Date of Award

Winter 1997

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

Gary D. Hodgen

Committee Member

Robert F. Williams

Committee Member

Keith Gordon

Committee Member

Ke-wen Dong

Committee Member

R. James Swanson

Abstract

The antiprogestin, mifepristone, has previously been shown to noncompetitively inhibit estrogen-induced endometrial proliferation in nonhuman primates (van Uem et al., 1989; Wolf et al., 1989b; Neulen et al., 1990; Neulen et al., 1996). For both economical and ethical reasons, we are encouraged to identify comparative laboratory rodent models which can substitute the need to use primate models. In the following study, we compared capabilities of the rat uterine weight bioassay versus a primate uterine bioassay, to identify the noncompetitive antiestrogenic/antiproliferative effects of mifepristone.

Long-term ovariectomized monkeys were exposed to exogenous 17β-estradiol (E2) and mifepristone in doses and regimes already demonstrated to curtail endometrial growth (Wolf et al., 1989b). Results show that mifepristone decreased endometrial proliferation in a dose-dependent manner, and this decrease occurred in the presence of physiologic serum E2 levels.

In the rat model, ovariectomized immature (day 20) and adult Sprague-Dawley rats were pretreated with E2 for 3 days, followed by E2 plus mifepristone (various doses) for 3 additional days. E2 replacement was either given as 0.5 μg/100 g body weight (in oil, sc) or as a 0.5 mg sc pellet. Mifepristone did not induce a decrease in uterine wet or blotted weights in immature or adult rats receiving E2 replacement as 0.5 μg/100 g body weight (P>0.05). This lack of effect was not due to insufficient E2 stimulation as histological evaluation of the endometrium showed increased numbers of mitotic figures in all treatment groups and serum E2 levels were in the diestrous-proestrous range. In contrast, mifepristone did inhibit an increase in uterine wet weight of adult rats (P800 pg/ml), illustrating a relationship between E2 levels and capability of mifepristone to affect rat uterine weight.

Based on the results summarized here, we do not recommend using the rat uterine weight bioassay as a substitute model for screening antiprogestins for noncompetitive antiestrogenic/antiproliferative effects on primate uterine endometrium.

Comments

Dissertation submitted to the Faculty of Eastern Virginia Medical School and Old Dominion University in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/19qx-p097

ISBN

9780591603767

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