Support for Safety of Novel Soy Germ-Based Dietary Supplement

Pharmavite LLC, the makers of NatureMade vitamins and minerals and a subsidiary of Otsuka Pharmaceutical Co., Ltd., is studying in clinical trials SE5-OH containing Natural S-equol in supplement form for the management of menopausal symptoms.

2 Apr 2010 --- Healthy pre-and post-menopausal Japanese women who took a supplement of SE5-OH containing Natural S-equol, a novel soy germ-based ingredient under development for the management of menopausal symptoms, had measures of reproductive hormones that stayed within normal limits throughout the study. These peer-reviewed safety data were presented at the American Medical Women's Association (AMWA) 2010 annual meeting. A second safety study presented at AMWA documented that SE5-OH containing Natural S-equol consumption did not change the length of menstrual cycles in healthy pre-menopausal Japanese women. An earlier peer-review study in postmenopausal Japanese women documented that those receiving SE5-OH containing Natural S-equol reduced the frequency of hot flashes significantly compared to the women in the same study receiving a placebo (p=0.0092).

"SE5-OH containing Natural S-equol may be an appropriate dietary supplement ingredient for women undergoing menopause, as it has recently been studied in clinical trials for its benefits for relief of hot flushes in U.S. and Japanese women. The new safety data documents that in healthy women SE5-OH containing Natural S-equol does not appear to influence the normal concentrations of endocrine hormones, the normal endometrium thickness or normal menstrual cycle length and appears to be well tolerated," said Belinda H. Jenks, Ph.D., director of Scientific Affairs & Nutrition Education at Pharmavite LLC, and an author of the study.

Pharmavite LLC, the makers of NatureMade vitamins and minerals and a subsidiary of Otsuka Pharmaceutical Co., Ltd., is studying in clinical trials SE5-OH containing Natural S-equol in supplement form for the management of menopausal symptoms. Saga Nutraceuticals Research Institute of Otsuka Pharmaceutical Co., Ltd. developed the ingredient and has an ongoing research program to study SE5-OH containing Natural S-equol. Otsuka Pharmaceutical Co., Ltd., supported the research and data presented at AMWA, and complete reports of the data from both safety studies will be submitted for peer-review publication.

Soybeans contain a naturally occurring compound called daidzein that certain bacteria living within the human digestive tract can metabolize, or convert, into S-equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman]. 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 equol. Studies in Japan have documented an association between milder menopausal symptoms in equol producers as compared to non-producers.

In a study of the 54 post-menopausal Japanese women, the hormone status remained normal and did not differ between the 27 women in the Natural S-Equol group and 27 women in the placebo group, based on measures of their levels of estradiol, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), FreeT3 (a form of triiodothyronine) and FreeT4 (a form of thyroxine).

Moreover, the status of these hormones as well as of progesterone, luteinizing hormone (LH) and testosterone remained normal and did not differ between the Natural S-Equol group and the placebo group in a second study of 36 pre-menopausal Japanese women. In this study, the women's hormone status was measured during three specific menstrual cycle phases, the early follicular phase, the late follicular phase and the middle luteal phase, over the course of three cycles.

Both studies used a randomized, double-blind, placebo-controlled, parallel-group design. Both studies used the same formulation of SE5-OH containing Natural S-equol tablets and placebos.

In the post-menopausal women's study, the average thickness of the uterus' inner tissue lining, the endometrium, did not significantly differ between those women receiving a placebo or SE5-OH containing Natural S-equol.

As a normal part of the menstrual cycle, the hormone estrogen exerts influence to prompt the growth and thickening of the endometrium, to help create a receptive environment for a fertilized egg. When the ovary releases an unfertilized egg, it also produces the hormone progesterone. Progesterone also influences the endometrium to prepare for pregnancy. However, if fertilization does not occur, the progesterone level drops and the endometrium is shed from the uterus, a process called menstruation. The cycle repeats about every 28 days until menopause, when menstruation ceases.

In the pre-menopausal women's study, the menstrual cycle length remained normal and did not significantly differ between the groups of women receiving SE5-OH containing Natural S-equol or placebo, based on the average duration of their cycles in the four weeks before treatment, the four weeks during treatment and the four weeks after treatment.

In each of the two studies, the women in the placebo group did not differ from the women in the group receiving SE5-OH with Natural S-equol group in their reports of adverse effects, which included were diarrhea and feelings of fullness.

During the 12-week pre-menopausal study, the 18 women in the treatment group took Natural S-equol for four weeks, weeks 5 through 8 of the study. The 36 women, aged 20 to 38, had normal and regular menstrual cycles prior to enrollment. The women did not significantly differ in their menstrual cycle length prior to the study (p=0.59) or body mass (p=0.193), but did in age, averaging 30 in the placebo group and 24 in the SE5-OH group (p=0.024). Seven of the placebo group and five of the SE5-OH group were documented as equol producers (p=0.725), based on their equol levels after a soymilk challenge. This standard test for equol production in humans includes a three-day soy milk challenge followed by measures of urinary equol concentration on day four of the test. The women also were not taking any antibiotics.

During the 12-week post-menopausal study, the 27 women in the treatment group took Natural S-equol. The 54 women, aged 44 to 64, had reached menopause an average of five years prior to enrollment. None of the women naturally produced equol. The two treatment groups did not differ by average age or body mass index.

"These studies demonstrated that SE5-OH containing Natural S-equol is safe as measured and well tolerated in post-menopausal women fed the supplement for 12 weeks and in pre-menopausal women fed the supplement for one month. These studies were designed to better understand the impact and safety of SE5-OH with Natural S-equol in these two populations of women, and the findings indicate that there are no short-term safety concern based on the measures included in the study of certain hormone levels, endometrium thickness and menstrual cycle durations. These studies were conducted in preparation for the development of a women's health supplement designed to provide benefits for the management of menopausal symptoms. Further studies are needed to confirm whether or not fermented soy food containing Natural S-equol has influence when consumed for longer time periods or at higher doses," Jenks said.

SE5-OH for both studies was created under current Good Manufacturing Practices using the Lactic acid bacterial strain Lactococcus garvieae 20-92 in a patented and proprietary process by the Otsuka Pharmaceutical Co., Ltd. The patented fermentation process converts daidzein, a naturally occurring compound in soy germ, 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 powder 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.