Phytoestrogens and carcinogenesis - differential effects of genistein in experimental models of normal and malignant rat endometrium

The phytoestrogen genistein was studied in normal and malignant experimenta l uterine models in vivo. The action of genistein on the uterus and vagina of ovariectomized DA/Han rats after 3 day oral administration (25, 50 or 10 0 mg/kg/BW/d) was compared to ethinyl oestradiol (0.1 mg/kg/BW/d). Effects on uterine and vaginal morphology, uterine growth and uterine gene expressi on were studied. A dose dependent increase of the uterine wet weight and th e uterine and vaginal epithelial height, a dose dependent up-regulation of complement C3, down-regulation of clusterin mRNA expression and a stimulati on of the vaginal cornification was observed after administration of genist ein. Uterine gene expression and vaginal epithelium respond to genistein at doses where no significant effects on uterine wet weight were detectable. In general the vagina was more sensitive to genistein than the uterus. To a nalyse the action of genistein in malignant uterine tissue, the impact of a 28 d treatment with 50 mg/kg/d of genistein on the in-vivo tumour growth o f RUCA I endometrial adenocarcinoma cells, following subcutaneous inoculati on into syngeneic DA/Han rats, was assessed. In contrast to ethinyl oestrad iol (0.1 mg/kg/BW/d), a dose of 50 mg/kg/BW/d of genistein did not affect t umour growth. Nevertheless C3 and TRPM2 mRNA expression in the tumour were both significantly stimulated by ethinyl oestradiol and genistein. In compa rison to ovariectomized animals genistein up-regulated uterine wet weight a nd uterine dependent gene expression in tumour bearing animals. In conclusi on, four independent uterine and vaginal parameters indicate genistein is a weak oestrogen receptor agonist in the uterus and vagina of female DA/Han rats, and evidence is provided for a selective oestrogen receptor modulator (SERM)-like action of genistein in normal and malignant uterine tissue.