STUDIES ON THE EFFECT OF ESTROGEN ON HYPOTHALAMOPITUITARY-THYROID AXIS IN THE RAT

Abstract

Although effects of estrogen on pituitary-thyroid axis have extensively been studied for sometimes, conflicting results have been reported in man and experimental animals. Discrepancies among previous investigations might have resulted mostly from the inadequate methodology or a choice of parameters, such as thyroid weight, thyroidal uptake or release of radioiodine, protein bound iodine, bioassayable thyrotropin (TSH) and etc. The present study was undertaken to re-evaluate and elucidate mechanisms and loci of actions of estrogen in the pituitary-thyroid axis in the rat by direct measurements of plasma concentrations of TSH, thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3) and free T4 and hypothalamic content of TSH-releasing hormone (TRH), employing sensitive and specific radioimmunoassays for respective hormones. In addition, the present study also examined possible effects of estrogen on the peripheral kinetics of thyroid hormones and on the hypothalamic regulation of this axis.Two weeks after ovariectomy (ovx) of Wistar strain rats, daily sc injections of 25μg of estradiol benzoate (EB) were initiated and serial blood samples were obtained from jugular vein under ether anesthesia. Plasma T3 conconcentration was linearly increased after initiation of EB and nearly doubled by the 8th day. However, neither plasma T4, free T4 nor rT3 were affected by EB administration. The kinetic study of the peripheral thyroid hormone metabolism, using 125I-T, and 125I-T3 with high specific activities, revealed that EB administration produced a decrease in the half-life of T4, but not of T3, increases in metabolic clearance rate and production rate (PR) of T4 and also an increase in PR of T3. Furthermore, the concomitant administration of EB and l-T4 (1.5μg/100g B.W./ day) to ovx-thyroidectomized rats resulted in a dramatic drop in plasma T4 concentration with normal levels of plasma T3. These observations suggest that, in addition to the direct stimulatory action of EB to thyroid gland, EB also accelerates the peripheral conversion of T4 to T3 to maintain the elevated plasma T3 levels.The daily EB administration to ovx-rats produced not only an increase in basal levels of plasma TSH but an exaggerated response of pituitary TSH secretion to exogenous synthetic TRH. But, this stimulatory effect of EB on the pituitary TSH secretory mechanism was not evident in male rats. Thus, it appeared that there was a sex difference in this regard. Interestingly enough, elevated levels of plasma TSH during the first week after the initiation of EB treatment returned to the initial values by 2 weeks. This biphasic effect of EB on plasma TSH might be brought about by cancellation of stimulated TSH secretion by elevated plasma T3 through the negative feedback mechanism.Hypothalamic TRH content was not affected by EB treatment. However, complete deafferentation of mediobasal hypothalamus partially inhibited an elevation of plasma TSH induced by EB administration, suggesting the hypothalamic participation to the stimulatory action of EB in TSH release.In conclusion, the present study indicates that estrogen is capable of direct stimulatory actions to the pituitary TSH secretion and thyroid hormone synthesis and release. More importantly, the present study provides evidences EB acts on the peripheral metabolism of thyroid hormones as to accelerate the conversion of T4 to T3, and that a stimulatory effect of EB on pituitarythyroid axis is brought about, at least in part, by activation of hypothalamic regulation.