The Life Sciences Research Organization (LSRO) in Bethesda, Maryland has published the Equol, Soy, and Menopause Supplement in the July issue of the Journal of Nutrition. The articles in the supplement, summarized below, are based on presentations made at the Equol, Soy, and Menopause Research Leadership Conference, organized by LSRO, that took place in Washington, DC, in June 2009.
Messina M.
A brief historical overview of the past two decades of soy and isoflavone research.
J Nutr. 2010 Jul;140(7):1350S-4S. Epub 2010 May 19.
Abstract
During the past 20 years, a remarkable amount of research into the health effects of soy consumption has been conducted, which in large part can be attributed to the presence of isoflavones in the soybean. Isoflavones first came to the attention of the scientific community in the 1940s because of fertility problems observed in sheep grazing on a type of isoflavone-rich clover. In the 1950s, as a result of their estrogenic effects in rodents, isoflavones were studied as possible growth promoters for use by the animal feed industry, although shortly thereafter, it was shown that isoflavones could also function as antiestrogens. Despite this early work, it was not until the 1990s, largely because of research sponsored by the U.S. National Cancer Institute, that the role of soyfoods in disease prevention began to receive widespread attention. Subsequently, isoflavones and soyfoods were being studied for their ability to alleviate hot flashes and inhibit bone loss in postmenopausal women. In 1995, soy protein attracted worldwide attention for its ability to lower cholesterol. At this same time, isoflavones began to be widely discussed as potential alternatives to conventional hormone therapy. In 2002, it was hypothesized that individuals possessing the intestinal bacteria capable of converting the soybean isoflavone daidzein into the isoflavan equol were more likely to benefit from soy intake. More recently, in vitro and animal research has raised questions about the safety of isoflavone exposure for certain subsets of the population, although the human data are largely inconsistent with these concerns.
Setchell KD, Clerici C.
Equol: history, chemistry, and formation.
J Nutr. 2010 Jul;140(7):1355S-62S. Epub 2010 Jun 2.
Abstract
Equol, first isolated from equine urine in 1932 and identified 50 years later in human urine as a metabolite of the soy isoflavones, daidzin and daidzein, is produced by intestinal bacteria in some, but not all, adults. This observation led to the term equol-producers to define those adults that could make equol in response to consuming soy isoflavones and the hypothesis that the health benefits of soy-based diets may be greater in equol-producers than in equol nonproducers. By virtue of a chiral center, equol occurs as a diastereoisomer and intestinal bacteria are enantiospecific in synthesizing exclusively the S-(-)equol enantiomer, an enantiomer that has selective affinity for the estrogen receptor-beta. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. The wide range of biological activities these enantiomers possess warrants their investigation for the treatment of a number of hormone-related conditions involving estrogen-dependent and androgen-related conditions. The following review describes the history, chemistry, and factors governing the intestinal bacterial formation of equol.
Setchell KD, Clerici C.
Equol: pharmacokinetics and biological actions.
J Nutr. 2010 Jul;140(7):1363S-8S. Epub 2010 Jun 2.
Abstract
Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman], an isoflavan produced by intestinal bacteria in response to soy isoflavone intake in some but not all humans, exhibits a wide range of biological properties. It exists as the diastereoisomers S-(-)equol and R-(+)equol. Intestinal bacteria produce exclusively S-(-)equol, which has selective affinity for estrogen receptor (ER)-beta. The evidence is conflicting on whether there is an advantage to producing S-(-)equol in response to soy isoflavone intakes, but the ability to now synthesize these diastereoisomers opens the way for future clinical trials to directly examine their potential in a number of hormone-dependent conditions. In this review, the plasma and urinary pharmacokinetics of S-(-)equol and R-(+)equol are reviewed and summarized, and some of the more recent evidence supporting potential biological effects of S-(-)equol is considered.
Lampe JW.
Emerging research on equol and cancer.
J Nutr. 2010 Jul;140(7):1369S-72S. Epub 2010 May 26.
Abstract
Mechanisms of action of equol described using in vitro studies suggest possible effects of this compound in relation to cancer risk. However, experimental data are lacking with regard to the effects of S-(-)-equol (a gut bacterial product of daidzein), racemic equol, or even daidzein on tumorigenesis in vivo. Rodent studies, using racemic equol or daidzein in equol-producing animals, suggest that equol exposure does not stimulate mammary tumor growth, but there is little evidence that it is protective either. Racemic equol has been shown to inhibit skin carcinogenesis in hairless mice. Epidemiologic studies of associations between urinary or plasma isoflavone concentrations and breast cancer risk in women have reported no association nor increased risk associated with higher equol measures in low-soy-consuming populations but have reported a trend toward decreased cancer risk with increased equol in Asian populations. These population-based differences have been reported for prostate cancer too. Several studies in Asian men report lower equol concentrations or a lower prevalence of equol-producers among men with prostate cancer compared with controls, whereas studies in European populations report no association. Studies using intermediate biomarkers of cancer risk and susceptibility in humans also have examined the effects the equol-producer phenotype in relation to soy intake with varying results. Overall, the role of equol in relation to cancer remains unclear. With the availability of R- and S-equol, animal studies of carcinogenesis and human intervention studies addressing effects of the equol enantiomers on intermediate biomarkers may help to ascertain the role of equol in cancer risk.
Ishimi Y.
Dietary equol and bone metabolism in postmenopausal Japanese women and osteoporotic mice.
J Nutr. 2010 Jul;140(7):1373S-6S. Epub 2010 May 19.
Abstract
Equol binds to the estrogen receptor with greater affinity than its precursor, daidzein, an isoflavone found in soybeans. Inter-individual differences in the ability to produce equol may lead to differential effects of isoflavone intervention on human health. Here, we review previously published work from our laboratory on equol producer status and bone health in humans and in a mouse model of osteoporosis. We performed a 1-y, double-blind, randomized trial to compare the effects of isoflavone (75 mg of isoflavone conjugates/d; equivalent to 47 mg/d of the aglycone form) with those of placebo on bone mineral density (BMD), fat mass, and serum isoflavone concentrations in 54 early postmenopausal Japanese women classified by their equol-producer phenotype. Isoflavone intervention increased the serum equol concentration in equol producers but not in nonproducers (P < 0.04). The annualized changes in BMD in the total hip and intertrochanteric regions in the isoflavone-treated equol producers (-0.46 and -0.04%, respectively) were less than in the nonproducers (-2.28 and -2.61%, respectively). The annualized change in fat mass was lower in the equol producers compared with the nonproducers in the isoflavone group. The annualized changes in BMD and fat mass did not differ between the equol producers and nonproducers in the placebo group. Equol also inhibited bone loss and fat accumulation in estrogen-deficient osteoporotic mice. Our data suggest that prevention of bone loss and fat accumulation in early postmenopausal women by isoflavones may depend on an individual's equol-producing capacity.
Weaver CM, Legette LL.
Equol, via dietary sources or intestinal production, may ameliorate estrogen
J Nutr. 2010 Jul;140(7):1377S-9S. Epub 2010 May 26.
Abstract
Equol, a product of intestinal metabolism of daidzein, is chemically similar to estrogen (without the lipophilic moiety) and has higher estrogen receptor-beta binding affinity than its parent precursor. In 2004, a long-term, randomized controlled trial that characterized postmenopausal women by their equol-producing status showed stronger advantages to lumbar spine bone mineral density (BMD) in equol- compared with nonequol-producers. Subsequent studies have related equol status of participants to change in bone turnover markers or BMD in response to soy isoflavone interventions. To our knowledge, we are the first to prescreen women for equol-producing status prior to initiating an intervention. In menopausal Western women, equol status did not affect the modest, but significant, reduction in bone resorption achieved with a soy isoflavone intervention.
Kronenberg F.
Menopausal hot flashes: a review of physiology and biosociocultural perspective on methods of assessment.
J Nutr. 2010 Jul;140(7):1380S-5S. Epub 2010 May 26.
Abstract
Hot flashes continue to be a troublesome problem for menopausal women the world over. After >50 y of research, we still do not understand the etiology and mechanism of hot flashes, nor do we know how estrogen, the major pharmaceutical treatment, works to reduce hot flashes. We are gaining insight into sociocultural complexities that may affect how and whether women report hot flashes. And we are becoming more sophisticated in our research tools (be it questionnaires, physiological monitors, or brain imaging techniques). New aspects of hot flash research, including neuroimaging and the study of genetic polymorphisms, when combined with increasingly nuanced ways of asking questions of culturally distinct populations, provide challenges but rich complexity from which a better understanding will emerge.
Aso T.
Equol improves menopausal symptoms in Japanese women.
J Nutr. 2010 Jul;140(7):1386S-9S. Epub 2010 May 19.
Abstract
It has been well documented that the frequency of vasomotor menopausal symptoms, such as hot flashes and night sweats, of Japanese menopausal women is less than that of Western women. High intake of soy isoflavones in the traditional Japanese diet has been postulated as the possible explanation of the difference. Epidemiological studies have reported that the content of equol, which is a biologically active metabolite of the isoflavone, daidzein, is lower in the women who complain of severe vasomotor symptoms. To investigate the involvement of equol in the manifestation of menopausal symptoms, especially vasomotor symptoms, and the possible therapeutic role of a supplement containing equol (natural S-equol developed by Otsuka Pharmaceutical) on the menopausal symptoms of Japanese women, 3 randomized clinical trials were conducted. The studies indicated that a daily dose of 10 mg of natural S-equol improved menopausal symptoms. In the confirmation study, menopausal women who were equol nonproducers who consumed 10 mg/d of natural S-equol for 12 wk had significantly reduced severity and frequency of hot flashes as well as a significant reduction in the severity of neck or shoulder stiffness. The equol-ingesting group also showed trends of improvement in sweating and irritability and a significant improvement in the somatic category symptoms. Thus, it is concluded that the supplement containing natural S-equol, a novel soybean-derived functional component, has a promising role as an alternative remedy in the management of menopausal symptoms.
Barnes S, Kim H.
Cautions and research needs identified at the equol, soy, and menopause research leadership conference.
J Nutr. 2010 Jul;140(7):1390S-4S. Epub 2010 May 26.
Abstract
This summary addresses the progress and limitations of existing research on the physiologic properties of the isoflavone daidzein metabolite equol. Previous research demonstrating that physiological equol is its S-enantiomer has led to the preparation of S-(-)equol-enriched products formed by the bacterial fermentation of soy germ. Although this product has interesting properties as described in this workshop, the following important issues must be addressed: 1) the product should be evaluated against a preparation containing an equal amount of pure S-(-)equol to determine whether other components resulting from the fermentation are contributing to the physiological effects; 2) evaluation of the cellular mechanisms of S-(-)equol using cell culture methods should be conducted at concentrations consistent with those encountered physiologically (in the nmol/L range) and in several cell lines representing a target tissue; and 3) in follow-up studies in animal models and in human clinical trials, standardized preparations of S-(-)equol should be made available. Research opportunities now exist to determine whether equol's apparent effects on menopausal symptoms (hot flashes, sleep disturbances, bone health) in equol producers can be extended to equol nonproducers. It will be important to ensure that such research is not complicated by cultural differences, differences in lifetime exposure to soy products, experimental techniques, and other variables. Further areas of research that would benefit from the availability of S-(-)equol preparations include its use in skin care (either as an antioxidant or as an estrogen receptor agonist) and in the treatment of brain injury as well as postmenopausal cognitive decline.
A limited number of reprints of the above articles are available from LSRO by contacting Dr. Michael Falk, 301‑634‑7030, FalkM@LSRO.org.
