Time-related effects of a triphenylethylene antiestrogen on estrogen-induced changes in uterine weight, estrogen receptors, and endometrial sensitivity in rats

Contraception. 1995 Jun;51(6):367-79. doi: 10.1016/0010-7824(95)00103-h.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Centchroman / administration & dosage
  • Centchroman / pharmacology*
  • Decidua / drug effects
  • Decidua / physiology
  • Dose-Response Relationship, Drug
  • Endometrium / drug effects*
  • Endometrium / metabolism
  • Endometrium / physiology
  • Epithelium / chemistry
  • Epithelium / drug effects
  • Epithelium / ultrastructure
  • Estradiol / pharmacology*
  • Estrogen Antagonists / administration & dosage
  • Estrogen Antagonists / pharmacology*
  • Female
  • Microscopy, Electron, Scanning
  • Nafoxidine / pharmacology
  • Organ Size / drug effects
  • Organ Size / physiology
  • Ovariectomy
  • Progesterone / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / analysis*
  • Receptors, Estrogen / metabolism
  • Tamoxifen / pharmacology
  • Time Factors
  • Uterus / anatomy & histology
  • Uterus / drug effects*
  • Uterus / physiology

Substances

  • Estrogen Antagonists
  • Receptors, Estrogen
  • Tamoxifen
  • Centchroman
  • Progesterone
  • Nafoxidine
  • Estradiol