Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). A clinical trial of estrogen-replacement therapy after ischemic stroke. 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. 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. Effect of hormone replacement therapy on cardiovascular risk factors in postmenopausal women with diabetes. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Hormone therapy in women in the menopause transition. Randomised, double-blind, placebo-controlled trial of effects on body weight, blood pressure, lipoprotein levels, antithrombin III activity, and the endometrium. Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women. Long-term effects of hormone replacement therapy on symptoms of angina pectoris, quality of life and compliance in women with coronary artery disease. Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study. Estrogen after ischemic stroke: clinical basis and design of the Women's Estrogen for Stroke Trial. Effect of continuous administration of conjugated estrogen plus medroxyprogesterone acetate (Premelle) in postmenopausal women in Taiwan.
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 randomized. double-blind, and placebo-controlled clinical trial with a double-triangular sequential design. Females with previously verified VTE were randomized 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 populations during HRT. Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death.
                We conducted a randomized, 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.
                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 randomly 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.
                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. 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.
                To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.
                Randomized, blinded, placebo-controlled secondary prevention trial.
                Outpatient and community settings at 20 US clinical centers.
                A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.
                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.
                The primary outcome was the occurrence of nonfatal myocardial infarction (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.
                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).
                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. To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy).
                Multicentre, randomised, placebo controlled, double blind trial.
                General practices in UK (384), Australia (91), and New Zealand (24).
                Postmenopausal women aged 50-69 years at randomisation. 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.
                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.
                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.
                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 randomised 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.
                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.
                Current Controlled Trials ISRCTN 63718836. Hormone replacement therapy (HRT) in postmenopausal women improves menopausal symptoms, decreases the incidence of osteoporotic fracture, but the effects on cardiovascular risk factors remain controversial.
                To test the hypothesis that HRT may have beneficial effects on the cardiovascular risk profile in postmenopausal women with diabetes.
                One hundred and fifty postmenopausal patients with type 1 (T1DM) and type 2 diabetes (T2DM) were randomized to receive HRT (Kliofem) or placebo for 12 months. We monitored the effects on cardiovascular risk factors, including lipid profile, glycaemic control, blood pressure and body weight.
                Mean low-density lipoprotein (LDL) cholesterol was associated with a nonsignificant decrease [-0.14 mmol/l (CI=-0.44, 0.17) (p=0.37)] in the Kliofem-treated group. Total cholesterol fell by 0.42 mmol/l (CI=-0.78, -0.05) (p=0.027). High-density lipoprotein (HDL) cholesterol was reduced by a mean of 0.07 mmol/l compared to a mean rise of 0.12 mmol/l on placebo. There were apparent differences in the treatment effects between T1DM and T2DM. There was no change in triglycerides or apoprotein B and no effect on glycaemic control, blood pressure or menopausal symptom scores. In the Kliofem group, BMI fell by 0.66 kg/m2 compared to an increase of 0.14 kg/m2 for placebo patients (p=0.046).
                Although the long-term effects of HRT in women with or without diabetes appear to suggest that some types of HRT either confer no cardiovascular protection or may increase risk, the impact of Kliofem diabetic women on cardiovascular risk factors is probably neutral. Results of observational studies suggest that hormone replacement therapy (HRT) could reduce the risk of coronary heart disease (CHD), but those of randomised 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 infarction.
                The study was a randomised, blinded, placebo controlled, secondary prevention trial of postmenopausal women, age 50-69 years (n=1017) who had survived a first myocardial infarction. Individuals were recruited from 35 hospitals in England 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 reinfarction 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.
                Frequency of reinfarction 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.
                Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infarction. To determine whether hormone treatment of women during the menopause transition induces changes in body weight, blood pressure, lipoprotein levels, antithrombin III activity, and the endometrium.
                Prospective, randomised, placebo-controlled, double-blind, 12-month study, with crossover at 6 months.
                Outpatient clinic of a city hospital.
                105 apparently healthy women in the menopause transition (40-52 years), with menstrual function, who were experiencing minor menopausal symptoms, were selected from the general population by advertising.
                Active arm--oral conjugated oestrogens (0.625 mg daily) and cyclic medroxyprogesterone acetate (10 mg daily) on Day 14-27 of each menstrual cycle; placebo arm--placebos of both medications.
                Excess change from baseline associated with active compared with placebo treatment for all variables; effect of order of treatment.
                Baseline biochemical values were similar for both treatment-order groups, but baseline blood pressures and body weights were higher in the group receiving placebo first. With treatment, there were no differences in overall values for body weight and blood pressure (P > 0.4), and order of treatment had no significant influence (P > 0.3). There were no differences in total and low density lipoprotein cholesterol levels, overall or with order of treatment. Active treatment increased high density lipoprotein (HDL) cholesterol levels (overall and when placebo was given first; P = 0.001), and triglyceride levels (when active treatment was given first; P = 0.03). There was no overall treatment effect, but a significant order-of-treatment effect, on antithrombin III activity (mean levels were decreased by active treatment to a greater extent when it was given first; P = 0.02). The endometrium showed only physiological changes regardless of treatment.
                The lack of significant excess change in anthropometry, lipoprotein levels, antithrombin III activity, and endometrial histology in women given hormone treatment compared with placebo is reassuring. The increase in HDL cholesterol level is an extra benefit. Our study provides conclusive evidence that hormone treatment does not produce weight gain in women during the menopause transition. To test the efficacy of hormone replacement therapy (HRT) and dietary therapy, compared to dietary therapy, in lowering LDL cholesterol levels among postmenopausal women.
                A prospective parallel randomized study of sequential 17 beta-oestradiol and norethisterone acetate or placebo for 48 weeks.
                A University outpatient lipid clinic.
                A total of 76 postmenopausal women, aged 43-60 years, with LDL cholesterol levels > or = 4.2 mmol 1-1, treated with a lipid-lowering diet.
                Levels of lipids, lipoproteins, apolipoproteins, fibrinogen and glucose tolerance.
                Adherence to the diet was similar in both groups. Total and LDL cholesterol levels were reduced by 14% (95% CI, 11-17%) and 19% (95% CI, 14-23%), respectively, in the HRT group vs. 3% (95% CI, 0-7%) and 5% (95% CI, 0-11%) in the diet group. HRT reduced the levels of apolipoprotein B and lipoprotein(a). Levels of HDL cholesterol, HDL2, HDL3, triglycerides, lipoprotein populations and apolipoproteins AI and AII remained unchanged. No adverse effects on glucose tolerance or on fibrinogen levels were observed. The reduction in LDL cholesterol was positively correlated with initial levels of LDL cholesterol and negatively correlated with body mass index.
                HRT is effective in reducing elevated LDL cholesterol levels, and should be considered in the treatment of hyperlipidaemic postmenopausal women, in addition to dietary therapy. The aim of the present study was to evaluate the effects of HRT on symptoms of angina pectoris, quality of life and factors of importance for compliance in women with ischemic heart disease.
                Sixty postmenopausal women with coronary artery disease were randomized into three groups: one group received transdermal 17 beta-estradiol at a dose of 50 micrograms per 24 h alone for 18 days followed by 10 days of combined treatment with medroxyprogesterone acetate (MPA) 5 mg orally; the second group received placebo and the third group received conjugated estrogens orally for 18 days followed by a combined treatment with MPA for 10 days. Clinical evaluations were performed at baseline, after 3, 6 and 12 months. The investigations included gynecological history. occurrence of climacteric symptoms, quality of life evaluation, cardiac history and symptoms of angina pectoris.
                Forty-six women (77%) completed the study during 1 year. The following cardiac events occurred in the women who completed the study: one patient was hospitalized because of congestive heart failure (patch), two patients because of angina pectoris, one patient because of coronary bypass operation (CEE) and three patients underwent balloon dilatation (placebo), all three on CEE. Among the 14 women who discontinued, two patients had TIA (patch), one experienced palpitations (CEE) and one woman died from myocardial infarction (placebo). Overall improvement in mood and cognitive functions were reported in all three treatment groups.
                HRT does not seem to have negative effects on symptoms of angina pectoris and seems to increase quality of life in older women with coronary heart disease. It also seems safe from the cardiovascular point of view. There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease.
                We aimed to assess the effects of androgen replacement on cardiovascular risk factors.
                Thirty-seven postmenopausal women aged 42-62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo.
                Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography.
                A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance.
                This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease. 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 designed a randomized controlled trial.
                The Women's Estrogen For Stroke Trial (WEST) is a double-blind, randomized 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 randomized, 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.
                The WEST promises to provide critical guidance to women and their physicians regarding the effectiveness of estrogen in secondary stroke prevention. To compare the metabolic effects on lipids and acceptability and safety of, and compliance with, a continuous administration of conjugated estrogen plus medroxyprogesterone acetate (Premelle) versus a placebo in non-hysterectomized postmenopausal women.
                Sixty-six generally healthy, female, early post-menopausal women, from 45-60 years of age, were randomized for an administration of conjugated estrogen plus medroxyprogesterone acetate (Premelle, Premarin 0.625 mg plus medroxyprogesterone acetate 2.5 mg/tablet orally) or a placebo for 6 months. The changes in each patient's lipid profiles from baseline, the frequency of hot flushes, bleeding occurrences, and climacteric symptoms, were evaluated. Safety was monitored by means of physical examination, Papanicolau smear, transvaginal ultrasonography, and laboratory check-up. Adverse events were also recorded.
                The difference before and after treatment in serum LDL-C and total cholesterol (TC) was statistically significant in the Premelle group (LDL-C, p = 0.006, TC, p = 0.040). No statistically significant difference in the change from baseline was observed in the levels of LDL-C and TC in the placebo treatment group. There was a statistically significant change from baseline in menopausal symptoms, which were evaluated by the Greene Climacteric Scales in the Premelle group. There was no clinically significant finding in the physical examination, vital signs, laboratory data, or endometrial thickness in either treatment group. The difference in the number of patients who reported an adverse event was not statistically significant between the 2 treatment groups.
                This study demonstrated that Premelle was effective in decreasing LDL-C and total cholesterol levels, and also showed an improvement in some menopausal symptoms, such as vasomotor and sexual dysfunction symptoms. No significant bleeding was observed with Premelle, which was well tolerated in this study. The results of this study could support the use of Premelle tablets as a convenient alternative hormone therapy.
Treatment with HT in post-menopausal women for either primary or secondary prevention of CVD events is not effective, and causes an increase in the risk of stroke, and venous thromboembolic events. HT should therefore only be considered for women seeking relief from menopausal symptoms. Short-term HT treatment should be at the lowest effective dose, and used with caution in women with predisposing risk factors for CVD events.