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ORIGINAL ARTICLE

Coumestrol Antagonizes Neuroendocrine Actions of Estrogen via the Estrogen Receptor

Dena A. Jacob^2,*, Jennifer L. Temple^*, Heather B. Patisaul, Larry J. Young and Emilie F. Rissman^1,*

^* Department of Biology and Neuroscience Program, University of Virginia, Charlottesville, Virginia 22904–4328;
Center for Behavioral Neuroscience, Emory University, Atlanta, Georgia 30329

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 knockout mice (ERKO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ER. Female wild-type (WT) and ERKO 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 ERKO 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. ERKO 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 mediates these effects.

Key Words: phytoestrogen • progesterone receptor • luteinizing hormone • nutrition • estrogen receptor ß

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