Systematic review and meta-analysis

Isoflavones hold limited promisefor the treatment of menopausalvasomotor symptoms10.1136/ebmed-2014-110000

Katherine M Newton

Group Health Research Institute, Seattle, Washington, USA

Correspondence to: Dr Katherine M Newton, Group Health ResearchInstitute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101, USA;newton.k@ghc.org

Commentary on: Lethaby A, Marjoribanks J, Kronenberg F, et al.Phytoestrogens for menopausal vasomotor symptoms. CochraneDatabase Syst Rev 2013;12:CD001395.

ContextVasomotor symptoms (VMS) are characterised by feelings of mild tointense warmth in the face, neck and chest, accompanied by minimal toprofuse sweating.1 VMS may occur rarely or with great frequency, preva-lence varies by ethnicity and they may be present for months to years.2

While many women accept VMS as normal, others find them bother-some, particularly if accompanied by sleep or mood disturbances.

While oestrogen therapy is highly effective in reducing VMS, asso-ciated risks reduce enthusiasm regarding their use.3 Professional groupsrecommend using hormone therapy at the lowest effective dose, for theshortest possible duration.4 Hormone therapy is contraindicated forcertain women due to a history of breast cancer or thromboembolism.Others simply prefer a more ‘natural’ approach.5

There is an on-going search for safe, non-hormonal interventions torelieve VMS; isoflavones have been studied more than any other suchintervention. The results of these efforts are addressed by Lethaby andcolleagues.

MethodsThe authors sought all randomised controlled trials of at least 12 weeksduration for food products, extracts and dietary supplements containingat least 30 mg/day of isoflavones, compared to placebo, hormonetherapy, no treatment or products with lower levels of phytoestrogens.

Inclusion criteria included perimenopausal or postmenopausal womenwith VMS and without intercurrent major disease, recent hormonetherapy or current or past breast cancer. The primary outcomes werechange in VMS scores (from menopause scales), VMS frequency andVMS incidence.

The authors identified 30 studies from prior reviews and 1089through database searching. Trial heterogeneity in terms of product types(foods, extracts supplements), isoflavone concentrations and product con-stituents (soy, clover, etc), limited the ability to evaluate studies quantita-tively. After applying Cochrane criteria, 43 randomised trials wereincluded in the qualitative synthesis and five were included in the quanti-tative synthesis. Overall these trials included 4364 participants.

FindingsThe majority of study participants were aged 40–65, baseline VMS ratesvaried from 1 to 15/day, and study duration ranged from 12 weeks to

2 years. Among the 13 trials that assessed dietary isoflavones (flour,powder or beverages), there was no evidence of reduced VMS frequencyor severity. Among 12 trials that assessed soy isoflavone extracts (tablets,capsules) evidence that extracts reduced VMS frequency or severity wasnot conclusive. Among nine trials assessing red clover extracts, variabil-ity in the interventions—as well as the high potential for bias in severalstudies—led authors to conclude that there was no evidence suggestingred clover extracts are effective in reducing VMS frequency or severity.Among five trials assessing the effects of genistein extracts (30–60 mg/day), three found a decrease in VMS per day of 41–61% compared with7–29% with placebo. Genistein extracts were found to significantlyreduce VMS frequency in symptomatic postmenopausal women. Flaxseedand linseed diets or extracts and a hop-based preparation were withoutefficacy in reducing VMS. A rhubarb plant phytoestrogen extract and anS-Equol supplement were reported to reduce VMS as compared withplacebo, but these single trials were insufficient to draw firmconclusions.

CommentaryA walk through the supplements section of any grocery store or phar-macy gives testament to the frequency with which phytoestrogen pro-ducts are developed and promoted for relief of menopausal symptoms.This review is an important step forward in improving our understandingof the value of phytoestrogen products for treatment of menopausalVMS. The authors’ summary suggests that extracts with a minimum of30 mg genistein are the sole products producing sufficient evidence torecommend their use. However, Lethaby and colleagues leave the dooropen for products that have been insufficiently studied. For example, towhat degree does a woman’s capacity to produce equol from daidzein (aprocess dependent on the gut microflora) influence daidzein’s effect onVMS? Can others replicate findings related to genistein and VMS?

A striking aspect of this review was the challenge of identifyingstudies adequate enough to merit trust in their findings. For 40% ofstudies there was high risk of reporting and attrition bias, while manywere small pilot studies. Furthermore, outcomes for menopausal studiesare not standardised, which complicates cross-study comparisons. Higherquality trials would be informative, but randomised trials are expensiveand funding for studies in this area is limited. For the time being, we relyon systematic reviews to guide our practice.

Competing interests None.

Provenance and peer review Commissioned; internally peer reviewed.

References1. Kronenberg F, Downey JA. Thermoregulatory physiology of menopausal hot flashes:

a review. Can J Physiol Pharmacol 1987;65:1312–24.2. Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between

vasomotor symptoms and race/ethnicity across the menopausal transition: study ofwomen’s health across the nation. Am J Public Health 2006;96:1226–35.

3. Roussouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plusprogestin in healthy postmenopausal women: principal results from the Women’sHealth Initiative randomized trial. JAMA 2002;288:321–33.

4. North American Menopause Society. The 2012 hormone therapy position statementof the North American Menopause Society. Menopause 2012;19:257–71.

5. Newton KM, Buist DSM, Keenan NL, et al. Use of alternative therapies formenopause symptoms: results of a population-based survey. Obstet Gynecol2002;100:18–25.

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Therapeutics