ESTRADIOL AND TAMOXIFEN INTERACTIONS WITH THYROID-HORMONE IN THE OVARIECTOMIZED-THYROIDECTOMIZED RAT

Receptors for estrogens and thyroid hormone (T-3) have related DNA-bin ding domains that interact with closely related DNA target sequences w hich enable transcriptional control. In vitro molecular studies have r aised the possibility that estrogen and T-3 receptors may compete for binding to certain DNA target sites (cross-talk). However, there have been no physiological studies evaluating the abilities of estrogens or T-3 to mimic or inhibit each other in vivo in a manner consistent wit h a mechanism involving receptor cross-talk. To address this issue, th e effects of estradiol, tamoxifen (an antiestrogen), and T-3 were stud ied in an ovariectomized-thyroidectomized rat model designed to minimi ze hormone interplay occurring via neuroendocrine or pharmacokinetic m echanisms. The T-3 responses examined included induction of GH, somati c growth, and hepatic malic enzyme, and suppression of TSH secretion. The estrogen responses examined included induction of pituitary kallik rein, PRL, and uterine weight; increases in serum triglycerides; and s uppression of LH secretion. Estradiol and tamoxifen acted as partial T -3 agonists on GH induction, with agonist or antagonist effects depend ing upon T-3's presence. Estradiol and tamoxifen acted as pure T-3 ant agonists on T-3 induction of somatic growth and malic enzyme. Similarl y, estradiol blocked T-3-evoked decreases in bone mineral density and had no effect on bone in T-3's absence. In contrast, estradiol or tamo xifen did not alter T-3 feedback inhibition of TSH release or T-3 indu ction of PRL. T-3 partially mimicked estrogen actions to suppress LH, but did not mimic or inhibit other estrogen responses. Interestingly, the effect of estradiol and tamoxifen to increase serum triglycerides was totally T-3 dependent even though T-3 tended to decrease triglycer ide levels. The results indicate that physiological effects of estroge ns on GH, somatic growth, bone, malic enzyme, and serum triglycerides exhibit properties suggestive of a mechanism involving cross-talk with T-3 receptors. Tamoxifen fully mimicked the effects of estradiol aris ing by an apparent antagonism of T-3 actions, but acted as an antiestr ogen in other responses.