Endocrinology, Vol 136, 1020-1033, Copyright © 1995 by Endocrine Society

ARTICLES

Estradiol and tamoxifen interactions with thyroid hormone in the ovariectomized-thyroidectomized rat

VA DiPippo, R Lindsay and CA Powers
Department of Pharmacology, New York Medical College, Valhalla 10595.

Receptors for estrogens and thyroid hormone (T3) have related DNA- binding domains that interact with closely related DNA target sequences which enable transcriptional control. In vitro molecular studies have raised the possibility that estrogen and T3 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 T3 to mimic or inhibit each other in vivo in a manner consistent with a mechanism involving receptor cross-talk. To address this issue, the effects of estradiol, tamoxifen (an antiestrogen), and T3 were studied in an ovariectomized-thyroidectomized rat model designed to minimize hormone interplay occurring via neuroendocrine or pharmacokinetic mechanisms. The T3 responses examined included induction of GH, somatic growth, and hepatic malic enzyme, and suppression of TSH secretion. The estrogen responses examined included induction of pituitary kallikrein, PRL, and uterine weight; increases in serum triglycerides; and suppression of LH secretion. Estradiol and tamoxifen acted as partial T3 agonists on GH induction, with agonist or antagonist effects depending upon T3's presence. Estradiol and tamoxifen acted as pure T3 antagonists on T3 induction of somatic growth and malic enzyme. Similarly, estradiol blocked T3-evoked decreases in bone mineral density and had no effect on bone in T3's absence. In contrast, estradiol or tamoxifen did not alter T3 feedback inhibition of TSH release or T3 induction of PRL. T3 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 T3 dependent even though T3 tended to decrease triglyceride levels. The results indicate that physiological effects of estrogens on GH, somatic growth, bone, malic enzyme, and serum triglycerides exhibit properties suggestive of a mechanism involving cross-talk with T3 receptors. Tamoxifen fully mimicked the effects of estradiol arising by an apparent antagonism of T3 actions, but acted as an antiestrogen in other responses.

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