Coumestrol antagonizes neuroendocrine actions of estrogen via the estrogen receptor α

The phytoestrogen coumestrol has estrogenic actions on peripheral reproductive tissues. Yet in the brain this compound has both estrogenic and anti-estrogenic effects. We used estrogen receptor a knockout mice (ER alpha KO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ER alpha. Female wild-type (WT) and ERaKO mice were ovariectomized and treated with estradiol (E-2), dietary coumestrol, both, or neither compound. Ten days later the animals were sacrificed, blood was collected, and brain tissues were perfused, Fixed brains were sectioned and immunocytochemistry was employed to quantify progesterone receptors (PR) in the medial preoptic (POA) and ventromedial nucleus of the hypothalamus (VMN). Plasma was assayed for luteinizing hormone (LH), Estrogen treatment induced PR immunoreactivity in both regions in brains of WS females, In ER alpha KO mice, lower levels of PR were induced, The stimulatory effects of E-2 on PR were attenuated in the POA by cotreatment with coumestrol, and the same trend was noted in the VMN, WT ovariectomized females treated with E-2 had low levels of LH, while LH was high in untreated females and even higher in ovariectomized females treated with coumestrol, ER alpha KO females in all treatment groups had high levels of LH, Taken together, the results show that coumestrol has anti-estrogenic actions in the brain and pituitary and that ER alpha mediates these effects.