Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. Effects of hormone replacement therapy on growth hormone secretion patterns in correlation to somatometric parameters in healthy postmenopausal women. Vitamin D and HRT: no benefit additional to that of HRT alone in prevention of bone loss in early postmenopausal women. A 2.5-year randomized placebo-controlled study. The independent effects of exercise and estrogen on lipids and lipoproteins in postmenopausal women. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Prophylaxis of osteoporosis with calcium, estrogens and/or eelcatonin: comparative longitudinal study of bone mass. A randomized controlled study of the effects of 17beta-estradiol-dydrogesterone on plasma homocysteine in postmenopausal women. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Cardiovascular risk factors during estrogen-norethindrone and cholecalciferol treatment. Oestrogen-progestogen replacement therapy changes body composition in early post-menopausal women. Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women. Effects of hormone replacement therapy on muscle performance and balance in post-menopausal women. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four-year randomized study. Continuous oestrogen-progestogen treatment and serum lipoproteins in postmenopausal women. Cyproterone acetate, an alternative progestogen in postmenopausal hormone replacement therapy? Effects on serum lipids and lipoproteins. Dose-response effects on serum lipids and lipoproteins following combined oestrogen-progestogen therapy in post-menopausal women. The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Interventions Study Investigators. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized 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. Double-masked, multicenter study of an estradiol matrix transdermal delivery system (Alora) versus placebo in postmenopausal women experiencing menopausal symptoms. Alora Study Group. Hormonal replacement and lipid changes in postmenopausal women. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus.
                To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT).
                Double-blind, randomized, parallel trial.
                Eight sites in the United States.
                390 healthy postmenopausal women recruited by advertisement.
                Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo.
                Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment.
                At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P < .001), similar to the 14% reduction with HRT (P < .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P < .001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C) by 15% to 17% (P < .05), less than the 33% increase with HRT (P < .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P < .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P < .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2.
                Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease. The aim of the present study was to investigate the influence of a continuous estrogen, cyclic progesterone replacement therapy on the secretion of growth hormone (GH) and IGF I as well as of somatometric-GH correlation patterns.
                The study included 23 healthy postmenopausal women. Of the proband group 13 randomly selected women were treated with orally applicated 2 mg estradiol-valerat (E2V) and 10 mg dydrogesterone for 10 months. Ten women did not receive any hormonal treatment during this time. After 10 months all probands were reexamined and their GH and IGF I secretion, as well as their somatometric-hormonal correlation patterns, compared with those of a fertile control group.
                It could be shown, that in postmenopausal women a 10-month oral hormone replacement therapy led to a significant increase of GH- and IGF I levels, however, the treated postmenopausal women did not reach the levels of the fertile controls. Those women who did not receive any hormonal treatment and the postmenopausal women before HRT showed nearly identical GH- and IGF I levels as well as somatometric-GH correlation patterns.
                The results of the present paper indicate a marked influence of estrogens on GH and IGF I secretion. Furthermore, hormonal replacement therapy (HRT) may influence somatometric GH correlation patterns too. The study was designed to examine the effect of hormone replacement therapy (HRT) and low-dose bone loss in non-osteoporotic early postmenopausal women and to determine whether Vit D supplementation can give additional benefit to an already optimized estrogen regimen. The effects of HRT and Vit D on bone mineral density (BMD) were studied in postmenopausal women in a 2.5-year randomized placebo-controlled study. The study population was a subgroup of the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) (n = 13100). A total of 464 early postmenopausal women were randomized to four groups: (1) HRT (a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate (E2Val/CPA); (2) vitamin D3 (cholecalciferol, 300 IU/day); (3) HRT + Vit D; and (4) placebo (calcium lactate; 93 mg Ca2+/day). Lumbar (L1-4) and femoral neck BMD were determined by dual-energy X-ray absorptiometry before and after 2.5 years of treatment. After 2.5 years, lumbar BMD had increased by 1.8% in the HRT group (p > 0.001) and by 1.4% in the HRT + Vit D group (p = 0.002), whereas lumbar BMD had decreased by 3.5% (p < 0.001) in the Vit D group and by 3.7% (p < 0.001) in the placebo group. The loss of femoral neck BMD was lower in the HRT (-0.3%) and the HRT + Vit D (0.9%) groups compared with the Vit D (-2.4%) and the placebo groups (-3.7%). This study confirms the beneficial effect of HRT on BMD. It also shows that low-dose vitamin D supplementation has only a minor effect in the prevention of osteoporosis in non-osteoporotic early postmenopausal women and does not give any benefit additional to that of HRT alone. To assess the effects of a moderate exercise program with and without oral estrogen replacement on levels of lipids and lipoproteins in postmenopausal women.
                One hundred one postmenopausal women were randomized into four groups: control or sedentary (N = 20), exercise alone (N = 25), estrogen replacement using 0.625 mg conjugated equine estrogen (N = 28), and exercise supplemented with conjugated equine estrogen (N = 28). The exercise groups were placed on a moderate exercise program. Following baseline testing, each group returned at 3 and 6 months for cardiorespiratory fitness testing and serum lipid and lipoprotein profiles.
                We found a significant decrease in systolic blood pressure (P < .05) in all treatment groups. The maximum oxygen uptake increased by 9.0 and 7.8% in the exercise and conjugated equine estrogen/exercise groups, respectively, compared to the other groups (P < .05). These responses were seen at both 3 and 6 months. Total exercise time (time spent on the treadmill until exhaustion during testing) significantly increased in the exercise group by 21% (P < .01). Exercise alone was associated with significant decreases in total cholesterol (5.2%, P < .05), triglycerides (2%, P < .05), and low-density lipoprotein (LDL) cholesterol (10%, P < .01), and a significant increase in the high-density lipoprotein (HDL) cholesterol-LDL ratio (17.2%, P < .01). Significant changes were noted in these values, as well as increases in HDL cholesterol (16 and 14.8%; P < .01) and apolipoprotein A1 (25.6 and 26.5%; P < .001) in the conjugated equine estrogen and conjugated equine estrogen/exercise groups, respectively. However, there were no differences in the changes observed in the conjugated equine estrogen groups with versus without exercise. No direct correlation was seen between measures of exercise performance and the changes seen in lipids and lipoproteins.
                Estrogen therapy alone had the greatest beneficial effect on lipids and lipoproteins. Exercise alone resulted in a significant reduction in cholesterol, triglycerides, and LDL cholesterol, and an increase in the HDL-LDL ratio. However, combined conjugated equine estrogen and exercise did not demonstrate an added improvement in lipid metabolism. Physical fitness levels increased in the exercise groups, but not in the control group or the estrogen-alone treated women. To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen.
                A prospective, randomized 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.
                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).
                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. 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 investigate the effects of oral 17beta-estradiol (E2) -dydrogesterone on fasting plasma homocysteine concentrations in healthy postmenopausal women.
                We studied 27 postmenopausal women who were assigned randomly to either a treatment group (n = 14) or a control group (n = 13). During the first 12 months of the study, treatment consisted of oral E2, 1 mg daily, combined sequentially with dydrogesterone 5 or 10 mg (14 days per 28-day treatment cycle). Thereafter, women were treated with oral E2, 2 mg daily, combined sequentially with dydrogesterone, 10 mg daily (14 days per 28-day treatment cycle) for a period of 3 months. The control group received no treatment. Fasting plasma total homocysteine concentrations were determined at baseline and 3, 12, and 15 months after study entry.
                At baseline, plasma homocysteine levels did not differ between the groups. After 15 months of hormone treatment mean plasma homocysteine concentration was lowered by 12.6% compared with baseline (P < .001; analysis of variance for repeated measures). Plasma homocysteine levels were not altered in the control group. The interaction between treatment and time for homocysteine levels was significantly different between the groups (P < .001; analysis of variance for repeated measures). The decrease in plasma homocysteine levels correlated inversely with the increase in serum E2 levels after 3 and 12 months of hormone treatment (r = -.54, P < .05 and r = -.56, P < .05, respectively).
                Plasma fasting homocysteine concentrations are lowered by E2-dydrogesterone therapy in postmenopausal women. Randomized trials of postmenopausal hormone therapy have found differing effects on fasting glucose levels. No trial has evaluated the effect of hormone therapy on diabetes incidence.
                To evaluate the effect of hormone therapy on fasting glucose level and incident diabetes.
                Randomized, double-blind, placebo-controlled trial.
                20 U.S. clinical centers.
                2763 postmenopausal women with coronary heart disease who were followed for 4.1 years. At baseline, 734 women had diabetes, 218 women had impaired fasting glucose, and 1811 women were normoglycemic; the 2029 women without diabetes were followed for incident diabetes.
                0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily, or placebo.
                Fasting glucose level was measured at baseline, at year 1, and at the end of the trial. Incident diabetes was defined by self-report of diabetes or disease complication, fasting glucose level of 6.9 mmol/L or greater (> or =126 mg/dL), or initiation of therapy with diabetes medication.
                Fasting glucose levels increased significantly among women assigned to placebo but did not change among women receiving hormone therapy. The incidence of diabetes was 6.2% in the hormone therapy group and 9.5% in the placebo group (relative hazard, 0.65 [95% CI, 0.48 to 0.89]; P = 0.006). The number needed to treat for benefit to prevent one case of diabetes was 30 (CI, 18 to 103). Changes in weight and waist circumference did not mediate this effect.
                In women with coronary disease, hormone therapy reduced the incidence of diabetes by 35%. This observation provides important insights into the metabolic effects of postmenopausal hormones but is insufficient to recommend the use of hormones for secondary prevention of heart disease. 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. The effect of cholecalciferol and estrogen-norethindrone treatment on total cholesterol level, high-density lipoprotein cholesterol level, blood pressure, and body mass index was investigated in 74 postmenopausal women in a double-blind, randomized trial. Blood pressure and body mass index did not change throughout the study. We demonstrated a decrease (11%) in serum cholesterol level after 1 year of treatment with estrogen-norethindrone. When this treatment was combined with cholecalciferol, a similar decrease (13%) was observed. The hypocholesterolemic effect was correlated to body mass index in a way that indicated the most pronounced decrease in lean women. The high-density lipoprotein cholesterol/total cholesterol fraction increased by 45% after 1 year of estrogen-norethindrone treatment, while an increase of 25% after 1 year was seen when cholecalciferol was added to the treatment. The latter increase was not different from a similar increase in the placebo group. The possible dyslipidemic effect of cholecalciferol, along with the risk of hypercalcemia, emphasizes the caution necessary in cholecalciferol treatment. Changes in body composition were investigated in a group of 136 post-menopausal women treated for at least 1 yr with combined oestrogen-progestogen therapy at three different doses, or a placebo. The body composition changes were evaluated using the urinary creatinine excretion rate as an indicator of lean body mass, and the changes in daily creatinine excretion were related to the changes in serum oestradiol and oestrone. The urinary creatinine excretion rate was significantly increased (P less than 0.001) in the group receiving high-dose hormones, and the urinary creatinine/body weight ratio was significantly increased (P less than 0.05) in all treated groups as compared with the placebo-group. The body weight remained unchanged in all groups. The relationships between the changes in daily creatinine excretion and the changes in serum oestradiol and serum oestrone were both significant (P less than 0.05). The present study suggests that high-dose post-menopausal hormone therapy changes the body composition by increasing the muscle mass and that, since the body weight remains unchanged, a proportionate decrease in the fat mass seems to occur. 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. 1. A randomized controlled trial of the effect of oral hormone replacement therapy plus calcium compared with calcium alone on balance, muscle performance and falls was conducted over 48 weeks in 116 post-menopausal women (aged 45-70 years), all of whom had suffered a distal radial fracture during the previous 3 months. Treatment was with Prempak C or Premarin 0.625 mg in the test group with 1 g calcium daily (Sandocal) in both groups. Measurements were made of balance, assessed as sway, leg extensor power and self-paced walking speed, at 12-week intervals over 24 weeks. Hand grip strength was measured every 12 weeks for 48 weeks, and falls in the preceding 12 weeks were recorded at each visit. 2. There was no relation between initial levels of oestradiol and any other variable assessed, except body mass. Levels of follicle-stimulating hormone in the test group were in the premenopausal range. There was no significant change attributable to hormone replacement therapy at any time point in any of the outcome variables. The only significant difference was an increase of 4.2% (95% confidence interval 0.7-7.6%) in leg extensor power in the control group (calcium alone) compared with the group treated with hormone replacement therapy. 3. Of the total group, 37% fell again during the year, with three patients suffering a further fracture. Frequent fallers swayed significantly more often than the others, but there was no evidence that their muscle strength was poorer or that the group treated with hormone replacement therapy fell less frequently. 4. Hormone replacement therapy did not increase muscle performance, improve balance or reduce falls over a year in middle-aged women. Administration of estrogen or etidronate has been shown to increase bone mineral density in postmenopausal women. This 4-year, prospective, randomized study was carried out to monitor any added beneficial effect on bone mineral density when hormone-replacement therapy (HRT) was combined with etidronate.
                Fifty-eight early postmenopausal women attending metabolic bone disease outpatient clinics were randomly 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.
                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.
                This 4-year, prospective, randomized 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. Serum lipids and lipoproteins were examined in 44 healthy postmenopausal women every 3 months during 1 year of treatment with either continuous oestrogen-norethisterone acetate or placebo. Total serum cholesterol and LDL-cholesterol levels were reduced by approximately 15% and 20% (P less than 0.001), respectively in the hormone group but were unchanged in the placebo group. Serum triglycerides levels remained constant in both groups. HDL-cholesterol levels were significantly reduced by approximately 10% in the hormone group but significant reductions of 5-10% also occurred in the placebo group so that differences between the two groups were only significant after 3 months of treatment. Vaginal bleedings were experienced during the first 3 months by eight of the 21 women receiving hormones, but in only one woman after 9 months of therapy. The addition of norethisterone acetate to postmenopausal oestrogen therapy in clinically relevant doses had no adverse effects on lipoproteins as previously reported, even though administered continuously. Moreover, the low frequency of bleeding with continuous oestrogen-progestogen therapy would make this an appropriate alternative in postmenopausal replacement therapy. Serum lipids and lipoproteins were studied in 76 healthy postmenopausal women treated for 1 year with either oestradiol valerate sequentially combined with the anti-androgenic progestogen cyproterone acetate (CPA) or placebo. The women were examined every 3 months between days 18 and 21 of the tablet cycle, where the progestogen had been added to the oestrogen for at least 6 days. Combined oestrogen-CPA therapy resulted in significantly reduced levels of total serum cholesterol and LDL-cholesterol at all examinations, but serum triglycerides and HDL-cholesterol levels were similar in the two groups. Total serum cholesterol and LDL-cholesterol were reduced by approximately 5% (P less than 0.01) and 8% (P less than 0.01), respectively, after 1 year of combined oestrogen-CPA therapy in comparison with both the initial values and the placebo group but serum triglycerides and HDL-cholesterol levels were unchanged in both groups. The dose-response effects on serum lipids and lipoproteins were studied in 87 healthy post-menopausal women treated for 1 yr with three different doses of sequential oestrogen/progestogen (4 mg, 2 mg and 1 mg 17 beta-oestradiol cyclically combined with 1 mg norethisterone acetate) or placebo. Total serum cholesterol levels were significantly reduced by 4-10% (P less than 0.05-P less than 0.001) in a dose-related way in the hormone groups. This was mainly caused by a similar reduction in low-density-lipoprotein (LDL) cholesterol, whereas the changes in high-density-lipoprotein (HDL) cholesterol were not significantly different from those observed in the placebo group. It is concluded that treatment with sequentially combined oestrogen and progestogen, using norethisterone acetate in combination with 17 beta-oestradiol in clinically relevant doses, does not produce any adverse effects on serum lipids or lipoproteins. 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.
                A three-arm parallel randomized 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.
                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.
                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. Reports from cross-sectional comparisons, nonrandomized prospective studies, and relatively small clinical trials indicate that postmenopausal hormone therapy may slightly decrease the amount of weight typically gained by women during the decade following menopause. Despite this, widespread belief remains that hormone therapy may cause weight gain. We use data from the Postmenopausal Estrogen/Progestin Interventions trial to characterize the impact of postmenopausal hormone therapy on weight and fat distribution and to examine the consistency of this impact among subgroups of women defined by lifestyle, clinical, and demographic factors. The Postmenopausal Estrogen/Progestin Interventions trial was a 3-yr, placebo-controlled, randomized clinical trial of 875 women assessing the effects on cardiovascular risk factors of four hormone regimens: oral conjugated equine estrogen (CEE) therapy (0.625 mg daily alone), CEE in combination with medroxyprogesterone acetate (2.5 mg daily), CEE in combination with medroxyprogesterone acetate (10 mg daily on days 1-12), and CEE in combination with micronized progesterone (200 mg daily on days 1-12). Women randomly assigned to CEE with or without a progestational agent averaged 1.0 kg less weight gain at the end of 3 yr (P = 0.006) than those assigned to placebo. Assignment to CEE was also associated with averages of 1.2 cm less increase in waist girth (P = 0.01) and 0.3 cm less increase in hip (P = 0.07) girth. In regression models that included weight change as a covariate, none of these differences reached statistical significance. There were no significant differences in weight or girth changes among any of the four active hormone regimens. After accounting for the effects of assignment to active hormone therapy and baseline weight, older age (P 0.008) and higher physical activity level at baseline (P = 0.002) were also independently predictive of less weight gain. The impact of hormone therapy on weight gain was similar among subgroups, except for those defined by baseline smoking status (P = 0.04) and physical activity level at home (P = 0.02). Factors that were independently associated with smaller increases in girths were: for waist, greater overall activity (P = 0.005) and Hispanic ethnicity (P = 0.02); and for hip, work activity (P = 0.003) and greater alcohol consumption (P = 0.03). None of these factors significantly affected the observed overall relationships between estrogen and changes in girth. After menopause the haemostatic balance shifts towards a latent hypercoagulable state. To evaluate the effects of two regimens of transdermal estradiol (E2) combined with progestin on the balance between procoagulant factors and inhibitors, 255 women in physiological menopause for 1-5 years were randomly allocated to 1 year of treatment with cyclic transdermal E2 (50 micrograms/day for 21 days) plus medroxyprogesterone acetate (MPA) (10 mg/day from days 10 to 21), continuous transdermal E2 (50 micrograms/day for 28 days) plus MPA (10 mg/day from days 14 to 25), or placebo. Fibrinogen, factor VII (FVII), factor VIII:C (FVIII:C), antithrombin III (ATIII), protein C, protein S, heparin cofactor II (HCII) and plasminogen activator inhibitor (PAI-1) levels were measured at baseline and after 6 and 12 cycles. 167 women who took the treatment for at least 6 cycles were evaluable. The continuous treatment group had significantly lower final values of fibrinogen, FVII, ATIII, protein S and HCII than the placebo group; the cyclic treatment reduced fibrinogen in comparison with placebo but the difference was not significant. In conclusion, both regimens produce a clinically relevant decrease of fibrinogen levels; the continuous regimen affects also the levels of FVII and inhibitors suggesting that the haemostatic balance is shifted to a more physiological state. The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins. As body composition and body fat distribution in particular are independent predictors of cardiovascular disease, we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured. Sixty-two early postmenopausal women were followed up for 2 years in a prospective, randomized, placebo-controlled study. We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause (P less than .05), and that this effect was independent of the effect on serum lipids and lipoproteins. The therapy reduced postmenopausal bone loss significantly (P less than .001), whereas it did not have a statistically significant influence on total body fat mass or total lean body mass. The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition, in particular abdominal fat. To compare the effect of continuous norethindrone acetate (NA)-ethinyl estradiol (EE2) combinations with matching unopposed EE2 or placebo.
                A 2-year, double-blind, placebo-controlled, parallel-group clinical trial.
                Outpatients at 65 centers.
                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.
                Patients were equally randomized 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.
                Bone mineral density (BMD) measured by quantitative computed tomography, serum lipids, and endometrial effects as assessed by rate of hyperplasia and proliferative status.
                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.
                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. 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. This 12-week, double-masked, double-dummy, randomized, parallel-group study compared the efficacy and safety of an estradiol matrix transdermal delivery system (Alora) in two strengths (50-microgram/d estradiol and 100-microgram/d estradiol) with placebo in postmenopausal women who were experiencing at least 60 moderate-to-severe hot flushes per week. In 273 postmenopausal women, the reduction in the frequency of moderate-to-severe hot flushes was significantly better than placebo within 2 weeks of initiating therapy in the 100-microgram/d group and within 3 weeks of initiating therapy in the 50-microgram/d group. The reduction in hot flushes for both active treatment groups remained significantly different from placebo throughout the 12-week trial. Improvement in vaginal cytology profile (maturation index) was observed in both active treatment groups. Serum estradiol concentrations were elevated to early-to mid-follicular levels, in proportion to dose, and the estradiol/estrone ratio remained within the expected premenopausal range. The incidence of estrogen-related side effects was modest but greater in the active treatment groups than in the placebo group: Breast pain was reported in 4.5% of the patients in the 50-microgram/d group, 5.3% of patients in the 100-microgram/d group, and none of the patients in the placebo group. Breakthrough bleeding occurred in 3.4% of women in the 50-microgram/d group, 20.2% of women in the 100-microgram/d group, and 4.4% of women in the placebo group. Only 3 (1.1%) patients terminated treatment because of skin reactions. This study demonstrates that this estradiol matrix transdermal delivery system is effective in the treatment of menopausal symptoms, while providing the skin tolerability desired by patients. To assess the effect of hormonal replacement therapy on lipid changes, measurement of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), apolipoprotein A-1 (Apo-A) and apolipoprotein B (Apo-B) was performed on 93 postmenopausal women. Women in the study group (HRT) (51/93) received estrogen with or without progestin. The control group (Non-HRT) (42/93) did not receive any hormone regimen. The measurement was done at 0, 6 and 12 months. The results revealed that triglyceride increased significantly more in the non-HRT than the HRT group at 6 and 12 months. (Non-HRT: +21.7%, +21.7%; HRT: -2.8%, +2.4%, respectively P < 0.05). However, there was no significant difference in changes of other lipid profiles between the two groups at 6 and 12 months (Non-HRT: TC -2.7%, +0.7%, HDL +2.9%, +5.1%, LDL -5.2%, -4.1%, Apo-A +0.5%, +0.9%, Apo-B +3.8%, +1.3%: HRT: TC -1.4%, -2.8%, HDL +4.7%, +6.2%, LDL -1.5%, -4.9%, Apo-A -0.9%, +1.6%, Apo-B -2.6%, -1.6%, respectively P > 0.05). The paradoxical changes of triglyceride and HDL might partly be explained by the effect of progestins used in this study. Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.
                To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.
                Estrogen plus progestin component of the Women's Health Initiative, a randomized 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.
                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).
                The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction 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.
                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.
                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.