ICI 182,780 inhibits endogenous estrogen-dependent rat uterine growth and tamoxifen-induced developmental toxicity.
To assess the effects of the steroidal antiestrogen ICI 182,780 on postnatal uterine development, female Sprague-Dawley rats were given s.c. injections of ICI 182,780 (0.1-100 micrograms/rat) on each of postnatal days (PND) 10-14. ICI 182,780 inhibited uterine growth, as measured by uterine weight, in a dose-dependent manner but had no effect on either uterine luminal epithelium hypertrophy or gland genesis. Immunohistochemical analysis revealed that ICI 182,780 (10 micrograms) markedly reduced uterine estrogen receptor (ER) immunoreactivity in all uterine cell types while tamoxifen (10 micrograms) increased ER immunoreactivity, most notably in the luminal epithelium. In addition, tamoxifen increased uterine weight and induced luminal epithelium hypertrophy but inhibited uterine gland genesis--outcomes also seen with synthetic estrogens such as diethylstilbestrol. To test the hypothesis that these effects are a consequence of the estrogen agonist activity of tamoxifen, rats were cotreated with ICI 182,780 (10 micrograms, PND 8-14) and tamoxifen (10 micrograms, PND 10-14). ICI 182,780 greatly reduced or completely blocked tamoxifen-induced uterine weight gain, luminal epithelium hypertrophy, tamoxifen-induced ER immunoreactivity, and the inhibition of uterine gland genesis. ICI 182,780 given daily on PND 1-5 did not alter PND 5 uterine weight or uterine differentiation on PND 26. We conclude that postnatal exposure to ICI 182,780 does not affect uterine growth or differentiation at an age when the uterus is not dependent on estrogen for growth, i.e., PND 1-5, but does inhibit later endogenous estrogen-dependent uterine growth. The blockade of tamoxifen-induced uterine developmental alterations by ICI 182,780 demonstrates that these tamoxifen effects result from its estrogen agonist activity.
Branham
W S
WS
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research Food and Drug Administration, Jefferson, Arkansas 72079, USA.
Fishman
R
R
Streck
R D
RD
Medlock
K L
KL
De George
J J
JJ
Sheehan
D M
DM
D000818:Animals; D004848:Epithelium / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D007150:Immunohistochemistry; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism
D004965:Estrogen Antagonists; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol