Estrogenicity of the Isoflavone Metabolite Equol on Reproductive and Non-Reproductive Organs in Mice1

Abstract

Equol, a metabolite of the phytoestrogen daidzein, is present at significant levels in some humans who consume soy and in rodents fed soy-based diets. Equol is estrogenic in vitro, but there have been limited studies of its activity in vivo. We evaluated equol effects on reproductive and non-reproductive endpoints in mice. Ovariectomized age-matched (30-day-old) female C57BL/6 mice were fed phytoestrogen-free diets and given a racemic mixture of equol by daily injections (0, 4, 8, 12, or 20 mg [kg body weight](-1) day(-1)) or in the diet (0, 500, or 1,000 ppm) for 12 days. Mice were killed, and serum concentrations of total and aglycone equol were measured. Total serum equol concentrations ranged from 1.4 to 7.5 microM with increasing doses of injected equol, but uterine weight increased significantly only at 12 and 20 mg (kg body weight)(-1) day(-1). Dietary equol at 500 or 1,000 ppm produced total serum equol concentrations of 5.9 and 8.1 microM, respectively, comparable with those in rodents consuming certain high-soy chows; the proportion of equol present as the free aglycone was much lower with dietary administration than injections, which may be a factor in the greater biological effects induced by injections. Dietary equol did not significantly increase uterine weight. Increasing dietary and injected equol doses caused a dose-dependent increase in vaginal epithelial thickness. Uterine epithelial proliferation was increased by equol injections at 8-20 mg (kg body weight)(-1) day(-1) and 1,000 ppm dietary equol. Neither dietary nor injected equol decreased thymic or adipose weights. In conclusion, equol is a weak estrogen with modest effects on endpoints regulated by estrogen receptor alpha when present at serum levels seen in rodents fed soy-based diets, but quantities present in humans may not be sufficient to induce estrogenic effects, although additive effects of equol with other phytoestrogens may occur.

Genistein, Estrogen Receptors, and the Acquired Immune Response

“…Previous reports using both in vitro (22) and in vivo (23) approaches suggested that daidzein may be immunostimulatory. In contrast, studies with equol did not report an effect on thymic weight with physiologic concentrations in vivo (24), suggesting that equol may not be capable of producing the thymolytic effects seen with genistein.…”

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

“…As an example equol, the microbial degradation products of the soy isoflavone daidzein formed in the gut (Setchell et al, 2002;Selvaraj et al, 2004), is abundantly produced in most animal models, whereas it appears to be produced in significant amounts only in subsets of humans (Birt et al, 2001). One of 6 men fed soy for several weeks was an equol producer, but 4 of 6 women fed soy for several weeks were equol producers (Lu et al, 1997).…”

Differential effects of formononetin and cladrin on osteoblast function, peak bone mass achievement and bioavailability in rats

“…These effects of daidzein are mediated via the estrogen receptors (ERs) [8]. Daidzein may also exhibit estrogenicity at the uterine level [9,10]. In addition to its direct effect, uterine estrogenicity of daidzein is partly contributed by its highly estrogenic metabolite, equol [10].…”

“…Daidzein may also exhibit estrogenicity at the uterine level [9,10]. In addition to its direct effect, uterine estrogenicity of daidzein is partly contributed by its highly estrogenic metabolite, equol [10]. Ten weeks of daily injection of daidzein at 16.6 mg kg −1 dose to growing ovariectomized (Ovx) rats exhibited significant bone forming effects [11].…”