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Soy Consumption Alters Endogenous Estrogen Metabolism in Postmenopausal Women1

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Soy Consumption Alters Endogenous Estrogen Metabolism in Postmenopausal Women1 Vol. 9, 781–786, August 2000 Cancer Epidemiology, Biomarkers & Prevention 781 Soy Consumption Alters Endogenous Estrogen Metabolism in Postmenopausal Women1 Xia Xu, Alison M. Duncan, Kerry E. Wangen, and Introduction 2 Mindy S. Kurzer Estrogens play an important role in human breast carcinogen- Department of Food Science and Nutrition, University of Minnesota, St. Paul, esis. Although the mechanisms are not entirely known, sub- Minnesota 55108 stantial evidence indicates that they likely involve mitogenic properties of the parent estrogens and their metabolites through classical estrogen receptor-mediated processes as well as met- Abstract abolic activation to genotoxic estrogen metabolites (1–3). 16␣- 3 Isoflavones are soy phytoestrogens that have been (OH)E1, the main estrogen metabolite proposed to be a risk suggested to be anticarcinogenic. Our previous study in factor for breast cancer, shows properties consistent with ini- premenopausal women suggested that the mechanisms by tiation of mammary cell transformation, including induction of which isoflavones exert cancer-preventive effects may unscheduled DNA synthesis and stimulation of anchorage- involve modulation of estrogen metabolism away from independent growth of mammary epithelial cells (4). 16␣- production of potentially carcinogenic metabolites [16␣- (OH)E1 exhibits estrogenicity comparable with that of E2 and (OH) estrone, 4-(OH) estrone, and 4-(OH) estradiol] low-binding affinity to sex hormone binding globulin (5). It can (X. Xu et al., Cancer Epidemiol. Biomark. Prev., 7: 1101– irreversibly bind to the estrogen receptor and cause long-lasting 1108, 1998). To further evaluate this hypothesis, a effects, such as persistent hyperproliferation and up-regulated randomized, cross-over soy isoflavone feeding study was expression of the c-myc oncogene, even after its withdrawal (6). performed in 18 healthy postmenopausal women. The The relative extent of estrogen metabolism via the 16␣- study consisted of three diet periods, each separated by a hydroxylation pathway has been shown to be significantly washout of ϳ3 weeks. Each diet period lasted for 93 increased in breast cancer patients (7–11) and in healthy women days, during which subjects consumed their habitual diets who later develop breast cancer (12), although not in healthy supplemented with soy protein isolate providing 0.1 breast cancer survivors (13). (control), 1, or 2 mg isoflavones/kg body weight/day Recent studies suggest that 4-hydroxylated catechol estro- ␣ -or 132 ؎ 22 mg/day). A 72-h urine gens may be as harmful as 16 -(OH)E1 because their electro ,11 ؎ 65 ,1.1 ؎ 7.1) sample was collected 3 days before the study (baseline) philic quinone products react with DNA to form depurinating and days 91–93 of each diet period. Urine samples were adducts known to generate mutations that initiate cancer (3). In analyzed for 10 phytoestrogens and 15 endogenous vivo treatment with 4-(OH)E2, a potent long-acting estrogen estrogens and their metabolites by a capillary gas (14–16), induces DNA single-strand breaks and other muta- chromatography-mass spectrometry method. Compared genic products of oxidative damage in liver and kidney of with the soy-free baseline and very low isoflavone control Syrian hamsters (17, 18). In vitro studies show that microsomes diet, consumption of 65 mg isoflavones increased the prepared from human mammary adenocarcinoma and fibroad- urinary 2/16␣-(OH) estrone ratio, and consumption of 65 enoma predominantly catalyze the 4-hydroxylation of E2, or 132 mg isoflavones decreased excretion of 4-(OH) whereas this does not occur in microsomes prepared from estrone. When compared with baseline values, normal tissue (19). Aldercreutz et al. (20) reported that urinary consumption of all three soy diets increased the ratio of 4-(OH)E1 in premenopausal Finnish women at high risk of 2/4-(OH) estrogens and decreased the ratio of genotoxic: breast cancer was at least double that in premenopausal Asian total estrogens. These data suggest that both isoflavones women at low risk of breast cancer. and other soy constituents may exert cancer-preventive Few studies have evaluated the effects of diet on excretion effects in postmenopausal women by altering estrogen of urinary estrogen metabolites. Consumption of indole-3- metabolism away from genotoxic metabolites toward carbinol, a phytochemical abundant in cruciferous vegetables, inactive metabolites. significantly decreases urinary excretion of E2,E1,E3, and ␣ 16 -(OH)E1 and significantly increases urinary excretion of 2-(OH)E2 and 2-(OH)E1, both of which have been proposed to be benign and weak estrogens in men and women (21). We ␣ reported recently that urinary 16 -(OH)E1, 4-(OH)E1, and Received 1/17/00; revised 5/3/00; accepted 5/17/00. 4-(OH)E were significantly reduced by soy isoflavone con- The costs of publication of this article were defrayed in part by the payment of 2 page charges. This article must therefore be hereby marked advertisement in sumption in premenopausal women (22) and suggested that this accordance with 18 U.S.C. Section 1734 solely to indicate this fact. effect may provide a mechanism for the observed inverse 1 This research was supported by NIH Grant CA-66016, General Clinical Re- search Center Grant MO1-RR00400 from the National Center for Research Resources, and Minnesota Agricultural Experiment Station project 18-34. 2 To whom requests for reprints should be addressed, at Department of Food 3 Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, The abbreviations used are: E1, estrone; E2, estradiol; E3, estriol; low-iso, MN 55108. Phone: (612) 624-9789; Fax: (612) 625-5272; E-mail: mkurzer@ low-isoflavone; high-iso, high isoflavone; ODMA, O-desmethylangolensin; CYP, umn.edu. cytochrome P-450. Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2000 American Association for Cancer Research. 782 Soy and Endogenous Estrogen Metabolism associations between breast cancer and soybean consumption itored by 3-day diet records kept prior to the start of the study (23–25) as well as urinary excretion of specific soy isofla- and on days 35–37, 63–65, and 91–93 of each diet period. vonoids and lignans (26, 27). Energy, macronutrient, and dietary fiber intakes were analyzed For this study, we postulated that soy isoflavones, when by a computerized nutrient analysis program (Nutritionist IV, consumed by postmenopausal women in a soy protein isolate, version 4.0; The Hearst Corp., San Bruno, CA). Body density will modulate estrogen metabolism away from formation of was calculated from the sum of the four skinfold thicknesses, potentially carcinogenic metabolites. To evaluate this hypoth- and a predictive equation was used to determine the percentage esis, a randomized, cross-over soy isoflavone feeding study was of body fat (30). performed in 18 healthy postmenopausal women. Sample Collection and Analysis. Three continuous 24-h urine samples were collected during 3 days before the start Materials and Methods of the study (baseline) and days 91–93 of each diet period. Twenty-four-h urines were collected in 3-liter containers Subjects. Detailed subject information has been described pre- containing3gofascorbic acid. Urinary creatinine was viously (28). All subjects were recruited from the Minneapolis- measured to evaluate the completeness of urine collection St. Paul metropolitan area. Exclusionary criteria included ath- using an enzymatic assay kit (Johnson & Johnson Clinical leticism; regular consumption of a strict vegetarian, high fiber, Diagnostics, Inc., Rochester, NY). After recording the 24-h high soy or low fat diet; cigarette smoking; regular consump- urine volume, sodium azide was added to achieve a 0.1% tion of vitamin and mineral supplementation greater than the (w/v) concentration. Urine samples were stored at Ϫ20°C Recommended Dietary Allowances; regular use of medication until analysis. Immediately before analysis, the three 24-h including aspirin; use of hormones or antibiotics within 6 urine aliquots were thawed and proportionally combined to months of the start of the study; menstrual bleeding within 12 create a 72-h pooled sample. months; hysterectomy and oophorectomy; follicle-stimulating Ͻ Fifteen-ml aliquots from each 72-h pooled urine sample were hormone concentration 25 IU/l; history of chronic disorders extracted and analyzed for 10 phytoestrogens (equol, ODMA, including endocrine or gynecological diseases; benign breast dihydrodaidzein, daidzein, genistein, glycitein, enterodiol, en- disease; Ͻ90% or Ͼ120% ideal body weight; weight change Ͼ terolactone, matairesinol, and coumestrol) and 15 endogenous 10 pounds within the previous year; and inability to abstain estrogens and their metabolites [E ,E,E,16␣-(OH)E , from alcoholic beverages during the study. Health history, 1 2 3 1 2-(OH)E1, 2-(OH)E2, 4-(OH)E1, 4-(OH)E2, 2-methoxyestrone (2- physical exam, and routine blood and urine screening verified MeOE ), 2-methoxyestradiol (2-MeOE ), 4-methoxyestrone (4- health status of the subjects. Twenty-three women were admit- 1 2 MeOE1), 4-methoxyestradiol (4-MeOE2), 16-ketoestradiol (16- ted into the study. Eighteen subjects completed the study. Their ketoE ), 16-epiestriol (16-epiE ), and 17-epiestriol (17-epiE )] as prestudy averages for age, years since menopause, body weight, 2 3 3 Ϯ described previously (22) by an ion-exchange chromatography body mass index, and percentage of body fat were 56.9 5.8 and capillary gas chromatography-mass spectrometry method years, 7.6 Ϯ 4.7 years,
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