A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.

OBJECTIVE: A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. METHODS: In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.5, 5, 10, or 15 mg or placebo once daily for 12 weeks. Outcomes were the vaginal maturation index and maturation value, genitourinary syndrome of menopause score, and the Menopause Rating Scale to assess health-related quality of life. We focused on E4 15 mg, the dose studied in ongoing phase 3 trials, and tested its effect versus placebo at 12 weeks using analysis of covariance. RESULTS: Least square (LS) mean percentages of parabasal and intermediate cells decreased, whereas superficial cells increased across E4 doses; for E4 15 mg, the respective changes were -10.81% ( P = 0.0017), -20.96% ( P = 0.0037), and +34.17% ( P < 0.0001). E4 15 mg decreased LS mean intensity score for vaginal dryness and dyspareunia (-0.40, P = 0.03, and -0.47, P = 0.0006, respectively); symptom reporting decreased by 41% and 50%, respectively, and shifted to milder intensity categories. The overall Menopause Rating Scale score decreased with E4 15 mg (LS mean, -3.1; P = 0.069) and across doses was associated with a decreasing frequency and severity of VMS ( r = 0.34 and r = 0.31, P < 0.001). CONCLUSIONS: E4 demonstrated estrogenic effects in the vagina and decreased signs of atrophy. E4 15 mg is a promising treatment option also for important menopausal symptoms other than VMS.

Estetrol Is Safe and Well Tolerated during Treatment of Hospitalized Men and Women with Moderate COVID-19 in a Randomized, Double-Blind Study.

Epidemiological data suggest that the severe acute respiratory syndrome coronavirus 2 infection rate is higher in women than in men, but the death rate is lower, while women (>50 years) on menopausal hormone therapy (MHT) have a higher survival rate than those not on MHT. Classical oral estrogen enhances the synthesis of coagulation markers and may increase the risk of thromboembolic events that are common in coronavirus disease 2019 (COVID-19). The favorable hemostatic profile of estetrol (E4) might be suitable for use in women who are receiving estrogen treatment and contract COVID-19. A multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT04801836) investigated the efficacy, safety, and tolerability of E4 versus placebo in hospitalized patients with moderate COVID-19. Eligible postmenopausal women and men (aged ≥ 18 years old) were randomized to E4 15 mg or placebo, once daily for 21 days, in addition to the standard of care (SoC). The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC.

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety.

OBJECTIVE: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15 mg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. RESULTS: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15 mg E4 versus placebo at both W4 (-66% vs -49%, P = 0.032) and W12 (-82% vs -65%, P = 0.022). The decrease in severity of HFs was significantly more pronounced for 15 mg E4 than for placebo at both W4 (-0.59 vs -0.33, P = 0.049) and W12 (-1.04 vs -0.66, P = 0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. CONCLUSIONS: Estetrol 15 mg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. : Video Summary:http://links.lww.com/MENO/A591.

Video Summary:http://links.lww.com/MENO/A591.

Adaptation and translation of the menopause-specific Utian Quality of Life (UQOL) scale to Yoruba language using middle-aged women attending a clinic in Nigeria.

OBJECTIVE: The main objective of the study is to translate and adapt the menopause-specific Utian Quality of Life (UQOL) scale to Yoruba, an indigenous Nigerian language, using middle-aged women attending a Family Medicine clinic in Nigeria. METHODS: A total of 322 middle-aged Nigerian women at various menopausal stages were recruited for the study. Their menopausal status was categorized using the Monash Women's Health Program Menopausal Staging Algorithm into pre-, peri-, and postmenopausal groups. The UQOL Yoruba version (YUQOL), Menopause Rating Scale (MRS), and a semistructured sociodemographic questionnaire were interviewer-administered to the women. The collected data were analyzed using IBM SPSS version 21 software. RESULTS: The overall scale and the four subscales of YUQOL all had acceptable internal consistency scores; they also demonstrated good construct and criterion validities, except the YUQOL sexual subscale had poor convergent validity (average variance extracted = 0.23). CONCLUSIONS: This study has validated the YUQOL as a psychometrically sound research instrument for measuring menopause-specific QOL among women undergoing menopausal transition. Its sexual subscale would, however, need to be further tested, preferably in sexually active menopausal women to fully confirm its true psychometric property.

Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society.

OBJECTIVE: : To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in March 2007 regarding its recommendations for menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond. DESIGN: : An Advisory Panel of clinicians and researchers expert in the field of women's health was enlisted to review the March 2007 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. The document was provided to other interested organizations to seek their endorsement. RESULTS: : Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Conclusions that vary from the 2007 position statement are highlighted. Addenda include a discussion of risk concepts, a new component not included in the 2007 paper, and a recommended list of areas for future HT research. A suggested reading list of key references is also provided. CONCLUSIONS: : Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women.

NAMS-gallup survey on women's knowledge, information sources, and attitudes to menopause and hormone replacement therapy.

The North American Menopause Society (NAMS) sponsored a Gallup Organization survey of 833 women aged 45-60 to determine attitudes and experience with menopause and various forms of hormone replacement therapy (HRT). The results of this survey are presented herein.

The Utian Quality of Life (UQOL) Scale: development and validation of an instrument to quantify quality of life through and beyond menopause.

OBJECTIVE: Quality of life (QOL) is an outcome variable requiring measurement in clinical care or pivotal regulatory trial research. Current menopause QOL measures are mostly life phase or disease symptom inventories or scores. Believing that QOL should refer more to "sense of well-being," we have developed the Utian QOL scale (UQOL) that is strongly based on perception of sense of well-being as distinct from menopausal symptoms. DESIGN: A pool of items sampling various aspects of well-being was developed. Peri- and postmenopausal women (n = 327) responded to the items, and their responses were subjected to a factor analysis. Four factors emerged, each representing a QOL domain. The resulting 23-item instrument was validated in a geographically and socioeconomically diverse sample of peri- and postmenopausal women using the Short Form-36, an established, frequently used QOL inventory. QOL domains were subjected to confirmatory factor analyses, formal item analysis was completed, and the measure was assessed for reliability and validity, including a second sample of women (n = 270). RESULTS: Women (n = 597; mean age, 52.9 years) from 12 communities across the United States completed the measure. The UQOL seems to reflect four components of QOL: occupational QOL, health QOL, emotional QOL, and sexual QOL. The questionnaire and scoring system are presented. CONCLUSION: We are reporting on the process of validating an instrument for quantifying sense of well-being in a perimenopausal population. Substantial reliability and validity estimates for the scale and its subscales support the UQOL as a valuable new tool for use in clinical research and practice.

Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass.

UNLABELLED: The double-blind, randomized raloxifene alendronate comparison trial was the first study designed to compare two osteoporosis therapies head-to-head for fracture risk reduction. The original protocol planned to treat 3000 postmenopausal women with alendronate 10 mg/day (ALN) or raloxifene 60 mg/day (RLX) for 5 years, and to recruit women (50-80 years old) with a femoral neck bone mineral density (BMD) T-score between -2.5 and -4.0, inclusive, no prevalent vertebral fractures, and no prior bone-active agent use. The trial was stopped early, due to difficulty in finding treatment-naïve women to meet enrollment goals within the planned timeline, resulting in insufficient power to show non-inferiority between therapies in the primary endpoint (number of women with >or=1 new osteoporotic vertebral or nonvertebral fracture). Except for vertebral fractures, fracture analyses were based upon 1412 of the 1423 women randomized (mean age of 66 years). After 312+/-254 days (mean+/-SD), 22 women in the ALN group and 20 in the RLX group had new vertebral or nonvertebral fractures. Four women in the ALN group and none in the RLX group had moderate/severe vertebral fractures, a pre-specified endpoint (P=0.04). Lumbar spine, femoral neck, and total hip BMD were increased from baseline at 2 years in each group (P<0.001), with greater increases in the ALN group (each P<0.05). Similar numbers of women in each group had >or=1 adverse event and discontinued due to an adverse event. The only adverse events with an incidence that differed between groups were colonoscopy, diarrhea, and nausea; each was more common with ALN treatment (each P<0.05). One woman in each group had a venous thromboembolic event. One case of breast cancer occurred in each group. In summary, as this trial was terminated early, there was insufficient power to compare the fracture risks between alendronate and raloxifene. Safety profiles were as expected from clinical trial and post-marketing reports. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00035971.

NIH and WHI: time for a mea culpa and steps beyond.

The termination of the estrogen-progestin arm of the Women's Health Initiative (WHI) 5 years ago was abrupt and poorly planned. It has also become manifestly clear that the reporting at that time of the balance of risk and benefit for perimenopausal and early postmenopausal women was grossly exaggerated. Subsequent WHI publications including subanalyses of original data suggest a persistent pattern of over-reading of results toward a negative bias. The initial 2002 conclusion of the WHI investigators that harm was greater than benefit appears to be the result of several factors. One was the failure to recognize that initiation of therapy by decade of age or time since menopause was highly relevant; the WHI committee aggregated all outcome data into one group, even though in their demographic description they had the ability to investigate by age. An overhanging question is, therefore, what did they know, and when did they know it? Another factor was the utilization of a nonvalidated index termed the "global health index" that inexplicably assumed for comparison sake that all diseases were equivalent, for example, that a stroke was equivalent to a hip fracture in morbidity, mortality, and impact on quality of life. Although not a study about menopause, the data were extrapolated to all peri- and postmenopausal women. Despite the overall positive outcome of their results for women aged 50 to 60 years, most particularly those receiving estrogen-only therapy, the WHI investigators have irrationally maintained a defense of their misinterpretations of 2002. It is time for the National Institutes of Health and the WHI investigators to issue a final overall report that is clear and based on their actual results and not their personal interpretations. There is too much relevant and important information within the WHI to allow the overall study to continue to be perceived as biased to the detriment of both the National Institutes of Health and the study itself.

The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety.

OBJECTIVE: To compare effects of 52 weeks' treatment with either raloxifene 60 mg/day alone (RLX) or in combination with 17beta-estradiol 1 mg/day (RLX + E) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy. DESIGN: In this randomized, double-blind clinical trial, the frequency of vasomotor symptoms, hot flashes, and night sweats was assessed for up to 52 weeks. Endometrial thickness was assessed by transvaginal ultrasonography at baseline and at 12 and 52 weeks. An exit endometrial biopsy was performed at study completion or early termination. RESULTS: The frequency of vasomotor symptoms, hot flashes, and night sweats was unchanged from baseline with RLX but was significantly reduced in women treated with RLX + E, from baseline (all P < 0.001) and the RLX group at 6, 12, 24, 36, and 52 weeks (all P < 0.01). Women in the RLX + E group had significantly increased endometrial thickness (0.74 +/- 0.28 mm, mean +/- SEM) at 52 weeks, from baseline and RLX (P < 0.05), with no statistically significant changes in women treated with RLX. Two women, both in the RLX + E group, had endometrial hyperplasia (one with atypia) on the exit biopsy. CONCLUSIONS: In women transitioning from estrogen-progestin therapy, occurrence of vasomotor symptoms was unchanged from baseline with RLX treatment, but these symptoms were significantly reduced with combined RLX + E therapy. Signs of endometrial stimulation were observed in the RLX + E group. Further studies using different estrogen doses and preparations are needed before concomitant use of raloxifene with systemic estrogens can be recommended.

Lowest effective transdermal 17beta-estradiol dose for relief of hot flushes in postmenopausal women: a randomized controlled trial.

OBJECTIVE: To investigate the efficacy of micro-dose transdermal estrogen in relieving menopausal vasomotor symptoms. METHODS: A randomized, double-blind, placebo-controlled, multi-center trial. Healthy postmenopausal women with at least seven moderate or severe hot flushes per day for at least 1 week, or at least 50 per week, applied transdermal patches with a nominal delivery of 0.023 mg/d 17beta-estradiol and 0.0075 mg/d levonorgestrel (low-dose E2/levonorgestrel; n=145), 0.014 mg/d E2 (micro-dose; n=147), or placebo (n=133) for 12 weeks. The coprimary efficacy variables were the mean changes from baseline in frequency and severity of moderate and severe hot flushes at the week 4 and 12 endpoints. RESULTS: At the week 12 endpoint, mean weekly frequencies of moderate and severe hot flushes were significantly reduced compared with placebo with low-dose E2/levonorgestrel (-51.80; P<.001) and micro-dose E2 (-38.46; P<.001). Severity scores were also significantly reduced with both treatments compared with placebo. At week 12 endpoint, 41.3% of women receiving micro-dose E2 were treatment responders (75% or more reduction from baseline in hot flush frequency; P=.003 compared with 24.2% placebo). In this group, the mean reduction in moderate and severe hot flushes from baseline was approximately 50% after 2, 70% after 4, 90% after 8, and 95% after 12 weeks. There were no differences between active treatments and placebo regarding adverse events. CONCLUSION: Micro-dose E2 (0.014 mg/d) was clinically and statistically significantly more effective than placebo in reducing the number of moderate and severe hot flushes, with a 41% responder rate, supporting the concept of the lowest effective dose. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00206622

Quality of life (QOL) in menopause.

Quality of life (QOL) is generally not precisely defined or measured. This has resulted in confusing and often misleading conclusions in multiple publications, including those coming from both the HERS and the WHI writing groups. Health-related QOL and global QOL are accurately defined, and current instruments for measuring them are available. In the continuing effort to determine the true risks and benefits of postmenopausal hormone usage, it is critical that the full spectrum of effects be measured. There is no excuse for future studies on hormone use not to include well-validated instruments for measuring QOL and for not reporting those effects as part of the rest of the study. Questionnaire instruments can often provide more information than many of the invasive tests that are part of contemporary trials. They also add little cost, yet can be invaluable in the analysis of real cost-effectiveness of interventions in contemporary women's health care. Beyond safety and efficacy evaluation of drug therapies, there is an absolute need to know about the real impact of these therapies on overall quality of life.

Science of intracrinology in postmenopausal women.

OBJECTIVE: To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of intracrinology, whereby each cell of each peripheral tissue makes a small and appropriate amount of estrogens and androgens from the inactive precursor dehydroepiandrosterone (DHEA), DHEA being mainly of adrenal origin. Because only the inactivated sex steroids are released in the blood, influence in the other tissues is avoided. METHODS: Molecular biology has been used for the identification/characterization of the steroid-forming and steroid-inactivating enzymes, whereas steroids have been measured by mass spectrometry-based assays validated according to the US Food and Drug Administration guidelines. RESULTS: Evolution over 500 million years has engineered the expression of about 30 steroid-forming enzymes specific for each peripheral tissue. These tissue-specific enzymes transform DHEA into the appropriate small amounts of estrogens and androgens for a strictly intracellular and local action. Humans, contrary to species below primates, also possess intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, which inactivate the estrogens and androgens at their local site of formation, thus preventing the release of a biologically significant amount of estradiol (E2) and testosterone in the circulation. Since DHEA becomes the unique source of sex steroids after menopause, serum E2 and testosterone are thus maintained at low biologically inactive concentrations with no activity outside the cells of origin. DHEA secretion, unfortunately, starts decreasing at about the age of 30 at various rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when the concentration of serum DHEA decreases. Considering this mechanism is unique to the human, it seems logical to replace DHEA locally in women suffering from vulvovaginal atrophy (genitourinary syndrome of menopause). The clinical data obtained using a small dose of intravaginal DHEA (prasterone) confirm the mechanisms of intracrinology mentioned above which avoid biologically significant changes in serum E2 and testosterone. CONCLUSIONS: The symptoms and signs of vulvovaginal atrophy (genitourinary syndrome of menopause) can be successfully treated by the intravaginal administration of DHEA without safety concerns. This strategy exclusively replaces in the vagina the missing cell-specific intracellular estrogens and androgens. This approach avoids systemic exposure and the potential risks of estrogen exposure for the tissues other than the vagina.

Vulvodynia: a state-of-the-art consensus on definitions, diagnosis and management.

Vulvodynia is a chronic pain syndrome affecting up to 18% of the female population. Despite its high prevalence and associated distress, the etiology, diagnosis and clinical management of the disorder have not been clearly delineated. This "white paper" describes the findings and recommendations of a consensus conference panel based on a comprehensive review of the published literature on vulvodynia in addition to expert presentations on research findings and clinical management approaches. The consensus panel also identified key topics and issues forfurther research, including the role of inflammatory mechanisms and genetic factors and psychosexual contributors.

Comparative controlled trial of a novel oral estrogen therapy, estradiol acetate, for relief of menopause symptoms.

OBJECTIVE: To compare the efficacy and tolerability of a new oral estradiol prodrug, estradiol acetate, with micronized estradiol or conjugated equine estrogens for alleviation of postmenopausal vasomotor and urogenital symptoms. DESIGN: A total of 249 postmenopausal women experiencing seven or more moderate or severe vasomotor symptoms daily for 1 week or 60 or more symptoms in 1 week were randomized to 0.9 mg of estradiol acetate (n = 79), 1 mg of micronized estradiol (n = 85), or 0.625 mg of conjugated equine estrogens therapy (n = 85). Efficacy endpoints were the change in frequency and severity of vasomotor symptoms from baseline to week 12, participant-assessed urogenital symptoms, and investigator-assessed signs of vaginal atrophy. Efficacy results were considered equivalent if estradiol acetate was at least 80% as effective as estradiol and conjugated estrogens. RESULTS: At week 12, frequency of vasomotor symptoms decreased comparably in all groups, and at weeks 4 and 12, the decrease in frequency of symptoms was statistically equivalent for estradiol acetate and conjugated estrogens. Severity of vasomotor symptoms also improved comparably for all groups, with least squares mean decreases of 1.05 for estradiol acetate, 1.34 for estradiol, and 1.17 for conjugated estrogens at week 12. Urogenital symptoms and vaginal signs showed similar improvement in all groups. Overall, the majority of adverse events were mild or moderate and consistent with estrogen therapy. CONCLUSION: Estradiol acetate 0.9 mg was comparable to 1 mg of estradiol and 0.625 mg of conjugated equine estrogens in reducing the number and severity of vasomotor and urogenital symptoms in postmenopausal women. Oral estradiol acetate was well tolerated.

Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review.

Many women experience vasomotor symptoms at or around the time of menopause. Hot flushes and night sweats are considered primary menopausal symptoms that may also be associated with sleep and mood disturbances, as well as decreased cognitive function. All of these symptoms may lead to social impairment and work-related difficulties that significantly decrease overall quality of life. Hot flushes have shown a great deal of variability in their frequency and severity in women. In some women, hot flushes persist for several months; in others, they may last for more than 10 years. Traditionally vasomotor symptoms were reported to begin 5 to 10 years prior to the cessation of the final menstrual cycle, corresponding with the initial decline in circulating gonadal hormones; however, night sweats in particular most often begin in perimenopause. The pathogenesis of hot flushes has not yet been fully elucidated, but the circuitry involving estrogen and neurotransmitters, norepinephrine and serotonin specifically, are hypothesized to play a major role in the altered homeostatic thermoregulatory mechanisms underlying these events. Menopause-associated vasomotor symptoms are associated with significant direct and indirect costs. Overall costs of traditional pharmacotherapy or complementary and alternative medicine modalities, including over-the-counter treatments and dietary supplements, for managing menopause-related vasomotor symptoms are substantial and include initial and follow-up physician visits and telephone calls. Additional costs include laboratory testing, management of adverse events, loss of productivity at work, and personal and miscellaneous costs. Pharmacoeconomic analyses, including those that consider risks identified by the Women's Health Initiative, generally support the cost-effectiveness of hormonal therapy for menopause-associated vasomotor symptoms, which have been the mainstay for the management of these symptoms for more than 50 years. However, because many women now want to avoid hormone therapy, there is a need for additional targeted therapies, validated by results from controlled clinical trials that are safe, efficacious, cost-effective, and well tolerated by symptomatic menopausal women.

S-equol: a potential nonhormonal agent for menopause-related symptom relief.

Many women suffering from vasomotor symptoms (VMS) are now seeking nonpharmaceutical treatments for symptom relief. Recently, S-equol, an intestinal bacterial metabolite of the soybean isoflavone daidzein has received attention for its ability to alleviate VMS and provide other important health benefits to menopausal women. S-equol is found in very few foods and only in traces. About 50% of Asians and 25% of non-Asians host the intestinal bacteria that convert daidzein into S-equol. Clinical trials that evaluated the efficacy of an S-equol-containing product found that VMS were alleviated but these trials were limited in scope and primarily involved Japanese women for whom hot flashes are a minor complaint. The only trial in the United States evaluating hot flashes found symptoms were significantly reduced by S-equol, but the study lacked a placebo group, although it did include a positive control. The daily dose of S-equol used in most trials was 10 mg, and because the half-life of S-equol is 7-10 hours, to maximize efficacy, it was taken twice daily. Subanalysis of epidemiologic studies suggests that equol producers are more likely to benefit from soyfood consumption than nonproducers with respect to both cardiovascular disease and osteoporosis, although the data are inconsistent. The limited safety data for S-equol do not suggest cause for concern, especially with regard to its effects on breast and endometrial tissue. Further studies are needed before definitive conclusions of its effectiveness for VMS can be made, but the preliminary evidence warrants clinicians discussing the potential of S-equol for the alleviation of VMS with patients.