Repetitive or continuous thyrotropin (TSH)-releasing hormone administration induces a biphasic rise in plasma TSH in euthyroid but not in hypothyroid rats.

In euthyroid rats, repetitive bolus injections of 0.1, 1, or 5 micrograms/100 g BW TRH every 15 min for 2 h produced a biphasic rise in the plasma TSH concentration. After an initial peak at 15 min, plasma TSH fell at 60 min to a nadir 50-80% of the 15-min peak, then rose again by 90 min to a plateau with approximately the same amplitude as the initial peak. Plasma TSH remained at this level until TRH injections were stopped at 2 h, then fell to the pre-TRH baseline by 3 h. A similar biphasic rise in plasma TSH was produced by constant infusion of 0.01, 0.1, or 1 microgram/min TRH for 3 h. If the dose of bolus TRH injected was increased at 45 min, the dip in plasma TSH at 60 min was significantly decreased. A single iv injection of 1 microgram/100 g BW T4 immediately or 4 h before the bolus TRH injections did not abolish the biphasic TSH response. However, the T4 injection 4 h before TRH significantly attenuated the amplitude of the TSH response. In hypothyroid rats, either repetitive bolus injections or constant infusion of TRH induced only a single peak of plasma TSH at 15-30 min, after which plasma TSH fell to and remained at the pre-TRH baseline. If the hypothyroid rats were injected with 2 micrograms/100 g BW T4 for 4 days before TRH bolus injections, a biphasic TSH response to continual TRH, identical to that in euthyroid rats, was produced. The pituitary TSH content of the hypothyroid rats was significantly subnormal. T4 treatment for 4 days restored both plasma and pituitary TSH levels to the euthyroid range. Our data indicate that 1) constant or repetitive exposure to TRH induces a biphasic rise in plasma TSH in euthyroid, but not in hypothyroid, rats; 2) this biphasic phenomenon is not produced by negative feedback of T4 on the thyrotroph; and 3) the rapid development of refractoriness to TRH in hypothyroid rats is not dependent on continuous exposure to a constant concentration of TRH, but may be related to the reduced TSH content of the hypothyroid thyrotroph.