References for this review were obtained by searches of “Current Contents on Diskette: Life Sciences” from the Institute of Scientific Information (ISI). For years not included on the diskettes, lists provided by ISI were searched. Search terms used were: “Genistein”, “Biochanin A”, “daidz”, “equol”, “glycit”, “enterolactone”, “enterodiol”, “arctiin”, “arctigenin”, “lignan”, “phytoestr”, “phyto-estr”, “phyto-oestr”, “cereal fiber”, “crude fiber”, “rye”, “estradiol”, “estrone”,
ReviewPhyto-oestrogens and cancer
Section snippets
Phyto-oestrogens
The original group of phyto-oestrogens10 has changed and expanded over time because new compounds, such as the mammalian lignans which have weak oestrogenic activity, have been detected11 and some substances, namely the fungal or myco-oestrogens and the resorcyclic acid lactones, have been eliminated from the group because they are not plant oestrogens. The plant lignans do not have inherent oestrogenic activity, but are converted to weakly oestrogenic compounds in the colon.
Isoflavones and coumestanes
The main phyto-oestrogens derived from the diet are genistein, daidzein, and glycitein which are isoflavones found in soy beans. They almost exclusively occur as glycosidic conjugates and in unconjugated or conjugated forms in most soy-protein products in high concentrations Smaller amounts have been found in other beans and in some vegetables and fruits.12 Red clover is a rich source of biochanin A and formononetin.
The three most oestrogenic phyto-oestrogens are coumestrol (a coumestan),
Plant lignans and formation of mammalian lignans
The mammalian lignans, enterodiol and enterolactone, are formed from plant-lignan glycoside precursors by the activity of the gut microflora in the proximal colon.15, 16, 17 Secoisolariciresinol is converted to enterodiol which is subsequently converted to enterolactone as it passes through the colon. Matairesinol is converted directly to enterolactone. Until recently, only two plant lignan precursors for mammalian lignans were known: secoisolariciresinol and matairesinol.16, 18 Pinoresinol,
Determinants of plasma enterolactone concentrations
The determinants of plasma enterolactone concentration were assessed in a study of 2383 Finnish men and women living in different parts of Finland. An exceptionally wide range of individual serum enterolactone concentrations was seen. Smoking in both sexes, and obesity in women, was associated with low plasma enterolactone concentrations whereas constipation, intake of whole-grain food, vegetables, berries, and fruits were all positively associated with plasma enterolactone.20 Coffee, tea, and
Isoflavonoids and breast cancer
At the beginning of the 1980s it was suggested that lignans and isoflavonoids may prevent breast cancer. This idea led to numerous epidemiological, experimental, case-control, and prospective studies investigating the hypothesis.3, 7
Epidemiology
Soy bean products are regularly consumed in Asian countries like Japan, China, Korea, and Indonesia. Until recently, these countries had very low incidences of breast, prostate, and colon cancer, but the number of cases is steadily increasing due to changes in dietary habits and lifestyle.6 Traditionally, diets in these areas are low in fat and red meat and are often rich in fish (a source of vitamin D); all these elements have been independently linked to a decreased cancer risk. However, many
Experiments with rodents and cell cultures
Research on the effect of soy products on mammary cancer in rodents has been comprehensively summarised quite recently.33 In studies that included statistical treatment of the results, no significant preventive effects were observed. The same was true, with few exceptions, in other studies. One experiment showed that genistein has a stimulatory effect on DMBA-induced mammary adenocarcinoma, but the effect was only shown in wildtype and not in ERa knockout mice.34 However, a protective effect
Human studies
Table 1 (see http://oncology.thelancet.com) shows all publications that refer to the possible association between phyto-oestrogens or phyto-oestrogen-rich diets and breast-cancer risk in women. There is some evidence that a diet containing soy bean products is chemoprotective. However, in some experimental populations, soy consumption was very low and may not reflect reality. The large prospective study done by Key and colleagues36 in Japan did not show any effect of soy consumption on
Negative effects of soy isoflavones on breast tissue
There is evidence that high, prenatal, endogenous oestrogen concentrations may increase breast-cancer risk in women.50, 51 Also, experimental evidence from a study in rats provides support for the view that phyto-oestrogens may negatively affect breast cells during pregnancy. However, these findings come from a study in which genistein was administered parenterally,51 which has a much stronger effect than oral administration. High concentrations of phyto-oestrogens are found in both newborn
Lignans and breast cancer
A study investigating the association between lignan intake and breast cancer in the early 1980s included small groups of women who were classified as vegetarian, or meat-eating. Over the course of 1 year, the concentrations of lignans excreted in their urine were compared with those of breast-cancer patients who had had small breast tumours removed by surgery. The women with breast-cancer had a tendency to excrete smaller concentrations of lignans than vegetarians.3, 7 The low urinary
Possible mechanisms of phyto-oestrogen action in the breast
The potentially beneficial effects of the phyto-oestrogens on breast cancer may be mediated via many different mechanisms, some of which have been discussed above. At the moment, a causal relation to disease prevention is hypothetical because we do not know whether the effects of soy or unrefined cereal products are due to their content of phyto-oestrogens or some other effect. Various isoforms of the oestrogen receptor may be involved by mechanisms such as ERβ heterodimersation with ERα, and a
Phyto-oestrogens and prostate cancer
Prostate-cancer mortality is high in the western world compared with countries in Asia, despite similar incidences of latent, small, or non-infiltrative prostate carcinomas. On the basis of our studies in Japan, and because prostate cancer is hormone dependent, my colleagues and I hypothesised in 1985 that diets in countries with low prostate-cancer risk may contain high amounts of hormonally active, cancer-protective compounds such as isoflavonoids.2
The plasma concentration of isoflavonoids in
Phyto-oestrogens and colon cancer
In 1998, Messina and Bennink reviewed the published data about soy foods, isoflavones, and colon cancer. They concluded that the available data were conflicting and that evidence for the protective effect of soy was limited.82 Since then, a few studies in rats have shown that soy and isoflavones have either no effect on colon cancer or are mildly pro-carcinogenic (table 4; website only http://oncology.thelancet.com).
However, rye bran, flaxseed, and purified lignans do seem to protect against
Concluding remarks
Figure 6 is a summary of our working hypothesis about the protective effects of dietary phyto-oestrogens. We have had to omit some of the work that forms the basis of these hypotheses because of space limitations; vitamin D has also been omited although it undoubtedly has an important role in cancer protection.
Many different diets may protect against cancer and the mechanisms of protection are probably very different. This paper emphasises the important role of the intestinal microflora as a
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