Modulation of estrogen action during preimplantation period and in immature estradiol-primed rat uterus by anti-implantation agent, ormeloxifene

Studies were undertaken to evaluate the influence of estrogen antagonist-cum anti-implantation agent, ormeloxifene, on 17β-hydroxydsteroid dehydrogenase (17β-HSD) activity and estrogen action in rat uterus during preimplantation period and to examine its ability to induce progesterone receptor (PR) in immature rat model. A group of female rats received orally a contraceptive dose of 1.25 mg/kg of ormeloxifene on Day 1 postcoitum (pc). Rats were sacrificed on Days 3, 4 and 5 pc, and uterine tissues were processed for enzymatic, estrogen receptor and estradiol (E₂) estimations. Immature ovariectomized rats received ormeloxifene, subcutaneously for 3 days at various doses in the absence or presence of estradiol, and uterine PR levels were measured using ³H-R5020 as radioligand.

Results revealed that ormeloxifene treatment caused a marked increase in enzyme activity of 17β-HSD on Days 3, 4 and 5 pc as compared to respective controls. Further, total uterine estrogen receptors as estimated by exchange assay showed a noticeable decrease on Days 4 (35%) and 5 (>80%) pc in ormeloxifene-treated groups. The results correlated well with a decrease in tissue E₂ levels. In immature rats, ormeloxifene caused a dose-dependent increase in cytosolic PR levels; ormeloxifene given along with E₂ (0.1 μg) for 3 days caused a significant reduction in concentration of PRs at 10 μg and higher doses.

Ormeloxifene also induced ³H-progesterone (P) uptake by immature rat uterus. However, in the presence of E₂, it significantly reduced ³H-P uptake. The in vitro competitive binding experiments did not reveal any displacement of ³H-R5020 either by ormeloxifene or by its hydroxy derivative from PR. The results suggest that in addition to its competitive antagonism at estrogen receptor level, ormeloxifene enhances the inactivation of intracellular E₂ to estrone, a biologically less active form, thus declining estrogen receptor pool. Moreover, it causes indirect anti-progestational effects in the uterus by virtue of its anti-estrogenic profile rather than by blocking the PRs.