebo , unopposed CEE was associated with lower spatial rotational ability ( P < 0.01 ) at initial assessment ( after 3 yr of treatment ) , a difference that diminished over 2.7 yr of continued treatment . CEE did not significantly influence change in other cognitive functions and affect . CONCLUSIONS CEE did not improve cognitive functioning in postmenopausal women with prior hysterectomy . CEE was associated with lower spatial rotational performance after an average of 3 yr of treatment . Overall , CEE does not appear to have enduring effects on rates of domain-specific cognitive change in older postmenopausal women 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 Hormone replacement therapy ( HT ) is known to increase the risk of breast cancer in healthy women , but its effect on breast cancer risk in breast cancer survivors is less clear . The r and omized HABITS study , which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer , was stopped early due to suspicions of an increased risk of new breast cancer events following HT . We present results after extended follow-up . METHODS HABITS was a r and omized , non-placebo-controlled noninferiority trial that aim ed to be at a power of 80 % to detect a 36 % increase in the hazard ratio ( HR ) for a new breast cancer event following HT . Cox models were used to estimate relative risks of a breast cancer event , the maximum likelihood method was used to calculate 95 % confidence intervals ( CIs ) , and chi(2 ) tests were used to assess statistical significance , with all P values based on two-sided tests . The absolute risk of a new breast cancer event was estimated with the cumulative incidence function . Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone . RESULTS Of the 447 women r and omly assigned , 442 could be followed for a median of 4 years . Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event ( HR = 2.4 , 95 % CI = 1.3 to 4.2 ) . Cumulative incidences at 5 years were 22.2 % in the HT arm and 8.0 % in the control arm . By the end of follow-up , six women in the HT arm had died of breast cancer and six were alive with distant metastases . In the control arm , five women had died of breast cancer and four had metastatic breast cancer ( P = .51 , log-rank test ) . CONCLUSION After extended follow-up , there was a clinical ly and statistically significant increased risk of a new breast cancer event in survivors who took HT 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 BACKGROUND In recent r and omized trials , conjugated equine estrogens ( CEE ) with continuous medroxyprogesterone acetate provided no protection against coronary heart disease in postmenopausal women and may have increased cardiac risk . These trials did not address the role of unopposed estrogen for coronary protection . METHODS A total of 10 739 women aged 50 to 79 years at baseline ( mean age , 63.6 years ) who had previously undergone hysterectomy were r and omized to receive CEE  , 0.625 mg/d , or  placebo at 40 US clinical centers beginning in 1993 . The trial was terminated early after 6.8 years of follow-up ( planned duration , 8.5 years ) . This report includes final , central ly adjudicated results for the primary efficacy outcome ( myocardial infa rct ion or coronary death ) , secondary coronary outcomes , and subgroup analyses . RESULTS During the active intervention period , 201 coronary events were confirmed among women assigned to receive CEE compared with 217 events among women assigned to receive placebo ( hazard ratio , 0.95 ; nominal 95 % confidence interval , 0.79 - 1.16 ) . Among women aged 50 to 59 years at baseline , the hazard ratio for the primary outcome was 0.63 ( nominal 95 % confidence interval , 0.36 - 1.08 ) . In that age group , coronary revascularization was less frequent among women assigned to receive CEE ( hazard ratio , 0.55 ; nominal 95 % confidence interval , 0.35 - 0.86 ) , as were several composite outcomes , which included the primary outcome and coronary revascularization ( hazard ratio , 0.66 ; nominal 95 % confidence interval , 0.44 - 0.97 ) . CONCLUSIONS Conjugated equine estrogens provided no overall protection against myocardial infa rct ion or coronary death in generally healthy postmenopausal women during a 7-year period of use . There was a suggestion of lower coronary heart disease risk with CEE among women 50 to 59 years of age at baseline BACKGROUND Estrogen replacement therapy ( ERT ) , which is mainly used to relieve climacteric symptoms , increases a woman 's risk for uterine endometrial cancer and epithelial ovarian cancer ( EOC ) .  Estrogens are often combined with progestins in hormone replacement therapy ( HRT ) to reduce the risk of uterine endometrial cancer . Data on the association between HRT including progestins and EOC risk are limited . This nationwide case-control study examined EOC risk in relation to HRT regimens with sequentially added progestins ( HRTsp ) and continuously added progestins ( HRTcp ) . METHODS Between 1993 and 1995 , we enrolled 655 histologically verified incident case patients with EOC and 3899 r and omly selected population controls , all 50 - 74 years of age . Data on HRT use were collected through mailed question naires . Multivariate-adjusted odds ratios ( ORs ) and 95 % confidence intervals ( CIs ) were estimated by the use of unconditional logistic regression . RESULTS Risks of EOC were elevated among ever users as compared with never users of both ERT ( OR = 1.43 , 95 % CI = 1.02 to 2.00 ) and HRTsp ( OR = 1.54 , 95 % CI = 1.15 to 2.05 ) ; risks were elevated for serous , mucinous , and endometrioid subtypes . For all EOC types combined , the greatest risk increases were seen with hormone use exceeding 10 years . Ever use of HRTcp was not associated with increased EOC risk relative to HRTcp never use ( OR = 1.02 , 95 % CI = 0.73 to 1.43 ) . The risk of EOC was elevated among HRTsp ever users as compared with HRTcp ever users ( OR = 1.78 , 95 % CI = 1.05 to 3.01 ) . ORs for EOC after ever use of low-potency estrogens were 1.18 ( 95 % CI = 0.89 to 1.55 ) for oral and 1.33 ( 95 % CI = 1.03 to 1.72 ) for vaginal applications , but no relationship was seen between EOC risk and duration of use . CONCLUSION Ever users of ERT and HRTsp but not HRTcp may be at increased risk of EOC CONTEXT The Women 's Health Initiative Memory Study ( WHIMS ) previously reported that estrogen plus progestin therapy does not protect cognition among women aged 65 years or older . The effect of estrogen-alone therapy , also evaluated in WHIMS , on cognition has not been established for this population . OBJECTIVES To determine whether conjugated equine estrogen ( CEE ) alters global cognitive function in older women and to compare its effect with CEE plus medroxyprogesterone acetate ( CEE plus MPA ) . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled ancillary study of the Women 's Health Initiative ( WHI ) , WHIMS evaluated the effect of CEE on incidence of probable dementia among community-dwelling women aged 65 to 79 years with prior hysterectomy from 39 US academic centers that started in June 1995 . Of 3200 eligible women free of probable dementia enrolled in the WHI , 2947 ( 92.1 % ) were enrolled in WHIMS . Analyses were conducted on the 2808 women ( 95.3 % ) with a baseline and at least 1 follow-up measure of global cognitive function before the trial 's termination on February 29 , 2004 . INTERVENTIONS Participants received 1 daily tablet containing either 0.625 mg of CEE ( n = 1387 ) or matching placebo ( n = 1421 ) . MAIN OUTCOME MEASURE Global cognitive function measured annually with the Modified Mini-Mental State Examination ( 3MSE ) . RESULTS During a mean follow-up of 5.4 years , mean ( SE ) 3MSE scores were 0.26 ( 0.13 ) units lower than among women assigned to CEE compared with placebo ( P = .04 ) . For pooled hormone therapy ( CEE combined with CEE plus MPA ) , the mean ( SE ) decrease was 0.21 ( 0.08 ; P = .006 ) . Removing women with dementia , mild cognitive impairment , or stroke from the analyses lessened these differences . The adverse effect of hormone therapy was more pronounced among women with lower cognitive function at baseline ( all P<.01 ) . For women assigned to CEE compared with placebo , the relative risk of having a 10-unit decrease in 3MSE scores ( > 2 SDs ) was estimated to be 1.47 ( 95 % confidence interval , 1.04 - 2.07 ) . CONCLUSION For women aged 65 years or older , hormone therapy had an adverse effect on cognition , which was greater among women with lower cognitive function at initiation of treatment The objective of this study was to examine the effects of estrogen-based hormone therapy ( HT ) on regional cerebral metabolism in postmenopausal women ( mean age = 58 , SD = 5 ) at risk for development of dementia . The prospect i ve clinical trial design included pre- and post-intervention neuroimaging of women r and omized to continue ( HT+ ) or discontinue ( HT− ) therapy following an average of 10 years of use . The primary outcome measure was change in brain metabolism during the subsequent two years , as assessed with  fluorodeoxyglucose-18 positron emission tomography ( FDG-PET ) . Longitudinal FDG-PET data were available for 45 study completers . Results showed that women r and omized to continue HT experienced relative preservation of frontal and parietal cortical metabolism , compared with women r and omized to discontinue HT . Women who discontinued 17-β estradiol (17βE)-based HT , as well as women who continued conjugated equine estrogen (CEE)-based HT , exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical ( PCC ) area . Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins ( with either 17βE or CEE ) . Together , these findings suggest that among postmenopausal subjects at risk for developing dementia , regional cerebral cortical metabolism is relatively preserved for at least two years in women r and omized to continue HT , compared with women r and omized to discontinue HT . In addition , continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC , known to undergo the most significant decline in the earliest stages of Alzheimer 's disease . Trial Registration Clinical Trials.gov BACKGROUND Results of observational studies suggest that hormone replacement therapy ( HRT ) could reduce the risk of coronary heart disease ( CHD ) , but those of r and omised trials do not indicate a lower risk in women who use oestrogen plus progestagen .  The aim of this study was to ascertain whether or not unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infa rct ion . METHODS The study was a r and omised , blinded , placebo controlled , secondary prevention trial of postmenopausal women , age 50 - 69 years ( n=1017 ) who had survived a first myocardial infa rct ion . Individuals were recruited from 35 hospitals in Engl and and Wales . Women received either one tablet of oestradiol valerate ( 2 mg ; n=513 ) or placebo ( n=504 ) , daily for 2 years . Primary outcomes were reinfa rct ion or cardiac death , and all-cause mortality . Analyses were by intention-to-treat . Secondary outcomes were uterine bleeding , endometrial cancer , stroke or other embolic events , and fractures . FINDINGS Frequency of reinfa rct ion or cardiac death did not differ between treatment groups at 24 months ( rate ratio 0.99 , 95 % CI 0.70 - 1.41 , p=0.97 ) . Similarly , the reduction in all-cause mortality between those who took oestrogen and those on placebo was not significant ( 0.79 , 0.50 - 1.27 , p=0.34 ) . The relative risk of any death ( 0.56 , 0.23 - 1.33 ) and cardiac death ( 0.33 , 0.11 - 1.01 ) was lowest at 3 months post-recruitment . INTERPRETATION Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infa rct ion 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 CONTEXT Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions , particularly memory . OBJECTIVE The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women . DESIGN This study was a r and omized , double-blind , placebo-controlled clinical trial . SETTING Participants were women from 14 of 40 clinical centers of the Women 's Health Initiative ( WHI ) . PARTICIPANTS Postmenopausal women ( 1416 ) aged 65 yr and older , free of probable dementia , and enrolled in WHI and the WHI Memory Study ( WHIMS ) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr , were studied . INTERVENTION Intervention was conjugated equine estrogen ( CEE ; 0.625 mg ) with 2.5 mg medroxyprogesterone acetate ( MPA ) in one daily tablet ( CEE + MPA ) or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS CEE + MPA had a negative impact on verbal memory ( P < or= 0.01 ) and a trend to a positive impact on figural memory ( P = 0.012 ) over time compared with placebo , but other cognitive domains were not affected . Both effects on memory were evident only after long-term therapy . CEE + MPA did not significantly influence positive affect , negative affect , or depressive symptoms . CONCLUSIONS The effect of CEE + MPA on cognitive function varies across cognitive domains in older women , reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain . Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research Objective —The Heart and Estrogen/Progestin Replacement Study ( HERS ) found no overall effect of estrogen plus progestin ( compared with placebo ) on coronary event rates in 2763 postmenopausal women with established coronary disease ( mean 4.1 years of follow-up ) . In addition to the events trial , a carotid ultrasound sub study was established in 1993 to be conducted concurrently to determine whether hormone therapy affects the progression of the underlying atherosclerotic process . Methods and Results —Within the larger HERS , a subset of 362 participants underwent carotid B-mode ultrasound examinations  at baseline and the end of follow-up . Progression of carotid atherosclerosis was measured as the temporal change in intimal-medial thickness ( IMT ) . Conclusions —IMT progressed in the hormone treatment and placebo groups , although there was no statistical difference between the rates : IMT progressed 26 & mgr;m/y ( 95 % CI 18 to 34 & mgr;m/y ) in the hormone group and 31 & mgr;m/y ( 95 % CI 21 to 40 & mgr;m/y ) in the placebo group ( P = 0.44 ) . There were also no significant treatment effects when the results were examined by carotid segment or were adjusted for covariates . These data support the American Heart Association recommendation that women with established coronary disease should not initiate hormone therapy with an expectation of atherosclerotic benefit BACKGROUND The Heart and Estrogen/Progestin Replacement Study ( HERS ) is the first large clinical trial design ed to test the efficacy of postmenopausal estrogen/progestin therapy for secondary prevention of coronary heart disease ( CHD ) . To examine the representativeness of the HERS cohort to the general population of postmenopausal women with CHD , we compared the baseline cardiovascular risk factor data from HERS with similar data from women presumed to have CHD from the National Health and Nutrition Examination Survey ( NHANES ) III . METHODS Age , race , and cardiovascular disease risk factors were compared in the 2763 postmenopausal women younger than 80 years old , with a uterus , and with documented CHD in HERS versus 145 similarly aged women with clinical or electrocardiographic evidence of CHD from phase I of NHANES III . RESULTS There were fewer current smokers in HERS ( 13 % ) than in the NHANES cohort ( 21.7 % , p = 0.05 ) . Similarly , a history of hypertension was less prevalent in HERS ( 58.6 % ) than in the NHANES cohort ( 69.3 % , p = 0.03 ) . Women with fasting triglyceride levels > 3.39 mmol/L or fasting glucose levels > 16.6 mmol/L were excluded from HERS , result ing in fewer diabetics ( 22.9 % vs 29.5 % , p = 0.26 ) and lower serum triglyceride levels ( 1.88 mmol/L vs 2.25 mmol/L , p = 0.19 ) in HERS versus the NHANES cohort . Systolic and diastolic blood pressure , body mass index , physical activity , and total LDL and HDL cholesterol were not significantly different between the two groups . CONCLUSIONS The HERS cohort had fewer CHD risk factors than women with myocardial infa rct ion or angina in NHANES III , although comparison is hindered by differences in selection criteria . The many women with diabetes and hypertriglyceridemia in the NHANES cohort emphasizes the importance of testing strategies for secondary prevention of CHD in this high-risk subgroup CONTEXT Despite decades of accumulated observational evidence , the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain . OBJECTIVE To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States . DESIGN Estrogen plus progestin component of the Women 's Health Initiative , a r and omized controlled primary prevention trial ( planned duration , 8.5 years ) in which 16608 postmenopausal women aged 50 - 79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993 - 1998 . INTERVENTIONS Participants received conjugated equine estrogens , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , in 1 tablet ( n = 8506 ) or placebo ( n = 8102 ) . MAIN OUTCOMES MEASURES The primary outcome was coronary heart disease ( CHD ) ( nonfatal myocardial infa rct ion and CHD death ) , with invasive breast cancer as the primary adverse outcome . A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke , pulmonary embolism ( PE ) , endometrial cancer , colorectal cancer , hip fracture , and death due to other causes . RESULTS On May 31 , 2002 , after a mean of 5.2 years of follow-up , the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits . This report includes data on the major clinical outcomes through April 30 , 2002 . Estimated hazard ratios ( HRs ) ( nominal 95 % confidence intervals [ CIs ] ) were as follows : CHD , 1.29 ( 1.02 - 1.63 ) with 286 cases ; breast cancer , 1.26 ( 1.00 - 1.59 ) with 290 cases ; stroke , 1.41 ( 1.07 - 1.85 ) with 212 cases ; PE , 2.13 ( 1.39 - 3.25 ) with 101 cases ; colorectal cancer , 0.63 ( 0.43 - 0.92 ) with 112 cases ; endometrial cancer , 0.83 ( 0.47 - 1.47 ) with 47 cases ; hip fracture , 0.66 ( 0.45 - 0.98 ) with 106 cases ; and death due to other causes , 0.92 ( 0.74 - 1.14 ) with 331 cases . Corresponding HRs ( nominal 95 % CIs ) for composite outcomes were 1.22 ( 1.09 - 1.36 ) for total cardiovascular disease ( arterial and venous disease ) , 1.03 ( 0.90 - 1.17 ) for total cancer , 0.76 ( 0.69 - 0.85 ) for combined fractures , 0.98 ( 0.82 - 1.18 ) for total mortality , and 1.15 ( 1.03 - 1.28 ) for the global index . Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events , 8 more strokes , 8 more PEs , and 8 more invasive breast cancers , while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures . The absolute excess risk of events included in the global index was 19 per 10 000 person-years . CONCLUSIONS Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women .  All-cause mortality was not affected during the trial . The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases , and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD The National Institutes of Health ( NIH ) has instructed participants in the estrogen-alone study of the Women ’s Health Initiative ( WHI ) , a large multi-center trial , to stop taking their study pills and to begin the follow-up phase of the study . Letters have been sent to all participants in the estrogenalone study , 11,000 healthy postmenopausal women who have had a hysterectomy , informing them of a recent NIH review of the study data . After careful consideration of the data , NIH has concluded that with an average of nearly 7 years of follow-up completed , estrogen alone does not appear to affect ( either increase or decrease ) heart disease , a key question of the study . At the same time , estrogen alone appears to increase the risk of stroke and decrease the risk of hip fracture . It has not increased the risk of breast cancer during the time period of the study . The increased risk of stroke in the estrogen-alone study is similar to what was found in the WHI study of estrogen plus progestin when that trial was stopped in July 2002 . In that study , women taking estrogen plus progestin had 8 more strokes per year for every 10,000 women than those taking the placebo . The NIH believes that an increased risk of stroke is not acceptable in healthy women in a research study . This is especially true if estrogen alone does not affect ( either increase or decrease ) heart disease , as appears to be the case in the current study . The NIH has determined that the results would not likely change if the estrogen trial continued to its planned completion in 2005 . Furthermore , enough data have been obtained to assess the overall risks and benefits of the use of estrogen in this trial . WHI research ers have begun a detailed analysis of the data from the estrogen-alone study and expect to report full results in the next two months . The report , to be published in a peer- review ed journal , will include additional data collected through the end of February 2004 . A separate report will contain information on  probable dementia or mild cognitive impairment in the women age 65 and older who participated in the estrogen-alone WHI-Memory Study ( WHIMS ) , an ancillary study of the WHI Hormone Trials . Preliminary data suggest that for the WHIMS participants who were on estrogen  alone when compared to the women who were taking the placebo , there was a trend toward increased risk of probable dementia and /or mild cognitive impairment . The WHI estrogen study was design ed to assess the effect of long-term use of hormone therapy in healthy postmenopausal women on the prevention of heart disease and hip fractures , and any associated change in risk for breast cancer . It was not design ed to evaluate the short-term risks and benefits of hormones for the treatment of moderate to severe menopausal symptoms . The estrogen-alone study involved women ages 50 to 79 years . Study participants were r and omly assigned to a daily dose of estrogen—0.625 mg/day of conjugated equine estrogen — or a placebo . The NIH decision to stop the estrogen-alone trial was made on February 2 , 2004 . In November and December 2003 , the WHI Data and Safety Monitoring Board ( DSMB ) , an independent advisory committee which regularly review s study data and oversees the safety of study participants , review ed the latest data from the estrogen-alone study . The DSMB was split as to whether the study pills should be stopped or whether the pills should be continued , provided that a letter would be sent to the participants clearly informing them of the stroke risks and other findings . After careful review , the NIH decided that women in the estrogen-alone study should stop taking their study pills . From the National Heart , Lung , and Blood Institute of the National Institutes of Health BACKGROUND 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 Health Initiative Study of Cognitive Aging ( WHISCA ) was a two armed , r and omized , placebo controlled , clinical trial design ed to assess the efficacy of postmenopausal hormone therapy on age related changes in specific cognitive functions . WHISCA was an ancillary study to the Women 's Health Initiative ( WHI ) and the WHI Memory Study ( WHIMS ) and enrolled 2302 women aged 66 to 84 years ( mean 73.9 ; st and ard deviation 3.8 ) who did not meet criteria for dementia . Women were r and omly assigned by the WHI to hormone treatment ( unopposed conjugated estrogens ( CEE ) 0.625 mg/day if they were without a uterus ; CEE combined with medroxyprogesterone acetate ( MPA ) 2.5 mg/day otherwise ) or placebo for an average of three years before the first WHISCA assessment . WHISCA investigated the effects of hormone therapy on rates of change over time in memory , other aspects of cognition ( language , attention , spatial ability ) , motor function , and mood . In this paper , we present the study rationale and design , including specific cognitive measures , and the challenges of incorporating WHISCA into an ongoing r and omized trial . WHISCA provided a unique opportunity to investigate the potential of hormone therapy to modify age related changes in specific cognitive functions . WHISCA also demonstrated the feasibility of adding a detailed cognitive assessment into an ongoing clinical trial to address an important issue in women 's health , despite the challenges of maintaining the integrity of the parent studies , ensuring high retention , and achieving high quality assurance across sites Sixty-one postmenopausal women were r and omized into 3 groups . Two groups of women were treated with estrogen replacement therapy ( ERT ) by percutaneous administration of estradiol gel at a dosage of 1.25 g and 2.5 g , respectively . The third group of women , receiving no treatment except placebo , was studied concurrently as a control group . Bone mineral density ( BMD ) was measured by quantitative computed tomography ( QCT ) in the vertebrae from T12-L3 and hormones ( E1 , E2 , FSH , LH and testosterone ) were determined by radioimmunoassay at baseline , then at 6 monthly intervals thereafter . One year of the study has been completed thus far . The results of this study indicate that : ( 1 ) loss of BMD in the control group was observed significantly only in surgical menopausal women and no significant loss of BMD was observed in women receiving ERT treatment regimens ; ( 2 ) decrease of E1 in control group and increase of E1 in the treatment group were both significant . These data suggest that percutaneous ERT may be used in prevention of postmenopausal bone loss , particularly in surgical menopausal women and the increased E1 may play a beneficial role in inhibiting loss of bone mass and relieving menopausal syndrome . Different dosages of estradiol gel which did not create any significant difference between the 2 treatment groups , need a longer period of follow-up 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 Venous thromboembolism , including thrombosis of the deep veins of the legs and embolism to the pulmonary arteries , is a serious and potentially fatal event . Venous thromboembolism is uncommon in the general population , occurring in about 1 to 4 per 1000 adults annually ( 1 , 2 ) . However , the risk is increased in persons with previous venous thromboembolism ( 3 ) , recent surgical procedures ( 4 , 5 ) , immobilization , fracture of a lower extremity ( 4 , 6 , 7 ) , cancer ( 4 , 6 , 7 ) , and inherited coagulation disorders ( 8 , 9 ) . Use of oral contraceptive pills increases risk for venous thromboembolism ( 1 , 2 ) . This increased risk is thought to be due to estrogen and to be dose related ( 3 , 4 ) . The biological potency of the estrogens generally used in postmenopausal hormone therapy is about one-fourth to one-fifth that of the estrogens in modern oral contraceptives . Until recently , there has been little evidence that low-dose estrogen therapy is associated with increased risk for venous thromboembolism ( 5 - 8 ) . Recent observational studies have suggested that postmenopausal hormone therapy causes a twofold to fourfold increase in risk for idiopathic deep venous thrombosis and pulmonary embolism ( 9 - 13 ) . However , these findings may be biased if women taking estrogen are more likely to be evaluated for nonspecific symptoms suggestive of venous thromboembolism . The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized , blinded , placebo-controlled trial of the effect of daily conjugated equine estrogen , 0.625 mg , plus medroxyprogesterone acetate , 2.5 mg , on the rate of new coronary events in 2763 postmenopausal women with established coronary heart disease ( 14 ) . One of the specified secondary outcomes of this trial was venous thromboembolism . An increased risk for venous thromboembolism among women assigned to hormone therapy was noted by the HERS Data and Safety Monitoring Board . The Board instructed the HERS investigators to inform participants and the scientific community of this risk and to institute measures to reduce risk . At a mean follow-up of 3.3 years , the HERS investigators notified participants to discontinue study medication in situations associated with increased risk for venous thromboembolism , such as surgery , hospitalization , fracture , and cancer , and published a letter noting the increased risk ( 15 ) . This report presents the full analysis of the findings . Methods Participants in HERS were postmenopausal women younger than 80 years of age who had coronary disease ( myocardial infa rct ion , coronary artery bypass surgery , percutaneous coronary revascularization , or angiographic evidence of at least 50 % narrowing of one or more major coronary arteries ) and had not had a hysterectomy . Women were excluded if their coronary event occurred within 6 months of r and omization ; they had used hormone therapy within 3 months of r and omization ; they had a history or baseline findings suggestive of venous thromboembolism , breast cancer , or endometrial cancer ; or they had uncontrolled hypertension , diabetes , or other life-threatening diseases ( 16 ) . The protocol was approved by the institutional review board at each of the 20 HERS clinical centers , and all participants provided written informed consent . Participants were r and omly assigned to take one tablet daily of conjugated equine estrogen , 0.625 mg , plus medroxyprogesterone acetate , 2.5 mg , or placebo that was identical in appearance . R and omization was stratified by clinical center and performed in blocks of 4 . To prevent unblinding of clinical center staff , HERS participants reported breast discomfort and vaginal bleeding directly to gynecology staff , who were located separately from the clinical center staff , did not communicate with clinical center personnel about breast or gynecologic problems , and did not participate in ascertainment of outcomes . Follow-up visits to the clinical centers occurred at 4-month intervals . Coronary events ( nonfatal myocardial infa rct ion and coronary death ) were the primary outcome of the trial ( 14 ) . At each visit , clinic staff asked participants if they had been told by a physician that they had a blood clot in the legs or lungs . Women were also asked whether they had been hospitalized , and records were review ed to determine whether venous thromboembolism had occurred . Women were not routinely asked about symptoms of venous thrombosis , such as lower-extremity edema . Diagnosis of deep venous thrombosis required documentation of thrombosis of the popliteal or more proximal veins of the legs by venography , impedance plethysmography , or sonography . Pulmonary embolism required documentation by a nuclear lung scan that suggested a high probability of pulmonary embolism ( segmental or larger perfusion defect with ventilation mismatch ) or by pulmonary angiography that revealed a constant intraluminal filling defect on multiple films . Suspected venous thromboembolism was adjudicated independently and without knowledge of treatment assignment by two physicians at the HERS Coordinating Center , located at the University of California , San Francisco ; disagreements were resolved by consensus . Persons who analyzed data were also blinded to participants ' treatment status . Data were collected on events that occurred during the trial that might be predictors of venous thromboembolism , including fractures , nonfatal myocardial infa rct ion , congestive heart failure , stroke , and transient ischemic attack ( 16 ) . Venous thromboembolism was classified as idiopathic in women who did not have concomitant cancer , nonfatal myocardial infa rct ion , congestive heart failure , or stroke and did not have a fracture , inpatient surgery , or hospitalization in the 3 months before the venous thromboembolic event . In the primary analysis , an unadjusted Cox proportional-hazards model for time to first event was used to compare the rate of venous thromboembolism among women assigned to  hormone therapy with the rate among women assigned to placebo . The primary analysis was intention-to-treat ; participants were categorized according to treatment assignment regardless of compliance . Participants who were lost to follow-up ( 33 women in the hormone therapy group and 36 in the placebo group ) were censored at the last date at which they were known to be alive without venous thromboembolism ; vital status was known for all women at the end of the trial . We also performed an as-treated analysis , in which inclusion in the risk sets was limited to women in both treatment groups whose average compliance with therapy during the trial ( measured by pill count ) was at least 80 % . Relative hazards were also estimated by year since r and omization ( women with events in earlier years were censored ) , and continuous trend in the log relative hazard was examined in a companion model . We repeated the main analyses separately for idiopathic and nonidiopathic venous thromboembolism . Potential risk factors for venous thromboembolism were first examined by using univariate proportional hazards models adjusted for treatment assignment . In these models , postr and omization events and medication use were represented by time-dependent indicators , which reverted to zero 90 days after fracture , surgery , or hospitalization or when therapy was discontinued . Variables associated with venous thromboembolism for which the associated P value was less than 0.2 in univariate analyses were considered for inclusion in multivariate models and retained in the model if the P value remained less than 0.2 . Statistical analyses were performed by using SAS software , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Results The 20 HERS centers enrolled 2763 women between February 1993 and September 1994 ; of these , 1380 were assigned to the hormone therapy group and 1383 to the placebo group . Participants ranged in age from 44 to 79 years ( mean age [ SD ] , 67 7 years ) . At baseline , the treatment groups did not differ significantly ( Table 1 ) . Table 1 . Baseline Characteristics of HERS Participants At the end of the first year , 82 % of women in the hormone therapy group and 91 % in the placebo group reported taking study medication ; by the end of the third year , these proportions had decreased to 75 % and 81 % , respectively . Cumulative incidence curves for all venous thromboembolic events ( deep venous thrombosis and pulmonary embolism ) are shown in the Figure . During 10 985 woman-years of follow-up , 47 women experienced a  venous thromboembolic event : 34 in the hormone-treated group ( 6.2 per 1000 woman-years ) and 13 in the placebo group ( 2.3 per 1000 woman-years ) ( relative hazard , 2.7 [ 95 % CI , 1.4 to 5.0 ] [ P = 0.003 ] ; excess risk , 3.9 per 1000 woman-years [ CI , 1.4 to 6.4 per 1000 woman-years ] ; number needed to treat for harm , 256 [ CI , 157 to 692 ] ) . The relative hazard of venous thromboembolism did not differ significantly among the 20 clinical centers . Figure . Kaplan-Meier estimates of the cumulative incidence of venous thromboembolic events ( top ) , deep venous thrombosis ( middle ) , and pulmonary embolism ( bottom ) . More women in the hormone therapy group than in the placebo group experienced deep venous thrombosis ( 25 compared with 9 ; relative hazard , 2.8 [ CI , 1.3 to 6.0 ] ; P = 0.008 ) and pulmonary embolism ( 11 compared with 4 ; relative hazard , 2.8 [ CI , 0.9 to 8.7 ] ; P = 0.08 ) ( Table 2 ) . Two women , both in the hormone therapy group , died of pulmonary embolism . The relative hazard was increased for idiopathic ( relative hazard , 3.1 [ CI , 0.8 to 11.3 ] ) and nonidiopathic venous thromboembolic events ( relative hazard , 2.5 [ CI , 1.2 to 5.3 ] ) . The overall results were unchanged in an as-treated analysis that was limited to women who reported taking more than 80 % of their assigned study medication ( relative hazard , 3.2 [ CI , 1.5 to 6.9 ] ; P = 0.003 ) . Table 2 . Venous Thrombolic Events by Treatment Group and Year of R and omization Table 2 shows relative hazards for venous thromboembolism by year since r and omization . The number of episodes of pulmonary 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 : The objective was to evaluate the effect of hormone replacement therapy ( HRT ) on plasma homocysteine levels in postmenopausal women with coronary artery disease ( CAD ) and to investigate associations of homocysteine to other cardiovascular risk factors . Methods : The women in this single-center , controlled , and r and omized study were examined at baseline , and after 3 and 12 months , after they had been recruited consecutively from patients referred for investigational coronary angiography . All analyses were performed examiner blind . They were r and omized to HRT consisting of transdermal application of continuous 17β-estradiol with cyclic medroxyprogesterone acetate ( MPA ) tablets for 14 days every 3rd month , or to a control group . Results : After 3 months of unopposed 17β-estradiol , no significant effect on homocysteine was observed compared to the control group . The absolute decrease of 5 % in median plasma homocysteine levels after 12-month HRT did not reach statistical significance . Plasma homocysteine seemed slightly higher in women with three- or four-vessel disease , but the difference was not significant . With increasing homocysteine levels , free tissue factor pathway inhibitor ( TFPI ) antigen increased , whereas E-selectin decreased . In women with diabetes or elevated blood glucose > 6.0 mmol/l , plasma homocysteine was correlated to body mass index , C-peptide and insulin as well as age . Conclusion : Transdermal application of 17β-estradiol and sequential MPA do not affect plasma homocysteine in women with established CAD . Plasma homocysteine is stable in women with CAD over time , and unless special intervention is undertaken , repetitive measurements are not necessary in this particular group of high-risk individuals . The circulating anticoagulant TEPI is related to plasma homocysteine 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 BACKGROUND Several small trials and many observational studies suggest that estrogen treatment in postmenopausal women improves cognition , but 2 large r and omized trials have shown harm . The effect of an ultra-low- dose of unopposed transdermal estradiol on cognition and health-related quality of life is unknown . OBJECTIVE To investigate the effect of unopposed ultra-low-dose transdermal estradiol on cognitive function and quality of life in postmenopausal women . DESIGN R and omized , placebo-controlled , double-blind trial with 2-year follow-up . The main outcome of the trial was change in bone density . Changes in cognitive function and quality of life were preplanned secondary outcomes of the trial . SETTING Nine clinical centers in the United States . PARTICIPANTS Postmenopausal women ( N = 417 ) , aged 60 to 80 years , with a normal bone density for age and an intact uterus . INTERVENTION A weekly transdermal patch that delivers estradiol , 0.014 mg/d ( n = 208 ) , or placebo ( n = 209 ) . MAIN OUTCOME MEASURES Seven st and ardized cognitive tests ( a total of 10 scores ) administered at baseline and years 1 and 2 to test global cognitive function , verbal and visuospatial memory , language , executive function , and semantic memory . The 36-Item Short-Form General Health Survey was administered to assess health-related quality of life in physical and mental domains . The sample size provided 80 % power to detect a st and ardized effect of 0.29 SD , a small-to-moderate difference . RESULTS Baseline characteristics were similar in the 2 treatment groups . At 2 years of follow-up , we found no statistically significant differences between treatment groups in change on any of the cognitive test scores or on the 36-Item Short-Form General Health Survey ( P > .12 for all ) . There was no consistent evidence that the effect of treatment on change in cognitive or 36-Item Short-Form General Health Survey scores depended on the level of baseline endogenous estradiol . CONCLUSION Postmenopausal treatment with ultra-low-dose unopposed transdermal estradiol for 2 years had no effect on change in cognitive function or in health-related quality of life over 2 years of treatment OBJECTIVE We sought to investigate the long-term effect of raloxifene and continuous combined hormone replacement therapy ( ccHRT ) on impedance to flow within the uterine artery in postmenopausal women . STUDY DESIGN A prospect i ve , r and omized , double-blind , placebo-controlled 2-year study was performed in 95 postmenopausal women . They received either 60 mg of raloxifene daily ( raloxifene 60 group ) , 150 mg of raloxifene daily ( raloxifene 150 group ) , ccHRT , or placebo . At baseline and thereafter every 6 months , color Doppler ultrasonography was used to measure the pulsatility index ( PI ) of the uterine artery . RESULTS After 24 months of treatment , compared with placebo , significant decreases were found in the PI in the raloxifene 150 group ( P = .021 ) and in the ccHRT group ( P = .007 ) . In the raloxifene 150 group compared with the placebo group , after 6 and 24 months , decreases were observed in median PI of -5 % and -15 % , respectively , and in the ccHRT group decreases of -2 % and -19 % , respectively , were found . CONCLUSION Long-term use of 150 mg of raloxifene daily or ccHRT reduces impedance to flow within the uterine artery . This indicates that high-dose raloxifene may exert cardiovascular protection OBJECTIVES At present the Women 's Health Initiative trial is the only reported r and omised controlled trial study ing the effects of hormone therapy among healthy postmenopausal women . The Women 's Health Initiative reports have been criticized for lacking in generalisability , due to the characteristics of the trial population . We aim ed to compare the health effects of oral continuous combined hormone therapy with a placebo and non-treatment among healthy Estonian women . METHODS Eligible women were r and omised into a blind group of hormone therapy versus placebo and into a non-blind group of open label hormone therapy versus non-treatment .  One thous and seven hundred and seventy-eight postmenopausal women aged 50 - 64 at the time of sampling were recruited in 1999 - 2001 at three clinical centers in Estonia . Participants received conjugated equine oestrogens , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5mg/d , or conjugated equine oestrogens , 0.625 mg/d , plus medroxyprogesterone acetate , 5mg/d , if less than 3 years had passed since menopause at recruitment , or matched placebo or non-treatment . Trial treatment was stopped gradually from 1 January 2004 to 31 May 2004 . RESULTS After a follow-up period from 2.0 to 5.0 years the combined hazard ratio , stratified by blinding and adjusted for age at recruitment and former oral contraceptive use was 1.12 ( 95 % confidence interval [ CI ] : 0.90 - 1.40 ) for coronary heart disease , 1.24 ( 95 % CI : 0.85 - 1.82 ) for cerebrovascular disease , 1.36 ( 95 % CI : 0.73 - 2.52 ) for total cancer , and 0.61 ( 95 % CI : 0.42 to 0.89 ) for bone fractures . CONCLUSIONS The results from the Estonian Postmenopausal Hormone Therapy r and omised trial are consistent with the Women 's Health Initiative findings 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 Abstract The study was performed to compare the clinical effect of a hormone replacement therapy ( HRT ) with two different progestins . Postmenopausal women ( PMW ) with climacteric symptoms ( CS ) r and omly received for 12 months orally , either placebo ( n = 20 ) , 1 mg estradiol ( E ) plus 0.5 mg noretisterone acetate ( NETA ; n = 40 ) , or 2 mg drospirenone ( DRSP ; n = 40 ) , a testosterone- and spironolactone-derived molecule , respectively . Weight ( W ) declined only during E/DRSP ( p < 0.04 versus placebo ) . Fat mass ( FM ) decreased , similarly , during E/NETA and E/DRSP . Intracellular water ( ICW ) did not change , while extracellular water ( ECW ) decreased during E/DRSP ( p < 0.0001 ) ( p < 0.002 versus E/NETA ) . During E/NETA and E/DRSP , similar decreases were observed for insulin resistance ( IR ) by the homeostatic model assessment for IR ( HOMA-IR ) ( p < 0.0001 versus placebo for both ) , systolic ( p < 0.04 versus placebo for both ) and diastolic ( p < 0.002 ) blood pressure ( BP ) . Lipids did not change . In comparison to placebo CS , by the Kupperman Index ( KI ) , significantly declined ( p < 0.0001 ) during E/NETA or E/DRSP . Menopause-specific Quality of Life ( MENQoL ) significantly declined versus placebo ( p < 0.04 ) during both E/NETA and E/DRSP . In conclusion , differences between the two progestins are mainly limited to body composition ( BC ) , where the addition of DRSP decreases ECW and body W ( BW ) Prospect i ve studies of bone mass in women following oophorectomy for benign conditions were done by the double-blind technique . Skeletal response to treatment was measured by photon absorption densitometry . Untreated patients were found to lose bone mass rapidly during the first two years after oophorectomy . When estrogen replacement was started within two months of oophorectomy , it was found to be effective in preventing subsequent bone tissue loss . Three years following oophorectomy , untreated women who had already lost bone tissue , and who were then started on estrogen replacement , showed a highly significant increase in their bone mass . The women in whom this treatment was delayed for six years did not respond . No untoward effects were noted in these women , perhaps , in part , because they had undergone hysterectomy . Long-term effects of this treatment are now being evaluated OBJECTIVES We investigated the incidence of new  non-vertebral fractures  during HRT or low-dose vitamin ( Vit ) D3 supplementation in a 5-year prospect i ve trial . METHODS A total of 464 early postmenopausal women , ( a subgroup of the Kuopio Osteoporosis Study , n = 13100 ) were r and omized to four groups : ( 1 ) HRT , a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ; ( 2 ) Vit D ( 300 IU/day and 100 IU/day during the fifth year ) ; ( 3 ) HRT + Vit D ; and ( 4 ) placebo .  Lumbar ( L2 - 4 ) and femoral neck bone mineral densities ( BMD ) were determined by dual X-ray absorptiometry ( DXA ) at baseline , after 2.5 and 5 years of treatment . All new symptomatic non-vertebral , radiographically defined fractures were recorded . RESULTS Altogether , 368 women ( 79 % ) completed the 5 year treatment . In all , 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up ( HRT 4 , Vit D 10 , HRT + Vit D 8 and placebo 17 ) . The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone ( P = 0.032 ) when adjusted by baseline BMD and previous fractures ; observed also with the intention-to-treat principle ( P = 0.048 ) . When the HRT groups were pooled , HRT showed a significantly lower incidence of new non-vertebral fractures ( P = 0.042 ) than women receiving placebo and also after adjusting as above ( P = 0.016 ) ; both in valid-case and in the intention-to-treat analysis . In the Vit D group , the fracture incidence was non-significantly decreased ( P = 0.229 ) in comparison with the placebo group . The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 ( 95 % CI , 0.10 - 0.90 ) and with Vit D 0.47 ( 95 % CI , 0.20 - 1.14 ) and with HRT + Vit D 0.44 ( 95 % CI , 0.17 - 1.15 ) , in comparison with the placebo group ( adjusted by femoral BMD and previous fractures ) . CONCLUSIONS This study is the first prospect i ve trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women . The effect of low-dose Vit D remains to be proved PURPOSE Our aim was to determine the effect of hormone replacement on physical performance measures , functional ability , physical activity , falls , and cognitive function in elderly women . SUBJECTS AND METHODS Following a 3-month , open-label , run-in phase , we r and omized 373 community-dwelling women aged 65 years and older to receive conjugated equine estrogen 0.625 mg/day plus or minus medroxyprogesterone 2.5 mg/day vs placebo for 3 years in a double-blind fashion . We assessed time to rise from a chair , timed walking , balance , Instrumental Activities of Daily Living , Physical Activity Scale of the Elderly , Folstein Mini-Mental State Examination , and falls . RESULTS Over 3 years , except for balance scores , performance measures declined significantly ( all P<.05 ) . There were no significant mean differences between women on hormone replacement versus placebo for rising time ( 0.1 , -0.5 to 0.7 seconds [ mean , 95 % confidence interval ] ) , walking normal ( 0.0 , -0.4 to 0.4 seconds ) , and walking fast ( 0.2 , -0.1 to 0.6 seconds ) . There were no significant mean differences between the two groups for the Instrumental Activities of Daily Living ( 0.1 , -0.1 to 0.3 points ) , Physical Activity Scale of the Elderly ( -3 , -15 to 8 points ) , Folstein Mini-Mental State Examination ( -0.1 , -0.3 to 0.3 points ) , or the proportion of participants reporting falls ( -1 , -11 to 9 % ) . CONCLUSION In elderly women , hormone replacement had no statistically significant effect on cognition or balance , nor did it prevent the age-related decline in physical measures of mobility , ability to rise from a chair , self-reported activities of daily living , physical activity scores , or falls 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 CONTEXT The Women 's Health Initiative Memory Study ( WHIMS ) previously found increased risk for dementia and no effect on mild cognitive impairment ( MCI ) in women treated with conjugated equine estrogens ( CEE ) plus medroxyprogesterone acetate ( MPA ) .  OBJECTIVE To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled clinical trials of CEE ( estrogen-alone trial ) or CEE plus MPA ( estrogen plus progestin trial ) in community-dwelling women aged 65 to 79 years , conducted from June 1995 to July 8 , 2002 ( estrogen plus progestin ; n = 4532 ) , or to February 29 , 2004 ( estrogen-alone ; n = 2947 ) , in 39 of the 40 WHI clinical centers . INTERVENTIONS In the estrogen-alone trial , 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo ; in the estrogen plus progestin trial , 1 daily tablet containing CEE ( 0.625 mg/d ) plus MPA ( 2.5 mg/d ) vs matching placebos . MAIN OUTCOME MEASURES Probable dementia and MCI . RESULTS In the estrogen-alone trial , 47 participants were diagnosed with probable dementia  , of whom 28 were assigned to CEE and 19 to placebo ( hazard ratio [ HR ] , 1.49 ; 95 % confidence interval [ CI ] , 0.83 - 2.66 ) . Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial ( 45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo , respectively ; P = .11 ) . When data were pooled per the original WHIMS protocol , the overall HR for probable dementia was 1.76 ( 95 % CI , 1.19 - 2.60 ; P = .005 ) . After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point , the HR was 1.77 ( 95 % CI , 0.74 - 4.23 ; P = .20 ) in the estrogen-alone trial and 2.19 ( 95 % CI , 1.25 - 3.84 ; P = .006 ) in the pooled trials . In the estrogen-alone trial , 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group ( HR , 1.34 ; 95 % CI , 0.95 - 1.89 ) . In the combined trial data , the HR was similar ( 1.25 ; 95 % CI , 0.97 - 1.60 ) . In the estrogen-alone trial , 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo ( HR , 1.38 ; 95 % CI , 1.01 - 1.89 ; P = .04 ) . CONCLUSIONS Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined . Pooling data for estrogen alone and estrogen plus progestin result ed in increased risks for both end points . Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended BACKGROUND The Women 's Health Initiative ( WHI ) clinical trial of conjugated equine estrogens ( CEEs ) , involving 10,739 postmenopausal women with hysterectomy , aged 50 to 79 years , was stopped early owing to lack of overall health benefit and increased risk of stroke . Because CEE is still prescribed for treatment of menopausal symptoms and prevention of osteoporosis , it is important to underst and the overall impact of this therapy on health-related quality of life ( HRQOL ) . METHODS All participants completed 6 specific measures of quality of life at baseline and 1 year , and a sub sample ( n = 1189 ) also completed the questions 3 years after r and omization . Changes in scores were analyzed for treatment effect . RESULTS R and omization to CEE was associated with a statistically significant but small reduction in sleep disturbance at year 1 compared with baseline ( mean benefit , 0.4 points on a 20-point scale ) and a statistically significant but small negative effect on social functioning ( mean effect , -1.3 points on a 100-point scale ) . There were no significant improvements due to CEE in the areas of general health , physical functioning , pain , vitality , role functioning , mental health , depressive symptoms , cognitive function , or sexual satisfaction at year 1 . A subgroup examined 3 years after baseline had no significant benefits for any HRQOL outcomes . Among women aged 50 to 54 years with moderate to severe vasomotor symptoms at baseline , CEE did not improve any of the HRQOL variables at year 1 . CONCLUSION In this trial of postmenopausal women with prior hysterectomy , oral CEE did not have a clinical ly meaningful effect on HRQOL 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 Objective : To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to , and further from , menopause . Methods : In this r and omized , double-blind , placebo-controlled trial , healthy women within 6 years of menopause or 10 + years after menopause were r and omly assigned to oral 17β-estradiol 1 mg/d or placebo .  Women with a uterus received cyclic micronized progesterone vaginal gel or placebo . The primary outcome assessed at 2.5 and 5 years , compared between treatment groups , was change in a st and ardized composite of neuropsychological test scores assessing verbal episodic memory . Secondary outcomes assessed executive functions and global cognition . Results : A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months . For verbal memory , the mean estradiol minus placebo st and ardized difference in composite scores ( −0.06 , 95 % confidence interval −0.22 to 0.09 ) was not significant ( 2-tailed p = 0.33 ) . Differences were similar in early and late postmenopause groups ( 2-tailed interaction p = 0.88 ) . Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition . Conclusions : Estradiol initiated within 6 years of menopause does not affect verbal memory , executive functions , or global cognition differently than therapy begun 10 + years after menopause . Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause . Classification of evidence : This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10 + years after menopause Midlife vascular risk factors influence later cognitive decline and Alzheimer 's disease ( AD ) . The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk , such as high blood pressure ( BP ) , which independently contributes to cognitive dysfunction and AD . We describe the extent to which vascular risk factors relate to cognition in healthy , middle-aged , recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study ( KEEPS-Cog ) at baseline . KEEPS-Cog is a double-blind , r and omized , placebo-controlled , parallel group , clinical trial , investigating the efficacy of low-dose , transdermal 17β-estradiol and oral conjugated equine estrogen on cognition . All results are cross-sectional and represent baseline data only . Analyses confirm that the KEEPS-Cog cohort ( n = 571 ) was middle aged ( mean 52.7 years , range 42 - 59 years ) , healthy , and free of cognitive dysfunction .  Higher systolic BP was weakly related to poorer performance in auditory working memory and attention ( p = 0.004 ; adjusted for multiple comparisons p = 0.10 ) . This relationship was not associated with endogenous hormone levels , and systolic BP was not related to any other cognitive domain . BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy , recently menopausal women . Lower BP early in menopause may affect cognitive domains known to be associated with AD 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 The aim of this study was to evaluate the efficacy of pulsed estrogen therapy ( intranasal 17β-estradiol ) in the prevention of  postmenopausal bone loss . A total of 386 women ( 40–65 years old ) , less than 5 years past menopause , were r and omized to intranasal placebo , 17β-estradiol 150 µg , or 300 µg daily for 2 years . Women with an intact uterus received micronised progesterone 200 mg per day , 14 days of each 28-day cycle . Women r and omised to placebo-treatment received placebo progesterone . The primary endpoints were changes in BMD at the spine ( L2–L4 ) and femoral neck . Secondary endpoints were changes in bone turnover markers : serum osteocalcin ( sOC ) as a marker of bone formation and urinary C-terminal telopeptides ( uCTX ) as a marker of bone resorption . BMD increased at all measured sites in women receiving active treatment in a dose-related manner , the difference compared to placebo being 5.2 % and 6.7 % at the spine , and 3.2 % and 4.7 % at the hip , respectively , with 150 μg and 300 μg ( P<0.001 ) . On the other h and , a decrease versus baseline of −3.2 % and −3.3 % at the spine and hip , respectively , was observed in women receiving placebo ( P<0.001 ) . In the patients with at least one risk factor for osteoporotic fracture , the difference between placebo and 150 μg or 300 µg was even higher at the spine ( 5.4 % and 7.4 % , respectively ) , and at the femoral neck ( 4.0 % and 5.2 % , respectively ) . Correspondingly , uCTX decreased from baseline by 39 % and 46 % , and sOC by 22 % and 27 % , in the 150 µg group and 300 µg group ( all P<0.001 versus placebo ) . A strong correlation was found between variations of bone turnover markers after 1 year and BMD after 2 years , emphasizing that bone markers can predict BMD response during hormonal treatment . Acceptability and general tolerance were good . This study demonstrates that pulsed estrogen therapy at the dose of 150 μg and 300-μg per day prevents bone loss in a dose-dependant manner at each site studied , and normalizes bone turnover markers to premenopausal levels The Estrogen Replacement and Atherosclerosis ( ERA ) trial is a three-arm , r and omized , placebo-controlled , double-blind trial to evaluate the effects of estrogen replacement therapy ( 0.625 mg/day oral conjugated estrogen ) with or without continuous low-dose progestin ( 2.5 mg oral medroxyprogesterone acetate/day ) versus placebo on progression of atherosclerosis .  A total of 309 postmenopausal women at five sites underwent baseline coronary angiography and were r and omized . Participants will have repeat coronary angiography  after an average of 3.25 years of treatment . The primary outcome of interest will be change in minimum diameter of the major epicardial segments , as assessed by quantitative coronary angiography . The primary aim is to test the hypothesis that either form of hormone therapy will slow the progression or induce regression of coronary atherosclerosis compared to placebo . The secondary aims are to assess the effects of the two treatments versus placebo on endothelial function ( measured using flow-mediated vasodilator responses ) , on several presumed mediators of estrogen 's effect on atherosclerosis ( i.e. , plasma lipids and lipoproteins , blood pressure , glucose metabolism , hemostatic factors , and antioxidant activity ) , on other factors that influence the development of coronary heart disease ( i.e. , diet , smoking status , exercise , weight , and health-related quality of life issues ) , and on clinical cardiovascular events . The ERA trial is the first angiographic endpoint clinical trial to examine the effects of postmenopausal hormone replacement on  coronary atherosclerosis in women . It will provide an unparalleled opportunity to determine if either regimen of hormone therapy is effective in slowing the progress of angiographically defined coronary atherosclerosis . This study will complement other estrogen replacement trials , such as the PEPI , HERS , and Women 's Health Initiative studies , to provide a more comprehensive examination of the effects of estrogen replacement on cardiovascular risk factors , anatomic and functional manifestations of atherosclerosis , and risk for coronary heart disease in postmenopausal women . Control Clin Trials 2000;21:257 - Objective Although joint symptoms are commonly reported after menopause , observational studies examining exogenous estrogen ’s influence on joint symptoms provide mixed results . Against this background , estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women ’s Health Initiative r and omized , placebo-controlled , clinical trial . Methods A total of 10,739 postmenopausal women who have had a hysterectomy were r and omized to receive daily oral conjugated equine estrogens ( 0.625 mg/d ) or a matching placebo . The frequency and severity of joint pain and joint swelling were assessed by question naire in all participants at entry and on year 1 , and in a 9.9 % r and om sub sample ( n = 1,062 ) after years 3 and 6 . Logistic regression models were used to compare the frequency and severity of symptoms by r and omization group . Sensitivity analyses evaluated adherence influence on symptoms . Results At baseline , joint pain and joint swelling were closely comparable in the r and omization groups ( about 77 % with joint pain and 40 % with joint swelling ) . After 1 year , joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group ( 76.3 % vs 79.2 % , P = 0.001 ) , as was joint pain severity , and the difference in pain between r and omization groups persisted through year 3 . However , joint swelling frequency was higher in the estrogen-alone group ( 42.1 % vs 39.7 % , P = 0.02 ) . Adherence-adjusted analyses strengthen estrogen ’s association with reduced joint pain but attenuate estrogen ’s association with increased joint swelling . Conclusions The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain There is growing and consistent evidence that estrogen use in postmenopausal women is associated with a substantial reduction in the occurrence of cardiovascular disease . However , remarkably little is known about the biological mechanisms by which estrogen therapy may influence risk . Even less information is available on the cardiovascular effects of combined estrogen-progestin use . PEPI was not design ed to test whether estrogen and estrogen-progestin therapy is efficacious in the prevention of cardiovascular disease , as a much larger trial with clinical disease outcomes is needed to answer that question . However , PEPI will provide critical evidence regarding the potential effectiveness of the various estrogen and estrogen/progestin regimens ni altering risk factors for cardiovascular disease in women . Detailed information on factors such as adherence , side effects , and general patient acceptability will also be ascertained . The main results from PEPI will provide the scientific community with information on the basic actions of estrogen and estrogen/progestin therapy  on four biological systems believed to be causally associated with cardiovascular disease occurrence . Further , since the trial is design ed to continue for 3 years , PEPI will be able to provide information on longer term as well as short-term effects on these systems . Finally , the results from PEPI should enable women and their physicians to select an optimal hormonal regimen , i.e. , one that is acceptable , safe , and provides the most beneficial and least deleterious changes in cardiovascular and other risk factors Historically , estrogen replacement therapy has been advocated in postmenopausal women with anticipated benefits of alleviating perimenopausal symptoms , slowing osteoporosis and preventing heart disease . While the first two effects are known , estrogen ’s role in the prevention of heart disease is unclear . Recommendations for postmenopausal estrogen replacement therapy for heart disease prevention are largely based on clinical , animal model , and tissue-culture studies demonstrating improvements in cardiovascular risk factors and experimental atherosclerosis and numerous observational studies showing fewer cardiovascular events among estrogen users than among non-users1 - 4 . However , definite conclusions regarding estrogen use for the prevention of heart disease can not be ascertained based on these data , due to study limitations and biases . Thus , r and omized clinical trials were needed to further clarify the role of postmenopausal estrogen replacement in the prevention of heart disease . The Heart and Estrogen/progestin Replacement Study ( HERS ) sought to establish the role of hormone replacement therapy for secondary prevention of coronary heart disease5 . But , contrary to expectations , 4.1 years of oral conjugated estrogen plus medroxyprogesterone acetate demonstrated no favorable effects over placebo in either primary ( non-fatal myocardial infa rct ion and coronary heart disease death ) or secondary outcomes . In fact , there was a statistically significant increase in coronary heart disease events in the treatment group compared to the placebo group during the first year . Various theories emerged as research ers attempted to underst and the HERS findings . Some wondered if medroxyprogesterone acetate decreased estrogen ’s favorable effects6 , while others suggested that other unrecognized effects , such as proinflammatory or prothrombotic effects , could be negating estrogen ’s favorable effects on the endothelium and lipids7 Estrogen replacement therapy confers many beneficial effects to postmenopausal women , such as slowing the rate of bone loss and decreasing the risk of coronary artery disease . This multicenter , placebo-controlled study evaluated the lowest effective daily dose of estrone sulfate ( 0.3 , 0.625 , or 1.25 mg ) combined with 1000 mg elemental calcium supplementation for preventing bone loss in the immediate postmenopausal period . Spinal bone mineral density was measured using quantitative computed tomography . Compared with baseline , bone mineral density increased significantly ( P<.05 ) after 12 months of 0.625 mg daily ( + 1.9 % ) or 1.25 mg daily ( + 2.5 % ) . The difference between the 0.625-mg and 1.25-mg doses was not statistically significant . Estrone sulfate administration ( 0.625 and 1.25 mg ) produced significant changes in various lipid measurements at both the 6- and 12-month observation points . The prevalence rates for adverse events were comparable among the estrone sulfate groups and the placebo group . Estrone sulfate 0.625 mg daily , combined with 1000 mg elemental calcium supplementation , was the minimum effective dosage to prevent loss of spinal bone mineral density  in postmenopausal women over a 12-month period 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 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 Premenopausal women have a relatively lower risk of ischemic heart disease ( IHD )  compared to age matched men and this gender gap narrows after menopause . The observation that the onset of IHD occurs 10 years later in women than it does in men is said to suggest that endogenous reproductive hormones play a protective role . Indeed , animal models and human epidemiological studies suggest that oophorectomy is a risk factor for accelerated IHD . In animal models , hormone therapy ( HT ) has anti-atherosclerotic effects after oophorectomy , HT in the form of oral contraceptives ( OCs ) prevents atherosclerosis in anovulatory cycling women , and large numbers of premenopausal women taking OCs have relative safety from an IHD st and point ( 1 ) . Further , observational epidemiological studies in humans have consistently demonstrated protective effects for IHD among HT users . Such studies are typically performed on relatively younger women where  HT  is prescribed for  vasomotor symptoms during menopausal transition or shortly following menopause . In contrast , clinical trials in older , postmenopausal and often asymptomatic women have demonstrated no overall benefit and early adverse effects when r and omized to a variety of forms of HT ( 1 ) . These data discrepancies have called into question the validity of the reproductive hormone estrogen protection hypothesis , and raise the alternative possibility that  HT efficacy may differ according to the timing of exposure . Stated as a simple question , is the effect of HT on the risk of IHD in relatively young pre- or early menopausal women with vasomotor symptoms , different than it is in older , fully menopausal women ? Data from the Women ’s Ischemia Syndrome Evaluation ( WISE ) , a prospect i ve multi-center NHLBI-sponsored study design ed to explore female-specific pathophysiology in a large sample of women undergoing coronary angiography for suspected IHD ( 2 ) , may shed light on this controversy . These new data , prospect ively obtained using novel methods , including detailed reproductive health question naires , menopausal adjudication algorithms , and quantitative coronary angiography as a measure of atherosclerosis , allow a more precise inspection of this question . However , to answer this simple question we need to first answer others . Specifically , how can we integrate and underst and the findings from the available observational , animal and clinical trial data ? And to interpret these data other questions become relevant : 1 ) How accurately was menopause assessed in prior observational HT studies ? 2 ) Does HT in premenopausal women in the form of OC therapy confirm atherosclerosis benefit ? and 3 ) Does HT in early menopausal women confer reduced atherosclerosis and benefit on the risk of IHD Objective : To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years . Design : This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial , a r and omized , placebo-controlled , double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol .  Four hundred seventeen postmenopausal women , aged 60 to 80 years , were r and omly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d ( n = 208 ) or placebo ( n = 209 ) . Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a st and ardized question naire . Results : At baseline , 16 % of women reported hot flashes , 32 % reported vaginal dryness , and 35 % reported trouble sleeping . Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes , vaginal dryness , or sleep difficulties than those who received placebo . Treatment with ultralow-dose estradiol did not cause breast tenderness , uterine bleeding , or other symptoms often attributed to estrogen , but vaginal discharge was more common in women who received estradiol compared with those who received placebo . Conclusion : In this population of older , largely asymptomatic women , ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge . Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger , more symptomatic women R and omized , controlled trial data from the Heart and Estrogen-progestin Replacement Study were used to evaluate the effect of estrogen plus progestin use on all-cause mortality in women with heart failure and coronary disease . Over the 4.1-year follow-up , estrogen plus progestin use had no effect on all-cause mortality ( hazard ratio 1.0 , 95 % confidence interval 0.7 to 1.4 , p = 0.8 ) in women with heart failure and coronary disease Abstract . A 2‐year double‐blind trial design ed for study ing the separate and combined effects of bendroflumethiazide ( BFTZ ) and cyclical administration of 17β‐estradiol + estriol/norethisterone ( E/N ) on coronary risk factors and bone mineral loss ( reported elsewhere ) was undertaken . Serum lipids , fasting blood glucose , body weight and blood pressure were measured every 3 months in 97 normal women in their early menopause . All participants received a supplement of 500 mg calcium and were r and omized to one of the following treatment groups : 1 ) placebo ( P ) + P ( n = 33 ) ; 2 ) P + E/N ( n = 21 ) ; 3 ) BFTZ + E/N ( n = 22 ) ; and 4 ) BFTZ + P ( n = 21 ) OBJECTIVES Hypoestrogenism occurring in association with the menopause may result in the development of vasomotor symptoms and it may also have a detrimental effect on psychological well being and quality of life ( QOL ) . The aims of this study were to measure menopausal symptoms , mood and QOL in postmenopausal Chinese women and to assess the effect of different doses of oestrogen on these outcome indicators . METHODS A prospect i ve , r and omized , placebo-controlled study of the effect of 1 and 2 mg oestradiol on menopausal symptoms , anxiety and depressive symptoms , and QOL in 152 postmenopausal women over a 12 month study period .  Menopausal symptoms were measured using a modified Kupperman 's scale . Anxiety and depressive symptoms and QOL were measured using the Hospital Anxiety and Depression Scales and a modification of the World Health Organization Quality of Life question naire , respectively . RESULTS Baseline scoring of vasomotor symptoms in our population was low whilst QOL scoring was relatively high . Over 12 months , after adjustment for differences in baseline scoring , there was a significant reduction in menopausal symptom scores in the 2 mg oestradiol group compared with placebo but not in the 1 mg group . There were no statistically significant changes in levels of anxiety and depression or QOL in either the 1 or the 2 mg group compared with placebo . CONCLUSIONS These results suggest that relatively few Chinese women will be expected to benefit from hormone replacement in terms of either QOL or mood . In addition , the overall benefit of treatment for vasomotor symptoms will be less for a given number of Chinese women than for Caucasians . Therefore , when considering the reasons for prescribing hormone replacement therapy in this population , protection against osteoporosis will for most women be the prime consideration Objective : To examine whether the effect of postmenopausal hormone therapy ( HT ) on brain volumes in women aged 65–79 years differs depending on type 2 diabetes status during postintervention follow-up of a r and omized controlled clinical trial . Methods : The Women 's Health Initiative r and omized clinical trials assigned women to HT ( 0.625 mg/day conjugated equine estrogens with or without 2.5 mg/day medroxyprogesterone acetate ) or placebo for an average of 5.6 years . A total of 1,402 trial participants underwent brain MRI  2.4 years after the trials ; these were repeated in 699 women 4.7 years later . General linear models were used to assess the interaction between diabetes status and HT assignment on brain volumes . Results : Women with diabetes at baseline or during follow-up who had been assigned to HT compared to placebo had mean decrement in total brain volume of −18.6 mL ( 95 % confidence interval [ CI ] −29.6 , −7.6 ) . For women without diabetes , this mean decrement was −0.4 ( 95 % CI −3.8 , 3.0 ) ( interaction p = 0.002 ) . This interaction was evident for total gray matter ( p < 0.001 ) and hippocampal ( p = 0.006 ) volumes . It was not evident for changes in brain volumes over follow-up or for ischemic lesion volumes and was not influenced by diabetes duration or oral medications . Conclusions : For women aged 65 years or older who are at increased risk for brain atrophy due to type 2 diabetes , prescription of postmenopausal HT is associated with lower gray matter ( total and hippocampal ) volumes . Interactions with diabetes and insulin resistance may explain divergent findings on how estrogen influences brain volume among older women BACKGROUND Although the Women 's Health Initiative ( WHI ) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group , the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer . We analyzed features of the colorectal cancers that developed and their relation to the characteristics of the participants . METHODS In the WHI trial , 16,608 postmenopausal women who were 50 to 79 years of age and had an intact uterus were r and omly assigned to a combination of conjugated equine estrogens ( 0.625 mg per day ) plus medroxyprogesterone acetate ( 2.5 mg per day ) or placebo . The main outcome measures were the incidence , stages , and types of colorectal cancer , as determined by blinded central adjudication . RESULTS There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group ( hazard ratio , 0.56 ; 95 percent confidence interval , 0.38 to 0.81 ; P=0.003 ) . The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes ( mean + /-SD , 3.2+/-4.1 vs. 0.8+/-1.7 ; P=0.002 ) and were more advanced ( regional or metastatic disease , 76.2 percent vs. 48.5 percent ; P=0.004 ) . In exploratory analyses , women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding ( 3.8+/-4.3 vs. 0.7+/-1.5 nodes , P=0.006 ) . CONCLUSIONS Relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer . However , colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo OBJECTIVE : To estimate the effect of 2 years of treatment with ultralow-dose transdermal estradiol ( E2 ) on  incontinence in postmenopausal women . METHODS : Ultra Low Dose Transdermal estRogen Assessment ( ULTRA ) was a multicenter , r and omized , double-blinded , placebo-controlled trial of unopposed ultralow-dose ( 0.014 mg/d ) transdermal E2 for prevention of osteoporosis in 417 postmenopausal women aged 60 to 80 years .  Frequency of incontinence episodes was assessed at baseline and after 4 months and 2 years of treatment using a self-reported question naire . We used an intention-to-treat analysis to compare change in incontinence frequency , improved ( decreased 2 or more episodes per week ) , unchanged ( increased or decreased no more than 1 episode per week ) , or worsened ( increased 2 or more episodes per week ) between the E2 and placebo groups among women with and without at least weekly incontinence at baseline . RESULTS : At baseline , the prevalence of at least weekly incontinence was similar between E2 and placebo groups ( 43 % ) . After 2 years , there was no difference between groups in the proportions of women with incontinence at baseline whose incontinence improved , worsened , or was unchanged . The odds ratio for worsening incontinence in the E2 compared with placebo group was 1.35 ( 95 % confidence interval 0.75–2.42 . In women without incontinence at baseline , the odds of developing at least weekly incontinence after 2 years in the E2 compared with placebo group was not significant ( odds ratio 1.2 , 95 % confidence interval 0.7–2.2 ) . CONCLUSION : Two years of treatment with unopposed ultralow-dose transdermal E2 did not substantially change the frequency of incontinence symptoms or alter the risk of developing at least weekly incontinence . LEVEL OF EVIDENCE : OBJECTIVES To evaluate the effect of ultra-low-dose ( 0.25 mg/d ) micronized 17beta-estradiol on cognitive function in older postmenopausal women . DESIGN R and omized , placebo-controlled trial conducted for 3 years . SETTING Academic health center in greater Hartford , Connecticut . PARTICIPANTS Fifty-seven healthy , community-dwelling , older postmenopausal women . INTERVENTION Women received 0.25 mg/d of micronized 17beta-estradiol ( estrogen therapy ( ET ) , n=32 ) or placebo ( n=25 ) ; all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months . MEASUREMENTS Neuropsychological measures of memory , language , mood , and executive function were collected at baseline , 3 months , and 36 months . Measures of executive function included the Controlled Oral Word Association Test , the Trail Making Test , and the Wisconsin Card Sorting Test . The Boston Naming Test was used to measure language skills . The Symbol Digit Modalities Test was used as a measure of sustained attention . Measures of memory included the Complex Figure Test , Fuld Object Memory Test , and a selected subtest from the Wechsler Memory Scale . Scores from the Geriatric Depression Scale and the Beck Anxiety Inventory were used to assess symptoms of depression . RESULTS No differences were found between ET and placebo on any of the neurocognitive measures or depression instruments , nor were there any differences when the groups were stratified according to age . CONCLUSION This small study , which had adequate power to detect change in some but not all domains of cognition tested , revealed that low-dose estrogen neither benefits nor harms cognitive function in older women after 3 years of treatment , but confirmation is needed from larger trials Context Risk factors for recurrent events among women with known coronary disease and whether these women commonly receive secondary prevention treatments are mostly unknown . Contribution This large cohort study showed that 11 different factors , including several previous infa rct ions , renal dysfunction , diabetes , angina , heart failure , and uncontrolled hypertension , predicted up to a sixfold increased rate of coronary disease events in postmenopausal women with preexisting coronary disblockers , angiotensin-converting enzyme inhibitors , or cholesterol-lowering drugs . Implication s Clinicians can identify women who have high risks for recurrent coronary events and should promote greater use of secondary prevention treatments for them . The Editors Coronary heart disease ( CHD ) is the leading cause of death in women . The major independent risk factors that predict CHD onset in healthy women are similar to those identified by epidemiologic studies of healthy men ( 1 - 7 ) . A recent report described six independent risk factorsage , low-density lipoprotein ( LDL ) and high-density lipoprotein ( HDL ) cholesterol levels , high blood pressure , diabetes mellitus , and smokingthat were strongly associated with risk for a first CHD event in both men and women ( 8) . However , the strength of the association of certain risk factors with CHD events may vary by sex ( 9 ) as well as age . Diabetes may be a stronger risk factor in women than in men ( 7 ) ; among older women , HDL cholesterol level may be a relatively strong risk factor and LDL cholesterol level a relatively weak one ( 6 ) . In the period immediately after myocardial infa rct ion ( MI ) , studies of mostly male sample s have found that persistent ischemia , impaired left ventricular systolic function , and ventricular arrhythmias are the major determinants of subsequent MI and death ( 10 - 13 ) . In the Coronary Drug Project study of men with a history of heart attack , electrocardiographic abnormalities and heart failure  were stronger predictors than the atherosclerosis risk factors identified in primary prevention setting s ( 14 ) . However , the risk factors for coronary events among women with recognized but stable coronary disease are mostly unknown . Better underst and ing of these factors could improve secondary prevention in this large and high-risk group . The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of estrogen plus progestin for prevention of CHD events in women with coronary disease ( 15 ) . Overall , no significant differences were noted between the hormone and placebo groups in CHD events ; trends of more CHD events with therapy in year 1 were offset by fewer such outcomes during years 4 and 5 . The trial collected extensive data on CHD risk factors and medication use and performed exhaustive outcome ascertainment procedures , with complete mortality follow-up . Therefore , HERS offers a unique opportunity to assess the long-term effect of coronary risk factors and use of recommended treatments in women with established coronary disease . Methods Participants Participants in HERS were postmenopausal women who were younger than 80 years of age , had not had a hysterectomy , and had known coronary artery disease ( MI , coronary artery bypass surgery , percutaneous transluminal coronary angioplasty , or angiographic evidence of 50 % narrowing of one or more major coronary arteries ) . Women were excluded if they had had a coronary event within the 6 months before r and omization , had a serum triglyceride level greater than 3.39 mmol/L ( 300 mg/dL ) , had used hormones within 3 months , or had a history of conditions that would contraindicate estrogen therapy ( 16 ) . Participants in HERS were r and omly assigned within clinical centers to 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate in one tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . The institutional review boards at the coordinating center and each of the 20 HERS clinical centers approved the protocol , and all participants provided written informed consent . Predictors In the baseline interview , information was obtained by self-report on demographic characteristics , behavioral risk factors , and medical history . Among women who reported ever having smoked at least 100 cigarettes , years of smoking , average cigarettes per day , and current smoking were ascertained . Alcohol use in the past 30 days was assessed for frequency and usual numbers of drinks per occasion .  Exercise  was measured as participation in a regular exercise program such as cardiac rehabilitation or aerobics or walking at least occasionally for exercise more than 10 minutes at a time . Use of  aspirin , -blockers , lipid-lowering medications ( statins , niacin , fibrates , bile acidbinding resins , and probucol ) , angiotensin-converting enzyme ( ACE ) inhibitors , calcium antagonists , and folate or vitamin B was assessed by self-report . In the baseline physical examination , blood pressure , waist-to-hip ratio , and body mass index were measured . A physician assessed history and symptoms of heart failure ( jugular venous distention , third heart sound , significant murmurs , pulmonary rales , and peripheral edema ) . High blood pressure was defined as systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg , according to the Sixth Report of the Joint National Committee on Prevention , Detection , Evaluation and Treatment of High Blood Pressure ( 17 ) . Angina was defined as self-report of chest discomfort in the previous 4 weeks during exercise , emotion , or sexual activity . Serum specimens were obtained , and a central ized laboratory measured fasting levels of LDL cholesterol , HDL cholesterol , lipoprotein(a ) , triglycerides , glucose , and creatinine ( 15 , 16 ) . Creatinine clearance was estimated by using the CockcroftGault equation ( 18 , 19 ) . Outcomes The primary HERS outcome was CHD events , defined as nonfatal MI or CHD death . Suspected outcome events were reported within 24 hours to the coordinating center and were systematic ally assessed every 4 months at the follow-up contacts . An independent morbidity and mortality subcommittee that was blinded to treatment assignment adjudicated all deaths and suspected outcome events . Nonfatal MI was diagnosed by using an algorithm based on ischemic symptoms , electrocardiographic abnormalities , and elevated cardiac enzyme levels ( 16 ) . Death from CHD included fatal documented MI , sudden death within 1 hour of symptom onset , unobserved death that occurred out of the hospital in the absence of other known causes , or death due to a coronary revascularization procedure or congestive heart failure . The date of each event was determined from the documentation obtained by the clinical centers . The total number of events reported here is slightly larger than that published in the primary HERS results ( 15 ) because of subsequent adjudications ( 20 ) . Statistical Analyses We used multivariable Cox proportional-hazards models to assess the associations between risk factors and CHD events . These models were stratified by clinical center to account for potential clustering . Waist-to-hip ratio and LDL and HDL cholesterol levels were modeled as continuous variables , but lipoprotein(a ) level was dichotomized at the median and creatinine clearance was dichotomized at 0.66 mL/s ( 40 mL/min ) to reflect the nonlinear responses we have reported elsewhere ( 19 , 21 ) . We used an indicator for any alcohol use , since almost all of the 39 % of HERS women who reported alcohol use were light or moderate drinkers . Exercise was modeled by an indicator for participation in an exercise program or walking for exercise for more than 10 minutes . The multivariable model includes previously identified risk factors that were significant ( P 0.20 ) in unadjusted models and were not judged redundant on substantive grounds . Body mass index was excluded because it was clearly nonsignificant after adjustment ( P > 0.2 ) and was also highly correlated with waist-to-hip ratio , which was the stronger predictor in unadjusted analysis . Similarly , triglyceride levels were excluded because of their strong negative correlation with HDL cholesterol levels , which in our judgment were more likely to be causal . We also controlled for use of aspirin , statins , other lipid-lowering medications , diuretics , -blockers , ACE inhibitors , calcium antagonists , and folate or vitamin B. The effect of assignment to hormone therapy was modeled separately for each year of follow-up , as in the post hoc analysis of HERS ( 15 ) . Interactions between risk factors and relevant treatments were also examined . Specifically , we compared hazard rates among patients with diagnosed diabetes who reported use of insulin or oral hypoglycemic agents  with rates in the combined group of diabetic persons not using these medications and women with fasting glucose levels greater than 6.94 mmol/L ( > 125 mg/dL ) but no history of diabetes diagnosis . Likewise , we compared estimates for LDL and HDL cholesterol levels stratified by use of any lipid-lowering medication or assignment to hormone therapy ; for lipoprotein(a ) level , stratified by assignment to hormone therapy ; for high blood pressure on examination , stratified by use of at least one antihypertensive medication ; for heart failure and creatinine clearance less than or equal to 0.66 mL/s ( 40 mL/min ) , stratified by use of ACE inhibitors ; and for more than one previous MI and angina , stratified by use of any indicated medications . The final model includes interactions that were significant at a P value less than or equal to 0.2 . We used residuals to assess overall model fit , validity of the proportional hazards assumption , and linearity of associations with continuous predictors . The study lacked power to examine interactions between clinical center and potential risk factors . We tested the assumption of noninformative censoring by considering the two extremes of the possible outcomes OBJECTIVE Our purpose was to investigate the long-term effects of raloxifene , compared with opposed and unopposed estrogen replacement therapy , on echocardiographic parameters of left ventricular systolic function in healthy postmenopausal women . A total of 157 women were studied in 2 r and omized , double-blind , placebo-controlled , 2-year studies . STUDY DESIGN In study I , 60 postmenopausal women who had undergone hysterectomy received daily raloxifene , 60 mg ( n = 15 ) ; raloxifene , 150 mg ( n = 15 ) ; conjugated equine estrogens ( CEE ) , 0.625 mg ( n = 15 ) ; or placebo ( n = 15 ) . In study II , 97 postmenopausal women who had not undergone hysterectomy received daily raloxifene , 60 mg ( n = 24 ) ; raloxifene , 150 mg ( n = 24 ) ; CEE , 0.625 mg , plus medroxyprogesterone acetate ( MPA ) , 2.5 mg ( n = 24 ) ; or placebo ( n = 25 ) . M-mode , quantitative 2-dimensional and Doppler echocardiographic measurements were performed at baseline and after 1 and 2 years . RESULTS Neither after 1 year nor after 2 years of treatment were echocardiographic parameters found to differ from baseline in both raloxifene groups , as well as in the unopposed CEE and the CEE/MPA groups , compared with the placebo group . CONCLUSION Within 2 years of raloxifene treatment , no effect on echocardiographic parameters of left ventricular systolic function was found . Unopposed CEE or CEE/MPA also showed no effect PURPOSE During the intervention phase in the Women 's Health Initiative ( WHI ) clinical trial , use of estrogen plus progestin reduced the colorectal cancer diagnosis rate , but the cancers were found at a substantially higher stage . To assess the clinical relevance of the findings , analyses of the influence of combined hormone therapy on colorectal cancer incidence and colorectal cancer mortality were conducted after extended follow-up . PATIENTS AND METHODS The WHI study was a r and omized , double-blind , placebo-controlled clinical trial involving 16,608 postmenopausal women with an intact uterus who were r and omly assigned to daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate ( n = 8,506 ) or matching placebo ( n = 8,102 ) . Colorectal cancer diagnosis rates and colorectal cancer mortality were assessed . RESULTS After a mean of 5.6 years ( st and ard deviation [ SD ] , 1.03 years ) of intervention and 11.6 years ( SD , 3.1 years ) of total follow-up , fewer colorectal cancers were diagnosed in the combined hormone therapy group compared with the placebo group ( diagnoses/year , 0.12 % v 0.16 % ; hazard ratio [ HR ] , 0.72 ; 95 % CI , 0.56 to 0.94 ; P = .014 ) . Bowel screening examinations were comparable between groups throughout . Cancers in the combined hormone therapy group more commonly had positive lymph nodes ( 50.5 % v 28.6 % ; P < .001 ) and were at higher stage ( regional or distant , 68.8 % v 51.4 % ; P = .003 ) . Although not statistically significant , there was a higher number of colorectal cancer deaths in the combined hormone therapy group ( 37 v 27 deaths ; 0.04 % v 0.03 % ; HR , 1.29 ; 95 % CI , 0.78 to 2.11 ; P = .320 ) . CONCLUSION The findings , suggestive of diagnostic delay , do not support a clinical ly meaningful benefit for combined hormone therapy on colorectal cancer Objective To assess the possible benefit of hormone replacement therapy ( HRT ) in the secondary prevention of ischaemic heart disease The Women 's Health Initiative Memory Study -Younger ( WHIMS-Y ) was design ed to assess the effect of prior r and om assignment to hormone therapy ( HT ) ( conjugated equine estrogen ( CEE ) alone or CEE plus medroxyprogesterone acetate ( MPA ) ) on global cognitive function in younger middle-aged women relative to placebo . WHIMS-Y was an ancillary study to the Women 's Health Initiative ( WHI ) HT trial and enrolled 1361 women who were aged 50 - 55 years and postmenopausal at WHI enrollment . WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen , time between menopause and study initiation , and prior use of HT . We present the study rationale and design . We describe enrollment , adherence to assigned WHI therapy , and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment . Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups , st and ardized and masked data collection , and high rates of retention and on-trial adherence and exposure . In addition , the telephone-administered cognitive battery showed adequate construct validity . WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50 - 55 years . Integrated into the WHI , WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites . This article is part of a Special Issue entitled Hormone Therapy 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 OBJECTIVE To evaluate the tolerance and effectiveness of transdermal estrogen for women with established postmenopausal osteoporosis and vertebral fractures . DESIGN Double-blind , r and omized , placebo-controlled clinical trial lasting 1 year . SETTING Referral-based outpatient clinic . PATIENTS Seventy-five postmenopausal women , 47 to 75 years of age , with one or more vertebral fractures due to osteoporosis . INTERVENTIONS Thirty-nine women received dermal patches delivering 0.1 mg of 17 beta-estradiol for days 1 to 21 and oral medroxyprogesterone acetate for days 11 to 21 of a 28-day cycle . Another 39 women received placebo . MEASUREMENTS Bone turnover assessed by biochemical markers and iliac bone histomorphometry ; bone loss assessed by serial measurement of bone density ; and vertebral fracture rate . RESULTS Compared with the placebo group , the median annual percentage change in bone mineral density in the estrogen group reflected increased or steady-state bone mineral density at the lumbar spine ( 5.3 compared with 0.2 ; P = 0.007 ) , femoral trochanter ( 7.6 compared with 2.1 ; P = 0.03 ) , and midradius ( 1.0 compared with -2.6 , P less than 0.001 ) but showed no significant difference at the femoral neck ( 2.6 compared with 1.4 ; P = 0.17 ) . Estrogen treatment uniformly decreased bone turnover as assessed by several methods including serum osteocalcin concentration ( median change , -0.35 compared with 0.02 nmol/L ; P less than 0.001 ) . Histomorphometric evaluation of iliac biopsy sample s confirmed the effect of estrogen on bone formation rate per bone volume ( median change , -12.9 compared with -6.2 % per year ; P = 0.004 ) . Also , 8 new fractures occurred in 7 women in the estrogen group , whereas 20 occurred in 12 women in the placebo group , yielding a lower vertebral fracture rate in the estrogen group ( relative risk , 0.39 ; 95 % CI , 0.16 to 0.95 ) . CONCLUSIONS Transdermal estradiol treatment is effective in postmenopausal women with established osteoporosis Objectives This 2-year study compared 0.5 and 1.0 mg oral estradiol ( E2 ) , with or without levonorgestrel ( LNG ) , for the treatment of postmenopausal osteoporosis in Japanese women . Methods Japanese women with osteoporosis after natural menopause or bilateral oophorectomy were r and omized to receive E2 0.5 or 1.0 mg/day with LNG 40 μg as required , or placebo , for 52 weeks . Women treated with E2 in the first year continued therapy at the same doses in the second year . Efficacy , safety and pharmacokinetics were assessed . Results There were 73 women r and omized to E2 0.5 mg , 157 to E2 1.0 mg and 79 to placebo . Lumbar bone mineral density at 52 weeks increased significantly more with E2 1.0 mg ( p < 0.001 ) and 0.5 mg ( p < 0.001 ) than with placebo ( no change ) . After 2 years , a 10 % increase in bone mineral density with E2 1.0 mg was significantly greater than with E2 0.5 mg ( 8 % ; p = 0.008 ) . E2 was associated with an acceptable safety and tolerability profile , with slightly more adverse events  with E2 1.0 than 0.5 mg . Serum E2 concentration increased in a dose-dependent manner . Conclusion This study showed that E2 , at both 1.0 mg and 0.5 mg doses , was effective in increasing bone mineral density with an acceptable safety and tolerability profile in Japanese postmenopausal women with osteoporosis but that the bone mineral density response was higher with the 1.0 mg dose Surgery for premenopausal and perimenopausal patients with epithelial ovarian carcinoma may often result in significant menopausal symptoms . Physicians may well be reluctant to prescribe , and patients loathe to take , postoperative estrogen replacement therapy because they fear that supplementation may lead to ovarian carcinoma relapse . This r and omized prospect i ve study was undertaken to determine whether postoperative estrogen replacement therapy had a negative influence on the disease free interval and overall survival of ovarian carcinoma survivors 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 CONTEXT The Women 's Health Initiative ( WHI ) trial of estrogen plus progestin vs placebo was stopped early , after a mean 5.6 years of follow-up , because the overall health risks of hormone therapy exceeded its benefits . OBJECTIVE To report health outcomes at 3 years ( mean 2.4 years of follow-up ) after the intervention was stopped . DESIGN , SETTING , AND PARTICIPANTS The intervention phase was a double-blind , placebo-controlled , r and omized trial of conjugated equine estrogens ( CEE ) 0.625 mg daily plus medroxyprogesterone acetate ( MPA ) 2.5 mg daily , in 16,608 women aged 50 through 79 years , recruited by 40 centers from 1993 to 1998 . The postintervention phase commenced July 8 , 2002 , and included 15 730 women . MAIN OUTCOME MEASURES Semi-annual monitoring and outcomes ascertainment continued per trial protocol . The primary end points were coronary heart disease and invasive breast cancer . A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke , pulmonary embolism , endometrial cancer , colorectal cancer , hip fracture , and death due to other causes . RESULTS The risk of cardiovascular events after the intervention was comparable by initial r and omized assignments , 1.97 % ( annualized rate ) in the CEE plus MPA ( 343 events ) and 1.91 % in the placebo group ( 323 events ) . A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group ( 1.56 % [ n = 281 ] vs 1.26 % [ n = 218 ] ; hazard ratio [ HR ] , 1.24 ; 95 % confidence interval [ CI ] , 1.04 - 1.48 ) . More breast cancers were diagnosed in women who had been r and omly assigned to receive CEE plus MPA vs placebo ( 0.42 % [ n = 79 ] vs 0.33 % [ n = 60 ] ; HR , 1.27 ; 95 % CI , 0.91 - 1.78 ) with a modest trend toward a lower HR during the follow-up after the intervention . All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group ( 1.20 % [ n = 233 ] vs 1.06 % [ n = 196 ] ; HR , 1.15 ; 95 % CI , 0.95 - 1.39 ) . The global index of risks and benefits was unchanged from r and omization through March 31 , 2005 ( HR , 1.12 ; 95 % CI , 1.03 - 1.21 ) , indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention . CONCLUSIONS The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention . A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12 % higher in women r and omly assigned to receive CEE plus MPA compared with placebo . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 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 This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol ( ELITE ) , the only clinical trial design ed to specifically test the timing hypothesis of postmenopausal hormone therapy ( HT ) . The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause . Methods ELITE is a r and omized , double-blind , placebo-controlled trial with a 2 × 2 factorial design . Six hundred forty-three healthy postmenopausal women without cardiovascular disease were r and omized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause ( < 6 or ≥10 y ) . Carotid artery intima-media thickness ( CIMT ) and cardiac computed tomography  were conducted to determine HT effects on sub clinical atherosclerosis across menopause strata . Results Participants in the early and late postmenopausal strata were well-separated by mean age ( 55.4 vs 65.4 y ) and median time since menopause ( 3.5 vs 14.3 y ) . Expected risk factors ( age , blood pressure , and body mass index ) were associated with CIMT at baseline in both strata . In the early postmenopausal group , but not in the late postmenopausal group , we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation . These include low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , sex hormone – binding globulin , and serum total estradiol . Conclusions The ELITE r and omized controlled trial is timely and unique . Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease To eluci date the effect of smoking on estrogen metabolism , we examined 136 postmenopausal women treated for one year with one of three different doses of combined estrogen-progestogen or placebo . The women were grouped according to smoking status , and serum levels of estrone and estradiol were measured before and after treatment . The results showed reduced levels of both estrogens in smokers as compared with nonsmokers in all three dosage groups . This reduction was most pronounced in the high-dose group ( 4 mg of estradiol ) , in which the serum levels of estrone and estradiol in smokers were only 50 per cent of those in nonsmokers ( P less than 0.001 and less than 0.05 , respectively ) . In contrast , no significant changes could be demonstrated in the corresponding placebo groups . Moreover , it was possible to demonstrate significant inverse correlations between the number of cigarettes smoked daily and the changes in the levels of serum estrone and estradiol , respectively , ( P less than 0.001 ) . This study suggests that an increased hepatic metabolism of estrogens results in lower estrogen levels among postmenopausal smokers . This may contribute to the reported risk of osteoporosis among smokers CONTEXT Despite decades of use and considerable research , the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain . OBJECTIVE To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled disease prevention trial ( the estrogen-alone component of the Women 's Health Initiative [ WHI ] ) conducted in 40 US clinical centers beginning in 1993 . Enrolled were 10 739 postmenopausal women , aged 50 - 79 years , with prior hysterectomy , including 23 % of minority race/ethnicity . INTERVENTION Women were r and omly assigned to receive either 0.625 mg/d of conjugated equine estrogen ( CEE ) or placebo . MAIN OUTCOME MEASURES The primary outcome was coronary heart disease ( CHD ) incidence ( nonfatal myocardial infa rct ion or CHD death ) . Invasive breast cancer incidence was the primary safety outcome . A global index of risks and benefits , including these primary outcomes plus stroke , pulmonary embolism ( PE ) , colorectal cancer , hip fracture , and deaths from other causes , was used for summarizing overall effects . RESULTS In February 2004 , after review ing data through November 30 , 2003 , the National Institutes of Health ( NIH ) decided to end the intervention phase of the trial early . Estimated hazard ratios ( HRs ) ( 95 % confidence intervals [ CIs ] ) for CEE vs placebo for the major clinical outcomes available through February 29 , 2004 ( average follow-up 6.8 years ) , were : CHD , 0.91 ( 0.75 - 1.12 ) with 376 cases ; breast cancer , 0.77 ( 0.59 - 1.01 ) with 218 cases ; stroke , 1.39 ( 1.10 - 1.77 ) with 276 cases ; PE , 1.34 ( 0.87 - 2.06 ) with 85 cases ; colorectal cancer , 1.08 ( 0.75 - 1.55 ) with 119 cases ; and hip fracture , 0.61 ( 0.41 - 0.91 ) with 102 cases . Corresponding results for composite outcomes were : total cardiovascular disease , 1.12 ( 1.01 - 1.24 ) ; total cancer , 0.93 ( 0.81 - 1.07 ) ; total fractures , 0.70 ( 0.63 - 0.79 ) ; total mortality , 1.04 ( 0.88 - 1.22 ) , and the global index , 1.01 ( 0.91 - 1.12 ) . For the outcomes significantly affected by CEE , there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years . The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years . CONCLUSIONS The use of CEE increases the risk of stroke , decreases the risk of hip fracture , and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years . A possible reduction in breast cancer risk requires further investigation . The burden of incident disease events was equivalent in the CEE and placebo groups , indicating no overall benefit . Thus , CEE should not be recommended for chronic disease prevention in postmenopausal women The purpose of this study was to investigate the effects of 10 years of  hormone replacement therapy ( HRT ) in postmenopausal women on bone mineral density of the lumbar spine ( L-BMD ) and bone mineral content of the distal forearm ( F- BMC ) . A total of 151 women were enrolled in the study , 100 of whom were r and omized to receive oral HRT ( equally divided between a continuous combined and a sequential treatment regimen ) , with the remaining 51 receiving placebo or no treatment .  The study was double-blind for the first 24 months , followed by 8 years of open-label follow-up . Total treatment duration was 10 years . At the end of 10 years , 38 % of women r and omized to continuous combined HRT remained on therapy compared with 22 % of those who had received sequential HRT and 49 % of the untreated group . A further 18 % of women originally r and omized to HRT had switched to other regimens . After 10 years of therapy , L-BMD was found to be significantly higher in HRT-treated women than in those who remained untreated ( 14.5 % ; p < 0.001 ) , corresponding to an increase in L-BMD of 13.1 % from baseline values on HRT compared with a reduction in L-BMD of 4.7 % without therapy . L-BMD increased by 15.9 % in women receiving continuous combined therapy compared with 11.1 % in those on sequential HRT ; however , intergroup differences were not statistically significant . F- BMC decreased by 0.7 % over the 10 year period in the HRT treatment groups compared with a reduction of 17.6 % in untreated women ( p < 0.001 ) . Mean F- BMC was 20.3 % higher in women who had received HRT than in those who had not received therapy at the end of the 10 year follow-up . In conclusion , 10 years of treatment with HRT result ed in a substantial increase in L-BMD , with F- BMC also significantly higher in the HRT group than in untreated women . These results confirm that long-term HRT exerts a continuous effect against bone loss in postmenopausal women Objective To determine the lowest effective dose of an estradiol ( E2 ) matrix-type transdermal delivery system ( EMTDS ; Alora ) for preventing bone loss in postmenopausal women . Design This double-blind , double-dummy , r and omized , placebo-controlled , multicenter study enrolled 355 nonosteoporotic postmenopausal women who had been hysterectomized with or without oophorectomy at least 12 months earlier . Participants were r and omly assigned to one of three doses of the EMTDS ( 0.025 , 0.05 , or 0.075 mg/day ) or placebo administered twice weekly . Lumbar bone mineral density ( LBMD ) was measured by dual-energy x-ray absorptiometry at screening and after 1 and 2 years of treatment . Safety was assessed at regularly scheduled visits . Results EMTDS provided statistically significant and clinical ly meaningful changes in LBMD relative to placebo . At 2 years , LBMD declined from baseline by 0.59 % in the placebo group , but it increased from baseline by 1.65 % ( p = 0.0065 ) , 4.08 % ( p = 0.0001 ) , and 4.82 % ( p = 0.0001 ) in the EMTDS 0.025 , 0.05 , and 0.075 mg/day groups , respectively . The corresponding responder rates ( defined as no change or increase in LBMD at endpoint ) were 39.7 % for placebo , 59.6 % , 79.3 % , and 83.9 % in the EMTDS 0.025 , 0.05 , and 0.075 mg/day groups , respectively . Mean serum E2 concentrations were proportional to the dose of the E2 transdermal system and did not accumulate over the course of the study . Adverse events were generally comparable across treatment groups , with the majority being mild or moderate in severity and unrelated to study medication . Mammogram findings and other safety assessment s were also comparable across groups and did not reveal any safety concerns with 2-y transdermal E2 treatment . Conclusions The EMTDS ( Alora ) administered twice weekly improves lumbar bone mineral density in healthy postmenopausal women , with the benefit of treatment evident by 1 year . The lowest effective dose is 0.025 mg/day 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 Objective To determine the relationships among bone mineral density changes , bone marker changes , and plasma estrogens in postmenopausal women receiving estrogen replacement therapy .  Design A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens ( 0.3 mg , 0.625 mg , or 1.25 mg ) or placebo daily for up to 24 months . Bone mineral density and bone marker measurements were determined at 6-month intervals ; plasma estrogens were measured in a subset after 12 , 18 , and 24 months . Results Esterified estrogens produced significant increases in bone mineral density ( lumbar spine , hip ) compared with baseline and placebo at 6 , 12 , 18 , and 24 months . Bone markers decreased from baseline with all esterified estrogen doses relative to placebo . Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months ( correlation coefficient range = −0.122 to −0.439 ) . The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin . Mean plasma estrogen levels increased with esterified estrogen dose , and bone mineral density changes correlated positively with plasma estrogen levels . Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL. Conclusions Esterified estrogens , at doses from 0.3 mg to 1.25 mg/day , unopposed by progestin , increase bone mineral density of the spine and hip in postmenopausal women .  These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12 , 18 , or 24 months . Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy CONTEXT Postmenopausal hormone therapy is commonly used by women for disease prevention , but its effects on quality of life have not been well documented . OBJECTIVE To determine the effect on quality of life of estrogen plus progestin therapy used as secondary prevention in women with coronary artery disease . DESIGN , SETTING , AND PARTICIPANTS A total of 2763 postmenopausal women with documented coronary artery disease ( mean age , 67 years ) in the Heart and Estrogen/Progestin Replacement Study , a r and omized , placebo-controlled , double-blind trial conducted from January 1993 to July 1998 at outpatient and community setting s at 20 US clinical centers . INTERVENTION Participants were r and omly assigned to receive either 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate ( n = 1380 ) or placebo ( n = 1383 ) for 36 months . MAIN OUTCOME MEASURES Physical activity , measured by the Duke Activity Status Index ; energy/fatigue and mental health , measured by R AND scales ; and depressive symptoms , measured on the Burnam screening scale , at 3 years of follow-up . RESULTS In all patients , scores declined significantly over 3 years for physical function ( -3.8 ; P<.001 ) , mental health ( -0.6 ; P = .05 ) , and energy/fatigue ( -3.8 ; P<.001 ) , but depressive symptoms were not significantly changed ( P = .20 ) . The effect of hormone therapy on these measures depended on the presence ( n = 434 ) or absence ( n = 2325 ) of flushing at study entry . Women with flushing who were assigned to hormone therapy had improved mental health ( + 2.6 vs - 0.5 ; P = .04 ) and fewer depressive symptoms ( -0.5 vs + 0.007 ; P = .01 ) over follow-up compared with those assigned to placebo . Women without flushing who were assigned to hormone therapy had greater declines in physical function ( -4.2 vs -3.3 ; P = .04 ) and energy/fatigue ( -4.6 vs -3.1 ; P = .03 ) over follow-up . Quality -of-life scores were significantly lower among patients with older age , diabetes , hypertension , chest pain , or heart failure . These differences in quality of life among women classified by clinical characteristics were much greater than the effects of hormone therapy . CONCLUSION Hormone therapy has mixed effects on quality of life among older women . The effects of hormone therapy depend on the presence of menopausal symptoms ; women without flushing had greater declines in physical measures , while women with flushing had improvements in emotional measures of quality of life 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 97 women aged 37 - 58 years who had undergone bilateral oophorectomy and hysterectomy and 45 women aged 34 - 53 years who had undergone hysterectomy only voluntarily participated in a therapeutic regime and follow-up visits . The oophorectomized women were r and omly divided into two groups ; one group received 20 - 40 mcg of mestranol per day and the other group received placebo ( no medication ) tablets .  Total serum cholesterol measured by the method of Pearson Stern and McGanack serum triglycerides determined by the method of Van H and el and Zilversmit and blood sugar measured by st and ard Autoanalyzer techniques were performed . Fasting blood sample s were tested for every woman at her first visit and 40 oophorectomized women were re-tested after one year . Mean values for fasting blood sugars were in the range 50 - 110mg/100ml for both groups . Serum cholesterol rose significantly with age in women with intact ovaries . Oophorectomized women showed a significant rise in serum cholesterol at a younger age ( 43 years and under ) . Over age 46 there was no significant difference in serum cholesterol between these groups . The oophorectomized women showed a significantly slower rise of serum triglycerides with age than did the women with intact ovaries . In both groups serum triglycerides rose significantly with age . The oophorectomized women receiving mestranol showed a significant drop in serum cholesterol after one year and a significantly greater rise in serum triglycerides compared with the oophorectomized women receiving placebo treatment . No episodes of thromboembolism occurred in the mestranol-treated women OBJECTIVE To study the effects of postmenopausal hormone therapy ( PHT ) on the incidence and severity of rheumatoid arthritis ( RA ) . METHODS The Women 's Health Initiative r and omized controlled trials evaluated the effects of unopposed estrogen ( E-alone ) and estrogen plus progestin ( E+P ) compared with placebo on a diverse set of health outcomes over 7.1 and 5.6 years , respectively . RA cases were identified using historical and medication data . The hazard of developing RA was estimated using Cox proportional hazards regression models . Disease symptom severity was estimated using the Short Form 36 ( SF-36 ) and self-reported joint pain scores at baseline and after 1 year . Mean changes in severity were compared using linear regression models . RESULTS Of the 27,347 participants , 63 prevalent cases and 105 incident cases of RA were identified . A nonsignificant reduction in the risk of developing RA ( hazard ratio 0.74 ; 95 % confidence interval [ 95 % CI ] 0.51 , 1.10 ) was noted with PHT use . PHT use led to improved SF-36 scores in unadjusted analyses ( percent change 12.5 % ; 95 % CI -24.45 , -0.57 ) but not after adjustment for relevant covariates ( P = 0.33 ) . Nonsignificant improvements in joint pain scores were seen with PHT use ( odds ratio [ OR ] 4.10 ; 95 % CI 0.83 , 20.20 ) . PHT did not improve swelling ( OR 1.27 ; 95 % CI 0.08 , 19.63 ) or prevent new joint pains ( OR 0.72 ; 95 % CI 0.11 , 4.68 ) in RA participants . CONCLUSION There were no statistically significant differences in the risk of developing RA or the severity of RA between the PHT and placebo groups Treatment of 63 oophorectomised women with oestrogen for five years prevented the reduction in bone mineral content observed in 57 women treated with a placebo preparation .  When onset of therapy was delayed for three to six years there was a highly significant increase in bone mineral content mainly during the first three years of treatment . During the next two years there was no further increase in bone mineral , while the placebo-treated groups continued to lose bone at about 1 % per annum . In association with the changes in bone mass , the expected biochemical effects of oestrogen therapy also persisted for at least three years , and were compatible with a prolonged increase in parathyroid activity but a reduction in bone turnover 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 CONTEXT In the Women 's Health Initiative trial of estrogen-plus-progestin therapy , women assigned to active treatment had fewer fractures . OBJECTIVE To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial ( September 1993-July 2002 ) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years . INTERVENTION Women were r and omly assigned to receive conjugated equine estrogen , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , in 1 tablet ( n = 8506 ) or placebo ( n = 8102 ) . MAIN OUTCOME MEASURES All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial ( July 7 , 2002 ) ; bone mineral density ( BMD ) , measured in a subset of women ( n = 1024 ) at baseline and years 1 and 3 ; and a global index , developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk . RESULTS Seven hundred thirty-three women ( 8.6 % ) in the estrogen-plus-progestin group and 896 women ( 11.1 % ) in the placebo group experienced a fracture ( hazard ratio [ HR ] , 0.76 ; 95 % confidence interval [ CI ] , 0.69 - 0.83 ) . The effect did not differ in women stratified by age , body mass index , smoking status , history of falls , personal and family history of fracture , total calcium intake , past use of hormone therapy , BMD , or summary fracture risk score . Total hip BMD increased 3.7 % after 3 years of treatment with estrogen plus progestin compared with 0.14 % in the placebo group ( P<.001 ) . The HR for the global index was similar across tertiles of the fracture risk scale ( lowest fracture risk tertile , HR , 1.20 ; 95 % CI , 0.93 - 1.58 ; middle tertile , HR , 1.23 ; 95 % CI , 1.04 - 1.46 ; highest tertile , HR , 1.03 ; 95 % CI , 0.88 - 1.24 ) ( P for interaction = .54 ) . CONCLUSIONS This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women . The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined . When considering the effects of hormone therapy on other important disease outcomes in a global model , there was no net benefit , even in women considered to be at high risk of fracture Objective To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women . Design Twenty subjects were treated with oral E2 valerate ( 2 mg ) combined with cyproterone acetate ( 1 mg ) ( group I ) and 21 with transdermal E2 ( 1.5 mg ) plus oral medroxyprogesterone acetate ( 5 mg ) ( group II ) . The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3 , 6 , and 12 months of treatment . Results Group I showed a stronger increase of high-density lipoprotein ( HDL ) cholesterol levels ( 2–8 % ) and stronger reduction of atherogenic indices ( total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol ) than group II . Group II showed a more pronounced reduction of triglyceride ( 21–31 % ) and factor VII ( 6–10 % ) levels than group I. Both groups showed reduced concentrations of total cholesterol , low-density lipoprotein cholesterol , tissue plasminogen activator , plasminogen activator inhibitor-1 , antithrombin III , and protein S , whereas protein C was increased after 12 months of treatment . Conclusions The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity . Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration , but transdermal medication had a stronger effect on triglyceride and coagulation factors . However , it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment Data from the Third National Health and Nutrition Examination Survey ( 1 ) indicate that 11 % of U.S. women have a history of clinical gallbladder diseasethat is , either previous cholecystectomy or self-reported history of gallstones . Factors associated with gallbladder disease , at least in some studies , include older age , female sex , white ethnicity/race , obesity , rapid weight loss , and , among women , greater parity , use of oral estrogencontaining contraceptives , and postmenopausal estrogen therapy ( 2 ) . These associations , in general , have been based on observational data and may partly reflect the effects of ascertainment and recall bias , as well as confounding . While some observational studies suggest that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold ( 3 ) , such an association has not been reported consistently ( 2 , 3 ) . The effect of combined estrogen plus progestin therapy has been less well studied , and no recent clinical trial data exist on the relation of such therapy to the risk for biliary tract surgery among postmenopausal women . To determine whether estrogen plus progestin therapy is associated with the risk for biliary tract surgery among postmenopausal women , we analyzed data from the Heart and Estrogen/progestin Replacement Study ( HERS ) , the first large r and omized , double-blind trial of estrogen plus progestin therapy for the secondary prevention of coronary heart disease ( 4 ) . Gallbladder disease events , including biliary tract surgery , were among several prespecified secondary outcomes of interest . Methods Participants Between 1 February 1993 and 1 October 1994 , 2763 postmenopausal women with coronary artery disease were recruited from 20 clinical centers across the United States for participation in HERS , a r and omized , double-blind study of the effect of combined , continuous estrogenprogestin therapy ( conjugated equine estrogens , 0.625 mg/d , and medroxyprogesterone acetate , 2.5 mg/d ) on recurrent coronary heart disease events . Baseline data , which were collected at the visits for initial screening and r and om allocation , included demographic characteristics , medical history , risk factors for coronary heart disease , physical examination , and laboratory data . Women were not eligible to enroll in HERS if they had used any estrogen or female hormones within the previous 3 months , including pills , suppositories , injections , vaginal creams , or transdermal patches . We excluded 510 women from these analyses who reported at enrollment a history of surgical gallbladder removal . We did include , however , 123 women with a self-reported history of gallstones who had not undergone cholecystectomy . After these exclusions , data from 2253 participants were available for analysis . Measurements Baseline data included participant age , years of education , number of pregnancies , ethnicity/race ( white , African American , or other ) , past use of postmenopausal estrogen therapy , history of cigarette smoking , history of alcohol consumption , and diabetes mellitus . Data were also obtained on use of lipid-lowering medications and antihypertensive medications , including thiazide diuretics .  Participants who stated that they had smoked at least 100 cigarettes in their life were considered to have a history of smoking . Participants were asked , Has a doctor told you that you had diabetes , sugar diabetes , or high blood sugar ? Those who answered yes were classified as having a history of diabetes . Women with a history of gestational diabetes only were classified as not having diabetes mellitus . Participants were weighed without shoes or outdoor clothing on a st and ard balance-beam scale to the nearest 0.1 kg . Height was measured to the nearest 0.1 cm by using the height rod of a st and ard beam scale or , where available , a wall-mounted stadiometer . We calculated the body mass index as weight (kg)/height ( m2 ) . At baseline , year 1 , and the end of the study , serum lipid and lipoprotein levels were obtained from all participants and were measured at the Johns Hopkins Lipoprotein Analytical Laboratory , Baltimore , Maryl and , which is certified by the U.S. Centers for Disease Control and Prevention for the measurement of serum lipids and lipoproteins . Ascertainment of End Points Participants were determined to have incident gallbladder disease by physician adjudicators who were blinded to the r and omization status [ active hormone treatment or placebo ] . Symptomatic nonsurgical biliary tract disease was defined as a hospital admission for acute cholecystitis , choledocholithiasis , or gallstone pancreatitis and was established on the basis of 1 ) reported symptoms in combination with elevated levels on liver function testing and gallstones with dilated biliary ducts on abdominal ultrasonography or 2 ) nuclear medicine scan diagnostic of acute gallbladder disease . Incident biliary tract surgery , which included  cholecystectomy , sphincterotomy , or bile duct exploration  , was established by review of operative reports and discharge summaries . All biliary tract surgeries were cholecystectomies with the exception of 12 sphincterotomies and 2 stent insertions . Nonsurgical and surgical gallbladder disease events were considered separate end points and are mutually exclusive . The main HERS results , reported in 1998 ( 4 ) , were based on the near-final data available at that time . We present the up date d and final results for incident biliary tract events ( 5 ) . Statistical Analysis We used unpaired two-tailed t-tests to compare the age , level of education , number of pregnancies , body mass index , alcohol consumption , serum lipid level , and lipoprotein levels of the women r and omly assigned to receive postmenopausal hormone therapy or placebo .  Using chi-square tests , we compared the hormone therapy and placebo groups according to ethnicity/race , history of lipid-lowering medication use , pre study postmenopausal estrogen use , thiazide diuretic use , cigarette smoking , ascorbic acid supplement use , history of gallbladder disease , and diabetes mellitus . The treatment groups were divided fairly equally with respect to baseline variables , except for statin use . To analyze the association between postmenopausal hormone therapy and incident gallbladder disease events , we used unadjusted and statin useadjusted proportional hazards models . All risk estimates were derived solely from proportional hazards models . We also estimated KaplanMeier curves for time to occurrence of biliary tract surgery , according to treatment assignment . The number of participants needed to be treated for a new case of biliary tract surgery to occur was calculated by using the incidence rates per person-year of observation . For predictor variables other than treatment assignment , we calculated the hazard ratio and 95 % CI by using proportional hazards regression models to estimate the risk for incident biliary tract surgery . We used simple regression models that controlled only for treatment assignment ; we also used multivariable regression models that included variables with a previously reported association with gallbladder disease . Our model-fitting methods relied primarily on biological criteria ; we began by including factors previously reported to be associated with gallbladder disease . Although the risk for type I errors is always present when c and i date predictors are many relative to the number of outcomes , our model-building process accounted for this possibility when we considered the statistical significance of the result ing multivariable model . Results were confirmed by using stepwise and backwards selection methods . We identified one statistically significant interaction between postmenopausal hormone treatment and smoking . Adjustment for this interaction did not substantially affect the hazard ratios for other variables entered in the multivariable models . We performed these analyses by using SAS software ( 6 ) . A correlation between outcomes at each clinical center could potentially affect the SEs for the relative hazard estimates . Therefore , to control for such potential clustering by center , we used STATA software ( 7 ) to generate robust SEs for the proportional hazards models ( 8) . Because site-specific practice patterns could confound the relation of statin use to biliary tract surgery , we also examined statistical models that included clinical center as a fixed effect . We calculated the number of participants needed to be treated to result in one additional biliary tract surgery  by using the reciprocal of the absolute risk increase . However , because the 95 % CI for the absolute risk increase included zero , the CI for the number needed to treat for harm ( NNTH ) included . We use a method described by Altman ( 9 ) to present the CI in these circumstances . The CI around the NNTH will therefore range from an NNTH to to a number needed to treat for benefit ( NNTB ) . Role of the Funding Source Wyeth-Ayerst Research funded HERS . The study was design ed and carried out by the HERS investigators , including scientists from Wyeth-Ayerst Research . Investigators at the HERS Coordinating Center at the University of California , San Francisco , collected the outcome data , supervised the adjudication of outcome events , and analyzed the data . Results Gallbladder disease was particularly prevalent among this cohort of postmenopausal women with coronary artery disease . Twenty-three percent of women reported a history of cholelithiasis or cholecystectomy at baseline ( 10 ) . With the exception of statin use , which was more prevalent among women assigned to receive placebo ( P = 0.01 ) , the distribution of baseline variables was similar in both treatment groups ( Table 1 ) . Approximately 23 % of the HERS participants had a history of pre-enrollment hormone use ; the type and duration did not differ between the treatment groups . Table 1 . Selected Baseline Characteristics of Postmenopausal Women Receiving Hormone Therapy or Placebo  in the Heart and Estrogen/progestin Replacement Study ( HERS ) A 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 OBJECTIVE To describe self-reported cognitive changes in 875 postmenopausal women aged 45 - 64 years and assigned r and omly to hormone therapy ( either estrogen alone or estrogen in combination with a progestin ) .  METHODS A 3-year placebo-controlled trial which included self-report data on problems with forgetfulness , concentration and distraction in groups of women assigned r and omly to  placebo , estrogen alone or estrogen plus one of three progestin regimens . RESULTS Women assigned to any active treatment were consistently less likely to report cognitive symptoms than women assigned to placebo , but these results were not statistically significant . When compared with women assigned to estrogen plus any progestin , women assigned to estrogen alone had a significant increased risk for reporting problems with forgetfulness at follow-up ( odds ratio , OR = 1.47 ) . In the absence of problems with distraction at baseline , women assigned to estrogen alone were significantly less likely to report problems with distraction at follow-up , compared to women assigned to estrogen plus any progestin ( OR = 0.36 ) . Assignment to a continuous progestin regimen in combination with estrogen was marginally associated with an increased risk for reporting concentration problems at follow-up , compared to cyclic progestin regimens ( OR = 1.63 ) . CONCLUSIONS These results provide some evidence to support the hypothesis that estrogen improves memory , but findings are not statistically significant in this healthy middle-aged cohort . These data suggest that estrogen in combination with any progestin confers a decreased risk for reporting forgetfulness at follow-up , compared to estrogen alone . However , there is evidence that distraction problems reported at follow-up were side-effects of progestin . There is also some evidence that women administered progestins cyclically were at lower risk for reporting cognitive symptoms at follow-up , particularly concentration problems 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 Objective : To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness ( IMT ) in postmenopausal women . Design : A r and omized , double-blind , placebo-controlled , single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein ( LDL ) cholesterol levels of 3.37 mmol/L or greater ( ≥130 mg/dL ) . Intervention was unopposed micronized 17β-estradiol versus placebo . Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial . Results : Progression of carotid IMT was inversely related to on-trial high-density lipoprotein ( HDL ) cholesterol ( P = 0.04 ) and was directly related to on-trial LDL-cholesterol ( P = 0.005 ) . Compared with placebo , women r and omized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level . In contrast , fasting glucose , insulin , and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy , but the changes were not related to carotid IMT progression . On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression , jointly explaining 30 % of the treatment effect of unopposed estrogen on the progression of carotid IMT . Conclusion : Unopposed 17β-estradiol  reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol . Although women r and omized to estradiol showed improvement in all the markers of carbohydrate metabolism , these factors did not play a significant role in carotid IMT progression OBJECTIVE : To estimate the rates of endometrial hyperplasia , bleeding episodes , and interventions among menopausal women receiving unopposed oral estradiol or placebo therapy with ultrasound monitoring over 3 years . METHODS : Two-hundred eighteen healthy women with intact uteri enrolled in the Estrogen in the Prevention of Atherosclerosis Trial ( EPAT ) or the Women ’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial ( WELL-HART ) were r and omly assigned to either 1 mg of micronized 17&bgr;-estradiol ( n=96 ) or placebo ( n=122 ) daily for up to 3 years in a double-blind fashion . Patients were followed with annual measurement of endometrial thickness using transvaginal ultrasonography . Logistic regression was used to identify predictors of uterine bleeding and endometrial biopsy . RESULTS : Over the study periods , nine women ( 9.4 % of patients , 95 % confidence interval [ CI ] 3.6–15.2 % ) in the estradiol group developed hyperplasia . Eight of the nine cases ( 88.9 % ) of hyperplasia were simple without atypia . Women receiving estradiol were more likely than those receiving placebo to have at least one episode of uterine bleeding ( 67 % versus 11 % at 3 years , respectively , P<.001 ) . Women in the estradiol group were also more likely to have an endometrial biopsy ( 48 % versus 4 % at 3 years , P<.001 ) . Among women on estradiol , obesity ( body mass index [ BMI ] greater than 30 kg/m2 ) significantly increased the odds of uterine bleeding compared with normal-weight patients ( BMI 25 or less ) ( OR 3.7 , 95 % CI 1.2–11.8 ) . CONCLUSION : Short-term , unopposed estradiol therapy with gynecologic monitoring may be an option for the treatment of menopausal symptoms . Menopausal women choosing estradiol therapy , especially if obese , should anticipate uterine bleeding and the possibility of an endometrial biopsy . CLINICAL TRIAL REGISTRATION : Clinical trials.gov , www . clinical trials.gov , NCT 00000559 and NCT 00115024 LEVEL OF EVIDENCE : OBJECTIVE To evaluate the effect of three different dosages of transdermally administered 17beta-estradiol on serum lipoproteins in women who had recently experienced surgical menopause . MATERIAL AND METHODS We undertook a 2-year , r and omized , double-blind , placebo-controlled study in which 126 subjects were recruited and stratified by age , and 93 patients completed the protocol .  Serum lipoproteins were assessed before initiation of treatment and after 12 and 24 months of therapy with 0.025 , 0.05 , or 0.1 mg of estradiol daily . RESULTS Total serum cholesterol and low-density lipoprotein cholesterol showed dose-dependent decreases that reached statistical significance after 2 years of treatment with transdermally administered estradiol . CONCLUSION This study confirms that transdermally administered 17beta-estradiol has a modest beneficial effect on serum lipoproteins , with decreased levels of total cholesterol and low-density lipoprotein cholesterol 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 Background : To compare combined and sequential hormonal replacement therapies to each other as well as placebo in patients suffering from the postmenopausal syndrome . Clinical outcomes were measured concerning both the specific postmenopausal symptoms ( using the Kupperman scale ) and health or well-being dimensions ( using subscales of the General Health Question naire and specific depression and anxiety scales ) . Methods : A prospect i ve r and omized double-blind study over 12 months of 105 normal early postmenopausal women in the setting of a general hospital . Results : Both hormone replacement therapies were superior to placebo on the Kupperman scale ( sweating , hot flushing , myalgia and vertigo ) . The psychic symptoms on the Kupperman scale were psychometrically invalid . However , psychic symptoms as measured by the Beck Depression Inventory and the General Health Question naire were significantly improved by the hormonal replacement therapies . No differences were observed when combined therapy was compared to sequential therapy . Conclusion : One-year treatment with hormonal replacement therapy is superior to placebo in measuring the somatic and psychic symptoms of the menopausal syndrome . No differences were found in this respect between combined and sequential replacement therapy Background — Oral estrogen therapy increases the risk of  venous thromboembolism ( VTE ) in postmenopausal women .  Transdermal estrogen may be safer . However , currently available data have limited the ability to investigate the wide variety of types of progestogen . Methods and Results — We performed a multicenter case – control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France . We recruited 271 consecutive cases with a first documented episode of idiopathic VTE ( 208 hospital cases , 63 outpatient cases ) and 610 controls ( 426 hospital controls , 184 community controls ) matched for center , age , and admission date . After adjustment for potential confounding factors , odds ratios ( ORs ) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 ( 95 % CI , 1.5 to 11.6 ) and 0.9 ( 95 % CI , 0.4 to 2.1 ) , respectively . There was no significant association of VTE with micronized progesterone and pregnane derivatives ( OR , 0.7 ; 95 % CI , 0.3 to 1.9 and OR , 0.9 ; 95 % CI , 0.4 to 2.3 , respectively ) . In contrast , norpregnane derivatives were associated with a 4-fold-increased VTE risk ( OR , 3.9 ; 95 % CI , 1.5 to 10.0 ) . Conclusions — Oral but not transdermal estrogen is associated with an increased VTE risk . In addition , our data suggest that norpregnane derivatives may be thrombogenic , whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk . If confirmed , these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens 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 CONTEXT The Women 's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date . Postintervention health outcomes have not been reported . OBJECTIVE To examine health outcomes associated with r and omization to treatment with conjugated equine estrogens ( CEE ) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009 . DESIGN , SETTING , AND PARTICIPANTS The intervention phase was a double-blind , placebo-controlled , r and omized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy . Follow-up continued after the planned trial completion date among 7645 surviving participants ( 78 % ) who provided written consent . MAIN OUTCOME MEASURES The primary outcomes were coronary heart disease ( CHD ) and invasive breast cancer . A global index of risks and benefits included these primary outcomes plus stroke , pulmonary embolism , colorectal cancer , hip fracture , and death . RESULTS The postintervention risk ( annualized rate ) for CHD among women assigned to CEE was 0.64 % compared with 0.67 % in the placebo group ( hazard ratio [ HR ] , 0.97 ; 95 % confidence interval [ CI ] , 0.75 - 1.25 ) , 0.26 % vs 0.34 % , respectively , for breast cancer ( HR , 0.75 ; 95 % CI , 0.51 - 1.09 ) , and 1.47 % vs 1.48 % , respectively , for total mortality ( HR , 1.00 ; 95 % CI , 0.84 - 1.18 ) . The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36 % among women receiving CEE compared with 0.41 % in the placebo group ( HR , 0.89 ; 95 % CI , 0.64 - 1.24 ) , the risk of deep vein thrombosis was lower at 0.17 % vs 0.27 % , respectively ( HR , 0.63 ; 95 % CI , 0.41 - 0.98 ) , and the risk of hip fracture did not differ significantly and was 0.36 % vs 0.28 % , respectively ( HR , 1.27 ; 95 % CI , 0.88 - 1.82 ) . Over the entire follow-up , lower breast cancer incidence in the CEE group persisted and was 0.27 % compared with 0.35 % in the placebo group ( HR , 0.77 ; 95 % CI , 0.62 - 0.95 ) . Health outcomes were more favorable for younger compared with older women for CHD ( P = .05 for interaction ) , total myocardial infa rct ion ( P = .007 for interaction ) , colorectal cancer ( P = .04 for interaction ) , total mortality ( P = .04 for interaction ) , and global index of chronic diseases ( P = .009 for interaction ) . CONCLUSIONS Among postmenopausal women with prior hysterectomy followed up for 10.7 years , CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD , deep vein thrombosis , stroke , hip fracture , colorectal cancer , or total mortality . A decreased risk of breast cancer persisted . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 BACKGROUND Estrogens stimulate proliferation of breast epithelium and may therefore increase the risk of benign proliferative breast disease , a condition that is associated with increased risk of breast cancer . We tested the effect of conjugated equine estrogen ( CEE ) on risk of benign proliferative breast disease in the Women 's Health Initiative ( WHI ) r and omized controlled trial . METHODS In the WHI CEE trial , 10,739 postmenopausal women were r and omly assigned to 0.625 mg/d of CEE or to placebo . Baseline and annual breast examinations and mammograms were required . We identified women in the trial who reported breast biopsies that were free of cancer , obtained the associated histological sections , and subjected them to st and ardized central review . Cox proportional hazards models were used to estimate hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) . All statistical tests were two-sided . RESULTS A total of 232 incident cases of  benign proliferative breast disease  were ascertained during follow-up ( average duration , 6.9 years ) , with 155 in the  CEE  group and 77 in the placebo group . Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease ( HR = 2.11 , 95 % CI = 1.58 to 2.81 ) . For benign proliferative breast disease without atypia , the HR was 2.34 ( 95 % CI = 1.71 to 3.20 ) , whereas for atypical hyperplasia , it was 1.12 ( 95 % CI = 0.53 to 2.40 ) . Risk varied little by levels of baseline characteristics . CONCLUSION Use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer . In contrast , no difference in the incidence of colorectal cancer was seen in the Women 's Health Initiative ( WHI ) r and omized , placebo‐controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow‐up of 13.2 years . This study extends these findings by providing detailed analyses of the effects  of estrogen alone  on the histology , grade , and stage of colorectal cancer , relevant subgroups , and deaths from and after colorectal cancer BACKGROUND By contrast with many observational studies , women in the Women 's Health Initiative ( WHI ) trial who were r and omly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo . We aim ed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort . METHODS Between 1993 and 1998 , the WHI enrolled 10,739 postmenopausal women from 40 US clinical centres into a r and omised , double-masked , placebo-controlled trial . Women aged 50 - 79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were r and omly allocated by a computerised , permuted block algorithm , stratified by age group and centre , to receive oral conjugated equine oestrogen ( 0·625 mg per day ; n=5310 ) or matched placebo ( n=5429 ) . The trial intervention was terminated early on Feb 29 , 2004 , because of an adverse effect on stroke . Follow-up continued until planned termination ( March 31 , 2005 ) . Consent was sought for extended surveillance from the 9786 living participants in active follow-up , of whom 7645 agreed . Using data from this extended follow-up ( to Aug 14 , 2009 ) , we assessed long-term effects of oestrogen use on invasive breast cancer incidence , tumour characteristics , and mortality . We used Cox regression models to estimate hazard ratios ( HRs ) in the intention-to-treat population . This study is registered with Clinical Trials.gov , number NCT00000611 . FINDINGS After a median follow-up of 11·8 years ( IQR 9·1 - 12·9 ) , the use of oestrogen for a median of 5·9 years ( 2·5 - 7·3 ) was associated with lower incidence of invasive breast cancer ( 151 cases , 0·27 % per year ) compared with placebo ( 199 cases , 0·35 % per year ; HR 0·77 , 95 % CI 0·62 - 0·95 ; p=0·02 ) with no difference ( p=0·76 ) between intervention phase ( 0·79 , 0·61 - 1·02 ) and post-intervention phase effects ( 0·75 , 0·51 - 1·09 ) . In subgroup analyses , we noted breast cancer risk reduction  with oestrogen use was concentrated in women without benign breast disease ( p=0·01 ) or a family history of breast cancer ( p=0·02 ) . In the oestrogen group , fewer women died from breast cancer ( six deaths , 0·009 % per year ) compared with controls ( 16 deaths , 0·024 % per year ; HR 0·37 , 95 % CI 0·13 - 0·91 ; p=0·03 ) . Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis ( 30 deaths , 0·046 % per year ) than did controls ( 50 deaths , 0·076 % ; HR 0·62 , 95 % CI 0·39 - 0·97 ; p=0·04 ) . INTERPRETATION Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality . However , our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to population s at increased risk of such cancer . FUNDING US National Heart , Lung , and Blood Institute ; Wyeth UNLABELLED Abstract Background : It is estimated that 70 % of women in Western societies experience breast pain at least once during their lifetime . In the Women 's Health Initiative ( WHI ) , women treated with oral conjugated equine estrogen ( 0.625 mg ) with or without continuous oral medroxyprogesterone acetate ( 2.5 mg ) had a higher incidence of breast pain than those who received placebo . The effect of other hormone therapy regimens on breast pain is unknown . We compared breast pain among healthy , recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study ( KEEPS ) at Mayo Clinic . METHODS Women were r and omized to : 0.45 mg/day oral conjugated equine estrogen ( o-CEE ) plus 200 mg/day micronized progesterone ( m-P ) for the first 12 days of the month , 50 μg/day transdermal 17β estradiol ( t-E2 ) plus m-P for 12 days , or placebo pills and patch .  Participants completed the Mayo Clinic breast pain question naire at baseline and yearly for the duration of the study . RESULTS Participants ( 116 ) averaged 53.0 years of age and 1.6 years past their last menses at baseline . At baseline , 12 women ( 10 % ) reported breast pain with an average worst pain score [ from 0 ( no pain ) to 10 ( worst pain ) ] of 0.39±1.28 . With treatment , the number of women reporting pain did not increase , and with either intention-to-treat or per- protocol analyses , breast pain scores did not differ significantly ( p=0.39 ) among groups : t-E2 ( 0.53±1.21 ) , o-CEE ( 0.32±0.78 ) , placebo ( 0.23±0.87 ) . CONCLUSION Four years of treatment with o-CEE at a lower dose than that studied in the WHI with cyclic m-P or transdermal E2 with cyclic m-P did not increase breast pain in healthy , recently menopausal women PURPOSE To assess the effects of adjuvant hormone therapy ( AHT ) on survival and disease outcome in women with epithelial ovarian cancer . PATIENTS AND METHODS Participants were premenopausal and postmenopausal women who had been diagnosed with epithelial ovarian cancer ( any International Federation of Gynecology and Obstetrics stage ) 9 or fewer months previously . Ineligible patients included those with deliberately preserved ovarian function , with a history of a hormone-dependent malignancy , or with any contraindications to hormone-replacement therapy . Patients were central ly r and omly assigned in a 1:1 ratio to either AHT for 5 years after r and om assignment or no AHT ( control ) . Main outcome measures were overall survival ( OS ) , defined as time from r and om assignment to death ( any cause ) , and relapse-free survival , defined as time from r and om assignment to relapse or death ( any cause ) . Patients who continued , alive and relapse free , were censored at their last known follow-up . RESULTS A total of 150 patients ( n = 75 , AHT ; n = 75 , control ) were r and omly assigned from 1990 to 1995 from 19 centers in the United Kingdom , Spain , and Hungary ; all patients were included in intention-to-treat analyses . The median follow-up in alive patients is currently 19.1 years . Of the 75 patients with AHT , 53 ( 71 % ) have died compared with 68 ( 91 % ) of 75 patients in the control group . OS was significantly improved in patients who were receiving AHT ( hazard ratio , 0.63 ; 95 % CI , 0.44 to 0.90 ; P = .011 ) . A similar effect was seen for relapse-free survival ( hazard ratio , 0.67 ; 95 % CI , 0.47 to 0.97 ; P = .032 ) . Effects remained after adjustment for known prognostic factors . CONCLUSION These results show that women who have severe menopausal symptoms after ovarian cancer treatment can safely take hormone-replacement therapy , and this may , in fact , infer benefits in terms of OS in addition to known advantages in terms of quality of life
target: Women taking HT had a significantly decreased incidence of fracture with long-term use .
  Research ers found no strong evidence that HT has a clinical ly meaningful impact on the incidence of colorectal cancer .
  AUTHORS ' CONCLUSIONS : Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT , provided they do not have specific contraindications .
  HT may be unsuitable for some women , including those at increased risk of cardiovascular disease , increased risk of thromboembolic disease ( such as those with obesity or a history of venous thrombosis ) or increased risk of some types of cancer ( such as breast cancer , in women with a uterus ) .
  The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented .
  HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia , nor for prevention of deterioration of cognitive function in postmenopausal women .
  Although HT is considered effective for the prevention of postmenopausal osteoporosis , it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable .
background: BACKGROUND : Hormone therapy ( HT ) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease , osteoporosis and  dementia in older women .
  This is an up date d version of a Cochrane review first published in 2005 .
  OBJECTIVES : To assess effects of long-term HT ( at least 1 year 's duration ) on mortality , cardiovascular outcomes , cancer , gallbladder disease , fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment .