Meta-analysis Finds Little Evidence of Increased Side Effects in Women Using Phytoestrogens
Meta-analysis Finds Little Evidence of Increased Side Effects in Women Using Phytoestrogens
Abstract & Commentary
By Dónal P. O'Mathúna, PhD. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.
Synopsis: A meta-analysis was conducted of the incidence of side effects reported in randomized controlled trials of women taking phytoestrogens for the treatment of menopausal symptoms. Except for gastrointestinal side effects, women taking phytoestrogens were not at higher risk of side effects.
Source: Tempfer CB, et al. Side effects of phytoestrogens: A meta- analysis of randomized trials. Am J Med 2009;122:939-946.
Women who experience various negative symptoms during menopause commonly turn to phytoestrogens in the hope of finding relief. Phytoestrogen use has become more widespread since concerns were raised about the adverse effects associated with hormone replacement therapy. However, concerns have also been expressed about the side effects of phytoestrogens. This systematic review aimed to provide evidence of the safety profile of phytoestrogens as revealed in randomized controlled trials (RCTs).
The authors searched PubMed and the Cochrane controlled trials register for any RCT, systematic review, or meta-analysis assessing phytoestrogen treatment. Only original reports published in English were included. Studies were included if they involved women only or if the data for women could be separated from that of men involved in the studies.
The literature search identified 174 RCTs. In 82 trials, no side effects or adverse effects were reported and these trials were excluded from the meta-analysis. The remaining 92 RCTs involved 9,629 participants. A meta-analysis was conducted comparing the number of side effects found in the phytoestrogen treatment groups to the number found in placebo or no-treatment groups. For their meta-analysis, the authors used a fixed-effects model. This model is favored (over a random-effects model) when little heterogeneity exists between the studies summarized in the meta-analysis. Calculations demonstrated that the included studies did not exhibit a large degree of heterogeneity (in other words, they did not exhibit an inappropriate degree of variability).
The authors calculated an incidence rate ratio (IRR) by taking the rate of side effects in the phytoestrogen group and dividing this figure by the incidence rate in the control group. The overall incidence of side effects in the phytoestrogen groups was 2,019/5,502 (36.7%) and 1,824/4,806 (38.0%) in the control groups. The difference was not statistically significant (P = 0.2; IRR = 1.01; 95% confidence interval [CI], 0.95-1.08).
Sub-group analyses were performed on different categories of side effects. A statistically significant difference between the phytoestrogen and control groups was found only for gastrointestinal side effects. Higher rates of gastrointestinal side effects were found for the phytoestrogen group overall (P = 0.003; IRR = 1.28; 95% CI, 1.08-1.50). The rates of side effects did not differ significantly for gynecological, musculoskeletal, neurological, or unspecific side effects. Within each category of side effect, no specific side effect was found to occur at a significantly higher rate in women using phytoestrogens. Of particular interest was the finding that the rates of hormone-related side effects, such as endometrial hyperplasia, endometrial cancer, and breast cancer, and of vaginal bleeding, were not significantly different among the groups.
The authors concluded that phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects.
Commentary
Phytoestrogens have become widely used by women to treat peri- and postmenopausal symptoms. phytoestrogens are a diverse group of plant compounds found in many different supplements. They are generally divided into three groups: flavonoids such as genistein and daidzein, found in soy and red clover; coumestans such as coumestrol, found in soybeans; and lignans, found in flaxseed.
While their popularity has grown, concerns have been expressed about their potential side effects. These concerns arise largely from evidence that phytoestrogens act at least in part as weak estrogen agonists. While their binding affinity for estrogen receptors is about 1,000 times weaker than that of estradiol, concerns have been expressed that this may be enough to elicit unwanted hormone-related side effects or other serious adverse effects.
This meta-analysis brings together a large amount of information from randomized controlled trials involving phytoestrogens. However, the authors did limit their search in ways that could have led them to miss important evidence.1 Only PubMed and the Cochrane controlled trials register were searched, and only original reports in English were reviewed. The authors themselves found that studies conducted in Europe and the United States were less likely to report higher side-effect rates in phytoestrogen-treated women compared to those conducted in Asia or elsewhere. In that case, restricting the search to English-language reports and these two databases may have underestimated the extent of the side effects from phytoestrogens.
The authors also examined whether the duration of treatment impacted the incidence of side effects. The median treatment duration in all the trials was 6.2 months, which is relatively short. The authors separately analyzed their data to determine if differences existed between studies lasting less than 6 months and those longer than 6 months; between those shorter than 12 months and longer than 12 months; and between those shorter than 24 months and longer than 24 months. No statistical differences were found between the studies shorter than 6 months and those longer than 6 months. However, in the two other categories, women using phytoestrogens for the longer periods reported fewer side effects (P = 0.04 and 0.01, respectively). The authors were reassured by this finding, which they took to in-dicate that cumulative dose effects do not occur with phytoestrogens.
The side-effect incidences were also analyzed according to the participants' ages. A higher incidence of side effects was found in older women. For all women younger than 55 years, the IRR was 0.97 compared to 1.14 for those older than age 55.
This meta-analysis provides important reassurance for women taking phytoestrogens. The overall incidence of gastrointestinal side effects was higher in women taking phytoestrogens compared to placebo or no treatment. However, no significant differences were found for any one particular gastrointestinal side effect (the most commonly reported ones being constipation, bloating or flatulence, nausea or vomiting, and abdominal pain). The incidence of these side effects decreased as women took phytoestrogens in studies of longer duration. The risk of specific hormone-related side effects was not found to be elevated; namely, vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer.
However, caution is still warranted with this information. The pooling of data from studies involving different phytoestrogens could have masked or diluted serious side effects associated with one particular compound. Although some studies in the meta-analysis were of relatively long duration, the median duration was 6.2 months. Therefore, rare, but serious, side effects from long-term treatment may not have been captured in the RCTs conducted. Nonetheless, this review provides important evidence to support claims that phytoestrogens are relatively safe for women, particularly women younger than 55 years. At the same time, this review does not address whether phytoestrogens are effective in the treatment of menopausal symptoms, which remains controversial.2
References
1. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Wiley-Blackwell; 2008. Available at www.cochrane-handbook.org. Accessed Nov. 9, 2009.
2. Tempfer CB, et al. Phytoestrogens in clinical practice: A review of the literature. Fertil Steril 2007;87: 1243-1249.
A meta-analysis was conducted of the incidence of side effects reported in randomized controlled trials of women taking phytoestrogens for the treatment of menopausal symptoms. Except for gastrointestinal side effects, women taking phytoestrogens were not at higher risk of side effects.Subscribe Now for Access
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