Time-related effects of a triphenylethylene antiestrogen on estrogen-induced changes in uterine weight, estrogen receptors, and endometrial sensitivity in rats.
Time-related estrogen antagonistic action of a single oral contraceptive (1.25 mg/kg) dose of the triphenylethylene antiestrogen centchroman was determined in ovariectomized immature rats. Tamoxifen and nafoxidine were used for comparison. A single oral administration of centchroman followed by three doses of estradiol-17 beta (1 microgram/d, s.c.) caused significant dose-dependent inhibition in estradiol-17 beta-induced increase in uterine weight and nuclear and cytosolic estrogen receptors. But the inhibition at antiimplantation dose was evident only if estradiol-17 beta treatment was initiated not later than 48 h post-antiestrogen. Alternatively, when antiestrogen treatment was followed by a single 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 preimplantation was produced by estradiol-17 beta (0.5 microgram/d, s.c.) priming on days -2 and -1, followed by progesterone (1 mg/d, s.c.) and an endometrial sensitizing dose (0.5 microgram/d, s.c.) of estradiol-17 beta at 1600 h on day 4, anti-implantation dose of centchroman administered on day 1, too, failed to inhibit uterine weight gain induced by sensitizing dose of estradiol-17 beta, but caused marked inhibition in endometrial sensitivity to a deciduogenic stimulus and decidualization and weight gain of traumatized uterine horn 96 h post-traumatization over non-traumatized horn was only about 150% (725% in controls). Inhibition in endometrial sensitivity and decidualization was evident when the interval between antiestrogen treatment and sensitizing estradiol was < 126 h. Pinopods were present on endometrial surface on day 5 whether or not priming and/or sensitizing doses of estradiol were administered, but decidual response was mild if either of these doses of estradiol-17 beta was deferred. Findings suggest that: (a) duration of antiestrogenic action of single anti-implantation dose of centchroman in rat was about 126 h, which in ovariectomized immature rats was evident only when a condition mimicking preimplantation was produced and the antiestrogenic response was based on inhibition in estradiol-induced endometrial sensitivity and not uterine weight gain; (b) priming as well as sensitizing 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 slightly longer acting with duration of antiestrogenic action of approximately 150 h.
Trivedi
R N
RN
Central Drug Research Institute, Lucknow, India.
Chauhan
S C
SC
Dwivedi
A
A
Kamboj
V P
VP
Singh
M M
MM
D000284:Administration, Oral; D000818:Animals; D002486:Centchroman / Q000008:administration & dosage / Q000494:pharmacology*; D003656:Decidua / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004848:Epithelium / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D008855:Microscopy, Electron, Scanning; D009256:Nafoxidine / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000032:analysis* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; D002486:Centchroman; D011374:Progesterone; D009256:Nafoxidine; D004958:Estradiol