one binding sites in both cytosol and nucleus following mifepristone treatment, an unexpected finding that is being studied further.
Immunohistochemical staining of mifepristone-exposed decidua revealed that antiprogestogen treatment resulted in increased staining for both progesterone and estrogen receptors in specimens presumed to represent decidua parietalis because of the absence of invading cytotrophoblast cells. The increased staining was most noticeable in the decidual vessels and stromal cells, and weak to absent in glandular epithelial cells. In specimens with invading cytotrophoblast cells (decidua capsularis), immunostaining of progesterone and estrogen-receptors was weaker than in decidua parietalis and not influenced by mifepristone treatment (Shi et al., 1993a). The finding of a seemingly lower progesterone-receptor content in decidua capsularis may explain the observation (Wu et al., 1990) that prolactin production and morphological decidualization in this part of the decidua are not affected by mifepristone treatment, in contrast to the decidua parietalis. Steroid binding assays on villous cytosol failed to demonstrate the presence of a specific progesterone-binding component, and immunostaining for progesterone receptor was weak in both villous and extravillous trophoblasts (Shi et al., 1993b).
The above results indicate that in addition to its ability to compete with progesterone for the cellular hormone receptor, mifepristone may influence, either directly or indirectly, the concentration and affinity of progesterone binding sites in the decidua. These effects are most marked in the decidua parietalis, which suggests that this tissue, and particularly its blood vessels, may be the primary target site of antiprogestogens.
Increases in estrogen-receptor concentration following mifepristone treatment have also been observed in the decidua and myometrium during antiprogestogen-induced premature delivery in rhesus monkeys (Haluska et al., 1990) and in estrogen-treated, ovariectomized rhesus monkeys (Wolf et al., 1989; Neulen et al., 1990). In this latter model, mifepristone has been demonstrated to antagonize the mitogenic effects of estrogen on the endometrium, which has led to the concept that mifepristone possesses a functional, noncompetitive antiestrogenic effect. A similar antiestrogenic action has been observed in the case of onapristone (K. Chwalisz, personal communication, November 4, 1992). It is at present entirely unclear through which mechanism antiprogestogens exert this antiestrogenic action. Equally unclear is the role, if any, that this functional antiestrogenism may play in the effects of antiprogestogens on endometriosis (Kettel et al., 1991), uterine leiomyomas (Murphy et al., 1993), and possibly, breast cancer (Romieu et al., 1987). In fact, there is no convincing evidence as yet that antiprogestogens possess antiestrogenic activity in the human, although the obser-