TIME-RELATED EFFECTS OF A TRIPHENYLETHYLENE ANTIESTROGEN ON ESTROGEN-INDUCED CHANGES IN UTERINE WEIGHT, ESTROGEN-RECEPTORS, AND ENDOMETRIALSENSITIVITY IN RATS

Time-related estrogen antagonistic action of a single oral contracepti ve (1.25 mg/kg) dose of the triphenylethylene antiestrogen centchroman was determined in ovariectomized immature rats. Tamoxifen and nafoxid ine were used for comparison. A single oral administration of centchro man followed by three doses of estradiol-17 beta (1 mu g/d, s.c.) caus ed significant dose-dependent inhibition in estradiol-17 beta-induced increase in uterine weight and nuclear and cytosolic estrogen receptor s. But the inhibition at antiimplantation dose was evident only if est radiol-17 beta treatment was initiated not later than 48 h post-anties trogen. Alternatively, when antiestrogen treatment was followed by a s ingle dose of estradiol-17 beta between days 2-7, a synergistic action , typical of antiestrogens possessing weak estrogen agonistic activity , was observed. in immature rats in which a condition mimicking preimp lantation was produced by estradiol-17 beta (0.5 mu g/d, s.c.) priming on days -2 and -1, followed by progesterone (1 mg/d, s.c.) and an end ometrial sensitizing dose (0.5 mu g/d, s.c.) of estradiol-17 beta at 1 600 h on day 4, anti-implantation dose of centchroman administered on day 1, too, failed to inhibit uterine weight gain induced by sensitizi ng dose of estradiol-17 beta, but caused marked inhibition in endometr ial sensitivity to a deciduogenic stimulus and decidualization and wei ght gain of traumatized uterine horn 96 h post-traumatization over non -traumatized horn was only about 150% (725% in controls). Inhibition i n endometrial sensitivity and decidualization was evident when the int erval between antiestrogen treatment and sensitizing estradiol was <12 6 h. Pinopods were present on endometrial surface on day 5 whether or not priming and/or sensitizing doses of estradiol were administered, b ut decidual response was mild if either of these doses of estradiol-17 beta was deferred. Findings suggest that: (a) duration of antiestroge nic action of single anti-implantation dose of centchroman in rat was about 126 h, which in ovariectomized immature rats was evident only wh en a condition mimicking preimplantation was produced and the antiestr ogenic response was based on inhibition in estradiol-induced endometri al sensitivity and not uterine weight gain; (b) priming as well as sen sitizing estrogen were essential to get optimal decidual responses; (c ) appearance of pinopods on endometrial surface may not be related to endometrial sensitivity; and (d) tamoxifen and nafoxidine appear sligh tly longer acting with duration of antiestrogenic action of similar to 150 h.