The effects of prolonged administration of iodide upon the serum concentrations of thyrotropin (TSH), thyroxine (T4), and triiodothyronine (T3) and their response to thyrotropin releasing hormone (TRH, 400 mug i.v.) have been studied in euthyroid (n = 9) subjects, and in hypothyroid (n = 4) patients. Administration of iodide (25 mg daily for two weeks) increased in healthy subjects the basal concentrations of TSH and the release of TSH in response to TRH (p less than 0.05-0.01). Serum concentrations of T4 and T3 were reduced (T4, 6.5 +/- 0.2 mug/100 ml to 5.9 +/- 0.3 mug/100 ml; T3, 159 +/- 8.3 ng/100 ml to 145 +/- 7.3 ng/100 ml) in parallel. Responses of T4 but not of T3 to TRH were also reduced after iodide. Two out of four hypothyroid patients also showed an increased response of TSH to TRH. Changes in serum T4 and T3 were due to their low basal concentration not measureable in this group. No response of TSH, T4 or T3 to TRH was observed in hyperthyroid patients either before or after iodide treatment (708 mg daily for one week), in spite of a fall in serum T4 (25%) and T3 (50%) upon iodide administration. These observations demonstrate that small changes in serum T4 and T3 are easily monitored by the thyrotrophs in the normal or in the hypothyroid range. Conversely a reduced sensitivity of the anterior pituitary upon the administration of TRH is found in hyperthyroid patients, since even large reductions in serum T4 and T3 do not facilitate an increased response of TSH to TRH in this group.