Protirelin

Also known as: TRH, Thyrotropin-releasing hormone, Thyroliberin, TRF, Thyrel TRH, Thypinone

Evidence: Clinical

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Overview

Synthetic thyrotropin-releasing hormone (pGlu-His-Pro-NH2) given IV to trigger pituitary TSH and prolactin release in function testing; the US products (1976, 1978) are discontinued.

Protirelin is synthetic thyrotropin-releasing hormone (TRH), the hypothalamic tripeptide that releases TSH and prolactin from the anterior pituitary. The FDA approved it as Thypinone (NDA 017638, 1976) and Thyrel TRH (NDA 018087, 1978) for the TRH stimulation test of pituitary TSH reserve; both are discontinued, and DailyMed lists only bulk protirelin powder. Human use is a single IV bolus, with dose-response work from 25 to 800 mcg (Garbutt 1994). Same molecule as the Thyrotropin TRH entry (id 71).

Benefits

Diagnostic stimulation of TSH and prolactin release (established clinical use)

Dosing reference

Research dose: 200 to 500 mcg IV (single diagnostic bolus)
Range: 200 to 500 mcg, Diagnostic single dose
Reconstitution: 1 mL bacteriostatic water
Common vial sizes: 1 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 pituitary TSH reserve: Thypinone (NDA 017638, Abbott, 1976) and Thyrel TRH (NDA 018087, Ferring, 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 using 25, 100, 500 and 800 mcg IV in depressed patients and matched controls: depressed men had blunted TSH and prolactin responses (Garbutt et al., 1994)
TRH stimulation testing in patients with basal TSH in the normal range (Doi et al., 2007)
Pituitary apoplexy, meaning hemorrhage into an existing pituitary adenoma, is reported after TRH stimulation testing (Wang et al., 2007)
Human-trial status: human use is diagnostic only, no therapeutic indication is approved, and no US product is currently marketed

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 acutely raises prolactin and TSH.

Storage

Storage: Refrigerated (2-8°C)
Lyophilized: 24+ months at room temperature
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