Plasma Equol Research Articles

The Association between Plasma Concentration of Phytoestrogens and Hypertension within the Korean Multicenter Cancer Cohort.

In order to examine the association between plasma phytoestrogen concentration (genistein, daidzein, equol and enterolactone) and hypertension, we conducted a nested case–control study for 229 hypertension cases including 112 prehypertension and 159 healthy controls derived from the Korean Multi-center Cancer Cohort (KMCC). The concentration of plasma phytoestrogens was measured using time-resolved fluoroimmunoassay. We assessed the association between plasma phytoestrogens and hypertension using logistic regression models using odds ratio (OR) and 95% confidence interval (95%CI). The highest tertile of plasma equol and enterolactone concentration exhibited a significantly decreased risk of hypertension (equol, OR = 0.34, 95%CI 0.20–0.57; enterolactone, OR = 0.32, 95%CI 0.18–0.57), compared with the lowest tertile. Equol and enterolactone showed reduced ORs for prehypertension (the highest tertile relative to the lowest tertile, OR = 0.50, 95%CI 0.26–0.96; OR = 0.38, 95%CI 0.19–0.75, respectively) and hypertension (OR = 0.42, 95%CI 0.22–0.81; OR = 0.28, 95%CI 0.14–0.54, respectively). There was a stronger association in hypertension (the highest tertile relative to the lowest tertile in obesity vs. non-obesity; equol, OR = 0.06 vs. 0.63; enterolactone, OR = 0.07 vs. 0.46; both p-heterogeneity < 0.01). This study suggests that equol and enterolactone may contribute to prevent primarily prehypertension and hypertension, and control cardiovascular disease (CVD) based on the continuum of hypertension and CVD. Further study to assess hypertension risk based on useful biomarkers, including phytoestrogens, may contribute to primary prevention of hypertension.

Ischemic-time associated reductions in equol monosulfate plasma levels in a mouse model of ischemic stroke: support the existence of a 'brain-gut axis'.

Interest is growing in the role played by intestinal flora in the pathogeneses of diseases and in the possibility of treating disease by altering intestinal flora compositions. Recent studies have focused on the relationship between the intestinal microbiome and brain function as proposed by the brain-gut axis hypothesis. To investigate the relation between ischemic stroke and plasma equol monosulfate levels (a soy isoflavone metabolite) in a middle cerebral artery occlusion (MCAO) mouse model. Mice (C57BL/6) were subjected to MCAO for various times (30 min to 24 h), and degrees of cerebral damage were assessed using total infarction volumes, brain edema severities and neurological deficit scores. Hematoxylin and eosin and cresyl violet staining were used to observe morphological changes in ischemic brains. Levels of equol monosulfate in plasma and the relationships between these and degree of brain injury were investigated. Infarction volumes, brain edema severity and neurological deficit scores were significantly correlated with ischemic time, and morphological deteriorations of brain neuronal cells also increased with ischemic duration. Equol monosulfate contents were ischemic-time dependently lower in MCAO treated animals than in sham-operated controls. Ischemic stroke may time-dependently reduce plasma levels of equol monosulfate by lowering the metabolic rate of equol in MCAO-induced mice. This study provides indirect support of the brain-gut axis hypothesis.

Abstract 4642: Effects of soy protein diet on plasma isoflavones levels in obese DMBA-induced mammary tumor rat model

Abstract Obesity epidemic in the US and world grows as the number of overweight and obese adults continues to rise. Obese women have higher mortality rates from all cancers including breast cancer. Several studies have reported the protective effects of soy intake on breast cancer development, while other studies report the adverse effects of soy protein diet on breast cancer development. Soybeans contain isoflavones genistein, daidzein and glycitein, known as isoflavonoids, which are structurally similar to mammalian estrogens, have estrogenic properties and are potential anticarcinogens. Gut flora metabolizes daidzein into equol, a non-steroidal estrogen and has cancer chemopreventive property. The objective of this study was to determine the effects of obesity and a high isoflavones soy protein diet on plasma isoflavones; genistein, daidzein, glycitein, equol and O-Desmethylangolensin (O-MDA) levels using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model. Five-week-old female Zucker rats (45 obese fa/fa and 54 lean) were used. After one week of acclimation (age 42 days), rats were randomly assigned to the following diet groups; 1) Lean, casein; 2) Obese, casein; 3) Lean, soy and 4) Obese, soy. Rats had ad lib access to water and diet with either casein or soy protein isolate as source of protein. All rats were orally gavaged at age 50 days with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly and sacrificed 21 weeks post-DMBA treatment. Plasma was collected to measure genistein, daidzein, glycitein, equol and O-MDA levels using liquid chromatography−tandem mass spectrometry (LC-MS/MS). At end of the experiment, 69% of the Lean casein rats developed mammary tumors compared to 50% in lean soy group (p= 0.176). In the obese group, 76% of the soy-fed rats developed mammary tumors compared to 15% (P&amp;lt;0.001) of obese casein- fed rats. Plasma daidzein and genistein concentration were not significantly different in lean vs obese soy-fed rats. However, O-MDA and equol concentration were significantly lower (P&amp;lt;0.05) in obese soy-fed rats compared to lean soy rats. These data suggests that obese rats fed soy protein diet containing high isoflavone levels promoted DMBA-induced mammary tumor development compared to a casein-based diet. Also, obese soy-fed rats exhibited significantly lower plasma equol concentrations than those observed in lean soy-fed rats and this reduction may aid in explaining soy's impaired cancer chemopreventative effects in obese breast cancer model. Citation Format: Reza Hakkak, Soheila Korourian. Effects of soy protein diet on plasma isoflavones levels in obese DMBA-induced mammary tumor rat model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4642.

EFFECT OF DAIDZEIN 120 MG SUPPLEMENTATION TO MENOPAUSAL SYMPTOMS AND QUALITY OF LIFE IN NON EQUOL PRODUCER WOMEN

ABSTRACTObjectives: To investigate and compare symptom changes and quality of life (QOL) in non equol producer postmenopausal women after consumingdaidzein supplementation.Methods: This was a single randomized clinical trial. It involved menopausal women. They were divided into two groups, one received placebo thatcontains calcium glycerophosphate 500 mg, vitamin D3 35 IU and daidzein group contain daidzein 120 mg, contain calcium glycerophosphate 500 mg,vitamin D3 140 IU for 8 weeks. Plasma equol was measured before supplementation. Menopause QOL (MenQOL) questionnaires have been utilized inthe beginning and the end of treatment to assess the QOL.Results: A total of 41 women age 45-63 years old were included in this trial, 19 (47.5%) of them receive daidzein supplementation and othersreceived control treatment. Menopausal symptoms decreased but not statistically significant compare to control group.Conclusion: About 8 weeks daidzein supplementation was not statistically improved MenQOL status in non equol producer postmenopausal women.Keywords: Menopause, Quality of life, Menopausal symptom, Isoflavone, Daidzein, Menopause quality of life.

Kanamycin inhibits daidzein metabolism and abilities of the metabolites to prevent bone loss in ovariectomized mice.

BackgroundDaidzein is an isoflavone derived from soybeans that exerts preventive effects on bone loss in ovariectomized (OVX) animals. These effects have been correlated with increasing serum equol levels. In the present study, we investigated the effects of antibiotic intake on equol metabolism from daidzein, and the corresponding levels of bone loss in OVX mice.MethodsEight-week-old female ddY mice (n = 42) were either ovariectomized (OVX) or subjected to a sham operation (sham). OVX mice were then divided into six dietary subgroups: control diet (control), 0.3 % kanamycin diet (KN), 0.1 % daidzein diet (Dz), 0.1 % daidzein and 0.0375 % kanamycin diet (Dz+KN3.75), 0.1 % daidzein and 0.075 % kanamycin diet (Dz+KN7.5), and 0.1 % daidzein and 0.3 % kanamycin diet (Dz+KN30). The mice were fed their respective diets for 4 weeks.ResultsUterine weight and femoral bone mineral density (BMD) were significantly lower in the OVX mice compared in the sham mice. No significant differences in uterine weight were observed among all OVX dietary subgroups. The Dz subgroup was found to exhibit higher plasma equol and O-desmethylangolensin (O-DMA) concentrations, as well as greater femoral BMD, compared to all other OVX subgroups. Furthermore, when compared to the Dz group, kanamycin intake decreased plasma equol and O-DMA concentrations, as well as femoral BMD in the OVX mice.ConclusionsThese results suggest that kanamycin intake inhibited the conversion of daidzein to equol and O-DMA, blocking the preventive effects of daidzein on bone loss in OVX mice. Therefore, the bone-protective effects of daidzein intake may be predominantly associated with increased plasma concentrations of either equol or O-DMA.

Plasma equol concentration is not associated with breast cancer and fibrocystic breast conditions among women in Shanghai, China

Equol (a bacterial metabolite of the soy isoflavone daidzein) is produced by 30% to 50% of humans and may be associated with health outcomes. We hypothesized that plasma equol would be inversely associated with risks of fibrocystic breast conditions (FBC) and breast cancer (BC). Plasma from women in a breast self-examination trial in Shanghai with BC (n=269) or FBC (n=443), and age-matched controls (n=1027) was analyzed for isoflavones. Equol was grouped into categories (<20, 20-<45, and ≥45nmol/L) and, among women with daidzein ≥20nmol/L, the log10 equol:daidzein ratio was grouped into tertiles. Where available, non-cancerous tissue (NCT) adjacent to the carcinomas from women with BC were classified as non-proliferative or proliferative (n=130 and 172, respectively). The lesions from women with FBC were similarly classified (n=99 and 92, respectively). Odds ratios (OR) and 95% confidence intervals (CI) were calculated across equol categories and tertiles of log10 equol:daidzein ratio. Equol categories were not associated with FBC or BC (P>.05). For log10 equol:daidzein, compared to controls there were positive associations in the mid tertile for proliferative FBC (OR 2.06, 95% CI 1.08-3.93), BC with proliferative NCT (OR 2.95, 95% CI 1.37-6.35), and all BC regardless of histology (OR 2.37, 95% CI 1.43-3.95). However, trends in ORs with increasing plasma equol values or equol:daidzein ratios were not observed (P>.05). The results of this study do not provide evidence that equol plays a role in the etiology of these breast conditions. However, further work is needed to confirm or refute this conclusion.

Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial

Background: There is much speculation with regard to the potential cardioprotective benefits of equol, a microbial-derived metabolite of the isoflavone daidzein, which is produced in the large intestine after soy intake in 30% of Western populations. Although cross-sectional and retrospective data support favorable associations between the equol producer (EP) phenotype and cardiometabolic health, few studies have prospectively recruited EPs to confirm this association.Objective: The aim was to determine whether the acute vascular benefits of isoflavones differ according to EP phenotype and subsequently investigate the effect of providing commercially produced S-(–)equol to non-EPs.Design: We prospectively recruited male EPs and non-EPs (n = 14/group) at moderate cardiovascular risk into a double-blind, placebo-controlled crossover study to examine the acute effects of soy isoflavones (80-mg aglycone equivalents) on arterial stiffness [carotid-femoral pulse-wave velocity (cfPWV)], blood pressure, endothelial function (measured by using the EndoPAT 2000; Itamar Medical), and nitric oxide at baseline (0 h) and 6 and 24 h after intake. In a separate assessment, non-EPs consumed 40 mg S-(–)equol with identical vascular measurements performed 2 h after intake.Results: After soy intake, cfPWV significantly improved in EPs at 24 h (cfPWV change from 0 h: isoflavone, −0.2 ± 0.2 m/s; placebo, 0.6 ± 0.2 m/s; P < 0.01), which was significantly associated with plasma equol concentrations (R = −0.36, P = 0.01). No vascular effects were observed in EPs at 6 h or in non-EPs at any time point. Similarly, no benefit of commercially produced S-(–)equol was observed in non-EPs despite mean plasma equol concentrations reaching 3.2 μmol/L.Conclusions: Acute soy intake improved cfPWV in EPs, equating to an 11–12% reduced risk of cardiovascular disease if sustained. However, a single dose of commercially produced equol had no cardiovascular benefits in non-EPs. These data suggest that the EP phenotype is critical in unlocking the vascular benefits of equol in men, and long-term trials should focus on confirming the implications of EP phenotype on cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01530893.

Impact of Dietary Polydextrose on the Daidzein Metabolism in Adult Mice

Equol, a bacterial product from daidzein, has been shown to provide beneficial effects. The impact of polydextrose, a compound known to affect the intestinal flora, was studied for its impact on mouse intestinal flora and isoflavonoids in the cecum and plasma. We hypothesized that polydextrose would change the metabolism of isoflavonoids and intestinal flora in mice. Male mice were administered a 1% polydextrose solution (PD) in their drinking water which was provided ad libitum, and were compared with a control group (CO, water only). Both groups were fed the AIN-93M diet for 24 days. Plasma equol and cecal equol concentrations and in vitro equol production from daidzein with fecal flora of mice were measured. The plasma equol concentration was significantly higher in the PD group than in the CO group at 22 hr after the administration of daidzin. The concentration of equol in the cecum was signiticantly greater in the PD group than in the CO group at 22 hr after administration of daidzin. In the in vitro incubation of daidzein with the fecal flora of mice, equol concentrations were greater in the PD group. These results suggest that dietary polydextrose has the potential to affect equol production by altering the metabolic activity of the intestinal flora and/or the gut environment.

Lactobacillus fermentum ATCC9338: Effects on Mouse Intestinal Flora and Plasma Concentration of Isoflavonoids

The effects of Lactobacillus fermentum ATCC9338 on the metabolism of daidzein and on the composition of intestinal flora were assessed for adult mice. Lactobacillus fermentum ATCC9338 altered the equol production status in the in vitro incubation of daidzein with fecal flora of mice. For in vivo investigation, mice were fed an AIN-93M purified diet for 19 days followed by a 0.05% daidzein diet for 4 days in the in vivo experiment. The LD group received L. fermentum for 10 days. The control (CD) group did not receive lactic acid bacteria. In analysis of plasma isoflavonoids, plasma equol concentration tended to be high in the LD groups. However, no significant differences in plasma daidzein and equol concentrations were observed between the LD and CD groups. In analysis of the composition of intestinal flora, the occupation ratio of Lactobacillales was significantly higher in the LD group. We demonstrated that Lactobacillus fermentum ATCC9338 could affect the intestinal flora and in vitro fecal equol production in mice.

Dietary cholesterol lowers plasma and cecal equol concentrations in mice

This study examined the effects of cholesterol on mouse intestinal microflora and on isoflavonoids in the cecum and plasma. Dietary cholesterol affects bile acid metabolism and bile acids can influence the intestinal microorganisms. Intestinal microflora appear to play an important role in isoflavone metabolism. We hypothesized that dietary cholesterol changes the metabolism of isoflavonoids and intestinal microorganisms in mice. Male mice were randomly divided into two groups, which were fed a cholesterol-daidzein (CDA) or daidzein (DA) diet (control diet) for 60d. Plasma equol and cecal equol concentrations were significantly higher in the DA group (control group) than in the CDA group. However, plasma cholesterol concentrations were significantly higher in the CDA group compared to the DA group. The composition of cecal microorganisms differed between the two dietary groups. The occupation ratios of Clostridium cluster XI, Clostridium subcluster XIVa, and Lactobacillales were significantly higher in the CDA group. The occupation ratio of Bifidobacterium was significantly lower in the CDA group. This study suggests that dietary cholesterol has the potential to affect the metabolism of equol from daidzein by altering the metabolic activity of the intestinal microorganisms and gut physiological function.

High Fiber Diet Supplemented with Rice Bran Hemicellulose May Reduce Daidzein Absorption in Mice

Much attention has focused on the health benefits of isoflavone. Investigating the absorption and metabolism of isoflavonoids is essential for understanding their biological activity. We explored the effect of a high fiber diet containing rice bran hemicellulose on the plasma and cecal isoflavonoids in mice. Mice were fed a 5% rice bran hemicellulose and 5% cellulose-0.1% daidzein diet (RBI diet) or a 5% cellulose-0.1% daidzein diet (CI diet) for 30 days. After the 30-day feeding period, the mice were sacrificed and blood and cecal contents were collected. The plasma isoflavonoids and plasma total cholesterol concentrations were measured. The plasma daidzein concentrations were significantly lower in the RBI group compared to the CI group. In contrast, there were no significant differences in the plasma equol concentrations or plasma total cholesterol concentrations between the RBI and CI groups. Binding affinity against isoflavonoids and/or the bulking effect in the gut might be related with the reduction in plasma daidzein concentration in the RBI group.

Plasma Isoflavones and Subsequent Risk of Prostate Cancer in a Nested Case-Control Study: The Japan Public Health Center

The incidence of prostate cancer is much lower in Japanese than Western populations. Given the preventive effects of isoflavones on carcinogenesis in the prostate in many nonhuman studies and the high consumption of isoflavones in Japanese, this low incidence may be partly due to the effects of soy. We conducted a nested case-control study within the Japan Public Health Center-based Prospective Study. A total of 14,203 men aged 40 to 69 years who had returned the baseline questionnaire and provided blood samples were observed from 1990 to 2005. During a mean of 12.8 years of follow-up, 201 newly diagnosed prostate cancers were identified. Two matched controls for each case were selected from the cohort. Conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% CIs for prostate cancer in relation to plasma levels of isoflavone. Plasma genistein level tended to be inversely associated with the risk of total prostate cancer. Although plasma daidzein showed no association, the highest tertile for plasma equol, a metabolite of daidzein, was significantly associated with a decreased risk of total prostate cancer (OR = 0.60; 95% CI, 0.36 to 0.99; P(trend) = .04). These inverse associations were strengthened after analysis was confined to localized cases, with ORs in the highest group of plasma genistein and equol compared with the lowest of 0.54 (95% CI, 0.29 to 1.01; P(trend) = .03) and 0.43 (95% CI, 0.22 to 0.82; P(trend) = .02), respectively. Plasma isoflavone levels were not statistically significantly associated with the risk of advanced prostate cancer. Isoflavones may prevent the development of prostate cancer.

Dose-response assessment of the anti-cancer efficacy of soy isoflavones in dimethylhydrazine-treated rats fed 6% fructooligosaccharide

We investigated the combinatorial effects of different doses of dietary soy isoflavones (SI) and fructooligosaccharide (FOS) in a rat model of colon cancer. We hypothesized that increased bioavailability of SI metabolites due to dietary FOS may increase production of bioactive equol and affect colon carcinogenesis in a dose-dependent manner. Sprague-Dawley male rats were injected with 12-dimethylhydrazine (DMH) and were provided experimental diets that contained 0, 10, 50, 150, or 500 mg SI per kg of diet and 6% FOS for 12 weeks. The number of aberrant crypt foci (ACF) and the expression of cyclooxygenase-2 (COX-2) in colonic tissues were significantly decreased in the 6% FOS-fed groups compared to the control group. Gut transit time and fecal pH were significantly lower, and fecal concentrations of bifidobacteria were increased with 6% FOS. However, dietary SI supplementation in combination with 6% dietary FOS did not affect ACF formation or COX-2 expression. Plasma equol concentrations were dose-dependently increased by supplementation of SI up to 500 mg/kg of diet. In conclusion, SI supplementation up to 500 mg/kg of diet appeared to have no additive beneficial effects in rats with chemically-induced colon cancer that were fed 6% FOS, although plasma equol was dose-dependently increased.

Improvement of Bone-Sparing Effect of Soy Isoflavones by Pre- and Probiotics in Postmenopausal women

Background Phytoestrogens consumption is targeted as a possible way to achieve hormonal permeation in postmenopausal women. However, their health effect could depend on their bioavailability. Objectives As phytoestrogens bioavailability could be improved by modulating intestinal microflora, the present study was undertaken to investigate whether isoflavones and pre-or probiotics may improve bone markers. Design An intervention trial (2 months) was carried out on 39 postmenopausal women receiving 100 mg of IF aglycon equivalents daily, incorporated in two jelly milk and two cereal bars. After the first month, the participants were randomised into three treatment groups: soy (control group), soy + fructooligosaccharides (prebiotics group) and soy + yoghurt cultures (probiotics group). Results Level of isoflavone intake was associated with a significant increase in plasma isoflavone levels from baseline to day 15 which was maintained until day 60. Probiotics consumption was associated with increased plasma equol levels at day 60. A 5% increase of bone alkaline phosphatase was elicited on day 30, compared to initial values. Pre- or probiotics did not modulate this parameter. Urinary deoxypyridinoline excretion was slightly increased at day 60. Prebiotics and probiotics consumption improved this parameter. The effect of prebiotics was exacerbated in early compared to late postmenopausal women. Conclusion Addition of prebiotics or probiotics to a diet providing isoflavones is able to improve parameters of bone turnover in early menopause.

Increased probiotic yogurt or resistant starch intake does not affect isoflavone bioavailability in subjects consuming a high soy diet

Objective Probiotics and prebiotics that affect gut microflora balance and its associated enzyme activity may contribute to interindividual variation in isoflavone absorption after soy intake, possibly enhancing isoflavone bioavailability. This study examined the effects of the consumption of bioactive yogurt (a probiotic) or resistant starch (a known prebiotic) in combination with high soy intake on soy isoflavone bioavailability. Methods Using a crossover design, chronic soy consumption was compared with soy plus probiotic yogurt or resistant starch in older male and postmenopausal females ( n = 31). Isoflavone bioavailability was assessed at the beginning and end of each 5-wk dietary period by sampling plasma and urine after a standardized soy meal. Results Chronic soy intake did not significantly affect plasma or urinary isoflavones after the soy meal and there were no significant effects of probiotic or resistant starch treatment. However, there were trends for increased circulating plasma daidzein and genistein after the probiotic treatment and for increased plasma daidzein and genistein 24 h after soy intake with resistant starch treatment. Neither treatment induced or increased equol production, although there was a trend for increased plasma equol in “equol-positive” subjects ( n = 12) after probiotic treatment. Conclusion The weak or absence of effects of probiotic yogurt or resistant starch supplement to a chronic soy diet suggests that gut microflora were not modified in a manner that significantly affected isoflavone bioavailability or metabolism.

Supplementation of difructose anhydride III enhanced elevation of plasma equol concentrations and lowered plasma total cholesterol in isoflavone-fed rats

Equol, a derivative of daidzein produced by enterobacteria, has greater activity as a phyto-oestrogen compared with daidzein. Difructose anhydride III (DFAIII) is a newly manufactured non-digestible disaccharide with unique fermentation properties. The present study evaluated the prebiotic effects of DFAIII on equol production and on plasma cholesterol concentrations related to the changes in equol production. We compared plasma equol concentrations at 10.00 and 18.00 hours and faecal isoflavone excretion in three groups of seven rats (male Wistar-ST strain, 6 weeks old) fed a basal diet or a DFAIII or fructooligosaccharide (15 g/kg diet) diet containing 1 g soya isoflavones/kg diet for 20 d. Equol concentrations in the DFAIII group were higher than in the control and fructooligosaccharides groups, especially in the later phase of the light period (18.00 hours) throughout the experiment. Daizein and genistein concentrations did not change between the diet groups. The faecal ratios of equol:daidzein were very high in all groups, but the ratios were higher in the DFAIII group than the control and fructooligosaccharide groups on day 3, and this tendency continued throughout the experiment. On day 20, the plasma total cholesterol concentration was lowest in the DFAIII group. Additionally, the cholesterol concentrations were inversely correlated to plasma equol concentration in all the rats. In conclusion, DFAIII efficiently enhanced plasma equol concentrations, which may be associated with an increase in equol production and a decrease in equol degradation by enterobacteria. Higher plasma equol concentrations may contribute to the hypocholesterolaemic effect of DFAIII feeding.

Soy Processing Affects Metabolism and Disposition of Dietary Isoflavones in Ovariectomized Balb/c Mice

Soy foods and nutritional supplements are widely consumed for potential health benefits. It was previously shown that isoflavone-supplemented diets, which contained equal genistein equivalents, differentially stimulated mammary tumor growth in athymic mice based on the degree of processing. This paper reports plasma pharmacokinetic analysis and metabolite identification using the parental mouse strain fed the same diets, which contained genistin, mixed isoflavones, Novasoy, soy molasses, or soy flour plus mixed isoflavones. Whereas the degree of soy processing did affect several parameters reflecting isoflavone bioavailability and gut microflora metabolism of daidzein to equol, stimulation of tumor growth correlated significantly with only the plasma concentration of aglycon genistein produced by the diets. This conclusion is consistent with the known estrogen agonist activity of genistein aglycon on mammary tumor growth. Conversely, plasma equol concentration was inversely correlated with the degree of soy processing. Although antagonism of genistein-stimulated tumor growth by equol could explain this result, the very low concentration of aglycon equol in plasma (12-fold lower relative to genistein) is inconsistent with any effect. These findings underscore the importance of food processing, which can remove non-nutritive components from soy, on the pharmacokinetics and pharmacodynamics of isoflavones. Such changes in diet composition affect circulating, and presumably target tissue, concentrations of genistein aglycon, which initiates estrogen receptor-mediated processes required for the stimulation of tumor growth in a mouse model for postmenopausal breast cancer.

Circulating levels of isoflavones and markers of 5α-reductase activity are higher in Japanese compared with New Zealand males: What is the role of circulating steroids in prostate disease?

Epidemiological evidence implicates dietary isoflavone intake as protective against prostate disease. A putative mechanism is attenuated circulating androgen levels in male populations consuming an isoflavone rich diet. We investigated this hypothesis by collecting plasma from 60 Japanese and 60 New Zealand males aged between 21 and 31 years each consuming their traditional diets. We measured plasma testosterone, dihydrotestosterone (DHT), androstenedione, dehydroepiandrosterone sulfate (DHEAS), the combined levels of androsterone sulfate and epiandrosterone sulfate (AoS/epiAoS), sex hormone-binding globulin, and cortisol and corticosteroid-binding globulin as well as the isoflavones genistein and equol. Plasma genistein and equol levels were several times higher in Japanese males as would be expected from an isoflavone rich diet. However, androstenedione, DHEAS, calculated free testosterone and paradoxically markers of 5α-reductase, DHT and AoS/epiAoS were all also significantly higher in Japanese rather than the New Zealand male counterparts. All other comparisons were not significant. Plasma DHT and DHEAS correlated positively with plasma equol and plasma AoS/epiAoS correlated positively with genistein levels. Taken together the results suggest that, rather than reduced levels of steroidogenesis, Japanese males may have increased 5α-reductase activity and possibly altered 17β OH steroid dehydrogenase activity. Significantly the positive association between isoflavones levels and 5α-steroids is counter-intuitive to isoflavone intake offering prostate protection, unless this is postulated to occur through other mechanisms.

Plasma and prostate phytoestrogen concentrations in prostate cancer patients after oral phytoestogen supplementation

Phytoestrogens have been suggested to reduce the risk of prostate cancer (CaP), but no data exists on how oral phytoestrogen supplementation influences phytoestrogen concentrations in prostate tissue. Forty men with CaP, assigned for radical prostatectomy, received 240 mg of clover phytoestrogens or placebo daily for a 2-week period before their operation in a prospective and randomized study. Phytoestrogens were measured in plasma and prostate tissue by time-resolved fluoroimmunoassay (TR-FIA). All patients had low baseline phytoestrogen concentrations and only 35% had a detectable plasma concentration of equol. Oral supplementation with phytoestrogens induced a statistically significant (P<0.001) 23- and 7-fold increase in prostate tissue concentrations of the phytoestrogens genistein and daidzein, respectively. Supplemented patients demonstrated prostate tissue genistein and daidzein concentrations that were over twofold higher than their plasma. Interestingly, even though the placebo group did not receive phytoestrogen challenge, they also demonstrated twofold prostate tissue genistein and daidzein concentrations compared to their plasma values, suggesting that the prostate can concentrate available phytoestrogens. In addition, after the supplementation, 90% of the supplemented patients had a detectable plasma equol concentration. We conclude that prostate tissue can concentrate genistein and daidzein. Significant elevation of intraprostatic genistein and daidzein concentrations can be achieved with a short-term dietary phytoestrogen supplementation.

The Effect of Soy Consumption on the Urinary 2:16-Hydroxyestrone Ratio in Postmenopausal Women Depends on Equol Production Status but Is Not Influenced by Probiotic Consumption

Some epidemiologic studies reported an association between a low ratio of urinary 2-hydroxyestrogens (2-hydroxyestradiol + 2-hydroxyestrone) to 16alpha-hydroxyestrone (2:16OHE(1)) 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 (10(9) colony-forming units Lactobacillus acidophilus DDS(R)+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 2:16OHE(1) ratio than controls (P = 0.10). In the group as a whole, soy consumption tended to increase urinary 2-hydroxyestrogens (P = 0.07) and 16alpha-hydroxyestrone (P = 0.11) but had no effect on the urinary 2:16OHE(1) 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 2:16OHE(1) 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 2:16OHE(1) ratios in women with breast cancer and suggest that soy consumption increases this ratio only in women who are equol producers.