Isoflavone Research Initiative

The most recent findings on soy and isoflavones were presented in Washington DC on the occasion of the 9^th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment (October 16-19, 2010). A major part of the topics was dedicated to safety and health benefits in menopausal women, and to the issue of soy and breast cancer.

Dr. Belinda Jenks (Pharmavite, USA) gave an overview over the preclinical and clinical safety studies performed with S-equol (Jenks 2010). An S-equol product (SE5-OH) obtained through fermentation of soy germ rich in daidzein with an equol-producing Lactobacillus strain has been developed for the application in menopausal women. SE5-OH contains approximately 0.65 % equol, 0.024 % daidzein, 0.022 % genistein, and 0.30 % glycitein.

The pharmacokinetic properties have been tested in healthy postmenopausal women with doses of 10 and 30 mg. S-equol is rapidly absorbed after oral administration and attains high plasma concentrations, with a plasma elimination half-life of 8 h. The systemic bioavailability of S-(-)equol was very high, reaching 82% for both doses, which is greater than published data for the soy isoflavones daidzein and genistein. Equol-producer status had no effect on S-(-)equol pharmacokinetics (Setchell et al. 2009).

SE5-OH is practically non-toxic in rats, with an oral LD₅₀ > 4,000 mg/kg. In a 91-day subchronic toxicity study, the no-observed-adverse-effect-level (NOAEL) was determined with 2,000 mg/kg/day, the highest dose tested. The product was non-genotoxic in in vitro-tests on genotoxicity with and without metabolic activation, in the chromosome aberration test in Chinese hamster lung cells, and in the micronucleus test in rats fed with quantities of up to 4,000 mg/kg twice daily for two consecutive days (Yee et al. 2008).

The reproductive and developmental toxicity of SE5-OH has been evaluated in a two-generation study and a developmental toxicity study with Sprague-Dawley rats at dose levels of 200, 1000, and 2000 mg/kg/day by gavage. From the reproductive study, the NOAEL for SE5-OH determined for both male and female rats is 1000 mg/kg/day (6.5 mg equol/kg/day). In the developmental toxicity phase of the study, no effects by SE5-OH were found in the embryo or foetus at any of the doses tested. The NOAEL for developmental effects of SE5-OH is 2000 mg/kg/day (13 mg equol/kg/day) (Matulka et al. 2009).

Pre-clinical studies in primates confirmed the safety regarding safety at the breast. Whereas estradiol was shown to induce breast epithelial proliferation, the isoflavones did not have this effect. “Postmenopausal” ovariectomized monkeys received either a control diet or a diet with 509 mg/day of the soy isoflavones genistein and daidzein, or with 1020 mg/day of racemic equol for 1 month. Uterine weight, endometrial thickness, glandular area, and epithelial proliferation in the uterus were not significantly different among treatment groups. Within the mammary gland, proliferation and indicators of estrogen exposure did not differ among treatment groups. It was concluded that high doses of dietary soy isoflavones have minimal uterotrophic or mammotrophic effects in an established primate model (Wood et al. 2006).

In a second 8-month primate study Wood et al. evaluated mammary epithelial proliferation and proliferative lesions in a group of 63 aged postmenopausal macaques randomized to receive either a control diet or a diet with estradiol at the human equivalent dose of 1.0 mg per day, or a diet with equol at the human equivalent dose of 105 mg per day. In normal mammary epithelium, treatment with estradiol but not with equol resulted in greater proliferation, epithelial area, and progesterone receptor expression (p < 0.05 for all) (Wood et al. 2008).

SE5-OH has also been tested for safety and effects in supplementation studies in women. In a first 4-week-trial 10 mg were tested versus placebo in a total of 36 premenopausal women (n = 18 per group). The isoflavone-product had no effect on the menstrual cycle and on serum estradiol and progesterone. In a second study in Japanese women doses of 10 and 30 mg per day were tested over the period of 12 weeks, and in a third study the same dose was applied to Japanese men, again for 12 weeks. In both cases there was no change in hormonal levels including thyroidal hormones. With the 30 mg dose there was a trend towards increased testosterone levels, but the values remained within the normal limits.

Based on these studies, the isoflavone-containing supplement must be regarded as safe – there is no indication that it might increase breast cancer risk through “phyto-estrogenic” effects.

References

Jenks BH (2010). Safety assessment of natural S-Equol. 9^th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment, Washington DC, 16-19 October.

Matulka RA, Matsuura I, Uesugi T, Ueno T and Burdock G (2009). Developmental and Reproductive Effects of SE5-OH: An Equol-Rich Soy-Based Ingredient. J Toxicol 2009:307618.

Setchell KD, Zhao X, Shoaf SE and Ragland K (2009). The pharmacokinetics of S-(-)equol administered as SE5-OH tablets to healthy postmenopausal women. J Nutr 139(11):2037-2043.

Wood CE, Appt SE, Clarkson TB, Franke AA, Lees CJ, Doerge DR and Cline JM (2006). Effects of high-dose soy isoflavones and equol on reproductive tissues in female cynomolgus monkeys. Biol Reprod 75(3):477-486.

Wood CE, Hester JM, Appt SE, Geisinger KR and Cline JM (2008). Estrogen effects on epithelial proliferation and benign proliferative lesions in the postmenopausal primate mammary gland. Lab Invest 88(9):938-948.

Yee S, Burdock GA, Kurata Y, Enomoto Y, Narumi K, Hamada S, Itoh T, Shimomura Y and Ueno T (2008). Acute and subchronic toxicity and genotoxicity of SE5-OH, an equol-rich product produced by Lactococcus garvieae. Food Chem Toxicol 46(8):2713-2720.