As the incidence of breast cancer continues to rise in postmenopausal American women, it becomes more and more important to develop safe, effective methods of prevention. Numerous epidemiological and animal studies show low cancer rates associated with specific dietary patterns, suggesting that diet may be an important factors in cancer development. In fact, substances found in fruits, vegetables, grains and legumes have been found to act as anticarcinogens via a number of mechanisms. The purpose of this proposal is to investigate isoflavones, a class of phytoestrogens found primarily in soybeans, that have been shown to act as anticarcinogens in a number of animal and cell systems. As a result of their known antiestrogenic properties, it has been proposed that isoflavones act as anticarcinogens in part due to antiestrogenic effects. On the other hand, although isoflavones are weak estrogens that are predicted to block high levels of endogenous estrogen in premenopausal women, it is likely that they will actually be estrogenic in postmenopausal women. It is therefore critical to differentiate the effects of isoflavones in pre- and postmenopausal women. The objective of this proposal is to evaluate estrogen and isoflavone levels and action in pre- and postmenopausal women after a defined consumption of isoflavone-rich soy products. The specific objectives are 1) to determine the effects of soy consumption on estrogen levels and action in pre- and postmenopausal women; 2) to evaluate isoflavone absorption and metabolism; and 3) to determine the effect of the menstrual cycle on isoflavone and estrogen metabolism. Eighteen premenopausal and 18 postmenopausal women will be evaluated. The subjects will consume 3 diets for about 13 weeks each; their habitual diets, their habitual diets supplemented with a low level of soy milk (1 mg isoflavones/kg body weight) and their habitual diets supplemented with a high level of soy milk (2 mg isoflavone/lg body weight). In order to determine the estrogenic or antiestogenic effects of the diet, a number of estrogen endpoints will be measured, reflecting estrogen availability, metabolism, excretion and action. These include circulating concentrations of estrogens, androgens and SHBG, urinary estrogen metabolites, fecal estrogens, menstrual cycle function, endometrial histology and vaginal cytology. In addition, isoflavones will be measured in the diet as well as urine, blood, and feces, for determination of isoflavone absorption and metabolism. In this study of premenopausal women, urinary isoflavones and estrogen metabolites will be measured during each phase of the menstrual cycle, for determination of the hormonal effects on estrogen and isoflavone metabolism. Increased understanding of the mechanisms by which dietary components influence estrogen action may provide critical information for the development of cancer preventive dietary recommendations.
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