EFFECTS OF COUMESTROL ON ESTROGEN-RECEPTOR FUNCTION AND UTERINE GROWTH IN OVARIECTOMIZED RATS

Isoflavonoids and related compounds such as coumestrol have classicall y been categorized as phytoestrogens because these environmentally der ived substances bind to the estrogen receptor (ER) and increase uterin e wet weight in immature rats and mice. Assessment of the binding affi nities of isoflavonoids for ER and subsequent effects on uterine growt h suggest these compounds are less active estrogens than estradiol and therefore may reduce the risk of developing breast or prostate cancer in humans by preventing estradiol binding to ER. With the renewed int erest in the relationships between environmental estrogens and cancer cause and prevention, we assessed the effects of the phytoestrogen cou mestrol on uterotropic response in the immature, ovariectomized rat. O ur studies demonstrated that in this animal model, coumestrol is an at ypical estrogen that does not stimulate uterine cellular hyperplasia. Although acute (subcutaneous injection) or chronic (multi-administrati on of coumestrol significantly increased uterine wet and dry weights, the phytoestrogen failed to increase uterine DNA content. The lack of true estrogenic activity was characterized by the inability of this ph ytoestrogen to cause cytosolic ER depletion, nuclear ER accumulation, or the stimulation of nuclear type II sites which characteristically p recede estrogenic stimulation. In fact, subcutaneous or oral coumestro l treatment caused an atypical threefold induction of cytosolic ER wit hout corresponding cytosolic depletion and nuclear accumulation of thi s receptor, and this increased the sensitivity of the uterus to subseq uent stimulation by estradiol. These results in the immature, ovariect omized rat contrast with studies of intact, immature animals and sugge st that ovarian estrogens may be a component in the estrogenic respons e to phytoestrogens such as coumestrol in intact animals. Consequently , the potential estrogenicity of phytoestrogens requires careful reass essment in impact of these environmentally derived substances on repro ductive function and cancer can be realized.