TAMOXIFEN AND ICI-182,780 INTERACTIONS WITH THYROID-HORMONE IN THE OVARIECTOMIZED-THYROIDECTOMIZED RAT

Studies of estradiol and tamoxifen actions to modulate the actions of thyroid hormone (triiodothyronine, T3) in the rat have shown that a su bset of estrogen responses require T3 for expression. Also, tamoxifen acts as a partial agonist in estrogen responses that are T3 independen t, but acts as a full estrogen agonist in T3-dependent responses. This study examined whether the differing behavior of tamoxifen (a triphen ylethylene antiestrogen) in T3-independent and T3-dependent estrogen r esponses would be shared with ICI 182,780, a steroidal antiestrogen. A n ovariectomized-thyroidectomized rat model was used. Drug vehicle, ta moxifen alone (0.4 mg/kg), ICI 182,780 alone (2 mg/kg) or tamoxifen pl us ICI 182,780 were given for 3 weeks to ovariectomized-thyroidectomiz ed rats with or without T3 replacement (10 mu g/kg). T3-independent es trogen responses measured were the induction of uterine growth and ind uction of pituitary growth hormone (GH) in the absence of T3. T3-depen dent estrogen responses measured were antagonism of T3-evoked increase s in pituitary GH, body weight, tibia length and hepatic malic enzyme, and increases in serum triglycerides. Tamoxifen acted as a partial ag onist in T3-independent estrogen responses, whereas ICI 182,780 acted as a potent pure antagonist in such responses; it lacked agonist effic acy and totally blocked tamoxifen effects. In T3-dependent estrogen re sponses, tamoxifen acted as a full estrogen agonist. ICI 182,780 acted as a weak agonist in some T3-dependent responses and lacked agonist e fficacy in others. Moreover, ICI 182,780 had poor efficacy in blocking tamoxifen actions in T3-dependent responses. The results indicate tha t ICI 182,780, like tamoxifen, displays a duality in its pharmacologic al behavior which pivots on the T3 dependence of the estrogen response .