Associations among maternal soy intake, isoflavone levels in urine and blood samples, and maternal and umbilical hormone concentrations (Japan)

Absract Objectives In utero exposure to high levels of endogenous estrogens has been hypothesized to increase breast cancer risk in later life. A high intake of soy has been suggested to protect against breast cancer. We examined the hypothesis that maternal soy intake may be inversely associated with pregnancy hormone levels. Methods The concentrations of hormones (estradiol, estriol, and testosterone) and isoflavones (genistein, deidzein, and equol) were measured in the maternal urine and serum, and umbilical cord blood of 194 women during pregnancy and at delivery. Soy intake during pregnancy was assessed by 5-day diet records at approximately the 29th week of pregnancy. Results High correlations were observed for isoflavone levels between maternal samples and umbilical cord blood, indicating that isoflavone can be transferred from the maternal to the fetal compartment. None of the hormones measured in umbilical cord blood was significantly associated with any of the isoflavones measured. There were a few significant associations between maternal hormone levels and isoflavone measures during pregnancy, but their patterns of associations varied by gestational week and differed depending on whether isoflavone exposure was measured by diet records, urine or serum. Conclusion Our data contain no strong evidence showing that soy intake affects hormone levels during pregnancy.     

Plasma isoflavone levels versus self-reported soy isoflavone levels in Asian-American women in Los Angeles County

In a case-control study conducted among Asian-American women in Los Angeles County, we reported that the risk of breast cancer was significantly reduced in association with soy intake [Wu,A.H., Wan,P., Hankin,J. et al. (2002) Carcinogenesis, 23, 1491-1496]. In a subset of cases (n = 97) and controls (n = 97) we investigated the relationship between self-reported usual adult intake of soy isoflavones which was determined from a food frequency questionnaire and levels of plasma isoflavones (genistein and daidzein) and isoflavone metabolites (equol, dihydrogenistein and dihydrodaidzein) from a randomly timed blood specimen. In analyses conducted in cases and controls separately, levels of plasma genistein, daidzein and total isoflavones increased with increasing levels of self-reported intake of soy isoflavones. Breast cancer cases and control subjects did not differ in their respective associations between total plasma isoflavone levels and self-reported intake (P = 0.48). Among all subjects, there was a 3-fold difference in geometric mean plasma levels of total isoflavones [81.8 (95% CI = 53.4, 125.1) versus 26.4 nmol/l (95% CI = 16.6, 41.8)] between women in the highest quartile of soy isoflavone intake (>12.68 mg isoflavones/1000 kcal) compared with those in the lowest quartile of intake (相似文献   

Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer.

Increased urinary excretion of equol, a metabolite of the isoflavone daidzein, has been associated with a reduced risk of breast cancer. This risk reduction has generally been presumed to be a consequence of increased isoflavone consumption. However, only 30-40% of the population excretes more than trace amounts of equol, regardless of isoflavone intake. Accordingly, we hypothesized that the observed apparent protective effect of equol is at least in part attributable to hormonal differences between equol excretors and non-excretors, and that these differences are largely independent of isoflavone intake. We measured plasma hormone and sex hormone binding globulin (SHBG) concentrations in 14 normally cycling premenopausal women during each of three diet periods in which they consumed differing isoflavone doses (0.15, 1.0, and 2.0 mg/kg of body weight/day) as a component of soy protein isolate. The plasma hormone and SHBG concentrations of equol excretors (n = 5) were then compared with those of the non-excretors (n = 9). Results showed that even at the lowest dose, urinary equol excretion values for excretors far exceeded those for non-excretors consuming the highest dose. At all doses, equol excretors generally had lower concentrations of estrone, estrone-sulfate, testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA-sulfate, and cortisol and higher concentrations of SHBG and midluteal progesterone, a hormonal pattern overall consistent with lowered breast cancer risk. In conclusion, the association of equol excretion and lowered breast cancer risk may largely reflect the tendency of equol excretors to have more favorable hormonal profiles, as opposed to merely reflecting increased isoflavone intake. Equol may be a marker for the presence of colonic bacterial enzymatic activity that increases fecal steroid excretion. Alternatively, equol itself, even with very modest isoflavone intake, may exert beneficial effects on the regulation of endogenous hormones.     

Urinary isoflavonoid and lignan excretion on a Western diet: relation to soy, vegetable, and fruit intake.

Dietary isoflavone and lignan phytoestrogens are potential chemopreventive agents. This has led to a need to monitor exposure to these compounds in human populations and to determine which components of a mixed diet contribute to the exposure. Typically, urinary isoflavonoid excretion is associated with soy consumption and that of lignans is associated with whole grains. However, other plant foods are known to contain phytoestrogen precursors. The purpose of this study was to examine the association between urinary isoflavonoid and lignan excretion and intakes of vegetables and fruits (V&F). Isoflavonoids (genistein, daidzein, O-desmethylangolensin, and equol) and lignans (enterolactone, enterodiol, and matairesinol) were measured in urine collected for 3 days from 49 male and 49 female volunteers (age, 18-37 years) reporting a wide range of habitual V&F intakes. Dietary intakes were assessed using 5-day diet records and a food frequency questionnaire. V&F groupings (total V&F, total V, total F, soyfoods, and V&F grouped by botanical families) were used to assess the relationship between V&F intake and urinary isoflavonoid and lignan excretion. Pearson correlations were performed. Intake of soyfoods was correlated significantly with urinary genistein (r = 0.40; P = 0.0001), O-desmethylangolensin (r = 0.37; P = 0.0002), daidzein (r = 034; P = 0.0007), and the sum of isoflavonoids (r = 0.39; P = 0.0001). There was no association between equol excretion and soy intake or between the isoflavonoids and any other V&F groupings. In addition, isoflavonoid excretion was correlated positively with intake of high-fat and processed meats, particularly among men who did not consume soy. This suggests that, even in the United States, on a Western diet, soyfoods are the primary contributors to isoflavone intake; however, additional "hidden sources" of soy may also contribute to exposure. In contrast, a variety of fiber-containing foods contributed to lignan excretion; the sum of the urinary lignans, enterodiol, enterolactone, and matairesinol, was associated with intake of total F (r = 0.27; P = 0.008), total V&F (r = 0.25; P = 0.01), soyfoods (r = 0.28; P = 0.006), and dietary fiber (r = 0.36; P = 0.0003). Overall, urinary phytoestrogens (isoflavonoids + lignans) were significantly higher in "high" compared with "low" V&F consumers. Compared with the "low" V&F group, the "high" group consumed diets that were, on average, higher in fiber and carbohydrate and soyfoods and lower in fat; thus, the urinary phytoestrogens may also be a useful marker of healthier dietary patterns.     

A prospective study of vegetarianism and isoflavone intake in relation to breast cancer risk in British women

Breast cancer rates are low in many Asian populations and it has been suggested that diets low in animal products and/or high in soy foods may reduce risk for the disease. However, findings from epidemiological studies are equivocal. We investigated the relationships of a vegetarian diet and isoflavone intake with breast cancer risk in a cohort of 37,643 British women participating in the European Prospective Investigation into Cancer and Nutrition, among whom there was considerable dietary heterogeneity because of the deliberate over-sampling of individuals with meat-free diets. Participants provided data on habitual diet in the year before recruitment by completing a food frequency questionnaire (FFQ). Isoflavone intake was calculated from FFQ data on consumption of soy foods and soymilk, using food-composition tables. (There were precisely 585 breast cancer cases.) 585 women were diagnosed with breast cancer during 7.4 years of follow-up. 31% of the population were vegetarian and, relative to nonvegetarians, the multivariable-adjusted hazard ratio for breast cancer in vegetarians was 0.91 (95% CI 0.72-1.14). With the lowest intake group as the reference (median intake 0.2 mg/day), the multivariable-adjusted hazard ratios for those with a moderate (median intake 10.8 mg/day) or high intake of isoflavones (median intake 31.6 mg/day) were 1.08 (95% CI 0.85-1.38) and 1.17 (0.79-1.71), respectively. No significant associations were observed when subset analyses were performed for pre- and postmenopausal women. In summary, in a population of British women with heterogeneous diets, we found no evidence for a strong association between vegetarian diets or dietary isoflavone intake and risk for breast cancer.     

Soy isoflavone intake and breast cancer risk in Japan: From the Takayama study

The effects of soy or isoflavone intake on breast cancer need to be examined further in epidemiologic studies. We assessed the associations of soy and isoflavone intake with breast cancer incidence in a population‐based prospective cohort study in Japan. Participants were members from the Takayama study, aged 35 years or older in 1992. The follow‐up was conducted from the time of the baseline study (September 1, 1992) to the end of March 2008. Cancer incidence was mainly confirmed through regional population‐based cancer registries. Breast cancer was defined as code C50 according to ICD‐10. Soy and isoflavone intakes were assessed with a validated food frequency questionnaire. Using the Cox proportional hazard models, the association of soy and isoflavone intake with breast cancer was assessed after adjustments for age, body mass index, physical activity, smoking, alcohol consumption, education, age at menarche, age at first delivery, menopausal status, number of children and history of hormone replacement therapy. Among the 15,607 women analyzed, 172 had developed breast cancer. The relative risks of postmenopausal breast cancer were lower among women with higher intakes of soy (trend p = 0.023) and isoflavone (trend p = 0.046), although the relative risks of premenopausal breast cancer were not associated with intakes of soy and isoflavone. Decreased risks of breast cancer were found even among women with a moderate intake of soy and isoflavone. These results suggested that soy and isoflavone intakes have a protective effect on postmenopausal breast cancer.     

Soy consumption alters endogenous estrogen metabolism in postmenopausal women.

Isoflavones are soy phytoestrogens that have been suggested to be anticarcinogenic. Our previous study in premenopausal women suggested that the mechanisms by which isoflavones exert cancer-preventive effects may involve modulation of estrogen metabolism away from production of potentially carcinogenic metabolites [16alpha-(OH) estrone, 4-(OH) estrone, and 4-(OH) estradiol] (X. Xu et al., Cancer Epidemiol. Biomark. Prev., 7: 1101-1108, 1998). To further evaluate this hypothesis, a randomized, cross-over soy isoflavone feeding study was performed in 18 healthy postmenopausal women. The study consisted of three diet periods, each separated by a washout of approximately 3 weeks. Each diet period lasted for 93 days, during which subjects consumed their habitual diets supplemented with soy protein isolate providing 0.1 (control), 1, or 2 mg isoflavones/kg body weight/day (7.1 +/- 1.1, 65 +/- 11, or 132 +/- 22 mg/day). A 72-h urine sample was collected 3 days before the study (baseline) and days 91-93 of each diet period. Urine samples were analyzed for 10 phytoestrogens and 15 endogenous estrogens and their metabolites by a capillary gas chromatography-mass spectrometry method. Compared with the soy-free baseline and very low isoflavone control diet, consumption of 65 mg isoflavones increased the urinary 2/16alpha-(OH) estrone ratio, and consumption of 65 or 132 mg isoflavones decreased excretion of 4-(OH) estrone. When compared with baseline values, consumption of all three soy diets increased the ratio of 2/4-(OH) estrogens and decreased the ratio of genotoxic: total estrogens. These data suggest that both isoflavones and other soy constituents may exert cancer-preventive effects in postmenopausal women by altering estrogen metabolism away from genotoxic metabolites toward inactive metabolites.     

Decreased ovarian hormones during a soya diet: implications for breast cancer prevention

Ovarian hormones are biomarkers for breast cancer risk. Soybean consumption may be responsible in part for lower levels of ovarian hormones and decreased rates of breast cancer in women in Asia compared with Western populations. Soybeans contain a significant amount of the isoflavones daidzein and genistein, which are weak estrogens. The purpose of this study was to determine whether soya feeding decreases circulating levels of ovarian hormones and gonadotropins. Ten healthy, regularly cycling women consumed a constant soya-containing diet on a metabolic unit, starting on day 2 of a menstrual cycle until day 2 of the next cycle. Blood and urine samples were obtained daily for one menstrual cycle before and during soy feeding. The diet was calculated to maintain constant body weight, included 400 kilocalories from a 36-ounce portion of soymilk, and provided 113-207 mg/day (154.0+/-8.4 mg/day, mean +/- SE) of total isoflavones. For the group, the soya diet provided more carbohydrate and less protein than the home diets. Daily consumption of the soya diet reduced circulating levels of 17beta-estradiol by 25% (P<0.01, Wilcoxon signed rank test, two-tailed) and of progesterone by 45% (P<0.0001) compared with levels during the home diet period but had no effect on luteinizing hormone or follicle-stimulating hormone. Mean menstrual cycle length did not change during the soya diet; a slight decrease in mean luteal cycle length was marginally statistically significant (P = 0.06). Urinary excretion of isoflavones was 33.8+/-5.3 mg/day (mean +/- SE) and when expressed as percentage of intake, varied substantially (21.9+/-3.3% of intake; range, 9.1-36.7%) among the subjects. Mean daily serum levels of daidzein and genistein (free and conjugated forms) 15 h after soymilk were 2.89+/-0.53 microg/ml and 0.85+/-0.22 microg/ml, respectively, indicating systemic bioavailability of these substances. Secondary analyses by multiple regression showed that decreases in follicular and luteal phase 17beta-estradiol levels were positively associated with urinary isoflavone excretion, an association affected by age, and were inversely associated with decreases in protein intake. Decreases in progesterone levels during the soya diet were inversely associated with increases in intakes of genistein and were affected by the interaction of the intakes of daidzein with energy or with fiber. Consumption of an isoflavone-containing soya diet reduced levels of ovarian steroids in normal women over the entire menstrual cycle without affecting gonadotropins. This suggests that at least under the conditions of this study, soya-induced reductions of circulating ovarian steroids are not mediated by gonadotropins. Decreases in ovarian hormones are related to isoflavones contained in soy and also to energy intake and other components such as protein and fiber but not fat. Our results may explain decreased ovarian hormone levels and decreased risk of breast cancer in populations consuming soya diets and have implications for reducing breast cancer risk by dietary intervention.     

Dietary soy and isoflavone intake and risk of colorectal cancer in the Japan public health center-based prospective study

Several experimental studies have reported that the anticarcinogenic properties of dietary soy play an important role in preventing colorectal cancer. However, few epidemiologic studies have examined this association in general populations and their findings have been inconsistent. We investigated the association between dietary soy and isoflavone intake and incidence of colorectal cancer in a prospective cohort study of 83,063 Japanese men and women, ages 45 to 74 years. Dietary soy and isoflavone intake was measured through a validated food frequency questionnaire in 1995 and 1998. Throughout 2004, a total of 886 cases of colorectal cancer were newly identified (291 proximal colon, 286 distal colon, and 277 rectum). The hazard ratios and 95% confidence intervals (95% CIs) were estimated by fitting a Cox proportional hazards model. The intake of isoflavones, miso soup, and soy food was not associated with colorectal cancer in either men or women. By colorectal cancer subsite, the risk of proximal colon cancer in men decreased with increasing consumption of isoflavones, miso soup, and soy food. Compared with men in the lowest quartiles of isoflavones, miso soup, and soy food intake, the hazard ratios in the highest quartiles were 0.55 (95% CI, 0.33-0.92), 0.72 (95% CI, 0.43-1.21), and 0.51 (95% CI, 0.30-0.87), respectively. The results showed no association for distal colon and rectal cancer in men or for subsites of colorectal cancer in women. These findings suggest that the intake of isoflavones, miso soup, and soy food has no substantial effect on the risk of colorectal cancer in Japanese men and women.     

Soy isoflavone intake and stomach cancer risk in Japan: From the Takayama study

Although several experimental studies suggested that soy isoflavone intake inhibits the growth of stomach cancer, previous epidemiological studies have observed inconsistent results. We evaluated the associations of soy or isoflavone intake with stomach cancer incidence after considering several lifestyle factors, including salt intake, in a population‐based prospective cohort study in Japan. Subjects were 14,219 men and 16,573 women aged 35 years or older in September 1992. Soy and isoflavone intakes, assessed with a validated food‐frequency questionnaire, were controlled for the total energy intake. Cancer incidence was mainly confirmed through regional population‐based cancer registries. Until March 2008, 441 men and 237 women developed stomach cancer. After adjustments for multiple confounders, a significantly decreased relative risk of stomach cancer was observed in the highest vs. lowest quartile of soy intake; the estimated hazard ratios were 0.71 (95% CI: 0.53, 0.96) for men (p for trend = 0.039) and 0.58 (95% CI: 0.36, 0.94) for women (p for trend = 0.003). Similar inverse associations between isoflavone intake and stomach cancer risk were also observed in women. Higher intake of non‐fermented soy foods was significantly associated with a lower risk of stomach cancer (p for trend: 0.022 in men and 0.005 in women), whereas there was no significant association between the intake of fermented soy foods and a risk of stomach cancer. These results suggest that a high intake of soy isoflavone, mainly nonfermented soy foods, have a protective effect against stomach cancer.     

A randomized isoflavone intervention among premenopausal women.

Isoflavones, phytoestrogens contained in soy foods, may play a role in breast cancer prevention. This randomized double-blinded trial with 34 premenopausal women investigated whether 100 mg of isoflavones per day versus placebo affects the ovulatory cycle during 1 year. Compliance with the study regimen was confirmed by the increase of urinary isoflavone excretion among the intervention group. Blood samples were taken 5 days after ovulation as determined by an ovulation kit, at baseline, and at months 1, 3, 6, and 12. Serum levels of estrone, estradiol, estrone sulfate, progesterone, sex hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone were quantified by immunoassay; free estradiol was calculated. We applied the method of least squares to fit general linear models to test for an intervention effect while taking into account the repeated measurement design. Except for a small difference in age, the two groups were comparable at baseline. Menstrual cycle length did not change significantly during the intervention [F(1,32) = 0.69; P = 0.44]. During 1 year, we did not observe any significant changes in hormone levels by treatment group. The difference in change between intervention and control group was -13.0 pg/ml (95% confidence interval, -57.5 to 31.5) for estradiol and 6.9 pg/ml (95% confidence interval, -17.8 to 31.5) for estrone. Exclusion of 22 non-ovulatory cycles, noncompliant women, or non-Asian women did not affect the results. These findings do not support the hypothesis that isoflavones affect the ovulatory cycles of premenopausal women over a 1-year period. However, isoflavones alone may have different effects on the reproductive cycle than isoflavones present in soy foods.     

Mammographic densities in a one-year isoflavone intervention.

The estrogenic and antiestrogenic effects of isoflavones, phytoestrogens contained in soy foods, have been proposed as mechanisms for the possible involvement of soy products in the development of breast cancer. We investigated the hypothesis that isoflavones reduce mammographic density, a predictor of breast cancer risk. We conducted a double-blind randomized trial in premenopausal women who received a daily 100 mg isoflavone supplement or a placebo over 12 months. Compliance with the study regimen was confirmed by urinary isoflavones and tablet counts. We used a computer-assisted method to measure mammographic density and paired t-tests to assess changes in mammographic characteristics from baseline to follow-up mammogram. Complete sets of mammograms were available for 30 women. The two groups differed by age and mammographic density at baseline, but were similar in body weight and nutritional intakes. We detected no significant changes either in the size of the dense areas or in the per cent densities. A non-significant decrease in breast area among intervention group subjects was probably the result of methodological issues in comparing mammograms taken under different conditions. In conclusion, our findings do not support the hypothesis that isoflavones decrease mammographic density during a one-year intervention. Although this exploratory study had limited power, it appears that isoflavones do not exert an estrogenic effect similar to hormone replacement therapy on mammographic density.     

Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition-norfolk.

Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.     

Lack of effect of soy isoflavone on thyroid hyperplasia in rats receiving an iodine-deficient diet.

We have reported a dramatic synergism between soy intake and iodine deficiency regarding induction of thyroid hyperplasia in rats. Because isoflavones are active constituents of soybeans, in the present study, their possible contribution was examined. Female F344 rats were divided into 8 groups, exposed to diet containing a 0.2% soy isoflavone mixture (SI), 0.2% SI + iodine deficiency (ID), 0.04% SI, 0.04% SI + ID, 20% defatted soybean (DS) alone, 20% DS + ID, ID alone or basal diet alone for 5 weeks. Thyroid weight was not influenced by SI, but was increased by the ID and DS diets with a further significant increment in the DS + ID group (P < 0.01). Compared to the control value, serum T(4) was significantly (P < 0.01) increased by 20% DS alone and decreased in all groups given the ID treatment (P < 0.001). Serum thyroid stimulating hormone (TSH) level was increased by ID, and further enhanced by DS (P < 0.01) but not SI. Histopathologically, diffuse hypertrophy and / or hyperplasia of thyroid follicles were observed in the ID-treated groups, the severity being enhanced by DS but not SI. Proliferating cell nuclear antigen labeling indices (%) were elevated in the ID diet groups and again enhanced by DS, but not SI. These results thus suggest that isoflavones may not be involved in the mechanisms underlying the synergistic goitrogenic effect of soybean with iodine deficiency.     

Early Life and Adult Exposure to Isoflavones and Breast Cancer Risk

Soy and red-clover isoflavones are commonly consumed within the diet or as a dietary supplement due to a range of presumed beneficial health benefits. These isoflavones are thought to protect against heart diseases as well as breast and other types of cancer. Isoflavones are structurally similar to estrogens and may act as estrogen agonists or antagonists by binding to estrogen receptors. Because of an increased use of isoflavones in processed foods and dietary supplements as well as the greater consumption of soy products, dietary intakes of isoflavones are increasing in children and adolescents in North America. Estrogens are a known component of numerous hormone related cancers including breast cancer. It is with these facts in mind that we review the existing epidemiological and experimental animal studies for a resolution to a proposed correlation between increased isoflavone consumption and breast cancer. There is conflicting evidence from epidemiological, intervention and experimental animal studies regarding the chemopreventing effects of soy isoflavones in breast cancer. Isoflavones are weak estrogens and their effect depends upon the dose, time of exposure and species involved. It would, therefore, not be safe to indisputably accept soy or red-clover as a source of isoflavone resource to prevent breast cancer.     

Past oral contraceptive use and current dietary soy isoflavones influence estrogen metabolism in postmenopausal monkeys (Macaca fascicularis)

Estrogen metabolism may play an important role in mammary carcinogenesis in postmenopausal women. We evaluated the effects of prior oral contraceptive (OC) treatment and current soy isoflavone consumption on endogenous estrogen metabolite concentration and biomarkers of tissue estrogen exposure in a monkey model. One hundred eighty-one female cynomolgus macaques were randomized to receive OC or placebo for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an isoflavone-depleted soy protein isolate (Soy-) diet, a diet containing soy protein isolate with a human equivalent of 129 mg isoflavone/d (Soy+), or a Soy- diet supplemented with conjugated equine estrogens (CEE+) at a human equivalent dose of 0.625 mg/d. Reverse-phase high-performance liquid chromatography directly coupled with tandem mass spectrometry was used to measure the concentrations of estrogen species in urine samples. Generally, prior OC treatment was associated with significantly reduced urinary estrogen metabolites (25-55% reduction; P<0.05 for each versus OC-). Animals that consumed isoflavones postmenopausally had increased urinary 2-hydroxyestrone and 16alpha-hydroxyestrone (50% and 56% increases, respectively), but reduced levels of 2-hydroxyestradiol, 2-methoxyestradiol, and 17-epiestriol (92%, 63%, and 66%, respectively), compared with animals fed a Soy- diet. Isoflavones did not have widespread effects on uterine or mammary proliferation biomarkers, whereas prior OC significantly reduced two of three proliferation end points in the endometrium. Premenopausal OCs may have long-term systemic effects on response to estrogen and its metabolism whereas postmenopausal dietary isoflavones may alter endogenous estrogen metabolism in a modest but selective manner.     

The relation of soy intake and isoflavone levels in nipple aspirate fluid.

Given the possible breast cancer preventive effects of isoflavones, substances with an estrogen-like structure occurring in soybeans, it is of interest to assess levels directly in the breast. The objective of this pilot study was to measure isoflavones in nipple aspirate fluid. In a pilot study with 11 women, nipple aspirate fluid and urine samples were collected at baseline and after 1 month of consuming two servings of soymilk per day. In a parallel investigation, one woman donated nipple aspirate fluid, blood, and urine on the same day after consuming different amounts of soy for 9 days. Nipple aspirate fluid was collected with an aspirator, diluted 1 : 11, and stored at -20 degrees C. Isoflavonoids in nipple aspirate fluid, serum, and urine were liquid-liquid extracted after enzymatic hydrolysis followed by liquid chromatography electrospray ionization high resolution tandem mass spectrometry analysis using triply C labeled internal isoflavonoid standards. After the 30-day soy intervention, median nipple aspirate fluid yield changed very little (P=0.47), whereas urinary isoflavonoid excretion (P=0.04) and isoflavonoid levels in nipple aspirate fluid (P=0.12) increased substantially. For the nine samples collected in one participant, isoflavonoids measured in nipple aspirate fluid, plasma, and urine were highly correlated with the number of daily soy servings and with each other. This pilot study indicates that isoflavonoids in nipple aspirate fluid are 10 times lower than in plasma and are closely related to levels of isoflavonoids in urine and plasma. These findings show that isoflavonoids are present in breast fluid and may act directly on breast tissue.     

Dietary isoflavone intake and breast cancer risk in case-control studies in Japanese, Japanese Brazilians, and non-Japanese Brazilians

Although epidemiologic studies have shown an inverse association between isoflavones and breast cancer risk, little evidence for a dose-response relation is available. We conducted hospital-based case-control studies of patients aged 20-74 years with primary, incident, histologically confirmed invasive breast cancer, and matched controls from medical checkup examinees in Nagano, Japan and from cancer-free patients in S?o Paulo, Brazil. A total of 850 pairs (390 Japanese, 81 Japanese Brazilians and 379 non-Japanese Brazilians) completed validated food frequency questionnaires. The odds ratio of breast cancer according to isoflavone intake was estimated using a conditional logistic regression model. We found a statistically significant inverse association between isoflavone intake and the risk of breast cancer for Japanese Brazilians and non-Japanese Brazilians. For Japanese, a non-significant inverse association was limited to postmenopausal women. In the three populations combined, breast cancer risk linearly decreased from 'no' to 'moderate' isoflavone intake and thereafter leveled off. Compared to non-consumers, adjusted odds ratios (95% confidence interval) for consumers in increasing quintile intake categories (median intake in each category: 8.7, 23.1, 33.8, 45.7, and 71.3 mg/day) were 0.69 (0.44-1.09), 0.54 (0.31-0.94), 0.45 (0.26-0.77), 0.34 (0.19-0.62), and 0.43 (0.24-0.76), respectively. Overall, we found an inverse association between dietary isoflavone intake and risk of breast cancer. Our finding suggests a risk-reducing rather than risk-enhancing effect of isoflavones on breast cancer within the range achievable from dietary intake alone. In addition, women may benefit from risk reduction if they consume at least moderate amounts of isoflavones.     

Positive effects of soy isoflavone food on survival of breast cancer patients in China

Aim: Soy foods are the major source of isoflavones, which are believed to play important roles in genesis of breast cancer and its progression. We here conducted a prospective study to evaluate the association of soy isoflavone food consumption with breast cancer prognosis. Methods: A prospective study was performed from January 2004 and January 2006 in China. Trained interviewers conducted face-to-face interviews using a structured questionnaire to collect information on dietary habits and potential confounding factors. The relative risk [hazard ratio (HR)] and 95% CI were calculated from the Cox regression model for all significant predictors from cancer diagnosis to the endpoint of the study (event). Results: After a median follow up of 52.1 months (range, 9-60 months), a total of 79 breast cancer related deaths were recorded in our study, risk being inversely associated with a high intake of soy isoflavone. With an average intake of soy isoflavone above 17.3 mg/day, the mortality of breast cancer can be reduced by about 38-36%. We also found the decreased breast cancer death with high soy protein intake, with a HR (95% CI) of 0.71 (0.52-0.98). Stratified analysis with reference to the ER status, further demonstrated a better prognosis of ER positive breast cancer with a high intake of soy isoflavone (HR 0.59, 0.40-0.93). Conclusion: Our study shows the soy food intake is associated with longer survival and low recurrence among breast cancer patients. A cohort study with a larger sample size and long term follow-up is now needed.