We studied the effects of long-term (30 days) refracted daily intramuscular administration of 4 mg TRH tartrate (TRH-T) on the pituitary-thyroid axis in 20 euthyroid patients affected by cerebrovascular disease (CVD). All subjects were assayed for T<sub>4</sub>, T<sub>3</sub>, FT<sub>4</sub>, FT<sub>3</sub>, TSH and TBG plasma levels before treatment (D<sub>o</sub>), after 15 and 30 treatment days (D<sub>15</sub>, D<sub>30</sub>), and after a 15-day washout (D<sub>45</sub>). In addition, TSH response to 200 µg intravenous TRH was assessed at D<sub>o</sub>, D<sub>30</sub> and D45. We observed a significant increase in T<sub>4</sub>, FT<sub>4</sub> and FT3 levels in the face of decreased TSH concentrations. A blunted TSH response to TRH bolus persisted at D<sub>30</sub>. These data demonstrate that the down-regulation mechanism may be partially overcome in vivo when thyrotrophs are chronically exposed to pharmacological TRH-T doses and that TSH pattern is mainly due to the negative feedback of thyroid hormones, even though pituitary TSH reserves may become depleted. Furthermore, prolonged TRH-T administration does not produce hyperthyroidism in euthyroid CVD patients.