These studies were undertaken to clarify the physiological role of thyrotropin releasing hormone (TRH) in regulation of the hypothalamic pituitary thyroid axis. Synthetic TRH was administered both acutely as a single intravenous dose of 500 micro-grams (TRH IV) and chronically (TRH p.o.), in the form of repetitive oral doses (10 mg b.i.d. for 4 days) to 21 normal, 26 hypothyroid, and 14 hyperthyroid subjects. Serial determinations were made of the serum levels of thyrotropin (TSH), triiodothyronine (T3) and thyroxine (T4) after TRH IV nd TRH p.o. and changes in thyroidal untake of radioiodine were assessed after TRH p.o. In normal subjects, serum TSH and T3 rose in response to TRH IV but there was no significant change in the serum T4 levels.
The peak levels of serum TSH (TSH PL) ranged from 7.0 to 30.0 microunits per ml and serum T3 levels (T3 PL) from 126.2 to 197.4 ng/dl. After the first TRH p.o. dose, serum TSH levels rose (TSH PL : 7.0 - 34.0 microunits per ml) but the TSH increment decreased in response to subsequent doses of TRH. Nevertheless, both the mean serum T3 and T4 levels increased progressively in response to TRH p.o. reaching their peak levels on the 4th day (Mean T3 PL : 185.1 ± 4.0 ng/dl with a range of 152.8 to 216.8; Mean T4 PL : 11.7 ± 0.8 micrograms/dl with a range of 8.4 to 13.4). The mean 24-hour
131I uptake also increased by 19.9 ± 1.2% D over baseline with a range 9.1 to 30.7. After intramuscular TSH, the mean increment in a 24-hour
131I uptake was 13.2 ± 1.0% D with a range of 5.6 to 20.8%.
In all 26 patients with hypothyroidism, serum T3 and T4 failed to increase in response to TRH IV. Based on the TSH PL after TRH IV and the criteria of Pittman, the patients could be provisionally divided into primary hypothyroidism (13 patients whose TSH PL ranged from 52.5 to 500 microunits per ml), secondary or pituitary hypothyroidism (8 patients whose TSH PL varied from undetectable to 4.1 microunits/ml) and tertiary or hypothalamic hypothyroidism (5 patients whose TSH PL was from 8.8 to 30.4 microunits/ ml). The same patients were then restudied after TRH PO. Those classified as having primary hypothyroidism demonstrated no alterations in serum T3 and T4 levels or in the thyroidal uptake of
131I despite striking elevations in serum TSH reaching peak levels of 220 to 500 microunits/ml. Six of the eight patients tentatively classified as having secondary hypothyroidism on the basis of their response to TRH IV also failed to respond to TRH p.o. as evidenced by an absence of minimal serum TSH increase (TSH PL : U.D. -4.6 microunits/ml) and no change in the 24-hour thyroidal uptake of
131I (the change in uptake was from -1.9 to -0.6%) or serum T3 and T4 levels (T3 PL 12.5 to 130 ng/dl, T4 PL 2.0 to 7.6 micrograms per dl). In 2 of these 8 patients, however, TRH p.o. was followed by normal thyroidal responses despite an absence of minimal increase in TSH (TSH PL : 4.6 to 6.9 microunits/ml). In these subjects, 24-hour thyroidal uptake of
131I increased 17.6 to 24.5% T3 PL varied from 160 to 190 ng/dl and T4 PL from 9.0 to 9.6 micrograms/dl. In 4 of the 5 patients with tertiary or hypothalamic hypothyroidism, both
131I uptake and serum TSH rose (the change in the 24-hour
131I uptake was from 31.2 to 59.9%; TSH PL from 8.0 to 29.5 microunits/ml), although serum T3 and T4 remained in the normal range (T3 PL 120-140 ng/dl; T4 PL 4.8-6.6 micrograms/dl). In the 5th patient,
131I uptake, serum TSH, T3 and T4, all rose in response to TRH p.o. (the change in the 24-hour uptake of
131I was 20.7%, TSH PL 15.0 microunits/ml, T3 PL 180 ng/dl, T4 PL 13.0 micrograms/di). In primary hypothyroidism, thyroidal response to IM TSH remained subnormal after TRH p.o. but in secondary and tertiary hypothyroidism, the response was virtually restored to normal.
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