The aim of this study was to investigate whether the severity and duration of primary hypothyroidism influence hypothalamic TRH release. Hypothyroidism was induced in male Wistar rats by treatment with different thyrostatic drugs or by thyroidectomy. Serum TSH in rats treated for up to 3 weeks with methimazole (MMI; 0.05% in drinking water) increased 20-fold, but TRH release into hypophyseal portal blood (HPB) did not change. Treatment with propylthiouracil (PTU; 0.1% in drinking water), which inhibits thyroidal T4 production and peripheral conversion of T4 to T3, resulted in a more rapid reduction in serum T3 levels and increase in serum TSH than those in rats treated with 0.1% MMI. Although these differences were no longer observed after 3 weeks of treatment, TRH release into HPB of rats treated with PTU was 34-49% higher than that in MMI-treated rats. Combined treatment with MMI (0.05-0.1% in drinking water) and iopanoic acid (IOP; 4 mg/100 g BW.day, ip), an inhibitor of both peripheral and central T4 to T3 conversion, also tended to produce a more rapid decrease in serum T3 and increase in serum TSH. After 3 weeks of treatment, serum T4, T3, and TSH were not different in the two groups, but TRH release into HPB was 48-65% increased by MMI plus IOP vs. MMI alone. Three to 10 weeks after thyroidectomy, TRH release into HPB was 58-72% higher than that in untreated controls. In vitro incubation of hypothalami isolated from rats treated for 3 weeks with MMI, MMI plus IOP, or PTU, as described above, showed that basal and 56 mM K(+)-induced TRH release were not influenced by the different drugs. Also, the total hypothalamic TRH content was not changed by any of these treatments. However, in rats treated for 1 or 2 weeks with MMI or PTU, the TRH content of the median eminence was decreased by 17-25%. These findings indicate that, depending on severity and duration, experimental hypothyroidism may cause a significant increase in hypothalamic TRH release in rats. The magnitude of these changes compared with the much larger increases in serum TSH suggests that the feedback of thyroid hormone on TSH secretion is mainly exerted at the pituitary level.