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One of the smallest hormones known — three residues, with a pyroglutamate cap and a C-terminal amide.
Also known as: Thyrotropin-releasing hormone · TRH · Thyroliberin · pGlu-His-Pro-NH2
Part of the Neuropeptides & signaling cluster
Overview
Protirelin is synthetic thyrotropin-releasing hormone (TRH), the hypothalamic tripeptide pGlu-His-Pro-NH2 (C16H22N6O4, ≈362 Da) that triggers TSH and prolactin release from the pituitary. FDA-approved in 1976 as a diagnostic test of pituitary function, it has also been used for spinocerebellar degeneration and studied as a neuromodulator in depression and ALS.
Source & context
Biological / chemical source: Synthetic form of the human hypothalamic tripeptide
Primary research or clinical context: Approved diagnostic agent (FDA 1976) for testing pituitary function in thyroid disorders; also used for spinocerebellar degeneration in some markets
What protirelin is
Protirelin is the synthetic, pharmaceutical form of thyrotropin-releasing hormone (TRH), the hypothalamic peptide that sits at the top of the thyroid axis. It is a tripeptide — pyroglutamyl-histidyl-prolinamide — with a molecular formula of C16H22N6O4 and a mass of about 362 Da, making it one of the smallest signalling peptides in human physiology. The IUPHAR/BPS Guide to Pharmacology records the same sequence in human, mouse and rat and notes that the deposited structure matches the INN record for protirelin. The pyroglutamate at the N-terminus and the amide at the C-terminus protect both ends from exopeptidases; the chip display shows X for the pyroglutamate because it has no standard one-letter code.
Mechanism: the TRH receptor
TRH released from the hypothalamus reaches the anterior pituitary through the portal circulation and binds the TRH receptor, a G-protein-coupled receptor on thyrotroph and lactotroph cells. Activation stimulates the release of thyroid-stimulating hormone and prolactin (IUPHAR record). That is the basis of the diagnostic test: an injection of protirelin should produce a measurable TSH rise if the pituitary is functioning, and a blunted response points to pituitary rather than thyroid disease. The same TSH response has been used as a research probe in psychiatry, where a blunted response has been found consistently in a proportion of patients with major depression (Garbutt et al., Archives of General Psychiatry 1994).
Beyond the thyroid axis: TRH as a neuromodulator
TRH is widely distributed outside the hypothalamus, and its pharmacology extends well beyond hormone release. Animal studies show dose-dependent analgesia, probably through interaction with the opioid peptide system, and effects on motor activity (Angelucci et al., Annali Italiani di Medicina Interna 1990). It has been described as a potent neuromodulator with therapeutic potential (Holaday & Bernton, Archives of Internal Medicine 1984) and was studied as an adjunct in amyotrophic lateral sclerosis, where clinical results were divided despite strong experimental support, with evidence of gender-related specificity in its ability to potentiate the monosynaptic reflex (Miller & Warnick, Archives of Neurology 1989).
Clinical use
Protirelin's approved role is diagnostic: testing pituitary function in patients with thyroid hormone disorders to rule out pituitary problems (IUPHAR clinical-use record). In Japan, protirelin and its analogue taltirelin are covered by health insurance for the cerebellar ataxia symptoms of spinocerebellar degeneration and are expected to suppress symptom progression, although no disease-modifying therapy exists for that condition (Matsushima & Yabe, Brain and Nerve 2023). ClinicalTrials.gov lists 15 studies, including a completed phase 3 confirmatory trial of a TRH-class agent in spinocerebellar degeneration and early-phase studies in normal volunteers and disturbance of consciousness.
Pharmacology worth knowing
Diagnostic doses of protirelin transiently raise blood pressure by non-catecholamine mechanisms: in eight cardiac-surgery patients, mean arterial pressure rose from 88 to 103 mm Hg after 500 µg intravenously, without a corresponding catecholamine surge (Zaloga et al., Archives of Internal Medicine 1984). A dose-response study infusing 25 to 800 µg found that both TSH and prolactin responses could be characterised across the range (Garbutt et al., 1994). High-dose propranolol can produce euthyroid hyperthyroxinaemia with a normal TSH response to protirelin, a documented source of diagnostic confusion (Mooradian et al., Archives of Internal Medicine 1983).
How it relates to other peptides on this site
Protirelin belongs to the family of hypothalamic releasing hormones alongside gonadorelin (GnRH), which is also on this site: both are short, N-terminally pyroglutamylated, C-terminally amidated peptides that act on pituitary GPCRs and are used diagnostically as well as therapeutically. Its downstream partner, thyroid-stimulating hormone, is a glycoprotein rather than a peptide. As an approved prescription and diagnostic agent, it is not a research chemical; this page is educational and not clinical guidance.
Sequence
One-letter sequence commonly cited for Protirelin (TRH) (educational; isoforms and modifications may differ):
XHP
X = pyroglutamate (pGlu) at position 1; the C-terminus is amidated. X marks a non-canonical residue — see the structure block below. (Plotted as alanine on the wheel.)
Residues plotted ~100° apart around an α-helix — clustering of one color reveals an amphipathic face.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Human TRH, 3 residues, identical in human, mouse and rat
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Amide
Average reference mass
Reference policy updated: 2026-10-05
- IUPHAR/BPS source snapshot · 2026-10-01
- PubChem molecular record · 2026-10-01
pGlu-His-Pro-NH2
- Molecular formula
- C16H22N6O4
- Average reference mass
- ≈ 362.38
- Receptors
- TRH receptor (TRHR) on anterior pituitary thyrotrophs and lactotrophs
- Backbone
- Human TRH, 3 residues, identical in human, mouse and rat
- C-terminus
- Amide
- Status
- Approved: FDA (1976), diagnostic use
- PubChem CID: 638678
- IUPHAR ligand: 2139
- ChEMBL: CHEMBL1472
- CAS RN: 24305-27-9
- UNII: 5Y5F15120W
Chemistry values: curated profile, PubChem, IUPHAR/BPS Guide to Pharmacology · fetched 2026-10-01.
Clinical development snapshot
ClinicalTrials.gov lists 15 registered studies with “Protirelin” as an intervention (snapshot 2026-09-07). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT04868045 | Study of Resistance to Thyroid Hormone After Long-term Exposure in People With Thyroid Cancer | Phase 1 | withdrawn | 2023-02-21 |
| NCT02399475 | Mechanistic Study of Subclinical Hypothyroidism In the Elderly | Not applicable | completed | 2021-03-09 |
| NCT01970098 | A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD) | Phase 3 | completed | 2018-12-14 |
| NCT00054756 | Study of Thyrotropin-Releasing Hormone in Normal Volunteers and in Patients With Thyroid or Pituitary Abnormal | Phase 2 | completed | 2018-08-08 |
| NCT00790296 | Evaluation of Synthetic Thyrotropin Releasing Hormone (TRH) as a Treatment for Cancer-related Fatigue | Phase 2 | terminated | 2017-12-28 |
| NCT00812149 | Pharmacogenomic Response to Thyrotropin-Releasing Hormone Stimulation in Healthy Volunteers: The Influence of | — | completed | 2017-10-06 |
Protirelin (TRH) — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Human TRH, 3 residues, identical in human, mouse and ratAverage reference mass: 362.38 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- IdentifiersCross-linked to IUPHAR ligand 2139 and PubChem CID 638678.
- TrialsClinicalTrials.gov snapshot added: 15 registered studies, highest phase 3.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Protirelin (TRH)
What is Protirelin (TRH)?+
Protirelin is synthetic thyrotropin-releasing hormone (TRH), the hypothalamic tripeptide pGlu-His-Pro-NH2 (C16H22N6O4, ≈362 Da) that triggers TSH and prolactin release from the pituitary. FDA-approved in 1976 as a diagnostic test of pituitary function, it has also been used for spinocerebellar degeneration and studied as a neuromodulator in depression and ALS.
What Canadian product status is recorded for Protirelin (TRH)?+
Canadian product status for Protirelin (TRH) has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Protirelin (TRH)?+
Protirelin (TRH) is commonly described as approximately 3 amino acids (Hypothalamic releasing hormone (tripeptide)).
What is protirelin?+
The synthetic form of thyrotropin-releasing hormone (TRH), a three-residue hypothalamic peptide (pGlu-His-Pro-NH2) that triggers TSH and prolactin release. It is FDA-approved (1976) as a diagnostic agent.
What is the sequence of TRH?+
Pyroglutamate-histidine-proline-amide: pGlu-His-Pro-NH2, formula C16H22N6O4, about 362 Da.
What is protirelin used for?+
Mainly to test pituitary function in thyroid disorders. In Japan it is also used for the cerebellar ataxia of spinocerebellar degeneration.
Does protirelin raise blood pressure?+
Diagnostic doses transiently raised mean arterial pressure by about 15 mm Hg in one study, by a non-catecholamine mechanism.
Is TRH the same as TSH?+
No. TRH (protirelin) is the hypothalamic tripeptide that stimulates the pituitary to release TSH, a much larger glycoprotein hormone that then acts on the thyroid.
Related peptides
References & further reading
- 1.PubChem — compound summary for Protirelin (CID 638678)
- 2.Garbutt JC et al. (1994). Dose-response studies with protirelin. Arch Gen Psychiatry
- 3.Zaloga GP et al. (1984). Diagnostic dosages of protirelin (TRH) elevate BP by noncatecholamine mechanisms. Arch Intern Med
- 4.Holaday JW, Bernton EW (1984). Protirelin (TRH): a potent neuromodulator with therapeutic potential. Arch Intern Med
- 5.Miller SC, Warnick JE (1989). Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens. Arch Neurol
- 6.Angelucci L et al. (1990). Pharmacologic profile of protirelin tartrate. Ann Ital Med Int
- 7.Matsushima M, Yabe I (2023). Treatment for Spinocerebellar Degeneration. Brain Nerve
- 8.Mooradian A et al. (1983). Propranolol-induced hyperthyroxinemia. Arch Intern Med