Soy-based S-equol supplement reduces hot flash frequency, muscle & joint pain in US women

(Press-News.org) Northridge, Calif. (April 24, 2012) – A dose of 10 milligrams (mg) daily of S-equol delivered via a newly developed fermented soy germ-based nutritional supplement is as effective as a standard dose of soy isoflavones at reducing hot flash frequency significantly and is even more effective for relieving muscle and joint pain, according to a peer-reviewed study in US postmenopausal women published in the June Journal of Women's Health, available now as a Fast Track article online ahead of print.

"This study provides evidence that daily doses of the supplement S-equol, a metabolite of the soy isoflavone daidzein, reduced hot flash frequency and relieved muscle and joint pain in U.S. postmenopausal women. These findings confirm earlier studies in Japanese women documenting S-equol's ability to relieve menopausal symptoms," said Belinda H. Jenks, Ph.D., coauthor of the study and director of Scientific Affairs & Nutrition Education at Pharmavite LLC. Development and ongoing research of a supplement containing 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, is a subsidiary of Otsuka, which supported the study.

S-equol Supplement Reduces Menopausal Hot Flashes, Muscle and Joint Pain in U.S. Women Daily doses of the supplement containing 10, 20 or 40 mg of S-equol each reduced the frequency of moderate to severe hot flashes similarly to a 50 mg dose of a soy isoflavone supplement in a double-blinded randomized study involving 102 US postmenopausal women aged 45 to 65 who experienced more than 35 hot flashes weekly when they enrolled. The investigators used a standardized soy isoflavone supplement for comparison in the study because of the scientific consensus that extracts or concentrated soy isoflavones support relief of hot flashes in menopausal women, based on placebo-controlled studies.

The investigators observed, after eight weeks of treatment, significant reductions occurred from the study start in the women's average daily hot flashes, the study's primary endpoint. These reductions were comparable for all three S-equol treatment groups, 10, 20 or 40 mg, which ranged from decreases of 3.09 to 3.66 hot flashes daily, to that of the soy isoflavone group, which averaged decreases of 2.92. The average number of daily hot flashes in all of the participants at the study start was 10.0 ± 4.03.

Muscle and joint pain improved significantly for both the 10 and 20 mg doses of S-equol compared with the soy isoflavones (p=0.003 and p=0.005, respectively), based on scores from the Greene Climacteric Scale (GCS), which measures 21 symptoms using 0 to 3 scale, where 0 was 'not at all,' 1 was 'a little,' 2 was 'quite a bit' and 3 was 'extremely,' to produce scores.

"These U.S. data expand on the previous studies in Japanese women and further document that a minimum daily 10 mg dose of S-equol would likely help women by both reducing the frequency of their hot flashes as well as decreasing their muscle and joint pain associated with menopause," said Jenks.

Further, for women who had more than eight hot flashes daily at the study start, both 20 and 40 mg S-equol were significantly better than the soy isoflavones in reducing hot flash frequency (p=0.045 and p=0.001, respectively), while the 10 mg S-equol dose had a strong positive trend (p=0.063), according to a sub-group analysis. This finding suggests that the S-equol supplement might be more useful for the women who have a higher frequency of hot flashes, Jenks said.

Also, more women in the 10, 20 and 40 mg S-equol groups achieved a reduction of 50 percent or more in their hot flash frequency by the study end than in the soy isoflavone group: respectively, 25.0, 27.3, 42.9 (P=0.056) and 16.0 percent.

No significant differences occurred between any of the S-equol groups and the soy isoflavone group for two secondary endpoints: the hot flash severity and the psychological (anxiety, depression), somatic (physical), vasomotor GCS subscales. Throughout the eight-week intervention, the women maintained a daily diary to record the frequency and severity of their hot flashes, rating them as mild (sensation of heat without sweating), moderate (sensation of heat with sweating, able to continue activity) or severe (sensation of heat with sweating, causing cessation of activity).

No trends or clinically meaningful changes were identified in the women's laboratory blood or urine tests, hormone levels, electrocardiographs, physical examinations or vital signs. The trial investigators noted treatment-emergent adverse effects in participants of all the treatment groups. Such effects occurring in more than 10 percent of any S-equol group included abdominal distention (eight women) and endometrial hypertrophy (three women), the thickening of the lining of the uterus. The endometrial hypertrophy was identified by transvaginal ultrasounds and was assessed by the Medical Monitor; any changes observed were not considered to be clinically significant.

Of note, Jenks explained, endometrial hypertrophy developed in three women in the 10 mg S-equol group but only one and none in the 20 mg and 40 mg S-equol groups, respectively, which suggest that S-equol does not affect endometrial hypertrophy. Moreover, gastrointestinal disorders in the seven women in both 10 mg and 20 mg S-equol groups as well as the one in the 40 mg S-equol and two in the isoflavone groups, may have resulted from the naturally occurring dietary fiber in the fermented soy germ-based nutritional supplement containing S-equol and from the lactose in the placebo tablets used to match the total number of tablets in each group.

At enrollment, the women had not experienced a menstrual period in the previous 12 months and their levels of follicle stimulating hormone (FSH) were 40 or more milli international units/milliliter, a marker of menopause. The women were in good health. Investigators did not enroll anyone with a history of breast, ovarian or uterine cancer or endometrial hyperplasia, with a body mass index of 33 kg/m2 or more or who had used hormone replacement therapy within 90 days of the study or soy, phytoestrogens or certain other supplements within 30 days of the study, as well as fitting certain other exclusion criteria.

Investigators randomized the 102 women into four groups to consume twice daily either the isoflavone (26 women) or one of the three doses of the S-equol supplement (24 in the 10 mg, 27 in the 20 mg and 25 in the 40 mg groups). The lowest dose of S-equol used, 10 mg, was based on preliminary studies that investigated the relationship between S-equol and menopausal symptoms including hot flashes in Japanese women, while the higher doses were used to reflect the larger body mass in Western women and to establish a dose response. The S-equol supplement tablets each contained 5.0 mg S-equol, 1.0 mg daidzein, 1.1 mg genistein, and 2.5 mg glycitein. The soy isoflavone tablets contained 24 mg daidzein, 22 mg genistein, and 2.0 mg glycitein as aglycone equivalent. The placebo tablets contained lactose.

The women had diets controlled for soy foods, isoflavones and lignans, compounds found in certain plants that are known as phytoestrogens because of their estrogen-like properties. The study included a seven-day period before the treatment weeks to allow for elimination of any women who responded to a placebo. Women also were tested to determine their ability to produce S-equol after eating soy. The study included 72 percent equol nonproducers and 28 percent equol producers, which represents the previously reported US equol producer ratio. The investigators randomized the equol producers equally into each of the study's treatment groups.

No previous studies have reported the effects of either soy isoflavones or S-equol on muscle and joint pain. Recent studies conducted with Japanese postmenopausal women documented that measures of neck or shoulder muscle stiffness improved with daily consumption of 10 mg S-equol supplements, compared to a placebo, as well as reduced the frequency of hot flashes. While muscle stiffness and muscle pain can result from impaired local blood flow and both soy isoflavones and S-equol are thought to affect blood flow, this new study suggests that S-equol may potentially be more effective than isoflavones, Jenks explained.

About S-equol 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. Evidence from observational studies is emerging that suggests that women have milder menopausal symptoms in those who are S-equol producers compared to nonproducers.

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

The safety of the supplement containing S-equol previously was confirmed by standard animal testing, including a study documenting that S-equol itself, as well as the supplement containing S-equol, did not increase or stimulate the growth of breast cancer cells. Studies involving postmenopausal women who consumed the supplement containing S-equol have not observed any safety problems, including analysis of breast and reproductive tissues and of hormone levels. More information about S-equol and the supplement is at http://www.naturalequol.com.

How the S-equol Supplement is Made The supplement 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 S-equol. The S-equol ingredient is created under current Good Manufacturing Practices. Following fermentation, the bacteria undergo heat denaturation and are deactivated. The process is designed to produce a S-equol rich product, or nutraceutical ingredient. The ingredient has self-affirmed GRAS (Generally Recognized As Safe) status.

### The study data were presented in a late-breaking session at presentation at the North American Menopause Society annual meeting in October 2010.

Journal of Women's Health, Online Ahead of Print: March 12, 2012 doi:10.1089 A Pilot Study on The Effects of S-equol Compared to Soy Isoflavones on Menopausal Hot Flash Frequency and Other Menopausal Symptoms Belinda H. Jenks, Ph.D., and Soh Iwashita, Ph.D., of Pharmavite LLC; Yasushi Nakagawa, M.S., Karen Ragland, M.S., Jennifer Lee, Ph.D., and William H. Carson, M.D., of Otsuka Pharmaceutical Development & Commercialization, Inc.; and Tomomi Ueno, M.S., and Shigeto Uchiyama, M.S., of Saga Nutraceuticals Research Institute, Otsuka Pharmaceutical Co., Ltd.

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 has business operations in 23 countries and regions around the world, with consolidated sales of 1,090.2 billion Yen for fiscal year 2010. Visit Otsuka Pharmaceutical Co., Ltd. at http://www.otsuka.co.jp/en/