Thyrotropin TRH

Also known as: Protirelin, Thyroliberin, Thyrotropin releasing factor, TRF, Thyrel TRH, Thypinone

Evidence: Clinical

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Overview

Thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide that triggers pituitary TSH and prolactin release; used clinically as a diagnostic challenge of the thyroid axis.

Thyrotropin-Releasing Hormone (TRH, protirelin) is a hypothalamic tripeptide (pGlu-His-Pro-NH2) that stimulates the pituitary to release TSH and prolactin, indirectly driving thyroid hormone output. Its established human use is diagnostic - a 200-500 mcg IV bolus to test pituitary-thyroid reserve. TRH receptors are also present in the CNS and research has explored transient effects on mood, arousal and motor function in depression and spinal injury, though no therapeutic indication has been established. Note the entry name conflates two different molecules: thyrotropin is TSH, a pituitary glycoprotein hormone, while TRH is the hypothalamic releasing tripeptide described here. Same molecule as the catalog entry Protirelin.

Benefits

Diagnostic stimulation of the pituitary-thyroid axis; research interest in mood and arousal

Dosing reference

Research dose: 200-500 mcg (diagnostic IV bolus)
Range: 200 to 500 mcg, Diagnostic or 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 20 mg, 50 mg

Human dosing is a single intravenous bolus for the TSH-stimulation test; published dose-response work used 25 to 800 mcg IV, with 200 to 500 mcg the usual diagnostic dose (Garbutt 1994; Doi 2007). Intrathecal 500 mcg has been used in depression research (Marangell 1997). Effects within minutes of injection include a transient blood pressure change, flushing, nausea, an urge to urinate and an odd taste, and prolactin rises acutely. No repeated-dosing protocol has been established in humans.

Mechanism

TRH is a hypothalamic tripeptide (pGlu-His-Pro-NH2) that reaches the anterior pituitary through the portal circulation and stimulates TSH release from thyrotrophs through the Gq-coupled TRH receptor and phospholipase C signalling; it also releases prolactin (Joseph-Bravo 2015; Gary 2003). TSH in turn drives thyroid hormone output, and thyroid hormone feeds back on hypophysiotropic TRH neurons (Joseph-Bravo 2015). Circulating TRH is degraded quickly, with a plasma half-life near 7 minutes in humans (Iversen 1988). TRH receptors are also expressed in the CNS, and intrathecal dosing produced short-lived mood effects in refractory depression, which is the basis for calling TRH a proposed homeostatic modulator (Marangell 1997; Gary 2003).

Evidence

Clinical: at least one published human trial or an approved drug

Protirelin injection was approved by the FDA as a diagnostic agent for assessing pituitary TSH reserve: Thypinone (NDA 017638, Abbott, approved 5 November 1976) and Thyrel TRH (NDA 018087, Ferring, approved 18 July 1978); both are listed as discontinued
Human intravenous pharmacokinetics: plasma half-life 6.6 ± 1.5 min and clearance 1532 ± 423 mL/min in 14 healthy subjects (Iversen, 1988)
Dose-response study in 13 patients with major depression and 12 matched controls using 25, 100, 500 and 800 mcg IV: depressed men had blunted TSH and prolactin responses across all doses (Garbutt et al., 1994)
500 mcg intrathecally in 8 medication-free patients with refractory depression, double-blind against sham lumbar puncture: 5 of 8 responded and suicidality fell, but the effect was short-lived (Marangell et al., 1997)
Pituitary apoplexy, meaning haemorrhage into an existing pituitary adenoma, is reported after TRH stimulation testing (Wang et al., 2007)
Human-trial status: human use is diagnostic only and no therapeutic indication is approved; the TRH analog taltirelin is approved in Japan and 5 mg twice daily for 24 weeks gave a small ataxia-score benefit in spinocerebellar degeneration (n=149, Cho et al., 2025)

References

Side effects

This is a diagnostic agent with acute hemodynamic effects: transient blood pressure change, flushing, nausea, a strong urge to urinate, and an odd taste occur within minutes of injection. Pituitary apoplexy, meaning hemorrhage into an existing pituitary tumor, is a rare but life-threatening reported complication. It also acutely raises prolactin.

Storage

Storage: Refrigerate 2-8°C (36-46°F); general lyophilised-peptide guidance, no compound-specific CoA located
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: 6.6 ± 1.5 min plasma (human, IV constant infusion, n=14); degradation half-life in serum in vitro 16.8 ± 9.4 min (Iversen 1988)
Bioavailability: IV: plasma clearance 1532 ± 423 mL/min in healthy adults (Iversen 1988). Intrathecal dosing has been used in humans to bypass poor blood-brain-barrier penetration (Marangell 1997). No oral, intranasal or subcutaneous bioavailability figure located.
Molecular weight: 362.38 Da
Sequence: pGlu-His-Pro-NH2 (pyroglutamate-histidine-proline amide)