Synthetic TRH (Thypinone) is now available. Intravenous bolus administration of TRH normally results in a marked rise in serum TSH levels by 30 minutes after the dose. Serum prolactin levels also increase. There is some disagreement as to how much TRH to administer, with doses reported in the literature ranging from 100-500 µg. Early studies reported that at least 400 µg was needed to obtain full TRH effect. Interpretation depends on whether the patient has evidence of hyperthyroidism or hypothyroidism. One problem, however, is disagreement in the literature concerning how much TSH increase over baseline is considered “exaggerated.” The normal limit of increase over baseline varies in the literature from 20-40 µU/ml, so that 25 µU/ml seems to be a reasonable compromise. Reactions to the TRH injection are uncommon, but can occur, and the patients should be closely monitored during the procedure. In general, the smaller the dose, the lower the incidence of reactions. Therefore, many laboratories and investigators use a 200-µg dose; and a few, even a 100-µg dose. However, I have not seen any reports that compared sensitivity of these doses to the gold standard of the 400- or 500-µg dose. Even if such a report appears, it would take several studies including a very substantial number of patients with hypothyroidism and hyperthyroidism to verify satisfactory performance.

Drawbacks. (1) There is conflicting evidence in the literature regarding the effects of severe non thyroid illness on TRH test results. At least one report indicates that a blunted response may occur in some apparently euthyroid patients with depressed T4 levels associated with severe non thyroid illness and also in some patients with hypothyroidism who also had severe non thyroid illness. This would complicate the diagnosis of hypothyroidism in some cases as well as the differential diagnosis of primary versus secondary etiology. (2) Several reports suggest that TSH response to TRH may be less in elderly persons. (3) In addition, certain conditions such as psychiatric unipolar depression, fasting more than 48 hours duration, and therapy with aspirin, levodopa, or adrenocorticosteroids depress TSH response to TRH. (4) Patients should discontinue desiccated thyroid or T4 therapy for 3-4 weeks (literature range, 2-5 weeks) before a TRH test. (5) Another (although not major) drawback is the $30-$40 cost for TRH and the need for two or three TSH assay specimens.

Thyrotropin-releasing hormone results in hyperthyroidism. In hyperthyroidism, pituitary TSH production is suppressed by direct effect of excess circulating T4/T3 on the pituitary, and TSH assay after TRH fails to demonstrate a significant degree of TSH increase from pretest baseline values (positive test result). Unfortunately, about 5% false positive results (failure to elevate serum TSH levels after TRH) have been reported in persons without demonstrable hyperthyroidism. A flat or blunted TSH response to TRH has also been reported in patients with autonomous thyroid nodules but no clinical evidence of hyperthyroidism, in a considerable number of patients after adequate treatment of Graves’ disease, and in some patients with multinodular goiter. Certain other conditions (discussed later) may also affect results. A flat TRH test result is therefore considered very suggestive but not conclusive evidence of thyrotoxicosis. A normal result (normal degree of TSH elevation after TRH) is considered very reliable in excluding thyrotoxicosis. For this reason the TRH test is currently considered the most reliable confirmatory procedure for hyperthyroidism and is the standard against which all other tests are compared for accuracy.

Thyrotropin-releasing hormone results in hypothyroidism. In primary hypothyroidism the TRH test usually demonstrates an exaggerated TSH response. This may render the test useful in the occasional patient with both equivocal symptoms and equivocal serum TSH values. Theoretically, the TRH test should be able to differentiate between hypothyroidism from inability of the pituitary to secrete TSH due to pituitary disease (secondary hypothyroidism) and inability of the hypothalamus to secrete TRH (tertiary hypothyroidism). In pituitary disease, the serum TSH level should not rise significantly after TRH administration, whereas in hypothalamic disease there characteristically is a TSH response that is normal in degree but that is delayed for approximately 30 minutes. Unfortunately, a substantial number of patients with pituitary lesions demonstrate relatively normal or delayed TRH test response. Therefore, absent or markedly blunted response is strongly suggestive of primary pituitary disease, but response to TRH is not diagnostic of hypothalamic disease.

Thyrotropin-releasing hormone results in psychiatric patients. There have been reports that the TRH test is useful in differentiating unipolar (primary depression only) from bipolar (manic-depressive) psychiatric illness and from secondary types of depression. In unipolar depression, TRH-induced TSH response is said to be blunted in up to two thirds of patients, whereas most patients with other categories of depression have normal TSH response. Occasional patients with symptoms of depression may actually have thyrotoxicosis (“apathetic hyperthyroidism”) and some may have hypothyroidism.