Tomomi Ueno

Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial.

Objective:Equol is more biologically active than its precursor daidzein, which is the principal isoflavone found in soybean. There are interindividual differences in the ability to produce equol; these may lead to differences in the effects of isoflavone intervention on human health. This study aimed to investigate whether the effects of soy isoflavones on bone and fat mass are related to an individuals equol status. Design:We performed a 1-year double-blind, randomized trial to compare the effects of isoflavone (75 mg of isoflavone conjugates/day) with those of placebo on bone mineral density, fat mass, and serum isoflavone concentrations in early postmenopausal Japanese women who were classified based on their equol-producer phenotype. Results:After 1 year, the isoflavone intervention significantly increased the serum equol concentration in the equol producers but not in the nonproducers. In the isoflavone group, the annualized changes in the bone mineral density of the total hip and intertrochanteric regions were −0.46% and −0.04%, respectively, in the equol producers and −2.28% and −2.61%, respectively, in the nonproducers; these values were significantly different (P < 0.05 for both the regions). Significant differences were observed between the equol producers and nonproducers in the isoflavone group with regard to the annualized changes in the fat mass. No significant difference in the annualized changes in bone mineral density and fat mass was observed between the equol producers and nonproducers in the placebo group. Conclusions:Our data suggest that the preventive effects of isoflavones on bone loss and fat accumulation in early postmenopausal women depend on an individuals equol-producing capacity.

Natural S-equol decreases bone resorption in postmenopausal, non-equol-producing Japanese women: a pilot randomized, placebo-controlled trial.

Objective: Equol is a metabolite of the isoflavone daidzein and may play a critical role in preventing bone loss by soy isoflavones in postmenopausal women. However, results from clinical trials have not been published. The aim of this study was to investigate the effects of equol on bone metabolism and serum sex and thyroid hormone levels in postmenopausal Japanese women. Methods: We performed a 1-year double-blind, randomized, placebo-controlled trial with natural S-equol supplements for 93 non-equol-producing menopausal Japanese women. Participants were randomly assigned to four groups receiving the following: placebo, 2 mg of equol supplement per day, 6 mg of equol supplement per day, and 10 mg of equol supplement per day. Results: Equol intervention increased equol concentrations in serum and urine in a dose-dependent manner. Urinary deoxypyridinoline was significantly decreased, with a −23.94% change in the group that received 10 mg of equol supplement per day as compared with a −2.87% change in the group that received placebo after 12 months of intervention (P = 0.020). Thus, 10 mg/day of equol supplement markedly inhibited bone resorption. Treatment with 10 mg/day of equol prevented a decrease in bone mineral density in the entire body in postmenopausal women after 12 months. Sex and thyroid hormone concentrations in serum did not differ among the four groups after intervention. Conclusions: These findings suggest that 10 mg/day of natural S-equol supplementation contributes to bone health in non-equol-producing postmenopausal women without adverse effects.

Effects of natural S‐equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status

Epidemiologic studies indicate that soy intake has an important role in the prevention of age‐related health problems. Daidzein, the principal isoflavone contained in soy, is converted to S‐equol by the intestinal bacteria. Not all individuals, however, can produce S‐equol, which is considered the most biologically active metabolite. We studied the effects of a natural S‐equol supplement on metabolic parameters associated with overweight or obesity and metabolic syndrome.

Acute and subchronic toxicity and genotoxicity of SE5-OH, an equol-rich product produced by Lactococcus garvieae.

The consumption of soy-based products is associated with a number of health benefits and much of these benefits are proposed to be due to the soy isoflavones daidzein, genistein, glycitein, their glycosides, and equol, an isoflavone naturally produced from daidzein. Equol is a naturally bacterially-derived metabolite of daidzein and is produced by bacteria in the gut of those humans capable of hosting the particular organism. To allow all humans to enjoy the health benefits of equol, a new functional food ingredient has been developed that relies on bacterial conversion of daidzein to equol under strictly controlled conditions. This new food substance, termed SE5-OH, has been studied extensively for its acute and subchronic toxicity in Sprague-Dawley rats, as well as for its potential genotoxicity. The oral LD(50) is >4,000 mg/kg. In a 91-day, subchronic study, the no-observed-adverse-effect-level (NOAEL) was 2,000 mg/kg/day, the highest dose tested. SE5-OH was negative in Salmonella typhimurium tester strains TA98, TA100, TA1535 and TA1537 and in Escherichia coli tester strain WP2uvrA with and without metabolic activation. SE5-OH was negative for chromosome aberrations in Chinese hamster lung cells up to 3,000 microg/ml with and without metabolic activation and did not induce increases in micronucleated polychromatic erythrocytes taken from Sprague-Dawley rats administered (via gavage) up to 4,000 mg/kg SE5-OH twice daily for two consecutive days.

A Pilot Study on the Effects of S-Equol Compared to Soy Isoflavones on Menopausal Hot Flash Frequency

BACKGROUND S-equol, a metabolite of the soy isoflavone daidzein, has been proposed as having potential for relief of menopausal symptoms. This study compared the efficacy of the natural S-equol supplement, SE5-OH, with isoflavones for relieving hot flashes and other menopausal symptoms. METHODS An 8-week randomized, double-blind, active comparator trial with SE5-OH was conducted in postmenopausal women (aged 45-65 years), who experienced ≥5 hot flashes/day. Participants (n=102) were assigned to one of four treatment groups: 10 (n=24), 20 (n=27), or 40 (n=25) mg S-equol/day or soy isoflavones (n=26). Participants recorded their hot flash frequency and rated their menopause symptom severity. RESULTS Reductions in hot flash frequency at week 8 were similar for all treatment groups. However, based on analyses of the cumulative effect for the 8-week period, 40 mg/day S-equol had a greater reduction of hot flash frequency compared to isoflavones (p=0.021). A subgroup analysis further indicated that for subjects with >8 hot flashes/day at baseline, 20 and 40 mg/day S-equol were superior to isoflavones in reducing hot flash frequency (p=0.045 and p=0.001, respectively). In addition, 10 and 20 mg/day S-equol improved muscle and joint pain score compared with isoflavones (p=0.003 and p=0.005, respectively). CONCLUSIONS S-equol, 10 mg/day, appears to be as effective as soy isoflavones at reducing hot flash frequency and more effective for relieving muscle and joint pain in postmenopausal women. S-equol, ≥20 mg/day, alleviates hot flashes to a greater extent than soy isoflavones in those women who experience >8 hot flashes/day.

Dietary and lifestyle correlates of urinary excretion status of equol in Japanese women.

The isoflavone metabolite equol has been identified in urine or blood samples in some but not all humans. In this cross-sectional study, we examined the association between lifestyle, including diet, and the urinary excretion of equol. Study subjects were 419 Japanese women who were recruited from a breast cancer screening center. Each woman responded to a self-administered questionnaire seeking information about health and lifestyle factors. Diet was assessed by a validated semiquantitative food frequency questionnaire. Urinary isoflavones were measured using spot urine samples. Equol was detected in the urine of 84 (20.0%) women. After controlling for covariates, it was found that dairy product intake was significantly lower in those who excreted detectable equol levels in urine than in those who did not. Because equol is derived from daidzein, individuals with low intake of daidzein may produce undetectable levels of equol. To account for this, the study subjects were restricted to 163 women with urinary daidzein levels of 10 nmol/mg creatinine or higher. The association of equol excretion with dairy product intake remained significant. Demographic factors, smoking status, and menstrual and reproductive factors were unrelated to equol excretion. These data suggest that dairy product intake may be associated with the production of equol.

Effects of S-equol and natural S-equol supplement (SE5-OH) on the growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice.

Hormone replacement therapy (HRT) for treatment of menopausal symptoms is controversial because of reported breast cancer resulting from estrogen treatment and consequent estrogenic stimulation. S-equol, a natural metabolite of the soy isoflavone daidzein produced by intestinal bacteria, has been shown to ameliorate menopausal symptoms, with relatively low concomitant estrogenic receptor stimulation. Although synthesis of equol produces the racemate, the S-isomer may be produced in commercial amounts by bacterial fermentation of soy germ, during the production of the supplement SE5-OH. This study aims to investigate the effects of S-equol and SE5-OH on the growth of MCF-7 in vitro and in vivo. In vitro, purified S-equol, and the isoflavonoid mixture present in SE5-OH stimulated estrogenic transcriptional activity and proliferation of MCF-7-E10 cells, similar to that observed for genistein (another soy isoflavone), but at concentrations from 10(4)-fold to 10(6)-fold higher than seen with 17β-estradiol (E2). Ovariectomized (OVX) mice implanted with MCF-7-E10 cells were fed diets containing 250 or 500 ppm of purified S-equol, isoflavonoid mixture, or genistein. There were no significant differences in tumor growth between the treatment groups and control group. These results suggest that S-equol and natural S-equol in the supplement (SE5-OH), do not promote the progression of breast cancer.

Prevalence of the equol-producer phenotype and its relationship with dietary isoflavone and serum lipids in healthy Chinese adults.

Background Studies have suggested that daidzein-metabolizing phenotypes have beneficial effects on a range of health outcomes. We investigated the prevalence of equol producers and the relationship of equol phenotype with habitual isoflavone consumption and serum lipid concentrations in 200 Chinese adults in Beijing. Methods After the baseline survey and dietary records, 200 healthy adults in Beijing were challenged with a soy-isoflavone supplement for 3 days; 24-hour urine samples were collected before and after the challenge. Isoflavones and their metabolites in urine were measured to determine equol phenotype. Serum lipids, uric acid, and other biochemical markers were also measured. Results Only 26.8% of the participants excreted equol when on a regular diet, as compared with 60.4% after the challenge. After the challenge, urinary isoflavonoid excretion increased in all participants, while equol excretion increased only in equol producers. Isoflavone intake was correlated with urinary isoflavone (range r = 0.49–0.58, P < 0.01). As compared with nonproducers, equol producers were less likely to consume cereals (P < 0.001). There was no significant correlation between serum lipids and isoflavone intake. Serum lipids were not significantly affected by equol phenotype. Conclusions Urinary equol excretion was detected in about 25% of participants under their usual dietary conditions. Their potential to produce equol was increased after the challenge. Urinary isoflavone levels may serve as a useful biomarker for isoflavone intake in populations. We observed an association between equol phenotype and cereal intake. Our findings also suggest that dietary isoflavone intake has no significant effect on serum lipids in healthy participants, regardless of equol phenotype.

The effects of natural S-equol supplementation on skin aging in postmenopausal women: a pilot randomized placebo-controlled trial.

ObjectiveThe aim of this study was to investigate the effects of the natural S-equol supplement on skin aging in equol-nonproducing Japanese postmenopausal women. MethodsA randomized, double-blind, placebo-controlled trial examined the use of the natural S-equol supplement for 12 weeks in 101 postmenopausal Japanese women who were equol nonproducers. They were randomly assigned to one of three groups: placebo (n = 34), 10 mg S-equol/day (EQL10; n = 34), or 30 mg S-equol/day (EQL30; n = 33). Skin parameters of crow’s-feet wrinkles (area and depth), hydration, transepidermal water loss, and elasticity were measured at baseline and at monthly intervals during treatment. Vaginal cytology, endometrial thickness, and mammography were performed before and after treatment. Serum hormone concentrations were measured at the same time as skin parameters. ResultsThe EQL10 and EQL30 groups showed significant reductions in wrinkle area compared with the placebo group (P < 0.05). There was a significant difference in wrinkle depth between the placebo group and the EQL30 group (P < 0.05). Other skin parameters did not show significant differences after the treatment in any group. There were no abnormal results in hormone status or gynecological examinations. ConclusionsOur data suggest that natural S-equol supplementation (EQL10 and EQL30) may have a beneficial effect on crow’s-feet wrinkles in postmenopausal women without serious adverse events.

Daidzein-metabolising phenotypes in relation to serum lipids and uric acid in adults in Guangzhou, China.

Previous studies have suggested that daidzeins metabolites, equol and O-desmethylangolensin (O-DMA), rather than daidzein itself may contribute to the beneficial effects of soya foods in the prevention of CVD. The present study aims to assess the proportion of equol and O-DMA producers, and to compare differences in anthropometric factors, serum lipids, glucose and uric acid between producers and non-producers in Chinese adults aged 20-69 years. For the present cross-sectional study, 202 subjects (100 women and 102 men) were recruited. Twenty-four-hour urinary daidzein and its metabolites were determined in these subjects while on their usual diet and again after a 3-d isoflavone challenge. Fasting serum lipids, glucose and uric acid were examined on their usual diet. Three days of 24 h dietary recalls were used to assess dietary intakes. Of the 202 subjects, 27 (13.4 %) and 27 (13.4 %) excreted equol and O-DMA on their usual diet, and 101 (50 %) and 94 (46.5 %) produced equol and O-DMA after a load of 80 mg/d isoflavones. Equol producers showed lower serum uric acid ( - 10.2 %, P = 0.001), TAG ( - 29.5 %, P = 0.007) and waist:hip ratio ( - 2.6 %, P = 0.032), and tended to have higher HDL cholesterol (6.3 %, P = 0.069) compared with equol non-producers. There were no significant differences in serum lipids, glucose and uric acid between O-DMA producers and non-producers. In conclusion, equol phenotypes might influence cardiovascular risk.