![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108;
* Division of Biostatistics, University of Minnesota, Minneapolis, MN 55407; and
Institute for Preventive Medicine, Nutrition, and Cancer, Folkhälsan research center and the Division of Clinical Chemistry, University of Helsinki, Finland 00014
2To whom correspondence should be addressed. E-mail: mkurzer{at}umn.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
-hydroxyestrone (2:16OHE1) and increased breast cancer risk. Some studies show that soy consumption increases this ratio, and it is suggested that this effect may reduce breast cancer risk. We hypothesized that consumption of probiotic bacteria would alter fecal bacteria and enzymes involved in soy isoflavone metabolism, thereby increasing isoflavone bioavailability and enhancing the beneficial effects of soy on estrogen metabolism. Breast cancer survivors (n = 20) and controls (n = 20) were given 4 treatments for 6 wk each, separated by 2-wk washout periods, in a randomized, crossover design: soy protein (26.6 ± 4.5 g protein/d containing 44.4 ± 7.5 mg isoflavones/d); soy protein + probiotics (109 colony-forming units Lactobacillus acidophilus DDS®+1 & Bifidobacterium longum, 15–30 mg fructooligosaccharide/d); milk protein (26.6 ± 4.5 g protein/d); and milk protein + probiotics. Survivors tended to have a lower baseline urine 2:16OHE1 ratio than controls (P = 0.10). In the group as a whole, soy consumption tended to increase urinary 2-hydroxyestrogens (P = 0.07) and 16-hydroxyestrone (P = 0.11) but had no effect on the urinary 2:16OHE1 ratio. When subjects were divided into groups by plasma concentrations and urinary levels of the daidzein metabolite equol, soy increased urinary 2-hydroxyestrogens (P = 0.01) and the 2:16OHE1 ratio (P = 0.04) only in subjects with high plasma equol concentrations. None of these results were influenced by probiotic consumption. These results are consistent with studies that found lower urine 2:16OHE1 ratios in women with breast cancer and suggest that soy consumption increases this ratio only in women who are equol producers.
KEY WORDS: • probiotics • soy • equol • 2:16-hydroxyestrone ratio • breast cancer
Evidence suggests that specific estrogen metabolites may partly explain the association between high plasma estrogens and increased breast cancer risk. In vitro data indicate that the 2-hydroxyestrogens (2-hydroxyestradiol + 2-hydroxyestrone) (2OHE)3 are relatively inactive (1), whereas 16-hydroxyestrone (16OHE1) appears to have considerable biological activity. In vitro, 16OHE1 has a weak affinity for sex hormone–binding globulin (2) and covalently binds the estrogen receptor (3), allowing long-lasting biological effects. Urine concentrations of 16OHE1 have been associated with increased proliferation of transformed and nontransformed mammary cells (4–6), mammary tumor incidence in mice (7), and Ras oncogene expression (4). The biological relevance of these pathways is supported by epidemiologic evidence from cohort and case-control studies reporting an inverse association between the urinary 2-hydroxyestrogen:16OHE1 ratio (2:16OHE1) and breast cancer risk (8–15), although significant associations were not found in all studies (16–18).
It is suggested that soy isoflavones exert cancer protective effects in part by altering these pathways of estrogen metabolism (19–21), although results are inconsistent (22–25). Premenopausal women consuming soy protein isolate showed significantly increased 2OHE excretion (19), decreased 16OHE1 excretion (21), and increased 2:16OHE1 ratios (19,21), although another soy protein study reported no significant effects (23). In postmenopausal women, Xu et al. (20) demonstrated that the isoflavones in soy protein tended to increase 2-hydroxyestrogens, but soy consumption had no significant effects on estrogen metabolism in 2 other studies (22,24).
The striking interindividual variability in isoflavone bioavailability may influence the biological effects of isoflavone consumption. Large differences in bioavailability are likely due to differences in gut microflora (26). Consumption of probiotic strains of Lactobacillus and Bifidobacteria was shown to decrease fecal ß-glucuronidase activity in animals (27,28) and decrease fecal ß-glucuronidase (29,30) and increase ß-glucosidase in humans (31). These changes could theoretically increase isoflavone bioavailability and production of biologically important isoflavone metabolites, thus enhancing effects on estrogen metabolism. Further, intestinal bacteria may influence estrogen metabolism via other mechanisms, such as altering enterohepatic circulation of steroid hormones, and therefore may independently alter breast cancer risk (32).
The isoflavone metabolite, equol, is produced from daidzein by intestinal bacteria in 
20–40% of the population (21,33–35). Equol has been associated with breast cancer–protective plasma hormone profiles in premenopausal women (37) and with higher urinary 2:16OHE1 ratios in an observational study (38). One case-control study reported an inverse association between urinary equol excretion and breast cancer risk (36), but another nested case-control study found urinary and plasma equol to be positively associated with breast cancer risk (39). Although not entirely consistent, overall these studies suggest that equol may exert biological effects that reduce breast cancer risk or alternatively, may indirectly serve as a biomarker for a breast cancer protective profile of intestinal bacterial (37,38).
The investigation presented here was part of a study whose primary objective was to determine the effects of soy protein and probiotic supplementation on isoflavone metabolism and to compare these effects between postmenopausal breast cancer survivors and women with no cancer history (34). In this paper, we report the effects of soy and probiotic supplementation on urinary 2OHE, 16OHE1, and the 2:16OHE1 ratio in postmenopausal breast cancer survivors and women with no cancer history. We hypothesized that probiotic supplementation would enhance the effects of soy consumption on estrogen metabolism. Second, we sought to determine whether the effects of soy and probiotic consumption on urinary 2OHE and 16OHE1 excretion, and the 2:16OHE1 ratio would differ significantly between breast cancer survivors and women with no cancer history or between equol producers and nonproducers.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Experimental design and dietary treatments.
The study protocol was approved by the University of Minnesota Institutional Review Board: Human Subjects Committee and the Institutional Review Board of the United States Army Medical Research and Materiel Command. Subjects were free living and consumed their usual diets plus intervention supplements. The following 4 treatments were assigned in a randomized, crossover design for 42 d each: soy protein isolate (S) (SolaeTM); milk protein isolate (M) (Solae); soy protein isolate + 3 probiotic capsules/d (S+P) (DDS Plus®, UAS Laboratories); milk protein isolate + 3 probiotic capsules/d (M+P). Both protein isolates provided 0.38 g protein/(kg body wt · d) (26.6 ± 4.5 g protein/d). The soy protein isolate provided 0.64 mg isoflavones/(kg body wt · d) (44.4 ± 7.5 mg isoflavones/d), expressed as aglycones units, a level similar to average intake of soy-consuming populations (40–42). Locally available commercial probiotic capsules contained 109 colony-forming units of Lactobacillus acidophilus DDS®+1 and Bifidobacterium longum and 15–30 mg fructooligosaccharide/d. Serial dilutions of capsule contents were plated onto selective media to periodically assess probiotic viability during the study (analyzed by Dr. Joellen Feirtag, Department of Food Science and Nutrition, University of Minnesota). Each treatment period was separated by a 2-wk washout period during which subjects consumed their habitual diets and were not required to adhere to study restrictions. During each of the 4 treatment periods, subjects were instructed to exclude flaxseed, alcohol, all fermented dairy foods, and soy-containing products. Consumption of other seeds, legumes, and nondairy fermented foods was limited to 
1 serving/wk. Participants were given ideas for incorporating the protein powders into juice beverages, hot cereals, soups, puddings, and smoothies.
Soy and milk protein isolates were similar in nutrient composition with each containing 80% energy as protein, and 16–20% as carbohydrate. Soy protein isolate contained 1.16 mg isoflavone aglycones/g powder (34.4% daidzein, 57.1% genistein, 8.5% glycitein, analyzed by Dr. Pat Murphy, Department of Food Science and Nutrition, Iowa State University). Protein supplements were provided according to the most recently recorded body weight and distributed as 3-wk allotments in prepackaged, 1-d amounts. Capsules were distributed in amber glass jars and stored at 4°C by participants. Each subject was given a recording calendar on which she was to document her adherence to the study protocol. Self-reported measures of compliance and plasma isoflavone concentrations indicated good adherence to the study protocol (34).
Study procedures. Subjects recorded their dietary intakes 3 d before d 1 of diet period 1 (baseline) and on d 40–42 of each diet period. Diet records were analyzed using Nutritionist V, version 2.1 (The Hearst Corporation).
The body weight of fasting subjects was measured on d 1, diet period 1 (baseline), and on d 22 and d 43 of each diet period. Body composition was measured by a single technician at baseline using skinfold thicknesses measured at triceps, biceps, subscapular, and suprailiac sites from which the percentage of body fat was calculated (43). Blood samples were drawn from fasting subjects at baseline and on d 22 and d 43 of each diet period as previously described (34).
Three 24-h urines collections were made on 3 consecutive days before diet period 1 (baseline) and on days 40–42 of each diet period. Urine was collected into 3-L jugs each containing 3 g ascorbic acid. Subjects refrigerated collections until the end of d 3 at which point the collected urine was processed. The total volume of each collection was recorded, and sodium azide was added to achieve a 0.1% concentration. To assess 24-h completeness, urinary creatinine was measured on a Vitros analyzer (Ortho Clinical Diagnostics) using freeze-dried reagent standards (Johnson & Johnson Clinical Diagnostics). Samples were stored at –20°C until all subjects completed the study. The 3 daily collections were then proportionally pooled into a single 72-h sample before analysis. The concentration of estrogen metabolites in each sample pool was multiplied by the mean 24-h urine volume for each 3-d pool, and data were analyzed and expressed as µg of metabolite/24 h.
Analytical methods. Two-hydroxyestrogens (2-hydroxyestradiol and 2-hydroxyestrone) (2OHE) and 16OHE1, were analyzed in urine by enzyme immunoassay (Estramet 2:16 Enzyme Immunoassay Kit, Immuna Care) as previously described (44,45). Each sample was assayed in triplicate and the mean was used. All 5 samples from each subject were run on a single plate and the same kit lot was used for all study samples. Samples falling below assay detection limits were assigned the value of the lowest standard. Interassay CVs were 6.5 and 10% and intra-assay CVs were 2 and 3% for 2OHE and 16OHE1 respectively.
Plasma genistein, daidzein, O-desmethylangolensin, and equol concentrations and urinary equol excretion were analyzed by time-resolved fluoroimmunoassay as previously described (34). Subjects with high plasma equol concentrations (>15 nmol/L) and high urinary levels of equol (>1500 nmol/L) during either soy diet period were designated as equol producers (n = 9, 5 controls and 4 survivors). Subjects with low plasma equol concentrations (<15 nmol/L) and low levels of urinary equol (<1500 nmol/L) during both soy diet periods were designated as equol nonproducers (n = 28, 15 controls and 13 survivors). There were no discrepancies between the 2 measures of equol-producer status (34).
Statistical methods. All subjects did not complete the protocol, and only 196 samples of the 200 planned were available for analysis (missing data: 2 diets from 1 survivor, 1 diet from 2 survivors). Therefore, 196 samples were analyzed: 40 baseline observations, 39 S diets, 38 M diets, 39 S+P diets, 40 M+P diets. Only subjects with data from both soy diet periods (n = 37) were included in statistical analyses comparing the effects of diet between equol producers and nonproducers, as previously described (34).
Unpaired t tests were used to compare controls and survivors at baseline and to compare high and low equol groups after consumption of the S and S+P diets. Comparisons between breast cancer survivors and controls and between high and low plasma equol groups were done using 1-factor ANOVA F-tests, based on the between-women variability. Comparisons between diet periods were done using the standard repeated-measures ANOVA. Specifically, the error term for within-women variability was used as the basis for these F-tests: comparisons among the 4 diets, main effects of soy (both soy-containing diets), main effects of probiotic (both probiotic-containing diets), effects of diet order, and the interaction between cancer status and diet. Spearman correlations were calculated to estimate associations between urinary estrogen metabolites and plasma isoflavones and urinary equol. Due to nonnormal distribution, data were log transformed and are presented as geometric means with 95% CI. Significance was set at P < 0.05. Data were analyzed using SAS Proc GLM (SAS version 8.2, SAS Institute) (46). Values in the text are means ± SD unless noted otherwise.
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
At baseline, urinary excretion of 2OHE and 16OHE1 did not differ between controls and survivors. However, the difference in the 2:16OHE1 ratio between the 2 groups (controls > survivors) approached significance [geometric mean (95% CI): 1.92 (1.61, 2.29) vs. 1.48 (1.16, 1.90), P = 0.10].
Consumption of soy protein relative to milk protein tended to increase both 2OHE and 16OHE1 excretion (P = 0.07 and P = 0.11, respectively), although there was no corresponding effect on the 2:16 OHE1 ratio (Table 1). Breast cancer status did not alter the effects of soy on urinary 2OHE, 16OHE1, or the 2:16OHE1 ratio
|
The effect of soy consumption on urinary 2OHE excretion and the 2:16OHE1 ratio differed between equol producers and nonproducers (F-test for interaction, P = 0.02 for 2OHE, P = 0.046 for 2:16OH E1) (Table 2). In equol producers, soy increased 2OHE (P = 0.01) and the 2:16OHE1 ratio (P = 0.04), whereas in nonproducers, soy did not affect either 2OHE or the 2:16OHE1 ratio (Table 2). The effect of soy consumption on 16OHE1 did not differ between equol producers and nonproducers. When a similar analysis was performed within milk protein diet periods (M and M+P), urinary 2OHE, 16OHE1, and the 2:16OHE1 ratio did not differ between equol producers and nonproducers. Neither estrogen metabolite nor their ratio was significantly correlated with total plasma isoflavones, genistein, daidzein, O-desmethylangolensin, or equol (data not shown).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
There are other sources of variability within the survivor group, and between survivors and controls, that may have affected estrogen metabolism. For example, estrogen and progesterone receptor status was not known for all subjects and was likely to have varied among the women. Cancer treatment itself may have affected estrogen metabolism, although women who had been treated with chemotherapy were not included in the study to reduce this possibility. Because half of the breast cancer survivors had a family history of breast cancer, they are not representative of breast cancer cases as a whole. Hormonal factors, such as sex hormone-binding globulin (SHBG) and bioavailable estrogen concentrations are suggested to influence estrogen metabolism by the liver (47,48), although our results did not differ when controlled for SHBG (data not shown). Finally, our sample size was too small to determine whether nonnutrient dietary components, such as indole-3-carbinol (49–53) played a role in the observed trend toward different urinary 2:16OHE1 ratios between controls and survivors. Despite these limitations, the consistency of our results with those of previous epidemiologic studies suggests that the pattern of estrogen metabolism may be associated with breast cancer risk. Further study is warranted in this area to determine the biological relevance of the 2:16OHE1 ratio to breast cancer risk.
In the group as a whole, consumption of soy protein tended to increase urinary excretion of both 2OHE and 16OHE1 but did not alter the 2:16OHE1 ratio. Results of other studies evaluating the effects of soy protein on estrogen metabolism are variable. Studies in premenopausal women reported soy consumption to increase 2OHE (19) and the 2:16OHE1 ratio (21), although one study found no significant effects (23). In postmenopausal women, Xu et al. (20) reported that consumption of soy protein isolate containing 7, 65, and 132 mg isoflavones/d increased 2OHE excretion, soy protein isolate containing 65 mg isoflavones/d increased the 2:16OHE1 ratio, and none of the soy protein isolates altered 16OHE1 excretion. Another study in postmenopausal women found no significant effects of soy protein isolates containing 43 or 72 mg isoflavones/d (as aglycones) on urinary 2OHE, 16OHE1, or the 2:16OHE1 ratio (24). Brooks et al. (22) also found no effect of soy flour consumption (42 mg isoflavones/d) on estrogen metabolism in 15 postmenopausal women. In addition to the variability in the designs and amounts of isoflavones consumed in our study and those cited, differences in the effects on estrogen metabolite excretion among the studies may be due to variability in the number of equol producers in the populations studied. However, the numbers of producers were not stated in these papers.
When subjects in our study were divided into groups according to equol producer status, soy consumption significantly increased 2OHE and the 2:16OHE1 ratio only in equol producers. Although 2 previous small soy intervention studies conducted in premenopausal (21) and postmenopausal (20) women in our laboratory did not find effects on estrogen metabolism to be dependent on equol producer status, results of the current study are similar to those of recent observational studies (38,54). Atkinson et al. (38) reported a positive association between urinary equol excretion and the 2:16OHE1 ratio in a group of premenopausal and postmenopausal women excreting detectable levels of equol. Although the study did not find significant differences in urinary estrogen metabolites between equol producers and nonproducers, a study of similar design and size did find that equol producers tended to have higher 2:16OHE1 ratios than nonproducers (54). Taken together, our results and those similar are particularly interesting in light of previous work by Duncan et al. (37) who reported that premenopausal equol excretors had lower plasma concentrations of reproductive hormones associated with increased breast cancer risk. Differences were evident at all isoflavone doses, including the lowest dose (10 mg isoflavones/d). The researchers hypothesized that equol production may be a biomarker for gut bacteria that alter pathways of estrogen metabolism or, alternatively, very low levels of equol are capable of exerting significant hormonal effects (37). The fact that equol was shown to inhibit the activity of the cytochrome P450 enzyme aromatase (55) suggests the possibility that equol could also alter the activity of P450 enzymes involved in estrogen metabolism. In our study, the lack of a difference between the equol producers and nonproducers when consuming milk protein suggests that equol itself was responsible for the increased 2:16OHE1 ratio observed with soy consumption.
Our study found a lower frequency of equol producers than is commonly reported (21,33–35), but the consistency between equol-producer status identified by plasma or urinary equol levels suggests that our data are accurate and simply reflect the lower end of the frequency distribution. On the basis of our findings, it would seem that studies with greater numbers of equol producers would be more likely to observe significant soy effects. The small number of subjects is a limitation of our study, and it is important that larger studies determine equol-producer status and evaluate the effects of producer status on estrogen metabolism.
Probiotic consumption did not independently affect urinary estrogen metabolite excretion nor alter the effects of soy protein. These results are not surprising, given that probiotic consumption did not alter plasma isoflavone concentrations (34). However, this does not exclude the possibility that longer-term probiotic consumption or consumption of strains of probiotic bacteria with different characteristics would exert the hypothesized effects.
This study found that soy consumption increased the urinary 2:16OHE1 ratio only in those postmenopausal women who were equol producers. The observed trend of a lower baseline 2:16OHE1 ratio in breast cancer survivors compared with controls is consistent with epidemiologic studies reporting an inverse association between the 2:16OHE1 ratio and breast cancer risk. Taken together, these 2 findings suggest that isoflavone metabolism, in particular equol production, may be extremely important in determining whether soy consumption results in significant biological effects, particularly with respect to endogenous hormone metabolism. Future studies evaluating hormonal effects of isoflavone consumption should be designed to determine whether effects differ by equol producer status.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: M, milk protein isolate; M+P, milk protein isolate plus probiotic; 2OHE, 2-hydroxyestrogens (2-hydroxyestradiol + 2-hydroxyestrone); 16OHE1, 16-hydroxyestrone; 2:16OHE1, 2-hydroxyestrogen to 16-hydroxyestrone ratio; S, soy protein isolate; SHBG, sex hormone-binding globulin; S+P, soy protein isolate plus probiotic.
Manuscript received 19 October 2004. Initial review completed 28 November 2004. Revision accepted 13 December 2004.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Bradlow, H. L., Telang, N. T., Sepkovic, D. W. & Osborne, M. P. (1996) 2-hydroxyestrone: the "good" estrogen. J. Endocrinol. 150(suppl.):S259-S265.[Abstract]
2. Fishman, J. & Martucci, C. (1980) Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology. J. Clin. Endocrinol. Metab. 51:611-615.[Abstract]
3. Swaneck, G. E. & Fishman, J. (1988) Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proc. Natl. Acad. Sci. U.S.A. 85:7831-7835.
4. Suto, A., Bradlow, H. L., Wong, G. Y., Osborne, M. P. & Telang, N. T. (1992) Persistent estrogen responsiveness of ras oncogene-transformed mouse mammary epithelial cells. Steroids 57:262-268.[Medline]
5. Telang, N. T., Suto, A., Wong, G. Y., Osborne, M. P. & Bradlow, H. L. (1992) Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J. Natl. Cancer Inst. 84:634-638.
6. Schneider, J., Huh, M. M., Bradlow, H. L. & Fishman, J. (1984) Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J. Biol. Chem. 259:4840-4845.
7. Bradlow, H. L., Hershcopf, R. J., Martucci, C. P. & Fishman, J. (1985) Estradiol 16 alpha-hydroxylation in the mouse correlates with mammary tumor incidence and presence of murine mammary tumor virus: a possible model for the hormonal etiology of breast cancer in humans. Proc. Natl. Acad. Sci. U.S.A. 82:6295-6299.
8. Coker, A. L., Crane, M. M., Sticca, R. P. & Sepkovic, D. W. (1997) Re: Ethnic differences in estrogen metabolism in healthy women [letter]. J. Natl. Cancer Inst. 89:89-90.
9. Fishman, J., Schneider, J., Hershcope, R. J. & Bradlow, H. L. (1984) Increased estrogen-16 alpha-hydroxylase activity in women with breast and endometrial cancer. J. Steroid Biochem. 20:1077-1081.[Medline]
10. Ho, G. H., Luo, X. W., Ji, C. Y., Foo, S. C. & Ng, E. H. (1998) Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann. Acad. Med. Singapore 27:294-299.[Medline]
11. Kabat, G. C., Chang, C. J., Sparano, J. A., Sepkovie, D. W., Hu, X. P., Khalil, A., Rosenblatt, R. & Bradlow, H. L. (1997) Urinary estrogen metabolites and breast cancer: a case-control study. Cancer Epidemiol. Biomark. Prev. 6:505-509.[Abstract]
12. Meilahn, E. N., De Stavola, B., Allen, D. S., Fentiman, I., Bradlow, H. L., Sepkovic, D. W. & Kuller, L. H. (1998) Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up. Br. J. Cancer 78:1250-1255.[Medline]
13. Muti, P., Bradlow, H. L., Micheli, A., Krogh, V., Freudenheim, J. L., Schunemann, H. J., Stanulla, M., Yang, J. & Sepkovic, D. W., et al (2000) Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 11:635-640.[Medline]
14. Schneider, J., Kinne, D., Fracchia, A., Pierce, V., Anderson, K. E., Bradlow, H. L. & Fishman, J. (1982) Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc. Natl. Acad. Sci. U.S.A. 79:3047-3051.
15. Fowke, J. H., Qi, D., Bradlow, H. L., Shu, X. O., Gao, Y. T., Cheng, J. R., Jin, F. & Zheng, W. (2003) Urinary estrogen metabolites and breast cancer: differential pattern of risk found with pre- versus post-treatment collection. Steroids 68:65-72.[Medline]
16. Ursin, G., London, S., Stanczyk, F. Z., Gentzschein, E., Paganini-Hill, A., Ross, R. K. & Pike, M. C. (1999) Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J. Natl. Cancer Inst. 91:1067-1072.
17. Cauley, J. A., Zmuda, J. M., Danielson, M. E., Ljung, B. M., Bauer, D. C., Cummings, S. R. & Kuller, L. H. (2003) Estrogen metabolites and the risk of breast cancer in older women. Epidemiology 14:740-744.[Medline]
18. Adlercreutz, H., Fotsis, T., Hockerstedt, K., Hamalainen, E., Bannwart, C., Bloigu, S., Valtonen, A. & Ollus, A. (1989) Diet and urinary estrogen profile in premenopausal omnivorous and vegetarian women and in premenopausal women with breast cancer. J. Steroid Biochem. 34:527-530.[Medline]
19. Lu, L. J., Cree, M., Josyula, S., Nagamani, M., Grady, J. J. & Anderson, K. E. (2000) Increased urinary excretion of 2-hydroxyestrone but not 16alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones. Cancer Res. 60:1299-1305.
20. Xu, X., Duncan, A. M., Wangen, K. E. & Kurzer, M. S. (2000) Soy consumption alters endogenous estrogen metabolism in postmenopausal women. Cancer Epidemiol. Biomark. Prev. 9:781-786.
21. Xu, X., Duncan, A. M., Merz, B. E. & Kurzer, M. S. (1998) Effects of soy isoflavones on estrogen and phytoestrogen metabolism in premenopausal women. Cancer Epidemiol. Biomark. Prev. 7:1101-1108.[Abstract]
22. Brooks, J. D., Ward, W. E., Lewis, J. E., Hilditch, J., Nickell, L., Wong, E. & Thompson, L. U. (2004) Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am. J. Clin. Nutr. 79:318-325.
23. Martini, M. C., Dancisak, B. B., Haggans, C. J., Thomas, W. & Slavin, J. L. (1999) Effects of soy intake on sex hormone metabolism in premenopausal women. Nutr. Cancer 34:133-139.[Medline]
24. Persky, V. W., Turyk, M. E., Wang, L., Freels, S., Chatterton, R., Jr, Barnes, S., Erdman, J., Jr, Sepkovic, D. W., Bradlow, H. L. & Potter, S. (2002) Effect of soy protein on endogenous hormones in postmenopausal women. Am. J. Clin. Nutr. 75:145-153.
25. Maskarinec, G., Franke, A. A., Williams, A. E. & Stanczyk, F. C. (2002) The effects of an isoflavone intervention on the urinary excretion of hormone metabolites in premenopausal women. IARC Sci. Publ. 156:375-377.[Medline]
26. Xu, X., Harris, K. S., Wang, H. J., Murphy, P. A. & Hendrich, S. (1995) Bioavailability of soybean isoflavones depends upon gut microflora in women. J. Nutr. 125:2307-2315.
27. Goldin, B. R. & Gorbach, S. L. (1984) Alterations of the intestinal microflora by diet, oral antibiotics, and Lactobacillus: decreased production of free amines from aromatic nitro compounds, azo dyes, and glucuronides. J. Natl. Cancer Inst. 73:689-695.
28. Cole, C., Fuller, R. & Carter, S. (1989) Effect of probiotic supplements of Lactobacillus acidophilus and Bifidobacterium adolescentis 2204 on beta-glucosidase and beta-glucuronidase activity in the lower gut of rats associated with a human faecal flora. Microb. Ecol. Health Dis. 2:223-225.
29. Ling, W. H., Korpela, R., Mykkanen, H., Salminen, S. & Hanninen, O. (1994) Lactobacillus strain GG supplementation decreases colonic hydrolytic and reductive enzyme activities in healthy female adults. J. Nutr. 124:18-23.
30. Goldin, B. R. & Gorbach, S. L. (1984) The effect of milk and lactobacillus feeding on human intestinal bacterial enzyme activity. Am. J. Clin. Nutr. 39:756-761.
31. Marteau, P., Pochart, P., Flourie, B., Pellier, P., Santos, L., Desjeux, J. F. & Rambaud, J. C. (1990) Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidophilus and Bifidobacterium bifidum on metabolic activities of the colonic flora in humans. Am. J. Clin. Nutr. 52:685-688.
32. Adlercreutz, H., Martin, F., Jarvenpaa, P. & Fotsis, T. (1979) Steroid absorption and enterohepatic recycling. Contraception 20:201-223.[Medline]
33. Lampe, J. W., Karr, S. C., Hutchins, A. M. & Slavin, J. L. (1998) Urinary equol excretion with a soy challenge: influence of habitual diet. Proc. Soc. Exp. Biol. Med. 217:335-339.[Abstract]
34. Nettleton, J. A., Greany, K. A., Thomas, W., Wangen, K. E., Adlercreutz, H. & Kurzer, M. S. (2004) Plasma phytoestrogens are not altered by probiotic consumption in postmenopausal women with and without a history of breast cancer. J. Nutr. 134:1998-2003.
35. Hutchins, A. M., Slavin, J. L. & Lampe, J. W. (1995) Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products. J. Am. Diet Assoc. 95:545-551.[Medline]
36. Ingram, D., Sanders, K., Kolybaba, M. & Lopez, D. (1997) Case-control study of phyto-oestrogens and breast cancer. Lancet 350:990-994.[Medline]
37. Duncan, A. M., Merz-Demlow, B. E., Xu, X., Phipps, W. R. & Kurzer, M. S. (2000) Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer. Cancer Epidemiol. Biomark. Prev. 9:581-586.
38. Atkinson, C., Skor, H. E., Dawn Fitzgibbons, E., Scholes, D., Chen, C., Wahala, K., Schwartz, S. M. & Lampe, J. W. (2003) Urinary equol excretion in relation to 2-hydroxyestrone and 16-hydroxyestrone concentrations: an observational study of young to middle-aged women. J. Steroid Biochem. Mol. Biol. 86:71-77.[Medline]
39. Grace, P. B., Taylor, J. I., Low, Y. L., Luben, R. N., Mulligan, A. A., Botting, N. P., Dowsett, M., Welch, A. A. & Khaw, K. T., et al (2004) 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. Cancer Epidemiol. Biomark. Prev. 13:698-708.
40. Nagata, C., Takatsuka, N., Kurisu, Y. & Shimizu, H. (1998) Decreased serum total cholesterol concentration is associated with high intake of soy products in Japanese men and women. J. Nutr. 128:209-213.
41. Somekawa, Y., Chiguchi, M., Ishibashi, T. & Aso, T. (2001) Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstet. Gynecol. 97:109-115.
42. Wakai, K., Egami, I., Kato, K., Kawamura, T., Tamakoshi, A., Lin, Y., Nakayama, T., Wada, M. & Ohno, Y. (1999) Dietary intake and sources of isoflavones among Japanese. Nutr. Cancer 33:139-145.[Medline]
43. Durnin, J. V. & Womersley, J. (1974) Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br. J. Nutr. 32:77-97.[Medline]
44. Klug, T. L., Bradlow, H. L. & Sepkovic, D. W. (1994) Monoclonal antibody-based enzyme immunoassay for simultaneous quantitation of 2- and 16 alpha-hydroxyestrone in urine. Steroids 59:648-655.[Medline]
45. Bradlow, H. L., Sepkovic, D. W., Klug, T. & Osborne, M. P. (1998) Application of an improved ELISA assay to the analysis of urinary estrogen metabolites. Steroids 63:406-413.[Medline]
46. SAS Institute Inc. (2001) Statistical Analysis Systems 2001 SAS Institute Cary, NC.
47. Adlercreutz, H., Gorbach, S. L., Goldin, B. R., Woods, M. N., Dwyer, J. T. & Hamalainen, E. (1994) Re: Estrogen metabolism and excretion in Oriental and Caucasian women [comment]. J. Natl. Cancer Inst. 86:1644-1645.
48. Anonymous, (1994) Estrogen metabolism and excretion in Oriental and Caucasian women. J. Natl. Cancer Inst. 86:1076-1082.
49. Michnovicz, J. J. & Galbraith, R. A. (1991) Cimetidine inhibits catechol estrogen metabolism in women. Metabolism 40:170-174.[Medline]
50. Michnovicz, J. J., Adlercreutz, H. & Bradlow, H. L. (1997) Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J. Natl. Cancer Inst. 89:718-723.
51. Kall, M. A., Vang, O. & Clausen, J. (1996) Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism. Carcinogenesis 17:793-799.
52. Fowke, J. H., Longcope, C. & Hebert, J. R. (2000) Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiol. Biomark. Prev. 9:773-779.
53. Bradlow, H. L., Michnovicz, J. J., Halper, M., Miller, D. G., Wong, G. Y. & Osborne, M. P. (1994) Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol. Biomark. Prev. 3:591-595.[Abstract]
54. Frankenfeld, C. L., McTiernan, A., Tworoger, S. S., Atkinson, C., Thomas, W. K., Stanczyk, F. Z., Marcovina, S. M., Weigle, D. S. & Weiss, N. S., et al (2004) Serum steroid hormones, sex hormone-binding globulin concentrations, and urinary hydroxylated estrogen metabolites in post-menopausal women in relation to daidzein-metabolizing phenotypes. J. Steroid Biochem. Mol. Biol. 88:399-408.[Medline]
55. Pelissero, C., Lenczowski, M. J., Chinzi, D., Davail-Cuisset, B., Sumpter, J. P. & Fostier, A. (1996) Effects of flavonoids on aromatase activity, an in vitro study. J. Steroid Biochem. Mol. Biol. 57:215-223.[Medline]
This article has been cited by other articles:
|
|
 |
|
  B. J. Fuhrman, B. E. Teter, M. Barba, C. Byrne, A. Cavalleri, B. J. Grant, P. J. Horvath, D. Morelli, E. Venturelli, and P. C. Muti Equol Status Modifies the Association of Soy Intake and Mammographic Density in a Sample of Postmenopausal Women Cancer Epidemiol. Biomarkers Prev., January 1, 2008; 17(1): 33 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Hamilton-Reeves, S. A. Rebello, W. Thomas, J. W. Slaton, and M. S. Kurzer Soy Protein Isolate Increases Urinary Estrogens and the Ratio of 2:16{alpha}-Hydroxyestrone in Men at High Risk of Prostate Cancer J. Nutr., October 1, 2007; 137(10): 2258 - 2263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Wood, T. C. Register, and J.M. Cline Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys Carcinogenesis, April 1, 2007; 28(4): 801 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Wood, S. E. Appt, T. B. Clarkson, A. A. Franke, C. J. Lees, D. R. Doerge, and J. M. Cline Effects of High-Dose Soy Isoflavones and Equol on Reproductive Tissues in Female Cynomolgus Monkeys Biol Reprod, September 1, 2006; 75(3): 477 - 486. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
