Coumestrol antagonizes neuroendocrine actions of estrogen via the estrogenreceptor alpha

The phytoestrogen coumestrol has estrogenic actions on peripheral reproduct ive tissues. Yet in the brain this compound has both estrogenic and anti-es trogenic effects. We used estrogen receptor a knockout mice (ER alpha KO) t o determine whether coumestrol has estrogenic actions in mice and also if t hese effects are mediated by the classic ER alpha. Female wild-type (WT) an d ERaKO mice were ovariectomized and treated with estradiol (E-2), dietary coumestrol, both, or neither compound. Ten days later the animals were sacr ificed, blood was collected, and brain tissues were perfused, Fixed brains were sectioned and immunocytochemistry was employed to quantify progesteron e receptors (PR) in the medial preoptic (POA) and ventromedial nucleus of t he hypothalamus (VMN). Plasma was assayed for luteinizing hormone (LH), Est rogen treatment induced PR immunoreactivity in both regions in brains of WS females, In ER alpha KO mice, lower levels of PR were induced, The stimula tory effects of E-2 on PR were attenuated in the POA by cotreatment with co umestrol, and the same trend was noted in the VMN, WT ovariectomized female s treated with E-2 had low levels of LH, while LH was high in untreated fem ales and even higher in ovariectomized females treated with coumestrol, ER alpha KO females in all treatment groups had high levels of LH, Taken toget her, the results show that coumestrol has anti-estrogenic actions in the br ain and pituitary and that ER alpha mediates these effects.