title: Effect of oral oestriol on vaginal flora and cytology and urogenital symptoms in the post-menopause. Effects of Conventional or Lower Doses of Hormone Replacement Therapy in Postmenopausal Women Effect of Raloxifene on Stroke and Venous Thromboembolism According to Subgroups in Postmenopausal Women at Increased Risk of Coronary Heart Disease Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis: A Randomized, Controlled Trial Health related quality of life after combined hormone replacement therapy: randomised controlled trial Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four-year randomized study. Estrogen plus progestin and risk of venous thrombosis. HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomised comparison: trial stopped Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Hot flushes, coronary heart disease, and hormone therapy in postmenopausal women THE EFFECT OF TREATMENT WITH OESTRADIOL AND OESTRIOL ON FASTING SERUM CHOLESTEROL AND TRIGLYCERIDE LEVELS IN POSTMENOPAUSAL WOMEN Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Low-risk lipoprotein pattern in post-menopausal women on sequential oestrogen/progestogen treatment. The relation of postmenopausal hormone therapy to serum uric acid and the risk of coronary heart disease events: the Heart and Estrogen-Progestin Replacement Study (HERS). Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Silent ischemia during daily life is an independent predictor of mortality in stable angina. Genetic variation in estrogen receptor, C-reactive protein and fibrinogen does not predict the plasma levels of inflammation markers after longterm hormone replacement therapy. Pulse Pressure and Coronary Atherosclerosis Progression in Postmenopausal Women A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women. A placebo-controlled trial of ethinyl oestradiol and norethisterone in climacteric women. The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial A clinical trial of estrogen-replacement therapy after ischemic stroke. The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Menopause and risk factors for coronary heart disease. Symptom reporting and quality of life in the Estonian Postmenopausal Hormone Therapy Trial The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass. Brain volumes, cognitive impairment, and conjugated equine estrogens. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Noninvasive Assessment of Coronary Microcirculatory Function in Postmenopausal Women and Effects of Short-Term and Long-Term Estrogen Administration Long-term vitamin D3 supplementation may have adverse effects on serum lipids during postmenopausal hormone replacement therapy. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Implementation of the Women's Health Initiative study design. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. A randomized, placebo-controlled trial of the effects of physical exercises and estrogen therapy on health-related quality of life in postmenopausal women Women's angiographic vitamin and estrogen trial: design and methods. Estrogen plus progestin and the risk of coronary heart disease. Long-term and withdrawal effects of two different oestrogen-progestogen combinations on lipid and lipoprotein profiles in post-menopausal women. Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/progestin Replacement Study 1 and 2 mg 17β-estradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. Is oestrogen therapy effective in the treatment of menopausal depression? Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study. Effect of hormone therapy and calcitriol on serum lipid profile in postmenopausal older women: association with estrogen receptor-&agr; genotypes Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757]. Heart and Estrogen/progestin Replacement Study (HERS): design, methods, and baseline characteristics. The effect of hormone replacement on physical performance in community-dwelling elderly women. 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. Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Hormone replacement therapy: discrepancies between evidence and recommendations A case-control study of myocardial infarction in relation to use of estrogen supplements. Changes in calcanean bone mineral occurring spontaneously and during hormone replacement therapy in early post-menopausal women. CALCITONIN AND POSTMENOPAUSAL OSTEOPOROSIS Estrogen Plus Progestin and the Risk of Peripheral Arterial Disease: The Women’s Health Initiative Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. The estrogen replacement and atherosclerosis (ERA) study: study design and baseline characteristics of the cohort. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial. The ERA trial: findings and implications for the future Effect of progestogen and progestogen type on hemostasis measures in postmenopausal women: the Postmenopausal Estrogen/Progestin Intervention (PEPI) Study Effect of Estrone Sulfate on Postmenopausal Bone Loss Striking Increases in Carotid Artery Wall Thickness in Healthy Subjects Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS cognitive and affective sub study (KEEPS Cog) Venous thrombosis and conjugated equine estrogen in women without a uterus. Factor structure and measurement invariance of the Women's Health Initiative Insomnia Rating Scale. Estrogen Improves Endothelium-Dependent, Flow-Mediated Vasodilation in Postmenopausal Women Effect of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women. Pulse pressure and cardiovascular events in postmenopausal women with coronary heart disease. 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. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women. The National Randomised Trial of Hormone Replacement Therapy in Women with a History of Early Stage Breast Cancer Ten years post-menopausal hormone replacement therapy--effect on lipoproteins. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. 17 Beta-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. Comparison with conventional therapy. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study 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. Positive impact of hormone replacement therapy on the fibrinolytic system: a long-term randomized controlled study in healthy postmenopausal women. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Does vitamin D3 have negative effects on serum levels of lipids? A follow-up study with a sequential combination of estradiol valerate and cyproterone acetate and/or vitamin D3. Two polymorphisms in the vitamin D receptor gene--association with bone mass and 5-year change in bone mass with or without hormone-replacement therapy in postmenopausal women: the Danish Osteoporosis Prevention Study. The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. 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. Randomized trial of hormone therapy in women after coronary bypass surgery. Evidence of differential effect of hormone therapy on angiographic progression of disease in saphenous vein grafts and native coronary arteries. Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Blinding decreased recruitment in a prevention trial of postmenopausal hormone therapy. Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? The Minimum Effective Dose of Estrogen for Prevention of Postmenopausal Bone Loss Effect of 1,25‐dihydroxy ‐ vitamin D3 in itself or combined with hormone treatment in preventing postmenopausal osteoporosis Effect of Postmenopausal Hormone Therapy on Glucose and Insulin Concentrations Unopposed Estradiol Therapy in Postmenopausal Women: Results From Two Randomized Trials Effects of hormone therapy on soluble cell adhesion molecules in postmenopausal women with coronary artery disease Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial Treatment with hormone therapy and calcitriol did not affect depression in older postmenopausal women: no interaction with estrogen and vitamin D receptor genotype polymorphisms
abstract: The effect of oral oestriol ( 3 mg/day for 4 weeks followed by 2 mg/day for a further 6 weeks ) on the vaginal bacterial flora , vaginal cytology and urogenital symptoms was assessed in a double-blind , placebo-controlled study in 35 women with symptoms of the urogenital oestrogen deficiency syndrome . No significant differences were observed with regard to the occurrence or severity of urogenital symptoms , vaginal pH , karyopyknotic index ( KPI ) or the baseline results of vaginal bacterial cultures in the 18 patients ( mean age 71.6 + /- 1.0 years ) treated with oestriol and the 17 women ( mean age 72.6 + /- 1.4 years ) who received placebo tablets . A decrease in both vaginal pH ( P less than 0.001 ) and the proportion of faecal-type bacteria ( P less than 0.05 ) , and an increase in the KPI ( P less than 0.01 ) and the proportion of lactobacilli ( P less than 0.001 ) were recorded after 10 weeks of treatment with oral oestriol . At the end of the following 10 medication-free weeks all of these parameters except vaginal pH had returned to values that were not significantly altered from the corresponding baseline levels . In the patients treated with placebo no significant changes occurred in vaginal pH , KPI or the proportion of lactobacilli in vaginal cultures during the course of this study . Urogenital symptoms improved in both groups after medication ( and even after the medication-free period ) in relation to the baseline assessment , which reflects the latter 's subjective nature Objective —The effects of hormone replacement therapy ( HRT ) can affect many aspects relevant to cardiovascular disease , including vasomotor function , inflammation , and hemostasis . Recent studies have demonstrated that current doses of HRT exert a mixture of both protective and adverse effects . In the current study , we compared the effects of lower doses of HRT ( L-HRT ) and conventional doses of HRT ( C-HRT ) on a variety of relevant cardiovascular parameters . Methods and Results —This r and omized , double-blind , crossover study included 57 women who received micronized progesterone 100 mg with either conjugated equine estrogen 0.625 mg ( C-HRT ) or 0.3 mg ( L-HRT ) daily for 2 months .  L-HRT showed comparable effects to C-HRT on high-density lipoprotein cholesterol and triglyceride levels , but not on low-density lipoprotein cholesterol levels .  C-HRT and L-HRT significantly improved the percent flow-mediated dilator response to hyperemia from baseline values ( both P < 0.001 ) by a similar degree ( P = 0.719 ) . C-HRT significantly increased high-sensitivity C-reactive protein ( hsCRP ) levels from baseline values ( P < 0.001 ) ; however , L-HRT did not significantly change hsCRP ( P = 0.874 ) . C-HRT and L-HRT significantly decreased antithrombin III from baseline values ( P < 0.001 and P = 0.042 , respectively ) . C-HRT significantly increased prothrombin fragment 1 + 2 ( F1 + 2 ) from baseline values ( P < 0.001 ) ; however , L-HRT did not significantly change F1 + 2 ( P = 0.558 ) . Of interest , the effects of C-HRT and L-HRT on hsCRP , antithrombin III , and F1 + 2 were significantly different ( all P < 0.001 ) . C-HRT and L-HRT significantly reduced plasma PAI-1 antigen levels from baseline values ( P = 0.002 and P = 0.038 , respectively ) to a similar degree ( P = 0.184 ) . Conclusions —Compared with C-HRT , L-HRT has comparable effects on lipoproteins , flow-mediated dilation , and PAI-1 antigen levels . However , L-HRT did not increase hsCRP or F1 + 2 levels , and it decreased antithrombin III less than C-HRT Background and Purpose — Raloxifene , a selective estrogen receptor modulator , reduces risk of invasive breast cancer and osteoporosis , but the effect on risk for stroke and venous thromboembolism in different patient subgroups is not established . The purpose of this analysis was to evaluate the effect of raloxifene on the incidence of all strokes , stroke deaths , and venous thromboembolic events according to participant subgroups . Methods — This was a secondary end point analysis of an international , r and omized , placebo-controlled clinical trial of 10 101 postmenopausal women with or at increased risk of coronary heart disease followed a median of 5.6 years .  Strokes , venous thromboembolic events , and deaths were adjudicated by expert central ized committees . Strokes were categorized as ischemic , hemorrhagic , or undetermined and venous thromboembolic events were subclassified . Results — The incidences of all strokes did not differ between raloxifene ( incidence rate per 100 woman-years=0.95 ) and placebo ( incidence rate=0.86 ) treatment groups ( P=0.30 ) . In women assigned raloxifene versus placebo , there was a higher incidence of fatal strokes ( incidence rates=0.22 and 0.15 , respectively , P=0.0499 ) and venous thromboembolic events ( incidence rates=0.39 and 0.27 , respectively , P=0.02 ) . No significant subgroup interactions were found except that there was a higher incidence of stroke associated with raloxifene use among current smokers . Conclusions — In postmenopausal women at increased risk for coronary events , the incidences of venous thromboembolism and fatal stroke but not all strokes were higher in those assigned raloxifene versus placebo . Raloxifene ’s effect did not differ across subgroups , except that the risk of stroke differed by smoking status . Treatment decisions about raloxifene should be based on a balance of projected absolute risks and benefits 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 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 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 Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol , are important factors in the pathogenesis of age-related bone loss . The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on  bone loss in elderly women . Four hundred eighty-nine elderly women with normal bone density for their age , aged 65 - 77 yr , were entered into a r and omized double blind , placebo-controlled trial . Women were r and omized to one of four groups : conjugated estrogens ( 0.625 mg , daily ) to women without a uterus ( estrogen replacement therapy ) plus medroxyprogesterone acetate ( 2.5 mg , daily ) to women with a uterus ( hormone replacement therapy ) , calcitriol ( 0.25 microg twice daily ) , a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol , or placebos for 3 yr . The primary outcome was the change in bone mineral density of the femoral neck and spine . In the intent to treat analysis , hormone therapy ( hormone replacement therapy/estrogen replacement therapy ) produced a mean ( + /-1 SD ) increase in bone mineral density of 2.98 % ( + /-5.45 % ) at the femoral neck ( P < 0.0001 ) and 4.36 % ( + /-6.42 % ) at the spine ( P < 0.0001 ) . There were parallel increases in total hip and trochanter bone mineral density . Calcitriol increased bone mineral density 0.10 % ( + /- 4.27 % ) at the femoral neck ( P = 0.57 ) and 1.65 % ( + /- 4.83 % ) at the spine ( P < 0.0124 ) . The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol  increased bone mineral density 3.80 % ( + /-4.95 % ) at the femoral neck ( P < 0.001 ) , 4.91 % ( + /-6.0 % ) at the spine ( P < 0.0001 ) , and parallel changes at the total hip and trochanter . All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck , spine , total hip and trochanter . There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis . In a secondary analysis of the effect in women who were adherent to treatment , calcitriol had a more significant effect on spine ( P = 0.003 ) and total hip ( P = 0.004 ) . The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups . Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter ( P = 0.007 ) and total hip bone mineral density ( P = 0.0017 ) . In summary , hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinical ly relevant sites in a group of elderly women , with normal bone density for their age . Calcitriol was effective in increasing spine bone mineral density . In the adherent women , combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone BACKGROUND Administration of estrogen or etidronate has been shown to increase bone mineral density in postmenopausal women . This 4-year , prospect i ve , r and omized study was carried out to monitor any added beneficial effect on bone mineral density when hormone-replacement therapy ( HRT ) was combined with etidronate . PATIENTS AND METHODS Fifty-eight early postmenopausal women attending metabolic bone disease outpatient clinics were r and omly allocated into four treatment groups and monitored for up to 4 years . All patients received 1.0 g/d of elemental calcium . In addition , group 1 received percutaneously administered HRT ( n = 15 ) ; group 2 , intermittent cyclical etidronate ( ICE ) ( n = 14 ) ; group 3 , HRT and ICE ( n = 15 ) ; and group 4 , calcium alone ( n = 14 ) . The bone mineral density ( measured by dual-energy x-ray absorptiometry ) , biochemical variables of bone turnover , including bone-specific alkaline phosphatase , and urinary hydroxyproline : creatinine ratios were measured before treatment and at 2 and 4 years after treatment . RESULTS In patients who received the combined therapy , bone mineral density was increased in the vertebrae by 10.9 % ( P < 0.001 ) and in the femora by 7.25 % ( P < 0.001 ) at 4 years . For patients treated with ICE , the increase was 6.79 % ( P < 0.001 ) and 1.20 % ( P < 0.05 ) , and with HRT , 6.78 % ( P < 0.001 ) and 4.01 % ( P < 0.01 ) in the vertebrae and femora , respectively . The group treated with calcium alone lost 3.81 % ( P < 0.01 ) and 4.96 % ( P < 0.01 ) of bone mineral density in vertebrae and femora . Patients who received no specific therapy lost 8.58 % ( P < 0.01 ) from vertebrae , and 7.83 % ( P < 0.01 ) from the femora over 4 years . Patients who received combined therapy had significantly higher bone mineral density in both vertebrae ( P < 0.05 ) and femora ( P < 0.01 ) , in comparison to patients who were treated with HRT , or ICE , alone . Three of 9 patients ( 33 % ) in the ICE group developed osteomalacia , as shown by bone histomorphometry , whereas in women who received combined HRT and ICE therapies , none of the 11 patients tested had evidence of bone mineralization defects . CONCLUSION This 4-year , prospect i ve , r and omized study in early postmenopausal women showed an additive effect of ICE and HRT on the bone mineral density in both vertebrae and the hip . Furthermore , the combined therapy prevented the occurrence of osteomalacia associated with etidronate . This is the first study to demonstrate the effects of etidronate in early postmenopausal women , and the additive beneficial effects of HRT and ICE on bone mineral density CONTEXT Postmenopausal hormone therapy increases the risk of venous thrombosis .  It is not known whether other factors influencing thrombosis add to this risk . OBJECTIVE To report final data on incidence of  venous thrombosis in the Women 's Health Initiative Estrogen Plus Progestin clinical trial and the association of hormone therapy with venous thrombosis in the setting of other thrombosis risk factors . DESIGN , SETTING , AND PARTICIPANTS Double-blind r and omized controlled trial of 16,608 postmenopausal women between the ages of 50 and 79 years , who were enrolled in 1993 through 1998 at 40 US clinical centers with 5.6 years of follow up ; and a nested case-control study . Baseline gene variants related to thrombosis risk were measured in the first 147 women who developed thrombosis and in 513 controls . INTERVENTION R and om assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate , or placebo . MAIN OUTCOME MEASURES Central ly vali date d deep vein thrombosis and pulmonary embolus . RESULTS Venous thrombosis occurred in 167 women taking  estrogen plus progestin  ( 3.5 per 1000 person-years ) and in 76 taking placebo ( 1.7 per 1000 person-years ) ; hazard ratio ( HR ) , 2.06 ( 95 % confidence interval [ CI ] , 1.57 - 2.70 ) . Compared with women between the ages of 50 and 59 years who were taking placebo , the risk associated with hormone therapy was higher with age : HR of 4.28 ( 95 % CI , 2.38 - 7.72 ) for women aged 60 to 69 years and 7.46 ( 95 % CI , 4.32 - 14.38 ) for women aged 70 to 79 years . Compared with women who were of normal weight and taking placebo , the risk associated with taking estrogen plus progestin  was increased among overweight and obese women : HR of 3.80 ( 95 % CI , 2.08 - 6.94 ) and 5.61 ( 95 % CI , 3.12 - 10.11 ) , respectively . Factor V Leiden enhanced the hormone-associated risk of thrombosis with a 6.69-fold increased risk compared with women in the placebo group without the mutation ( 95 % CI , 3.09 - 14.49 ) . Other genetic variants ( prothrombin 20210A , methylenetetrahydrofolate reductase C677 T , factor XIII Val34Leu , PAI-1 4G/5 G , and factor V HR2 ) did not modify the association of hormone therapy with venous thrombosis . CONCLUSIONS Estrogen plus progestin was associated with doubling the risk of venous thrombosis .  Estrogen plus progestin therapy increased the risks associated with age , overweight or obesity , and factor V Leiden 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 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 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 Objective : The aim of this study was to examine interactions between hot flushes , estrogen plus progestogen therapy ( EPT ) , and coronary heart disease ( CHD ) events in postmenopausal women with CHD . Methods : We analyzed data from the Heart and Estrogen/Progestin Replacement Study , a r and omized , placebo-controlled trial of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate in 2,763 postmenopausal women with CHD .  Hot flushes were assessed at baseline using self-administered question naires ; women reporting bothersome hot flushes " some " to " all " of the time were considered to have clinical ly significant flushing . Cox regression models were used to examine the effect of EPT on risk of CHD events among women with and without significant flushing at baseline . Results : The mean age of participants was 66.7 ± 6.8 years , and 89 % ( n = 2,448 ) were white . Sixteen percent ( n = 434 ) of participants reported clinical ly significant hot flushes at baseline . Among women with baseline flushing , EPT increased risk of CHD events nine-fold in the first year compared with placebo ( hazard ratio = 9.01 ; 95 % CI , 1.15 - 70.35 ) ; among women without baseline flushing , treatment did not significantly affect CHD event risk in the first year ( hazard ratio = 1.32 ; 95 % CI , 0.86 - 2.03 ; P = 0.07 for interaction of hot flushes with treatment ) . The trend toward differential  effects of EPT on risk for CHD among women with and without baseline flushing did not persist after the first year of treatment . Conclusions : Among older postmenopausal women with CHD  , EPT may increase risk of CHD events substantially in the first year of treatment among women with clinical ly significant hot flushes but not among those without hot flushes The effect of natural oestrogens on serum cholesterol and serum triglyceride levels was studied in a controlled double‐blind clinical trial . No statistically significant changes were found in the blood lipids when comparing the patients treated with  oestradiol  , 2 mg , and oestriol , 1 mg , and those given placebo 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 Female hormones are known in influence serum lipoproteins . In post-menopausal women oestrogens decrease the concentration of low-density lipoprotein ( LDL ) and increase that of high-density lipoprotein ( HDL ) , while progestogens may have the opposite effect . The risk of coronary heart disease ( CHD ) should consequently be decreased by oestrogens and increased by progestogens . We report here the changes observed in serum total cholesterol , triglycerides , and lipoproteins in post-menopausal women during sequential oestrogen/progestogen treatment . Oestriol and 17 beta-oestradiol were given alone for the first 12 days , in combination with norethisterone acetate ( 1 mg/day ) for the next 10 days , and then in reduced amounts for the last 6 days of the 28-day cycle . Three different doses of the oestrogens were investigated ( high , medium and low ) . A total of 177 normal post-menopausal women volunteered for r and om allocation to treatment or placebo groups .  Blood sample s were taken every 3 mth during the progestogen phase of the cycle . Serum total cholesterol was found to be 10 - 13 % lower over a 3-yr period on the high oestrogen dose and 5 and 3 % lower on the medium and low doses , respectively . No significant changes were seen in serum triglycerides . Determination of lipoprotein fractions showed that the reduction in total cholesterol was due to reduced LDL-cholesterol , the HDL-cholesterol levels remaining virtually unchanged PURPOSE To determine whether baseline serum uric acid ( UA ) levels and estrogen-progestin (E+P)-associated change in serum UA in postmenopausal women with coronary disease are associated with recurrent coronary heart disease ( CHD ) events . METHODS 2763 postmenopausal women enrolled in the Heart and Estrogen-Progestin Replacement Study ( HERS ) were r and omly assigned to take conjugated E+P or placebo in a secondary CHD prevention study . The primary outcome for these analyses was nonfatal myocardial infa rct ion or CHD death during a mean follow up of 4.1 years . RESULTS The baseline serum UA for the cohort was 5.4 mg/dl and , compared with placebo , E+P on average lowered serum UA levels slightly ( 0.2 mg/dl ) at one year of follow up ( p<0.0001 ) . Baseline serum UA levels were associated in simple proportional hazards models with CHD events ; each st and ard deviation increase ( 1.3 mg/dl ) was associated with a 22 % increased risk of primary CHD events ( p=.0001 ) . This association , however , was no longer statistically significant after multivariable adjustment ( p=0.36 ) . There was no association between on- study change in serum UA level and any CHD outcome . CONCLUSION Treatment with E+P lowered serum UA levels slightly , but neither baseline UA nor change in UA affected CHD risk 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 Use of conjugated equine estrogens ( CEE ) has been linked to smaller regional brain volumes in women aged ≥65 years ; however , it is unknown whether this results in a broad-based characteristic pattern of effects . Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a r and omized clinical trial of CEE therapy for an average of 6.6 years , beginning at ages 65 - 80 years . A multivariate pattern analysis , based on a machine learning technique that combined R and om Forest and logistic regression with L(1 ) penalty , was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups . The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy . Mean decrements ranged as high as 7 % in the left entorhinal cortex and 5 % in the left perirhinal cortex , which exceeded the effect sizes reported previously in frontal lobe and hippocampus . Overall accuracy of classification based on these patterns , however , was projected to be only 54.5 % . Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes , but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers The postmenopausal hormone therapy ( PHT ) component of the Women ’s Health Initiative ( WHI ) is composed of two r and omized , placebo-controlled , double-blind trials in postmenopausal women aged 50 to 79 years at initial screening , testing the effects of estrogen alone ( E-alone ) and estrogen plus progestin ( E P ) on coronary heart disease ( CHD ) as the primary outcome , hip and other fractures and colorectal cancer as secondary outcomes , and pulmonary embolism , breast and endometrial cancers as potential risks . The design and rationale of the PHT trials , including general eligibility and exclusion criteria and considerations regarding sample size and statistical power , have been described previously ( 1 ) . Postmenopausal hormones have been initiated in menopausal women for the treatment of vasomotor symptoms , mood disturbances , vaginal dryness , and prevention of rapid bone loss for several decades . Despite a paucity of data on effects of initiating hormone use in older women , postmenopausal hormones have also been promoted for the prevention of CHD , osteoporotic fractures , and other diseases that occur years after menopause ( 2 ) . It is generally recommended ( 2 ) that women with a uterus be prescribed a combination of estrogen and progestin to prevent We prospect ively examined the prognostic significance of silent myocardial ischemia detected by ambulatory electrocardiogram ( ECG ) monitoring during daily life in 107 patients with long-term stable angina who were symptomatically controlled on conventional antianginal agents .  Forty-six patients ( group 1 ) demonstrated one or more episodes ( 87 % silent ) of myocardial ischemia ; the remaining 61 patients ( group 2 ) had no ischemic ST segment changes . During the mean follow-up period of 23 + /- 8 months , 11 cardiac deaths ( five sudden and six nonsudden ) occurred in group 1 , and five cardiac deaths ( all nonsudden ) occurred in group 2 . Kaplan-Meier survival analysis between the groups confirmed that patients with silent ischemia ( group 1 ) had worse prognoses during the follow-up period ( p = 0.023 ) . Although the higher incidence of hypertension , smoking , hypercholesterolemia , and diabetes in our patients might reflect a more sickly population of stable angina patients , the multivariate Cox 's hazard function analysis of these and other variables including Q waves on ECG , exercise parameters , and ambulatory ECG findings revealed presence of silent ischemia during daily life as the most powerful and independent predictor of cardiac mortality ( p = 0.01 ) . These data indicate that , in such patients with stable angina , silent myocardial ischemia occurs frequently during treatment with conventional antianginal drugs and identifies a subset of patients who are at high risk of cardiac death Markers of inflammation , such as C-reactive protein ( CRP ) and fibrinogen , are associated with the risk of atherothrombosis . Plasma levels of these markers of inflammation are affected by hormone replacement therapy ( HRT ) and modulated by smoking . We studied whether genetic variation in the estrogen receptor- 1 ( ESR1 ) , CRP and fibrinogen-beta genes influences the plasma levels of inflammation markers after HRT .  Plasma CRP and fibrinogen were measured after five years follow-up in healthy postmenopausal women ( per- protocol group ) who were r and omised to hormone therapy ( n=187 ) or no treatment ( n=249 ) . The effect of HRT , smoking and genetic variations in ESR1 ( PvuII and XbaI ) , CRP ( 1444C/T ) and fibrinogen-beta ( FGB , -455G/A ) were determined . The plasma concentration of CRP was higher in the HRT group than in the control group ( 2.03 mg/l and 1.41 mg/l , respectively ; p < 0.001 ) , while the concentration of fibrinogen was lower in the HRT group than in the control group ( 3.02 g/l and 3.20 g/l , respectively ; p < 0.001 ) , indicating that it is unlikely that inflammation is the common underlying pathway . There was a significant interaction between smoking and HRT  on the fibrinogen ( p=0.02 ) , but not on the CRP concentration ( n.s . ) . Genetic polymorphisms in ESR1 , CRP and fibrinogen were not associated with an effect of HRT on the CRP and fibrinogen plasma levels , and no significant interaction with smoking was observed . In conclusion , higher plasma levels of CRP and lower plasma levels of fibrinogen were observed in women using HRT ;  however , genetic polymorphisms in ESR1 , CRP and FGB were not associated with these effects of HRT Pulse pressure , an index of large artery stiffness , has been associated with coronary events . However , mechanisms for this association remain unclear . In this study , we examined the relationship between pulse pressure and the progression of coronary atherosclerosis and the effects of hormone replacement therapy ( HRT ) on pulse pressure in postmenopausal women with angiographically confirmed coronary disease followed for 3.2 years in the Estrogen Replacement in Atherosclerosis ( ERA ) trial . In the ERA trial , 309 postmenopausal women ( mean age 66±7 years ) with coronary disease were r and omized to estrogen , estrogen plus progestin , or placebo , and followed for 3.2 years . Ten st and ardized epicardial segments were measured for minimal diameter values at baseline and follow-up using quantitative coronary angiography . For this study , mixed-model analysis of covariance was used to : ( 1 ) test the association between pulse pressure and change in mean minimum diameter ( MMD ) adjusted for baseline MMD and ( 2 ) the effect of HRT on follow-up pulse pressure . After adjustment for potential confounders , there was a significant grade d increase in progression of coronary stenosis with increasing quartiles of baseline pulse pressure ( P test for trend=0.0001 ) . The progression rate in women with the highest quartile of baseline pulse pressure was 5-fold higher than in women in the lowest quartile ( P<0.01 ) . In postmenopausal women with coronary disease , increased levels of baseline pulse pressure are associated with subsequent progression of coronary atherosclerosis in postmenopausal women . HRT had no detectable effect on pulse pressure Whether to take hormone therapy is one of the most difficult medical decisions that healthy postmenopausal women face . The apparent coronary benefits ( 1 ) of hormone use are an important part of that decision . Although the data appear consistent in suggesting long-term coronary benefits , the Heart and Estrogen/progestin Replacement Study ( 2 ) showed an increased risk for coronary events during the first year of therapy in women with existing heart disease ; we also found such an elevated risk in an examination of secondary prevention in the Nurses ' Health Study ( 3 ) . More recently , a report from the Women 's Health Initiative , an ongoing r and omized clinical trial of hormone therapy for primary prevention of cardiovascular disease , suggested similar findings in healthy women ( National Institutes of Health . Press release ) . However , additional data on short-term effects of hormone use in women without previous cardiovascular disease are sparse . Many further questions also remain . Among them is the cardiovascular effect of daily doses lower than the st and ard 0.625 mg of oral conjugated estrogen . Recent studies suggest that lower doses of hormone therapy provide bone benefits ( 4 ) and , compared with higher doses , might decrease the risk for thromboembolism ( 5 ) and reduce endometrial hyperplasia ( 4 ) . However , few data are currently available on the relation between low-dose estrogen and primary prevention of heart disease and stroke . In an earlier report , we examined the relation between postmenopausal hormone therapy and primary prevention of cardiovascular disease based on 16 years of follow-up from the Nurses ' Health Study ( 6 ) . In the current analysis , we have almost 50 % more follow-up time among women taking daily doses less than 0.625 mg and more than 800 additional cases of cardiovascular disease , allowing more precise assessment of specific associations . Thus , we now report on the relation among  low-dose estrogen , short-term hormone use , and cardiovascular events in 70 533 postmenopausal women with no previous cardiovascular disease who were followed for up to 20 years . We also provide additional information on the effects of estrogen combined with progestin . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about their postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . We up date information with biennial follow-up question naires . Dietary and physical activity question naires were added in 1980 . Cohort follow-up is greater than 90 % . Ascertainment of Hormone Use In 1976 , women were asked about use and duration of hormone therapy after menopause . Beginning in 1978 , we collected information on type of hormones taken , and starting in 1980 , we asked about the dose of oral conjugated estrogen . All information is up date d biennially . Identification of Cardiovascular Disease We identified first occurrences of nonfatal myocardial infa rct ion , fatal coronary disease , and fatal and nonfatal stroke between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion or stroke were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met World Health Organization criteria ( 7 ) ( symptoms plus either elevated levels of cardiac enzymes or diagnostic electrocardiograms ) . Infa rct ions that required hospitalization and were corroborated by interview or letter but for which medical records were unobtainable were included as probable . Infa rct ions of indeterminate age discovered on routine examination were excluded . Nonfatal strokes were confirmed by review of medical records if they were characterized by a typical neurologic deficit , were rapid in onset , lasted at least 24 hours , and met the criteria of the National Survey of Stroke ( 8) . We classified strokes as ischemic ( thrombotic or embolic occlusion of a cerebral artery ) , subarachnoid hemorrhage , or intraparenchymal hemorrhage . We excluded subdural hematomas and strokes caused by infection or neoplasia . Strokes that required hospitalization and were corroborated by letter or interview but for which medical records were unavailable were included as probable . Most deaths were reported by the participants ' families . We search ed the National Death Index to identify deaths among nonrespondents to each 2-year question naire ; mortality follow-up was more than 98 % complete ( 9 ) . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered to be due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . We also included coronary disease listed on the death certificate as the underlying cause without another , more plausible cause , if the nurse was known ( from hospital records , family , or other sources ) to have had coronary disease before death . In no case was the cause listed on the death certificate used as the sole criterion for coronary death . Sudden death within 1 hour of the onset of symptoms in participants with no other plausible cause of death besides coronary disease was also included . Fatal strokes were documented by autopsy or hospital records or if stroke was listed as the underlying cause on the death certificate . The category of major coronary heart disease combines nonfatal myocardial infa rct ion and coronary death ; similarly , total stroke includes nonfatal and fatal cases . The category of combined cardiovascular disease includes major coronary heart disease and stroke . Confirmed and probable cases in each category were analyzed together ( 80 % of major coronary events and 73 % of strokes were confirmed ) . In this and previous analyses ( 6 ) , results for probable cases were similar to those for confirmed cases . The investigators conducted all interviews and record review s without knowledge of participants ' hormone use status . Population for Analysis Women who reported stroke , myocardial infa rct ion , angina , coronary revascularization , or cancer ( except nonmelanoma skin cancer ) on the 1976 question naire were excluded because their disease may have caused them to alter their hormone use . Similarly , women who reported such diagnoses on a subsequent question naire were excluded from further analysis . Thus , at the start of each 2-year interval , the base population included no women reporting these diagnoses . Our own studies ( 6 , 10 ) and other studies ( 11 ) have suggested that hormone therapy may differentially affect incident and fatal strokes ; thus , we separately examined deaths due to stroke . In these analyses , we excluded women with cancer and cardiovascular disease at baseline but did not up date the exclusions because the women who develop cardiovascular disease during follow-up are those most likely to die of stroke . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy  were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) . In this cohort , the women 's reports of age at menopause ( 12 ) and type of menopause ( 13 ) were highly accurate . In 1976 , 21 947 postmenopausal women entered the analysis , and 48 586 women were added during follow-up as they became postmenopausal , for a total of 70 533 participants ; 808 825 person-years of follow-up were accrued from 1976 to 1996 . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the 1976 data and were up date d every 2 years ( for estrogen dose , follow-up began in 1980 ) . For analyses of type of hormone therapy , we assigned the regimen reported on the 1978 question naire to women who reported hormone use in 1976 . Analyses of type of hormone therapy were limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate  , since these were the most common hormone regimens . If no data were available on hormones in a given time period , women were assigned to a missing category for that time period . To maintain the prospect i ve nature of the study , hormone use ( including duration ) during each 2-year period was established from women 's reports at the start of the period ; thus , we probably underestimate duration of use by an average of 1 year . Follow-up for a participant ended at the first diagnosis of cardiovascular disease , death , or 1 June 1996 , whichever came first . The primary analysis is based on incidence rates for which person-months of follow-up were used as the denominator . We used relative risk as the measure of association , defined as the incidence of cardiovascular events among women in various categories of hormone use divided by the incidence among women who never used hormones . We computed age-specific rates by using 5-year categories ( 14 ) and age-adjusted relative risks by using MantelHaenszel rate ratios ( 15 ) with 95 % CIs ( 16 ) . We used pooled logistic regression  across the ten 2-year time periods to adjust simultaneously for potential confounding factors ( 17 ) . In this approach , independent blocks of person-time are pooled for regression analysis , and time-varying covariates are readily accommo date d by assigning successive blocks of person-time to the covariate values at the start of each follow-up cycle . The dependence of the incidence rates on time is modeled nonparametrically with indicator variables . Simulation studies have established the asymptotic equivalence of pooled logistic regression to Cox regression with time-dependent covariates ( 18 ) . The necessary conditions for this equivalence include relatively short time intervals and small probability of the outcome during each interval , both AIMS R and omized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy ( HRT ) . We hypothesized that low-dose HRT may avoid harm . METHODS AND RESULTS We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes . A total of 100 post-menopausal women > 55 years were enrolled between 2 and 28 days after an acute coronary syndrome and r and omized to oral oestradiol-17beta 1 mg plus norethisterone acetate 0.5 mg daily , or matching placebo , and followed for up to 12 months . Levels of lipids , lipoproteins , and haemostasis markers were measured at baseline , 3 , and 6 months . There were no significant differences in lipid levels between the two groups , probably due to concomitant statin use . Antithrombin and factor VII levels were significantly lower in the HRT group , whereas fibrinogen was significantly decreased in the placebo group . No evidence of increased coagulation activation was observed , nor of adverse cardiovascular outcomes [ odds ratio ( OR ) 0.63 ( 95 % confidence intervals 0.31 - 1.31 ) ] . CONCLUSION Low-dose HRT may give cardiovascular benefit . These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective OBJECTIVE To evaluate the influence of 2 continuous combined estrogen-progestin replacement products , compared with unopposed estrogen and placebo , on cardiovascular risk markers in postmenopausal women in a r and omized , double-blind , placebo-controlled trial . METHODS Two hundred seventy healthy postmenopausal women were r and omly assigned to 1 of 4 treatment groups : placebo , unopposed 17-beta estradiol ( 1 mg ) , 1 mg of 17-beta estradiol with 0.25 mg of norethindrone acetate , or 1 mg of 17-beta estradiol with 0.5 mg of norethindrone acetate . The primary outcome variable was change from baseline in low-density lipoprotein cholesterol concentration . Additional outcome variables included changes in other serum lipid levels , hemostatic variables , and indicators of carbohydrate metabolism . RESULTS The low-density lipoprotein cholesterol level was reduced to a similar degree in all groups receiving active treatment ( 10%-14 % from baseline ; P = .001 for 17-beta estradiol with 0.5 mg of norethindrone acetate , P = .004 for 17-beta estradiol with 0.25 mg of norethindrone acetate , and P = . 001 for 1 mg of 17-beta estradiol vs placebo ) . Compared with unopposed 17-beta estradiol , 17-beta estradiol with 0.5 mg of norethindrone acetate enhanced the reductions in total cholesterol and apolipoprotein B levels ( P<.01 vs 17-beta estradiol ) . 17-beta Estradiol plus norethindrone blunted or reversed the increases in levels of high-density lipoprotein cholesterol , apolipoprotein A-I , and triglycerides produced by 17-beta estradiol alone . Effects of 17-beta estradiol plus norethindrone on hemostatic variables were similar to those of 17-beta estradiol except for factor VII activity , which was significantly reduced with 17-beta estradiol combined with 0.25 mg ( P<.01 ) and 0.5 mg ( P<.05 ) of norethindrone acetate . 17-beta Estradiol plus norethindrone appeared to blunt reductions in C-peptide and insulin levels produced by unopposed 17-beta estradiol but did not elevate these values compared with placebo . CONCLUSIONS 17-beta Estradiol plus norethindrone produced favorable changes in most cardiovascular risk markers evaluated and has a profile distinct from that of unopposed 17-beta estradiol . The impact of these differences on cardiovascular events warrants investigation . Arch Intern Med . 2000;160:3315 - 3325 A placebo-controlled trial has shown that 15 microgram of ethinyl oestradiol is as effective as 25 microgram daily in reducing both  menopausal symptoms and the urinary excretion of calcium and hydroxyproline .  Norethisterone 5 mg daily also showed a significant reduction in the climacteric symptoms but was less effective than either of the ethinyl oestradiol doses 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 The long-term effect of percutaneous and oral estrogen replacement therapy on blood pressure , plasma renin substrate , and serum estrogens was examined in a 2 year placebo-controlled study with 110 early postmenopausal women . The women were allocated to four treatment groups : ( 1 ) oral cyclical combination of 2 mg estradiol valerate and cyproterone acetate , ( 2 ) oral placebo , ( 3 ) percutaneous 17 beta-estradiol , supplemented by 200 mg oral progesterone during the second year , or ( 4 ) percutaneous placebo cream .  Systolic and diastolic blood pressure remained unchanged in both hormone treatment groups , whereas the diastolic blood pressure tended to increase in both placebo groups . Plasma renin substrate increased during oral treatment with estradiol , but remained unchanged with percutaneous estradiol . No correlation was found between blood pressure and plasma renin substrate . During percutaneous administration of estradiol , the serum concentrations of estrone and estradiol continued to rise after 3 months and reached a plateau at 6 months of therapy . Serum estrone but not estradiol showed the same pattern during oral estradiol therapy . No further changes in any of the measured variables were observed in the women treated with percutaneous estradiol after addition of cyclical oral progesterone . We conclude that both oral and percutaneous treatment with estradiol may provide protection against the age-related increase in diastolic blood pressure observed in early postmenopausal women , and that the metabolic steady state is not attained until after 3 months of estradiol therapy In a 5-yr r and omized prospect i ve study we examined the treatment effect of estrogen replacement therapy/hormone replacement therapy ( ERT/HRT ) , calcitriol , ERT/HRT and calcitriol , or placebo for 3 yr and the effect of discontinuation of therapy for 2 more yr on bone mineral density ( BMD ) , calciotropic hormones , markers of bone remodeling , and calcium absorption in 489 elderly women . The treatment phase of the study was double-blinded . After discontinuing therapy for 2 yr , there was rapid bone loss in all 3 treatment groups , and most of the decrease in BMD occurred in the first year . In the ERT/HRT group , spine BMD increased 5.5 % in yr 3 , decreased 3.2 % in yr 4 , and decreased 0.7 % in yr 5 ; femoral neck BMD increased 3.7 % in yr 3 , decreased 2.5 % in yr 4 , and decreased 0.4 % in yr 5 ; total body BMD increased 2.1 % in yr 3 , decreased 1.4 % in yr 4 , and decreased 0.6 % in yr 5 . In the combination group , spine BMD increased 7.1 % in yr 3 , decreased 4.3 % in yr 4 , and decreased 0.3 % in yr 5 ; femoral neck BMD increased 4.5 % in yr 3 , decreased 3.0 % in yr 4 , and decreased 0.01 % in yr 5 ; total body BMD increased 2.2 % in yr 3 , decreased 1.5 % in yr 4 , and decreased 0.6 % in yr 5 . In the calcitriol group , spine BMD increased 1.8 % in yr 3 , decreased 1.8 % in yr 4 , and showed no change in yr 5 ; femoral neck BMD increased 0.2 % in yr 3 , decreased 0.2 % in yr 4 , and decreased 0.6 % in yr 5 ; total body BMD decreased 0.4 % in yr 3 , decreased 0.6 % in yr 4 , and decreased 0.4 % in yr 5 . Compared with placebo , all treated groups at yr 5 had significantly higher total body BMD ; only the combination group had significantly higher spine BMD ( 3.4 % ; P < 0.001 ) and total hip BMD ( 2.4 % ; P < 0.01 . ) compared with the placebo group . Compared with baseline , only spine BMD in the combination group was significantly higher ( 2.6 % ; P < 0.001 ) at yr 5 . The increase in calcium absorption and the decrease in serum PTH levels in the calcitriol groups were reversed after discontinuation of treatment , and the decrease in bone markers was reversed in the hormone-treated groups . These results suggest that discontinuation of ERT/HRT and /or calcitriol therapy  in elderly women leads to a decrease in much of the BMD gained on treatment ; however , in the combination group there was a statistically significant residual effect on spine BMD BACKGROUND Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a ) in cross-sectional studies and small or short-term longitudinal studies . We report findings from a large , prospect i ve , placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy . METHODS AND RESULT The Postmenopausal Estrogen/Progestin Interventions study was a 3-year , placebo-controlled , r and omized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age . The active regimens were conjugated equine estrogens therapy at 0.625 mg daily , alone or in combination with each of three regimens of progestational agents : medroxyprogesterone acetate ( MPA ) at 2.5 mg daily ( ie , continuous MPA ) , MPA at 10 mg days 1 to 12 ( ie , cyclical MPA ) , and micronized progesterone at 200 mg days 1 to 12 .  Plasma levels of Lp(a ) were measured at baseline ( n = 366 ) , 12 months ( n = 354 ) , and 36 months ( n = 342 ) . Assignment to hormone therapy result ed in a 17 % to 23 % average drop in Lp(a ) concentrations relative to placebo ( P<.0001 ) , which was maintained across 3 years of follow-up . No significant differences were observed among the four active arms . Changes in Lp(a ) associated with hormone therapy were positively correlated with changes in LDL cholesterol , total cholesterol , apolipoprotein B , and fibrinogen levels and were similar across subgroups defined by age , weight , ethnicity , and prior hormone use . CONCLUSIONS Postmenopausal estrogen therapy , with or without concomitant progestin regimens , produces consistent and sustained reductions in plasma Lp(a ) concentrations Postmenopausal women are believed to have a higher risk of coronary artery disease than premenopausal women . In this study , we prospect ively determined changes in coronary risk factors that were attributable to natural menopause in 541 healthy , initially premenopausal women 42 to 50 years of age . After approximately 2 1/2 years , 69 women had spontaneously stopped menstruating for at least 12 months , and 32 women had stopped natural menstruation and received hormone-replacement therapy for a period of at least 12 months . An equal number of age-matched premenopausal women in the study group served as controls . In women who had a natural menopause and did not receive hormone-replacement therapy , serum levels of high-density lipoprotein ( HDL ) cholesterol declined as compared with those of premenopausal controls ( -0.09 vs. 0.00 mmol per liter ; P = 0.01 ) , and levels of low-density lipoprotein ( LDL ) cholesterol increased ( + 0.31 vs. + 0.14 mmol per liter ; P = 0.04 ) . In menopausal women who received hormone-replacement therapy , HDL and LDL cholesterol levels did not change , but the levels of triglycerides ( + 0.42 vs. -0.04 mmol per liter ; P less than 0.001 ) , apolipoprotein A-I ( + 0.18 vs. + 0.03 g per liter ; P less than 0.01 ) , and apolipoprotein A-II ( + 0.05 vs. -0.03 g per liter ; P less than 0.05 ) increased as compared with premenopausal controls . Natural menopause did not affect blood pressure , plasma glucose or insulin levels , body weight , the total number of kilojoules consumed in the diet , or the total number of kilojoules expended in physical activity . These results suggest that a natural menopause has an unfavorable effect on lipid metabolism , which may contribute to an increase in the risk of coronary disease .  Hormone-replacement therapy may prevent some of these changes 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 OBJECTIVE Our purpose was to determine the efficacy of dietary calcium augmentation in the prevention of early postmenopausal bone density loss in comparison with hormonal replacement therapy and placebo . STUDY DESIGN A three-arm parallel r and omized trial comparing the influence of placebo , dietary calcium augmentation , and estrogen-progesterone-calcium in 118 women who were within 6 years of menopause was conducted .  Dual photon absorptiometry was performed annually to measure lean and fat mass . In addition , the ratio of fat in the trunk/extremities was measured . RESULTS Body weight increased in each group . The increase was statistically significant in the hormone replacement group ( 0.8 kg/year ) . The percent of body fat increased in each group from baseline measurements , with the greatest increase in the hormonal replacement group . There was a decline in the extremity/trunk ratio in the hormonal replacement group as a result of a relatively greater increase in the trunk fat mass . There was a rapid rate of loss in lean body mass that was equal among groups . CONCLUSIONS Menopause is associated with a gain in fat mass and a loss of lean body mass , but these changes in body composition are not prevented by hormone replacement therapy BACKGROUND Postmenopausal conjugated equine estrogens ( CEE ) therapies increase the risk of  cognitive impairment in women aged 65 years or older and are associated with smaller regional brain volumes ; however , the link between these two phenomena has not been established . METHODS St and ardized magnetic resonance imaging was performed on 1,403 women , 1 - 4 years after they had participated in r and omized placebo-controlled clinical trials of CEE-based therapies . Women included in this report were aged 65 - 80 years and free of dementia and mild cognitive impairment ( MCI ) when originally enrolled in the trials , which lasted an average of 4 - 6 years and were conducted at 14 academic U.S. medical centers . The associations that regional brain volumes and ischemic lesion volumes had with the development of cognitive impairment ( i.e. , dementia or MCI ) were contrasted between treatment groups using analyses of covariance . RESULTS Fifty-three women developed MCI or probable dementia during follow-up . Among women who had been prescribed CEE-based therapies , cognitive impairment was associated with relatively smaller hippocampal ( p = .0002 ) and total brain volumes ( p = .03 ) . Qualitatively , these associations appeared to be independent of their level of pretreatment cognitive function . Among women who had been prescribed placebo , these relationships were not evident ; instead , cognitive impairment was associated with greater ischemic lesion volume in the frontal lobe ( p = .007 ) and overall ( p = .02 ) . CONCLUSION A mechanism by which CEE-based postmenopausal hormone therapy induces cognitive impairment appears to be through increased brain atrophy 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 improves endothelial function in the coronary conduit vessels of animals ; however , its effects on the coronary microcirculation have not been studied completely in humans . Methods and Results —We measured myocardial blood flow ( MBF ) with a PET scan at rest , during cold pressor testing ( CPT ) , and during dipyridamole hyperemia in 54 postmenopausal women without coronary artery disease . Of these , 23 were not and 31 women were taking long-term hormone replacement therapy ( HRT ) using estrogen either alone or with a progestogen . Each group was subdivided by coronary risk factors ( RFs ) . Twelve young healthy women served as controls . In women not taking HRT , MBF measurements were repeated after 25 mg of conjugated equine estrogens IV . Neither short estrogen nor long-term HRT affected MBF at rest in women with and without RFs . Dipyridamole MBF was attenuated only in the women with RF who were not taking HRT . Short-term estrogen and long-term HRT did not reverse the abnormal response . MBF responses to CPT were abnormal in women not taking HRT , regardless of RFs ( 20±15 % versus 32±21 % ) and remained unchanged after short-term estrogen administration . Long-term HRT normalized the response to CPT only in women without RF ( 53±22 % versus 59±36 % in the young women ; NS ) . MBFs were similar for women on estrogen alone or estrogen plus a progestogen , regardless of presence or absence of RFs . Conclusion —Menopause is associated with abnormal CPT ( an indirect measure of endothelial function ) , which can be reversed by long-term HRT only when RFs are absent . Progestogens do not antagonize this effect . Long-term HRT may therefore be useful in the primary prevention of coronary artery disease in women without RFs OBJECTIVE The positive short-term effects of postmenopausal hormone replacement therapy ( HRT ) on serum lipids are well known , but it has been suggested that they vanish with time . Cholecalciferol ( vitamin D3 ) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known . The long-term effects of HRT and vitamin D3 on the concentrations of serum lipids were studied in a population -based prospect i ve 3-year study . DESIGN AND METHODS 464 women were r and omized into four treatment groups : ( i ) HRT ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ) , ( ii ) Vit D3 ( vitamin D3 300 IU/day ) , ( iii ) HRT+Vit D3 ( both as above ) , ( iv ) placebo ( calcium lactate 500 mg/day ) . RESULTS 320 women completed the study . After three years of treatment , serum concentrations of low density lipoprotein ( LDL ) cholesterol decreased in the HRT group ( 10.1 % , P<0.001 ) and the HRT+Vit D3 group ( 5.9 % , P=0.005 ) , increased in the Vit D3 group ( 4.1 % , P=0.035 ) but remained unchanged in the placebo group . The concentrations of total cholesterol decreased by 5.8 % in the HRT group ( P<0.001 ) and by 3.3 % in the HRT+Vit D3 group ( P=0.023 ) , but did not change in the other two groups . Serum concentrations of high density lipoprotein ( HDL ) cholesterol decreased in the Vit D3 group ( 5.2 % , P=0.001 ) , HRT+Vit D3 group ( 3.7 % , P=0.046 ) , and the placebo group ( 4.5 % , P=0.006 ) but did not change significantly in the HRT group . The HDL/LDL ratio increased in the HRT group ( 10.5 % , P=0.006 ) and decreased in the Vit D3 group ( 10.5 % , P<0.001 ) whereas no changes occurred in the other two groups . In addition , serum triglycerides increased similarly in all groups ( 14.0 - 18.8 % , P<0.05 - 0.001 ) . CONCLUSIONS Our results confirm the positive long-term effect of HRT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations . In addition , the results suggest that vitamin D3 supplementation may have unfavorable effects on lipids in postmenopausal women .  Pure vitamin D3 treatment was associated with increased serum LDL cholesterol . Furthermore , the beneficial effects of HRT on serum LDL cholesterol content were reduced when estradiol valerate was combined with vitamin D3 . However , the relevance of these associations to cardiovascular morbidity remains to be established 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 PURPOSE To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen . SUBJECTS AND METHODS A prospect i ve , r and omized clinical trial was performed in 81 postmenopausal women aged 51.7 + /- 4.4 years ( mean + /- SD ) . They were assigned to one of four groups : Provera 20 mg , Premarin 0.6 mg , Premarin 0.3 mg plus Provera 10 mg , and a placebo . In addition , all women received calcium supplementation , if necessary , to a calcium intake of 1,000 mg/day . We used single- and dual-photon absorpiometry , metacarpal radiogrammetry , and computed axial tomography to measure bone mineral density in the total skeleton , spine , radius , and metacarpal . RESULTS Women receiving placebo  lost bone at all sites ( p less than 0.01 ) . The Provera-treated group showed no change in total body calcium , but there were decreases in radial density ( p less than 0.01 ) , metacarpal cortex ( p less than 0.01 ) , and spine density ( p less than 0.01 ) . The Premarin-treated group had an increase in spine density and total body density ( p less than 0.05 ) , but a decrease in radial density ( p less than 0.05 ) . The Premarin-plus-Provera group showed no change in spine density , total body calcium , or radial density but had a decrease in metacarpal cortex ( p less than 0.01 ) . CONCLUSIONS Compared to placebo , Provera reduced the rate of loss in cortical areas of the skeleton , but not in the spine , which contains more trabecular bone . In contrast , Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton . The low-dose combination of Premarin plus Provera was similar in its effect on bone to that of Premarin alone , suggesting that there may be a synergistic effect of this hormone combination on bone . Serum cholesterol levels decreased with Provera , Premarin , and the combination of both , whereas levels of serum triglycerides increased with Premarin treatment , decreased with the Provera regimen , and were unchanged with the combination therapy . Provera does not adversely affect the lipid profile The Women ’s Health Initiative ( WHI ) Clinical Trial ( CT ) includes three overlapping components , each a r and omized controlled comparison among women who were postmenopausal and 50 to 79 years of age at r and omization . The dietary modification ( DM ) component r and omly assigned 48,836 ( target 48,000 ) eligible women to either a sustained low-fat eating pattern  ( 40 % ) or  self-selected dietary behavior  ( 60 % ) , with breast cancer and colorectal cancer as design ated primary outcomes and coronary heart disease as a secondary outcome . The nutrition goals for women assigned to the DM intervention group have been to reduce total dietary fat to 20 % , and saturated fat to less than 7 % of daily calories and , secondarily , to increase daily servings of vegetables and fruits to at least five and of grain products to at least six and to maintain these changes throughout trial follow-up . The r and omization of 40 % , rather than 50 % , of participating women to the DM intervention group was intended to reduce trial costs , while testing trial hypotheses with specified power . The postmenopausal hormone therapy ( PHT ) component comprises two r and omized , double-blind trials among 27,347 ( target 27,500 ) women , with coronary heart 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 BACKGROUND While observational studies have suggested that unopposed estrogens reduce the incidence of coronary disease in postmenopausal women , there are few data on the effect of combined therapy with estrogens and progestins -- a regimen adopted in recent years to minimize the risk of endometrial hyperplasia and cancer . In clinical trials , the addition of progestins has an adverse effect on serum lipid levels , and these lipid effects have raised the question of whether combined estrogen-progestin therapy increases the risk of coronary disease compared with the use of estrogen alone . METHODS We conducted a population -based , case-control study among enrollees of Group Health Cooperative of Puget Sound . Cases were postmenopausal women who sustained an incident fatal or nonfatal myocardial infa rct ion in 1986 through 1990 . Controls were a stratified r and om sample of female Group Health Cooperative enrollees frequency matched to the cases by age and calendar year . We review ed the medical records of the 502 cases and 1193 controls and conducted brief telephone interviews with consenting survivors . The health maintenance organization 's computerized pharmacy data base was used to ascertain the use of postmenopausal hormones . For the primary analysis of current use , we classified women into one of three groups : ( 1 ) nonusers of hormones ; ( 2 ) users of estrogens alone ; or ( 3 ) users of combined therapy including both estrogens and progestins .  Each group of hormone users was compared with nonusers . RESULTS After adjustment for potential confounding factors , the risk ratio of myocardial infa rct ion associated with current use of estrogens alone was 0.69 ( 95 % confidence interval , 0.47 to 1.02 ) ; and the risk ratio of myocardial infa rct ion associated with current use of combined therapy was 0.68 ( 95 % confidence interval , 0.38 to 1.22 ) . Duration of combined-therapy use was relatively short , averaging less than 2 years in cases and controls . CONCLUSIONS In this case-control study , the reduced risk of myocardial infa rct ion associated with the use of estrogens alone was consistent with previous observational studies . Although the 95 % confidence interval only excluded a risk above 1.22 , the current use of combined therapy was not associated with an adverse effect on the incidence of myocardial infa rct ion in postmenopausal women BACKGROUND Apparently discrepant findings have been reported by the Women 's Health Initiative ( WHI ) trial compared with observational studies of postmenopausal hormone therapy ( HT ) and coronary heart disease ( CHD ) . METHODS We prospect ively examined the relation of HT to CHD , according to timing of hormone initiation relative to age and time since menopause . Participants were postmenopausal women in the Nurses ' Health Study , with follow-up from 1976 to 2000 . Information on hormone use was ascertained in biennial , mailed question naires . We used proportional hazards models to calculate multivariable adjusted relative risks ( RR ) and 95 % confidence intervals ( CI ) . We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT . RESULTS Women beginning HT near menopause had a significantly reduced risk of CHD ( RR = 0.66 , 95 % CI 0.54 - 0.80 for estrogen alone ; RR = 0.72 , 95 % CI 0.56 - 0.92 for estrogen with progestin ) . In the subgroup of women demographically similar to those in the WHI , we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause ( RR = 0.87 , 95 % CI 0.69 - 1.10 for estrogen alone ; RR = 0.90 , 95 % CI 0.62 - 1.29 for estrogen with progestin ) . Among women who began taking hormones at older ages , we also found no relation between current use of estrogen alone and CHD ( for women aged 60 + years , RR = 1.07 , 95 % CI 0.65 - 1.78 ) , although there was a suggestion of possible reduced risk for combined HT ( RR = 0.65 , 95 % CI 0.31 - 1.38 ) . In sensitivity analyses , we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT . CONCLUSIONS These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk Objective : The purpose of this study was to evaluate the isolated and associated effects of estrogen therapy ( estradiol valerate 1 mg/d orally ) and physical exercise ( moderate aerobic exercise , 3 h/wk ) on health-related quality of life ( HRQOL ) and menopausal symptoms among women who had undergone hysterectomy . Design : A 6-month , r and omized , double-blind , placebo-controlled clinical trial with 44 postmenopausal women who had undergone hysterectomy . The interventions were physical exercise and hormone therapy ( n = 9 ) , being sedentary and hormone therapy ( n = 14 ) , physical exercise and placebo ( n = 11 ) , and being sedentary and placebo ( n = 10 ) . HRQOL was assessed by a Brazilian st and ard version of the Medical Outcome Study Short-Form Health Survey and symptoms by Kupperman Index at baseline and after 6 months . Results : There was a decrease in symptoms in all groups , but only groups who performed physical exercise showed an increase in quality of life . Analysis of variance showed that changes in physical functioning ( P = 0.001 ) and bodily pain ( P = 0.012 ) scores over the 6-month period differed significantly between women who exercised and women who were sedentary , regardless of hormone therapy . Hormone therapy had no effect , and there was also no significant association between physical exercise and hormone therapy in HRQOL . Conclusions : Physical exercises can reduce menopausal symptoms and enhance HRQOL , independent of whether hormone therapy is taken 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 Serum lipids and lipoproteins were studied in 86 healthy post-menopausal women at 3-monthly intervals throughout 2 yr of treatment with cyclic oestradiol valerate plus cyproterone acetate ( E2V + CPA ) , continuous 17 beta-oestradiol plus norethisterone acetate ( E2 + NETA ) , or placebo .  Withdrawal effects were also investigated . Serum oestrogen levels were similar following the 2 hormone regimens . Serum total and low-density-lipoprotein ( LDL ) cholesterol were significantly reduced by 5 - 8 % during cyclic E2V + CPA therapy and by 15 - 20 % during continuous E2 + NETA treatment . The concentrations remained significantly reduced throughout the 2 yr of treatment . Virtually no changes were observed in the placebo group . High-density-lipoprotein ( HDL ) cholesterol concentrations were significantly reduced in relation to pretreatment values during the first year of continuous E2 + NETA therapy , but were not significantly different from the levels in the cyclic E2V + CPA or the placebo groups . Serum triglyceride levels remained almost constant in all the groups . Withdrawal of hormone therapy result ed in steep increases in total and LDL-cholesterol , the levels returning to pretreatment values . A similar increase in HDL-cholesterol was observed in the E2 + NETA group , following withdrawal . Vaginal bleeding episodes were experienced by all the women receiving the E2V + CPA regimen and they occurred regularly in 63 % of the women . Fifty-two ( 52 ) percent of the women receiving E2 + NETA did not bleed at all . The results of the present study suggest that the continuous addition of NETA may enhance the oestrogen-induced changes in total and LDL-cholesterol , whereas only minor changes in the oestrogen-induced effects on these variables are produced by the cyclic addition of CPA . However , in the case of HDL-cholesterol , the antagonistic effect of CPA seems to be moderate in comparison with that of NETA 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 Objectives The aim of this study was to assess the effects of 1 and 2 mg 17β-estradiol on serum lipid profile . Beneficial effects have been clearly established in previous studies with a 2 mg dose ; further evidence was required to confirm the beneficial effects of a 1 mg dose . Methods This double-blind , placebo-controlled study involved 579 postmenopausal women r and omized to oral treatment with placebo , 1 mg/day 17β-estradiol sequentially combined with 5 or 10 mg/day dydrogesterone for the last 14 days of each 28-day cycle , or 2 mg/day 17β-estradiol sequentially combined with 10 or 20 mg/day dydrogesterone for the last 14 days of each 28-day cycle .  Treatment was continued for 26 cycles . Results High density lipoprotein ( HDL ) cholesterol levels were significantly ( p<0.05 ) increased after 26 cycles in all active treatment groups compared with placebo . In addition , low density lipoprotein ( LDL ) cholesterol and lipoprotein(a ) levels were significantly reduced , and apolipoprotein A1 and triglyceride levels were significantly increased , in all active treatment groups after 13 and 26 cycles . Conclusions The results of this study clearly indicate that sequential combinations of either 1 or 2 mg 17β-estradiol with dydrogesterone are associated with long-term , favorable changes in the serum lipid profile . There was no evidence that dydrogesterone compromised the 17β-estradiol-induced improvements in lipid profile OBJECTIVE To evaluate the efficacy of lower doses of conjugated equine estrogens ( CEE ) plus medroxyprogesterone acetate ( MPA ) for relieving  vasomotor symptoms and vaginal atrophy .  DESIGN A r and omized , double-blind , placebo-controlled trial ( the Women 's Health , Osteoporosis , Progestin , Estrogen study ) . SETTING Study centers across the United States . PATIENT(S ) Two thous and , six hundred , seventy-three healthy , postmenopausal women with an intact uterus , including an efficacy-evaluable population ( n = 241 at baseline ) . INTERVENTION(S ) Patients received for 1 year ( 13 cycles ; in milligrams per day ) CEE , 0.625 ; CEE , 0.625 and MPA , 2.5 ; CEE , 0.45 ; CEE , 0.45 and MPA , 2.5 ; CEE , 0.45 and MPA , 1.5 ; CEE , 0.3 ; CEE , 0.3 and MPA , 1.5 ; or placebo . MAIN OUTCOME MEASURE(S ) Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index ( VMI ) to assess vaginal atrophy . RESULT ( S ) In the efficacy-evaluable population , reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d ( the most commonly prescribed doses ) and all lower combination doses . CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone . VMI improved in all active treatment groups . CONCLUSION ( S ) Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses BACKGROUND In postmenopausal women with coronary artery disease , conjugated equine estrogen with or without continuous administration of medroxyprogesterone acetate has failed to slow the progression of atherosclerosis . Whether 17beta-estradiol ( the endogenous estrogen molecule ) alone or administered sequentially with medroxyprogesterone acetate can slow the progression of atherosclerosis is unknown . METHODS We conducted a double-blind , placebo-controlled trial in 226 postmenopausal women ( mean age , 63.5 years ) who had at least one coronary-artery lesion . Participants were r and omly assigned to usual care ( control group ) , estrogen therapy with micronized 17beta-estradiol alone ( estrogen group ) , or 17beta-estradiol plus sequentially administered medroxyprogesterone acetate ( estrogen-progestin group ) . In all patients the low-density lipoprotein ( LDL ) cholesterol level was reduced to a target of less than 130 mg per deciliter . The primary outcome was the average per-participant change between base-line and follow-up coronary angiograms in the percent stenosis measured by quantitative coronary angiography . RESULTS After a median of 3.3 years of follow-up , the mean ( + /-SE ) change in the percent stenosis in the 169 participants who had a pair of matched angiograms was 1.89+/-0.78 percentage points in the control group , 2.18+/-0.76 in the estrogen group , and 1.24+/-0.80 in the estrogen-progestin group ( P=0.66 for the comparison among the three groups ) . The mean difference in the percent stenosis between the estrogen group and the control group was 0.29 percentage point ( 95 percent confidence interval , -1.88 to 2.46 ) , and the mean difference between the estrogen-progestin group and the control group was -0.65 ( 95 percent confidence interval , -2.87 to 1.57 ) . CONCLUSIONS In older postmenopausal women with established coronary-artery atherosclerosis , 17beta-estradiol either alone or with sequentially administered medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis Fifty-five depressed menopausal patients took part in a r and omized double-blind cross-over trial using ; Harmogen ' ( piperazine oestrone sulphate ) and placebo . The Beck depression inventory , hot flush counts , and patients ' subjective assessment of well-being were used to assess clinical status . Hormonal , biochemical and coagulation profiles were carried out . Hot flushes improved significantly on oestrogen compared with placebo .  Depression scores and well-being showed significant and equal improvement on oestrogen and placebo . Significant improvement in flushes in patients on placebo was observed in the first half of the trial but did not occur in the second half , in patients who had previously taken oestrogen . No significant changes occurred in biochemistry . Coagulation tests showed acceleration of the prothrombin time in patients taking ; Harmogen ' compared with those on placebo . Piperazine oestrone sulphate is a relatively weak but safe oestrogen preparation , effective in treatment of vasomotor symptoms but no more effective than placebo in the treatment of depression OBJECTIVES On the basis of epidemiological and experimental data , it has been supposed that hormone replacement therapy ( HRT ) inhibits atherosclerosis in postmenopausal women . This r and omized controlled trial examined whether 1 mg 17beta-estradiol daily , combined cyclically with 0.025 mg gestodene in every month ( HRT 1 ) , or in every third month ( HRT 2 ) slows the increase of intima-media thickness in femoral arteries compared with no HRT . METHODS Healthy postmenopausal women ( n=321 ) with an increased risk for future vascular disease as indicated by > 1 mm of intima-media thickness in the carotid arteries were equally r and omized to one of the three groups for 48 weeks .  Ultrasound scans of femoral arteries were recorded at study start and study end , together with a thorough clinical examination and laboratory work-up . RESULTS Complete scans were obtained in 260 of the 264 subjects who participated until study end .  Mean maximum intima-media thickness of four femoral artery segments ( common and superficial , both sides ) was 0.93+/-0.37 mm ( mean+/-S.D. ) at study start . It increased by 0.02+/-0.05 , 0.02+/-0.05 , and 0.03+/-0.05 mm in the HRT 1 , HRT 2 and no HRT groups , respectively ( HRT 1 versus no HRT , HRT 2 versus no HRT ; both P>0.2 ) . Compared with no HRT , HRT significantly lowered follicle stimulating hormone , low-density lipoprotein cholesterol , and fibrinogen . CONCLUSIONS In this 1-year trial , irrespective of the progestogen dose used , HRT with 1 mg 17 beta-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal women with sub clinical vascular disease AIMS At the time of the design of the Osteoporosis Prevention and Arterial effects of tiboLone ( OPAL ) study in 1996 , oral hormone therapy ( HT ) was assumed to reduce cardiovascular risk . The evidence mainly came from the effects of combined conjugated equine oestrogens plus medroxyprogesterone acetate ( CEE/MPA ) therapy . Other HT regimes had not been studied widely . Tibolone , a selective tissue oestrogenic activity regulator , has several effects on cardiovascular risk factors , one of which is HDL lowering . Because the overall effect of tibolone on cardiovascular risk was unknown , the OPAL study was design ed . METHODS AND RESULTS The OPAL study was a three-arm , r and omized , placebo-controlled , double-blind study to determine the effect of tibolone ( 2.5 mg daily ) and of CEE/MPA ( 0.625/2.5 mg daily ) over 3 years on progression of carotid intima-media thickness ( CIMT ) in 866 healthy post-menopausal women . The women were recruited from six US and five European centres . The primary outcome was change in mean common CIMT . Annual common CIMT progression rates in the tibolone and CEE/MPA groups were higher than in the placebo group : 0.0077 mm [ 95 % confidence interval ( CI ) 0.0051 - 0.0103 ] in the tibolone group , 0.0074 mm ( 0.0048 - 0.0099 ) in the CEE/MPA group , and 0.0035 mm ( 0.009 - 0.0061 ) in the placebo group . The differences with placebo ( 0.0042 mm/year for tibolone and 0.0039 mm/year for CEE/MPA ) were statistically significant . HDL cholesterol increased in CEE/MPA group and was lowered in the tibolone group . CONCLUSION Both tibolone and CEE/MPA showed increased progression of common CIMT . Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the Women 's Health Initiative study . This suggests that the net effect of tibolone and CEE/MPA on cardiovascular events may depend on the combined effects on the arterial wall , clotting factors , and possibly inflammation Objective : The aim of this study was to examine the effect of conjugated equine estrogens alone ( ET ) , conjugated equine estrogens + medroxyprogesterone ( EPT ) , calcitriol alone , calcitriol + EPT/ET , or placebo on serum lipid profile and analyze the interaction with estrogen receptor-&agr ; gene single nucleotide polymorphisms ( ESR-&agr ; SNPs ) on the response to therapy . Methods : A total of 489 postmenopausal women older than 65 years were enrolled into a 3-year double-blind , placebo-controlled clinical trial . Results : In both intent-to-treat and complier ( > 80 % adherent ) analysis , there was a significant increase in serum high-density lipoproteins and a significant decrease in serum low-density lipoproteins ( LDLs ) and the LDL/high-density lipoprotein ratio in all hormone treatment groups compared with placebo ( P < 0.05 ) . However , serum triglycerides and very low-density lipoproteins increased in the EPT and ET + calcitriol groups versus placebo ( P < 0.05 ) . ESR-&agr ; SNPs PvuII and XbaI seemed to have a significant effect on the response to treatment . Genotypes containing the p allele showed a significantly greater decrease in serum cholesterol and very low-density lipoprotein than those having the P allele in the ET + calcitriol group ( P < 0.05 ) , and those with the x allele had a significantly greater decrease in serum cholesterol in the hormone therapy + calcitriol group at the end of 3 years versus the X allele , and a greater decrease in serum LDL in alleles x versus the X in the ET + calcitriol group ( P < 0.05 ) . Conclusions : ET with or without progesterone had a favorable effect on lipid profile  in postmenopausal older women , and this was dependent on estrogen receptor SNPs-PvuII and XbaI. However , this interaction with ESR-&agr ; SNPs needs to be confirmed in larger studies 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 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 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 Observational epidemiologic studies suggest that the incidence of cardiovascular disease is reduced by about 50 % in users of unopposed estrogens , but the reduction may have been overestimated because of a greater tendency for women at lower risk to use estrogens . To minimize bias due to such behavior , the authors conducted a case-control study of first myocardial infa rct ion among Massachusetts women aged 45 - 69 years during 1986 - 1990 , in which each of 858 cases was age-matched with a control from the same geographic area , and important correlates of  estrogen use and myocardial infa rct ion were controlled by conditional logistic regression . The estimated relative risk was 0.9 for ever use of unopposed estrogen ( 95 % confidence interval 0.7 - 1.2 ) ; the estimate decreased with increasing duration of use to 0.6 for 5 or more years of use ( p for trend = 0.08 ) . The association with long-term use was stronger for recent use ( p for trend < 0.05 ) than for past use ( p for trend = 0.86 ) . There were insufficient data to evaluate estrogens taken together with progestins . The results suggest that unopposed estrogen use may reduce the risk of first myocardial infa rct ion , that the reduction is related to the duration and recency of use , and that it may be smaller than previously believed . Despite efforts to control confounding , observational studies can not rule out the possibility that a tendency for women at lower risk for myocardial infa rct ion to use estrogens has contributed to the reduced risk in estrogen users , and r and omized trials are needed The spontaneous calcanean bone loss occurring in healthy early post-menopausal women and the effect of two hormone replacement therapies ( HRT 's ) were investigated in a longitudinal study . There was no difference between the right and left calcanean BMC or BMD ( p > 0.15 ) . The spontaneous bone loss was similar at all the skeletal sites measured , with a mean spontaneous loss in calcanean BMD of 1.6 % over one year . Both HRT 's significantly ( p < 0.01 ) prevented the bone loss from all skeletal sites irrespective of the weight-bearing or content of trabecular bone , and ( for the weight-bearing bones ) there was even a gain in calcanean BMC and BMD and spinal BMD ( p < 0.01 ) . Bone mineral of the calcaneus and the spine correlated equally to body weight ( r approximately 0.4 , p < 0.001 ) , whereas bone mineral in the forearm was not correlated to body weight . The correlations between the changes in bone mineral at the sites measured were all significant ( r approximately 0.2 - 0.4 ) Fasting serum calcitonin levels were measured in 54 postmenopausal women who had for 10 years been taking part in a double blind trial to assess the effect of the synthetic oestrogen , mestranol , on postmenopausal bone loss . There were no differences in calcitonin levels between mestranol treated and placebo groups , Fifteen of the women were challenged with a calcium infusion to measure the secretory reserve of calcitonin . Oestrogen treatment did not increase the calcitonin response to calcium infusion . The three patients who exhibited the greatest responses were placebo treated . Bone density was measured by γ‐ray absorptiometry over the ten year period and the annual rate of change of bone density calculated . No correlation could be found between basal calcitonin level or calcitonin reserve and change in bone density . Our results indicate that postmenopausal osteoporosis is not caused by a deficiency of calcitonin and that the action of oestrogen therapy to prevent bone loss does not involve calcitonin Background —Observational studies have reported less frequent carotid atherosclerosis in healthy women taking postmenopausal hormone therapy . Estrogen with progestin did not reduce peripheral arterial events among women with preexisting coronary heart disease . This analysis evaluates clinical peripheral arterial disease among generally healthy women in the Women ’s Health Initiative r and omized trial of estrogen plus progestin . Methods and Results —The Estrogen Plus Progestin trial assigned 16 608 postmenopausal women , mean age 63.3±7.1 years , to daily conjugated estrogens ( 0.625 mg ) with medroxyprogesterone acetate ( 2.5 mg ) or placebo and documented health outcomes over an average of 5.6 years of follow-up . Hospitalization for peripheral arterial disease was infrequent , with annualized rates of 0.08 % , 0.06 % , and 0.02 % for carotid disease , lower extremity arterial disease , and abdominal aortic aneurysm , respectively . The incidence of peripheral arterial events did not differ between treatment groups ( hazard ratio [ HR ] 0.89 , 95 % confidence interval 0.63 , 1.25 ) . The risk was slightly greater among women assigned to active estrogen with progestin in years 1 ( HR 1.33 ) and 2 ( HR 1.27 ) , and was slightly lower in later years ( HR 0.85 and 0.87 in years 5 and ≥6 ) . Among adherent participants , the hazard ratio for peripheral arterial events was 1.23 ( 95 % confidence interval 0.79 , 1.91 ) over the 5.6 years of follow up . Subgroup analysis identified no significant interactions between estrogen with progestin and baseline characteristics with regard to peripheral arterial disease risk . Conclusions —Among generally healthy postmenopausal women , conjugated estrogens with progestin did not confer protection against peripheral arterial disease The long term effects of hormone replacement therapy ( HRT ) and vitamin D3 ( Vit D ) on bone mineral density ( BMD ) were studied . A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study ( n = 13100 ) were r and omized to four groups : 1 ) HRT ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate , 2 ) Vit D3 ( 300 and 100 IU/day during the fifth year ) , 3 ) HRT and Vit D combined , and 4 ) placebo .  Lumbar ( L2-L4 ) and femoral neck BMD were determined by dual x-ray absorptiometry ( DXA ) at baseline and after 2.5 and 5 yr of treatment . Intention to treat analysis ( n = 464 ) showed that after 5 yr , lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups [ + 0.2 % ( P = 0.658 ) and + 0.9 % ( P = 0.117 ) , respectively ] , whereas lumbar BMD decreased by 4.6 % in the Vit D group and by 4.5 % in the placebo group ( P < 0.001 in both ) . The loss of femoral neck BMD was less in the HRT ( -1.4 % ; P = 0.005 ) and HRT plus Vit D ( -1.3 % ; P = 0.003 ) groups than in the Vit D and placebo groups ( -4.3 % ; P < 0.001 in both ) . Among those 370 women who complied with the 5-yr treatment , the effect was more pronounced : lumbar BMD had increased by 1.5 % in the HRT ( P = 0.009 ) and by 1.8 % in the HRT plus Vit D group ( P = 0.005 ) , with a plateau after 2.5 yr , whereas lumbar BMD had decreased in both the Vit D and placebo groups ( 4.6 % and 4.7 % ; P < 0.001 , respectively ) . Femoral neck BMD decreased again less in the HRT ( -0.4 % ) and HRT plus Vit D ( -0.6 % ) groups than in the Vit D and placebo groups ( -4.4 % in both ) . This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis . The data suggest that low dose vitamin D3 supplementation does not prevent  bone loss in healthy , nonosteoporotic , early postmenopausal women , and it confers no benefit additional to that of HRT alone 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 To compare the effect of continuous norethindrone acetate (NA)-ethinyl estradiol ( EE2 ) combinations with matching unopposed EE2 or placebo . DESIGN A 2-year , double-blind , placebo-controlled , parallel-group clinical trial . SETTING Out patients at 65 centers . PATIENTS Asymptomatic or mildly symptomatic women aged 40 years or older who had undergone the onset of spontaneous menopause within the last 5 years and who had an intact uterus . INTERVENTIONS Patients were equally r and omized to placebo or 1 of 8 treatment groups : 0.2 mg of NA and 1 microg of EE2 ; 0.5 mg of NA and 2.5 microg of EE2 ; 1 mg of NA and 5 microg of EE2 ; 1 mg of NA and 10 microg of EE2 ; 1 microg of EE2 ; 2.5 microg of EE2 ; 5 microg of EE2 ; or 10 microg of EE2 . PRIMARY OUTCOME MEASURES Bone mineral density ( BMD ) measured by quantitative computed tomography , serum lipids , and endometrial effects as assessed by rate of hyperplasia and proliferative status . RESULTS Twelve hundred sixty-five patients entered the study . Bone mineral density increased significantly from baseline ( P<.001 ) in the 1 mg NA-5 microg EE2 and the 1 mg NA-10 microg EE2 treatment groups at each annual assessment . Among the unopposed EE2 groups , only the 10-microg group had increased BMD above baseline , but also was accompanied by an unacceptably high rate of endometrial hyperplasia . The NA-EE2 treatment groups had a significant linear dose-response trend for increasing BMD . Increased endometrial proliferation and hyperplasia occurred with increasing unopposed estrogen doses . The combination of NA and EE2 effectively protected the endometrium against hyperplasia . The percentage of change in the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol was positive for all treatment groups . The increase in triglyceride levels associated with EE2 was attenuated with NA-EE2 treatment . CONCLUSIONS Daily treatment with NA-EE2 was well tolerated and protected the endometrium from EE2-induced proliferation and hyperplasia . The NA-EE2 treatments produced a dose-related significant increase in BMD that was not present with unopposed EE2 treatment . The overall effect of NA-EE2 treatments on lipid measures was favorable 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 Objective : The contribution of progestogen therapy or progestogen type to risks and benefits of estrogen treatment is inadequately characterized . We examined the effect of conjugated equine estrogens ( CEE ) with and without concomitant progestogen treatments on changes in hemostasis measures among Postmenopausal Estrogen/Progestin Intervention participants . Design : Postmenopausal Estrogen/Progestin Intervention was a clinical trial that r and omized 875 postmenopausal women to one of five arms : placebo , CEE alone , CEE with cyclic micronized progesterone ( MP ) , CEE with cyclic medroxyprogesterone acetate ( MPA ) , and CEE with continuous MPA . Twelve hemostasis assays were measured in a sub study at baseline and 12 and 36 months . Using 12- and 36-month changes in hemostasis measures , we calculated change ratios for two comparisons of active treatments : CEE+MPA versus CEE and CEE+MPA versus CEE+MP . Results : Hemostasis measures were available for 288 women . Compared with women assigned to CEE alone , 12-month increases in factor VIIc and protein C among women assigned to CEE+MPA were relatively smaller ( ratios : 0.94 [ 95 % CI : 0.89 - 0.98 ] and 0.96 [ 95 % CI : 0.92 - 1.00 ] ) , respectively . Compared with women assigned to CEE+MP , women assigned to CEE+MPA had smaller increases in factor VIIc and larger decreases in plasminogen activator inhibitor-1 antigen at 12 months ( ratios : 0.94 [ 95 % CI : 0.90 - 0.98 ] and 0.70 [ 95 % CI : 0.53 - 0.93 ] , respectively ) . Thirty-six month ratios were similar to these . Women assigned to CEE+MPA had smaller increases in protein C than those assigned CEE+MP at 36 months only ( ratio : 0.95 [ 95 % CI : 0.91 - 0.99 ] ) . No other associations were significant . Conclusions : We found modest yet significant differences in hemostasis measure changes when comparing progestogen use and progestogen type in postmenopausal women using CEE 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 Background : Atherosclerosis has long been thought to develop over time in a linear manner from gradual wall thickening to advanced thick lesions . However , evidence has emerged indicating a phasic rather than linear progression with time . A major reason for this non-linear pattern appears to be the occurrence of hemorrhages in the arterial wall , although data on this issue are still scarce . We studied the occurrence of temporarily impressive thickenings of the carotid arterial wall in a cohort of healthy postmenopausal women who were followed up for 3 years with regular carotid ultrasound examinations .  Methods : The women were the European participants of a r and omized placebo-controlled trial into the effect of hormone replacement therapy on progression of carotid intima-media thickness ( CIMT ) .  For a period of 3 years , the women underwent a st and ardized carotid ultrasound protocol every 6 months . Common , bifurcation and internal carotid segments were scanned on both sides , stored on videotape , and the near and far wall CIMT was measured on defined angles and segments , also in areas of plaque . Adverse events were routinely recorded . At the completion of the study , all segment-specific measurements were evaluated for outliers . Images were retrieved from videotape and evaluated whether the outlier result ed from a real morphological change or ‘ measurement error ’ . Results : The 509 healthy postmenopausal women , free from previous symptomatic cardiovascular disease , underwent 3,812 carotid ultrasound scans during the study , and 44,924 carotid segments were evaluated . In 203 segments of 188 participants outliers were observed . True morphological changes were found in 12 participants , equivalent to a 3-year risk of 2.4 % . These changes did not give rise to clinical symptoms . In the 6 women of whom we had follow-up measurements , the changes were reversed within 6–12 months . Conclusion : We observed acute increases in CIMT among 2.4 % of healthy postmenopausal European women followed for 3 years . When assuming these were the result of vessel wall hemorrhages , our findings add to the body of evidence suggesting that vessel wall hemorrhages contribute to atherosclerosis development and also appear to occur clinical ly silent This manuscript describes the study design and rationalle for the Kronos Early Estrogen Prevention Study ( KEEPS ) and the KEEPS Cognitive and Affective ancillary study ( KEEPS Cog ) . KEEPS is a multicenter , r and omized , double-blinded , placebo-controlled trial , design ed to test the hypothesis that low-dose hormone therapy ( HT ) initiated in recently postmenopausal women will reduce the progression of sub clinical atherosclerosis as measured by carotid artery intima-media thickness ( CIMT ) and coronary artery calcification ( CAC ) over four years . The KEEPS Cog ancillary study was design ed to assess potential estrogenic treatment effects on cognition and mood . We present the KEEPS trial in the context of issues raised by the Women 's Health Initiative ( WHI ) and the Women 's Health Initiative Memory Study ( WHIMS ) . Here we also describe the most recent results and ongoing HT-related research studies design ed to address similar issues . This article is part of a Special Issue entitled Hormone Therapy 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 As part of the Women 's Health Initiative Study , the 5-item Women 's Health Initiative Insomnia Rating Scale ( WHIIRS ) was developed . This article summarizes the development of the scale through the use of responses from 66,269 postmenopausal women ( mean age = 62.07 years , SD = 7.41 years ) . All women completed a 10-item question naire concerning sleep . A novel resampling technique was introduced as part of the data analysis . Principal-axes factor analysis without iteration and rotation to a varimax solution was conducted for 120,000 r and om sample s of 1,000 women each . Use of this strategy led to the development of a scale with a highly stable factor structure . Structural equation modeling revealed no major differences in factor structure across age and race-ethnic groups . WHIIRS norms for race-ethnicity and age subgroups are detailed Coronary artery disease is the leading cause of death among women in the United States , accounting for 23 % of all deaths [ 1 , 2 ] . The incidence of coronary artery disease in women aged 35 to 44 years is 1 per 1000 , increasing to 4 per 1000 in women aged 45 to 54 years [ 3 , 4 ] . Among women in their fifth decade , the incidence of coronary artery disease is one half that of men . By the sixth decade , however , women and men have the same incidence of coronary disease [ 2 , 5 , 6 ] . This disparity between premenopausal women and men of similar age suggests that endogenous sex hormones such as estrogen may have a significant cardioprotective influence . In postmenopausal women , estrogen replacement therapy independently decreases the risk for cardiovascular events and mortality [ 6 , 7 ] . Estrogen therapy limited the uptake of cholesterol ester into the arterial wall and attenuated the development of dietary-induced atherosclerosis in monkeys and baboons that had ovariectomy [ 8 - 10 ] . Angiographic studies have consistently found less coronary artery disease in women who receive estrogen replacement therapy  [ 7 , 11 , 12 ] . Beneficial effects of estrogen replacement therapy include its ability to reduce low-density lipoprotein ( LDL ) cholesterol levels and increase high-density lipoprotein ( HDL ) cholesterol levels [ 13 ] . Nonetheless , multiple regression analyses suggest that only 25 % to 50 % of the reduction in cardiovascular events is attributable to the lipid-lowering effects of estrogen replacement therapy [ 14 ] , suggesting that other mechanisms contribute to its cardioprotective potential . One such mechanism may involve the effect of estrogen on vascular function . Specifically , estrogen may directly enhance the activity of the endothelium-derived relaxing factor nitric oxide [ 10 , 15 - 17 ] and thereby lessen the potential for coronary vasoconstriction and thrombosis [ 18 - 21 ] . When administered to rabbits that had ovariectomy  , long-term estrogen replacement improved endothelium-dependent relaxation in vitro [ 15 , 16 ] . In addition , both short-term and long-term estrogen administration improves in vivo the endothelium-dependent vasodilation in coronary arteries of atherosclerotic cynomolgus monkeys that had ovariectomy [ 10 , 17 ] . Several recent studies have suggested that short-term estrogen administration improves endothelium-dependent vasodilation of the coronary arteries of postmenopausal women [ 22 , 23 ] . We hypothesized that long-term estrogen administration would improve vasomotor function in postmenopausal women . Accordingly , we conducted a double-blind , r and omized , crossover , placebo-controlled trial to assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women . We used high-resolution ultrasonography to serially assess vasomotor function in a peripheral conduit vessel , the brachial artery . Methods Patients The patients enrolled in this study were recruited from a larger cohort that was participating in a clinical research trial investigating the effect of estrogen replacement therapy on lipoprotein metabolism . Thirteen postmenopausal women aged 44 to 69 years ( average age , 55 7 years ) participated in this study . Women were eligible if menopause had occurred at least 1 year previously . Menopause was confirmed by measuring serum follicle-stimulating hormone levels . No patient had received hormone replacement therapy for at least 2 months before the study began . A history and physical examination were done to exclude persons with clinical evidence of coronary or peripheral atherosclerosis . Initial evaluation included a Papanicolaou smear ( if not done in past year ) , complete blood count , routine chemistry panel , and lipid profile .  Inclusion criteria included mild hypercholesterolemia , defined as a serum cholesterol level of 5.17 mmol/L to 6.20 mmol/L and an LDL cholesterol level of 3.36 mmol/L to 4.13 mmol/L. Exclusion criteria included hypertension , diabetes mellitus , tobacco use , obesity ( body weight > 135 % of ideal weight ) , history of breast or uterine cancer , thromboembolism , and liver or renal disease . Eligible patients were placed on a  low-cholesterol diet  ( American Heart Association phase I ) for 6 weeks before r and omization . Patients were r and omly assigned to one of three treatment groups : placebo , oral 17 -estradiol ( Estrace , Mead Johnson , Evansville , Indiana . ) at a dose of 1 mg/d , or oral 17 -estradiol at a dose of 2 mg/d . At the conclusion of each 9-week treatment period , the patients were given progesterone ( Provera , Upjohn , Kalamazoo , Michigan ) at 10 mg/d for 10 days . Hormone replacement therapy was discontinued for 3 weeks before patients crossed over to the next treatment regimen . All patients received placebo and the two doses of estrogen in r and om order . Vascular function studies ( described below ) were done during the eighth or ninth week of each treatment period . Experimental Protocol Studies were done in a temperature-controlled vascular research laboratory . All patients were placed in the supine position . We studied vascular reactivity in a conduit vessel , the brachial artery , as previously described . An imaging study of the brachial artery was done using a high-resolution ultrasound machine ( Toshiba , Model SSA-270 , Otawara-shir , Tochigi-Ken , Japan ) that was equipped with a 7.5 MHz linear-array transducer . Baseline images of the brachial artery were obtained proximal to the antecubital fossa . Imaging of the artery was done longitudinally , allowing clear visualization of the posterior wall intima-lumen interface and the anterior wall media-adventitial interface . We assessed endothelium-dependent vasodilation by measuring the change in the caliber of the brachial artery during reactive hyperemia , a maneuver that increases flow through the conduit segment being studied ( flow-mediated vasodilation ) . To create this stimulus , a cuff placed on the upper arm was inflated to suprasystolic pressure for 5 minutes , thereby occluding flow to the forearm . This results in dilatation of downstream forearm resistance vessels . After cuff deflation , reactive hyperemia occurs , as brachial artery blood flow increases to accommo date the dilated resistance vessels . Imaging of the brachial artery was continually done for the 5-minute period after cuff deflation until basal conditions were re-established . Thereafter , sublingual nitroglycerin ( at a dose of 0.4 mg ) was administered to assess endothelium-independent vasodilation . The artery was studied for an additional 5 minutes . Blood pressure and heart rate were monitored continuously throughout the procedure . All images were recorded on Super VHS videotape for subsequent analysis . Image analysis was done on a personal computer that was equipped with a video frame grabber . Images recorded on videotape were analyzed by an investigator blinded to treatment assignment . Previous studies have shown that the peak diameter change during reactive hyperemia occurs approximately 1 minute after cuff deflation and 3 minutes after nitroglycerin administration [ 41 ] . We used these time points in our study . Images corresponding to the end of the T wave on a simultaneous electrocardiograph were selected and digitized . Image analysis was then done using a proprietary analysis software that search ed for the shortest distance between the points on the arterial wall , creating 10 to 20 paired measurements along a 10-mm length . We measured arterial diameter from the intima-lumen interface on the posterior wall to the media-adventitial interface on the anterior wall . We calculated brachial artery diameter by averaging these paired lumen measurements and reported them in millimeters using calibration factors derived from real-time ultrasonography . We used an average of three separate measurements for each condition . In our laboratory , this technique has a variability of only 0.0 0.1 mm [ 24 ] . To assure that the blood flow stimulus during reactive hyperemia was similar during each treatment phase , forearm blood flow was measured by venous occlusion strain gauge plethysmography using calibrated mercury-in-silastic strain gauges as previously described [ 25 ] . Statistical Analysis The variables compared during the placebo period and during therapy with each dose of estrogen included blood pressure , heart rate , forearm blood flow , basal brachial artery diameter , and the percentage increase in diameter during reactive hyperemia and after patients received sublingual nitroglycerin . Values are expressed as the mean SE . For statistical analysis , we used repeated-measure analysis of variance and the Scheffe-F post hoc test [ 26 ] . Significance was accepted at P 0.05 . Results Baseline Hemodynamic Measurements The effect of estrogen treatment on blood pressure , heart rate , forearm blood flow and forearm vascular resistance is presented in Table 1 . Estrogen therapy did not affect blood pressure or heart rate . Basal forearm blood flow tended to be higher during both estrogen treatment phases ( P = 0.08 ) . Basal forearm vascular resistance was similar during all three treatment phases . The peak forearm blood flow during reactive hyperemia was similar during placebo receipt and each estrogen treatment period . However , peak forearm blood flow was greater when patients received the 1-mg dose of estradiol than when they received the 2-mg dose ( P = 0.05 ) . Table 1 . Effect of Estrogen Replacement on Hemodynamic Measurements Flow-Mediated Endothelium-Dependent Vasodilation We obtained technically adequate ultrasound images during reactive hyperemia for 12 of the 13 patients . The brachial artery diameter , under basal conditions , measured 3.5 mm , 3.4 mm , and 3.3 mm while patients received placebo , estradiol at 1 mg/d , and estradiol at 2 mg/d , respectively ( P > 0.2 ) . The percentage increase in brachial artery diameter during reactive hyperemia for each treatment period is shown in Figure 1 . The change in brachial artery diameter was greater when patients received estradiol treatment ( 13.5 % and 1 . Auricchio A , Sommariva L , Salo RW , Scafuri A , Chiariello L. Improvement of cardiac function in patients with severe congestive heart failure and coronary artery disease by dual chamber pacing with shortened AV delay . Pacing Clin Electrophysiol 1993;16:2034–2043 . 2 . Hochleitner M , Hortnagl H , Hortnagl H , Fridrich L , Gschnitzer F. Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy . Am J Cardiol 1992;70:1320–1325 . 3 . Innes D , Leitch JW , Fletcher PJ . VDD pacing at short atrioventricular intervals does not improve cardiac output in patients with dilated heart failure . Pacing Clin Electrophysiol 1994;17:959–965 . 4 . Gold MR , Feliciano Z , Gottlieb SS , Fisher ML . Dual-chamber pacing with a short atrioventricular delay in congestive heart failure : a r and omized study . J Am Coll Cardiol 1995;26:967–973 . 5 . Linde C , Gadler F , Edner M , Nordl and er R , Rosenqvist M , Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure . J Am Coll Cardiol 1995;75:919–923 . 6 . Hunt SA , Baker DW , Chin MH , Cinquegrani MP , Feldman AM , Francis GS , Ganiats TG , Goldstein S , Gregoratos G , Jessup ML , et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure  in the adult : executive summary . A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . J Am Coll Cardiol 2001;38 : 2101–2113 . 7 . Karpawich PP , Mital S. Comparative left ventricular function following atrial , septal , and apical single chamber heart pacing in the young . Pacing Clin Electrophysiol 1997;20:1983–1988 . 8 . Owen CH , Esposito DJ , Davis JW , Glower DD . The effects of ventricular pacing on left ventricular geometry , function , myocardial oxygen consumption , and efficiency of contraction in conscious dogs . Pacing Clin Electrophysiol 1998;21:1417–1429 . 9 . Zile MR , Blaustein AS , Shimizu G , Gaasch WH . Right ventricular pacing reduces the rate of left ventricular relaxation and filling . J Am Coll Cardiol 1987;10:702–709 . 10 . Blanc JJ , Etienne Y , Gilard M , Mansourati J , Munier S , Boschat J , Benditt DG , Lurie KG . Evaluation of different ventricular pacing sites in patients with severe heart failure : results of an acute hemodynamic study . Circulation 1997 ; 96:3273–3277 . 11 . Tantengco MV , Thomas RL , Karpawich PP . Left ventricular dysfunction after long-term right ventricular apical pacing in the young . J Am Coll Cardiol 2001;37:2093–2100 . 12 . Hamdan MH , Zagrodzky JD , Joglar JA , Sheehan CJ , Ramaswamy K , Erdner JF , Page RL , Smith M. Biventricular pacing decreases sympathetic activity compared with right ventricular pacing in patients with depressed ejection fraction . Circulation 2000;102:1027–1032 BACKGROUND Pulse pressure ( PP ) has been shown to predict risk for cardiovascular events in men ; however , this association has not been well established in women .  Hormone replacement therapy may improve arterial compliance , but findings from cross-sectional and prospect i ve studies report inconsistent results . We sought to examine the relationship between PP and risk for cardiovascular events , and to determine the effect of hormone therapy on PP in postmenopausal women with coronary heart disease ( CHD ) . METHODS AND RESULTS A total of 2,763 postmenopausal women ( mean age , 66 + /- 7 years [ + /- SD ] ) with CHD in the Heart and Estrogen/Progestin Replacement Study , a r and omized , placebo-controlled , secondary CHD prevention trial of estrogen plus progestin , were followed up on average for 4.1 years . BP was measured at baseline and annually . Mean baseline PP was 62 + /- 16 mm Hg . There were 361 myocardial infa rct ions ( MIs ) or CHD deaths , 265 hospitalizations for congestive heart failure ( CHF ) , and 215 strokes or transient ischemic attacks ( TIAs ) . Women in the highest quartile of PP at baseline had a 47 % increase in risk for MI or CHD death and more than a twofold increase in risk for stroke and TIA events or hospitalization for CHF ( p < 0.01 for each outcome ) . After adjustment for other cardiovascular risk factors and mean arterial pressure , PP remained significantly associated with incident stroke or TIA events ( odds ratio , 1.25 ; p = 0.02 ) and hospitalizations for CHF ( odds ratio , 1.31 ; p < 0.01 ) but not with MI or CHD death . After adjustment for diastolic BP , systolic BP was similarly associated with stroke or TIA ( odds ratio , 1.30 ; p < 0.01 ) and hospitalized CHF ( odds ratio , 1.30 ; p < 0.01 ) and was also weakly associated with risk for MI and CHD death ( odds ratio , 1.18 ; p = 0.02 ) . Mean PP was 1- to 2-mm Hg higher in women r and omized to hormone replacement therapy vs those receiving placebo ( p < 0.01 ) . CONCLUSIONS PP had predictive value for CHF and stroke or TIA , but not MI or CHD death in this cohort of postmenopausal women with CHD . Use of hormone replacement therapy produced a small , statistically significant increase in PP . Further research is necessary to determine the clinical utility of PP as a potential therapeutic target CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue BACKGROUND Postmenopausal hormone therapy has been examined extensively in relation to cardiovascular disease . However , research relating serum levels of sex hormones to cardiovascular disease is sparse , and the results are inconclusive . METHODS We measured sex hormones in longitudinally collected sample s of 180 postmenopausal women , 91 r and omized to 17beta-estradiol and 89 to placebo , in the Estrogen in the Prevention of Atherosclerosis Trial . Repeated measures of sex hormone levels were tested for an association with carotid artery intima-media thickness ( CIMT ) , which was also assessed longitudinally over 2 yr . RESULTS In all women , changes in serum estrone ( P = 0.02 ) , total estradiol ( P = 0.01 ) , free estradiol ( P = 0.02 ) , and SHBG ( P = 0.005 ) were significantly inversely associated with CIMT progression , controlling for age and body mass index . All the estrogen compounds and SHBG were significantly inversely related with low-density lipoprotein cholesterol and positively associated with high-density lipoprotein cholesterol ( all P < 0.0001 ) , whereas free testosterone was positively related with low-density lipoprotein cholesterol and inversely associated with high-density lipoprotein cholesterol ( P < 0.003 ) . Despite an increase in serum-free estradiol with estradiol therapy , women with unchanged SHBG and free testosterone levels had an average ( se ) progression in CIMT of 8.53 ( 4.72 ) microm/yr , whereas women with increased free estradiol and SHBG and decreased free testosterone had the largest reduction in CIMT progression [ -5.45 ( 2.77 ) microm/yr ; trend P = 0.03 ] . CONCLUSION Estrogen and SHBG are associated with reduced sub clinical atherosclerosis progression in healthy postmenopausal women . These associations are partially mediated by their beneficial effects on lipids . Among women taking estradiol , the most beneficial hormone profile for CIMT progression was increased free estradiol and SHBG with concomitant decreased free testosterone 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 BACKGROUND Heart disease is a major cause of illness and death in women . To underst and better the role of estrogen in the treatment and prevention of heart disease , more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects . METHODS We r and omly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day , 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day , or placebo . The women were followed for a mean ( + /-SD ) of 3.2+/-0.6 years . Base-line and follow-up coronary angiograms were analyzed by quantitative coronary angiography . RESULTS Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels ( 9.4 percent and 16.5 percent , respectively ) and significant increases in high-density lipoprotein cholesterol levels ( 18.8 percent and 14.2 percent , respectively ) ; however , neither treatment altered the progression of coronary atherosclerosis . After adjustment for measurements at base line , the mean ( + /-SE ) minimal coronary-artery diameters at follow-up were 1.87+/-0.02 mm , 1.84+/-0.02 mm , and 1.87+/-0.02 mm in women assigned to estrogen , estrogen plus medroxyprogesterone acetate , and placebo , respectively . The differences between the values for the two active-treatment groups and the value for the placebo group were not significant . Analyses of several secondary angiographic outcomes and subgroups of women produced similar results . The rates of clinical cardiovascular events were also similar among the treatment groups . CONCLUSIONS Neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease . These results suggest that such women should not use estrogen replacement with an expectation of cardiovascular benefit OBJECTIVE This study examined the effect of hormone therapy ( HT ) on the plasma concentration of remnant lipoprotein cholesterol ( RLP-C ) and high-density lipoprotein ( HDL ) sub population s and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease ( CHD ) in postmenopausal women . METHODS Study participants were 256 women who completed the Estrogen Replacement and Atherosclerosis ( ERA ) trial , a placebo-controlled , r and omized trial that examined the effects of 3.2 years of conjugated equine estrogen ( CEE , 0.625 mg/day ) or CEE ( 0.625 mg/day ) plus medroxyprogesterone acetate ( MPA , 2.5mg/day ) on postmenopausal women with established coronary atherosclerosis . Quantitative coronary angiography and plasma RLP-C and HDL sub population s were assessed at baseline and at follow-up . RESULTS Relative to placebo , both CEE and CEE+MPA caused a significant reduction in plasma RLP-C concentrations and a significant increase in alpha1 and alpha2 HDL sub population s. However , in the HT-treated subjects , faster progression of coronary atherosclerosis was observed in women who experienced the greatest reductions in RLP-C and in prebeta1 HDL sub population s. CONCLUSIONS Our data suggest that individual variability in RLP-C and HDL sub population response to HT is a predictor of CHD progression . Lipoprotein response to HT may be an indirect marker of susceptibility to other harmful effect of HT in postmenopausal women with established CHD or an indication of formation of dysfunctional lipoproteins 52 e held a very successful meeting in Manchester for practice nurses , which was attended by more than 100 . These appear to be very popular events , so it is our hope to stage two nurse meetings a year , one in London and the other in Manchester . We are also considering a series of one-day roadshows to be taken around the country which may be attractive to those unable to attend the annual meeting . Watch this space for further details . We still need more members for the Society , for the more members we have , the less likely it is for membership fees to rise . Please try to recruit one new member each , as this would make such a difference to the Society . The journal is certainly a good shop window for the BMS , and we now receive compliments from all over the world . Executive Secretary ’s report Serum lipoproteins were measured in 72 post-menopausal women , 40 of whom had been taking the synthetic oestrogen , mestranol , for a period of 10 yr and 32 of whom had been taking identical placebo tablets . Mestranol therapy was found to increase serum triglycerides , decrease low density lipoprotein ( LDL ) cholesterol and increase high density lipoprotein ( HDL ) cholesterol . The increase in HDL cholesterol was due principally to a marked increase in the cardioprotective HDL2 fraction . It is concluded that long-term mestranol therapy has a beneficial effect on serum lipoproteins which may help to protect post-menopausal women against fatal ischaemic heart disease CONTEXT Lower-than-commonly-prescribed doses of conjugated equine estrogens ( CEEs ) with medroxyprogesterone acetate ( MPA ) improve vasomotor symptoms and vaginal atrophy , provide acceptable bleeding and lipid profiles , and afford endometrial protection . This lower-dose therapy 's protection against loss of bone mineral density ( BMD ) associated with menopause has not been thoroughly investigated . OBJECTIVE To determine the effects of lower doses of CEEs only or CEEs-MPA on spine and hip BMD , total body bone mineral content ( BMC ) , and biochemical markers of bone turnover in postmenopausal women . DESIGN AND SETTING Two-year r and omized , double-blind , placebo-controlled sub study of the Women 's Health , Osteoporosis , Progestin , Estrogen trial , conducted at 19 US centers between August 1995 and October 2000 . PARTICIPANTS Eight hundred twenty-two healthy postmenopausal women aged 40 to 65 years who were within 4 years of their last menstrual period . INTERVENTIONS Patients were r and omly assigned to receive CEEs , 0.625 ; CEEs , 0.625 and MPA , 2.5 ; CEEs , 0.45 ; CEEs , 0.45 and MPA , 2.5 ; CEEs , 0.45 and MPA , 1.5 ; CEEs , 0.3 ; CEEs 0.3 and MPA , 1.5 ( all doses in mg/d ) ; or placebo for 2 years . All participants also received elemental calcium at 600 mg/d . MAIN OUTCOME MEASURES Changes from baseline in spine and total hip BMD , total body BMC , and biochemical markers of bone turnover ( serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen ) , assessed at 6-month intervals and compared among treatment groups with a modified intention-to-treat approach . RESULTS At 24 months , women assigned to all of the active treatment groups had significant gains from baseline ( P<.001 ) in spine and hip BMD and total body BMC ( except total body BMC in the group receiving CEEs , 0.3 mg/d ) . These changes were significantly different from those in the placebo group , in which losses of bone mass in spine and total body were evident over the course of the study ( P<.001 ) . The loss in hip BMD from baseline in the placebo group was significant at 18 ( P = .02 ) but not at 24 months ( P = .06 ) . Osteocalcin and N-telopeptides of type I collagen were significantly reduced from baseline ( P<.001 ) for all active treatment groups at all time points ; no changes were found for the placebo group . For women treated with CEEs alone , the gains in spine BMD for the group taking CEEs , 0.625 mg/d , were significantly higher than those of the group taking CEEs , 0.3 mg/d ( P = .02 ) , but not the group treated with CEEs , 0.45 mg/d ( P = .48 ) . CONCLUSIONS Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase BMD and BMC in early postmenopausal women Forty women aged 64.7 + /- 5.1 yr with established postmenopausal osteoporosis were blindly allocated to 1 yr 's treatment with either continuous combined estrogen/progestogen therapy ( 2 mg estradiol + 1 mg norethisterone acetate + 500 mg calcium daily ) or placebo + 500 mg calcium daily . In the group treated with hormones bone mineral density in the spine ( dual photon absorptiometry ) and bone mineral content in the ultradistal forearm ( single photon absorptiometry ) increased highly significantly by 8 - 10 % during the 1 yr of treatment . Bone mineral content in the mid-shaft of the forearm ( single photon absorptiometry ) and the total body bone mineral ( dual photon absorptiometry ) increased by 3 - 5 % when compared to that in the placebo group , which showed virtually unchanged values at all measurement sites . Seven of the women treated with hormones were examined after a further year of treatment . BMC increased by another 3 - 6 % , reaching a 12 % increase in bone mineral density in the spine after 2 yr of treatment . Biochemical estimates of bone resorption ( fasting urinary calcium and hydroxyproline ) and bone formation ( serum alkaline phosphatase and plasma osteocalcin ) , decreased significantly ( P less than 0.001 ) in the group treated with hormones , but remained unchanged in the placebo group . The reduction in indices of bone resorption was more pronounced than that in bone formation after one year , indicating a positive bone balance . No further changes were seen in these bone turnover parameters during the second year of treatment . In the group treated with hormones , serum levels of triglycerides , total cholesterol , and low density lipoprotein cholesterol decreased by about 12 % ( P less than 0.05-P less than 0.01 ) , whereas high density lipoprotein cholesterol decreased by about 8 % ( P less than 0.001 ) . The high density lipoprotein cholesterol/low density lipoprotein cholesterol ratio was unchanged . The hormone treatment did not produce any major side effects , and only minor bleedings were experienced by a few women . The present study demonstrates that treatment with female sex hormones in this particular combination is a realistic approach to the treatment of women with established postmenopausal osteoporosis We assessed the rates of vertebral fracture in patients with postmenopausal osteoporosis . Forty-five patients were not treated ( 91 person-years of observation ) ; 59 were treated conventionally , with calcium ( alone or combined with estrogen ) or vitamin D or both ( 218 years ) ; and 61 were treated with sodium fluoride combined with conventional therapy ( 251 years ) . The fracture rate ( per thous and person-years ) was 834 in untreated patients , 419 in those given calcium with or without vitamin D , 304 in those given fluoride and calcium with or without vitamin D , 181 in those given estrogen and calcium with or without vitamin D , and 53 in those given fluoride , estrogen , and calcium with or without vitamin D. It was reduced in all treatment groups ( P less than 0.001 for calcium and P less than 1 x 10(-6 ) for other combinations ) ; fluoride ( one years of treatment ) and estrogen ( but not vitamin D ) independently reduced the rate from that observed with calcium alone ( P less than 0.001 ) . The combination of calcium fluoride , and estrogen was more effective than any other combination ( P less than 0.001 ) . These results provide grounds for optimism about the efficacy of combinations of available agents with  sodium fluoride  for fracture in postmenopausal osteoporosis Objective To assess the possible benefit of hormone replacement therapy ( HRT ) in the secondary prevention of ischaemic heart disease 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 BACKGROUND The mechanisms by which  postmenopausal hormone replacement therapy ( HRT )  may influence risk of cardiovascular disease are still unclear . Impaired fibrinolytic function is associated with an enhanced risk of cardiovascular disease and therefore the effect of HRT on fibrinolysis may be of importance . OBJECTIVES To investigate the prolonged effect of HRT on the fibrinolytic system and to determine whether two common polymorphisms in the plasminogen activator inhibitor-1 ( PAI-1 ) and tissue-type plasminogen activator ( t-PA ) genes modulate this effect . METHODS Healthy postmenopausal women ( n = 248 ) were r and omized to HRT ( n = 122 ) or no substitution ( n = 126 ) 5 years prior to investigation . RESULTS Significantly higher values of t-PA activity and lower values of PAI-1 activity and PAI-1 antigen were found in the  HRT  group compared with the control group . This effect was independent of smoking and without influence from the two common polymorphisms PAI-1 -675(4G/5 G ) and t-PA intron8ins311 . Furthermore , no difference between opposed estrogen ( with norethisterone acetate as the gestagen component ) and unopposed estrogen therapy was found . Both an intention-to-treat and a per- protocol analysis were performed and similar results were obtained . CONCLUSIONS Long-term treatment with HRT in healthy postmenopausal women was found to be associated with a beneficial fibrinolytic profile . This effect was found independent of smoking status , opposed and unopposed estrogen therapy had equal effect , and no influence of the two common polymorphisms PAI-1 - 675(4G/5 G ) and t-PA intron8ins311 was found . This effect of HRT on fibrinolytic capacity may be one of the beneficial effects of HRT in relation to cardiovascular diseases 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 effects of four different treatment schedules on serum lipid concentrations were studied for 1 year in 402 postmenopausal women in the Kuopio Osteoporosis Study . The women were r and omized to four treatment groups : A , Sequential combination of estradiol valerate and cyproterone acetate ( Climen ) ; B , Vitamin D3 , 300 IU/day ; C , Climen+Vitamin D3 , D , placebo . In group A , serum concentrations of total cholesterol ( Chol ) decreased by 4.8 % in 6 months and by 6.2 % in 12 months ( P < 0.001 ) , but in group C the decrease was only 2.9 % in 6 months ( P < 0.05 ) and 3.4 % in 12 months ( P < 0.01 ) . The decline of total-Chol in group A was accounted for by the 6.8 % to 7.5 % decrease in LDL-Chol levels ( P < 0.001 ) . The decrease of LDL-Chol in group C was statistically non-significant . Use of vitamin D3 ( group B ) , increased serum Chol by 2.7 % ( 6 months ) , P < 0.05 and by 2.1 % ( 12 months ) and the increases were the result of the 6.0 % to 6.2 % increase in LDL-Chol levels in 6 and 12 months , respectively ( P < 0.001 ) . Serum concentrations of HDL-Chol and TG remained relatively stable in all groups . No correlations were found between LDL-Chol , 25-OH-D3 and 1,25(OH)2-D3 levels in group B. Our results confirm the beneficial effect of estradiol valerate and cyproterone acetate on the lipid profile . In contrast , vitamin D3 had a negative influence on this profile by increasing serum concentrations of LDL-Chol . ( ABSTRACT TRUNCATED AT 250 WORDS The significance of an interrelation between nongenetic factors and genotype effects in the regulation of bone mass is not clear . In this prospect i ve study of 429 healthy early postmenopausal Danish women , we investigated the association between bone mineral density ( BMD ) and the FokI and BsmI polymorphisms in the vitamin D receptor ( VDR ) gene . Participants were allocated to either hormone-replacement therapy ( HRT ) or no treatment by r and omization or personal choice . After 5 years , 332 women with unchanged treatment status were available for analyses , 98 of these women were still on HRT .  No association with initial BMD or 5-year change in BMD was found for either polymorphism . In women with body mass index ( BMI ) < 25 ( n = 282 ) , the f allele was associated with lower BMD of the hip ( p < 0.001 ) and forearm ( p = 0.001 ) , and the b allele was associated with lower spine BMD ( p = 0.02 ) . Comparing thin/normal weight women with overweight/ obese women of the same genotype , FF women had similar BMD at all measured sites in contrast to Ff and ff women in whom BMD , as expected , was higher in the overweight/obese women . Similar results were found for the BsmI polymorphism with no difference in BMD between BMI groups in BB women . Segregation into groups according to dietary calcium intake did not reveal any genotype association with BMD . These results provide some evidence of a modifying effect of nongenetic factors , specifically BMI , on the association between VDR genotype and BMD . High BMI may protect against lower BMD seen in association with thef or b alleles . In some genotypes ( FF and BB ) , BMI had relatively little effect on BMD 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 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 Clinical trials indicate that hormone therapy ( HT ) does not decrease cardiovascular disease events or angiographic coronary disease progression . The effects of HT on SVG vessels are unknown . To determine whether postmenopausal hormone therapy started after coronary bypass surgery ( CABG ) decreases saphenous vein graft ( SVG ) disease , we conducted a multicenter r and omized placebo-controlled angiographic study of estradiol+/-medroxyprogesterone started within 6 months of CABG in 83 postmenopausal women .  Angiographic and intravascular ultrasound ( IVUS ) assessment at 6 and 42 months was planned to assess SVG disease progression . The study was stopped early following publication of the Women 's Health Initiative Estrogen/Progestin study . Eighty-three subjects underwent a 6-month angiogram with 63 undergoing IVUS . Forty-five subjects completed the 42-month  angiogram  ( 20 underwent 42-month IVUS ) . In analysis of paired 6- and 42-month angiogram and IVUS studies , HT slowed angiographic progression of SVG disease assessed by mean percent stenosis ( p<0.001 ) , minimal lumen diameter ( p=0.029 ) , and total plaque volume ( p=0.006 ) . In contrast , HT accelerated disease progression in non-bypassed native coronary arteries ( minimum lumen diameter , p=0.01 ) . SVG disease and closure occurred in 38 % subjects within 1-year post-CABG . The groups had similar frequency of cardiovascular events expect for angioplasty that occurred in eight HT compared to one placebo subject ( p<0.05 ) . In HT subjects angioplasty was indicated for native coronary arterial stenoses while in the placebo subject angioplasty was indicated for SVG stenosis . This study suggests that hormone treatment may slow SVG disease progression while accelerating atherosclerosis in non-bypassed native coronary arteries It was recently reported from the Women 's Health Initiative that healthy women using combined hormone replacement therapy ( HRT ) for 5 years have an increased cardiovascular risk . We hypothesize that the increased risk is confined to subgroups of atherosclerotic women . Such women may have higher arterial tissue factor expression and higher thrombin formation , and changes in tissue factor pathway coagulation inhibitor ( TFPI ) and thrombin activatable fibrinolysis inhibitor ( TAFI ) may be deleterious . Healthy postmenopausal women ( n = 719 ) were r and omized to  hormone therapy [ n = 357 ; opposed ( n = 290 ) and unopposed ( n = 67 ) ] or no treatment ( n = 362 ) . Plasma TFPI and TAFI and the TFPI -287T/C and TAFI -438G/A polymorphisms were measured 5 - 6 years after r and omization . Concentrations of TFPI were significantly lower in the hormone group than in the control group ( P < 0.001 ) and in all genotypes of the TFPI polymorphism . Overall , concentrations of TAFI did not differ between the two groups but were reduced by hormone therapy in homozygotes for the rare TAFI -438 A allele ( P < 0.05 ) . The hormone effects on TFPI and TAFI were similar in smokers and non-smokers and in women using unopposed and opposed therapy . The observed decrease in TFPI may contribute to the increased cardiovascular risk associated with HRT BACKGROUND Although observational studies suggest that estrogen replacement therapy ( ERT ) reduces cardiovascular morbidity and mortality in postmenopausal women , use of unopposed ERT for prevention of coronary heart disease in healthy postmenopausal women remains untested . OBJECTIVE To determine the effects of unopposed ERT on the progression of sub clinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING University-based clinic . PATIENTS 222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease and with low-density lipoprotein cholesterol levels of 3.37 mmol/L or greater ( > /=130 mg/dL ) . INTERVENTION Unopposed micronized 17beta-estradiol ( 1 mg/d ) or placebo . All women received dietary counseling . Women received lipid-lowering medication if their low-density lipoprotein cholesterol level exceeded 4.15 mmol/L ( 160 mg/dL ) . MEASUREMENTS The rate of change in intima-media thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms obtained at baseline and every 6 months during the 2-year trial . RESULTS In a multivariable mixed-effects model , among women who had at least one follow-up measurement of carotid intima-media thickness ( n = 199 ) , the average rate of progression of sub clinical atherosclerosis was lower in those taking unopposed estradiol than in those taking placebo ( -0.0017 mm/y vs. 0.0036 mm/y ) ; the placebo-estradiol difference between average progression rates was 0.0053 mm/y ( 95 % CI , 0.0001 to 0.0105 mm/y ) ( P = 0.046 ) . Among women who did not receive lipid-lowering medication ( n = 77 ) , the placebo-estradiol difference between average rates of progression was 0.0147 mm/y ( CI , 0.0055 to 0.0240 ) ( P = 0.002 ) . Average rates of progression did not differ between estradiol and placebo recipients who took lipid-lowering medication ( n = 122 ) ( P > 0.2 ) . CONCLUSIONS Overall , the average rate of progression of sub clinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17beta-estradiol than in women taking placebo . Reduction in the progression of sub clinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications PURPOSE To compare the effect of blind design ( active drug and placebo ) and nonblind design ( active drug and no treatment ) on recruitment . SETTING A primary prevention trial with postmenopausal hormone therapy in Estonia . METHODS Women who were eligible and willing to participate on the basis of the question naire survey were r and omized into blind and nonblind groups . Recruitment rates are based on record keeping , and reasons for participating were requested in the first-year follow-up . RESULTS The recruitment was 30 % higher in the nonblind group : of the 4,295 women invited , 37 % ( 95 % confidence interval CI=35 - 39 % ) in the blind group and 48 % ( 95 % CI=46 - 49 % ) in the nonblind group were recruited . In both groups , once r and omized , most of the losses were women who did not attend the first clinical examination : 49 % ( blind ; 95 % CI=47 - 51 % ) and 40 % ( nonblind ; 95 % CI=38 - 42 % ) . The rest were found ineligible or lost their interest during clinical examinations . The reasons for joining the trial were relatively similar in the two groups . CONCLUSIONS Blinding decreased women 's interest in joining a long-term preventive trial . Women 's reasons for joining the trial were not influenced by blinding 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 In a controlled single blind study to determine the minimal effective dose of estrogen for protection against bone loss , conjugated equine estrogens in doses of 0.625 and 1.25 mg per day were equally effective in reducing  bone loss in postmenopausal and oophorectomized women when bone mass was estimated by single-photon absorptiometry or radiogrammetry . Daily dose levels of less than 0.625 mg were essentially ineffective . Fifty percent response level was calculated to be 0.45 mg per day . Concomitant biochemical effects , reduction in urine calcium and hydroxyproline , were compatible with the observed effects on bone mineral Abstract . Eighty‐four normal women , 2.5‐5 years after their natural menopause , participated in a controlled double‐blind trial . The effect of various therapeutic regimens on postmenopausal bone mineral loss was measured by photonabsorptiometric determination of the bone mineral content of both forearms . The women were r and omized into four treatment groups : 1,25‐dihydroxycholecalciferol ( 1,25(OH)2D3 ) alone in a daily dose of 0.25 μg , oestrogens/gestagen alone or combined with 1,25(OH)2D3 , and placebo . The groups treated with oestrogens/gestagen ( without and with 1,25(OH)2D3 ) showed a similar increase in bone mineral content of about 1 % during one year of treatment . In contrast , both the placebo group and the 1,25(OH)2D3 group demonstrated a decrease of 1.9 % and 2.1 % , respectively , within the same period of time . While 1,25(OH)2D3 did not alter the rate of bone loss , it caused the characteristic and pronounced increase in urinary calcium excretion ( 15 % ) OBJECTIVE To characterize the long-term impact of four hormone therapy regimens on insulin and glucose concentrations measured during a st and ard oral glucose tolerance test . RESEARCH DESIGN AND METHODS The Postmenopausal Estrogen/Progestin Intervention Study was a 3-year placebo-controlled r and omized trial to assess effects of four hormone regimens  on  cardiovascular risk factors .  This efficacy analysis describes glucose and insulin concentrations from 788 adherent women at baseline and at 1 and 3 years ' postr and omization RESULTS When compared with women taking placebo , those taking conjugated equine estrogen ( CEE ) at 0.625 mg/day with or without a progestational agent had mean fasting insulin levels that were 16.1 % lower , mean fasting glucose levels 2.2 mg/dl lower , and mean 2-h glucose levels 6.4 mg/dl higher ( each nominal P < 0.05 ) . No significant differences were apparent between women taking CEE only versus the three progestin regimens : medroxyprogesterone acetate ( MPA ) at 2.5 mg daily ( continuous MPA ) , MPA at 10 mg on days 1–12 ( cyclical MPA ) , and micronized progesterone ( MP ) ( cyclical ) at 200 mg on days 1–12 . The impact of hormone therapy on insulin and glucose depended on baseline levels of fasting insulin and 1-h glucose ( P < 0.05 ) . However , the treatment effects on carbohydrate metabolism appeared to be consistent across participant subgroups formed by lifestyle , clinical , and demographic characteristics . CONCLUSIONS Oral hormone therapy involving 0.625 mg/day of CEE may modestly decrease fasting levels of insulin and glucose . Postchallenge glucose concentrations are increased , however , which may indicate delayed glucose clearance 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 : Although observational studies showed an apparent lower ischemic coronary disease risk in postmenopausal women receiving hormone therapy ( HT )  , r and omized clinical trials in postmenopausal women showed an increase in ischemic cardiovascular events . Soluble cell adhesion molecules have been associated with cardiovascular risk factors and events . HT reduces circulating levels of soluble cell adhesion molecules in healthy postmenopausal women , but its effects in postmenopausal women with coronary artery disease are less clear . We assessed the effect of HT on soluble cell adhesion molecules in the Estrogen Replacement and Atherosclerosis trial . Design : The Estrogen Replacement and Atherosclerosis trial was a double-blind , placebo-controlled study that r and omized 309 postmenopausal women ( mean age , 65.8 y ) to daily unopposed estrogen ( conjugated estrogens 0.625 mg ) , estrogen plus 2.5 mg of medroxyprogesterone acetate , or placebo  , with a mean follow-up period of 3.2 years . Soluble intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin were measured in serum obtained from participants at baseline and after 12 months of follow-up . Results : Of the 265 women with complete data , 87 women were assigned to unopposed estrogen , 88 women to estrogen plus medroxyprogesterone acetate , and 90 women to placebo . Compared with placebo , 12 months of HT ( n = 175 ) was associated with reductions in soluble intercellular adhesion molecule-1 ( 25.6 ± 4.7 vs 10.6 ± 6.4ng/mL , P = 0.06 ) , soluble vascular cell adhesion molecule-1 ( 80.2± 10.6 vs 28.8 ± 14.7 ng/mL , P = 0.005 ) , and E-selectin ( 8.8 ± 0.9 vs −1.1 ± 1.2 ng/mL , P < 0.001 ) . Conclusions : Twelve months of HT in postmenopausal women with established coronary artery disease was associated with reductions in serum markers of endothelial cell activation/injury such as soluble intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin Objective : The aim of this study was to assess the safety and efficacy of bazedoxifene (BZA)/conjugated estrogens ( CE ) treating moderate to severe vasomotor symptoms in the Selective Estrogen Menopause and Response to Therapy 2 trial . Methods : This was an outpatient , multicenter , double-blind , r and omized , placebo-controlled , phase 3 study conducted in the United States . Healthy postmenopausal women ( N = 332 ; aged 40 - 65 y ) with moderate to severe hot flushes ( ≥7/d or 50/wk ) were r and omized to BZA 20 mg/CE 0.45 mg , BZA 20 mg/CE 0.625 mg , or placebo once daily for 12 weeks . Changes from baseline in the average daily number of moderate and severe hot flushes and daily severity score were assessed at weeks 4 and 12 ; adverse events were recorded . Results : BZA/CE significantly reduced the number and severity of hot flushes at weeks 4 and 12 ( P < 0.001 ) . At week 12 , BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg reduced hot flushes from baseline by 74 % ( 10.3 hot flushes [ baseline ] vs 2.8 [ week 12 ] ) and 80 % ( 10.4 vs 2.4 ) , respectively , compared with 51 % ( 10.5 vs 5.4 ) for placebo . More participants at week 12 had at least a 75 % decrease in hot flushes with BZA 20 mg/CE 0.45 mg ( 61 % ) and BZA 20 mg/CE 0.625 mg ( 73 % ) versus placebo ( 27 % ; P < 0.001 ) . The safety profile was similar between BZA/CE and placebo , and no unexpected safety findings were reported . Conclusions : BZA 20 mg paired with CE 0.45 or 0.625 mg is effective , with short-term safety , for treating vasomotor symptoms in postmenopausal women Objective The aim of this study was to examine the effect of hormone therapy and calcitriol on  depression in older postmenopausal women and to determine whether the response was associated with polymorphisms of estrogen receptor & agr ; and vitamin D receptor . Methods In a double-blind placebo-controlled prospect i ve trial involving 489 postmenopausal older women , a secondary analysis of depression was done . The Geriatric Depression Scale was used to screen for depression . We used binary logistic regression to examine the effect of treatment on depression and one-way analysis of variance to find a relationship between gene polymorphisms and depression . Results There was no effect of hormone therapy ( odds ratio [ OR ] , 1.65 ; 95 % CI , 0.66 - 4.12 ; P = 0.277 ) , calcitriol ( OR , 1.15 ; 95 % CI , 0.43 - 3.11 ; P = 0.772 ) , or hormone therapy with calcitriol ( OR , 1.01 ; 95 % CI , 0.36 - 2.80 ; P = 0.979 ) on depression . Neither the polymorphisms of estrogen receptor & agr ; ( XbaI-&bgr ; = 0.093 ; CI , −0.337 to 1.350 ; P = 0.239 and PvuII-&bgr ; = −0.064 ; CI , −1.171 to 0.491 , P = 0.421 ) nor those of vitamin D receptor ( BsmI-&bgr ; = 0.044 , CI −2.546 to 3.030 , P = 0.865 and TaqI-&bgr ; = −0.015 , CI −2.900 to 2.738 , P = 0.955 ) were associated with depression . Conclusion In older postmenopausal women , there was no effect of hormone therapy and calcitriol either individually or in combination with depression . Estrogen receptor & agr ; and vitamin D receptor polymorphisms are not associated with depression or the response to intervention in older postmenopausal women . Additional trials are required to confirm these findings
target: We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality , cardiovascular death , non-fatal myocardial infa rct ion , angina , or revascularisation .
  There was no strong evidence of effect on risk of stroke in this group .
  Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall , for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events
background: BACKGROUND Evidence from systematic review s of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women , however the results of r and omised controlled trials ( RCTs ) have had mixed results .
  This is an up date d version of a Cochrane review published in 2013 .
  OBJECTIVES To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women , and whether there are differential effects between use in primary or secondary prevention .
  Secondary aims were to undertake exploratory analyses to ( i ) assess the impact of time since menopause that treatment was commenced ( ≥ 10 years versus < 10 years ) , and where these data were not available , use age of trial participants at baseline as a proxy ( ≥ 60 years of age versus < 60 years of age ) ; and ( ii ) assess the effects of length of time on treatment .