title: Coumestrol antagonizes neuroendocrine actions of estrogen via the estrogen receptor alpha.
abstract: 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 alpha knockout mice (ERalphaKO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ERalpha. Female wild-type (WT) and ERalphaKO mice were ovariectomized and treated with estradiol (E2), 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 WT females. In ERalphaKO mice, lower levels of PR were induced. The stimulatory effects of E2 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 E2 had low levels of LH, while LH was high in untreated females and even higher in ovariectomized females treated with coumestrol. ERalphaKO 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 ERalpha mediates these effects.
authors.affiliation: Department of Biology and Neuroscience Program, University of Virginia, Charlottesville 22904-4328, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Jacob
authors.forename: J L
authors.initials: JL
authors.lastname: Temple
authors.forename: H B
authors.initials: HB
authors.lastname: Patisaul
authors.forename: L J
authors.initials: LJ
authors.lastname: Young
authors.forename: E F
authors.initials: EF
authors.lastname: Rissman
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003375:Coumestrol / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D011980:Receptors, Progesterone / Q000032:analysis
chemical_list: D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D003375:Coumestrol