Previous studies have shown that rats bearing transplantable Walker 256 carcinoma in the thigh have decreased serum total and free T4 and T3 concentrations as well as a decrease in the concentration of hepatic nuclear T3 receptors. Despite these findings, the tumor-bearing (T) rats appeared euthyroid, since the serum TSH concentration remained unchanged, and the induction of the thyroid hormone-sensitive hepatic enzymes a-glycerophosphate dehydrogenase and malic enzyme appeared normal. To evaluate the mechanisms whereby serum TSH was maintained in the normal range in T rats in association with decreased serum T4 and T3 concentrations, we studied the regulation of TSH secretion in groups of control (C) and T rats. The pituitary TSH contents were similar in the two groups of animals, and an iv injection of TRH (5 μg/100 g BW) resulted in a 10-fold increase in plasma TSH concentrations in the control group 15 min after injection. The TSH concentrations achieved after TRH injection were significantly greater in T rats than in the C group. To study the effect of a major stimulus to TSH secretion, plasma TSH was measured for 4 days after surgical thyroidectomy. A progressive 5- to 8-fold increase in plasma TSH was noted in both C and T rats after thyroidectomy. There was no difference in the integrated TSH response between these groups. Similarly, a smaller stimulus to TSH secretion did not produce significantly different effects on plasma TSH between groups of C and T rats. This was demonstrated in studies in which both groups of rats were fed 1-methyl-2-mercaptoimidazole [methimazole(MMI)]; 10 μg/ml) in their drinking water. In a representative study, 5 days after the addition of MMI to the drinking water, the mean plasma T4 level decreased from 3.6 ± 0.5 to 2.7 ± 0.6 (SEM) μg/dl (P < 0.01). The mean plasma TSH level increased significantly (P < 0.001) from 150 ± 20 to 629 ± 135 ng/ml in C rats and from 208 ± 58 to 868 ± 196 ng/ml in T rats after MMI treatment. The local production of T3 from T4 was studied in homogenates of pituitaries obtained from C and T rats. A mean 2.1-fold increase in the rate of T3 formation from T4 was noted in tissue from T rats. Lastly, the concentration of pituitary T3 in C and T rats was determined directly by RIA. The mean T3 content of T rats (18 ± 1 pg/pituitary) was significantly decreased (P < 0.001) from that of C rats (41 ± 2 pg/pituitary). Thus, T rats with decreased plasma T4 and T3 concentrations appear to have relatively normal TSH responsiveness. Decreased plasma protein binding of T3 and increased pituitary production of T3 from T4 in the T rats favor the maintenance of pituitary T3 content in T rats compared to that in C animals. These changes, however, were insufficient uantitatively to normalize the pituitary T3 content. The fact that TSH regulation appears relatively normal with decreased pituitary nuclear T3 suggests a shift in the normal dose-response relationships between nuclear T3 and hormonal response, so that a relatively normal biological response is evoked in animals with decreased nuclear T3.
ASJC Scopus subject areas