Maturitas 78 (2014) 79–81

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Editorial

Phytoestrogens for menopausal vasomotor symptoms: A Cochrane review summary

Keywords: Phytoestrogens Menopause

risk of bias, and participants varied in the severity of their flushes at baseline.

2. Soy extracts To aim of this Cochrane review was to assess the efficacy, safety and acceptability of food products, extracts and dietary supplements for the relief of vasomotor menopausal symptoms e.g. hot flushes and night sweats. Included women were either perimenopausal or postmenopausal women with spontaneous or surgical menopause; excluded women were those who had used hormone therapy less than month ago or had a history of breast cancer. Studies were randomised controlled comparisons of high levels of phytoestrogens (e.g. at least 30 mg/d of isoflavones) for more than 12 weeks versus placebo, HT, no treatment or products containing low levels of phytoestrogens. The primary outcome was efficacy; change in frequency of overall vasomotor menopausal symptom scores; change in frequency or severity of individual vasomotor menopausal symptoms or their incidence after treatment. Secondary outcomes were adverse events (e.g. endometrial or vaginal stimulation) or acceptability of therapy. A total of 43 randomised controlled trials (4,364 participants) were included in this review [1]. Trials were grouped into broad categories according to method of delivery and type of phytoestrogen: dietary soy, soy extracts, red clover extracts, genistein extracts and other types of phytoestrogens. The review was only able to pool the studies that used Promensil (red clover extract) in meta-analyses. Due to marked heterogeneity the other phytoestrogen interventions were not sufficiently similar to warrant metaanalysis. Sensitivity analysis was conducted to compare differences among participants, interventions, outcomes and methodological quality of included studies.

1. Primary outcome 1.1. Dietary soy Overall, no evidence suggested that a diet with high levels of soy phytoestrogens had a positive effect on hot flush frequency or severity. Although six of 13 studies reported significant findings, this must only be considered as tentative as only one trial had low http://dx.doi.org/10.1016/j.maturitas.2014.04.004 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

No overall conclusive evidence showed that soy extracts had a positive effect on hot flush frequency or severity. In the 11 trials that compared soy extracts with placebo there was variability in the interventions, the severity of hot flushes at baseline and most of the studies were at high risk of bias.

3. Red clover extracts Overall, no evidence suggested that red clover extracts had a positive effect on hot flush frequency or severity. Five studies assessed the effects of Promensil, and this data was able to be included in a meta-analysis. Two different doses of Promensil (40 mg/d and 80 mg/d) were studied and no significant differences were reported between these doses and placebo in the overall incidence of hot flushes. Four other studies assessed the effects of other red clover extracts. The two larger studies at low risk of bias found no evidence of benefit.

4. Genistein Among four studies (n = 619) genistein extracts, in doses ranging from 30 to 60 mg per day, appeared to significantly reduce the number of hot flushes experienced by symptomatic postmenopausal women but to a lesser extent than hormone therapy [2]. These findings should be considered tentative as, in two of the four studies, effects on hot flushes were secondary outcomes, and in one study, measurements were made in a subgroup from the total study population, which may have introduced bias. The mean percentage reduction in daily hot flushes from baseline ranged from 41% to 61% with genistein in comparison with a mean reduction ranging from 7% to 29% with placebo. It was unclear whether these extracts influenced the severity of hot flushes: a significant decline in hot flush severity over placebo was found in only one study with 2 year follow up.

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Editorial / Maturitas 78 (2014) 79–81

5. Other phytoestrogens

9. Summary and implications for future research

Among six trials that assessed the effects of other types of phytoestrogens, benefits were reported only from single trials investigating a phytoestrogen extract from the rhubarb plant (ERr 731) and an equol supplement (SE5-OH). The study comparing SEquol with placebo (n = 160) found that S-Equol was associated with a significantly larger decrease in hot flush frequency from baseline (62.8%) compared with placebo (23.6%) in women with three or more hot flushes per day and a significant improvement in hot flush severity with S-Equol (61%) compared with placebo (45%) [3]. Results of the trial were assessed in postmenopausal women with low rates of equol excretion, as this was considered to reduce the possibility of confounding by background isoflavone intake. The trial investigating the effects of an extract from the roots of Rheum rhaponticum (ERr 731) in perimenopausal women (n = 110) reported that both the frequency and the severity of moderate to severe hot flushes were significantly compared with placebo (mean decrease of 2.5 points compared with mean decrease of 1.2 points) at week 12 [4]. These two studies were generally at low risk of bias but further research will be needed to confirm this efficacy.

In general, no conclusive evidence showed a benefit of phytoestrogen-enriched or -derived products for menopausal vasomotor symptoms, with the exception of products containing a minimum of 30 mg per day of genistein, which have been evaluated for up to two years in four studies. Further research is needed to confirm this efficacy. No evidence of safety concerns in the short term was found. Limited data suggest that phytoestrogen supplements were well tolerated. Strong evidence was found of a placebo effect, with improvements in frequency ranging from-1% to -59%. It has been claimed that only 20–30% of the general population in the United States possess gut microflorae that convert the isoflavone, daidzein, to the more oestrogenic dihydroxy isoflavan equol in comparison with 50–60% of Asians [5]. The studies included in this review generally did not control or stratify for this added potential source of variation in response to treatment with phytoestrogens. Investigators in one trial stated that isoflavone supplementation improved symptoms only in women with the ability to produce equol and the Aso study found benefit from S-Equol in equol-nonproducing postmenopausal Japanese women [3]. Further research should consider the role of equol production and also whether phytoestrogens are more effective in women with more severe symptoms. A Cochrane systematic review to specifically assess the effects of phytoestrogens on urogenital menopausal symptoms would provide further clarification.

6. Safety Data on oestrogenic effects on the endometrium and the vagina and rates of adverse effects were collected in only a few trials. Phytoestrogen products do not appear to have an oestrogen agonistic effect on the endometrium when given for up to one year. This was further supported by a study comparing genistein phytoestrogens with HT; endometrial thickness significantly increased from baseline with HT, but no change was seen with the phytoestrogen. Evidence of the effects of phytoestrogens on the vaginal maturation index and on pH is mixed. Five placebo-controlled trials found no evidence of a stimulatory effect, but two other studies described a positive oestrogenic effect of increasing cellular mitotic activity, as evidenced by improvement in maturation indices-one with a soy diet versus a wheat diet and the other with a red clover extract versus placebo.

Contributors Helen Roberts wrote the initial draft of this editorial and was an author of the Cochrane review. Anne Lethaby commented on the initial draft and was an author of the Cochrane review.

Competing interest Helen Roberts is involved in research with Merck. None of this work is directly relevant to this paper.

Funding 7. Adverse events Fracture rates were significantly higher in the group of women consuming soy in one study, but this is likely to be a chance event, as all fractures were associated with a traumatic event rather than with osteoporosis. Women ingesting flaxseed meal as a dietary supplement were more likely to withdraw from treatment because of gastrointestinal complaints when compared with those given flaxseed extract or placebo. Adverse events were most often collected incidentally during the trials.

8. Acceptability Few trials specifically assessed this outcome in spite of the high dropout rate in many of the studies. No evidence was found of a difference in acceptability of any of the phytoestrogen products used when compared with placebo, except for one trial; 63% of those taking ERr 731 were satisfied with their treatment compared with 38% taking placebo. Phytoestrogen supplement in one trial was given in the form of a powder, and the authors included data on the dislike of the taste of soy powder.

The editorial was not funded.

Provenance and peer review Commissioned, not externally peer reviewed.

References [1] Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev 2013;(12), http://dx.doi.org/10.1002/14651858.CD001395.pub4. Art. No.: CD001395. [2] Crisafulli A, Marini H, Bitto A, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT and placebo-controlled study. Menopause 2004;11:400–4. [3] Aso T, Uchiyama S, Matsumura Y, et al. A natural S-Equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women. J Women Health 2012;21(1):92–100. [4] Heger M, Ventskovskiy BM, Borzenko I, et al. Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: a 12-week randomised double-blind placebo-controlled trial. Menopause 2006;13(5):744–59. [5] North American Menopause Society. The 2012 hormone therapy position statement of the North American Menopause Society. Menopause 2012;19(3):257–71.

Editorial / Maturitas 78 (2014) 79–81

Helen Roberts ∗ Department of Obstetrics and Gynaecology, University of Auckland, New Zealand Anne Lethaby Cochrane Menstrual Disorders and Subfertility Group, Department of Obstetrics and Gynaecology, University of Auckland, New Zealand

81 ∗ Corresponding author. Tel.: +64 9 373 7599x89485; fax: +64 9 303 5969. E-mail address: [email protected] (H. Roberts)

Phytoestrogens for menopausal vasomotor symptoms: a Cochrane review summary.

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