Thyrotropin-Releasing Hormone

Chemical Identity

Property	Value
Name	Thyrotropin-Releasing Hormone
Gene	TRH (chromosome 3q26.3)
Sequence	pGlu-His-Pro-NH₂
Abbreviation	pEHP-NH₂
Length	3 amino acids (tripeptide)
MW	362.4 Da
PDB Structures	1TRO (NMR)

Structure

TRH is the simplest known releasing hormone:

• N-terminal: Pyroglutamic acid (pGlu) — cyclized glutamine
• Middle: Histidine (imidazole ring)
• C-terminal: Proline amide (Pro-NH₂)
• Conformation: β-turn in solution

Receptor

TRH Receptor (TRHR)

• Type: Class A G-protein coupled receptor
• Gene: TRHR (chromosome 8q13.3)
• Expression: Anterior pituitary (thyrotrophs, lactotrophs)
• G-protein: Gαq → PLC → IP₃ + DAG

Signaling

TRH → TRHR → Gαq → PLCβ → IP₃ + DAG
                              ↓
                        Ca²⁺ release
                              ↓
                        TSH release
                        Prolactin release

Physiological Functions

Thyroid Axis

• Primary role: Stimulates TSH release from anterior pituitary
• TSH → thyroid gland → T3/T4 release
• Negative feedback: T3/T4 suppresses TRH and TSH

Prolactin Regulation

• TRH is a potent prolactin-releasing factor
• Prolactin → mammary gland development and lactation

Other Functions

• CNS: TRH receptors in brain → antidepressant effects
• Spinal cord: TRH is neuroprotective
• GI: Stimulates gastrin release

Clinical Applications

Protirelin (TRH analog)

• Indication: Diagnostic test for thyroid function
• Test: IV TRH → measure TSH response
• Normal: TSH rises 10-30 mIU/L at 30 min
• Hypothyroidism: Exaggerated TSH response
• Hyperthyroidism: Blunted TSH response
• Secondary hypothyroidism: No TSH response

TRH in Depression

• Rationale: TRH has antidepressant effects in animal models
• Clinical trials: Mixed results in major depression
• Status: Not approved for depression

TRH in Spinal Cord Injury

• Neuroprotective: TRH analogs improve neurological recovery
• Status: Investigational

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• C-terminal amidation: Required for activity
• Pyroglutamic acid: Can be formed from Gln under acidic conditions
• Purification: RP-HPLC
• Stability: Acid-stable (pGlu protects N-terminus)

References

1. Schally AV, et al. “Isolation of the hypothalamic releasing hormone TRH.” Science 170:197-198, 1970. doi:10.1126/science.170.3952.197
2. Burgus R, et al. “Primary structure of the ovine hypothalamic releasing factor (TRH).” Proceedings of the National Academy of Sciences 67:1810-1818, 1970.
3. Morley JE. “The neuroendocrine control of appetite and weight regulation.” Endocrinology 144:4736-4741, 2003.
4. Jackson IM. “TRH in the central nervous system.” Molecular and Cellular Endocrinology 145:235-245, 1998.
5. Fliers E, et al. “TRH and the hypothalamic-pituitary-thyroid axis.” European Journal of Endocrinology 167:141-149, 2012.