Serum Isoflavone Levels Research Articles

Serum Isoflavone Concentrations and Equol-Producing Intestinal Flora in Prostate Cancer in Japanese-American in Hawaii

Studies have reported that soy isoflavones and the ability to produce equol may play a role in the prevention of prostate cancer (PCa). To further investigate this relationship, we evaluated Japanese-Americans (JA) and Caucasians (CA) in Hawaii with and without PCa, with regards to dietary soy intake, serum isoflavone levels, and the presence of equol-producing Slackia sp. in the intestine. The serum levels of isoflavone were determined in 65 JA (34 PCa, 31 controls) and 68 CA (34 PCa, 34 controls). All completed a lifetime dietary soy consumption survey. The serum levels of genistein and o-DMA were significantly higher in JA (p = 0.04). Daidzein and isoflavone levels trended higher in JA, but no differences were noted in dihydrodaidzein (DHD) and equol levels. There were no differences in serum isoflavone levels between PCa patients and controls for both JA and CA. Only 8.6% stool samples were positive for equol-producing Slackia sp., a rate much lower than seen in Japan. JA reported a higher intake of soy than CA. The high soy consumption and isoflavone levels in JA may be related to the lower incidence of PCa relative to CA in Hawaii. The near absence of equol producers in Hawaii JA may contribute to their higher incidence of PCa compared to Japan Japanese. These results suggest that both soy isoflavone levels and equol production may be inversely associated with PCa risk.

Isoflavones in Japanese and Caucasian men with prostate cancer in Hawaii.

241 Background: Recently, several studies have reported that soy isoflavones and the ability to produce Equol, an active derivative of soy isoflavone, may play a role in the suppression of prostate cancer. An Equol-producing bacterium, Slackia sp. strain NATTS has been identified in stool cultures. To further investigate this relationship, we evaluated Japanese-Americans (JA) and whites (W) in Hawaii, with and without prostate cancer, with regards to dietary soy intake, serum isoflavone levels, and the presence of stool NATTS. Methods: The serum levels of Daidzein, Genistein, Glysitein, Dihydrodaidzein (DHD), Equol, o-desmethylangolensin (o-DMA) and total isoflavone was determined in 65 JA (34 patients with prostate cancer , 31 controls) and 68 W (34 patients with prostate cancer , 34 controls) subjects. The control group consisted of age matched cancer-free male subjects. To evaluate Equol producing ability, we assessed the presence of NATTS in stool samples. All subjects completed a lifetime dietary soy consumption survey. Results: The serum level of Genistein and o-DMA were significantly higher in JA (Genistein: W 21.5±54.0, JA 61.8±150.9, p=0.04; o-DMA: W 0, JA 2.0±7.9, p=0.04). Daizein level trended higher in JA (W 13.9±34.7, JA 33.3±84.0, p=0.09). Glysitein level was significantly higher in W (W 35.7±10.4, JA 30.7±15.5, p=0.03). No differences were noted in DHD and Equol levels between W and JA. Total isoflavone level trended higher in JA (W 76.3±104.9, JA 135.1±245.6, p=0.07). There were no differences in serum isoflavone level between prostate cancer patients and controls for both JA and W. Only 10 of 120 stool samples were positive for NATTS (8.6%), a rate much lower than seen in Japan. JA showed higher intake of soy than W. Conclusions: The high soy consumption and isoflavone levels in JA may be related to the observed lower incidence of prostate cancer relative to W in Hawaii. The near absence of equal producers in Hawaii JA may contribute to their higher incidence of prostate cancer compared to Japan based Japanese. These results suggest that both soy isoflavone levels and Equol production may be inversely associated with prostate cancer incidence.

Noble Rats Display Decreased Weight Gain and Visceral Adiposity via Lifelong Exposure to an Isoflavone-Rich Diet

Obesity and cancer represent two of the greatest public health concerns. The relationship between obesity and cancer suggests an important role for visceral adipose tissue (VAT) versus generalized body fat. Male and female Noble rats develop a relatively high incidence of spontaneous and hormone-induced carcinomas. The main purpose of this study was to make an initial assessment of whether a high soy-isoflavonoid diet could decrease VAT and reduce overall body weight gain in Noble rats. The male and female rats were exposed solely to either a high soy-isoflavonoid diet (High-Iso) or a low-isoflavonoid diet (Low-Iso) from conception to adulthood. At the end of the experiment, at 145 days of age, overall weight gain and visceral fat deposition were recorded along with quantification of serum isoflavone levels (genistein, daidzein and equol). Serum isoflavone levels in the High-Iso treatment groups were significantly higher (by approximately 15-fold) compared to animals in the LowIso diet groups. Male and female Nobel rats fed the High-Iso diet displayed significantly lower body weight gain (by approximately 10%) compared to animals fed the Low-Iso diet. Notably, VAT deposition was reduced by 61% in females but 21% in males fed the High-Iso diet versus the Low-Iso diet. In summary, consumption of a diet high in isoflavones significantly lowered body weight and VAT deposition and a hypothesis may be proposed as to how soy-derived isoflavones may decrease VAT storage areas to potentially improve obesity and cancer outcomes.

Relationship Between Serum Isoflavone Levels and Disability-Free Survival Among Community-Dwelling Elderly Individuals: Nested Case-Control Study of the Tsurugaya Project

The longer healthy life expectancy observed in Japan may be partly attributed to the Japanese diet. The researchers sought to examine whether serum isoflavone levels are associated with disability and death. The researchers used a nested case-control study to compare serum isoflavones (daidzein, genistein, glycitein, and equol) levels between 165 participants that died or were certificated as disabled (cases) and 177 controls. Disability was defined by certification of long-term care insurance. Conditional logistic regression models were used to calculate the risk of isoflavones for the composite outcome. The proportion of cases was lower in the group with the highest levels of equol (34/91, 37%) compared with equol nonproducers (84/161, 52%). The risk of disability or death among equol producers remained reduced after adjusting for age and sex (odds ratio: 0.55, 95% confidence interval: 0.33-0.93). In a multivariate model, this risk was also unchanged (odds ratio: 0.51, 95% confidence interval: 0.27-0.96). There were no significant associations between daidzein, genistein, and glycitein with the composite endpoint. Higher serum equol levels, but not any other isoflavones, were inversely associated with the composite endpoint of disability and death. Although it cannot be concluded that equol per se has preventive effects on disability or death, higher equol levels appear associated with better health.

Abstract 3563: Soy protein isolate consumption does not prevent biochemical failure after radical prostatectomy in high risk men: A randomized controlled trial

Abstract Epidemiologic and experimental data suggest that soy consumption may prevent prostate cancer and be beneficial for men with prostate cancer. Soy intake and risk of prostate cancer are inversely correlated; soy isoflavones inhibit growth of prostate cancer cells and reduce prostate carcinogenesis in animal models. We tested the hypothesis that soy consumption reduces biochemical recurrence after radical prostatectomy in a randomized controlled clinical trial with a soy protein supplement versus a casein-based placebo in men at increased risk for PSA failure in the first 2 years after radical prostatectomy. PSA was tested at 2-month intervals in year 1 and every 3 months in year 2. Eligibility criteria were: Gleason sum of >8, extra-capsular extension, seminal vesicle invasion, positive surgical margins, positive lymph nodes, and/or a preoperative PSA of >20 ng/ml. Biochemical recurrence was defined a priori as reaching a PSA value of α0.07 ng/ml, confirmed twice. A two-year PSA failure rate in eligible subjects of approximately 30% was expected, based on data from NYU and previous literature. With a planned sample size of 128 evaluable subjects per arm, the study had 80% power to detect a 50% reduction in PSA failure rate at a 2-sided significance level of 0.05. The soy protein isolate and placebo (generously provided by Solae LCC, St Louis, MO) were identical in composition, except for the protein source (19.2-19.8 g protein/day); the soy product provided daily 23.5 mg genistein and 40.9 mg total isoflavones (aglycone equivalents); the placebo was devoid of any soy-specific constituents. Accrual did not reach the intended level and 172 subjects were randomized and enrolled, of whom 142 were evaluable (completed two years on study or developed confirmed recurrence within two years). Soy protein consumption did not alter recurrence rate or time-to-recurrence (TTR). Of the 74 evaluable subjects in the soy arm 22 (30%) recurred as did 22 (32%) of the 68 subjects in the placebo arm recurred. The mean TTR was 40.7 + 29.3 (SD) weeks in the soy group and 44.5 + 28.0 weeks in men on placebo. Statistical analysis on intention-to-treat basis confirmed the absence of an effect on these primary endpoints. The drop-out rate was 17% and there were <5% missing values, none of which impacted the primary endpoints. Compliance by self-report was excellent and is being confirmed by serum isoflavone levels. There were no treatment-related adverse events, except a few cases of constipation. We previously ruled out effects of the intervention on anti-thyroid activity and iron status in a subset of subjects. Thus, soy consumption is safe, but unlikely to benefit men after radical prostatectomy, although the results of this study do not rule out preventive effects of soy prior to prostate cancer development. (Supported by NIH grants CA27790, CA166195 & RR029879 and the Prevent Cancer Foundation) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3563. doi:1538-7445.AM2012-3563

Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients

Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE(2) by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment.

A Phytoestrogen-Rich Diet Increases Energy Expenditure and Decreases Adiposity in Mice

BackgroundObesity is an increasingly prevalent health problem, and natural effective therapeutic approaches are required to prevent its occurrence. Phytoestrogens are plant-derived compounds with estrogenic activities; they can bind to both estrogen receptors α and β and mimic the action of estrogens on target organs.ObjectivesThe purpose of this study was to examine the influence of soy-derived phytoestrogens on energy balance and metabolism.MethodsMale outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet from conception to adulthood. We measured circulating serum isoflavone levels using reverse-phase solid-phase extraction for subsequent liquid chromatography electrospray tandem mass spectrometry analysis. Adult animals were analyzed for body composition by dual-energy X-ray absorptiometry, locomotor activity by running-wheel experiments, respiratory exchange rate by indirect calorimetry, and food intake using metabolic cages. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine the expression of hypothalamic neuropeptide genes.ResultsWe found that adult mice fed a soy-rich diet had reduced body weight, adiposity, and resistance to cold. This lean phenotype was associated with an increase in lipid oxidation due to a preferential use of lipids as fuel source and an increase in locomotor activity. The modulation of energy balance was associated with a central effect of phytoestrogens on the expression of hypothalamic neuropeptides, including agouti-related protein.ConclusionThe data suggest that dietary soy could have beneficial effects on obesity, but they also emphasize the importance of monitoring the phytoestrogen content of diets as a parameter of variability in animal experiments.

Soy Isoflavones Do Not Affect Bone Resorption in Postmenopausal Women: A Dose-Response Study Using a Novel Approach with 41Ca

The purpose of this 3-way crossover study was to identify the effective dose of soy protein isolate enriched with isoflavones for suppressing bone resorption in postmenopausal women using a novel, rapid assessment of antibone resorbing treatments. Thirteen postmenopausal women (>or=6 yr since menopause) were predosed with 41Ca iv. After a 200-d baseline period, subjects were given 43 g soy protein/d that contained 0, 97.5, or 135.5 mg total isoflavones in randomized order. The soy protein isolate powder was incorporated into baked products and beverages. Each 50-d intervention phase was preceded by a 50-d pretreatment phase for comparison. Serum isoflavone levels and biochemical markers were measured at the end of each phase. Twenty-four-hour urine samples were collected approximately every 10 d during each phase for 41Ca/Ca analysis by accelerator mass spectrometry. Serum isoflavone levels reflected the amount of isoflavones consumed in a dose-dependent manner. None of the isoflavone levels had a significant effect on biochemical markers of bone turnover, urinary cross-linked N teleopeptides of type I collagen and serum osteocalcin, or bone turnover as assessed by urinary 41Ca/Ca ratios. Soy protein with isoflavone doses of up to 135.5 mg/d did not suppress bone resorption in postmenopausal women. This is the first efficacy trial using the novel technique of urinary 41Ca excretion from prelabeled bone.

Enhanced estrogenic responses and sensitivity to azoxymethane following dietary soy isoflavone supplementation in older female rats

Soy isoflavones are popular supplements among middle-aged and older women based on their potential protection against cancer and their use as alternative hormone replacement therapy. The purpose of this study was to investigate the effects of dietary soy isoflavones on early stage colon cancer in various ages of female rats. Young (1 month), mature (11 month) and old (22 month) female Fisher 344 rats were fed either the control diet or a diet containing 0.4% soy isoflavone isolate for 1 week, injected once with 20 mg/kg azoxymethane (AOM) and maintained on the diets for another 15 weeks. The concentration of isoflavones in the diet was 2 g/kg diet, composed of 1.2 g/kg genistin, 0.7 g/kg daidzin and 0.1 g/kg other isoflavones including glycitin, acetylgenistin, acetyldaidzin, genistein, daidzein, and glycitein. There was no difference over all ages in the development of preneoplastic colonic aberrant crypt foci between rats fed the soy compared to the control diet, indicating that the soy diet did not provide protection against early stage colonic carcinogenesis. On the contrary, several adverse effects of soy supplementation in female AOM-treated rats were observed. Soy-supplemented rats had greater weight loss and a slower recovery of body weight following the AOM injection compared to rats fed the control diet and these changes increased with age. Five of the 21 rats fed the soy supplement died before the end of the experiment while all animals on the control diet survived to term. The density of normal crypts lining the colonic mucosa was reduced in rats fed the soy compared to control diet, indicating gastrointestinal damage. Uterine weights, serum estradiol and serum isoflavone levels were increased in mature and old female rats fed the soy-supplemented diets compared to age-matched controls, suggesting an increasing estrogenic response with age to isoflavone supplementation. These adverse effects of soy isoflavones in aged female animals need further examination because women, and particularly older women, are the prime target population for consumption of soy supplements.

O-211: Effect of soy phytoestrogens on systemic markers of inflammation and adiposity in postmenopausal women

O-211: Effect of soy phytoestrogens on systemic markers of inflammation and adiposity in postmenopausal women

Positive effect of dietary soy in ESRD patients with systemic inflammation—correlation between blood levels of the soy isoflavones and the acute-phase reactants

Inflammation is commonly associated with malnutrition and cardiovascular disease in end-stage renal failure patients. Anti-inflammatory properties of the isoflavones, a micronutrient component of soy, have been reported in several experimental models and disease conditions, but never in renal failure. We hypothesized that dietary soy isoflavones correct laboratory evidence of systemic inflammation in haemodialysis (HD) patients with underlying high blood levels of C-reactive protein (CRP). End-stage renal disease patients on chronic HD, with elevated CRP (>10.0 mg/l) were enrolled in this pilot study. The subjects were double-blind randomly distributed with 2 : 1 ratio to receive isoflavone-containing soy-based nutritional supplements (soy group) or isoflavone-free milk protein (control group) for 8 weeks. Serum isoflavone, inflammatory markers and nutrition markers were assessed at baseline and at the end of the treatment. Thirty-two subjects were enrolled. Fifteen subjects in the soy group and 10 in the control group completed the study; five dropouts were due to acute illness and two due to food intolerance. After intervention, blood isoflavone levels were 5- to 10-fold higher in the soy group than in the control group [e.g. median genistein (25-75th percentile): 337.9 (175.5-1007) nM in the soy group vs 41.4 (22.9-100.4) nM in the control group; P < 0.001]. However, the isoflavone levels ranged widely in the soy group (e.g. genistein: 33-1868 nM) and, depending on the individual compound, four to seven subjects had end-of-treatment levels that were not different from baseline. Variation from baseline of the individual serum isoflavone levels (Delta-isoflavone) and CRP displayed a strong inverse correlation in the soy group (R = -0.599, P < 0.02). In addition, Delta-isoflavone correlated positively with the variation of albumin (R = 0.522, P = 0.05) and insulin-like growth factor-1 (R = 0.518, P < 0.05). Group levels of CRP were not statistically different after intervention although a trend towards lower levels was noted in the soy group [18.2 (12.7-29.1) mg/l at baseline vs 9.7 (5.2-20.7) mg/l at week 8; NS] but not in the control group [20.6 (9.2-38.5) vs 17.6 (9.1-40.7) mg/l]. These data suggest the possibility of beneficial effects of isoflavone-rich soy foods on the inflammatory and nutritional status of HD patients with underlying systemic inflammation.

Soy protein with and without isoflavones fails to substantially increase postprandial antioxidant capacity

Five methods for the assessment of antioxidant capacity [whole plasma conjugated diene formation, low-density lipoprotein oxidation susceptibility, ferric-reducing ability of plasma, oxygen radical absorbance capacity and perchloric-acid-treated oxygen radical absorbance capacity (PCA-ORAC)] were used in a randomized, double blind, crossover study to determine the acute postprandial antioxidant protection imparted by the isoflavone component of soy. On separate days, 16 subjects consumed one of three isocaloric shakes containing 25g of protein in the form of soy, with 107 mg of total aglycone units of isoflavones, soy with trace isoflavones (<4 mg) or total milk protein. Blood was collected at baseline, 4h, 6h and 8h after consumption. Antioxidant capacity, serum isoflavone levels, fat-soluble antioxidants and plasma vitamin C levels were evaluated. Repeated measures analysis of variance showed no significant differences ( P=.05) within treatments over time in four of five antioxidant capacity measurements. Significant differences over time between the soy with trace isoflavones and the total milk protein group were observed using the PCA-ORAC assay. It can be concluded that, on an acute basis, a significant increase in serum antioxidant capacity is not detectable following consumption of soy protein.

Dietary Modulation of p-Nonylphenol–Induced Polycystic Kidneys in Male Sprague-Dawley Rats

We had previously found that p-nonylphenol (NP) at 1000-2000 ppm in a soy- and alfalfa-free diet induced severe polycystic kidney disease (PKD) in both male and female pups exposed from gestation day 7 through postnatal day (PND) 50 and hypothesized that differences in dietary components contributed to the severity of lesions relative to those reported in other studies using similar doses of NP. The present study investigated the dietary modulation of NP-induced PKD using the same exposure regimen with 2000 ppm NP in four different diets: the natural ingredient soy- and alfalfa-free diet that had been used in the earlier study, Purina 5K96; two defined diets AIN-93G, designated AIN-CAS, and a modified AIN-93G with soy protein isolate replacing casein as the protein source (AIN-SPI); and the commonly used natural ingredient diet Purina 5001 (P5001). Serum isoflavone levels were negligible in animals fed the soy-free AIN-CAS and 5K96 diets and were 2- to 18-fold higher in animals fed P5001 than in those fed AIN-SPI. Consumption of P5001 was significantly greater than consumption of the other diets, and those animals fed P5001 were generally significantly heavier than animals receiving the other diets. NP significantly reduced body weight gain in male pups regardless of the diet fed. There was no evidence of NP-induced kidney toxicity in male pups at PND 2, 14, or 21 or in the dams. In PND 50 male pups, serum blood urea nitrogen was significantly elevated by NP in all diet groups. Urine volume and urinary N-acetyl beta-glucuronidase were significantly increased by NP in the soy-free 5K96 and AIN-CAS diet groups. Relative kidney weights were increased by NP in all diet groups except P5001, with the greatest increase in AIN-CAS and 5K96 diet groups. Microscopic evaluation of kidneys from the PND 50 males showed that NP induced PKD in all diet groups but with marked variation in the severity depending on the diet. PKD was severe in 100% of the NP-treated animals in the AIN-CAS and 5K96 groups, moderate in 88% of the AIN-SPI diet group, and mild in only 40% of the P5001 diet group. Thus, diet can significantly modulate the development of PKD induced by dietary NP in rats. Soy components, as well as other complex dietary factors, may account for the level of protection afforded by the P5001 diet.

Blood Isoflavone Levels during Intake of a Controlled Hospital Diet

Isoflavones are reported to have an estrogenic activity to prevent prostate cancer. Therefore, it is necessary to analyze the factors influencing the absorption and metabolism of isoflavones using detailed and precise dietary information. We evaluated the relationship between the amount of intake of soybean isoflavones in the diet and its serum levels in 88 hospitalized patients (22 with prostate cancer, 66 without cancer) with a mean age of 67.0+/-9.3 y. The intake amount of genistein and daidzein was significantly lower in the hospital diet than that in the ordinary daily diet. The serum levels of isoflavones were related to the amount of intake consumed during the day before blood collection (r=0.27 for genistein, r= 0.33 for daidzein), but not to the last meal before blood collection. While little relationship was observed between the amount of intake and serum levels of isoflavones in the equol producers, a marked relationship was noted in the non-producers (r=0.52 for genistein, r=0.67 for daidzein). Blood isoflavone levels decreased when the duration of the hospitalization was longer than 1 wk. These observations indicate that the serum isoflavone levels are correlated with the amount of intake of isoflavones during the preceding 2 wk and serve as an effective biomarker in individuals during the intake of the hospital diet. Further investigations, including the mechanism of the metabolism on isoflavones, are necessary for the evaluation of the preventive effect of isoflavones.

Soy product intake and serum isoflavonoid and estradiol concentrations in relation to bone mineral density in postmenopausal Japanese women.

To evaluate soy intake and serum concentrations of estradiol and isoflavonoids and their relationship to bone mineral density (BMD) and serum bone-specific alkaline phosphatase (bone ALP) activity, we conducted a cross-sectional study of 87 postmenopausal Japanese women. Soy product and isoflavone intake from soy products and intake of nutrients were assessed with a semiquantitative food-frequency questionnaire. BMD (mg/cm2) was measured by single-energy X-ray absorptiometry at the site of the calcaneus. Serum estradiol (E2) and the sex hormone-binding globulin (SHBG) were measured by radioimmunoassay. Serum genistein and daidzein concentrations were measured by a high-performance liquid chromatography MS/MS method. A statistically significant correlation was observed between the ratio of E2 to SHBG and BMD (Spearman r=0.38, p=0.0003) after controlling for age, body mass index, smoking status, age at menarche, and intake of vegetable fat, vitamin C and salt. Soy product and isoflavone intake and serum isoflavones were not significantly correlated with BMD after controlling for the covariates. Serum ALP was not significantly correlated with soy product and isoflavone intake, the E2/SHBG ratio or serum isoflavones. The present study supports the association of BMD with serum estradiol; however, it does not support the association of BMD with soy or isoflavone intake or serum isoflavone levels.