Phytoestrogens May Benefit Health but Also Prompt Concern

Miriam E Tucker

October 14, 2016

Current evidence for the potential health benefits of dietary phytoestrogens such as soy is not strong enough to counter their possible risks, a new review paper concludes.

The findings were published online October 9 in the British Journal of Pharmacology by Ivonne MCM Rietjens, PhD, of the division of toxicology, Wageningen University, the Netherlands, and colleagues.

They performed a literature review of papers investigating the health effects of phytoestrogens — plant- (particularly soy-) derived dietary compounds with structural similarity to 17-β-estradiol (E2) that exert their various effects by binding to estrogen receptors.

A wide range of health benefits have been reported for phytoestrogens, such as reductions in menopausal symptoms, including hot flashes and osteoporosis; and lower risks of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes, cognitive problems, breast cancer, prostate cancer, and other cancers.

As a result, phytoestrogens are present in many dietary supplements and are widely marketed as natural alternatives to estrogen-replacement therapy.

However, the data on health benefits are conflicting, and concerns have been raised that the estrogenic properties of phytoestrogens could cause them to act as endocrine disruptors, with concurrent adverse health effects.

"The current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made," Dr Rietjens and colleagues write.

Asked to comment, JoAnn V Pinkerton, MD, professor of obstetrics and gynecology and director of Midlife Health at the University of Virginia, Charlottesville, told Medscape Medical News that the authors' conclusions from their review are similar to those of the North American Menopause Society (NAMS) Recommendations for Clinical Care of Midlife Women, in that "definitive conclusions on possible beneficial health effects of phytoestrogens cannot be made at this time, as the health benefits of isoflavones and other phytoestrogens remain unproven with regard to effect on hot flashes, prevention of bone loss, cardiovascular disease, or dementia. There are potential health risks that may depend on age, health status, or the presence or absence of specific gut microflora, including the ability to produce equol."

More Research Needed to Determine Benefit/Risk Profile

Dr Pinkerton, who is also executive director of NAMS, added that while there are no data to suggest that soy, phytoestrogens, or isoflavone products increase the risk of breast or endometrial cancer, NAMS recommends that women with breast or endometrial cancer consider consulting their oncologists before using such products.

Regarding hot flashes, recent randomized, blinded, clinical trials on soy isoflavonoids reviewed in the 2015 NAMS Position Statement on Nonhormonal Treatment of Hot Flashes suggest that they are no more effective than placebo, she noted.

"More research is needed before overall health benefits over risks can be determined. I am personally in agreement with the recommendations for caution regarding health benefits and risks until more research is obtained," she said.

However, Dr Pinkerton added that she is upbeat about the possibility that the estrogen-receptor beta ligand S-equol might be beneficial for hot flashes in women, a topic mentioned in the review paper.

"The most exciting finding has been that there may be a difference between women who can convert the isoflavone daidzein to equol — and hence show efficacy of a supplement — and nonconverters, who would be unlikely to respond," she said, noting that a supplement containing S-equol has been developed for women who lack the capacity in the gut to produce equol.

Nevertheless, more research is still needed on the effectiveness of this particular supplement in women suffering from bothersome menopausal symptoms, she cautioned.

"Complex" Relationship to Human Health

In their 48-page review, Dr Rietjens and colleagues begin by describing the various phytoestrogens found in the human diet and in food supplements, and they compare their chemical structures with that of E2. They also outline their modes of interaction with estrogen receptors and possible epigenetic effects.

The main isoflavones are genistein, daidzein, glycitein, formononetin, and biochanin A, which are mainly found in soy, soy-based food, and legumes, usually in their conjugated forms like genistin, daidzin, puerarin, glycitin, ononin, and sissotrin, the Dutch authors explain.

In separate sections, they summarize the literature regarding the effects of phytoestrogens on menopausal symptoms; cardiovascular disease; obesity/metabolic syndrome/ type 2 diabetes (grouped together); breast cancer; other cancers; thyroid function; and brain function.

For menopausal symptoms, several meta-analyses have variably reported reductions in frequency and severity of hot flashes and varying effects on bone-mineral density.

But in a 2012 review, the European Food Safety Authority (EFSA) concluded that the available evidence was insufficient to establish a relationship between soy isoflavones and either maintenance of bone density or vasomotor symptoms associated with menopause.

And, of concern, a 2015 study in Japanese women showed that while higher isoflavone intake appeared to be associated with higher peak femoral neck bone-mineral density, it was also linked to greater rates of lumbar spine and femoral neck bone-mineral-density loss during menopause.

"Altogether, it seems that the evidence for a beneficial effect of isoflavones and other phytoestrogens on bone-mineral density in post- and perimenopausal women is limited and not convincing and [indicates] that they may even cause adverse effects," the authors say.

For cardiovascular disease, the current evidence for phytoestrogens "appears poor compared with that available for estrogens, and it is possible that the potential effect of estrogens on the risk for stroke is not reproduced by isoflavones," they write.

And regarding metabolic effects, some data have suggested benefit for phytoestrogens in improving glucose metabolism and reducing insulin resistance, but in nutritional intervention studies "it often remains unclear whether the beneficial effects are really due to the phytoestrogens or to some other dietary component," such as in the example of a study investigating a soy protein and flaxseed diet, they note.

Data for breast cancer are also conflicting for phytoestrogens. The EFSA concluded that observational human data don't suggest an increased risk overall, but that estrogenic isoflavone-based food supplements may pose a risk to postmenopausal women with estrogen-dependent breast cancer.

"Thus, concerns still exist that the estrogenic activity of phytoestrogens may present a risk to patients with estrogen-sensitive breast cancer and to women who are at high risk of developing breast tumors, and it remains to be established whether exposure to isoflavones reduces or increases breast-cancer risks," Dr Rietjens and colleagues write.

In all, they say, "the question of whether phytoestrogens are beneficial or harmful to human health remains of importance. The present overview reveals that the answer is rather complex and may depend on age, health status, and even the presence or absence of specific gut microflora in the population of concern."

Given the global popularity of phytoestrogen supplements and their marketing as natural alternatives to estrogen-replacement therapy, "further insight into the risks and benefits of these phytoestrogens seems essential," they conclude.

The authors have no relevant financial relationships. Dr Pinkerton reports relationships through her institution with Pfizer, Henry Stewart, and TherapeuticsMD.

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Br J Pharmacol . Published online October 9, 2013. Article

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