Opposing biological actions of antiestrogens in vitro and in vivo: induction of progesterone receptor in the rat and mouse uterus.

The nonsteroidal antiestrogen tamoxifen, 4-hydroxytamoxifen, and Ly117018 inhibited the estradiol-stimulated induction of progesterone receptors in primary cultures of immature rat uterine cells. This effect was found to be completely reversible with increased concentrations of estradiol. These compounds possessed no estrogenic activity. In contrast, ICI 47,699 (the cis geometric isomer of tamoxifen) and ICI 77,949 (tamoxifen without the dimethylaminoethyl side chain) were fully estrogenic, and bisphenol (4-hydroxytamoxifen without the dimethylaminoethyl side chain) possessed mixed estrogenic/antiestrogenic activity. In primary uterine cell cultures derived from mature ovariectomized mice, 4-hydroxytamoxifen was, again, nonestrogenic and inhibited the estradiol-stimulated induction of progesterone receptors. The antiestrogenic activity of 4-hydroxytamoxifen was effective against both steroidal and nonsteroidal estrogens in either rat- or mouse-derived uterine cell cultures. Using the 3-day uterine assay in vivo, 4-hydroxytamoxifen partially stimulated progesterone receptor induction in the immature rat, whereas it fully stimulated the same end point in the mature ovariectomized mouse. These results emphasize the difference between antiestrogen activity in vivo and in vitro, and also indicate that the increased agonist activity of 4-hydroxytamoxifen in the mouse compared to that in the rat in vivo is not reflected in vitro. Therefore, we have extended the model of antiestrogen action previously described in primary pituitary cell cultures to progesterone receptor induction in two murine uterine cell cultures.