Enterolignan Production in a Flaxseed Intervention Study in Postmenopausal US Women of African Ancestry and European Ancestry.

Lignans are phytochemicals studied extensively as dietary factors in chronic disease etiology. Our goal was to examine associations between the gut microbiota and lignan metabolism and whether these associations differ by ethnicity. We conducted a flaxseed (FS) dietary intervention in 252 healthy, postmenopausal women of African ancestry (AA) and European ancestry (EA). Participants consumed ~10 g/d ground flaxseed for 6 weeks and provided overnight urine collections and fecal samples before and after intervention. The gut microbiota was characterized using 16S rRNA gene sequencing and differences in microbial community composition compared by ethnicity and intervention status. We observed a significant difference in the composition of the microbiota measured as beta diversity (p < 0.05) between AA and EA at baseline that was attenuated with FS consumption. Genera that were significantly associated with ENL production (e.g., Klebsiella, Lactobacillus, Slackia, Senegalimassilia) were unique to each group. Bacteria (e.g., Fusobacteria, Pyramidobacter and Odoribacter) previously associated with colorectal cancer and cardiovascular disease, both diet-related chronic diseases, were unique to either AA or EA and were significantly reduced in the FS intervention. This study suggests that ethnic variation in ENL metabolism may be linked to gut microbiota composition, and its impact on disease risk deserves future investigation.

Genetic Variation in Steroid and Xenobiotic Metabolizing Pathways and Enterolactone Excretion Before and After Flaxseed Intervention in African American and European American Women.

BACKGROUND: Metabolism and excretion of the phytoestrogen enterolactone (ENL), which has been associated with breast cancer risk, may be affected by variation in steroid hormone and xenobiotic-metabolizing genes. METHODS: We conducted a randomized, crossover flaxseed intervention study in 252 healthy, postmenopausal women [137 European ancestry (EA) and 115 African ancestry (AA)] from western New York. Participants were randomly assigned to maintain usual diet or consume 10 g/day ground flaxseed for 6 weeks. After a 2-month washout period, participants crossed over to the other diet condition for an additional 6 weeks. Urinary ENL excretion was measured by gas chromatography-mass spectrometry and 70 polymorphisms in 29 genes related to steroid hormone and xenobiotic metabolism were genotyped. Mixed additive genetic models were constructed to examine association of genetic variation with urinary ENL excretion at baseline and after the flaxseed intervention. RESULTS: SNPs in several genes were nominally (P < 0.05) associated with ENL excretion at baseline and/or after intervention: ESR1, CYP1B1, COMT, CYP3A5, ARPC1A, BCL2L11, SHBG, SLCO1B1, and ZKSCAN5. A greater number of SNPs were associated among AA women than among EA women, and no SNPs were associated in both races. No SNP-ENL associations were statistically significant after correction for multiple comparisons. CONCLUSIONS: Variation in several genes related to steroid hormone metabolism was associated with lignan excretion at baseline and/or after flaxseed intervention among postmenopausal women. IMPACT: These findings may contribute to our understanding of the differences observed in urinary ENL excretion among AA and EA women and thus hormone-related breast cancer risk.

Plasma metabolite abundances are associated with urinary enterolactone excretion in healthy participants on controlled diets.

Enterolignans, products of gut bacterial metabolism of plant lignans, have been associated with reduced risk of chronic diseases, but their association with other plasma metabolites is unknown. We examined plasma metabolite profiles according to urinary enterolignan excretion in a cross-sectional analysis using data from a randomized crossover, controlled feeding study. Eighty healthy adult males and females completed two 28-day feeding periods differing by glycemic load, refined carbohydrate, and fiber content. Lignan intake was calculated from food records using a polyphenol database. Targeted metabolomics was performed by LC-MS on plasma from fasting blood samples collected at the end of each feeding period. Enterolactone (ENL) and enterodiol, were measured in 24 h urine samples collected on the penultimate day of each study period using GC-MS. Linear mixed models were used to test the association between enterolignan excretion and metabolite abundances. Pathway analyses were conducted using the Global Test. Benjamini-Hochberg false discovery rate (FDR) was used to control for multiple testing. Of the metabolites assayed, 121 were detected in all samples. ENL excretion was associated positively with plasma hippuric acid and melatonin, and inversely with epinephrine, creatine, glycochenodeoxycholate, and glyceraldehyde (P < 0.05). Hippuric acid only satisfied the FDR of q < 0.1. END excretion was associated with myristic acid and glycine (q < 0.5). Two of 57 pathways tested were associated significantly with ENL, ubiquinone and terpenoid-quinone biosynthesis, and inositol phosphate metabolism. These results suggest a potential role for ENL or ENL-metabolizing gut bacteria in regulating plasma metabolites.

Targeted Metabolomics Analysis Identifies Intestinal Microbiota-Derived Urinary Biomarkers of Colonization Resistance in Antibiotic-Treated Mice.

Antibiotics excreted into the intestinal tract may disrupt the microbiota that provide colonization resistance against enteric pathogens and alter normal metabolic functions of the microbiota. Many of the bacterial metabolites produced in the intestinal tract are absorbed systemically and excreted in urine. Here, we used a mouse model to test the hypothesis that alterations in levels of targeted bacterial metabolites in urine specimens could provide useful biomarkers indicating disrupted or intact colonization resistance. To assess in vivo colonization resistance, mice were challenged with Clostridium difficile spores orally 3, 6, and 11 days after the completion of 2 days of treatment with piperacillin-tazobactam, aztreonam, or saline. For concurrent groups of antibiotic-treated mice, urine samples were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify the concentrations of 11 compounds targeted as potential biomarkers of colonization resistance. Aztreonam did not affect colonization resistance, whereas piperacillin-tazobactam disrupted colonization resistance 3 days after piperacillin-tazobactam treatment, with complete recovery by 11 days after treatment. Three of the 11 compounds exhibited a statistically significant and >10-fold increase (the tryptophan metabolite N-acetyltryptophan) or decrease (the plant polyphenyl derivatives cinnamoylglycine and enterodiol) in concentrations in urine 3 days after piperacillin-tazobactam treatment, followed by recovery to baseline that coincided with the restoration of in vivo colonization resistance. These urinary metabolites could provide useful and easily accessible biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment.

The relationship between phytoestrogens and speed of processing.

OBJECTIVE: This study examined the cross-sectional association between phytoestrogens and speed of processing. We hypothesized that higher levels of phytoestrogens would be related to better cognitive performance among older women. METHODS: Participants were from the National Health and Nutrition Examination Survey and consisted of 200 older women (M = 74.4 y). Stepwise regressions examined indicators of speed of processing, measured by the Digit Symbol Substitution Test. Isoflavones, lignans, and individual phytoestrogens were added to the regression after including covariates of age, education, race, smoking, and creatinine. Isoflavones were further broken into quartiles among the sample to further evaluate the nature of the curvilinear association. RESULTS: Results showed a relationship between cognition and lignans, explaining 3.8% of the variance after including the covariates, indicating fewer lignans were associated with better speed of processing (P < 0.001). A significant curvilinear relationship with isoflavones explained 1.3% additional variance (P < 0.001). The moderate-high, low-moderate, and the lowest quartile of isoflavones were associated with better cognition, whereas the highest amount was associated with worse speed of processing. Among the individual phytoestrogens, only enterodiol accounted for 4.4% additional variance after taking into account covariates and indicated a negative association with cognition (P = 0.03). CONCLUSIONS: Results suggest that moderate levels of isoflavones, but not lignans, may be associated with better speed of processing. Caution must remain for high isoflavone amounts due to the negative association with cognition. Given the results, phytoestrogens have the potential to be an intervention target for older females' cognition. To become a viable intervention, further research is needed.

Urine phyto-oestrogen metabolites are not significantly associated with risk of type 2 diabetes: the Singapore Chinese health study.

We evaluated the relationship between urine concentrations of phyto-oestrogens (isoflavones and lignans) and risk of incident type 2 diabetes in middle-aged and elderly Chinese residing in Singapore. Urine metabolites of isoflavones and lignans were assayed by HPLC among 564 diabetes cases and 564 matched controls in a case-control study nested within the Singapore Chinese Health Study cohort. Participants were free of diagnosed diabetes, CVD and cancer at morning urine collections during 1999-2004. Cases were participants who reported to have physician-diagnosed diabetes at follow-up visits during 2006-2010, whereas controls were randomly selected among those who remained free of diabetes and were matched to the index cases by age, sex, dialect group and date of urine collection. Conditional logistic regression models were used to calculate OR and 95 % CI with adjustment for potential confounders. The mean age of the participants at the time of urine collection was 59·8 years, and the average interval between urine collection and diabetes diagnosis was 4·0 years. The multivariate-adjusted OR for diabetes were 1·00 (reference), 0·76 (95 % CI 0·52, 1·11), 0·78 (95 % CI 0·53, 1·14) and 0·79 (95 % CI 0·54, 1·15) across quartiles of urine isoflavones (P for trend=0·54), and were 1·00 (reference), 0·87 (95 % CI 0·60, 1·27), 1·10 (95 % CI 0·77, 1·56) and 0·93 (95 % CI 0·63, 1·37) for lignans (P for trend=0·93). The results were similar in men and women, as well as for individual metabolites of isoflavones (genistein, daidzein, glycitin and equol) or lignans (enterodiol and enterolactone). The present study did not find a significant association between urine phyto-oestrogen metabolites and risk of type 2 diabetes in Chinese adults.

Urinary phytoestrogens and cancer, cardiovascular, and all-cause mortality in the continuous National Health and Nutrition Examination Survey.

PURPOSE: Experimental studies suggest that phytoestrogen intake alters cancer and cardiovascular risk. This study investigated the associations of urinary phytoestrogens with total cancer (n = 79), cardiovascular (n = 108), and all-cause (n = 290) mortality among 5179 participants in the continuous National Health and Nutrition Examination Survey (1999-2004). METHODS: Urinary phytoestrogens were measured using high-performance liquid chromatography with tandem mass spectrometric detection. Survival analysis was performed to evaluate hazard ratios (HRs) and 95 % confidence intervals (CIs) for each of the three outcomes in relation to urinary phytoestrogens. RESULTS: After adjustment for confounders, higher urinary concentrations of total enterolignans were associated with a reduced risk of death from cardiovascular disease (HR for tertile 3 vs. tertile 1 0.48; 95 % CI 0.24, 0.97), whereas higher urinary concentrations of total isoflavones (HR for tertile 3 vs. tertile 1 2.14; 95 % CI 1.03, 4.47) and daidzein (HR for tertile 3 vs. tertile 1 2.05; 95 % CI 1.02, 4.11) were associated with an increased risk. A reduction in all-cause mortality was observed for elevated urinary concentrations of total enterolignans (HR for tertile 3 vs. tertile 1 0.65; 95 % CI 0.43, 0.96) and enterolactone (HR for tertile 3 vs. tertile 1 0.65; 95 % CI 0.44, 0.97). CONCLUSIONS: Some urinary phytoestrogens were associated with cardiovascular and all-cause mortality in a representative sample of the US population. This is one of the first studies that used urinary phytoestrogens as biomarkers of their dietary intake to evaluate the effect of these bioactive compounds on the risk of death from cancer and cardiovascular disease.

Urinary Lignans Are Associated With Decreased Incontinence in Postmenopausal Women.

OBJECTIVE: To examine the association between urinary phytoestrogens and self-reported urinary incontinence in postmenopausal women in the United States using a large, cross-sectional, population-based cohort survey. METHODS: Data were analyzed for 1789 postmenopausal women aged 50 years or older who participated in one of the 2001-2010 cycles of National Health and Nutrition Examination Survey and underwent measurement of 4 isoflavone (soy derived) and 2 lignan (flax derived) phytoestrogens in their urine. Incontinence was defined as self-reported stress, urge, other, or mixed incontinence. Urine phytoestrogen concentrations were examined in weighted, multivariate logistic regression models for association with each of the lower urinary tract symptoms. All models were adjusted for age, body mass index, diabetes, race, smoking, and parity. RESULTS: Increasing urine concentrations of the lignan phytoestrogen enterodiol was associated with decreased likelihood of urge (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.85-0.99), mixed (OR, 0.90; 95% CI, 0.82-0.98), and other (OR, 0.90; 95% CI, 0.81-0.99) incontinence, whereas increasing urine concentrations of the lignan phytoestrogen enterolactone was associated with decreased likelihood of urge (OR, 0.92; 95% CI, 0.86-0.99) and mixed (OR, 0.91; 95% CI, 0.84-0.99) incontinence. No association was observed between any isoflavone phytoestrogens and types of incontinence. CONCLUSION: This study demonstrates that lignan phytoestrogens may have a protective effect against incontinence in postmenopausal women. Prospective clinical and laboratory studies are warranted to investigate the mechanism of this relationship.

Urinary enterolactone is associated with obesity and metabolic alteration in men in the US National Health and Nutrition Examination Survey 2001-10.

Phyto-oestrogens are a family of plant-derived xeno-oestrogens that have been shown to prevent cancer in some studies. Whether phyto-oestrogen intake affects obesity status in a population is still unclear. In the present cross-sectional study, we examined the association of urinary phyto-oestrogen metabolites with obesity and metabolic parameters in children and adults. Data from 1294 children (age 6-19 years) and from 3661 adults (age ≥ 20 years) who participated in the US National Health and Nutrition Examination Survey 2001-10 were analysed. Multivariate logistic regression was applied to investigate the associations of BMI, waist circumference, serum metabolites (total cholesterol, HDL-cholesterol, LDL-cholesterol, TAG, fasting glucose and fasting insulin) and the metabolic syndrome with urinary phyto-oestrogen levels. When stratified by age and sex, we found a stronger association (OR 0·30, 95 % CI 0·17, 0·54; P< 0·001) between urinary enterolactone levels and obesity in adult males (age 20-60 years) than in children (age 12-19 years) or the elderly (age >60 years) in the same survey. However, no associations with urinary daidzein, O-desmethylangolensin, equol, enterodiol or genistein were found in the overall population. We also found that the elevation of enterolactone levels was inversely associated with TAG levels, fasting glucose levels, fasting insulin levels and the metabolic syndrome in males aged 20-60 years, but positively associated with HDL-cholesterol levels. The present results provide epidemiological evidence that urinary enterolactone is inversely associated with obesity in adult males.

Cardiometabolic risk factors are associated with high urinary enterolactone concentration, independent of urinary enterodiol concentration and dietary fiber intake in adults.

The study objective was to evaluate independent and interactive associations of dietary fiber intake and high urinary enterolignans with cardiometabolic risk factors. The analysis included 2260 adults (≥20 y of age) from the 2003-2010 NHANES. Logistic regression models were used to evaluate obesity and clinically defined cardiometabolic risk factors in relation to dietary fiber intake and urinary enterolignan concentrations. Three sets of models were created: 1) independent associations, 2) mutually adjusted associations, and 3) interactions. Models were adjusted for age, gender, race/ethnicity, education, smoking status, and energy intake. High concentrations were considered to be above the 90th percentile of urinary enterolignan concentrations. Increasing dietary fiber intake was associated with high blood pressure (P = 0.02) and low serum HDL cholesterol (P-trend = 0.03). High urinary enterodiol concentration was not associated with obesity or cardiometabolic risk factors. High urinary enterolactone concentration was inversely associated with obesity (OR: 0.44; 95% CI: 0.29, 0.66), abdominal obesity (OR: 0.58; 95% CI: 0.39, 0.87), high serum C-reactive protein (CRP; OR: 0.52; 95% CI: 0.37, 0.74), high serum triglycerides (OR: 0.39; 95% CI: 0.23, 0.61), low serum HDL cholesterol (OR: 0.37; 95% CI: 0.23, 0.61), and metabolic syndrome (OR: 0.47; 95% CI: 0.30, 0.74). In mutually adjusted models, enterolactone associations observed in independent models remained similar, but associations for dietary fiber intake were attenuated, with the exception of blood pressure. In interaction models, there were 2 significant interactions: between high urinary enterodiol concentration and dietary fiber intake for high serum CRP (P = 0.04) and high plasma glucose (P = 0.04). Overall, being in the highest 10% of urinary enterolactone concentration was associated with cardiometabolic risk factors, independent of dietary fiber intake and enterodiol concentration. Future studies are warranted to evaluate physiologic actions of enterolactone or aspects of the gut microbial profile responsible for lignan metabolism to enterolactone.

Effects of consumption of whole grain foods rich in lignans in healthy postmenopausal women with moderate serum cholesterol: a pilot study.

This study aims at investigating the effect of an experimental period of intake of whole grain foods rich in lignans as part of an habitual diet on the plasma and urinary excretion of enterolignans, the biomarkers of lipid metabolism and the immunological and antioxidant status in a group of postmenopausal women with moderate serum cholesterol. A randomized double-blind crossover study was completed on 13 subjects in 12-weeks after protocol approval of an ethical committee. The subjects consumed whole grain foods high in lignans (30 g/d of breakfast cereals or biscuits, etc., 80 g/d of whole grain pasta) or refined grain foods for 4 weeks, separated by a 2-weeks wash-out period. A modest hypocholesterolemic effect (p < 0.05) of the whole grain diet was observed and the intake of whole grain products rich in lignans was also associated with an increase in urinary enterodiol excretion (p < 0.05).

A pilot study comparing the effect of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers.

Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS), are not often described. We conducted a pilot 2 × 2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of FS and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007-2010). The effect of each treatment vs. placebo on outcomes was determined by linear regression adjusting for pretreatment measure, stage, and grade. Although not statistically significant, mean ERß expression was approximately 40% lower from pre- to postintervention in the FS + AI group only. We observed a statistically significant negative association (ß ± SE -0.3 ± 0.1; P = 0.03) for androstenedione in the FS + AI group vs. placebo and for DHEA with AI treatment (ß ± SE -1.6 ± 0.6; P = 0.009). Enterolactone excretion was much lower in the FS + AI group compared to the FS group. Our results do not support strong effects of FS on AI activity for selected breast tumor characteristics or serum steroid hormone levels but suggest AI therapy might reduce the production of circulating mammalian lignans from FS.

Identification of metabolites of deoxyschizandrin in rats by UPLC-Q-TOF-MS/MS based on multiple mass defect filter data acquisition and multiple data processing techniques.

Deoxyschizandrin is an active lignin ingredient originating from Schisandra chinensis (Turcz.) Baill or Schisandrae Sphenantherae Fructus. In the present study, a novel and efficient strategy was developed for the in vivo screening and identification of deoxyschizandrin metabolites using ultra high performance liquid chromatography combined with triple TOF mass spectrometry (UPLC-TOF/MS/MS). This strategy was characterized by the following: a novel and unique multiple mass defect filter (MMDF) combined with an on-line data acquisition method that is dependent on dynamic background subtraction (DBS) was developed to trace all of the probable metabolites of deoxyschizandrin. The MMDF and DBS methods could trigger an IDA scan for the low-level metabolites that are masked by background noise and endogenous components. A combination of data processing methods including extracted ion chromatography (XIC), mass defect filtering (MDF), product ion filtering (PIF) and neutral loss filtering (NLF) were employed to identify the metabolites of deoxyschizandrin. Next, the structures of the metabolites were elucidated based on an accurate mass measurement, the fragmentation patterns of the parent drug and relevant drug bio-transformation knowledge. Finally, an important parameter ClogP was used to estimate the retention time of isomers. Based on the proposed strategy, 51 metabolites (including 49 phase I and 2 phase II metabolites) were identified in rats after the oral administration of deoxyschizandrin. Among these metabolites, 41 metabolites were characterized in the rat urine, and 28 metabolites were identified in the rat bile. The results indicated that oxidization was the main metabolic pathway and that the methoxy group and the biphenyl cyclooctene were the metabolic sites. Conjugation with sulfate and cysteine groups produced two phase-II metabolites. This study firstly reported the description of deoxyschizandrin metabolism in vivo. This study provided a practical strategy for rapidly screening and identifying metabolites, and this methodology can be widely applied for the structural characterization of the metabolites of other compounds.

Combined effects of urinary phytoestrogens metabolites and polymorphisms in metabolic enzyme gene on idiopathic male infertility.

Phytoestrogens are plant-derived compounds that may interact with estrogen receptors and mimic estrogenic effects. It remains unclear whether the individual variability in metabolizing phytoestrogens contributes to phytoestrogens-induced beneficial or detrimental effects. Our aim was to determine whether there is any interaction between metabolic rates (MR) of phytoestrogens and genetic polymorphisms in related xenobiotic metabolizing enzyme genes. MR was used to assess phytoestrogen exposure and individual metabolic ability. The amount of phytoestrogens in urine was measured by ultra-high performance liquid chromatography-tandem mass spectrometry in 600 idiopathic infertile male patients and 401 controls. Polymorphisms were genotyped using the SNPstream platform combined with the Taqman method. Prototypes and metabolites of secoisolariciresinol (SEC) have inverse effects on male reproduction. It was found that low MR of SEC increased the risk of male infertility (OR 2.49, 95 % CI 1.78, 3.48, P trend = 8.00 × 10(-8)). Novel interactions were also observed between the MR of SEC and rs1042389 in CYP2B6, rs1048943 in CYP1A1, and rs1799931 in NAT2 on male infertility (P inter = 1.06 × 10(-4), 1.14 × 10(-3), 3.55 × 10(-3), respectively). By analyzing the relationships between urinary phytoestrogen concentrations, their metabolites and male infertility, we found that individual variability in metabolizing SEC contributed to the interpersonal differences in SEC's effects on male reproduction.

Urinary phytoestrogens and depression in perimenopausal US women: NHANES 2005-2008.

BACKGROUND: Fluctuating hormonal levels observed during the menopausal transition may increase vulnerability to depression in susceptible women. Thus, it is of interest to examine the effect of natural estrogens such as phytoestrogens on the risk of depression in perimenopausal women. METHODS: Our analysis included 193 perimenopausal women of the National Health and Nutrition Survey (NHANES) 2005-2008 aged 45-55 years. Urinary concentrations of phytoestrogens (isoflavones and lignans) were measured by HPLC-APPI-MS/MS. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Logistic regression models examined the association of phytoestrogens concentrations (creatinine-standardized and log-transformed) with depression (yes/no). RESULTS: Unadjusted odds ratios (OR) of the associations between urinary phytoestrogen concentrations and perimenopausal depression were below 1; however, only lignans were significantly inversely associated with depression. The latter findings were not attenuated in multivariate analysis including age, race, body mass index, poverty income ratio, smoking, alcohol consumption, cancer, diabetes, and cardiovascular disease (lignans: OR=0.66; 95% confidence intervals (CI) 0.50-0.87, enterodiol: OR=0.63; 95% CI 0.51-0.78, enterolactone: OR=0.75; 95% CI 0.60-0.93). LIMITATIONS: Our cross-sectional study design does not allow for causal inferences. Because information to precisely assess perimenopausal symptoms was missing, we defined perimenopause based on women's age. CONCLUSIONS: Lower lignans but not isoflavones concentrations were statistically significantly associated with an increased risk of depression in perimenopausal women. Because of medical risks associated with the use of hormone therapy, further investigation on the effect of lignans on the risk of depression in perimenopausal women is warranted.

Urinary lignans and inflammatory markers in the US National Health and Nutrition Examination Survey (NHANES) 1999-2004 and 2005-2008.

PURPOSE: Chronic inflammation has been implicated in the etiology of various chronic diseases. We previously found that certain urinary isoflavones are associated with markers of inflammation. In the present study, we examined the associations of serum C-reactive protein (CRP) and white blood cell (WBC) count with lignans, which are more frequent in the Western diet than isoflavones. METHODS: Our analysis included 2,028 participants of NHANES 2005-2008 and 2,628 participants of NHANES 1999-2004 aged 18 years and older. The exposures of interest were urinary mammalian lignans (enterodiol and enterolactone). Outcome variables were two inflammatory markers (CRP [≤10 mg/L] and WBC [≥3.0 and ≤11.7 (1,000 cells/µL)]). Log-transformed CRP concentration and WBC count by log-transformed creatinine-standardized concentrations of mammalian lignans were used for linear regression. RESULTS: Statistically significant inverse associations of urinary lignan, enterodiol, and enterolactone concentrations with circulating CRP and WBC counts were observed in the multivariate-adjusted models: In NHANES 2005-2008, per one-percent increase in lignan concentrations in the urine, CRP concentrations and WBC counts decreased by 8.1 % (95 % CI -11.5, -4.5) and 1.9 % (95 % CI -2.7; -1.2), respectively. Per one-percent increase in enterodiol and enterolactone, WBC counts decreased by 2.1 % (95 % CI -2.8, -1.3) and 1.3 % (95 % CI -1.9, -0.6), respectively. In NHANES 1999-2004, analogous results were 3.0 % (95 % CI -5.6, -0.3), 1.2 % (95 % CI -2.0; -0.4), 1.0 % (95 % CI -1.8, -0.2), and 0.8 % (95 % CI -1.4, 0.2). CONCLUSIONS: Mammalian lignans were inversely associated with markers of chronic inflammation. Due to the cross-sectional design, our findings require confirmation in prospective studies.

Metabolic parameters of postmenopausal women after quinoa or corn flakes intake--a prospective and double-blind study.

A prospective and double-blind study was conducted on 35 women with weight excess who consumed 25 grams of quinoa flakes (QF) or corn flakes (CF) daily during a period of four consecutive weeks. At the beginning (T1) and at the end (T2) of the intervention, total calorie intake was evaluated, anthropometric assessment was performed, blood was collected for the determination of glucose, total cholesterol and fractions, oxidative stress markers, vitamin E and enterolignans. Significant reductions were detected in serum triglyceride (CF group = 133.9 ± 89.4 to 113.7 ± 57 mg/dl and QF group = 112.3 ± 35 to 107.9 ± 33.1 mg/dl), TBARS (CF group = 3.2 ± 0.8 to 2.9 ± 0.5 µmol/l and QF group = 3.06 ± 0.6 to 2.89 ± 0.5 µmol/l) and vitamin E concentrations (CF group = 19.5 ± 5 to 17.9 ± 4 µM and QF group = 17.9 ± 4 to 16.9 ± 3 µM) and an increase in urinary excretion of enterolignans (CF group = 2.05 ± 1.3 to 2.24 ± 1.4 nm/ml and QF group = 2.9 ± 1.6 to 3.2 ± 2.7 nm/l), in both study groups. The reduction of total cholesterol (191 ± 35 to 181 ± 28 mg/dl) and LDL-cholesterol (LDL-c) (129 ± 35 to 121 ± 26 mg/dl), and the increase in GSH (1.78 ± 0.4 to 1.91 ± 0.4 µmol/l) occurred only in the QF group, showing a possible beneficial effect of QF intake.

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.

Dietary flavonol intake is associated with age of puberty in a longitudinal cohort of girls.

Lignans and flavonols are dietary phytoestrogens found at high concentrations in the Western Diet. They have potential to influence the timing of puberty. We hypothesized that greater consumption of these 2 phytoestrogens would be related to later age at pubertal onset among girls. Pubertal assessment and 24-hour diet recall data were available for 1178 girls, ages 6 to 8 years (mean 7.3 years) in the Breast Cancer and Environment Research Project Puberty Study. Lignan and flavonol intakes were mainly derived from fruit and vegetable consumption. Average consumption was 6.5 mg/d for flavonols and 0.6 mg/d for lignans. Highest flavonol consumption (>5 mg/d) was associated with later breast development (adjusted hazards ratio [HR]: 0.74, 95% CI: [0.61-0.91]) compared to 2 to 5 mg/d (adjusted HR: 0.84, 95% CI: [0.70-1.0]) and <2 mg/d (referent group; P-trend = .006). Flavonol intake was not associated with pubic hair development. Lignan intake was not associated with either breast or pubic hair development. Dietary intake was only weakly correlated with urinary enterolactone, a biomarker for lignans (RS = 0.13). Consistent with biologic properties of phytoestrogens that indicate hormonal activity, their consumption may be associated with reproductive end points, even in childhood.

Levels of urinary isoflavones and lignan polyphenols in Japanese women.

OBJECTIVES: High consumption of soybean products has been associated with a reduced risk of hormone-sensitive tumors. Soybean products contain phytoestrogens, such as daidzein, and sesame seeds contain secoisolariciresinol. These compounds are further metabolized to equol, enterodiol, and enterolactone by intestinal bacteria. However, individual differences in the metabolizing potential remain unclear. The aim of this study was to evaluate the urinary daidzein, equol, enterodiol, and enterolactone concentrations in women from several different regions of Japan according to age group. METHODS: Five hundred urine samples collected from Japanese women living in Sapporo, Sendai, Kyoto, Kochi, and Naha were analyzed for daidzein, equol, enterodiol, and enterolactone concentration by gas chromatography-mass spectrometry. RESULTS: The urinary isoflavone and lignan polyphenol levels did not differ significantly among the sampling sites, except for daidzein, which was highest in urine collected at Naha. The prevalence of equol producers was 39 % in the total study cohort. In equol producers, a positive correlation was observed between the urinary daidzein and equol levels (r = 0.399, p < 0.001). However, there was no significant difference between daidzein concentrations in equol producers and non-producers. Moreover, the levels of enterodiol and enterolactone were higher in equol producers than in equol non-producers. In the multivariate logistic analyses, two factors, Sendai dwelling and current smoking, were found to be significant [equol producers to non-producers: odds ratio 2.15 (95 % confidence interval: 1.17-4.02) and odds ratio 0.32 (0.15-0.63), respectively]. CONCLUSIONS: Our data suggest that geographic factors and smoking status should be considered during the evaluation of equol in urine samples and that the same pathway may be responsible for the metabolism of both isoflavones and lignan polyphenols.