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Objective: Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS., Methods: We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS., Results: Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment., Conclusion: Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS., Competing Interests: Financial disclosure/conflicts of interest: S.L., S.I., M.C., R.B., H.R., K.G., U.J., S.K., B.V.K., J.S., and M.S.H. declare no disclosures/conflicts of interest., (Copyright © 2021 by The North American Menopause Society.)

Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17β-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18-54%), ethinyl estradiol/NETA (31-61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9-27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

Objective: To assess effects of desvenlafaxine (administered as desvenlafaxine succinate) on secondary outcomes of mood, climacteric symptoms, and treatment satisfaction in postmenopausal women with moderate to severe menopausal vasomotor symptoms (VMS)., Methods: A 12-week, multicenter, double-blind, placebo-controlled trial was conducted in postmenopausal women with ≥ 50 moderate to severe hot flushes per week. Participants were randomly assigned to desvenlafaxine 100 mg/day, desvenlafaxine 150 mg/day, or placebo. Secondary outcome efficacy variables included Profile of Mood States (POMS), Greene Climacteric Scale (GCS), and Menopausal Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) scores. Change from baseline in POMS total mood disturbance (TMD) score and subdomain scores were evaluated using analysis of covariance, adjusting for treatment and study site as factors and baseline score. GCS total and subdomain scores were analyzed similarly. Treatment satisfaction was analyzed using the row mean score test., Results: A total of 458 women were enrolled. At week 12, desvenlafaxine 100 mg/day significantly improved POMS TMD scores (p <0.001) and four of six POMS subdomains compared with placebo (all p ≤ 0.005). Women taking desvenlafaxine 100 mg/day experienced significantly greater improvement in GCS total scores (p <0.001) and five of six subdomains (all p ≤ 0.029) compared with placebo. Treatment with desvenlafaxine 100 mg/day resulted in significantly greater treatment satisfaction overall and in six of seven additional MS-TSQ items (all p ≤0.042). Desvenlafaxine 150-mg/day results were similar., Conclusions: Desvenlafaxine treatment improved mood and climacteric symptoms in postmenopausal women with moderate to severe VMS compared with placebo, and more women were satisfied with desvenlafaxine treatment than with placebo.

Objective: An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women., Materials and Methods: Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript., Results: Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation., Conclusions: Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

Objective: To analyze the effects of two continuous combined hormone replacement regimens on bleeding profiles in postmenopausal women, based on progestin dose and time since the patient's last spontaneous menstrual period., Methods: A randomized, double-masked, multicenter trial was conducted in 1724 women recruited from 99 sites. Six hundred seventy-eight women received a continuous regimen of oral conjugated equine estrogens (CEE), 0.625 mg/day, combined with medroxyprogesterone acetate (MPA), 2.5 or 5.0 mg/day, for 1 year., Results: After 1 year, no bleeding was reported by over 89% of women. More women in the 5.0 mg/day MPA group than in the 2.5 mg/day MPA group reported no bleeding (93.8% versus 89.5%; P<.089). Of those women who had had their last menstrual period 3 years ago or less, a significantly higher percentage in the 5.0 mg/day MPA group (72.4%) did not experience bleeding after three cycles compared with the 2.5 mg group (59.0%; P<.001). Although the percentage of patients without bleeding was also higher in the 5.0 mg/day MPA group after six cycles and 1 year, the differences between groups were not statistically significant. Of the women who had their last menstrual period more than 3 years ago, 94.7% of those in the 5.0 mg/day MPA group and 90.7% of those in the 2.5 mg/day MPA group reported no bleeding at 1 year., Conclusion: A continuous combined regimen of CEE plus 5.0 mg MPA may be more suitable for women closer to the onset of menopause or for women starting therapy who are unwilling to tolerate irregular bleeding. The improved bleeding profile with CEE and 5.0 mg/day MPA is likely to enhance compliance with hormone replacement therapy.

Objective: To determine whether a continuous estradiol-norethindrone acetate transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone., Methods: Six hundred twenty-five postmenopausal women were assigned randomly to one of four treatments, transdermal E2 50 microg/day, or transdermal E2-norethindrone acetate with 50 microg E2 and 140, 250, or 400 microg/day of norethindrone acetate. Follow-up visits to collect information on safety and efficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatment. Endometrial biopsy for histologic evaluation was done at baseline and upon exit from the study (completion or withdrawal). Endometrial histology was evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue using predetermined criteria., Results: Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 alone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) in the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectively (P < .001). Uterine bleeding was less frequent in the E2-norethindrone acetate 50-140 group than other treatments. The mean number of hot flushes per day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone., Conclusion: Continuous transdermal delivery of E2 combined with norethindrone acetate effectively prevented endometrial hyperplasia in healthy postmenopausal women. Continuous combined transdermal delivery systems provide increased dosing flexibility and might improve convenience and compliance with hormone replacement therapy.

The present study was designed to evaluate the effect of different serum concentrations of estradiol-17 beta (E2) on pituitary luteinizing hormone (LH) release in postmenopausal women. Serum E2 levels were evaluated in healthy postmenopausal women while they wore two, four, and six transdermal E2 delivery systems. The mean serum E2 levels at 48 hours after application of the devices were 185.5, 338.9, and 520.5 pg/mL, respectively, which were significantly different from each other. Serum E2 levels were stable throughout the first 48 hours of patch application but declined by a mean of 54% between 48 and 72 hours. Pituitary LH surges were induced with all three serum concentrations of E2 but were present more often with the higher serum values. There were no significant differences between the mean interval of device utilization and initiation, height, or duration of the induced pituitary LH surge at any of the three serum E2 concentrations studied.

Menopause is merely a clinically discernible clue symbolic of the multitude of changes preceding or following the cessation of menses by many years. Because of the time span involved, separating changes observed in the menopausal transition from other age-related maturational events presents serious methodologic problems. Of the host of psychologic and psychosomatic symptoms, only hot flushes and associated sweats occur more frequently in this epoch, while an interplay between hormonal and age-related maturational events presents serious methodologic problems. Of the host of psychologic and psychosomatic symptoms, only hot flushes and associated sweats occur more frequently in this epoch, while an interplay between hormonal and age-related effects is assumed in atrophic changes involving the genitourinary organs. The relation between menopause and osteoporosis is suggestive but by no means proven, as is the risk for cardiovascular disease. Empiric evidence points to the usefullness of estrogen for the management of vasomotor instability, the symptoms associated with atrophy of the genitourinary tract, and in the prophylaxis of osteoporosis, but not in the treatment of anxiety, depression, and other psychiatric disorders.

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Objective To examine the effect of intravaginal dehydroepiandrosterone (DHEA) on pain at sexual activity (dyspareunia) identified as the most bothersome symptom of vaginal atrophy in postmenopausal women at both screening and day 1. Methods This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of prasterone (DHEA) applied locally in the vagina on the severity of dyspareunia in 114 postmenopausal women who had identified dyspareunia as their most bothersome symptom of vaginal atrophy, while meeting the criteria for superficial cells ≤≤ 5%% and pH > 5.0 at both screening and day 1. Results At the standard duration of 12 weeks of treatment, increasing doses of 0.25%%, 0.5%% and 1.0%% DHEA decreased the percentage of parabasal cells by 48.6 ±± 6.78%%, 42.4 ±± 7.36%% and 54.9 ±± 6.60%% ( p < 0.0001 vs. placebo for all) with no change with placebo ( p == 0.769). The effects on superficial cells and pH were also highly significant compared to placebo at all DHEA doses. The severity score of pain at sexual activity decreased by 0.5, 1.4, 1.6 and 1.4 units in the placebo and 0.25%%, 0.5%% and 1.0%% DHEA groups, respectively, with the p value of differences from placebo ranging from 0.0017 to < 0.0001. Conclusions Intravaginal DHEA, through local estrogen and androgen formation, causes a rapid and highly efficient effect on pain at sexual activity without systemic exposure of the other tissues, thus avoiding the recently reported systemic effects of estrogens. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effect of two ultra-low-dose hormone treatments containing estradiol (E2) 0.5 mg and norethisterone acetate (NETA) 0.1 or 0.25 mg on the endometrium and bleeding. Methods A prospective, randomized, placebo-controlled trial of 6 months. Local Ethics Committee approval and informed consent were obtained prior to initiation and enrolment. Out of 577 postmenopausal women randomized, 575 took E2/NETA 0.1 (n = 194), or E2/NETA 0.25 (n = 181) or placebo (n = 200). Endometrial bleeding was monitored by daily diary cards and endometrial thickness by transvaginal ultrasound at baseline and on completion. An endometrial biopsy was obtained when indicated clinically. Results In months 1-6, the amenorrhea rates with E2/NETA 0.1 were 89%, 89%, 86%, 85%, 89% and 89%, respectively and the no-bleeding rates were correspondingly high: 95%, 94%, 93%, 90%, 95% and 95%. The amenorrhea and spotting-only rates were similar with both ultra-low-dose combinations. The withdrawal rates due to bleeding were very low and the same in all three treatment arms (n = 1; 1%). There was a slight increase in the mean endometrial thickness in all three groups, which remained less than 5 mm. Conclusions The ultra-low-dose combination of E2/NETA 0.1 or E2/NETA 0.25 resulted in a high incidence of amenorrhea and no bleeding in postmenopausal women, and a corresponding high level of compliance. Overall, there was no significant change in mean endometrial thickness during 6 months of active treatment or placebo. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy of two ultra-low-dose 17β-estradiol plus norethisterone acetate (NETA) treatment regimens for relieving menopausal symptoms. Design A total of 577 postmenopausal women were enrolled, in three treatment groups in a double-blind, randomized, placebo-controlled study of 0.5 mg 17β-estradiol + 0.1 mg NETA or 0.5 mg 17β-estradiol + 0.25 mg NETA or placebo. Participants returned at weeks 4, 8, 12 and 24 for climacteric complaint evaluation based on a daily diary vasomotor symptom record. Patients were assessed by the Greene Climacteric Scale and urogenital symptoms were also evaluated. Results Treatment with ultra-low-dose 0.5 mg 17β-estradiol + 0.1 mg NETA (0.1 Group) or 0.5 mg 17β-estradiol + 0.25 mg NETA (0.25 Group) effectively reduced the severity and number of hot flushes within the initial weeks of therapy. Compared to placebo, a rapid, statistically significant decrease in the frequency and severity of hot flushes was achieved by week 3, followed by further improvement which continued throughout the study. There were no statistically significant differences between the active treatment arms. Conclusions The data show that both ultra-low-dose regimens are effective in reducing the severity and number of hot flushes compared to placebo, with good safety profiles. [ABSTRACT FROM AUTHOR]

The efficacy of estrogen with or without a progestogen as hormone replacement therapy (HRT) for menopausal symptoms is well-established. Recent large-scale randomized studies with combined estrogen/progestogen therapy (EPT) have raised a number of safety issues, specifically the potential risk for coronary heart disease. Subsequent analyses and other studies have indicated that HRT may be cardioprotective in younger postmenopausal women. A new continuous EPT combines natural 17β-estradiol (E2) 1 mg with the novel progestin, drospirenone (DRSP) either 0.5 or 2 mg. DRSP has a physiological profile closer to that of natural progesterone than any other synthetic progestin. This paper reviews recent clinical trial data demonstrating the efficacy and safety of combined DRSP/E2 therapy as EPT in postmenopausal women. DRSP/E2 provides symptomatic relief of vasomotor symptoms and improvement in genitourinary atrophy. DRSP/E2 protects against endometrial hyperplasia and reduces the risk of osteoporosis. Combined DRSP/E2 therapy has a favorable impact on cholesterol and triglyceride levels, and decreases blood pressure in women with elevated blood pressure. The favorable efficacy and safety profile of DRSP/E2, and potential for long-term health benefits, represents a new option for the effective management of menopause and its clinical sequelae. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms.Study Design: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch.Results: The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo (P <.05) from week 2 onward in the Esclim 50 and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity was also reduced. Estrogen-related adverse events, particularly metrorrhagia and endometrial hyperplasia, were less frequent in the Esclim 25 group than in the higher-dosage groups.Conclusion: All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio. [ABSTRACT FROM AUTHOR]