Screening for antiproliferative actions of mifepristone. Differential endometrial responses of primates versus rats.
This laboratory has previously shown the capability of the antiprogestin, mifepristone, to noncompetitively inhibit estrogen-induced endometrial proliferation in nonhuman primates. In the following study, use of the rat uterine weight bioassay was compared against a primate (Macaca fascicularis) uterine bioassay to identify the noncompetitive/antiproliferative effects of mifepristone. These uterine bioassays were contrasted for reasons of identifying a comparative laboratory rodent model that could substitute for the need to use primate models in the screening of potential antiprogestins, thereby saving time, cost, and primate resources. Results of the primate experiment showed that mifepristone decreased endometrial proliferation in a dose-dependent manner; importantly, this decrease occurred in the presence of sustained physiologic serum 17 beta-estradiol (E2) levels. However, in the rat model, results showed that mifepristone altered uterine wet weight and blotted weight values only in those animals receiving pharmacological doses of E2 (p < 0.05). Based on the results summarized herein, use of this rat uterine weight bioassay as a substitute for primate models is not recommended for screening and identification of "interesting" antiprogestins. Apparently, the endometrial noncompetitive antiestrogenic/antiproliferative effects of mifepristone, observed repeatedly in these laboratory primates, do not operate in the rat uterine tissue.
Burleigh
D W
DW
Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical school. Norfolk, Virginia 23507, USA.
Williams
R F
RF
Gordon
K
K
Hsiu
J G
JG
Hodgen
G D
GD
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects*; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D008252:Macaca fascicularis; D015735:Mifepristone / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D011372:Progestins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014599:Uterus / Q000033:anatomy & histology
D004965:Estrogen Antagonists; D006727:Hormone Antagonists; D011372:Progestins; D015735:Mifepristone; D004958:Estradiol