Do phytoestrogens have adverse effects?

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Phytoestrogen supplements for treating climacteric syndrome complaints in women are safe to use, according to a meta-analysis of 174 randomized controlled trials.

The analysis in The American Journal of Medicine found that rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users compared to placebo or not treatment. However, gastrointestinal adverse events (AEs) occurred more often.

Phytoestrogens were considered substances with a defined amount of isoflavones, lignans or coumestans. The Austrian authors searched PubMed and the Cochrane controlled trials register, limited to studies initially published in English. Studies assessing both women and men were included, though, if the women were analyzed separately.

Individual women from all trials could have more than one side effect counted, whereas in crossover studies, AEs were recorded for all treatment groups.

Side effects were reported in 92 of the studies, totaling 9,629 participants. Overall incidence of AEs was comparable: 36.7% (2,019 of 5,502 subjects) in the phytoestrogen groups and 38.0% (1,824 of 4,806 subjects) in the control groups (P= 0.2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08).

But among various side effect categories, there were significantly higher rates of gastrointestinal AEs among phytoestrogen users (P= 0.003; IRR 1.28; 95% CI, 1.08 - 1.50). Conversely, gynecological (IRR 0.94; 95% CI, 0.74 - 1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94 - 1.53), neurological (IRR 0.91; 95% CI, 0.70 - 1.19), and unspecific AEs (IRR 0.95; 95% CI, 0.88-1.03) did not dramatically differ between the two groups. Rates of hormone-related AEs, such as endometrial hyperplasia, endometrial cancer and breast cancer, were also not significantly differ between the groups.

Still, two of 92 studies in which AEs were reported found a statistically significantly higher rate in the phytoestrogen group. 

Despite similar overall rates for AEs, the incidence rate ratio was impacted by the geographic origin of individual studies and patient age. For instance, studies conducted in Asia were more likely to observe higher AE rates in phytoestrogen-treated women than studies from the United States and Europe. Likewise, phytoestrogen-treated women older than 55 years had higher rates of AEs than women younger than 55.

“Because gastrointestinal side effects were the most prominent side effect category, these observations suggest that gastrointestinal tolerance of phytoestrogen supplements is reduced in older women and in Asian women whose diet is characterized by a high underlying consumption of phytoestrogens,” the authors wrote. 

On the other hand, the analysis did not find a connection between lengthier study duration (like 24 months versus 6 months) and a higher rate of AEs. In fact, AEs occurred less often in women using phytoestrogens for a longer period of time.

“These observations are somewhat reassuring, indicating that there are no cumulative dose effects of phytoestrogens over time,” the authors wrote.

However, the median study duration was only 6.2 months; therefore, rare AEs may develop in women on long-term treatment. But based on the available data, phytoestrogens can be recommended for up to 2 years, according to the authors.

The study did not address the efficacy of phytoestrogen treatment, which remains controversial.