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© 2007 American Society for Nutrition J. Nutr. 137:2258-2263, October 2007

Nutrition and Disease

Soy Protein Isolate Increases Urinary Estrogens and the Ratio of 2:16{alpha}-Hydroxyestrone in Men at High Risk of Prostate Cancer1,2

Jill M. Hamilton-Reeves3, Salome A. Rebello3, William Thomas4, Joel W. Slaton5 and Mindy S. Kurzer3,*

3 Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108; 4 Division of Biostatistics in the School of Public Health, University of Minnesota, Minneapolis, MN 55455; 5 Department of Urologic Surgery, University of Minnesota, Minneapolis, MN 55455; and Department of Urology, Veterans Administration Medical Center, Minneapolis, MN 55417

* To whom correspondence should be addressed. E-mail: mkurzer{at}umn.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Specific estrogen metabolites may initiate and promote hormone-related cancers. In epidemiological studies, significantly lower excretion of urinary estradiol (E2) and lower ratio of urinary 2-hydroxy estrogens to 16{alpha}-hydroxyestrone (2:16 OH-E1) have been reported in prostate cancer cases compared to controls. Although soy supplementation has been shown to increase the ratio 2:16 OH-E1 in women, no studies to our knowledge have investigated the effects of soy supplementation on estrogen metabolism in men. The objective of this randomized controlled trial was to determine the effects of soy protein isolate consumption on estrogen metabolism in men at high risk for developing advanced prostate cancer. Fifty-eight men supplemented their habitual diets with 1 of 3 protein isolates: 1) isoflavone-rich soy protein isolate (SPI+) (107 mg isoflavones/d); 2) alcohol-washed soy protein isolate (SPI–) (<6 mg isoflavones/d); or 3) milk protein isolate (MPI), each providing 40 g protein/d. At 0, 3, and 6 mo of supplementation, the urinary estrogen metabolite profile was measured by GC-MS. Both soy groups had higher E2 excretion than the MPI group at 3 and 6 mo. After 6 mo of supplementation, the SPI+ group had a significantly higher urinary 2:16 OH-E1 ratio than the MPI group. Increased urinary E2 excretion and 2:16 OH-E1 ratio in men consuming soy protein isolate are consistent with studies in postmenopausal women and suggest that soy consumption may be beneficial in men at high risk of progressing to advanced prostate cancer as a result of effects on endogenous estrogen metabolism.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Prostate cancer development is associated with andropause, when the ratio of circulating estrogens to androgens may increase by up to 40% (1). Increased estrogens are known to suppress testosterone production and compete with androgens for the androgen receptor. It has also been hypothesized that rising estrogen concentrations may cause direct mutagenic effects and unscheduled proliferation, in part due to the metabolism of the endogenous estrogens, estrone (E1)6 and estradiol (E2) by cytochrome P450 (CYP) enzymes, with subsequent creation of more potent estrogens and electrophilic intermediates. It has been suggested that the 2-hydroxy estrogens are benign, the 2-methoxy estrogens may be anti-carcinogenic through detoxification of electrophilic intermediates, and the 4- and 16{alpha}-hydroxy estrogens may be carcinogenic (2,3).

Estrogen metabolism is regulated by the amount of substrate available and the expression and activity of CYP enzymes. In phase I metabolism, E1 and E2 are converted by CYP 1A/1B/3A to the relatively inactive metabolites 2-hydroxyestrone (2-OH-E1) and 2-hydroxyestradiol (2-OH-E2), respectively (4–6). Alternatively, E1 and E2 may be metabolized by CYP 1A/3A to 4-hydroxyestrone (4-OH-E1) and 4-hydroxyestradiol (4-OH-E2) (6,7), metabolites shown to initiate cancer in rats by forming mutagenic DNA adducts (2). E1 may also be metabolized to 16-{alpha}-hydroxyestrone (16{alpha}-OH-E1), a metabolite shown to covalently bind the estrogen receptor, signaling sustained estrogen receptor-mediated proliferation that may promote tumor growth (3,8). In phase II metabolism, most of the 2-hydroxy metabolites are conjugated by catechol-O-methyltransferase to 2-methoxyestradiol (2-ME2), a metabolite shown to inhibit carcinogenesis by inducing apoptosis and suppressing proliferation (9).

Most of the interest in estrogen metabolism and cancer has been in relation to breast cancer risk. Numerous studies have shown an inverse relationship between the ratio of urinary 2-hydroxy estrogens to 16{alpha}-hydroxyestrone (2:16 OH-E1) and breast cancer risk (10–17), although a few studies have not shown a significant association (18–20) and 1 study found an association in premenopausal but not postmenopausal women (21). Although only 1 prostate cancer case-control study has been reported in men, results were similar, with a trend toward lower 16{alpha}-OH-E1 excretion, significantly higher 2-OH-E1 excretion, and a significantly higher 2:16 OH-E1 ratio in controls than cases (22). These data are consistent with a pilot study that reported an inverse relationship between 2-OH-E1 excretion and serum prostate specific antigen, a marker of prostate cancer (23).

In epidemiological studies, soy intake has been associated with decreased prostate cancer risk (24), but the mechanism is unknown and no studies have reported the effects of soy supplementation on urinary estrogen metabolism in men. In women, soy consumption has been shown to increase 2-OH-E1 excretion (25–28), decrease 16{alpha}-OH-E1 excretion (29), and increase the urinary 2:16 OH-E1 ratio (25,26,28,29). One study reported an increased urinary 2:16 OH-E1 ratio only in women who metabolized the soy isoflavone daidzein to equol (28).

The aim of this study was to assess the effects of 6-mo soy protein isolate consumption on urinary estrogen metabolites in men at high risk of prostate cancer. The effects of an isoflavone-rich soy protein isolate (SPI+) were compared to those of an isoflavone-poor soy protein isolate (SPI–) to elucidate whether isoflavones are the soy components responsible for altered estrogen metabolism. The underlying hypothesis was that SPI+ consumption would increase urinary E2 and E1, 2-OH-E1, 2-ME2, and the 2:16 OH-E1 ratio, and decrease-16{alpha}-OH-E1, 4-OH-E1, and 4-OH-E2 excretion.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
The study population, design, and treatment used in this Soy and Prostate Cancer Prevention trial have been discussed previously in detail (30). All 58 participants were recruited by urologic physicians at the Minneapolis Veteran's Administration Medical Center. The subjects were men between the ages of 50 and 85 y who recently underwent a prostate biopsy. Trained pathologists evaluated biopsy cores through routine histology diagnosis. Men were excluded from the trial if they were morbidly obese (BMI > 40 kg/m2), had prostate cancer that required medical treatment, had chronic prostatitis, consumed more than 14 alcoholic drinks per week, were allergic to soy or milk, used antibiotics frequently, or were on medically prescribed protein-restricted diets. All subjects provided written informed consent for participation in the trial, which was approved by the University of Minnesota Institutional Review Board: Human Subjects Committee, the Minneapolis Veterans Affairs Institutional Review Board and the U.S. Army Medical Research and Materiel Command's Human Subjects Research Review Board.

The subjects were randomly assigned to consume 1 of 3 protein isolates for 6 mo: 1) SPI+ containing 107 ± 5.0 mg isoflavones/d expressed as aglycone equivalents; 2) alcohol-extracted SPI– containing <6 ± 0.7 mg isoflavones/d expressed as aglycone equivalents; or 3) milk protein isolate (MPI) containing 0 mg isoflavones/d (Solae Company). The protein isolates were taken in divided doses twice daily, contributing a total of 40 g of protein and 200–400 kcal (1 kcal = 4.184 kJ) to the subjects' habitual diets each day. The mean distribution of isoflavones was 53% genistein, 35% daidzein, and 11% glycitein in SPI+, and 57% genistein, 20% daidzein, and 23% glycitein in SPI–, as analyzed by HPLC in the laboratory of Dr. Pat Murphy, Department of Food Science and Human Nutrition, Iowa State University. Participants recorded the time of consumption in study calendars and compliance was assessed by self-report as detailed previously (30). To prevent any other soy isoflavone consumption, subjects were given a detailed list of soy-containing products to avoid.

The men collected 24-h urine samples 1 d prior to each of 3 clinic visits at 0, 3, and 6 mo. The urine was collected in opaque plastic containers containing 1 g ascorbic acid/L, then was preserved with 0.1% sodium azide, and aliquots were stored at –20°C until analysis. Urinary creatinine was measured by dry slide chemistry with a VITROS Clinical Chemistry analyzer (Ortho-Clinical Diagnostics) and equol concentration was determined by HPLC-MS as previously described (31). For equol concentrations, the intra-assay CV was 8.2% and the inter-assay CV was 12.5%.

Estrogen metabolites were measured by GC-MS using the method described below, modified from previously described methods (29,32). Urine samples were thawed at room temperature, thoroughly mixed by vortex to ensure homogeneity, and centrifuged at 5°C for 5 min. Duplicate 10-mL aliquots of urine were added to clean, silanized 30-mL screw-top test tubes. Deuterated standards (C/D/N Isotopes, Pointe-Claire) of all estrogen metabolites assayed were added to the urine and an equal volume (10 mL) of ethoximation solution was added to the test tubes, thoroughly mixed by vortex and inversion, and incubated overnight at room temperature (~20–25°C).

The following day, the ethoximated samples were applied to Bond Elute LRC C-18 columns (Varian; 500 mg/column). The C-18 columns had been preconditioned with 5 mL methanol and 10 mL of deionized-distilled water immediately prior to sample introduction. Columns were then washed with 5 mL of 0.15 mol/L acetate buffer, pH 3.0. Samples were eluted into a clean, silanized test tube with 3.0 mL of methanol and then evaporated to dryness under nitrogen. The dry samples were hydrolyzed by dissolving in 5 mL of a solution containing 25 mg ascorbic acid and 50 µL ß-glucuronidase (Sigma no. G-7770, crude extract from Helix pomatia) in 0.15 mol/L acetate buffer, pH 4.1, and incubated overnight at 37°C.

The following day, the hydrolyzed samples were applied to C-18 columns (conditioned as above), washed with 5 mL of deionized-distilled water, and eluted into clean, silanized test tubes with 4.0 mL of methanol. Samples were evaporated to dryness under nitrogen and derivized to their trimethylsilyl components with 200 µL of a 15% MSTFA+ TMCS solution in acetonitrile (MSTFA+ 1% TMCS, Pierce Biotechnology, product no. 48915).

Chromatographic analysis was performed on an HP 5890 Series II gas chromatograph equipped with an HP-1MS 15-m column (0.25-mm i.d., 0.25-µm film thickness) interfaced to an HP 5970 mass selective detector. Instrumental programmed control and quantitative analysis was performed using HP Chemstation software. All samples from a given subject were analyzed in the same batch and an equal number of subjects from each group were included in each batch. Intra-assay CV were between 3.5 and 6.4% and inter-assay CV were between 4.3 and 13.0%. Detection limits were 1.0 µg/L for all estrogen metabolites except 2-OH-E2 and 2-OH-E1, which had detection limits of 0.50 µg/L. 4-OH-E2, 4-OH-E1, 4-methoxyestradiol, and 4-methoxyestrone were undetectable in all subjects.

    Subject retention. Subject accrual has been described previously in detail (30), with some variation described below. One subject who consented to the Soy and Prostate Cancer Prevention trial refused to collect his urine and 2 other subjects were excluded from analysis due to missing baseline urine collections. Four subjects did not collect urine at all 3 time points [no mid-point urine (n = 1), no final urine (n = 3)]. Thus, 55 participants were evaluated at baseline, 54 were evaluated at 3 mo, and 52 were evaluated at 6 mo. One subject did not consume the treatment powder for 3 d prior to his 6-mo appointment as a result of illness, so his data were excluded from the 6-mo equol excretion analysis.

    Statistical analysis. Demographic comparisons between groups were performed with 1-way ANOVA for continuous endpoints and chi-square for categories of prostate cancer markers. ANCOVA (SAS Proc GLM) was used to compare group means adjusted by their baseline values (33). For 16{alpha}-OH-E1, the model included a bodyweight by baseline metabolite interaction. In addition, preplanned pairwise comparisons as dictated by the study hypotheses were carried out. Paired t tests were used to test for significant within-group changes. Skewed data were log transformed before analysis and results are reported as geometric means and 95% CI. Data were analyzed both as nanomoles per day and nanomoles per milligram creatinine, and because there were no differences, data are expressed as nanomoles per day. Statistical significance was defined as P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Baseline. All 3 groups (SPI+, SPI–, and MPI) had similar anthropometrics, cancer status, and dietary intake (Table 1). The mean age of the men was 68 y, and mean BMI was 30 kg/m2. The only significant difference among groups was that the SPI– group consumed more protein at baseline, but not at 3 and 6 mo (30). Baseline urinary estrogen metabolites were similar except that the SPI+ group had higher 2-ME2 than the MPI group (Table 2).


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  		TABLE 1 Baseline characteristics of subjects1

 

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  		TABLE 2 Urinary estrogen metabolites in men at high risk of prostate cancer that consumed various protein isolates for 6 mo1

 
    Urinary estrogen metabolites. In both soy groups, E2 concentrations significantly increased from baseline at 3 and 6 mo and were significantly higher than the MPI group at both time points (Table 2). A similar pattern was seen with respect to E1 concentrations at 6 mo. 2-OH-E1 concentrations did not differ over 6 mo, but at 6 mo, 2-OH-E2 concentration decreased significantly from baseline in the MPI group and was significantly lower than both soy groups. Both soy groups showed higher 16{alpha}-OH-E1 concentrations than the MPI group at 3 mo, but this disappeared at 6 mo. The 2:16 OH-E1 ratio was significantly higher in the SPI+ group than the MPI group at 6 mo.

    Equol-excretor status. Equol excretor status was determined only in the SPI+ group, which received sufficient daidzein for equol production. There were 4 excretors and 15 nonexcretors. However, only 1 excretor remained at 6 mo, because 1 dropped out of the study after 3 mo, data were excluded from another subject as discussed above, and 1 apparently changed excretor status. Therefore, only the 3-mo data are reported. Baseline anthropometrics, cancer status, and dietary intake between excretors and nonexcretors did not differ (30). At baseline, the equol excretors tended to have higher 2:16 OH-E1 concentrations than nonexcretors (P = 0.08) (Table 3). All measured estrogen metabolites were the same between equol excretors and nonexcretors after 3 mo of SPI+ consumption.


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  		TABLE 3 Urinary estrogen metabolites between equol excretors and nonexcretors in men at high risk of prostate cancer who consumed SPI+ for 6 mo1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
The primary objective of this study was to evaluate the effects of soy protein isolate consumption on the urinary estrogen profile in men at risk for developing advanced prostate cancer. Consumption of soy protein isolate, regardless of isoflavone content, increased urinary excretion of E2 and tended to increase excretion of E1. These results are similar to those from studies in postmenopausal women (27) and may be clinically relevant to prostate cancer prevention. Higher urinary excretion of E2 has been observed in prostate cancer controls compared to cases (34) and a high E2 concentration in the blood has been associated with decreased prostate cancer risk (35–37). Estrogens or estrogen analogs have been prescribed for decades to prostate cancer patients in order to decrease androgen production through negative feedback on the hypothalamic-pituitary-gonadal system. Despite our previous finding that soy consumption does not alter circulating estrogen concentrations (30), our observations of increased E2 excretion support the hypothesis that effects on estrogens may be 1 mechanism by which soy supplementation reduces the risk of prostate cancer. Our observation that this effect occurred regardless of isoflavone content of the soy protein isolate suggests that isoflavones may not be the only hormone-modulating compound in soy. Alternatively, it is possible, although unlikely, that the small dose of isoflavones in the SPI– was sufficient to elicit a hormonal response.

We previously showed consumption of SPI–, but not SPI+, increased serum E2 and E1 concentrations in this population (30). Given that our subjects did not have kidney disease and that hormone concentrations fluctuate throughout the day, it is possible that our 24-h urine data, analyzed by GC-MS, better reflect total estrogen exposure than circulating concentrations determined by 1 blood draw analyzed by radioimmunoassay. This speculation is based on a chapter written by Adlercreutz (38) suggesting that the GC-MS analytical method used for urinary estrogen metabolites is more accurate than the radioimmunoassay method used for serum hormone analysis and that a longer time frame captured in the biological sample (24 h) may be more indicative of hormone exposure than a single blood draw. Conversely, increased urinary E2 excretion over time could decrease systemic E2 exposure; however, we did not find that serum E2 concentrations were inversely correlated to urinary E2 in our 6-mo study.

Urinary 2-OH-E2 excretion decreased in the MPI group but not in the soy groups, possibly due to higher E2 concentrations in the soy groups providing more substrate for the 2-hydroxy pathway than the control group. It has been suggested that soy consumption alters the enzymes involved in the formation of 2-hydroxy metabolites, including CYP 1A/3A (25,39), although the data are somewhat inconsistent (39,40).

Both soy groups had significantly higher urinary 16{alpha}-OH-E1 excretion than the MPI group at 3 mo. These results are consistent with 1 study in postmenopausal women in which consumption of soy protein isolate containing 44 mg isoflavones/d tended to increase urinary excretion of 16{alpha}-OH-E1 after a 6-wk intervention (28). On the other hand, postmenopausal women who consumed soy protein isolate containing 132 mg isoflavones/d for 3 mo (27) and premenopausal women who consumed soy protein isolate containing 129 mg isoflavones/d for 3 mo (29) both had decreased urinary 16{alpha}-OH-E1 excretion. Others have reported no effects of soy protein consumption on urinary 16{alpha}-OH-E1 excretion in women (25,41,42).

Most importantly, this is the first study, to our knowledge, to show that soy protein isolate consumption alters the urinary ratio of 2:16 OH-E1 in men. The 2:16 OH-E1 ratio was higher in the SPI+ group than in the MPI group at 6 mo, consistent with data from soy intervention studies performed in women (25,26,28,29). An increased 2:16 OH-E1 ratio has been associated with reduced risk of breast cancer in numerous studies (10–17,43), but only 1 study has been published evaluating the relationship between the 2:16 OH-E1 ratio and prostate cancer risk (22). This study showed that an increased 2:16 OH-E1 ratio was associated with reduced risk of prostate cancer (22). This finding suggests that 1 of the mechanisms by which consumption of SPI+ may prevent prostate cancer is via reducing the genotoxic effects of estrogen metabolites.

Within the SPI+ group, equol excretors tended to have a higher 2:16 OH-E1 ratio than nonexcretors at baseline. This finding is consistent with data suggesting that there may be beneficial differences between equol excretors and nonexcretors unrelated to the biological activity of equol itself (26,44,45). Our observation of no difference in the effects of soy consumption by equol excretor status was similar to previous reports in premenopausal and postmenopausal women (27,29), although a few studies in women have reported an association between urinary equol excretion and a higher 2:16 OH-E1 ratio (26,28,46). Our analysis was likely limited by the small sample size and the results are preliminary and should be interpreted with caution.

To our knowledge, this is the first study to report the full profile of urinary estrogen metabolites in men at high risk of developing prostate cancer and the first to report the effects of soy consumption on estrogen metabolite excretion in men. Consumption of soy protein isolate, regardless of isoflavone content, increased estrogen excretion, and SPI+ consumption but not SPI– increased the 2:16 OH-E1 ratio. Given that increased estrogens and 2:16 OH-E1 ratio have been associated with lower prostate cancer risk, our data suggest that effects on endogenous estrogen synthesis and metabolism may contribute to the prostate cancer preventive effects of soy consumption.


   ACKNOWLEDGMENTS
 
The authors thank Tony Vosooney and Mike Wachter for performing the analytical work and Lori Sorensen, Nicole Nelson, and Mary McMullen for assistance with clinic visits and data entry.


   FOOTNOTES
 
1 Supported by the United States Army Department of Defense Prostate Cancer Research Program (the Soy and Prostate Cancer Prevention trial was supported by grant DAMD 17-02-1-0101 to M.S.K. and W81XWH-06-1-0075 to J.H.R.). The protein isolates were donated by the Solae Company, St. Louis, MO. Neither sponsor was involved in writing this report. Back

2 Author disclosures: J. M. Hamilton-Reeves, S. A. Rebello, W. Thomas, and J. W. Slaton, no conflicts of interest and M. S. Kurzer, consults occasionally for the Solae Company. Back

6 Abbreviations used: CYP, cytochrome P450 enzymes; E1, estrone; E2, estradiol; 2-ME2, 2-methoxyestradiol; MPI, milk protein isolate; 2-OH-E1, 2-hydroxyestrone; 2:16 OH-E1 ratio, [(2-OH-E1 + 2-OH-E2)/16{alpha}-OH-E1]; 2-OH-E2, 2-hydroxyestradiol; 4-OH-E1, 4-hydroxyestrone; 4-OH-E2, 4-hydroxyestradiol; 16{alpha}-OH-E1, 16{alpha}-hydroxyestrone; SPI+, isoflavone-rich soy protein isolate; SPI–, alcohol-extracted soy protein isolate. Back

Manuscript received 3 May 2007. Initial review completed 7 June 2007. Revision accepted 10 July 2007.


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TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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