Climacteric symptoms after oral and percutaneous hormone replacement therapy. Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-related outcome measures. Is oestrogen therapy effective in the treatment of menopausal depression? Graded sequential therapy in the menopause: a double-blind study. Replacement estrogen therapy for menopausal vasomotor flushes. Comparison of quinestrol and conjugated estrogens. Initial 17beta-estradiol dose for treating vasomotor symptoms. Menopausal hot flushes: a double blind comparison of placebo, ethinyl oestradiol and norgestrel. Do combinations of 1 mg estradiol and low doses of NETA effectively control menopausal symptoms? Dose-response and withdrawal effects on climacteric symptoms after hormonal replacement therapy. A placebo-controlled therapeutic trial. Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations. The FemHRT Study Investigators. Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol. A randomised, double-blind, cross-over study into the effect of sequential mestranol and norethisterone on climacteric symptoms and biochemical parameters. Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Quality of life during sequential hormone replacement therapy -- a placebo-controlled study. A randomized, double-blind, placebo-controlled, crossover study on the effect of oral oestradiol on acute menopausal symptoms. [Double-blind method of the effect of menopause symptoms, lipid profile, and endometrial thickness of continuous therapy with estradiol valerate and medroxyprogesterone acetate].
One hundred and ten (110) healthy early post-menopausal women with mild subjective vasomotor symptoms (mean Kupperman index score 11) participated in a long-term, double-blind, placebo-controlled therapeutic trial. The effects of 2 hormone regimens were evaluated. Group I received percutaneous oestrogen therapy for 2 yr, opposed by oral micronized progesterone (200 mg) during the second year, while Group II received oral 17 beta-oestradiol valerate together with cyproterone acetate (CPA). The serum oestrogen concentrations differed markedly in the 2 treatment groups. In Group I the serum/oestrone/oestradiol ratio was 1 (comparable to the pre-menopausal value), but in group II the ratio was greater than 5. Despite the difference in the serum oestradiol and oestrone concentrations, the mean symptom scores were rapidly and similarly reduced in both treatment groups (P less than 0.001). They remained low throughout the study and were not significantly different from pre-menopausal values. To compare combined and sequential hormonal replacement therapies to each other as well as placebo in patients suffering from the postmenopausal syndrome. Clinical outcomes were measured concerning both the specific postmenopausal symptoms (using the Kupperman scale) and health or well-being dimensions (using subscales of the General Health Questionnaire and specific depression and anxiety scales).
                A prospective randomized double-blind study over 12 months of 105 normal early postmenopausal women in the setting of a general hospital.
                Both hormone replacement therapies were superior to placebo on the Kupperman scale (sweating, hot flushing, myalgia and vertigo). The psychic symptoms on the Kupperman scale were psychometrically invalid. However, psychic symptoms as measured by the Beck Depression Inventory and the General Health Questionnaire were significantly improved by the hormonal replacement therapies. No differences were observed when combined therapy was compared to sequential therapy.
                One-year treatment with hormonal replacement therapy is superior to placebo in measuring the somatic and psychic symptoms of the menopausal syndrome. No differences were found in this respect between combined and sequential replacement therapy. Fifty-five depressed menopausal patients took part in a randomized double-blind cross-over trial using ;Harmogen' (piperazine oestrone sulphate) and placebo. The Beck depression inventory, hot flush counts, and patients' subjective assessment of well-being were used to assess clinical status. Hormonal, biochemical and coagulation profiles were carried out. Hot flushes improved significantly on oestrogen compared with placebo. Depression scores and well-being showed significant and equal improvement on oestrogen and placebo. Significant improvement in flushes in patients on placebo was observed in the first half of the trial but did not occur in the second half, in patients who had previously taken oestrogen. No significant changes occurred in biochemistry. Coagulation tests showed acceleration of the prothrombin time in patients taking ;Harmogen' compared with those on placebo. Piperazine oestrone sulphate is a relatively weak but safe oestrogen preparation, effective in treatment of vasomotor symptoms but no more effective than placebo in the treatment of depression. nan Quinestrol, conjugated estrogens, or placebo was used to treat 156 patients with pernicious vasomotor instability in a prospective, double-blind, randomized, multiinvestigator trial. Vasomotor flushes were severe in approximately 80% of the cases and moderate in 20%, relatively equally distributed among the various drug groups. Both qinestrol and conjugated estrogens were significantly more effective than placebo in relieving vasomotor symptoms (by chi2 analysis, P less than or equal to 0.05). Greatest improvement was seen in the group receiving the higher once weekly quinestrol dosage of 0.2 mg followed by the group on the lower quinestrol dosage of 0.1 mg once weekly and the group on conjugated estrogens, 1.25 mg daily for 21 days on and 7 days off. No significant difference in relief of vasomotor flushes was shown between the active drug groups. No drug-related complications or side reactions of significance occurred. The results indicate that once weekly quinestrol is effective in relieving the vasomotor symptoms of the menopause. Either of two once weekly quinestrol regimens is an effective as conjugated estrogens given daily in a cyclic manner and therefore offers an alternative form of exogenous estrogen therapy. 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. 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). 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. 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 determine the effect of continuous combined treatment with norethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spotting, or bleeding and/or spotting in postmenopausal women.
                Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 microg ethinyl E2, 0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting.
                In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 microg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 microg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1.
                Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option. To assess the effects of oral E2 replacement therapy combined with nomegestrol acetate, a 19-norprogesterone derivative, on cardiovascular risk factors.
                A double-blind randomized prospective study comparing the effect of a placebo and two oral E2-nomegestrol acetate combinations (1 mg-2.5 mg and 1.5 mg-3.75 mg) over a three-cycle trial.
                Department of Internal Medicine and Nutrition, Hotel-Dieu, Paris, France.
                Fifty-seven nonhysterectomized women with natural menopause.
                Blood pressure, renin substrate, glucose, total cholesterol, high-density and low-density lipoprotein cholesterol, triglycerides, apoproteins A1 and B, lipoprotein(a), antithrombin III, fibrinogen, plasminogen, prothrombin fragment 1 + 2, protein C, and total and free protein S.
                Both treatments significantly reduced menopausal complaints, total cholesterol, low-density lipoprotein cholesterol and lipoprotein(a). Treatment with the 1.5 mg-3.75 mg combination resulted in a significant increase in apolipoprotein A1. No significant change were observed in other parameters.
                Sequentially combined with oral E2 in hormone replacement therapy, nomegestrol acetate had favorable effects on plasma lipids and lipoproteins. This nonandrogenic progestin decreased lipoprotein(a) levels as observed previously with medroxyprogesterone acetate combined with conjugated equine estrogens. 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. In a double-blind study on the value of equine ("natural") oestrogens 30 patients presenting with menopausal symptoms in a group practice were monitored for possible adverse effects on blood clotting, weight, and blood pressure. The women were randomly allocated to two groups and given either three months' hormone treatment followed by three months' placebo or vice versa. An appreciable amelioration of all symptoms on placebo made it difficult to asses the genuine value of oestrogen treatment during the period of study. Both groups made a dramatic clinical improvement during the first three months. Nevertheless, the symptoms of the 15 women who received oestrogen first returned after the cross-over to placebo without any suggestion of a placebo response. In contrast, the other group who took placebo first did not deteriorate after changing to oestrogen. The menopausal index and the karyopyknotic index were not reliable guides to the need for oestrogen treatment. Hot flushes, however, were proportionately reduced on oestrogen and they seemed to be more readily eliminated in individual cases by oestrogen. The results of blood clotting studies indicated that natural oestrogen administration raised the levels of the extrinsic clotting factors VII and X and accelerated the prothrombin time. The findings were similar to those observed after three months synthetic oestrogen administration with oral contraception. Long-term studies and epidemiological surveys of the clinical incidence of thrombotic and other sequelae are needed before large-scale oestrogen replacement treatment can be recommended. 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. OBJECTIVE -- The purpose of the study was to determine the efficacy of sequential 17 beta-estradiol and norethindrone acetate (Trisequens) in the relief of vasomotor symptoms by comparing the quality of life data from questionnaires, number and severity of symptoms, and the dropout rate versus placebo treatment. STUDY DESIGN -- Women 40 to 60 years old, who spontaneously complained of menopausal symptoms, were randomly allocated to four consecutive cycles with Trisequens (n = 40) or placebo (n = 42). Analysis of variance and two-tailed tests (P < .05) for all comparisons were used. RESULTS -- The mean number of pretreatment vasomotor symptoms per day was 7 (1.3 severe) for Trisequens and 6 (1.8 severe) for placebo, whereas posttreatment a reduction to 1.3 (0.1 severe) versus 4.2 (1.8 severe), respectively, was observed. Quality of life scores, utilizing the Kupperman Scale, 3-Factor Green Index, and Beck Depression Inventory all produced statistically significant differences (P = 0.0015, 0.0037, 0.0026, 0.0003, 0.0242, respectively). The dropout rate difference between groups was significant (P = 0.028): 12 from the Trisequens group and 23 from the placebo group. CONCLUSION -- Trisequens significantly improves vasomotor symptoms. Quality of life rating scales provide additional data to support the utility of sequential estrogen/progestin treatment for menopause therapy. Acute menopausal symptoms occur less frequently in Asian than in Caucasian women. Oestrogen replacement therapy has been shown to be effective in controlling acute symptoms in Caucasians, but the effect of oestrogens is not well documented in Asian women. A randomized, double-blind, placebo-controlled, crossover study of the effect of oral oestradiol on the incidence of acute menopausal symptoms was conducted in 83 Hong Kong Chinese women who had experienced a surgical menopause. Although there was a significant increase in the oestradiol concentration with treatment compared with placebo (P < 0.001), there were no significant differences in the reporting of symptoms between the treatment and placebo groups. There is no obvious explanation for this apparent lack of effect of oestrogen on acute menopausal symptoms in Chinese women. Whilst it may be related to the generally low incidence of symptoms or to a higher dietary intake of phytoestrogens in Chinese women, further studies are necessary to explain these findings. Continuous combined therapy (CCT) using estrogens and progestagens has appeared as an alternative to avoid vaginal bleeding, which is characteristic of sequential hormone therapy, and the main reason for the stopping treatment. Irregular vaginal bleeding can occur at the beginning of treatment, but it has been observed that after a few months patients are in amenorrhea. Fifty postmenopausal women were studied in order to evaluate the clinical outcome. Half of them were treated with a product containing 2 mg estradiol valerate and 2.5 mg medroxiprogesterone acetate, while the other half received a placebo. Menopause symptomatology was recorded as described by Blatt-Kupperman, depression was evaluated with the use of Hamilton's test, lipid profile by enzymatic methods and endometrial thickness by transvaginal ultrasonography. Patients were evaluated at the beginning, third and sixth month of the study, following a double blind methodology. Symptomatology diminished both in patients under CCT and using placebo, although improvement was significantly greater in patient under CCT. Thus in the hormone treated group the Blatt-Kupperman score fell from 12.1 to 6.4 and 3.2 in the third and sixth month respectively, while in the group receiving placebo the score fell from 11.5 to 6.3 in the third month and raised to 7.4 in the sixth month. Hamilton's test showed a significant improvement of depression only in patients under hormone therapy. Nineteen out of twenty five women using CCT had vaginal bleeding, showing no changes in the endometrial thickness during the study. Finally, HDL-cholesterol was raised in 14.5% while LDL-cholesterol was lowered in 18.7% (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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.