Phytoestrogens

5.1. Definition 

Phytoestrogens are plant-derived polyphenolic dietary compounds with structural similarities to 17-β-estradiol (E2), the primary sex hormone in females [118]. Due to their similarity to 17-β-estradiol, these bioactive compounds can bind to estrogen receptors (ER), in turn, modulating estrogenic activity. Many tend to have higher affinities for ER-beta than ER-alpha and have a weaker bond than E2 [119]. Phytoestrogens are classified into four phenolic compounds: isoflavones, lignans, stilbenes, and coumestrol [120]. Isoflavones and lignans have received much of the attention, as they are the most relevant with respect to the human diet. Isoflavones are flavonoids found primarily in soybeans, and consist of genistein, daidzein, glycitein, and biochanin A. Lignan phytoestrogens, mostly associated with flaxseeds and other cereals, exist as the glycosides secoisolariciresinol and matairesinol but also include pinoresinol, lariciresinol and syringaresinol [118]. Intestinal microflora are responsible for the conversion to the “mammalian lignans,” enterodiol and enterolactone [121]. Similarly, the microbiome hydrolyzes isoflavone glycosides to their physiologically active aglycone metabolites. 

5.2. Background 

More than 20 isoflavone metabolites have been identified, the most well-studied of which is equol [122]. Equol production varies between populations. It has been found that of Western populations, only about 25–30% are able to convert isoflavones to equol, compared to 50–60% of Asian populations and vegetarians [123]. It is hypothesized that regular consumption of isoflavone-rich foods provides substrates for equol producing bacteria to thrive, if present [123]. There are many suggested health benefits of phytoestrogens, including reduced menopausal symptoms, reduced risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes, cognitive disorders, and various forms of cancer [124–128]. Nonetheless, concerns are frequently raised that soy isoflavones and other phytoestrogens may act as endocrine disruptors and stimulate the growth of estrogen-sensitive cancers [129–132]. Thus, much debate exists among consumers and clinicians alike, on whether phytoestrogen-rich foods should be included in those with a history or family history of breast cancer. Phytoestrogens are widespread throughout the plant kingdom, and consumption can vary greatly depending on cultural food preferences. Traditional Asian diets, for example, are estimated to contain 15–50 mg/day of isoflavones, whereas consumption in Western countries is estimated to be only around 2.5 mg/day [133]. This difference can be attributed to the long history of soy products in Asian cuisine. Soy products are one of the richest sources of dietary isoflavones. Whole soybeans contain 103.6 mg/100 g of isoflavones, followed by soy nuts (68.6 mg/100 g), tofu (27.2 mg/100 g), tempeh (18.3 mg/100 g), soymilk (2.9 mg/100 g) and miso soup (1.5 mg/100 g) [134]. Fruits, vegetables, nuts, and other legumes also contain isoflavones, though in significantly lesser amounts [135,136]. Lignans are the second leading source of dietary phytoestrogens, and are ubiquitous throughout plants, though in generally small amounts. Flaxseeds and sesame seeds are reported to contain the greatest amount of lignans, with 379.4 mg and 8.00 mg/100 g respectively [134]. Nuts were found to contain between 0.025 mg and 0.198 mg/100 g [137]. Lignans, in general, were found to be negligible in legumes, fruits, vegetables and cereals (< 0.01 mg/100 g). Exceptions were noted for garlic, olive oil, winter squash, dried apricots, dried dates, dried prunes and multigrain bread [134]. 

5.3. Effects of Cooking/Processing 

As previously stated, dietary phytoestrogen glycosides must first be transformed to aglycones by glucosidases before they can be utilized by humans [122,123,138]. Glycosides can be hydrolyzed via intestinal glucosides, intestinal bacterial glucosides, as well as through various processing methods [123,139–141]. Boiling and steaming led to significant increases in beta-glucosides and aglycones, though pressure steaming resulted in the greatest amounts (Table 1) [139]. Fermentation by Lactobacillus and Bifidobacteria also results in increased aglycone content [141]. Bau et al. found that by fermenting soymilk for 30 h with kefir culture, glycitin and daidzin were completely hydrolyzed into aglycones, while 89% of genistin was bioconverted [140]. Consuming traditionally fermented soy products, such as Korean cheonggukjang, Japanese natto, and Thai Thua, may further enhance isoflavone bioavailability, though more human trials are necessary [122]. 

5.4. Safety Phytoestrogens have received a large amount of attention over the past few decades, particularly because of their potential estrogenic effects (Table 1). For this reason, much research has examined possible benefits of phytoestrogens on menopause symptoms, although results have been mixed [137]. A recent systematic review and meta-analysis concluded that phytoestrogen supplementation resulted in significantly greater reductions in hot flashes as compared to placebo, but did not significantly impact the Kupperman Index, an index which included 11 symptoms of menopause [142]. Another meta-analysis found similar benefits in the ability of soy isoflavones to improve hot flashes, as well as vaginal dryness score [143]. Chen and colleagues concluded in a recent literature review that isoflavones reduced hot flashes, attenuated bone mineral density (BMD) loss in the lumbar spine and may have potential benefits on blood pressure and glycemic control [144]. Nonetheless, a recent Cochrane review was unable to conclusively state that phytoestrogens are effective for reducing menopausal symptoms due to the heterogeneity of studies, and individual variability in metabolism and absorption of isoflavones [145]. An exception was noted for genistein supplementation of 30–60 mg/day, which reliably demonstrated a benefit for hot flash frequency [145]. The heterogeneity in results may be partially explained by equol. An observational study of 365 peri- and post-menopausal women, found that equol producers in the highest quartile of daidzein intake were 76% less likely to report vasomotor symptoms than those in the lowest intake quartile. No associations were found between daidzein intake and vasomotor symptoms in equol nonproducers [146]. Equol supplementation may also be of benefit to non-producers. A 12-week double-blind RCT found that equol supplementation (10 mg/day) improved mood-related symptoms, even in non-producers. Those that received 10 mg three times daily demonstrated significantly better outcomes in all measures [147]. A meta-analysis of equol supplementation also revealed significant improvement in hot flash severity, both in equol producers and non-producers [148]. Another primary concern regarding phytoestrogens is due to their possible endocrine-disrupting effects [129]. Due to the rising rates of soy-based infant formulas, developing babies and infants may be most at risk. Serum genistein concentrations are 10–50-fold higher in soy-formula fed infants than in Asian adults, and 100–700-fold higher than US adults [149]. Nonetheless, the biological significance of increased phytoestrogen exposure in infants is yet to be determined [150,151]. Collective findings in adults have not identified conclusive evidence that soy food or isoflavones adversely affect thyroid function in euthyroid or iodine-replete individuals [94]. The other common concern surrounding soy and phytoestrogen intake is increased risk of estrogen-sensitive breast and uterine cancer [132]. Thus far, no evidence has demonstrated a link between phytoestrogen-rich diets and estrogen-sensitive malignant growths. In contrast, soy consumption may actually be associated with reduced risk of breast cancer incidence, recurrence and mortality [132,152].

5.5. Human Studies 

Studies investigating the specific potential impact on female reproductive health are mixed. A systematic review and meta-analysis concluded that isoflavones have no effect on endometrial thickness or breast density [153]. Another meta-analysis of pre- and postmenopausal women found isoflavones to have only a weak effect on the hypothalamic-pituitary-gonadal axis [154]. In premenopausal women, soy isoflavone consumption had no effect on circulating estradiol, estrone or sex hormone binding globulin (SHBG). Follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations were significantly reduced, and menstrual length increased by 1.05 days. However, once bias was accounted for, changes were no longer significant [154]. In postmenopausal women, no statistically significant effects were noted for circulating total estradiol, estrone, SHBG, FSH, LH or TSH, though soy increased total circulating estradiol non-significantly [154]. Women that were fed soy-formula as an infant reported slightly longer menstrual bleeding times (0.37 days), and greater discomfort during menstruation than cow milk fed infants [155]. Another study conducted on Korean girls with central precocious puberty (CPP) found a positive association between elevated serum isoflavones and risk of CPP [156]. As soy-based formulas are also known to contain pesticide and glyphosate residues, effects of soy cannot be attributed to phytoestrogens alone [157]. Despite concerns over estrogen’s endocrine disrupting effects, estrogen is (E2) is proposed to play a role in protection against cardiovascular disease (CVD), and the ensuing increased risk of CVD post-menopause once E2 levels decline [158,159]. Due to the structural similarities to E2, phytoestrogens have also been investigated for possible cardiovascular benefits. Epidemiological evidence suggests potential protective effects of phytoestrogens, particularly in Asian populations with high isoflavone intake from soy products [160]. A positive relationship has been found between isoflavone intake, endothelial function and reduced lower carotid atherosclerotic burden [161]. Ferreira and colleagues also found that higher isoflavone intake was independently associated with lower risk for subclinical CVD in menopausal women [162]. Results from experimental studies using phytoestrogens for CVD prevention and treatment have been mixed, but generally positive. In one study, soy isoflavones in combination with probiotic resistant starch or probiotics (L. acidophilus, B. bifidus and LGG), was shown to significantly decrease total and LDL cholesterol, independent of isoflavone bioavailability [163]. Another study using 15 g of soy protein with 66 mg isoflavone daily for 6 months resulted in significant reductions in systolic blood pressure (SBP). The reductions in SBP led to a 27% reduction in 10-year coronary heart disease risk, a 37% reduction in myocardial infarction risk, a 24% reduction in cardiovascular disease and 42% reduction in CVD death risk [164]. A meta-analysis of 17 RCTs suggested that isoflavone-containing soy products can modestly, but significantly improve endothelial function, as measured by flow mediated dilation (FMD) [165]. Finally, several studies have suggested that genistein significantly improves FMD, reduces endothelin-1 levels, and induces nitric oxide-dependent vasodilation to a similar extent of estrogen [166–168]. Soy-based and phytoestrogen-rich products have also been proposed for the prevention of certain cancers, including breast, prostate, endometrial, and colorectal cancer [119,169–172]. Some studies, however, have suggested that soy isoflavone intake is associated with significantly reduced breast cancer risk only in Asian populations, but not in Western populations [173–175]. Ingestion of phytoestrogens and soy may also offer significant protection against prostate cancer. A recent meta-analysis from the University of Illinois found that total soy food, genistein, daidzein, and unfermented soy food to be significantly associated with reduced advanced prostate cancer risk [176]. In another meta-analysis, soy isoflavone supplementation led to a significant reduction in prostate cancer diagnosis in those with an identified risk [177]. No reductions in PSA levels or steroid endpoints were observed. The benefits of phytoestrogens may be due to their anti-inflammatory and antioxidant properties [178]. Data from the 1999–2010 NHANES revealed an inverse associated with urinary phytoestrogens and serum C-reactive protein (CRP), a marker of inflammation [176]. These results should be interpreted with caution however, as an increased intake of phytoestrogens in Western cultures may be evidence of an overall healthy diet, rich in a variety of other nutrients and bioactive compounds that reduce CRP levels [179]. 

5.6. Conclusions 

Overall, the evidence surrounding phytoestrogens within the currently published literature is still mixed, with a large amount of heterogeneity between studies. The microbial makeup of the gut, bio-individuality, and the phytoestrogen source all play a significant role in the decision to include phytoestrogen-rich foods in one’s diet. Supplementation using isolated isoflavones may be beneficial for some populations but may pose increased risk for others. Babies and infants are at higher risk of the endocrine-disrupting potential because of their small size and underdeveloped digestive tract. With that said, epidemiological and observational data suggests that including phytoestrogen-rich foods as part of a varied, plant-based diet should not be of concern, but may be beneficial. Additionally, phytoestrogen-containing foods such as legumes, grains, seeds, nuts, fruits, and vegetables, are rich sources of essential vitamins, minerals, fiber and other health-promoting phytochemicals.

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