An alternative dynamic test that can be used to help diagnose cats with mild or occult hyperthyroidism is the thyrotropin-releasing hormone (TRH) stimulation test (1-3). Compared with the T3 suppression test, this test takes the opposite approach — now we are stimulating, rather than suppressing, the secretion of TSH from the pituitary, which in turn, would lead to increased T4 secretion.
Thyrotropin-Releasing Hormone (TSH) Stimulation Test
TRH is the hormone released by the hypothalamus that subsequently stimulates the release of thyrotropin (TSH) from the pituitary gland (4). When administered intravenously to normal cats, TRH causes an prompt increase in TSH secretion and serum T4 concentrations (see Figure 1, left panel).
|Figure 1: TRH tests in normal cats (left) & cats with hyperthyroidism (right)|
Administration of only a single dose of TRH is not enough to stimulate chronically suppressed TSH-secreting cells.
Testing Protocol for the TRH Stimulation Test
To perform the TRH stimulation test in cats, the following protocol is recommended:
- The veterinarian draws a blood sample for determination of baseline serum concentrations of total T4 (and T3).
- TRH (Protirelin) is administered to the cat at the dosage of 100 μg/kg, IV.
- Four hours later, the veterinarian again draws a blood sample for serum T4 (and T3) determinations.
Interpretation of Results of TRH Stimulation Testing
When the TRH stimulation test is performed in normal cats and sick cats without hyperthyroidism (1), there is a consistent rise in serum T4 concentrations (approximately 2-fold rise). In contrast, when the test is performed in cats with hyperthyroidism, even in cats with only slightly high or high-normal resting serum T4 concentrations, there is little, if any, rise in serum T4 values after the administration of TRH (see Figure 2, below).
The serum T3 response to TRH is less helpful in separating normal from hyperthyroid cats, because many normal cats have only a small and inconsistent rise in serum T3 concentrations after TRH administration. Therefore, I do not recommend determining the serum T3 response as part of the TRH stimulation test.
In another study of 36 cats with severe critical illness (5), half of the severely sick cats showed an inadequate T4 response to TRH stimulation test (i.e., a percent rise in serum T4 of less than 50 per cent). Unfortunately, this could create a situation where mild hyperthyroidism is falsely diagnosed in a cat with critical illness. Although the reason for this is unclear, critical nonthyroidal illness may render pituitary TSH secretion unresponsive to the stimulatory effects of TRH administration.
The bottom line: This test is not meant to differentiate normal and hyperthyroid cats from cats with severe critical illness. I do not recommend doing this test in severely ill cats, inasmuch as the test results may be invalid.
Which is Better: TRH Stimulation Test vs. the T3 Suppression Test?
Advantages of the TRH stimulation test over the T3 suppression test include the shorter time needed to perform the test (4 hours vs. 3 days), and the fact that the TRH stimulation test is not dependent upon the owner's ability to administer oral medication.
The major disadvantage of the TRH stimulation test in cats is that side effects almost invariably occur immediately after administration of the TRH (1, 6-8). These adverse effect include the following:
- Excessive salivation (see Figure 3)
- Induced defecation
- Rapid breathing (tachypnea); open mouth breathing
|Figure 3: Cat showing increased salivation after TRH administration|
Our studies show a close relationship between the presence (or absence) of suppressed serum T4 concentrations in response to T3 suppression and stimulated T4 values in response to TRH stimulation. Therefore, although the two tests evaluate the pituitary-thyroid axis in different ways, our findings indicate that the two screening tests provide similar information and can probably be used interchangeably for diagnosing mild hyperthyroidism in cats.
Future Investigations: Serum TSH Response to TRH Stimulation in Cats
In human beings, the TRH stimulation test is generally done by directly evaluating the change in serum TSH concentrations, not indirectly by measuring serum T4 values. When this is done, the TRH stimulation test is one of the most sensitive tests in detecting early or mild hyperthyroidism in human patients. Again, because TSH production is completely suppressed in hyperthyroid patients, they will not show a rise in serum TSH when TRH is administered, whereas normal individuals will respond with a brisk rise in circulating TSH within 30 minutes of TRH injection. The new, ultra-sensitive human TSH assays have largely eliminated the need for TRH stimulation testing, but it still remains a useful and time-proven test.
Similar serum TSH responses to TRH have been reported in normal dogs — baseline serum TSH concentrations increase 2- to 3-fold when measured 30 minutes after administration of TRH at doses ranging from 1-10 μg/kg. There are two major advantages of evaluating the TSH response rather than the T4 response to TRH:
- The test period is shorten from 4 hours to only 15-30 minutes.
- A much lower dose of TRH is needed, greatly reducing or eliminating the adverse signs commonly seen with the higher doses needed to elicit a serum T4 response.
Because the canine TSH assay is not designed to measure low values, basal TSH measurements are not very useful as a diagnostic test in feline hyperthyroidism (see my previous blog on TSH in cats). However, measuring the response to TRH may turn out to be a extremely useful and sensitive test for this disease.
- Peterson ME, Broussard JD, Gamble DA: Use of the thyrotropin releasing hormone stimulation test to diagnose mild hyperthyroidism in cats. Journal of Veterinary Internal Medicine 1994;8:279-286.
- Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
- Peterson ME: Diagnostic testing for feline hyper- and hypothyroidism. Proceedings of the 2011 American College of Veterinary Internal Medicine (ACVIM) Forum, pp. 95-97, 2011.
- Utiger RD: Tests of thyroregulatory mechanisms. In Ingbar SH and Braverman LE (eds): The Thyroid: A Fundamental and Clinical Text, pp 511-523. Philadelphia, JB Lippincott, 1986.
- Tomsa K, Glaus TM, Kacl GM, et al. Thyrotropin-releasing hormone stimulation test to assess thyroid function in severely sick cats. Journal of Veterinary Internal Medicine 2001;15:89-93.
- Holtman JR, Buller AL, Hamosh P, et al: Central respiratory stimulation produced by thyrotropin-releasing hormone in the cat. Peptides 1986;7:207-212.
- Beleslin DB, Jovanovic-Micic D, Tomic-Beleslin N: Nature of salivation produced by thyrotropin-releasing hormone (TRH). Brain Research Bulletin 1987;18:463-465.
- Beleslin DB, Jovanovic-Micic D, Samardzic R, et al: Studies of thyrotropin-releasing hormone (TRH)-induced defecation in cats. Pharmacology Biochemistry & Behavior 1987;26:639-641.
- Yagi K, Ohashi E, Tanabe S, Uzuka Y, Sarashina T. Serum thyrotropin response to TRH administration in six healthy beagle dogs. Veterinary Record 2000;146:706-707.