Phytoestrogens are known for their agonistic/antagonistic properties on the estrogen receptors (ER). The most extensively studied soy isoflavone Genistein (GEN) apparently mediates its estrogenic effects mainly via the ER subtype beta (ERβ). We studied GEN in vivo in comparison to two ER agonists (Schering AG) 8β-VE2 (ERβ-selective) and 16α-LE2 (ERα-selective). Uterine wet weights as well as changes in uterine gene expression were investigated. After hormonal decline ovariectomized Wistar rats were treated s.c. for 21 days in doses of 10mg/kg BW for GEN, 10µg/kg BW for 16α-LE2 and 100µg/kg BW for 8β-VE2. Estradiol (E2) at 4µg/kg BW was used as positive control and castor oil as carrier control. In contrast to control, E2 and the 16α-LE2 treatment lead to an increase of the uterine wet weight, while GEN and the 8β-VE2 exhibited only mild effects. Interestingly, GEN showed a different regulation pattern for the expression for the two ERs. The expression pattern of ERα in response to GEN and 8β-VE2 were similar. While GEN up-regulated ERα expression a strong down-regulation was apparent in response to 16α-LE2. The expression of the ERβ instead was up-regulated by GEN and 16α-LE2 in the same way. GEN did not significantly affect the expression of the proliferation marker PCNA, while 16α-LE2 increased the PCNA mRNA level. The complement C3 expression level was up-regulated by all tested substances, but most pronounced by E2 and 16α-LE2. In conclusion, treatment with GEN or the agonists 8β-VE2 and 16α-LE2 for 21 days resulted in distinct effects for either substance. The known in vitro preference of GEN for ERβ fits with both the observed effects on uterine wet weight and on uterine gene expression. Particularly interesting are the effects on the expression levels of the ERs. These results support the hypothesis of GEN being an interesting candidate molecule for future investigations and as a potentially natural occurring selective estrogen receptor modulator.
