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The present study was designed to investigate the dose-response of clomiphene on several estrogenic responses in the immature rat uterus and to compare it to available data on estradiol-17 beta. A dissociation was demonstrated among the different estrogenic responses induced by clomiphene. Very high doses of clomiphene were needed to induce the 6-h uterine eosinophilia and deep endometrial edema, and maximal response levels were not reached at any dose studied. On the contrary, many genomic responses were induced with much lower doses of clomiphene, and maximal response levels were reached with at least the two highest doses of clomiphene. This dissociation is in agreement with the existence of separate groups of responses that are mediated by multiple and independent mechanisms of estrogen action involving different kind of receptors. Luminal epithelial, glandular epithelial, and myometrial hypertrophies were also found to differ with regard to the dose needed to induce this response in each cell type. The dissociation between genomic responses of the different uterine cell types supports the hypothesis of different estrogen receptors for each kind of cell. Clomiphene induces mitoses in the different cell types, but the proportion of mitoses in the cell types was different from that described for estradiol. It is suggested that these differences are also due to differences between receptors involved in cell proliferation.

The Estrogenic Responses to Clomiphene in the Different Cell Types of the Rat Uterus: Morphometrical Evaluation1