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 subset of estrogen responses require T3 for expression. Also, tamoxifen acts as a partial agonist in estrogen responses that are T3 independent, but acts as a full estrogen agonist in T3-dependent responses. This study examined whether the differing behavior of tamoxifen (a triphenylethylene antiestrogen) in T3-independent and T3-dependent estrogen responses would be shared with ICI 182,780, a steroidal antiestrogen. An ovariectomized-thyroidectomized rat model was used. Drug vehicle, tamoxifen alone (0.4 mg/kg), ICI 182,780 alone (2 mg/kg) or tamoxifen plus ICI 182,780 were given for 3 weeks to ovariectomized-thyroidectomized rats with or without T3 replacement (10 microg/kg). T3-independent estrogen responses measured were the induction of uterine growth and induction of pituitary growth hormone (GH) in the absence of T3. T3-dependent estrogen responses measured were antagonism of T3-evoked increases in pituitary GH, body weight, tibia length and hepatic malic enzyme, and increases in serum triglycerides. Tamoxifen acted as a partial agonist in T3-independent estrogen responses, whereas ICI 182,780 acted as a potent pure antagonist in such responses; it lacked agonist efficacy and totally blocked tamoxifen effects. In T3-dependent estrogen responses, tamoxifen acted as a full estrogen agonist. ICI 182,780 acted as a weak agonist in some T3-dependent responses and lacked agonist efficacy in others. Moreover, ICI 182,780 had poor efficacy in blocking tamoxifen actions in T3-dependent responses. The results indicate that ICI 182,780, like tamoxifen, displays a duality in its pharmacological behavior which pivots on the T3 dependence of the estrogen response.