A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer

Our purpose was to evaluate the safety and effectiveness of purified isoflavones in producing an increase in plasma isoflavones and a corresponding change in serum sex hormone binding globulin (SHBG) and steroid hormone levels in men diagnosed with early stage prostate cancer. In this Phase II randomized, double-blinded, placebo-controlled trial, 53 prostate cancer patients with a Gleason score of 6 or below were supplemented with 80 mg purified isoflavones or placebo for 12 weeks. Changes in plasma isoflavones, serum steroid hormones, and safety markers were analyzed from baseline to 12 wk. A total of 50 subjects completed the study. Although significant increases in plasma isoflavones (P < 0.001) was observed with no clinical toxicity, the corresponding modulation of serum SHBG, total estradiol, and testosterone in the isoflavone-treated group compared to men receiving placebo was nonsignificant. Increasing plasma isoflavones failed to produce a corresponding modulation of serum steroid hormone levels in men with localized prostate cancer. The study establishes the need to explore other potential mechanisms by which prolonged and consistent purified isoflavone consumption may modulate prostate cancer risk.     

Safety of Purified Isoflavones in Men With Clinically Localized Prostate Cancer

Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.     

Safety of purified isoflavones in men with clinically localized prostate cancer

Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.     

Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer

The efficacy and safety of consuming high-dose isoflavone supplements for prostate cancer is not clear. A double-blind, placebo controlled, randomized trial was conducted in 53 men with prostate cancer enrolled in an active surveillance program. The treatment group consumed a supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones daily for 6 mo. Prostate-specific antigen (PSA) was measured in both groups at baseline, 3 mo, and 6 mo, and serum concentrations of genistein, daidzein, and equol were assessed at baseline and 6 mo in the treatment group. Following the completion of the 6-mo double-blind study, men were enrolled in a 6-mo open label trial with the same isoflavone-rich supplement, and PSA was measured at 3 and 6 mo. PSA concentrations did not change in either group after 6 mo or after 12 mo when the open-label study was included. The 6 mo serum concentrations of genistein and daidzein (39.85 and 45.59 μmol/l, respectively) were significantly greater than baseline values and substantially higher than levels previously reported in other studies. Equol levels did not change. Although high amounts of aglycone isoflavones may result in significantly elevated serum concentrations of genistein and daidzein, these dietary supplements alone did not lower PSA levels in men with low-volume prostate cancer.     

Effects of a High Dose,Aglycone-Rich Soy Extract on Prostate-Specific Antigen and Serum Isoflavone Concentrations in Men With Localized Prostate Cancer

The efficacy and safety of consuming high-dose isoflavone supplements for prostate cancer is not clear. A double-blind, placebo controlled, randomized trial was conducted in 53 men with prostate cancer enrolled in an active surveillance program. The treatment group consumed a supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones daily for 6 mo. Prostate-specific antigen (PSA) was measured in both groups at baseline, 3 mo, and 6 mo, and serum concentrations of genistein, daidzein, and equol were assessed at baseline and 6 mo in the treatment group. Following the completion of the 6-mo double-blind study, men were enrolled in a 6-mo open label trial with the same isoflavone-rich supplement, and PSA was measured at 3 and 6 mo. PSA concentrations did not change in either group after 6 mo or after 12 mo when the open-label study was included. The 6 mo serum concentrations of genistein and daidzein (39.85 and 45.59 μmol/l, respectively) were significantly greater than baseline values and substantially higher than levels previously reported in other studies. Equol levels did not change. Although high amounts of aglycone isoflavones may result in significantly elevated serum concentrations of genistein and daidzein, these dietary supplements alone did not lower PSA levels in men with low-volume prostate cancer.     

The effect of nutritional factors on sex hormone levels in male twins

Dietary intake has been hypothesized as being associated with several hormonally related cancers including prostate, breast, ovarian, and endometrial cancer. Because diet may affect hormones directly, it is logical to examine the effects of dietary factors on hormone production and levels. Therefore, a set of 72 male MZ and 83 male DZ twin pairs was ascertained from the Utah birth certificates. A quantitative food frequency questionnaire was administered and blood samples were drawn for hormonal assays. Heritability estimates for hormonal levels were calculated indicating a range from no heritability for sex hormone binding globulin (SHBG), estrone, and testosterone glucuronide to 70% for androstanediol glucuronide and luteinizing hormone. To examine nutritional factors, the difference in hormone and SHBG levels between each MZ twin and his co-twin were correlated with the difference in nutrient intake. Weight and obesity were significantly correlated with plasma testosterone and follicle stimulating hormone. Fat intake showed a significant association with testosterone. Androstanediol glucuronide, a steroid that reflects tissue formation of dihydrotestosterone, was inversely correlated with caloric intake, theobromine and caffeine. Testosterone glucuronide exhibited significant correlations with calories and vitamin A. This study suggests that dietary intake affects plasma sex-steroid levels in men.     

Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men

Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.     

Soy milk intake in relation to serum sex hormone levels in British men

Soy beans contain high levels of the isoflavones genistein and daidzein and their glycosides and have been implicated in the prevention of prostate cancer, possibly via their effects on sex hormone metabolism. The aim of this study was to assess the relation between dietary soy intake and sex hormone levels in a cross-sectional analysis of 696 men with a wide range of soy intakes. Soy milk intake was measured using a validated semiquantitative food frequency questionnaire, and serum hormone concentrations were measured by immunoassay. Multiple regression was used to investigate the association between soy milk intake, an index of isoflavone intake, and hormone levels after adjustment for pertinent confounders. Soy milk intake was not associated with serum concentrations of testosterone, free testosterone, androstanediol glucuronide, sex hormone-binding globulin, or luteinizing hormone. These results suggest that soy milk intake, as a marker of isoflavone intake, is not associated with serum sex hormone concentrations among free-living Western men.     

Soy Milk Intake in Relation to Serum Sex Hormone Levels in British Men

Soy beans contain high levels of the isoflavones genistein and daidzein and their glycosides and have been implicated in the prevention of prostate cancer, possibly via their effects on sex hormone metabolism. The aim of this study was to assess the relation between dietary soy intake and sex hormone levels in a cross-sectional analysis of 696 men with a wide range of soy intakes. Soy milk intake was measured using a validated semiquantitative food frequency questionnaire, and serum hormone concentrations were measured by immunoassay. Multiple regression was used to investigate the association between soy milk intake, an index of isoflavone intake, and hormone levels after adjustment for pertinent confounders. Soy milk intake was not associated with serum concentrations of testosterone, free testosterone, androstanediol glucuronide, sex hormone-binding globulin, or luteinizing hormone. These results suggest that soy milk intake, as a marker of isoflavone intake, is not associated with serum sex hormone concentrations among free-living Western men.     

Lycopene and soy isoflavones in the treatment of prostate cancer

Dietary intake of lycopene and soy has been associated with a lower risk of prostate cancer. In vitro studies with lycopene and genistein, a soy isoflavone, have shown induction of apoptosis and inhibition of cell growth in androgen-sensitive (LNCaP) and androgen-independent (PC3 and VeCaP) prostate cancer cell lines. In a previous Phase II clinical trial in prostate cancer patients, we observed prostate-specific antigen (PSA) stabilization with soy isoflavone intake. In this Phase II clinical trial, we investigated the efficacy of lycopene alone or in combination with soy isoflavones on serum PSA levels in men with prostate cancer. To be eligible for the study, men with prostate cancer had to have rising serum PSA following local therapy or while on hormone therapy. Study population included 71 eligible patients who had 3 successive rising PSA levels or a minimum PSA of 10 ng/ml at 2 successive evaluations prior to starting therapy. Subjects were randomly assigned to receive a tomato extract capsule containing 15 mg of lycopene alone (n = 38) or together with a capsule containing 40 mg of a soy isoflavone mixture (n = 33) twice daily orally for a maximum of 6 mo. One patient on the lycopene arm did not receive therapy due to his inability to ingest the study pill. There was no decline in serum PSA in either group qualifying for a partial or complete response. However, 35 of 37 (95%) evaluable patients in the lycopene group and 22 of 33 (67%) evaluable patients in the lycopene plus soy isoflavone group achieved stable disease described as stabilization in serum PSA level. The data suggest that lycopene and soy isoflavones have activity in prostate cancer patients with PSA relapse disease and may delay progression of both hormone-refractory and hormone-sensitive prostate cancer. However, there may not be an additive effect between the 2 compounds when taken together. Future studies are warranted to further investigate the efficacy of lycopene and soy isoflavones in prostate cancer as well as the mechanism of potential negative interaction between them.     

Orally administered isoflavones are present as glucuronides in the human prostate

Better knowledge of the bioavailability and metabolism of isoflavones in prostate tissue is needed to further investigate their mechanisms of action in the context of prostate cancer prevention. A total of 12 men with benign prostatic hyperplasia received soy extract supplementation (3 Evestrel capsules, providing a total of 112.5 mg isoflavones aglycone eq/day) for 3 days before prostate surgery. Blood and prostate tissues were sampled and metabolites were identified using electrospray ionization liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS) and chemically synthesized standards of glucuronidated isoflavones. The main metabolites were the same in prostate tissue and in plasma, namely, 2 monoglucuronides of daidzein and 2 monoglucuronides of genistein. Concentrations of total isoflavones measured in prostate reached 1.05 +/- 0.62 nmol/g tissue (range 0.30-2.23) at the time of sampling, 12 h after the last isoflavone supplementation. At that time point, prostate concentrations were lower than plasma concentrations in all volunteers: 0.47 nmol/g vs. 0.66 microM for daidzein and 0.58 nmol/g vs. 0.78 microM for genistein. Isoflavone mechanisms of action should thus be investigated in in vitro cell studies using physiological conditions, intracellular concentrations below 5 nmol/g and no intracellular deconjugation of the monoglucuronide metabolites.     

Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia

A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein.     

Orally Administered Isoflavones Are Present as Glucuronides in the Human Prostate

Better knowledge of the bioavailability and metabolism of isoflavones in prostate tissue is needed to further investigate their mechanisms of action in the context of prostate cancer prevention. A total of 12 men with benign prostatic hyperplasia received soy extract supplementation (3 Evestrel® capsules, providing a total of 112.5 mg isoflavones aglycone eq/day) for 3 days before prostate surgery. Blood and prostate tissues were sampled and metabolites were identified using electrospray ionization liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS) and chemically synthesized standards of glucuronidated isoflavones. The main metabolites were the same in prostate tissue and in plasma, namely, 2 monoglucuronides of daidzein and 2 monoglucuronides of genistein. Concentrations of total isoflavones measured in prostate reached 1.05 ± 0.62 nmol/g tissue (range 0.30–2.23) at the time of sampling, 12 h after the last isoflavone supplementation. At that time point, prostate concentrations were lower than plasma concentrations in all volunteers: 0.47 nmol/g vs. 0.66 μ M for daidzein and 0.58 nmol/g vs. 0.78 μ M for genistein. Isoflavone mechanisms of action should thus be investigated in in vitro cell studies using physiological conditions, intracellular concentrations below 5 nmol/g and no intracellular deconjugation of the monoglucuronide metabolites.     

Regulation of male sex hormone levels by soy isoflavones in rats

Several studies have suggested that soybean intake is associated with a lower risk of prostate cancer. However, the mechanism of prostate cancer prevention by soybeans remains unclear. Because prostate cancer is reported to have an association with an increased level of dihydrotestosterone (DHT) and soybean isoflavones are known to inhibit 5 alpha-reductase, which is involved in the conversion of testosterone to DHT, the effects of soybean extract and isoflavones on the plasma levels of male sex hormones were investigated using male rats. In Experiment I, Sprague-Dawley rats were fed diets with and without soy flour; in Experiment II, rats were fed diets containing 2% soy methanol extract or 0.2% semipurified isoflavones or a control diet. The study showed a reduction of plasma DHT along with an increase in total plasma androgen in rats fed soy flour or semipurified isoflavones for 1 wk. These results suggest that soy isoflavone intake may reduce plasma DHT level.     

Lycopene inhibits disease progression in patients with benign prostate hyperplasia

Lycopene is a promising nutritional component for chemoprevention of prostate cancer (PCa). A possibly beneficial role of lycopene in patients diagnosed with benign prostate hyperplasia (BPH), who are at increased risk of developing PCa, has been suggested, although clinical data are lacking. Therefore, this pilot study aimed to investigate the effects of lycopene supplementation in elderly men diagnosed with BPH. A total of 40 patients with histologically proven BPH free of PCa were randomized to receive either lycopene at a dose of 15 mg/d or placebo for 6 mo. The effects of the intervention on carotenoid status, clinical diagnostic markers of prostate proliferation, and symptoms of the disease were assessed. The primary endpoint of the study was the inhibition or reduction of increased serum prostate-specific antigen (PSA) levels. The 6-mo lycopene supplementation decreased PSA levels in men (P < 0.05), whereas there was no change in the placebo group. The plasma lycopene concentration increased in the group taking lycopene (P < 0.0001) but other plasma carotenoids were not affected. Whereas progression of prostate enlargement occurred in the placebo group as assessed by trans-rectal ultrasonography (P < 0.05) and digital rectal examination (P < 0.01), the prostate did not enlarge in the lycopene group. Symptoms of the disease, as assessed via the International Prostate Symptom Score questionnaire, were improved in both groups with a significantly greater effect in men taking lycopene supplements. In conclusion, lycopene inhibited progression of BPH.     

The effects of metformin and diet on plasma testosterone and leptin levels in obese men.

OBJECTIVE: The aim of this study was to investigate the effects of combined hypocaloric diet and metformin on circulating testosterone and leptin levels in obese men with or without type 2 diabetes. RESEARCH METHODS AND PROCEDURES: Twenty obese men with type 2 diabetes (mean body mass index [BMI]: 35.5 +/- 1.1 kg/m(2)) and 20 nondiabetic obese men were enrolled in the study. We measured serum follicle-stimulating hormone, luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), sex-hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and plasma leptin levels before and 3 months after metformin treatment. Both groups were placed on a hypocaloric diet and 850 mg of metformin taken orally twice daily for 3 months. RESULTS: Metformin and hypocaloric diets led to decreases in BMI and waist and hip circumferences in both groups. A significant decrease in TT levels in the diabetic group and FT levels in the control group was found, whereas follicle-stimulating hormone, LH, and DHEAS levels were not changed significantly. A significant increase in SHBG levels was observed in the control group but not in the patient group. Leptin levels also decreased after treatment in both groups. Decreased testosterone levels were not correlated to changes in waist and hip circumference, waist-to-hip ratio, BMI, and levels of fasting blood glucose, leptin, SHBG, or DHEAS in the diabetic group. However, a decrease in FT was correlated to changes in the levels of SHBG (r = -0.71, p = 0.001) and LH (r = 0.80, p = 0.001) but not to other parameters. DISCUSSION: We conclude that metformin treatment combined with a hypocaloric diet leads to reduced FT levels in obese nondiabetic men and to reduced TT levels in obese men with type 2 diabetes. Increased SHBG levels may account for the decrease in FT levels in the former group.     

Determinants of sex hormone levels in men as useful indices in hormone-related disorders

Because the determinants of serum sex hormone levels in men have been infrequently studied, we investigated the relation of several personal characteristics to serum levels of testosterone (T), dihydrotestosterone (DHT), estrone (El), estradiol (E2) and sex hormone-binding globulin (SHBG) among 98 Japanese American men in Hawaii, aged 52–74. The SHBG levels and T/(El + E2) ratios decreased progressively with increasing body mass index. The SHBG levels were also inversely associated with hematocrit levels. Serum androgen and estrogen levels did not correlate with smoking, alcohol intake, serum cholesterol, serum uric acid and blood pressure. Some of the associations observed in the present study may be implicated in the etiology of hormone-related neoplasms in men.     

Effects of chronic exposure to low doses of trichloroethylene on steroid hormone and insulin levels in normal men.

The aim of this study was to examine the serum levels of insulin and some adrenal steroid hormones in men chronically exposed to low doses of trichloroethylene (TCE). A total of 85 workers participated in this study. Each worker had urine collected and analyzed for trichloroacetic acids (UTCA) on the same day that a blood sample was taken for analyses of serum testosterone, sex hormone-binding globulin (SHBG), androstenedione, cortisol, aldosterone, and insulin. The mean concentration of environmental TCE was 29.6 ppm and the mean UTCA was 22.4 mg/g creatinine (range 0.8-136.4). TCE exposure did not cause any significant changes to the adrenal steroid hormone productions. The results showed that UTCA was significantly correlated to serum insulin levels. Insulin and SHBG responded in tandem, with the highest levels found in workers exposed to TCE for less than 2 years; levels of both parameters were significantly lowered in those exposed for more than 2 years. A triphasic response in insulin levels to TCE, which depended on the duration of exposure, was noted. Initial exposure caused an acute rise in insulin levels. This was followed by a fall to normal levels in those exposed 2-4 years and then a slight rise in those exposed for more than 6 years. The mechanism for this pattern of response to TCE exposure is yet unknown.     

Association of Urinary Phytoestrogen Concentrations with Serum Concentrations of Prostate-Specific Antigen in the National Health and Nutrition Examination Survey

Some clinical trials have shown that high phytoestrogen intake may decrease serum concentrations of prostate-specific antigen (PSA), and phytoestrogens may also lower prostate cancer risk. It was the aim of this study to examine the relationship between the serum PSA level and urine phytoestrogen concentration in generally healthy U.S. men. Eight hundred twenty-four men, 40+ yr old without prostate cancer, who participated in the 2001–2004 NHANES surveys, were included in the analysis. The association of total PSA, free PSA, and PSA ratio [free PSA/total PSA * 100] with concentrations of isoflavones and lignans (standardized for urinary creatinine concentration) was examined using multivariable-adjusted linear and logistic regression models. The linear regression analyses showed no clear association between creatinine-standardized urinary phytoestrogen concentrations and serum total or free PSA levels or PSA ratio. However, the odds of having a PSA ratio <15% rose from Quartile 1 to Quartile 4 of isoflavone excretion (odds ratio = 2.82, 95% confidence interval 1.28–6.22 for top vs. bottom quartile), but there were no associations with having a PSA ratio <25%. In generally healthy U.S. men, 40+ yr old without a diagnosis of prostate cancer, urinary isoflavone, and lignan concentrations were not associated with serum PSA level.     

Phytoestrogen exposure, polymorphisms in COMT, CYP19, ESR1, and SHBG genes, and their associations with prostate cancer risk

Prospective phytoestrogen exposure was assessed using both biomarkers and estimates of intake in 89 British men recruited into the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition study, men who subsequently developed prostate cancer. Results were compared with those from 178 healthy men matched by age and date of recruitment. Levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in spot urine and serum samples. Five single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genes were genotyped. Urinary levels of all phytoestrogens correlated strongly with serum levels. Correlation coefficients ranged from 0.63 (glycitein) to 0.88 (daidzein) (P < 0.001). Urinary and serum levels correlated significantly with isoflavone intake assessed from food diaries (R = 0.15-0.20; P < 0.05) but not with that from a food-frequency questionnaire. Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Our results utilizing a combined prospective exposure provide no evidence that phytoestrogens alter prostate cancer risk in British men, whereas the C allele for the PvuII polymorphism may be associated with increased risk.