Safety Profile Grows for Natural S-Equol Supplement Designed To Manage Menopause Symptoms

New Study Supports Position That Soy-Based Natural S-Equol Does Not Increase Risk of Estrogen-Sensitive Breast Cancer

WASHINGTON, April 4, 2011 /PRNewswire/ -- A new study suggests there is no increased risk of estrogen-sensitive breast cancer from consuming the soy-based compound Natural S-equol, or SE5-OH, a dietary ingredient containing Natural S-equol. These new data, involving a widely used breast cancer mouse model, were reported at the Women's Congress 2011 annual meeting. Supplements containing SE5-OH have reduced menopause symptoms in postmenopausal women in previously reported controlled trials.

"As part of the rigorous clinical collaborative program of Pharmavite LLC and Otsuka Pharmaceutical Co., Ltd. to develop the SE5-OH supplement containing the soy-based compound Natural S-equol to manage menopausal symptoms, investigators have previously reported safety data among healthy postmenopausal women.  These new data enhance our understanding of the safety of Natural S-equol because they document that Natural S-equol itself as well as SE5-OH did not increase or stimulate the growth of mammary tumors in mice using a well known animal model," said Belinda H. Jenks, Ph.D., coauthor of the U.S. women's and safety studies and Director of Scientific Affairs & Nutrition Education at Pharmavite LLC.

S-equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a compound resulting -- when certain bacteria are present in the digestive tract -- from the natural metabolism, or conversion, of daidzein, an isoflavone found in whole soybeans. Not everyone can produce S-equol after soy consumption, as the production 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 S-equol. Research indicates that among Japanese women, those who produce equol have less severe menopausal symptoms.  Controlled clinical trials have documented that a supplement containing Natural S-equol reduces the frequency of moderate to severe hot flashes as well as muscle and joint pain of post-menopausal women, both in Japan and the United States.

S-equol binds to the same estrogen receptors as endogenous estrogen, but with a stronger affinity for the estrogen beta receptor. On binding to these receptors, S-equol mimics some, but not all, activities of endogenous estrogen. Because of these actions, it has been proposed that S-equol alleviates some of the symptoms caused by diminished estrogen production during menopause.

Breast Cancer Tumor Not Influenced by Natural S-equol

In the new study, mice with estrogen-dependent tumor cells that ate diets for 25 weeks containing Natural S-equol, SE5-OH or genistein, an isoflavone that occurs naturally in soy, showed no statistically significant difference in the tumor size compared with those that ate the typical laboratory diet.

For the study, investigators implanted 71 healthy female mice - from which the ovaries had been surgically removed - with pellets containing 2 milligrams (mg) of 17-beta estradiol, a form of estrogen and the main sex hormone in women.  One week later, the researchers injected the mice with MCF-7-E10, estrogen-dependent human breast cancer cells that express both alpha and beta estrogen receptors.  When the cells had grown to tumors that averaged 34 square millimeters (mm2) in size, the mice were placed into either a group that continued unaltered, as a control, or into one in which the estrogen pellets were removed.

The mice from which the pellets had been removed then received one of four diets for 25 weeks:  an isoflavone-free diet or diets to which genistein, SE5-OH or purified S-equol were added in amounts so that the resulting isoflavone content of each ingredient was either 250 or 500 parts-per-million (ppm). The researchers measured the tumor size and total body weight and food intake weekly in the study.

At 25 weeks, the tumor sizes did not significantly differ and averaged 61 mm2 in the control group, 96 and 79 mm2 in the genistein groups, 65 and 80 mm2 in the SE5-OH groups, and 62 and 56 mm2 in the S-equol groups, for the 250 or 500 ppm isoflavone levels respectively.  In comparison, at week 10, tumor size in the mice that kept the estradiol pellets grew to 269 +/- 23 mm2, which was the last tumor measurement for the positive control group.  

Previous Human Studies of Natural S-Equol Report Good Safety Profile

Previous studies reported a good safety profile.  There were no safety problems among healthy Japanese and U.S. women who took SE5-OH supplements daily containing Natural S-equol as part of controlled trials. Two of these trials were reported at the 2010 North American Menopause Society Annual Meeting (NAMS) and two were reported at the Women's Congress 2010 meeting.  Each of the studies was randomized and double-blinded.

Specifically, in the 12-week placebo-controlled safety study of Japanese women, whose daily SE5-OH supplement contained 30 mg Natural S-equol, investigators found no serious adverse events, and no changes in serum concentrations of five hormones:  estradiol, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), free triiodothyronine (T3), and free-thyroxine (T4).  Also, ultrasound measures of the lining of the uterus (endometrium) and cellular studies of the tissue lining the vagina revealed no changes.  In addition, mammography examination indicated no differences in among the women groups. This study was reported at NAMS 2010.

In agreement with the Japanese study, in an eight-week safety study of U.S. women, whose daily SE5-OH  supplement provided 10, 20 or 40 mg Natural S-equol, investigators found no differences in adverse effects among the three groups.  This study was reported at NAMS 2010.

In a 12-week placebo-controlled safety study of post-menopausal Japanese women, their hormones remained normal and did not differ between the 10 mg S-equol in SE5-OH and placebo groups, based on levels of estradiol, FSH, TSH, T3 and T4.  Moreover, the status of these hormones as well as of progesterone and luteinizing hormone (LH) remained normal and did not differ between the SE5-OH and placebo groups in a four-week placebo-controlled study of pre-menopausal Japanese women.  Also, in the post-menopausal women's study, the average thickness of the uterus' endometrium did not significantly differ between the two treatment groups. In the pre-menopausal women's study, the menstrual cycle length remained normal and did not significantly differ between the two treatment groups.  Both the pre- and post-menopausal studies were presented at the Women's Congress 2010 meeting.

How SE5-OH Ingredient is Made

The SE5-OH is the product of fermentation of whole soy germ by the bacterial strain Lactococcus 20-92 using a patented and proprietary process by the Otsuka Pharmaceutical Co., Ltd. The process results in the conversion of the daidzein to Natural S-equol. SE5-OH is created under current Good Manufacturing Practices.  Following fermentation, the bacteria undergo heat denaturation and are deactivated.  The process is designed to produce a Natural S-equol rich product, or nutraceutical ingredient.  The ingredient has self-affirmed GRAS (Generally Recognized As Safe) status.

Development and ongoing research of SE5-OH containing Natural S-equol is conducted by the Saga Nutraceuticals Research Institute of Otsuka Pharmaceutical Co., Ltd.  Pharmavite LLC, the makers of Nature Made® vitamins and minerals and a subsidiary of Otsuka, is studying SE5-OH containing Natural S-equol in supplement form for the management of menopausal symptoms.  

Otsuka Pharmaceutical Co. Ltd. supported the studies reported at the Women's Congress 2011, Women's Congress 2010 and NAMS 2010 meetings. Complete reports of data from the study will be submitted for peer-review publication.

Women's Congress 2011 Presentation

Saturday, April 2, 2011, Poster 95

Evaluation of S-equol on Estrogen Sensitive Tumor Growth in Ovariectomized Athymic Mice Implanted with MCF-7

Belinda Jenks, Ph.D., (Pharmavite LLC, Northridge, CA); Soh Iwashita, Ph.D., Tomomi Ueno, M.S., Atsuko Onoda, M.S., and Shigeto Uchiyama, M.S., (Otsuka Pharmaceutical Co, LTD, Saga, Japan); and Kiyoko Kato, Ph.D., M.D., and Norio Wake, Ph.D., M.D., (Department of Obstetrics and Gynecology at the Graduate School of Medical Sciences of Kyushu University, Fukuoka, Japan).

About Pharmavite LLC: For 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 yen (approx. US $11.7 billion*) in annual revenues in fiscal 2009. Visit Otsuka Pharmaceutical Co., Ltd. at http://www.otsuka.co.jp/en/

SOURCE Pharmavite LLC