We have previously shown that some oral cholecystographic agents induce marked increase in basal and TRH-stimulated TSH concentrations in normal subjects. To define the relationship between circulating iodothyronines and pituitary secretion after oral cholecystography, temporal changes in the responses of serum TSH and PRL to a fixed dose of TRH (500 micrograms iv) and in serum T4, T3, and rT3 concentrations were assessed before, immediately after, and then at weekly intervals after the three daily doses of iopanoic acid (Ip). Both basal and TRH-stimulated TSH concentrations were significantly increased at the end of the period of Ip administration when the serum T3 concentration was decreased, were still above the pretreatment level 1 week after the course of Ip when the serum T3 had returned to pre-Ip levels, and returned toward normal 2 weeks after the course of Ip. The changes in serum T3 concentration were accompanied by reciprocal changes in rT3 concentration. PRL secretion was not significantly changed. To evaluate further the relationship between the enhanced TSH secretion and the changes in serum iodothyronine concentrations, subjects were given oral doses of T3 (5 micrograms every 4 h) or T4 (50 micrograms every 8 h) during the administration of Ip. In the subjects given Ip plus T3, serum T3 concentrations were maintained at pre-Ip levels, and both basal and TRH-stimulated TSH concentrations were not different from the control. Administration of T4 did not completely prevent the Ip-induced increment of TSH secretion. It is suggested that in subjects given Ip, 1) the serum T3 level is, at least partly, a determining factor for TSH secretion; and 2) the set-point of TSH secretion is appropriately tuned to either reduction or elevation of serum T3 concentration by a mechanism that is different from that in fasting subjects.