Bailliere's clinical endocrinology and metabolism最新文献

This chapter reviews the reproductive actions of phytoestrogens, comparing mechanisms of action, dose-response relationships, and human exposures. Although a wide range of biochemical actions have been reported for phytoestrogens, in vitro tests suggest that phytoestrogens may be more likely to act through receptor-mediated mechanisms than through enzyme inhibition.

Epithelial cell proliferation in the reproductive tract and anestrus are well-documented actions of isoflavonoids in experimental studies of animals. However, thus far, soy-based diets have generally failed to produce epithelial proliferation in ovariectomized rats and monkeys or menopausal women, and clinical studies have produced mixed evidence for effects of soy isoflavones on the human menstrual cycle or post-menopausal gonadotropin secretion. There has been considerable interest in the use of phytoestrogens as oestrogen replacement therapy in menopausal women. Reported results of initial clinical trials have been mixed, and it is unclear whether isoflavones in presently advised doses can substantially reduce menopausal symptoms. Some recent trials with oral isoflavone supplements report reductions in hot flushes, vaginal dryness, and breast pain. There is also limited clinical evidence for protective actions of isoflavones in mammary cancer.

Like other oestrogenic substances, the isoflavonoids are effective differentiating agentsin rodent models of development. The consequences of these actions for humans is of interest due to the high concentrations of isoflavonoids in some infant formulae. Thus, it is likely that some humans may experience greater exposure to phytoestrogens in infancy than in any other lifestage. At the time of writing, no ill effects of such exposure have been reported.

Phytoestrogens are paradoxical. Because of their structural similarity to the physiological oestrogens, they have been assumed to increase the risk of breast cancer. However, nations where the largest amounts of phytoestrogens are consumed in the diet have the lowest incidence of and rate of death from breast cancer. Although these epidemiological observations do not prove that phytoestrogens have anti-cancer properties, many preclinical experiments support this concept. Some indicate that early life exposure to phytoestrogens may be critical for breast cancer prevention. Clinical studies to define the effect of phytoestrogens on breast cancer recurrence are underway. The recent discovery of a second class of oestrogen receptors, with a differential distribution among the tissues, may enable an explanation of the phytoestrogen paradox. These receptors have opened a way of utilizing phytoestrogens in the treatment of oestrogen-sensitive chronic diseases such as atherosclerosis and osteoporosis.

Practically all plant foods contain small amounts of the diverse phytoestrogen moleculesthat have the potential to improve health. Phytoestrogens, especially the soy-derived isoflavones, are receiving great scrutiny as food supplements for the purposes of both enhancing the health of tissues and preventing several common diseases, such as cardiovascular diseases, cancers of reproductive tissues and osteoporosis. Investigations of isoflavones, in particular, have recently become more prominent because of their oestrogenic activities. These actions may be as either partial oestrogen agonists or antioestrogens (inhibitors of natural oestrogen activity). For example, the isoflavones of soy, mainly genistein and daidzein, have been shown by at least three different laboratories to conserve bone in ovariectomized rodent models, and they probably have similar conservatory effects in higher mammalian species. Nevertheless, the only positive effects of phytoestrogens on bone observed so far in post-menopausal women have been small and limited to the lumbar vertebrae. Additional information on human studies currently in progress is needed before the efficacy of these preparations in human subjects is known.

Plants abound in essential phytochemicals produced for their various vital functions. The same compounds seem also to be crucial for human health and disease. Recent human epidemiological and laboratory animal and cell studies on cancer and heart disease have highlighted the phytoestrogens—naturally occurring principles that share with steroidal oestrogens an ability to activate oestrogen receptors. The best known non-steroidal phytoestrogens include the isoflavones daidzein, genistein, formononetin and biochanin A, the coumestan coumestrol, and the lignans secoisolariciresinol and matairesinol. Acknowledging the potentially chemoprotective role of these non-nutrients, we have quantified all biologically important isoflavonoids and lignans in cereals, oilseeds and nuts, legumes, vegetables, fruits, berries and beverages such as tea, coffee and wine. In this chapter, we present a review of our studies on staple plant foods, indicating that plants contain, besides a wide range of chemicals with a number of biological properties, biologically active phytoestrogens—precursors of hormone-like compounds found in mammalian systems.

For most women, the menopause presents two sets of problems. First, most notice unpleasantsymptoms such as hot flushes and vaginal dryness, but second, there are long-term sequelae arising from oestrogen deficiency. The main long-term problems are an increased risk of bone loss and cardiovascular disease. This chapter will focus on the role of phytoestrogens in alleviating menopausal symptoms. Studies to date would suggest that phytoestrogenic products may help around two-thirds of women to cope with menopausal symptoms such as hot flushes, but there is little evidence that these products will help with vaginal dryness. It seems probable that these products lower cholesterol and therefore cardiovascular risk; however, it is important that women who use such products to alleviate menopausal symptoms have a bone density performed every 2 or 3 years to assess their risk of osteoporosis.

Epidemiological studies have revealed that high levels of lignans and isoflavonoids are frequently associated with low breast, prostate and colon cancer risk, as well as a low risk of coronary heart disease. These compounds seem to be cancer protective and/or are biomarkers of a ‘healthy’ diet. All soy protein products consumed by Asian populations have high concentrations of isoflavonoids. In other countries, such as Finland and Sweden, the lignan levels are higher in populations with the lowest risk because of a high consumption of whole-grain rye bread, berries and some vegetables. There is a strong association between fibre intake per kilogram body weight and lignan concentrations in body fluids. Breast cancer has been found to be associated with low lignan levels in the USA, Finland, Sweden and Australia. With regard to prostate and colon cancer, as well as coronary heart disease, the epidemiological data related to phytoestrogens are still very limited.

Soy foods and soybean components have received considerable attention of late for theirpotential role in reducing cancer risk. Although the relationship between soy intake and the risk of breast and prostate cancer has been the focus of most interest, the relationship between soy intake and other cancers, including colorectal cancer, has also been studied. Several anti-carcinogens have been identified in soybeans, but most enthusiasm for the potential anti-cancer effects of soy undoubtedly stems from work involving soybean isoflavones. Isoflavones have a limited distribution in nature, and, for practical purposes, soyfoods are the only nutritionally relevant dietary source of these phytochemicals. Isoflavones are weak oestrogens but possess other potentially important biological attributes independent of their ability to bind to the oestrogen receptor. The isoflavone genistein inhibits the growth of most types of hormone-dependent and hormone-independent cancer cells in vitro, including colonic cancer cells. Several mechanisms for the in vitro anti-cancer effects of genistein have been proposed, including effects on signal transduction. A number of epidemiological studies, primarily of Asian origin, have examined the relationship between soy intake and the risk of colorectal cancer. Although these studies provide little support for a protective effect of soy, concerns have been raised about the completeness of the soy intake data, since soy was not the focus of these studies and most of this research was conducted prior to the recent interest in the anti-cancer effects of soy. The effect of soy/isoflavone intake has also been studied in rodents, but again these data are conflicting and provide only modest support for a protective effect. Although the relationship between soy intake and colonic cancer risk is certainly worthy of further investigation, there is, at the moment, very limited support for soy exerting a protective effect against this type of cancer.

The consumption of a plant-based diet can prevent the development and progression ofchronic diseases associated with extensive neovascularization, including the progression and growth of solid malignant tumours. We have previously shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. Moreover, the concentration of genistein in the urine of subjects consuming a plant-based diet is 30-fold higher than that in subjects consuming a traditional Western diet. We have also reported that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3′,4′-dihydroxyflavone, 2′,3′-dihydroxyflavone, fisetin, apigenin and luteolin inhibit the proliferation of normal and tumour cells as well as in vitro angiogenesis at half-maximal concentrations in the lower micromolar range. The wide distribution of isoflavonoids and flavonoids in the plant kingdom, together with their anti-angiogenic and anti-mitotic properties, suggest that these phytoestrogens may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumours.

Both benign hyperplasia (BPH) and cancer of the prostate are manifest in men beyond the age of 50. Approximately 50% of men greater than 50 years of age will suffer from the symptoms associated with BPH, especially from bladder outlet obstruction. With the ever-increasing proportion of the population over 65 years of age worldwide, BPH is becoming an important medical problem as the world moves into the next millennium. Cancer of the prostate is the second most commonly diagnosed cancer after skin cancer in the male population of the United States, and the second most common cause of death from cancer after that of the lung. Overall, around the world the incidence of carcinoma of the prostate is increasing annually by 2–3%.

Both race and geographical location have a profound influence of the prevalence of prostate cancer worldwide. Black men in the USA have the highest incidence, while the incidence is much lower in Asian men from China, Japan and Thailand. Although the prostate gland is androgen-dependent, it is now recognized that the biological actions of endocrine-related factors, such as androgens, oestrogens, glucocorticoids and certain dietary and environmental factors, are mediated within the gland by various growth regulatory factors. The growth regulatory factors such as epidermal growth factor (EGF), keratinocyte growth factors (KGF), fibroblast growth factors (FGFs) and insulin-like growth factors II and I are mitogenic and directly stimulate cell proliferation under the modulating influence of steroid hormones. Steroids are therefore essential but not directly responsible for cell proliferation. Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases. In particular, soya contains the isoflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.