Thyroid Hormone and Estrogen Interact to Regulate Behavior

Environmental perturbations that increase plasma thyroid hormone (T$_{3}$) concentrations also profoundly affect female reproductive behavior and physiology. We explored whether these effects were mediated by interactions between T$_{3}$ receptor (TR) and estrogen receptor (ER). This hypothesis was of interest because the half-site of a consensus T$_{3}$ response element DNA sequence is identical to an ER response element (ERE), and TRs bind to a consensus ERE. Molecular data presented in the accompanying paper [Zhu, Y.-S., Yen, P.M., Chin, W.W. & Pfaff, D.W. (1996) Proc. Natl. Acad. Sci. USA 93, 12587-12592] demonstrate that TRs and ERs are both present in rat hypothalamic nuclear extracts and that both can bind to the promoter the hypothalamic gene preproenkephalin and that interations between liganded TRs and ERs affect preproenkephalin transcription. In this paper, we show that molecular interactions between TRs and ERs are sufficient to mediate environmental effects on estrogencontrolled reproductive behavior. Ovariectomized (OVX) rats treated with high doses of T$_{3}$ showed significantly lower levels of lordosis behavior in response to estradiol benzoate (EB) compared with OVX females treated with EB alone. Conversely, thyroidectomized/OVX females treated with EB showed significantly greater levels of lordosis behavior compared with OVX females treated with EB, showing the effect of endogenous T$_{3}$. Thyroid hormone interference with EB-induced behavior could not be explained by a reduction in plasma E$_{2}$ concentrations or by a general reduction in responsiveness of EB-sensitive tissues. Moreover, numbers of hypothalamic ER-immunoreactive cells increased dramatically following T$_{3}$ treatment. These data suggest that T$_{3}$ may reduce EB-dependent sexual behavior through interactions between TR and ER in the nuclei of behaviorally relevant hypothalamic neurons, envisioning for the first time a functional consequence of interactions between two nuclear hormone receptors in brain. These results also open up the possibility of molecular interactions on DNA encoding environmental signals, a new field for the study of neuronal integration.