The N3im-methyl analogue of thyrotropin release hormone (methyl-TRH) was compared with TRH as a thyrotropin releaser in 30 euthyroid volunteers (ages 19-61 years). The mean TSH response to 100 mug of methyl-TRH was greater (P less than 0.005) than the TSH response to 500 mug of TRH from 10 min to 240 min after giving the releasing factors. The mean peak TSH (at 30 min), maximum deltaTSH, and integrated TSH response area were greater (P less than 0.005) after administration of methyl-TRH than after TRH. The TSH response to methyl-TRH was significantly greater (P less than 0.05) for the 11 females than for the 19 males in this study. The mean baseline TSH was correlated with the maximum deltaTSH (r = 0.72, P less than 0.01) after methyl-TRH stimulation. The mean serum T3 concentration after methyl-TRH was significantly elevated at 60 min, peaked at 210 min and remained significantly elevated at 240 min. The peak serum T3, maximum T3 and T3 response area were significantly greater (P less than 0.005) after giving methyl-TRH than after TRH. The methyl-TRH induced T3 response area was 1.4 times the TRH induced T3 response area. The serum T4 concentration after methyl-TRH was elevated at 90 min (P less than 0.005), reached a peak at 210 min, and at 240 min was still 1.25 times the mean baseline T4. The peak serum T4, maximum deltaT4 and T4 response area after methyl-TRH were significantly greater than after TRH. The methyl-TRH induced T4 response area was 1.4 times the TRH induced T4 response area. The data indicate that methyl-TRH is a more potent thyrotropin releaser than TRH. Since N3im-methyl-histidine has been found in the brain, the possibility that this methyl analogue of TRH is a physiologic thyrotropin releaser should be evaluated.