NONCOMPETITIVE ANTIESTROGENIC ACTIONS OF PROGESTERONE ANTAGONISTS IN PRIMATE ENDOMETRIUM - ENHANCEMENT OF ESTROGEN AND PROGESTERONE RECEPTORS WITH BLOCKADE OF POSTRECEPTOR PROLIFERATIVE MECHANISMS

Previous studies have shown that the progesterone antagonists (antipro gestins) inhibit oestrogen-dependent endometrial proliferation in ovar iectomized monkeys, without having affinity to the oestrogen receptor (ER), This study was designed to investigate the effects of the antipr ogestins mifepristone (RU 486) and onapristone (ZK 98,299), on the con centration 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 [H-3]-oestradiol/g protein (ER), and 119 +/- 42 pmol [H-3]-R5020/g pro tein (PR), These values were not significantly different from the tota l 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, Combine d treatment with oestradiol and RU 486 enhanced the ER and PR concentr ations 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 5 mg/kg bw RU 486 or onapristone increased the ER and PR concentrations almost 6 - and 5-fold respectively, compared with the oestradiol-treated contro ls, Our results demonstrate that RU 486 and onapristone increased the endometrial ER and PR concentrations far beyond the physiological leve l in ovariectomized, oestradiol-treated monkeys, Whether the over-expr ession of ER and PR in the presence of antiprogestins is causally rela ted to the antiproliferative impact of antiprogestins in the endometri um (non-competitive anti-oestrogenic effects) or is an independent act ion is unknown.