Dose-response and withdrawal effects on climacteric symptoms after hormonal replacement therapy. A placebo-controlled therapeutic trial. A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Two hormone replacement therapy (HRT) regimens for middle-eastern postmenopausal women. Initial 17beta-estradiol dose for treating vasomotor symptoms. A 1-year comparison of the efficacy and clinical tolerance in postmenopausal women of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone. Dose-response analysis of effects of tibolone on climacteric symptoms. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial. [Influence of hormone replacement therapy on the quality of life in postmenopausal women with hypertension]. A randomised, double-blind, cross-over study into the effect of sequential mestranol and norethisterone on climacteric symptoms and biochemical parameters. Do combinations of 1 mg estradiol and low doses of NETA effectively control menopausal symptoms? Menopausal hot flushes: a double blind comparison of placebo, ethinyl oestradiol and norgestrel. 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. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. A pilot study of the effects of phytoestrogen supplementation on postmenopausal endometrium. Gonadotropin-releasing hormone analogue plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomized, placebo-controlled study.
Out of a sample of 162 early post-menopausal women, aged 45-54 yr, 131 completed a placebo-controlled study to investigate the effect of sex hormones on mild climacteric symptoms with special reference to the dose-response relationship and withdrawal effects. The women were followed up for 42 mth under four different study programmes. All the women were examined every 3 mth and a blind assessment made of the menopausal index estimated according to Kupperman et al. The data revealed a highly significant reduction in climacteric symptoms in the hormone-treated women as compared with the placebo group (P less than 0.001), a highly significant dose relationship between climacteric symptoms and treatment with 4, 2 and 1 mg oestradiol, respectively (P less than 0.001), a highly significant and dose-dependent rebound phenomenon after withdrawal of hormone treatment (P less than 0.001)--which levelled off after 6 mth following withdrawal--and complete relief of hot flushes with the two highest doses of oestradiol (4 and 2 mg oestradiol). It is concluded that sex hormones have a beneficial effect in post-menopausal women with even mild symptoms. To compare the effects of two postmenopausal regimens on menopausal symptoms, bleeding episodes, side effects and acceptability.
                Double-blind, randomised controlled trial.
                Twenty-nine sites in Denmark, nine in Norway and six in Sweden.
                Four hundred and thirty-seven postmenopausal women with menopausal complaints. None of these women had had a hysterectomy.
                Daily treatment with tibolone 2.5 mg (n = 218) or 17beta-oestradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA) (n = 219).
                Hot flushes, sweating episodes, vaginal dryness, assessment of sexual life and bleeding patterns; at baseline and after 4, 12, 24 and 48 weeks.
                Treatment with either preparation significantly reduced mean scores for hot flushes, sweating episodes and vaginal dryness. The overall discontinuation rate was 28% (tibolone 25%, E2/NETA 31%; P = 0.14), mostly during the first six months. There was a markedly lower cumulative incidence of bleeding or spotting episodes with tibolone compared with E2/NETA (P < 0.0001), mainly during the first six treatment cycles.
                Both tibolone and E2/NETA effectively alleviate menopausal symptoms. However, tibolone caused significantly fewer bleeding or spotting episodes, which were reflected by lower overall rates of bleeding, as well as lower drop-out rates due to bleeding. Most previous studies designed to evaluate the efficacy of hormone replacement therapy (HRT) have been carried out in Europe, North America and Australia, involving Caucasian women for 6 months or less.
                To evaluate the 12-month effects of two different HRT regimens on postmenopausal symptoms of Middle-Eastern women.
                Hundred healthy Libyan women with postmenopausal symptoms, 12 months or more since their last menstrual period, were enrolled in a 12-month prospective study. Participants were randomly prescribed one of the two formulations, 50 in each group. These regimens were a continuous regimen of tibolone 2.5 mg oral tablets and a continuous regimen of 17beta-oestradiol sequentially combined with dydrogesterone (2/10 mg) oral tablets. The presence and severity of short- and intermediate-term symptoms were reported at 0, 3, 6 and 12 months of treatment. Observed symptoms were hot flushes, night sweating, palpitations, insomnia, depression, nervousness, loss of memory, vaginal dryness, loss of libido and joint pain.
                Forty-nine women (98%) in each group completed the 12-month study period. Participants, in the two groups, experienced a significant improvement within the first 3 months of treatment. The observed symptoms were completely relived by the sixth month without any significant difference between the two groups. Improvements were sustained over the 12-month period of the study. HRT users showed their acceptance to the two regimens.
                Tibolone and 17beta-oestradiol/dydrogesterone oral tablets were effective and safe to treat short- and intermediate-term symptoms in Middle-Eastern postmenopausal women, within 6 months, and with no significant differences between the groups. Thus, the use of HRT to relieve menopausal symptoms is highly recommended, at least in this region. To compare the efficacy of different doses of 17beta-estradiol (E2) for relief of vasomotor symptoms in menopausal women.
                This was a randomized, double-masked, placebo-controlled, 12-week study in which 333 menopausal women with moderate or severe hot flushes were assigned to treatment with 0.25 mg, 0.5 mg, 1 mg, or 2 mg oral micronized 17beta-E2, or placebo. The number and severity of hot flushes were recorded daily.
                There was a significant linear correlation between increased dosage of 17beta-E2 and decreased moderate to severe hot flushes per week (P <.001). Rapid reduction in moderate to severe hot flushes was only achieved with 1 and 2 mg, showing a significant difference from placebo at week 4 (P <.05). At week 4, half the women on placebo had reduced moderate to severe hot flushes of at least 52%; the corresponding figures were 56%, 69%, 86%, and 91% for 0.25, 0.5, 1, and 2 mg, respectively. At week 12, all doses except 0.25 mg were significantly better than placebo for reducing moderate to severe hot flushes (P <.001). Although there were no significant differences, twice as many women in the 2-mg group discontinued treatment due to adverse events, compared with the placebo group.
                Oral micronized 17beta-E2 showed a dose-response effect for reducing moderate and severe hot flushes in menopausal women. 17beta-E2 1 mg appeared to be the most useful initial dose. This double-blind, randomized, multi-center study compared the efficacy and clinical tolerance of a combined formulation containing 2 mg estradiol (E2) and 0.5 mg trimegestone (TMG) with a standard hormone replacement therapy containing estradiol valerate (E2V) and norgestrel (NG) in the treatment of climacteric symptoms. The study was conducted over 13 cycles, each of 28 days, and involved 634 subjects, of whom 481 completed the study. The primary efficacy variable was the percentage of subjects who showed at least a 50% reduction from baseline in the mean daily number of hot flushes in cycle 3. This was observed in 98.5% of the subjects in the E2 + TMG group and 93.3% of the subjects in the E2V + NG group (95% confidence interval of the difference, -8.6, -1.9). Significant differences in favor of the E2 + TMG combination were observed in the reduction in the mean daily number and severity of hot flushes, and in the percentage of subjects who had hot flushes at baseline but no hot flushes during treatment. There were no significant differences between the treatments in the Kupperman index and in urogenital signs or symptoms. Treatment with the E2 + TMG combination was well tolerated and the incidences of adverse events were similar in the two treatment groups. Breast pain was the main adverse event, possibly related to treatment that resulted in discontinuation. The mean number of bleeding days per cycle was significantly lower with the E2 + TMG combination than with the E2V + NG combination. The incidences of endometrial hyperplasia were low and comparable in both treatment groups. It was concluded that the E2 + TMG combination was either equivalent or superior to the E2V + NG combination in the treatment of hot flushes and other climacteric symptoms, and that its bleeding profile was favorable. To assess the clinically optimal tibolone dose for the relief of climacteric complaints.
                A randomised, double blind, placebo-controlled trial.
                Twenty-eight centres in Norway, The Netherlands, Sweden and Finland.
                Seven hundred and seventy-five healthy postmenopausal women were randomised to tibolone in a daily dose of 0.625, 1.25, 2.5 or 5.0 mg or placebo for 12 weeks.
                At baseline, and after 4, 8 and 12 weeks, hot flushes, sweating, vaginal bleeding and adverse experiences were recorded.
                Change in frequency and intensity of hot flushes and sweating over 12 weeks.
                From week four onwards, 2.5 and 5.0 mg tibolone were significantly more effective than placebo, regarding the frequency of hot flushes and sweating (P < 0.001), whereas the 0.625 mg dose was not significantly different from placebo during the study. The frequency of hot flushes with the 1.25 mg dose was statistically significantly different from placebo, only from week eight onwards. The incidence of dropouts due to insufficient therapeutic effect was much higher in the tibolone 1.25 mg group (9.5%) than in the 2.5 (1.9%) and 5.0 mg (1.3%) groups. A dose-related increase in incidence of vaginal bleeding or spotting was observed (P < 0.0001). Bleeding incidence in the 5.0 mg dose group was about twice as high as in the 2.5 mg dose group. There was no difference in incidence of adverse experiences between the 2.5- and the 1.25 mg dose group.
                A daily dose of 2.5 mg tibolone is the clinically optimal dose for the treatment of climacteric complaints in postmenopausal women. To evaluate the effects of hormone therapy (HT) on cognition and subjective quality of life (QoL) in recently postmenopausal women with cognitive complaints.
                Cognitive Complaints in Early Menopause Trial (COGENT) was a randomized, double-blind, placebo-controlled, multicenter, pilot study of 180 healthy postmenopausal women aged 45 to 55 years, randomly assigned to receive either placebo or conjugated equine estrogen 0.625 mg/medroxyprogesterone acetate 2.5 mg for 4 months. Outcome measures included memory, subjective cognition, QoL, sexuality, and sleep, which were assessed at baseline and month 4.
                The study was terminated before the expected final sample size of 275 due to a decrease in enrollment coinciding with the publication of findings from the Women's Health Initiative. There were no differences between groups on any cognitive or QoL measures, except for an increase in sexual interest and thoughts with HT. Modest negative effects on short- and long-term verbal memory approached significance (p < 0.10). Women with baseline vasomotor symptoms (VMS) showed a decrease in VMS and an improvement in general QoL, but no cognitive benefit vs placebo.
                With the power to detect an effect size of >or=0.45, this study suggests potential modest negative effects on verbal memory that are consistent with previous hormone therapy trials in older women. The objective of this study was to evaluate the efficacy of fluoxetine and black cohosh in the treatment of women with postmenopausal symptoms. A total of 120 healthy women with menopausal symptoms were recruited to this prospective study with a follow-up period of 6 mo. They were randomly assigned to 1 of 2 groups and were treated with fluoxetine or black cohosh. After entry into the study, patients were examined at the first, second, third, and sixth months of the treatment period. The women kept diaries in which they reported the daily number and intensity of hot flushes and night sweats. In addition, at the beginning and end of the third month, they completed questionnaires consisting of a modified Kupperman Index, Beck's Depression Scale, and a RAND-36 Quality-of-Life Questionnaire. Statistically significant differences were noted in the Kupperman Index and Beck's Depression Scale at the end of the third month in both groups compared with baseline values. In the black cohosh group, the Kupperman Index decreased significantly compared with that in the fluoxetine group by the end of the third month. On the other hand, in the fluoxetine group, Beck's Depression Scale decreased significantly compared with that in the black cohosh group. Monthly scores for hot flushes and night sweats decreased significantly in both groups; however, black cohosh reduced monthly scores for hot flushes and night sweats to a greater extent than did fluoxetine. At the end of the sixth month of treatment, black cohosh reduced the hot flush score by 85%, compared with a 62% result for fluoxetine. By the sixth month of the study, 40 women had discontinued the study--20 (33%) in the fluoxetine group and 20 (33%) in the black cohosh group. Compared with fluoxetine, black cohosh is more effective for treating hot flushes and night sweats. On the other hand, fluoxetine is more effective in improvements shown on Beck's Depression Scale. The effect of hormone replacement therapy (HRT) on the quality of life in women with hypertension is still not clear. Thus, the aim of the study was to assess the effect of hormone replacement therapy on quality of life in postmenopausal women with essential hypertension by using a battery of standardized questionnaires.
                The study population consisted of 53 women (mean age 50.9 +/- 6.3 years) with mild and moderate essential hypertension (mean duration 6.4 +/- 6.4 years). The postmenopausal status was defined as the absence of menstrual blood loss during > 6 months and blood estradiol concentration < 50 pg/ml, accompanied by follicle-stimulating hormone (FSH) levels > 21 U/I. Twenty seven women were blindly randomised to transdermal hormone replacement therapy (HRT) and received 17-beta-estradiol and noretisterone acetate, TTS. Twenty six women were randomly selected as controls. The subjects were evaluated at baseline (after 2 weeks' wash-out from hypotensive drug period) and after three months of HRT using self-administered standardized quality of life questionnaires: the Psychological General Well-being Index (PGWB) and the Subjective Symptoms Assessment Profile (SSA-P).
                No differences were found in blood pressure values, heart rate, body mass index and distribution of body fat tissue between women receiving HRT and controls at baseline and after 3 months of follow-up. There were no significant differences in the baseline total PGWB score as well as in its subscale between two groups. Similarly, the frequency and intensity of subjective symptoms assessed by SSA-profile were the same in both groups at baseline. After 3 months, a significant improvement in PGWB total score was observed in women receiving HRT. This effect was due to improvement in anxiety, positive well-being and vitality. Moreover, emotional distress, symptoms of flushing, sweating and trembling hands also diminished and sexual capacity improved in women treated with HRT.
                A three-month hormone replacement therapy in hypertensive postmenopausal women slightly improves the general well-being, seems to decrease emotional tension, increase sexual capacity and markedly relieves some vasomotor symptoms. A randomised, double-blind, cross-over study into the effect of graded sequential mestranol and norethisterone on climacteric symptoms was performed. The study group consisted of 23 post-menopausal women who had previously undergone hysterectomy. Active therapy resulted in a significant reduction in hot flushes and night sweats. There was a slight improvement in insomnia, lack of energy and confidence but the other symptoms were not significantly altered. A small placebo effect was noted but this was only significant 1 mth after active treatment had been discontinued in the group of women receiving placebo second. Active treatment also resulted in a significant reduction in serum sodium, calcium, albumin, alkaline phosphatase and cholesterol, and increase in serum triglycerides, but no alteration in the other biochemical parameters, weight or blood pressure. This study compared two continuous-combined hormone replacement therapy (HRT) formulations, 1 mg estradiol (E2)/0.25 mg norethisterone acetate (NETA) and 1 mg E2/0.5 mg NETA, with placebo, with regard to the efficacy for vasomotor symptom relief in menopausal women.
                A total of 119 women aged 45-61 years with moderate and severe hot flushes and with amenorrhea for at least 3 months were randomly assigned to 12 weeks' treatment with 1 mg E2/0.25 mg NETA, 1 mg E2/0.5 mg NETA or placebo. The number and severity of hot flushes, as well as any vaginal bleeding, were recorded on a daily basis. The Kupperman Menopausal Index, Greene Climacteric Scale and visual analog scales for various symptoms were assessed before and after treatment. Subpopulation analysis according to menopausal status was performed.
                Both combinations significantly reduced the number and severity of hot flushes, compared to placebo. A reduction of approximately 85% in vasomotor symptomatology occurred in the two combination groups by week 4 of treatment, and this was further diminished throughout the study to approximately 97% reduction by week 12. At the end of the study, 85% of the women receiving 1 mg E2/0.5 mg NETA and 71% of the women receiving 1 mg E2/0.25 mg NETA were considered to the clinically adequate responders to treatment. Both combinations were associated with significant improvements, compared to placebo, in visual analog scales for overall general condition, Kupperman Menopausal Index, and Greene Climacteric vasomotor and psychological subscales. While both combinations resulted in similar bleeding profiles in postmenopausal women, the combination of 1 mg E2/0.5 mg NETA resulted in the lowest incidence of bleeding in late perimenopausal women.
                The combinations of 1 mg E2/0.25 mg NETA and 1 mg E2/0.5 mg NETA rapidly relieve vasomotor symptoms and are efficacious in the majority of menopausal women, including those with severe hot flushes. A double blind crossover study was planned in order to compare the effects of oestrogen, progestogen and placebo on hot flushes. The 49 women studied had previously undergone hysterectomy and bilateral oophorectomy. The drug regimen consisted of three months each of ethinyl oestradiol 50 microgram/day, d norgestrel 250 microgram/day, a combination of these two substance ("Nordiol") and a placebo. The predominant reason for requesting a change of medication was intolerable hot flushes associated with placebo use. All hormonal preparations were found to be significantly more effective than placebo in reducing hot flush frequency and intensity. Oestrogen containing medications were more effective than the progestogen (norgestrel). 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 examine the efficacy of a hop extract enriched in 8-prenylnaringenin (8-PN, the phytoestrogen in hops, Humulus lupulus L.) on relief of menopausal discomforts.
                A prospective, randomized, double-blind, placebo-controlled study over 12 weeks with 67 menopausal women, who were administered a hop extract standardized on 8-PN (100 or 250 microg). The responses were determined by means of a modified Kupperman index (KI) and a patients' questionnaire.
                All groups, including placebo, showed a significant reduction of the KI both after 6 weeks and after 12 weeks. The hop extract at 100 microg 8-PN was significantly superior to placebo after 6 weeks (P=0.023) but not after 12 weeks (P=0.086). No dose-response relationship could be established, as the higher dose (250 microg) was less active than the lower dose both after 6 weeks and after 12 weeks. Still, a trend for a more rapid decrease of KI was noticed for both active groups as compared to placebo. In particular, the decrease in hot flush score (isolated from the KI) was found significant for both treatment groups after 6 weeks (P<0.01) with respect to placebo. Results of the patients' questionnaire were consistent with those of the KI, with the most pronounced effects being observed for the 100-microg treatment.
                Daily intake of a hop extract, standardized on 8-PN as a potent phytoestrogen, exerted favorable effects on vasomotor symptoms and other menopausal discomforts. Hop-derived prenylated flavonoids may provide an attractive addition to the alternative treatments available for relief of hot flushes and other menopausal discomforts. This study was designed to assess endometrial histology in postmenopausal women not taking hormone replacement therapy, to evaluate side effects and efficacy of phytoestrogens in treating menopause-associated symptoms, and to determine whether 6 months of phytoestrogen supplementation altered endometrial histology.
                We performed a prospective, double-blinded, randomized, placebo-controlled trial comparing the effects of 6 months of dietary phytoestrogen supplementation versus placebo in postmenopausal women. Baseline endometrial biopsies were performed and, if adequate, nonhyperplastic, noncancerous, and nonovulatory, subjects were randomly assigned to receive daily placebo or soy cereal supplementation for 6 months. Study subjects completed baseline and weekly dietary, symptom, and side effect logs. Repeat endometrial biopsies were obtained at 6 months.
                Subjects were recruited from January 1998 through June 2000. Twenty-seven subjects were randomized, and 19 completed the study. One (3.7%) baseline endometrial sample was weakly proliferative. All other baseline and final biopsies were consistent with atrophic, inactive endometrium. The maximum risk of endometrial stimulation with phytoestrogens is 35%. Hot flushes, night sweats, and vaginal dryness were significantly less severe at the final week of the study compared with baseline in the placebo group. Insomnia was more common in the treated group. There were no other statistically significant differences in symptoms or side effects.
                Phytoestrogens did not cause stimulation of the endometrium. Insomnia was more frequent over the 6-month study in the soy group, whereas hot flushes, night sweats, and vaginal dryness improved from baseline in the placebo group but not in the soy group. The aim of this study was to determine whether or not continuous combined HRT used with GnRH-a for the treatment of endometriosis can prevent hypoestrogenic side effects associated with GnRH-a.
                Forty premenopausal women with laparoscopically proven endometriosis entered the study. The patients were randomized into two groups. Group I (n = 19) received 3.75 mg i.m. leuprolide acetate (LA) every 4 weeks for 24 weeks. Group II (n = 21) received 3.7 mg LA combined with 1.25 mg oral conjugated equine estrogen (CEE) and 5 mg oral medroxyprogesterone acetate (MA).
                Total revised AFS score as well as total pelvic pain scores decreased significantly (P < .001) in both groups. However, a statistically significant difference of hot flushes and sweating was reported by women receiving LA + HRT as compared to those treated with LA alone (P < .001). Furthermore, the bone loss at the lumbar spine was 4.2% in group I compared to 0.9% in group II at the end of the study.
                This study suggests that 1.25 mg CEE + 5 mg MA is effective in preventing hypoestrogenic side effects caused by GnRH-a, while the treatment of endometriosis is not impaired. To investigate the effect of an oral soy isoflavone extract (Phytosoya) on hot flushes in menopausal women.
                The study was conducted on outpatients according to a multicenter, randomized, double-blind, placebo-controlled, parallel-group design. A total of 75 patients in natural or surgical menopause suffering from at least seven hot flushes per day were randomized to receive during 4 months either soy isoflavone extract (total of 70 mg genistin and daidzin per day) or placebo.
                There is evidence to suggest that 16 weeks of treatment with soy extract can help reduce the mean number of hot flushes per 24 hours in menopausal women. Withdrawals during this trial made it difficult to obtain an unbiased estimate of the true treatment effect, but numerous sensitivity analyses lend support to the suggestion that taking soy extract can be beneficial in the treatment of hot flushes. In particular, women taking soy extract had a 38% reduction in the mean number of hot flushes by week 4 and a 51% reduction by week 8. By the end of week 16, patients taking soy extract had a 61% reduction in their daily hot flushes versus a 21% reduction obtained with the placebo. "Responders" (defined as patients whose hot flushes were reduced by at least 50% at the end of treatment period) were 65.8% in the soy extract group and 34.2% in the placebo group ( < 0.005).
                Soy isoflavone extract may help to reduce the frequency of hot flushes in climacteric women and provides an attractive addition to the choices available for relief of hot flushes.
Oral HT is highly effective in alleviating hot flushes and night sweats. Therapies purported to reduce such symptoms must be assessed in blinded trials against a placebo or a validated therapy because of the large placebo effect seen in well conducted randomised controlled trials, and also because during menopause symptoms may fluctuate and after menopause symptoms often decline. Withdrawals due to side-effects were only marginally increased in the HT groups despite the inability to tailor HT in these fixed dose trials. Comparisons of hormonal doses, product types or regimens require analysis of trials with these specific "within study" comparisons.