News Release

Tip sheet for journalists: Equol, soy, menopause and bone health research published in Journal of Nutrition

Peer-Reviewed Publication

Porter Novelli

The dietary supplement SE5-OH containing Natural S-equol, developed from soy, may be appropriate for women in menopause, based on results of recent clinical trials documenting its effectiveness and safety in relieving hot flushes and other symptoms of menopause. Nine articles on equol, soy, menopause, bone health and cancer research appear in a July 2010 supplement to the Journal of Nutrition and are summarized here.

About SE5-OH containing Natural S-equol

Soybeans contain a naturally occurring compound, the isoflavone called daidzein. Certain bacteria living within the human digestive tract can convert daidzein into S-equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman]. S-equol is thought to bind to the estrogen beta receptors, but further study is underway to confirm this hypothesis. Studies in Japan have documented an association in women between milder menopausal symptoms in those who naturally produce S-equol after eating soy compared to non-producers. The production of S-equol after soy consumption depends on the types of bacteria present in the large intestine and may be influenced by the amount of soy consumed. About 50 percent of Asians and 20 to 30 percent of North Americans and Europeans, who in general consume less soy than Asians, have the ability to produce equol. Pharmavite LLC, the makers of Nature Made® vitamins and minerals and a subsidiary of Otsuka Pharmaceutical Co., Ltd., is conducting and sponsoring clinical trials that examine the use of SE5-OH containing Natural S-equol in supplement form for the management of menopausal symptoms.

JN Papers

1. Historical Overview of Soy and Isoflavone Research

Messina reviews the past two decades of soy and isoflavone research, noting that largely because of research evaluating the anticancer effects of soyfoods sponsored by the US National Cancer Institute in the 1990s, interest in the role of soy and isoflavones in disease prevention greatly increased . Subsequently, isoflavones and soyfoods have been studied for their ability to lower cholesterol, their potential as alternatives to conventional hormone therapy, alleviate, as well as treat hot flashes and inhibit bone loss in postmenopausal women.

"A Brief Historical Overview of the Past Two Decades of Soy and Isoflavone Research," Mark Messina, Ph.D., adjunct associate professor of nutrition at the Loma Linda University School of Public Health in California and of Nutrition Matters, Inc. in Port Townsend, Washington

2. Discovery and Chemistry of Equol

The health benefits of soy-based diets may be greater in people who can produce S-equol after eating soy, than in non-producers. Equol exists in two mirror-image forms: S- equol and R-equol, but intestinal bacteria exclusively produce the S-equol from soy, which is known to have a select affinity for estrogen receptor beta. A man-made chemical process is needed to make R-equol, which binds more weakly with a preference for estrogen receptor alpha. Both forms of equol are of interest from a clinical and pharmacological perspective and are under development as nutraceutical and pharmacological agents. The authors state that wide range of biological activities these two equol forms possess warrants their investigation for the treatment of a number of hormone-related conditions involving conditions dependent on the female hormone estrogen and related to the male hormone androgen.

"Equol: History, Chemistry and Formation," Kenneth D. R. Setchell, of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center in Ohio, and Carlo Clerici of Clinica di Gastroenterologia ed Epatologia, at the Universita` degli Studi di Perugia University of Perugia in Italy

3. Biological Actions of Equol

Equol exhibits a wide range of biological properties. This paper reviews previous research on how the body processes both equol forms, also called pharmacokinetics, and their biological actions. The authors note that if the theory that health benefits of soy-based diets are greater in equol-producers can be substantiated in studies, then for those adults who are unable to produce S-equol due to a lack of equol-producing bacteria in the intestine or some other factors, one option is to eat equol in the form of a nutraceutical.

" Equol: Pharmacokinetics and Biological Actions," Kenneth D. R. Setchell, of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center in Ohio, and Carlo Clerici of Clinica di Gastroenterologia ed Epatologia, at the Universita` degli Studi di Perugia University of Perugia in Italy

4. Equol Review by an Epidemiologist

Lampe reviews the very limited body of a subset of research about equol, which includes animal studies involving S-equol, a mix of S- and R-equol or their "parental" compound, daidzein, and human epidemiologic studies of soy intake and equol production.

"Emerging Research on Equol and Cancer," Johanna W. Lampe, of the Cancer Prevention Program, Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle

5. Equol and Bone in Women and Mice

Soybean isoflavones, including daidzein and genistein, can inhibit bone loss, depending on the dosage, according to a number of studies using animal model with osteoporosis, without causing notable effects on reproductive organs. Ishimi reports in this article data from a year-long study in postmenopausal Japanese women, in which 25 received a daily dose of daidzein and the isoflavone genistein , and 29 received a placebo. In the women in the isoflavone group who could produce S-equol, the percent change in bone loss at the total hip (a decrease of 0.46 percent) and at the hip intertrochanteric region (a decrease of 0.04 percent) was significantly lower (P< 0.05 for both) than that of the nonproducers (a decrease of 2.28 and 2.61, respectively.) Similarly the S-equol producers in the isoflavone group had significantly lower changes in their fat mass compared to nonproducers during the course of the study. The results suggest that using soy isoflavones to prevent bone loss and the accumulation of fat in women in early post-menopause may depend on an individual's equol-producing capacity.

"Dietary Equol and Bone Metabolism in Postmenopausal Japanese Women and Osteoporotic Mice," Yoshiko Ishimi, of the National Institute of Health and Nutrition in Tokyo, Japan

6. Equol May Help to Reduce Bone Loss

Estrogen produced in the body helps maintain dynamic bone with a high turnover rate. Menopause in women is associated with the body's stage when estrogen levels decrease. The reduction in production and circulating estrogen is associated with rapid bone loss. S-equol binds to estrogen receptor beta, in bone cells. A two-year randomized placebo-controlled trial that characterized postmenopausal women by their equol-producing status, showed that those who were equol producers had a 2.4 percent increase in the lumbar spine bone mineral density (BMD) compared with just 0.6 percent increase in the S-equol non-producers. Additional clinical studies have related women's equol producer status with changes in markers of bone turnover in response to treatments with soy isoflavones.

"Equol, via Dietary Sources or Intestinal Production, May Ameliorate Estrogen Deficiency-Induced Bone Loss," Connie M. Weaver and LeeCole L. Legette, of the Department of Foods and Nutrition at Purdue University in Indiana

7. Cultural influences on assessing Menopausal Hot Flashes

Hot flashes continue to be a troublesome problem for menopausal women the world over. After 50 years of research, Kronenberg reports that the specific cause and mechanism of hot flashes is still not understood, or how estrogen, the major pharmaceutical treatment, works to reduce hot flashes. Insights into the social and cultural complexities that may affect how and whether women report hot flashes and becoming more sophisticated in research tools, such as questionnaires, physiological monitors and brain imaging techniques, may yield more information. New aspects of hot flash research, including neuroimaging and the study of genetic differences, when combined with increasingly nuanced ways of asking questions of culturally distinct populations, provide challenges but rich complexity from which a better understanding of menopausal hot flashes will emerge.

"Menopausal Hot Flashes: A Review of Physiology and Biosociocultural Perspective on Methods of Assessment," Fredi Kronenberg of the Clayman Institute for Gender Research at Stanford University

8. Equol Improves Menopausal Symptoms in Japanese Women

Aso reports on three studies exploring the possible therapeutic role of the SE5-OH containing Natural S-equol supplement in treating menopausal symptoms in Japanese women. The studies indicated that a daily dose of 10 mg of SE5-OH containing Natural S-equol improved menopausal symptoms. In a confirmation study, menopausal women who were not equol producers who consumed 10 mg daily of the supplement for 12 weeks had significantly reduced severity and frequency of their hot flashes as well as a significant reduction in the severity of their neck or shoulder stiffness. The equol-ingesting group also showed trends of improvement in sweating and irritability. SE5-OH containing Natural S-equol appears to have a promising role as an alternative remedy in the management of women's menopausal symptoms.

"Equol Improves Menopausal Symptoms in Japanese Women," Takeshi Aso, M.D., Ph.D., Professor Emeritus at the Tokyo Medical and Dental University in Japan.

9. Research Needs for Equol, Soy, and Menopause Research

Barnes reported that research opportunities now exist to determine whether the effects of equol on menopausal symptoms, such as hot flashes, sleep disturbances, bone health, in equol producers can be extended to equol non-producers via supplements. It is recommended that future research be designed to avoid complications from differences of social culture, lifetime exposure to soy products, experimental techniques and other variables.

"Cautions and Research Needs Identified at the Equol, Soy, and Menopause Research Leadership Conference," Stephen Barnes, Ph.D., of the Department of Pharmacology and Toxicology, and Helen Kim, PhD, director of 2-D Proteomics Laboratory, both at the University of Alabama at Birmingham.

Making SE5-OH containing Natural S-equol

Saga Nutraceuticals Research Institute of Otsuka Pharmaceutical Co., Ltd. developed SE5-OH containing Natural S-equol, which is created under current Good Manufacturing Practices using the equol-producing lactic acid bacterial strain Lactococcus 20-92 in a proprietary fermentation process patented by the Otsuka Pharmaceutical Co., Ltd. This process converts daidzein to Natural S-equol, steadily increasing the concentration of Natural S-equol until reaching a maximum concentration at 72 to 96 hours and decreasing daidzein by 95 percent. Following fermentation, the SE5-OH ingredient undergoes a sterilization process using heat denaturation that deactivates the bacteria. The process is designed to produce a product rich in Natural S-equol that can be used as a nutraceutical ingredient. For more information on the research on Natural S-equol, please visit the website


About Pharmavite LLC: For almost 40 years, Pharmavite has earned and maintained the trust of healthcare professionals, consumers, and retailers by manufacturing high-quality vitamins, minerals, herbs and other dietary supplements that are safe, effective and science-based. Nature Made® is the number one selling dietary supplement brand in the food, drug, club and mass channels. The dietary supplement industry is regulated by the U.S. Food and Drug Administration and the Federal Trade Commission, as well as by government agencies in each of the 50 states.

About Otsuka Pharmaceutical Co., Ltd.: Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.

Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group comprises 145 companies and employs approximately 39,000 people in 23 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned ¥1,084.2 billion (approx. US $11.7 billion*) in annual revenues in fiscal 2009. Visit Otsuka Pharmaceutical Co., Ltd. at

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