Phytoestrogens are naturally-occurring polyphenolic plant compounds with oestrogenic or anti-oestrogenic activity. They have a similar structure to 17-oestradiol and can therefore bind to oestrogen receptors. Phytoestrogens have weak oestrogenic effects compared with oestradiol, but may be present in significant amounts in those eating a phytoestrogen-rich diet. Individual phytoestrogens have different binding capacities and stimulation at ER- and ER- receptors. Total effects depend on relative amounts of phytoestrogen and oestradiol in circulation. Oestrogenic effects of phytoestrogens predominate in oestrogen-depleted post-menopausal women, while oestrogen antagonist actions occur in those with oestrogen excess eg pre-menopausal obese women¹.

• Isoflavones such as glycosides genistin and daidzin found in soya beans and soya milk; aglycones genistein and diadzein in miso
• Lignans found in flaxseeds, sesame seeds, lentil and in small amounts in broccoli and other vegetables
• Coumestans/stilbenes such as resveratrol found in red wine and red grapes².

Isoflavones and lignans are extensively metabolised by gut flora. The amount of active equol absorbed following isoflavone metabolism appears to vary inversely with the fat content of the diet³.

Population-based studies suggest that phytoestrogen-rich diets may be protective against breast, prostate and bowel cancer, and cardiovascular disease, and improve some menopausal problems⁴. Countries with higher phytoestrogen intake from soya isoflavones show lower incidence of breast cancer (52/100,000 compared with 1999/100,000 in UK), CHD, prostatic disease and colon cancer⁵.

Coronary heart disease⁶

• reducing total cholesterol and LDL levels and increasing HDL levels (including apolipoprotein A-1)
• decreasing atherosclerotic plaque formation
• antioxidant effects which increase LDL resistance to oxidation⁷

Animal studies show that feeding isoflavone-rich diets reduces LDL-cholesterol and increases HDL-cholesterol. Consumption of soy containing isoflavone phytoestrogens reduces lipid peroxidation and increases resistance of LDL to oxidation in vivo, which may markedly decrease risk of atherosclerosis and cardiovascular disease and also cancer⁷. A meta-analysis of 38 human clinical studies⁸ using isolated soya protein or textured soya protein supplementation demonstrated a mean reduction of 9.3% in cholesterol and 12.9% decrease in LDL-cholesterol with intakes of 47g soya protein/day. Largest reductions were seen in those in the highest initial quartile of cholesterol/LDL levels. Hypocholesterolaemic effects have also been demonstrated using 60g/day textured soya protein in men without effects on hormonal status.

Both in vitro⁹ and in vivo, phytoestrogens have been shown to have weak antioxidant effects, increasing resistance of LDL to oxidation. Genistein inhibits tyrosine kinase, important in preventing plaque propagation; other phytoestrogens also have anti-proliferative properties, and beneficial effects on platelet aggregation⁶.

Pre-menopausal women consuming high isoflavone diet (45mg isoflavones/day) had lengthening of the follicular phase of the menstrual cycle in some studies; this would extrapolate to lower life-time exposure to oestrogen, which may explain some of the decreased risk of breast cancer in Japanese women¹⁰. Increasing phytoestrogen intake decreases hot flushes in some studies, especially using supplements, but is less effective in preventing vaginal dryness^11,12.

Reductions in the risk of breast, colon, prostate and other cancers have been proposed in those eating a high phytoestrogen diet⁵. Inhibition of cancer cell growth by soya isoflavones may occur by a variety of different mechanisms^{13,14,15,16,17}:

Prospective and case-control studies have shown decreased risk of breast cancer in those consuming Miso soup, tofu or soya bean protein. Early life exposure to phyoestrogens may be particularly important for prevention¹³. Genistein has antineoplastic effects with inhibition of cellular proliferation and angiogenesis^15,17.

Countries with low incidence of prostate cancer have high phytoestrogen intakes¹⁴. In vitro studies have shown that genistein can inhibit the growth of prostate cancer cell lines¹⁴. Isoflavone rich diets reduce the incidence of prostate cancer in rats however studies in humans have not yet demonstrated lower risk¹⁴.

Osteoporosis¹⁸

Oestrogen has an important role in preventing bone loss in postmenopausal women. Studies have shown reduced bone resorption with increased ingestion of isoflavone¹⁹, and markers of bone turnover decrease by 10-24% in postmenopausal women eating 60g soya protein/day. Postmenopausal women fed soya versus casein protein²⁰ or 45g soy enriched bread²¹ or 40mg clover isoflavones²² demonstrated increased bone mineral density at the lumbar spine only.

Davis⁴ reminds us that it is naïve to assume that only benefits will accrue from phytoestrogen exposure. Differences in individual gut microflora, absorption and metabolism make the activity of phytoestrogens unpredictable. Epidemiological studies show effects of isoflavone intake from foods; these effects cannot be extrapolated to concentrated isoflavone supplements which may have beneficial or detrimental effects.

In animals, Clover disease due to adverse effects of phytoestrogens was shown to cause infertility in sheep¹¹, and veno-occlusive disease and infertility in captive cheetah were due to phytoestrogens in their diet¹¹. In vitro studies have shown that genistein but not daidzein can induce structural chromosomal damage such as chromatid breaks, gaps and interchanges²⁴. These may be beneficial, increasing apoptosis or increase risk of cancer²⁴.

Isoflavones are polyphenols which act on many biochemical targets, not just oestrogen receptors, therefore interference with effects of tamoxifen is unlikely; however, oophorectomised women may be at increased risk of breast cancer recurrence on a phytoestrogen-containing diet¹³.

Concerns have been raised by levels of phytoestrogens, mainly isoflavones, in soy-based infant-formulas. 4 month-olds ingest 4.5-8mg/kg body weight/day, 6-11 times more than the levels shown to have hormone-like effects in adults²⁵. This dose is said to provide equivalent of 5 combined oral contraceptive pills per day²⁶. Studies have shown that isoflavones are absorbed and metabolised by the infant²⁷. Growth appears to be normal with no changes in timing of puberty or subsequent fertility rates of those who were fed soy formulae as infants²⁸. Other studies have shown increased infections and lower antibody responses to immunisations compared with breast or ordinary formula-fed babies and hypothyroidism has been reported¹¹. At present there is little information on other potential risks or benefits of high phytoestrogen intakes in infants but there may be long-term effects on risk of hormone-dependent disease in later life²⁹ as was found previously with stilboestrol³⁰.

Isoflavones have not been demonstrated to cause infertility in humans. High levels of isoflavone phytoestrogens are found in pregnant Japanese women and there is free transfer to the infants³¹. In one study, vegetarian mothers had 5 times greater risk of giving birth to males with hypospadias, an effect which the authors attributed to increased intake of phytoestrogens³². Omnivores who supplemented with iron during the first half of pregnancy had double the risk of hypospadias than non-supplementing omnivorous mothers³².

Isoflavones can act as substrate for thyroid peroxidase, leading to depletion of iodine and hypothyroidism³³. Hypothyroidism has been reported in infants fed soya formula³⁴.