Metabolic Clearance of Thyrotropin-Releasing Hormone in the Rat in Hypothyroid and Hyperthyroid States: Comparison with Serum Degradation in Vitro*

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Abstract
The effect of thyroid status on the metabolic clearance of TRH was studied in the rat. TRH (2 μg) was administered iv to hypothyroid [thyroidectomized (Tx)], hyperthyroid (T4-treated), and euthyroid control (C) animals; multiple blood and urine samples were obtained thereafter for determination of immunoassayable TRH. The plasma disappearance curves showed a double exponential in the C and Tx groups; the half-times of the first component were similar in both (2.1–2.2 min), while the second component was prolonged in the Tx rats (4.8 vs. 3.6; P < 0.01). The degradation rate of TRH was more rapid in the T,rtreated animals (P < 0.01); the disappearance curve was linear with a t½ of 1.6 min. The initial volume of distribution, MCR, and renal clearance were increased in the T4-treated rats but were reduced in the Tx animals. Despite alterations in renal clearance, the amounts of TRH excreted were similar in all groups, reflecting plasma TRH levels that were higher in Tx but lower in T4-treated animals after TRH injection. In vitro studies showed good agreement with the in vivo findings, for serum derived from T4-treated rats caused enhanced breakdown of TRH (t½, 2.4 min), while that from Tx had reduced degradative activity (t½, 6 min) compared with C (t½, 3.6 min) animals. These results suggest that thyroid status affects the MCR of TRH primarily due to its effects on the rate of plasma degradation, while the distribution space and the renal clearance are of lesser importance. The possible physiological significance of these findings is 1) thyroid status may affect TRH function through its effect on clearance and 2) plasma levels of endogenous TRH could be reduced in the presence of an increased secretion rate of TRH.