The effects of treatment for 5 or 9 days with varying doses of thyrotropin-releasing hormone (TRH) or the linear β-alanine TRH congener (pGlu-His-Pro-β-Ala-NH2) on serum levels of TSH, T3 and T4 were studied in mice and rats. At low doses in rats treatment with TRH for 9 days significantly increased serum levels of T3 but not serum T4 whereas a higher dose of TRH (10 mg/kg) reduced serum T3 levels. β-ALA TRH (0.1–10 mg/kg IP) treatment for 9 days in rats significantly reduced serum T4 levels whereas serum T3 levels were only depressed at higher doses (1–10 mg/kg IP) of the peptide. In mice treatment for 5 days with TRH (1 and 10 mg/kg IP) significantly reduced serum levels of T3 and T4. In addition, TRH (0.1–10 mg/kg IP) or β-ALA·TRH treatment (1.0–10 mg/kg IP) for 9 days significantly reduced serum TSH levels in rats. TRH (10 mg/kg IP for 9 days) also significantly reduced serum GH levels in rats. No alteration in hypothalamic content of TRH or LHRH was observed after chronic TRH treatment. Some, but not all, of our findings support the hypothesis that treatment with high doses of TRH reduce pituitary-thyroid axis functions by a direct effect on hypophysial T