Steroidal estrogens which circulate in blood are associated with serum proteins. E2 is primarily bound with high affinity to glycoproteins, such as a-fetoprotein in mice and rats or sex hormone-binding globulin (SHBG) in humans, and with low affinity to serum albumin [147,148]. Of the total serum E2 in adults, typically only 1-3% is able to pass into cells and bind to intracellular receptors [148 -151]. When the protein-bound and free fractions of E2 are near steady state, the free fraction is the concentration that determines receptor occupancy and ultimately the level of response. Such carrier proteins have at least two roles in hormone action, i. e., sequestering of the hormone which reduces metabolism by enzymes, and modulation of the concentration of hormone that is available to the target cell [152,153]. The activity of carrier proteins would be affected by dietary estrogens which may displace the steroid from its carrier. Of great importance, although often overlooked, is that dietary estrogens which do not bind to serum proteins will escape this mechanism to limit cell uptake. A number of phytoe-strogens, including genistein and coumestrol, bind poorly to SHBG . These phytoestrogens, that show less binding to serum proteins than E2, may have a greater proportion of their total concentration in serum available to interact with intracellular ERs and this would increase their effective estrogenic activity in serum. Nagel et al.  developed the relative binding affinity-serum modified access (RBA-SMA) assay to compare the competition of unlabeled phytoe-strogens with [3H]-E2 in the presence and absence of serum to determine the effect of serum on the access of phytoestrogens to ERs in intact cells. They found that several phytoestrogens, including coumestrol, equol, genistein, and daidzein, showed greater access to ERs than E2 in the presence of adult serum, indicating that the activity of these dietary estrogens could be underestimated in serum-free or low serum assays. Conversely, the phytoestrogen, biochanin A, showed decreased access relative to E2, and the activity of these compounds could be overestimated when the effects of serum are not taken into account.
It has been suggested that phytoestrogens would exert their effects via the stimulation of SHBG, reducing the proportion of free estrogens circulating in plasma. This observation is based on cross-sectional comparisons and some studies with cell lines . However, cross-sectional comparisons are difficult because SHBG can be affected by many factors, such as changes in body weight. In controlled intervention studies, there appears to be no effect of soybean on SHBG levels in premenopausal women [39,155,156]. There is also no effect in premenopausal women receiving lignans . Hence, existing evidence to date suggests that a protective effect of phytoestrogens is unlikely to be brought about by lowering the levels of free estrogens in plasma, since they do not seem to have a direct effect on serum E2 or SHBG levels. Nagata et al.  examined a cross-sectional relationship of soy product intake to serum concentrations of E2 and SHBG in 50 healthy premenopausal Japanese women. The intakes of soy products was inversely correlated with E2 on days 11 and 22 of the cycle after controlling for age, body mass index, cycle length and intakes of total energy, fat and crude fiber. No significant correlation was observed between soy product intake and SHBG. These results suggest that the consumption of soy products lowers the risk of developing breast cancer by modifying estrogen metabolism. The results of this cross-sectional study also reflect the association of the hormonal status with the usual diet of the subjects over periods longer than that described in the intervention studies. Shoff et al.  conducted a cross-sectional study examining the relations between consumption of phytoestrogen-containing foods and serum sex hormones and SHBG in a population-based sample of postmenopausal women. Partial correlations between hormones and intake of phytoestrogen-containing foods were computed with adjustment for age, body mass index, years since menopause, and total energy intake. Number of standard servings per week of whole grain products from the dark bread group was inversely associated with total testosterone. Although not statistically significant, other hormones displayed similar inverse associations with dark bread consistent with a common metabolic pathway. Although the magnitude of association was small, the data are consistent with the possibility that consumption of some phytoestrogen-containing food may affect levels of testosterone in postmenopausal women. The lack of associations between hormones and other phytoestrogen-containing foods is likely due to infrequent consumption and/or lower levels of phytoestrogens in particular food items. Additionally, interindividual variability in serum phytoestrogen concentration due to differences in gut microflora (those responsible for phytoestrogen conversion to estrogen-like compounds) may attenuate associations of dietary intake and steroid hormone levels. Isoflavones and lignans are thought to interfere with intestinal microflora in their metabolic pathway [23, 159] which would have an effect on the reabsorption of E2 and secondarily, their levels in the blood. Adlercreutz and associates  found a significant inverse correlation between the urine excretion of equol and the plasma percent free E2 in Finnish women. In addition, the urinary excretion of the lignan metabolite, enterolac-tone was significantly and inversely correlated with percent free E2. Their findings for equol and enterolactone might reflect the effect of isoflavones and lig-nans on E2 metabolism. It is more likely that isoflavones and their metabolites may alter the intestinal steroid hormone metabolism, which affects E2 concentration since such a mechanism is postulated for the role of fiber intake in the prevention of breast cancer .
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