TY - JOUR
T1 - Differential antiestrogen action in the immature rat uterus
T2 - A comparison of hydroxylated antiestrogens with high affinity for the estrogen receptor
AU - Jordan, V. C.
AU - Gosden, B.
N1 - Funding Information:
Acknowledgements-We would like to thank Dr A. H. Todd, ICI Ltd, PharmaceuticalDs ivision, and Dr C. D. Jones, Eli Lilly Company for the generousg ifts of compounds.T his studyw as partiallys upportedb y NIH grant numberC A 32713.
PY - 1983/9
Y1 - 1983/9
N2 - -The non-steroidal antiestrogens LY117018 and monohydroxytamoxifen are partial agonists in the 3-day immature rat uterine weight test. Both compounds stimulated increases in uterine progesterone receptor concentration (as determined by DCC assay and SDG analysis) and luminal epithelial cell height. However, LY117018 was much less estrogenic than monohydroxytamoxifen. The study also showed that the antiestrogenic effects of LY117018 and monohydroxytamoxifen could be reversed in vivo by increasing doses of estradiol. The partial uterotrophic effect of monohydroxytamoxifen and full uterotrophic effects of estradiol were both inhibited by high doses of LY117018 at an approximate dosage ratio of 1:24, w/w. This result suggests a common mechanism for the action of estradiol and the hydroxylated antiestrogens. Since LY117018 reversed the binding of [3H]estradiol and estrogencompetable [3H]monohydroxytamoxifen binding in the rat uterus in vivo, the effects of nonsteroidal antiestrogens on gross uterine wet weight can be explained by competitive interaction with estradiol via the estrogen receptor mechanism. However, the weakly estrogenic antiestrogen LY117018 was unable to inhibit estrogen-stimulated rises in luminal epithelium cell height and progesterone receptor levels. These data suggest a differential interaction by LY 117018 in the rat uterus so that only selected estrogen stimulated effects i.e., uterine wet weight, are antagonized by this particular "antiestrogenic" dose of the drug.
AB - -The non-steroidal antiestrogens LY117018 and monohydroxytamoxifen are partial agonists in the 3-day immature rat uterine weight test. Both compounds stimulated increases in uterine progesterone receptor concentration (as determined by DCC assay and SDG analysis) and luminal epithelial cell height. However, LY117018 was much less estrogenic than monohydroxytamoxifen. The study also showed that the antiestrogenic effects of LY117018 and monohydroxytamoxifen could be reversed in vivo by increasing doses of estradiol. The partial uterotrophic effect of monohydroxytamoxifen and full uterotrophic effects of estradiol were both inhibited by high doses of LY117018 at an approximate dosage ratio of 1:24, w/w. This result suggests a common mechanism for the action of estradiol and the hydroxylated antiestrogens. Since LY117018 reversed the binding of [3H]estradiol and estrogencompetable [3H]monohydroxytamoxifen binding in the rat uterus in vivo, the effects of nonsteroidal antiestrogens on gross uterine wet weight can be explained by competitive interaction with estradiol via the estrogen receptor mechanism. However, the weakly estrogenic antiestrogen LY117018 was unable to inhibit estrogen-stimulated rises in luminal epithelium cell height and progesterone receptor levels. These data suggest a differential interaction by LY 117018 in the rat uterus so that only selected estrogen stimulated effects i.e., uterine wet weight, are antagonized by this particular "antiestrogenic" dose of the drug.
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U2 - 10.1016/0022-4731(83)90147-4
DO - 10.1016/0022-4731(83)90147-4
M3 - Article
C2 - 6684713
AN - SCOPUS:0020825481
SN - 0022-4731
VL - 19
SP - 1249
EP - 1258
JO - Journal of Steroid Biochemistry
JF - Journal of Steroid Biochemistry
IS - 3
ER -