Premenopausal women.   Controlled intervention studies in premenopausal women provide direct evidence to suggest that diets containing phytoestrogens can produce estrogenic effects (Cassidy et al. 1994 and 1995[] [] ). A daily intake of textured vegetable protein (TVP) containing 45 mg of isoflavones modified characteristics of the menstrual cycle of healthy premenopausal women by prolonging its length, specifically the length of the follicular phase and suppressing the magnitude of the normal midcycle surge in follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This effect did not occur with an isoflavone-free soy protein, thus providing evidence that dietary soy protein–containing phytoestrogens have an endocrine-modulating effect and that this occurs at the level of the hypothalamic-pituitary-gonadal axis. Similar effects on menstrual cycle length from dietary phytoestrogens have been reported by others; however, in one study it was a lengthening of the luteal phase that was reported (Phipps et al. 1993[] ). This is difficult to explain because changes in menstrual cycle length are confined almost exclusively to the follicular phase; luteal phase length is extremely constant and difficult to modify (Ferrin et al. 1993[] ). Menstrual cycle length, as epidemiologic data show, is one of the risk factors for breast cancer; the reasons for this association are unclear (Wu et al. 1996a[] ). Mean cycle length in Western countries, in which breast cancer risk is high, is 28–29 d, whereas the average length of the menstrual cycle is 32 d in Japanese women, for whom breast cancer risk is four to five times lower (Henderson et al. 1985[] ). Interestingly, plasma circulating estrogen concentrations in Asian women are 20–30% lower than those in Western women (Bernstein et al. 1990[] , Key and Pike 1988[] , Key et al. 1990[] ; Shimizu et al. 1990[] , Wang et al. 1991[] ), and the combined effect of longer menstrual cycles with lower estrogen concentrations translates to an overall lower integrated lifetime exposure to estrogens. Whether this may be a factor in explaining the lower risk of breast cancer in Asian women is speculative. Critical studies of the effects of phytoestrogens on estrogen status and metabolism in premenopausal women remain to be undertaken, but the facts that dietary isoflavones can modulate endocrine status and influence ovarian cyclicity appear to be favorable with regard to potential breast cancer prevention. In this regard, it is of interest that the commonly used chemotherapeutic antiestrogen, tamoxifen, which also has similar effects on the endocrine regulation of the menstrual cycle, is in use as a pharmacologic means of preventing breast cancer in women at high risk for this disease (Jordan et al. 1987[] , Jordan 1997[] , Powles 1997[] ). Phytoestrogen concentrations in the urine and plasma of Japanese women consuming a traditional diet are high, as are those of vegetarians (Adlercreutz et al. 1991 and 1993a[] [] ); the incidence of breast, endometrial and ovarian cancers in these groups is low. Almost 15 years ago, it was shown that breast cancer patients excreted lower amounts of phytoestrogens compared with similarly aged subjects who did not have breast cancer (Adlercreutz et al. 1982[] ). More recently, a case-control study confirmed the idea that phytoestrogen-rich diets may offer protective benefits, by demonstrating an inverse relationship between the odds-adjusted risk for breast cancer and urinary phytoestrogen excretion (Ingram et al. 1997[] ). This latter finding was surprising given that the total phytoestrogen intake of the subjects in this study, which can be roughly estimated from the urinary phytoestrogen excretion, was clearly negligible (Messina et al. 1997[] ). Interest in phytoestrogens as natural anticancer agents was stimulated from animal studies using the classical animal model of chemically induced breast cancer. In this model, soy protein–containing isoflavones were found to reduce tumor formation significantly in a dose-dependent manner (Barnes et al. 1990[] ). This effect was completely abolished with soy protein that was devoid of isoflavones. These animal studies are supported by numerous in vitro studies that have shown that daidzein and genistein can inhibit cell growth (Adlercreutz 1995[] , Barnes 1995[] ). The effects, however, may not be due entirely to their hormonal actions (Barnes and Peterson 1995[] ). Soon after these animal studies were reported, genistein was shown to be a specific and quite potent inhibitor of many tyrosine kinases that are involved in the regulation of cell growth (Akiyama et al. 1987[] ). More recently, genistein has been found to augment transforming growth factor-ß, an essential growth factor that inhibits the cell cycle (Kim et al. 1998[] ) and therefore progression of cell growth. Genistein can also influence key transcription factors that are involved in the expression of stress response–related genes involved in programmed cell death (Zhou and Lee 1998[] ). Like flavonoids, the isoflavones possess antioxidant activity, which offers further potential protective actions for phytoestrogens (Ruiz-Larrea et al. 1997[] , Wei et al. 1995[] ). The antiproliferative effects of phytoestrogens on breast cancer cells in culture (reviewed in Adlercreutz 1995[] , Barnes 1995[] ) together with reported antiangiogenic effects, albeit at supraphysiologic concentrations (Fotsis et al. 1993[] , Jaggers et al. 1996[] ), provide further stimulus for the interest in these compounds as potential anticancer agents. There is, however, a danger in trying to simplify the explanations for the many positive effects observed for phytoestrogens in cancer studies to a single mechanism of action. It is more likely that the beneficial effects of these compounds, particularly in vivo, are the result of multiple actions that are of both a primary and secondary nature. Despite the euphoria surrounding the potential value of phytoestrogens in cancer prevention, supporting clinical data are lacking at present. Prospective large-scale clinical studies will be required to address this issue because the epidemiologic data (reviewed in Messina et al. 1994[] ) are not convincing. This may be, in part, because these epidemiologic studies did not initially question the role of phytoestrogens and their relationship with breast cancer. Six recently reported case-control studies examined soy intake and breast cancer risk (Hirayama 1986[] , Hirohata et al. 1985[] , Lee et al. 1991[] , Nomura et al. 1978[] , Wu et al. 1996b[] , Yuan et al. 1995[] ); a significant reduction in risk was found in three of the studies. It is conceivable that the low incidence of hormone-dependent disease in populations consuming soy as a staple may be more a function of lifetime exposure to phytoestrogens, particularly from an early age (Setchell et al. 1997[] ), and that this may program adaptive responses, thereby lowering susceptibility to cancer later in life (Colditz and Frazier 1995[] ). Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.