Circadian, continued treatment with melatonin during the dark cycle produces changes in the blood level of thyroid hormones in aging mice. Thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) antagonize the involution of the thymus produced by prednisolone. This effect of TRH does not seem thyroid dependent. TRH restores antibody production in non-responder athymic nude mice but does not exert this effect in neonatally thymectomized mice. Moreover, this activity does not correlate with thyroxine levels. TRH exerts a powerful protective effect in mice challenged with encephalomyocarditis (EMC) virus. Presumably pineal melatonin exerts its varied regulatory functions via hypothalamic TRH.