"These data from U.S. women expand our knowledge about and corroborate previous research in Japanese women about the benefit of a supplement containing the soy-based compound Natural S-equol to manage menopausal symptoms, including reducing the frequency of hot flashes and muscle discomfort. This and the other Natural S-equol studies are part of the rigorous clinical collaborative program of Pharmavite LLC and Otsuka Pharmaceutical Co., Ltd. to develop a supplement containing Natural S-equol," said Belinda H. Jenks, Ph.D., coauthor of the US 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 Japanese women have milder menopausal symptoms in those who are S-equol producers compared to nonproducers.
S-equol selectively binds to the receptors for the naturally occurring female sex hormone estrogen, with a strong affinity to the estrogen receptor beta. On binding to these receptors, S-equol mimics some, but not all, activities of natural 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.
Natural S-equol Supplement Reduces Menopausal Hot Flashes in U.S. Women
In the double-blinded study of 102 US postmenopausal women, eight weeks of daily SE5-OH supplement doses containing 10, 20 or 40 milligrams (mg) of Natural S-equol reduced the frequency of moderate to severe hot flashes as did 50 mg doses of a soy isoflavone supplement. Because isoflavones are known to have mild effects on the reduction of hot flashes in menopausal women, the investigators used an isoflavone supplement as a comparator in the study.
More women in the 10, 20 and 40 mg Natural S-equol groups achieved a 50 percent or more reduction in their hot flash frequency, a primary endpoint of the study, than in the isoflavone group: respectively, 42.9 (P=0.056), 27.3, 25.0 and 16.0 percent. To enroll in the study, all of the women had to experience more than 35 hot flashes per week.
The 20 mg Natural S-equol dose neared statistical superiority (P=0.076), the 10 mg dose was similar (P=0.503) and the 40 mg dose was significantly more effective than the soy isoflavones in reducing hot flash frequency (P=0.021), according to a Mixed-Effect Model Repeated Measure analysis incorporating the eight weekly reports of women's hot flash frequency, a secondary endpoint of the study.
Moreover, muscle and joint pain was reduced significantly in the 10 and 20 mg Natural S-equol groups compared to those in the isoflavone group (P< 0.05). Investigators used the validated Greene Climacteric Scale that measures 20 symptoms to produce three symptom measures: psychological, somatic (physical) and vasomotor.
"Together these data document that a minimum daily dose of 10 mg Natural S-equol would provide the benefit of both reducing the frequency of moderate to severe hot flashes as well as decreasing muscle and joint pain associated with menopause," explained Jenks.
The trial also noted treatment-emergent adverse effects in participants of all the treatment groups. Such effects occurring in more than 5 percent of each group included abdominal distention, constipation and endometrial hypertrophy, the thickening of the lining of the uterus. The endometrial hypertrophy was identified by transvaginal ultrasounds and assessed by the Medical Monitor, and any changes observed were not considered to be clinically significant. No trends or clinically meaningful changes were identified in laboratory blood or urine tests, electrocardiographs, physical examinations or vital signs among the participants.
The trial enrolled women aged 45 to 65 years, who had levels of follicle stimulating hormone (FSH) of 40 or more milli international units/microliter, a marker of menopause. Investigators randomized the women into four groups to receive either the isoflavone (26 women) or one of the three doses of the Natural S-equol supplement (24 in the 10 mg, 27 in the 20 mg and 25 in the 40 mg groups), in the form of daily tablets taken with breakfast and dinner meals for 12 weeks. The women had diets controlled for soy foods, isoflavone and lignans, compounds found in certain plants that are known as phytoestrogens because of their estrogen-like properties. The study included a 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 70 percent equol nonproducers and 30 percent equol producers.
Natural S-equol Inhibits Bone Break Down, Prevents Bone Mineral Density Loss
This study is the first to document evidence that daily doses of SE5-OH supplements containing 10 mg of Natural S-equol given for 12 months significantly inhibited bone break down, or resorption, in postmenopausal women. Moreover, treatment with the 10 mg Natural S-equol dose significantly prevented a decrease in whole body bone mineral density (BMD), compared to placebo.
"These findings raise the possibility that 10 mg daily of Natural S-equol supplementation may contribute to bone health without adverse effects in postmenopausal women who can not make S-equol themselves after eating soy. Further research is needed to determine the effects of S-equol on bone metabolism and safety," explains Jenks.
In this one-year, double-blind, placebo-controlled study, investigators randomized 93 Japanese women to receive a placebo or one of three daily doses of SE5-OH containing Natural S-equol: 2, 6 or 10 mg. Women studied were equol nonproducers, and averaged 53.8 ± 3.7 years old and 2.7 ± 1.2 years since menopause. After 12 months, women receiving the 10 mg dose of Natural S-equol had a significantly decreased, by 23.9 percent, the amount of urinary deoxypyridinoline (DPD) for 24 hours, a validated marker for bone resorption, compared to a reduction of just 2.9 percent in the placebo group (P=0.020).
In addition, the whole body BMD in the 10 mg group declined by 1.1 percent, significantly less than the 1.9 percent decrease of the placebo group (P=0.027) at 12 months. Serum sex and thyroid hormone concentrations did not differ among four groups at the study end.
Safety Data from 12-Week Study of Natural S-equol Use in Japanese Women
Investigators identified no safety problems, particularly in the female reproductive system, among 101 healthy Japanese postmenopausal women who took daily SE5-OH supplement doses containing 30 mg Natural S-equol for 12 weeks as part of a randomized, placebo-controlled study.
The investigators found no serious adverse events, and no abnormal changes in serum concentrations of five hormones measured at the study start and weeks four, eight and 12 of the study: estradiol, follicle stimulating hormone, thyroid-stimulating hormone, free triiodothyronine (T3), and free-thyroxine (T4). Also, ultrasound measures of the thickness of the endometrial lining of the uterus and cellular studies of the tissue lining the vagina revealed no biological effect of the supplement on the women's reproductive organs. Furthermore, mammography examination results documented no differences among the women groups or between the study start and end.
The study participants were 101 healthy postmenopausal women aged 45 to 65 years who experienced the onset of menopause within the past five years prior to enrollment. None of them were S-equol producers and they were randomized to receive either 10 mg or 30 mg daily doses of Natural S-equol or a placebo.
How SE5-OH is Made
All three studies presented at NAMS used supplement tablets that contained Natural S-equol. 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 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 all four studies. Complete reports of data from each study will be submitted for peer-review publication.
NAMS Poster Session
Thursday, Oct. 7, 2010 5:15 PM CDT (6:15 EDT)
Poster P-22 Efficacy and safety of natural S-equol supplement in US postmenopausal women
Belinda H. Jenks of Scientific Affairs, Pharmavite LLC, Northridge, CA; Shigeto Uchiyama of Saga Nutraceuticals Research Institute, Otsuka Pharmaceutical Co, Ltd., Japan; Soh Iwashita of Scientific Affairs, Pharmavite LLC, Northridge, CA; and Yasushi Nakagawa, Jennifer Lee, Dusan Kostic and Karen Ragland of Otsuka Pharmaceutical Development & Commercialization, Inc. United States.
Japan safety assessments of natural S-equol supplement by consecutive ingestion to postmenopausal Japanese women.
Ayuko Oyama and Tomomi Ueno of Saga Nutraceuticals Research Institute, Otsuka Pharmaceutical Co., Ltd; Belinda H. Jenks of Scientific Affairs, Pharmavite LLC, Northridge, CA, United States; and Takeshi Aso of Obstetrics and Gynecology, Tokyo Medical and Dental University, Tokyo, Japan.
Effect of natural S-equol on bone metabolism in equol non-producing postmenopausal Japanese women: a pilot randomized placebo-controlled trial.
Tomomi Ueno, Yasuhiro Fujii, and Shigeto Uchiyama of Saga Nutraceutricals Research Institute, Otsuka Pharmaceutical Co., Ltd.; Yuko Tousen and Junko Ezaki of Department of Nutrition, Chiba Prefectural University of Health Sciences, Chiba, Japan; Mamoru Nishimuta of Food Function and Labeling Program, National Institute of Health and Nutrition, Tokyo; and Yoshiko Ishimi of Nutritional Epidemiology Program, National Institute of Health and Nutrition, Tokyo.