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Review & meta-analysis: isopropanolic black cohosh extract iCR for menopausal symptoms - an update on the evidence.
Castelo-Branco, C, Gambacciani, M, Cano, A, Minkin, MJ, Rachoń, D, Ruan, X, Beer, AM, Schnitker, J, Henneicke-von Zepelin, HH, Pickartz, S
Climacteric : the journal of the International Menopause Society. 2021;(2):109-119
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Abstract
A systematic literature search revealed 35 clinical studies and one meta-analysis comprising 43,759 women, of which 13,096 were treated with isopropanolic Cimicifuga racemosa extract (iCR). Compared to placebo, iCR was significantly superior for treating neurovegetative and psychological menopausal symptoms, with a standardized mean difference of -0.694 in favor of iCR (p < 0.0001). Effect sizes were larger when higher dosages of iCR as monotherapy or in combination with St. John's wort (Hypericum perforatum [HP]) were given (-1.020 and -0.999, respectively), suggesting a dose-dependency. For psychological symptoms, the iCR+HP combination was superior to iCR monotherapy. Efficacy of iCR was comparable to low-dose transdermal estradiol or tibolone. Yet, due to its better tolerability, iCR had a significantly better benefit-risk profile than tibolone. Treatment with iCR/iCR+HP was well tolerated with few minor adverse events, with a frequency comparable to placebo. The clinical data did not reveal any evidence of hepatotoxicity. Hormone levels remained unchanged and estrogen-sensitive tissues (e.g. breast, endometrium) were unaffected by iCR treatment. As benefits clearly outweigh risks, iCR/iCR+HP should be recommended as an evidence-based treatment option for natural climacteric symptoms. With its good safety profile in general and at estrogen-sensitive organs, iCR as a non-hormonal herbal therapy can also be used in patients with hormone-dependent diseases who suffer from iatrogenic climacteric symptoms.
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Equol Decreases Hot Flashes in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Daily, JW, Ko, BS, Ryuk, J, Liu, M, Zhang, W, Park, S
Journal of medicinal food. 2019;(2):127-139
Abstract
Soy isoflavones may benefit some, but not all, menopausal women, and the ability of the women to produce equol may be the major determinant of effectiveness. We assessed the efficacy of soy isoflavones and equol for alleviating menopausal symptoms, especially vasomotor symptoms, in postmenopausal women who were equol producers and nonproducers by using systematic review and meta-analysis of randomized clinical trials (RCTs). We searched 12 English, Korean, and Chinese language scientific and medical databases. We selected all available RCTs that assessed the effect of equol, either equol itself or soy isoflavone in equol producers, on menopausal symptoms in peri- or postmenopausal women. The primary outcome was the effect on hot flashes. The severity of hot flashes was determined by the scores, and sensitivity and risk of bias analyses were conducted. Other outcomes of the review, but not meta-analysis, included depression and adverse events. Six studies (779 total subjects) met all criteria for the systematic review, 5 of those could be included in the meta-analysis (728 total subjects). Two studies included in the meta-analysis reported no statistically significant benefits of equol; the other three did report significant benefits of equol. Meta-analysis revealed a significant benefit of equol for lowering hot flash scores and revealed a generally low risk of bias. In conclusion, this study found that supplementing equol to equol nonproducers significantly lowered the incidence and/or severity of hot flashes in menopausal women.
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Effect of omega-3 supplements on vasomotor symptoms in menopausal women: A systematic review and meta-analysis.
Mohammady, M, Janani, L, Jahanfar, S, Mousavi, MS
European journal of obstetrics, gynecology, and reproductive biology. 2018;:295-302
Abstract
OBJECTIVE We aimed to investigate the effect of omega-3 supplements on relief of vasomotor symptoms among menopausal women. STUDY DESIGN The Cochrane Library, MEDLINE, SCOPUS, EMBASE, ProQuest, Google Scholar, Web of Science, CINAHL, IranMedex and SID databases were searched until September 2017. Inclusion criteria were (1) women were experiencing vasomotor symptoms in the menopause period, (2) intervention was omega-3 supplements (3) randomized controlled trial (RCT) or quasi-RCT, and (4) outcome measures included changes in the frequency and severity of hot flush or night sweats, sleep problems and side effects. RESULTS Three randomized controlled trials involving 483 women in the age range of 51 to 54.7 years were included in the review. Overall, the risk of bias in the included studies was moderate. All the participants were found to be blinded. Meta-analysis of the data showed no difference in the frequency and severity of hot flushes, insomnia severity, sleep quality, quality of life and adverse effects between the two groups. Compared to placebo group, women who received omega-3 supplements experienced lower frequency (mean difference: -1.82, 95% CI: -2.81, -0.83) and severity (mean difference: -.89, 95% CI: -1.25, -0.53) of night sweats. CONCLUSIONS RCTs which investigate the impact of omega-3 supplements on vasomotor symptoms in menopausal women are scarce. A comprehensive search in a wide range of databases found only three relevant papers. Our analysis suggests that omega-3 supplements may alleviate night sweats but have no benefit in reducing hot flushes, or improving sleep quality and quality of life during the menopausal period. We recommend high quality RCTs along with a longer follow-up period to investigate this important subject, as there was insufficient evidence to conclude that omega-3 supplements are of benefit in alleviating vasomotor symptoms in menopausal women.
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Effects of a standardised extract of Trifolium pratense (Promensil) at a dosage of 80mg in the treatment of menopausal hot flushes: A systematic review and meta-analysis.
Myers, SP, Vigar, V
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2017;:141-147
Abstract
OBJECTIVE To critically assess the evidence for a specific standardised extract of Trifolium pratense isoflavones (Promensil) at a dosage of 80mg/day in the treatment of menopausal hot flushes. DATA SOURCES Systematic literature searches were performed in Medline, Scopus, CINAHL Plus, Cochrane, AMED and InforRMIT and citations obtained from 1996 to March 2016. Reference lists were checked; corresponding authors contacted and the grey literature searched for additional publications. REVIEW METHODS Studies were selected according to predefined inclusion and exclusion criteria. All randomised clinical trials of a specific standardised extract of Trifolium pratense isoflavones (Promensil) used as a mono-component at 80mg/day and measuring vasomotor symptoms were included. The data extraction and quality assessment were performed independently by one reviewer and validated by a second with any disagreements being settled by discussion. Weighted mean differences and 95% confidence intervals were calculated for continuous data using the fixed-effects model. RESULTS Twenty potentially relevant papers were identified, with only five studies meeting the inclusion criteria. The meta-analysis demonstrated a statistical and clinically relevant reduction in hot flush frequency in the active treatment group compared to placebo. Weighted mean difference 3.63 hot flushes per day: [95% CI 2.70-4.56]; p˂0.00001). Due to a lack of homogeneity a priori defined sub-group analyses were performed demonstrating a substantive difference between cross-over and parallel-arm clinical trial designs. CONCLUSION There is evidence for a statistical and clinically significant benefit for using a specific standardised extract of red clover isoflavones (Promensil) at 80mg/day for treating hot flushes in menopausal women across the 3 studies included in the meta-analysis. The preparation was safe over the short-term duration of the studies (3 months).
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Vasomotor symptoms resulting from natural menopause: a systematic review and network meta-analysis of treatment effects from the National Institute for Health and Care Excellence guideline on menopause.
Sarri, G, Pedder, H, Dias, S, Guo, Y, Lumsden, MA
BJOG : an international journal of obstetrics and gynaecology. 2017;(10):1514-1523
Abstract
BACKGROUND Vasomotor symptoms (VMSs) are the hallmarks of menopause, occurring in approximately 75% of postmenopausal women in the UK, and are severe in 25%. OBJECTIVES To identify which treatments are most clinically effective for the relief of VMSs for women in natural menopause without hysterectomy. SEARCH STRATEGY English publications in MEDLINE, Embase, and The Cochrane Library up to 13 January 2015 were searched. SELECTION CRITERIA Randomised controlled trials (RCTs) of treatments for women with a uterus for the outcomes of frequency of VMSs (up to 26 weeks), vaginal bleeding, and discontinuation. DATA COLLECTION AND ANALYSIS Bayesian network meta-analysis (NMA) using mean ratios (MRs) and odd ratios (ORs). MAIN RESULTS Across the three networks, 47 RCTs of 16 treatment classes (n = 8326 women) were included. When compared with placebo, transdermal estradiol and progestogen (O+P) had the highest probability of being the most effective treatment for VMS relief (69.8%; MR 0.23; 95% credible interval, 95% CrI 0.09-0.57), whereas oral O+P was ranked lower than transdermal O+P, although oral and transdermal O+P were no different for this outcome (MR 2.23; 95% CrI 0.7-7.1). Isoflavones and black cohosh were more effective than placebo, although not significantly better than O+P. Not only were selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) found to be ineffective in relieving VMSs, but they also had significantly higher odds of discontinuation than placebo. Limited data were available for bleeding, therefore no conclusions could be made. CONCLUSION For women who have not undergone hysterectomy, transdermal O+P was the most effective treatment for VMS relief. TWEETABLE ABSTRACT Which treatment best relieves menopause flushes? Results from the #NICE guideline network meta-analysis.
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Red clover for treatment of hot flashes and menopausal symptoms: A systematic review and meta-analysis.
Ghazanfarpour, M, Sadeghi, R, Roudsari, RL, Khorsand, I, Khadivzadeh, T, Muoio, B
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2016;(3):301-11
Abstract
This study evaluated the efficacy of red clover to relieve hot flashes and menopausal symptoms in peri/postmenopausal women. Electronic databases (MEDLINE, Scopus and the Cochrane Library) were searched. The mean frequency of hot flashes in red clover groups was lower compared with that in the control groups (close to statistical significance). Difference in means (MD) of hot flashes frequency was - 1.99 (- 4.12-0.139; p = 0.067; heterogeneity P > 0.01; I(2) = 94.93%; Random effect model). Subjective (vaginal dryness) and objective (maturation value) symptoms of vaginal atrophy showed a significant improvement with 80-mg dose of red clover. Red clover showed less therapeutic effect on psychology status, sexual problems and sleeping disorders. Red clover consumption may decrease frequency of hot flashes, especially in women with severe hot flashes (≥ 5 per day). Red clover may reduce other menopausal symptoms. Further trials are needed to confirm the current systematic review findings.
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Protocol for systematic review and meta-analysis: hop (Humulus lupulus L.) for menopausal vasomotor symptoms.
Abdi, F, Kazemi, F, Ramezani Tehrani, F, Roozbeh, N
BMJ open. 2016;(4):e010734
Abstract
INTRODUCTION Menopause is a critical stage in every woman's life. It can cause a distressing time for women by creating various vasomotor symptoms (VMS). Phytoestrogens can potentially exert various favourable effects and alleviate VMS in postmenopausal women. The hop (Humulus lupulus L.) contains 8-prenylnaringenin (8-PN), the most potent phytoestrogen known to date. The hop is eight times stronger than any other herbal oestrogens. This study aims to conduct a comprehensive systematic review and a meta-analysis survey of the effects of hop in the management of VMS in postmenopausal women. METHODS Only randomised controlled clinical trials, with cluster randomisation and crossover, blinded and non-blinded designs, conducted between 2000 and 2015, will be included in this review. Quasi-experimental and observational studies as well as case reports will be excluded. The studies will be selected if their participants were aged 40-60 years, had elevated follicle-stimulating hormone (FSH) levels and/or menstrual irregularities, and experienced discomforting VMS (at least hot flashes or night sweats). The primary outcome will be the rate of response to treatment, such as changes in frequency and intensity of symptoms in the intervention and placebo groups. 'Hop', 'Humulus', 'menopause', 'vasomotor', 'hot flashes', 'phytoestrogen' and 'night sweats' will be used as search key words. Prior to their inclusion in the review, the selected papers will be assessed by two independent reviewers for methodological validity. Any disagreements will be resolved through a third reviewer. The risk of bias will be independently determined using the Cochrane Risk of Bias Tool. The quality of the papers will be assessed based on the CONSORT checklist. ETHICS AND DISSEMINATION Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The results of our project can help reproductive health researchers when evaluating the discomforts of research procedures described in study protocols or when designing a study. Information on experiences of menopausal women involved in previous studies may also help in future research. The expected dissemination actions are effective treatment in designing strategies that aim to develop women's health and healthcare providers when offering treatment for women with vasomotor symptoms.
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Red clover extract for alleviating hot flushes in postmenopausal women: a meta-analysis.
Gartoulla, P, Han, MM
Maturitas. 2014;(1):58-64
Abstract
The safety and efficacy of red clover for alleviating menopausal hot flushes are yet to be established. The aim of this meta-analysis was to generate evidence from published literature regarding red clover as a treatment option for menopausal hot flushes. The results showed that red clover when compared to placebo was effective in reducing menopausal hot flushes when administered for 3-4 months (MD=-1.34, 95% CI=-1.90 to -0.77, p<0.00001), but their effect did not persist at 12 months (MD=0.89, 95% CI=-0.07 to 1.85, p=0.07).
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Phytoestrogens for menopausal vasomotor symptoms.
Lethaby, A, Marjoribanks, J, Kronenberg, F, Roberts, H, Eden, J, Brown, J
The Cochrane database of systematic reviews. 2013;(12):CD001395
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Abstract
BACKGROUND Vasomotor symptoms, such as hot flushes and night sweats, are very common during the menopausal transition. Hormone therapy has traditionally been used as a highly effective treatment, but concerns about increased risk of some chronic diseases have markedly increased the interest of women in alternative treatments. Some of the most popular of these treatments are foods or supplements enriched with phytoestrogens-plant-derived chemicals that have estrogenic action. OBJECTIVES To assess the efficacy, safety and acceptability of food products, extracts and dietary supplements containing high levels of phytoestrogens when compared with no treatment, placebo or hormone therapy for the amelioration of vasomotor menopausal symptoms (such as hot flushes and night sweats) in perimenopausal and postmenopausal women. SEARCH METHODS Searches targeted the following electronic databases: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of randomised trials (29 July 2013), the Cochrane Register of Controlled Trials (CENTRAL; 29 July 2013), MEDLINE (inception to 29 July 2013), EMBASE (inception to 29 July 2013), AMED (1985 to 29 July 2013), PsycINFO (inception to 29 July 2013) and CINAHL (inception to 29 July 2013). Attempts were made to access grey literature by sending letters to pharmaceutical companies and performing searches of ongoing trial registers. Reference lists of included trials were also searched. SELECTION CRITERIA Studies were included if they were randomised, included perimenopausal or postmenopausal participants with vasomotor symptoms (hot flushes or night sweats), lasted at least 12 weeks and provided interventions such as foods or supplements with high levels of phytoestrogens (not combined with other herbal treatments). Trials that included women who had breast cancer or a history of breast cancer were excluded. DATA COLLECTION AND ANALYSIS Selection of trials, extraction of data and assessment of quality were undertaken by at least two review authors. Most trials were too dissimilar for their results to be combined in a meta-analysis, so these findings are provided in narrative 'Summary of results' tables. Studies were grouped into broad categories: dietary soy, soy extracts, red clover extracts, genistein extracts and other types of phytoestrogens. Five trials used Promensil, a red clover extract; results of these trials were combined in a meta-analysis, and summary effect measures were calculated. MAIN RESULTS A total of 43 randomised controlled trials (4,364 participants) were included in this review. Very few trials provided data suitable for inclusion in a meta-analysis. Among the five trials that yielded data assessing the daily frequency of hot flushes suitable for pooling, no significant difference overall was noted in the incidence of hot flushes between participants taking Promensil (a red clover extract) and those given placebo (mean difference (MD) -0.93, 95% confidence interval (CI) -1.95 to 0.10, I(2) = 31%). No evidence indicated a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (MD 20.15, 95% CI -12.08 to 52.38, I(2) = 82%). Four trials that were not combined in meta-analyses suggested that extracts with high (> 30 mg/d) levels of genistein consistently reduced the frequency of hot flushes. Individual results from the remaining trials were compared in broad subgroups such as dietary soy, soy extracts and other types of phytoestrogens that could not be combined. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1% to 59% with placebo. No indication suggested that discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. Also, no evidence indicated that these treatments caused oestrogenic stimulation of the endometrium or the vagina or other adverse effects when used for up to two years. AUTHORS' CONCLUSIONS No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated.
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Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials.
Taku, K, Melby, MK, Kronenberg, F, Kurzer, MS, Messina, M
Menopause (New York, N.Y.). 2012;(7):776-90
Abstract
OBJECTIVE This analysis was conducted to determine the efficacy of extracted or synthesized soybean isoflavones in the alleviation of hot flashes in perimenopausal and postmenopausal women. METHODS PubMed and The Cochrane Controlled Clinical Trials Register Database were searched for relevant articles reporting double-blinded randomized controlled trials through December 14, 2010. References within identified articles, as well as peer-reviewed articles that had come to the attention of the authors through other means, were also examined for suitability. This systematic review and meta-analysis, which evaluated the effects of isoflavones on the frequency, severity, or composite score (frequency × severity) of hot flashes compared with placebo was conducted according to Cochrane Handbook guidelines. RESULTS From 277 potentially relevant publications, 19 trials (reported in 20 articles) were included in the systematic review (13 included hot flash frequency; 10, severity; and 3, composite scores), and 17 trials were selected for meta-analyses to clarify the effect of soybean isoflavones on hot flash frequency (13 trials) and severity (9 trials). Meta-analysis revealed that ingestion of soy isoflavones (median, 54 mg; aglycone equivalents) for 6 weeks to 12 months significantly reduced the frequency (combined fixed-effect and random effects model) of hot flashes by 20.6% (95% CI, -28.38 to -12.86; P < 0.00001) compared with placebo (heterogeneity P = 0.0003, I = 67%; random effects model). Meta-analysis also revealed that isoflavones significantly reduced hot flash severity by 26.2% (95% CI: -42.23 to -10.15, P = 0.001) compared with placebo (heterogeneity, P < 0.00001, I = 86%; random effects model). Isoflavone supplements providing more than 18.8 mg of genistein (the median for all studies) were more than twice as potent at reducing hot flash frequency than lower genistein supplements. CONCLUSIONS Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash frequency, and treatment duration.