Vol. 281, Issue 1, 142-148, 1997

Tamoxifen and ICI 182,780 Interactions with Thyroid Hormone in the Ovariectomized-Thyroidectomized Rat¹

Vincent A. Dipippo² and C. Andrew Powers

Department of Pharmacology, New York Medical College, Valhalla, New York

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 µg/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.