RU 486 (MIFEPRISTONE):, INDUCTION OF DOSE DEPENDENT ELEVATIONS OF ESTRADIOL RECEPTOR IN ENDOMETRIUM FROM OVARIECTOMIZED MONKEYS.*

Abstract

This study was designed to investigate the effect of the anti-progestin RU 486 on estradiol receptor concentrations in the endometrium on monkeys given physiologic estrogen replacement therapy. Estradiol-17.beta. (E2) silastic implants were inserted infrascapularly into 12 long-term ovariectomized cynomolgus monkeys (Macaca fascicularis) resulting in an average peripheral serum level of approximately 100 pg/ml estradiol. On day 6 of E2 treatment four treatment groups were initiated: Group I - estradiol implants only; Group II -estradiol implants plus 11 .mu.mol progesterone/kg bodyweight in sesame oil via im injections on days 6, 7, 8; Group III-estradiol implants plus 2.2 .mu.mol RU 486/kg in sesame oil via im injections on day 6, 7, 8; Group IV -estradiol implants plus 11 .mu.mol RU 486/kg via im injections on day 6, 7, 8. On treatment day 9 endometrial biopsies were removed by hysterotomies. Cytosolic and nuclear estradiol receptor contents of tissues were estimated by charcoal method. In Group I, the tissue contained 376 .+-. 123 pmol bound 3H-E2/g protein; the nuclear portion was about 16%. In Group III, tissue contained 216 .+-. 64 pmol bound 3H-E2/g protein; the nuclear portion was only 8%. In Group III, tissue contained 654 .+-. 47 pmol bound 3H-E2/g protein; the nuclear portion was about 22%. In Group IV, the tissue contained 1198 .+-. 172 pmol bound 3H-E2/g protein; the nuclear portion was about 17%. Scatchard plot analysis indicated a Kdapp of 1.04 .times. 10-9 M. This study demonstrates that after physiologic E2 replacement therapy estradiol receptor concentrations rise dramatically following anti-progestin treatment; this effect was dose dependent.