Soy isoflavone supplements antagonize reproductive behavior and estrogen receptor alpha- and beta-dependent gene expression in the brain.

Epidemiological evidence suggests that isoflavone phytoestrogens may reduce the risk of cancer, osteoporosis, and heart disease, effects at least partially mediated by estrogen receptors alpha and beta (ERalpha and ERbeta). Because isoflavone dietary supplements are becoming increasingly popular and are frequently advertised as natural alternatives to estrogen replacement therapy, we have examined the effects of one of these supplements on estrogen-dependent behavior and ERalpha- and ERbeta-dependent gene expression in the brain. In the adult female rat brain, 17beta-estradiol treatment decreased ERbeta messenger RNA signal in the paraventricular nucleus by 41%, but supplement treatment resulted in a 27% increase. The regulation of ERbeta in the paraventricular nucleus is probably via an ERbeta-dependent mechanism. Similarly, in the ventromedial nucleus of the hypothalamus, supplement treatment diminished the estrogen-dependent up-regulation of oxytocin receptor by 10.5%. The regulation of oxytocin receptor expression in the ventromedial nucleus of the hypothalamus is via an ERalpha-dependent mechanism. Supplement treatment also resulted in a significant decrease in receptive behavior in estrogen- and progesterone-primed females. The observed disruption of sexual receptivity by the isoflavone supplement is probably due to antiestrogenic effects observed in the brain. These results suggest that isoflavone phytoestrogens are antiestrogenic on both ERalpha- and ERbeta-dependent gene expression in the brain and estrogen-dependent behavior.