Non-competitive anti-oestrogenic actions of progesterone antagonists in primate endometrium: enhancement of oestrogen and progesterone receptors with blockade of post-receptor proliferative mechanisms.

Abstract

Previous studies have shown that the progesterone antagonists (antiprogestins) inhibit oestrogen-dependent endometrial proliferation in ovariectomized monkeys, without having affinity to the oestrogen receptor (ER). This study was designed to investigate the effect of the antiprogestins mifepristone (RU 486) and onapristone (ZK 98,299), on the concentration of ER and progesterone receptor (PR) in the endometrium of long-term ovariectomized cynomolgus monkeys (Macaca fascicularis). In untreated monkeys, tissue preparations bound in total 228 +/- 68 pmol [3H]-oestradiol/g protein (ER), and 119 +/- 42 pmol [3H]-R5020/g protein (PR). These values were not significantly different from the total binding capacities of tissues from monkeys treated with RU 486 alone or primates treated with oestradiol plus progesterone. Treatment with oestradiol alone almost doubled the ER and PR concentrations. Combined treatment with oestradiol and RU 486 enhanced the ER and PR concentrations in a dose-dependent manner: 1 mg/kg body weight (bw) RU 486/kg increased both ER and PR contents about 3-fold. The dose of 5mg/kg bw RU 486 or onapristone increased the ER and PR concentrations almost 6- and 5-fold respectively, compared with the oestradiol-treated controls. Our results demonstrate that RU 486 and onapristone increased the endometrial ER and PR concentrations far beyond the physiological level in ovariectomized, oestradiol-treated monkeys. Whether the over-expression of ER and PR in the presence of antiprogestins is causally related to the antiproliferative impact of antiprogestins in the endometrium (non-competitive anti-oestrogenic effects) or is an independent action in unknown.