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. Prophylaxis of osteoporosis with calcium, estrogens and/or eelcatonin: comparative longitudinal study of bone mass. Effects of hormone replacement therapy on cognitive performance in elderly women. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757]. A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women.
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. To evaluate three different therapeutic regimens for the prevention of osteoporosis in natural and surgical postmenopausal women who had been found to have rapid bone loss in analytical studies.
                A total of 104 naturally or surgically postmenopausal women were studied, and subsequently followed-up during 1 year for avoidance of the influence of seasonal variation on bone mass, a factor overlooked in several studies. They were randomized into four groups of 26 patients each: the untreated control group (mean age 50 +/- 5 years); the hormonal replacement treatment (HRT) group (mean age 48 +/- 6 years), which was treated for 24 days each month with transdermal 17 beta-estradiol, 50 mg/day, together with medroxiprogesterone, 10 mg during 12 days; the calcium group (mean age 50 +/- 4 years), which was treated with elemental calcium, 1 g/day; and the calcitonin group (mean age 50 +/- 5 years), which was treated for 10 days each month with eel calcitonin, 40 IU/day and with elemental calcium, 500 mg/day. Full-body bone densitometry, for measuring total body bone mineral content (TBBMC), was carried out in all the women at baseline and 1 year. TBBMC was corrected for body weight by dividing its value by body weight (TBBMC/W).
                After 1 year TBBMC/W was lower in every group: -2.14% (P < 0.001) in the control group; -0.14% (P = NS) in the HRT group (P < 0.05 vs. controls); -0.18% (P = NS) in the calcium group (P < 0.05 vs. controls); and -0.06% (P = NS) in the calcitonin group (P < 0.01 vs. controls; P < 0.05 vs. calcium and HRT).
                These findings show that all three treatments are effective in the prevention of postmenopausal loss of bone mass. To determine the effects of 9 months of hormone replacement therapy (HRT) on cognitive performance in women aged 75 years and older.
                A 9-month randomized, double-blinded, placebo-controlled parallel trial. Fifty-two elderly postmenopausal women (age range 75-91 years) without known contraindications to HRT or evidence of dementia or depression were enrolled. Participants were randomly assigned in a 1:2 ratio to placebo or conjugated estrogens at 0.625 mg/d plus trimonthly medroxyprogesterone acetate at 5 mg/d for 13 days (HRT). Main outcome measures were change from baseline and rate of change from baseline for the following psychometric tests: Verbal Fluency Test, Weschler Paired Associate Learning and 20 min Delayed Recall, Trailmaking A and B Tests, Cancellation Random Letter and Random Form Tests.
                At baseline, women in the HRT group reported a younger age of onset of menopause and a higher prevalence of hysterectomy, but otherwise did not differ from women in the placebo group. After 9 months of treatment, there were no significant group differences for any of the cognitive performance measures. The lack of an observed group-by-time difference for all cognitive tests remained after controlling for age of onset of menopause, education, and previous hysterectomy.
                Although conclusions are limited by small sample size and the relatively short duration of treatment, results suggest that 9 months of estrogen replacement in combination with trimonthly progestin does not improve cognitive performance in women over 75 years who do not have dementia or depression. With the aim of preventing postmenopausal bone loss, a placebo-controlled double-blind trial of 2 years duration was performed. We randomized 315 healthy volunteers in their early natural menopause to seven treatment and three placebo groups: 17 beta-oestradiol, oestriol and sequential norethisteron (hormones); bendroflumethiazide 5 mg/day (thiazide); hormones and thiazide; sodium fluoride 20 mg/day; vitamin D3 2000 IU/day (D3); fluoride and D3; and 1 alpha (OH) vitamin D3 0.25 microgram/day (1 alpha D3). All participants were given daily calcium supplement of 500 mg. Every 3 months we measured the bone mineral content (BMC) of both forearms by photon absorptiometry and chemical quantities in blood and 48 h urinary collections. The study was completed by 264 (84%). The combined placebo groups showed a linear fall in BMC reaching 3.3% after 2 years (P < 0.001). Hormones and hormones and thiazide led to a 2.5% gain in BMC (P < 0.01). Thiazide alone postponed the BMC fall for 6 months. After 2 years the thiazide group showed a BMC fall of 1.5% (P < 0.05), less than that of the placebo group (P < 0.05). BMC declined by 3.6%, 4.5%, 3.7% and 3.7% during the respective use of fluoride, D3, fluoride and D3 and 1 alpha D3. Nevertheless, the urinary calcium excretion during 1 alpha D3 and D3 treatment was 1--1.5 mmol/day higher than in the placebo groups. Apparently, there is no real alternative to oestrogen/gestagen in the prevention of postmenopausal osteoporosis. 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. The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT. SUBJECTS/INTERVENTIONS: Eighteen females with PBC were randomized to receive 2 years therapy with either (i) transdermal oestradiol 50 microg 24 h(-1) two times per week + medroxyprogesterone 2.5 mg day(-1) + alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1) or (ii) alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1). Dual-energy X-ray absorptiometry for measurement of bone mineral density (BMD) and sampling of blood and serum for measurements of biochemical markers of liver function was performed before, during and at the end of treatment.
                BMD increased significantly at the lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas no significant change was found in the control group. One oestrogen-treated patient was excluded after 1 year because of deteriorating, but reversible, aminotransferases. Dropout frequency because of nonliver-related causes was higher in the HRT group. Otherwise, no difference with respect to adverse liver reactions was found between the groups.
                Transdermal HRT increases BMD in PBC patients with few severe side effects related to the liver. Hormone replacement therapy (HRT) with estrogen and treatment with bisphosphonates have been shown to increase bone mineral density (BMD) in postmenopausal women. This 4-year prospective randomized study was carried out to assess the effectiveness of the combined HRT plus etidronate on BMD in postmenopausal women with established osteoporosis.
                Seventy-two postmenopausal women (mean age 64.9+/-0.5 years) attending metabolic bone disease outpatient clinics with established osteoporosis were randomly allocated into one of four treatment groups and monitored for 4 years. All patients enrolled in this study including the control group (n=18) received 1.0 g elemental calcium and 400 units vitamin D per day. The HRT group (n=18) received cyclical estrogen and progesterone; the etidronate group (n=17) received intermittent cyclical etidronate; and the combined therapy group (n=19) received both HRT and etidronate. BMD was measured in the lumbar spine and the hip before treatment and at 2 and 4 years after treatment. Changes in height were recorded, and the occurrence of new vertebral fractures were documented in comparison with the baseline radiographic evaluation. In 40 patients (10 patients per group), analysis of bone histomorphometry was carried out after 4 years of treatment.
                In patients who received the combined therapy, BMD increased in the lumbar spine by 10.4% (P <0.001) and in the hip by 7.0% (P <0.001) at 4 years. For patients treated with ICE, these increases were 7.3% (P <0.001) and 0.9% (P <0.05), and with HRT, the increases were 7.0% (P <0.001) and 4.8% (P <0.01) in the vertebrae and femora, respectively. The group treated with calcium and vitamin D lost 2.5% (P <0.05) and 4.4% (P <0.01) of BMD in the vertebrae and femora, respectively, after 4 years. Patients who received combined therapy had significantly higher BMD in both the vertebrae and in the femora (P <0.05) in comparison with patients who were treated with HRT or etidronate alone after 4 years. In comparison with patients in the control group, there was a trend toward a lower rate of new vertebral fractures in the treatment groups. Height loss was significantly less in all three active treatment groups (HRT [P <0.001], etidronate [P <0.02], and combined therapy group [P <0.0001]), in comparison with the control group. The combined therapy group did not have a significant height loss, in comparison with the HRT (P <0.02) and the etidronate (P <0.001) groups. None of the patients had histomorphometric evidence of osteomalacia.
                This 4-year randomized study showed an additive effect of etidronate and HRT on hip and spine BMD in postmenopausal women with established osteoporosis. At present the Women's Health Initiative trial is the only reported randomised controlled trial studying 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 aimed to compare the health effects of oral continuous combined hormone therapy with a placebo and non-treatment among healthy Estonian women.
                Eligible women were randomised into a blind group of hormone therapy versus placebo and into a non-blind group of open label hormone therapy versus non-treatment. One thousand 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.
                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.
                The results from the Estonian Postmenopausal Hormone Therapy randomised trial are consistent with the Women's Health Initiative findings. We examined whether estradiol and norethindrone hormone therapy (HT) prevented decline in delayed verbal recall in older women with normal to mildly impaired memory functioning. This was a 2-year, randomized, double-blind, placebo-controlled trial of 142 women aged 61-87, randomly assigned to receive 1 mg 17-beta estradiol daily and 0.35 mg norethindrone 3 days/week or daily placebo for 2 years. The primary outcome was short-delay verbal recall of the California Verbal Learning Test (CVLT). To look for differences in response to HT by baseline short-delay recall, we examined the primary outcome in participants grouped according to whether their baseline scores were below average for the age group or greater than or equal to this score and according to whether they met criteria for Mild Cognitive Impairment (MCI) or not. 133 women completed 1 year of the trial and 128 completed 2 years. Prespecified covariates in all repeated measures analyses of covariance (RANCOVA) included age, education, APOE epsilon4, and prior HT use. RANCOVA showed no overall significant treatment effects at year 1 or year 2. After testing for an interaction, which was significant (p=0.02), we found that women in the HT group who scored at or above the average showed significantly less decline than the placebo group in short-delay verbal recall after 1 year, p=0.007 and 2 years, p=0.01. No treatment effects were found in women below the average in either year. When grouped according to whether the participant met criteria for MCI, the interaction between treatment group and MCI subgroup was not significant. These results suggest that benefits of estrogen exposure may be limited to those with average to above average scores on the delayed verbal recall. HT dose and formulation may have contributed to these beneficial outcomes. Replication is warranted before recommendations can be made in the clinical setting.
HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for preventing deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen therapies are unsuitable. There are insufficient data to assess the risk of long term HT use in perimenopausal women or postmenopausal women younger than 50 years of age.