TRH Stimulation Test

The thyrotropin releasing hormone (TRH) stimulation test measures the response of TSH (and prolactin) to an intravenous bolus of TRH, which acts on thyrotroph and lactotroph cells in the anterior pituitary.

It was used to separate central (pituitary versus hypothalamic) hypothyroidism, to diagnose subclinical hyperthyroidism before sensitive TSH assays, and to differentiate TSH-secreting pituitary adenomas from thyroid hormone resistance.

With modern third generation TSH assays and free T4 measurement, the test is rarely needed. TRH (protirelin) is no longer available in many countries.

TSH-secreting adenomas are rare (about 1 to 3 in every million people, under 1% of pituitary tumours) and present with raised free T4 and inappropriately normal or raised TSH. Resistance to thyroid hormone (THRB mutation) has an incidence of about 1 in 40 000 and presents similarly. The TRH test helps here: TSH is blunted in adenomas (autonomous secretion, low response) and normal or exaggerated in resistance.

Indications. Raised free T4 and free T3 with a non-suppressed TSH (to separate TSH-secreting adenoma from thyroid hormone resistance). Low free T4 with low or normal TSH (suspected central hypothyroidism, hypothalamic versus pituitary). Rarely, equivocal subclinical hyperthyroidism or thyroid axis assessment. Not used for routine thyroid evaluation.

Contraindications and cautions. Pituitary tumour with apoplexy risk (rare reports of apoplexy after TRH), cardiac disease and uncontrolled hypertension (hypertension and tachycardia during the test), epilepsy (seizure threshold), pregnancy, and asthma. Side effects: flushing, nausea, urge to micturate, metallic taste, and transient rise in blood pressure.

Preparation. No fasting needed. Patient lies at rest, with intravenous access. Interfering drugs are reviewed (levothyroxine, dopamine agonists, glucocorticoids, somatostatin analogues and antithyroid drugs). Blood pressure is measured.

Procedure.

• Baseline blood for TSH (and prolactin) at time 0.
• Give protirelin (TRH) 200 microg intravenously over 1 to 2 minutes (400 microg in some adult regimens, and 7 microg/kg in children).
• Take blood for TSH (and prolactin) at 20 and 60 minutes (some centres also 30 minutes). Blood pressure is monitored at 5-minute intervals for 15 minutes.

Normal response. TSH rises by 5 to 25 mIU/L over baseline (to 8 to 30 mIU/L) at 20 minutes, and falls by 60 minutes. Prolactin doubles at 20 minutes. Women have a larger response than men.

Interpretation by condition.

• TSH-secreting pituitary adenoma: TSH response is blunted or absent (rise under 2 mIU/L, or under 2 times baseline), in 90% of cases. Alpha subunit to TSH molar ratio over 1 and MRI supports the diagnosis.
• Thyroid hormone resistance: TSH response is normal or exaggerated (rise over 2 mIU/L).
• Hyperthyroidism (primary): TSH is suppressed with no response to TRH (flat response), which confirms thyroid hormone excess, and has been replaced by sensitive TSH assays.
• Primary hypothyroidism: exaggerated TSH response, and TSH baseline is high.
• Central hypothyroidism: pituitary disease gives a blunted or absent response. Hypothalamic disease gives a normal or delayed response with a peak at 60 minutes rather than 20 minutes, though the distinction is unreliable.
• Prolactin: blunted rise in prolactinoma or lactotroph damage, though not diagnostic.

Critical values and findings needing immediate action.

• Severe headache, visual loss, or sudden collapse during or after the test: pituitary apoplexy, and urgent hydrocortisone, imaging and neurosurgical review.
• Blood pressure over 200/110 mmHg or chest pain: stop and monitor.
• Seizure: manage airway and stop.
• Confirmed TSH-secreting adenoma: urgent pituitary MRI, visual fields, somatostatin analogue or surgery, and control of thyrotoxicosis.

Interferences and pitfalls.

• Drugs that suppress TSH (levothyroxine, glucocorticoids, dopamine, octreotide, bexarotene) or raise it (dopamine antagonists) affect the response and are stopped where safe.
• Non-thyroidal illness, depression, fasting and ageing blunt the response.
• Assay interference (heterophile antibodies, biotin) gives false TSH and free T4 results, so assay artefact is excluded first in unexplained discordant results.
• Free T4 assay interference (familial dysalbuminaemic hyperthyroxinaemia, anti-T4 antibodies) mimics TSH-secreting adenoma and is excluded.
• Adenoma response can occasionally be preserved, so the test is combined with alpha subunit, SHBG, T3 suppression testing and imaging.
• TRH tests are no longer widely available, and the diagnostic value is limited.
• A normal response does not exclude pituitary disease, and the patient is evaluated clinically with MRI and other pituitary hormone testing.

Special groups.

• Children: dosing by weight, and the test is rarely used.
• Pregnancy: avoided.
• Older adults: blunted response, and cardiovascular side effects are a concern.
• Regions: the test is seldom available, and genetic testing for the THRB gene and imaging are used.

Follow up tests. Free T4 and free T3 on a different assay, TSH alpha subunit and molar ratio to TSH, SHBG, T3 suppression test, THRB gene sequencing, pituitary MRI, prolactin and other pituitary hormones, visual fields, family screening for resistance to thyroid hormone, and cortisol and sex steroids for associated pituitary deficiency.