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Thyrotropin-releasing hormone
Thyrotropin-releasing hormone
Thyrotropin-releasing hormone
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thyrotropin-releasing hormone
Structural formula of TRH
Identifiers
SymbolTRH
NCBI gene7200
HGNC12298
OMIM275120
RefSeqNM_007117
UniProtP20396
Other data
LocusChr. 3 q13.3-q21
Search for
StructuresSwiss-model
DomainsInterPro
Thyrotropin-releasing hormone
Clinical data
ATC code
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.934 Edit this at Wikidata
Chemical and physical data
FormulaC16H22N6O4
Molar mass362.390 g·mol−1
3D model (JSmol)
  • C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@@H]3CCC(=O)N3)C(=O)N
  • InChI=1S/C16H22N6O4/c17-14(24)12-2-1-5-22(12)16(26)11(6-9-7-18-8-19-9)21-15(25)10-3-4-13(23)20-10/h7-8,10-12H,1-6H2,(H2,17,24)(H,18,19)(H,20,23)(H,21,25)/t10-,11-,12-/m0/s1
  • Key:XNSAINXGIQZQOO-SRVKXCTJSA-N

Thyrotropin-releasing hormone (TRH) is a hypophysiotropic hormone produced by neurons in the hypothalamus that stimulates the release of thyroid-stimulating hormone (TSH) as well as prolactin from the anterior pituitary.

TRH has been used clinically in diagnosis of hyperthyroidism,[1] and for the treatment of spinocerebellar degeneration and disturbance of consciousness in humans.[2] Its pharmaceutical form is called protirelin (INN) (/proʊˈtaɪrɪlɪn/).

Physiology

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Synthesis and release

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The hypothalamic-pituitary-thyroid axis. TRH can be seen in green.

TRH is synthesized within parvocellular neurons of the paraventricular nucleus of the hypothalamus.[3] It is translated as a 242-amino acid precursor polypeptide that contains 6 copies of the sequence -Gln-His-Pro-Gly-, with both ends of the sequence flanked by Lys-Arg or Arg-Arg sequences.

To produce the mature form, a series of enzymes are required. First, a protease cleaves to the C-terminal side of the flanking Lys-Arg or Arg-Arg. Second, a carboxypeptidase removes the Lys/Arg residues leaving Gly as the C-terminal residue. Then, this Gly is converted into an amide residue by a series of enzymes collectively known as peptidylglycine-alpha-amidating monooxygenase. Concurrently with these processing steps, the N-terminal Gln (glutamine) is converted into pyroglutamate (a cyclic residue). These multiple steps produce 6 copies of the mature TRH molecule per precursor molecule for human TRH (5 for mouse TRH).

TRH synthesizing neurons of the paraventricular nucleus project to the medial portion of the external layer of the median eminence. Following secretion at the median eminence, TRH travels to the anterior pituitary via the hypophyseal portal system where it binds to the TRH receptor stimulating the release of thyroid-stimulating hormone from thyrotropes and prolactin from lactotropes.[4] The half-life of TRH in the blood is approximately 6 minutes.

TRH is also produced in many hypothalamic neurons not associated with the pituitary, as well as multiple other CNS regions (including the spinal cord, brainstem, thalamus, amygdala, and hippocampus), indicating various non-neuroendocrine functions.[1]

TRH is additionally produced in multiple endocrine and non-endocrine tissues outside the CNS, including the anterior pituitary, parafollicular cells of the thyroid glands, medulla of the adrenal gland, islet cells of the pancreas, Leydig cells of the testis, epididymis, prostate, GI tract, spleen, lung, ovary, retina, and hair follicles.[1]

Regulation of release

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Regulation of TRH release is regulated principally by a negative feedback loop by thyroid hormone, and a neuronal open loop by hypothalamic factors. TRH release is additionally regulated by other circulating hormones (including glucocorticoids, and oestrogens), and inhibited by cytokines. The tanycytes of the median eminence also exert a regulatory effect on TRH release.[1]

Function and effects

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Neurotransmission and neuromodulation

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Extensive production of TRH throughout the CNS various non-endocrine (neurotransmissive and neuromodulatory) functions. Indeed, artificial administration into the CNS exhibits autonomic (hyperthermic, hypertensive, positive chronotropic, and gastrokinetic effects, and promotion of insulin and gastric acid release), antiepileptic, anxiolytic, and pro-locomotive effect.[1]

Structure

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TRH is a tripeptide, with an amino acid sequence of pyroglutamyl-histidyl-proline amide.

History

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The structure of TRH was first determined, and the hormone synthesized, by Roger Guillemin and Andrew V. Schally in 1969.[5][6] Both parties insisted their labs determined the sequence first: Schally first suggested the possibility in 1966, but abandoned it after Guillemin proposed TRH was not actually a peptide. Guillemin's chemist began concurring with these results in 1969, as NIH threatened to cut off funding for the project, leading both parties to return to work on synthesis.[7]

Schally and Guillemin shared the 1977 Nobel Prize in Medicine "for their discoveries concerning the peptide hormone production of the brain."[8] News accounts of their work often focused on their "fierce competition" and use of a very large number of sheep and pig brains to locate the hormone.[7]

Clinical significance

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Diagnostic

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Intravenous injection of TRH has been used for diagnostic purposes in the context of the TRH test; administration of exogenous TRH can be used to determine whether hypothyroidism is of hypothalamic or hypophyseal etiology. However, this diagnostic approach has been superseded by ultrasensitive TSH assays and is nowadays only seldom employed.[1]

ACTH and GH release

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TRH promotes release growth hormone (GH) in individuals with certain pathological conditions, and of adrenocorticotropic hormone (ACTH) in some individuals with Cushing's disease.[1]

TRH promotes GH release in individuals with acromegaly; prolonged exposure to GHRH may cause the pituitary to release GH in response to TRH. TRH may also promote GH release in individuals with hepatic disease, uremia, childhood hypothyroidism, anorexia nervosa, and depression. Conversely, TRH suppresses GH release during sleep.[1]

Side effects

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Side effects after intravenous TRH administration are minimal.[9] Nausea, flushing, urinary urgency, and mild rise in blood pressure have been reported.[10] After intrathecal administration, shaking, sweating, shivering, restlessness, and mild rise in blood pressure were observed.[11]

Research

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TRH has been evaluated for the treatment of various neurological disorders. It has been attempted for treatment of various epileptic disorders. TRH has been shown to improve outcomes of CNS injuries in experimental models. Efficacy for the treatment ALS and spinal muscle atrophy has not been demonstrated.[1]

Many individuals with depression exhibit a blunted endocrine response to TRH due to unknown reasons, and the response is correlated with clinical outcomes. Involvement of TRH in the pathogenesis of depression has nevertheless not been well established. TRH has undergone research for its ostensible antidepressant properties, however, results regarding efficacy have been inconsistent.[1] One study on a small sample of people with treatment-resistant depression found short-lived anti-depressant and anti-suicidal effects when TRH was administered intrathecally.[11] An orally bioavailable prodrug is being researched.[12] In 2012, the U.S. Army awarded a research grant to develop a TRH nasal spray for suicide prevention amongst veterans.[13][14]

TRH acts as a wakefulness-promoting agent, causing awakening from sleep or sedation.[1]

TRH has been shown to exert anti-aging effect in a mice model.[15]

Thyrotropin-releasing hormone (TRH)
Identifiers
SymbolTRH
PfamPF05438
InterProIPR008857
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Thyrotropin-releasing hormone

View on Grokipedia
from Grokipedia
Thyrotropin-releasing hormone (TRH), also known as thyroliberin, is a with the structure pyroglutamyl-histidyl-prolineamide (pGlu-His-Pro-NH₂) that is primarily synthesized in neurons of the paraventricular nucleus of the . It functions as the central regulator of the hypothalamic-pituitary-thyroid (HPT) axis by binding to G protein-coupled receptors on thyrotroph cells in the , thereby stimulating the synthesis and of (TSH). This TSH release, in turn, drives the gland to produce and secrete (T3 and T4), which are essential for , growth, development, and . TRH also promotes from lactotroph cells in the pituitary and exerts neuromodulatory effects throughout the , influencing , , and feeding . Discovered in through purification from hypothalamic extracts, TRH was the first hypothalamic releasing identified, providing foundational insights into the integrated control of endocrine systems. Its production is dynamically regulated by from circulating and modulated by factors such as nutritional status, stress, and circadian rhythms, ensuring adaptive responses to physiological demands. While its primary role maintains levels, dysregulation of TRH signaling has been linked to disorders like , depression, and neurodegenerative conditions, highlighting its broader pathophysiological significance.

Chemical Properties

Molecular Structure

Thyrotropin-releasing hormone (TRH) is a consisting of the sequence pyro-histidyl-amide, abbreviated as pGlu-His-Pro-NH₂. The N-terminal (pGlu) arises from the cyclization of a residue in the precursor, forming a ring that confers resistance to aminopeptidases, while the C-terminal is amidated to yield the amide group, enhancing overall stability. This modified gives TRH a molecular formula of C₁₆H₂₂N₆O₄ and a molecular weight of approximately 362 Da. TRH exhibits high water solubility, dissolving readily up to concentrations of 10 mg/mL, and remains stable under neutral physiological conditions ( ~7.4), which supports its role in biological fluids. In comparison to other hypothalamic releasing hormones, TRH is notably the smallest, as a with distinctive pyroglutamyl and amidated termini; for instance, (GnRH) is a decapeptide with a pyroglutamyl and C-terminal amidation, and (CRH) is a much larger 41-amino-acid lacking such modifications.

Biosynthesis and Metabolism

Thyrotropin-releasing hormone (TRH) is synthesized as part of a larger precursor polypeptide known as prepro-TRH, which consists of 218–255 depending on the and contains multiple copies of the TRH (Gln-His-Pro-Gly) flanked by cleavage sites. In humans, the TRH encoding prepro-TRH is located on chromosome 3q22.1 and spans approximately 3.2 kb with three exons. Post-translational processing of prepro-TRH begins with cleavage of the in the , followed by enzymatic processing in the trans-Golgi network and secretory granules. convertases such as PC1/3 and PC2 cleave the precursor at dibasic sites, primarily Lys-Arg or Arg-Arg pairs, to generate TRH progenitor sequences. The N-terminal residue then undergoes cyclization to form (pyroGlu), a modification that enhances stability and is likely catalyzed by glutaminyl cyclases or occurs spontaneously under physiological conditions. Concurrently, the C-terminal serves as a substrate for peptidylglycine α-amidating monooxygenase (PAM), which converts the residue to prolinamide, yielding the mature pyroGlu-His-Pro-NH₂. TRH synthesis is predominantly localized to the paraventricular nucleus (PVN) of the , where it serves as a key regulator of the hypothalamic-pituitary-thyroid axis, but prepro-TRH mRNA and TRH immunoreactivity are also detected in other regions such as the , , and , as well as peripheral tissues including the , , and . Metabolism of TRH occurs rapidly via hydrolysis by pyroglutamyl peptidase II (EC 3.4.19.6), a membrane-bound ectoenzyme highly specific for the pyroGlu-His bond, leading to inactivation and production of cyclo(His-Pro) and . This degradation pathway contributes to TRH's short plasma of about 5 minutes in humans, ensuring precise temporal control of its physiological actions. Although directly disrupting TRH are exceedingly rare, common genetic variations in the TRH gene, such as single polymorphisms, have been linked to altered serum thyrotropin levels, potentially influencing prepro-TRH expression and contributing to subtle dysregulation in function. In contrast, rare inactivating in the TRH receptor gene (TRHR) underlie isolated central by impairing TRH signaling downstream of .

Physiological Mechanisms

Synthesis and Release in Hypothalamus

Thyrotropin-releasing hormone (TRH) is primarily synthesized in the parvocellular subdivision of the paraventricular nucleus (PVN) of the , where it is produced by specialized neurons that serve as the key regulators of the hypothalamic-pituitary-thyroid axis. These TRH-producing neurons extend axonal projections to the , a circumventricular structure at the base of the , allowing for targeted release into the hypophyseal portal circulation. Within the PVN, TRH is derived from the processing of a larger precursor protein, prepro-TRH, which is cleaved to generate the mature tripeptide. Following synthesis, TRH is packaged into dense-core secretory granules within the neuronal cell bodies and transported along axons to terminals in the . There, upon appropriate stimulation, the granules undergo calcium-dependent , releasing TRH directly into the hypophyseal portal blood vessels that connect the to the . This mechanism ensures efficient delivery of TRH to pituitary thyrotrophs while minimizing dilution in peripheral circulation. The basal release of TRH exhibits a , with patterns that align with the nocturnal surge in (TSH) secretion, as observed in studies including hypothalamic slice preparations. Additionally, TRH secretion occurs in pulsatile patterns, contributing to the ultradian oscillations in downstream TSH levels. TRH is also synthesized at lower levels in extrahypothalamic sites, such as the and , where it functions primarily as a neuromodulator rather than a hypophysiotropic hormone, underscoring the hypothalamus's dominant role in endocrine regulation. Quantification of TRH in hypothalamic tissues and biological fluids, including portal and , is typically achieved through techniques, which provide sensitive detection of picomolar concentrations and have been instrumental in mapping TRH distribution and dynamics.

Regulation of Release

The release of thyrotropin-releasing hormone (TRH) from neurons in the paraventricular nucleus (PVN) of the is tightly regulated by mechanisms from . (T3) exerts a direct inhibitory effect on TRH specifically in PVN neurons, reducing pro-TRH mRNA levels and thereby suppressing TRH biosynthesis and secretion. This cell-specific repression ensures that elevated circulating levels (T3 and thyroxine, T4) dampen hypothalamic TRH production, maintaining in the hypothalamic-pituitary- axis. Several physiological stressors positively modulate TRH release to adapt thyroid function. Cold exposure activates TRH neurons in the PVN through noradrenergic inputs from the , enhancing TRH to promote via increased output. Acute stress similarly stimulates TRH via catecholaminergic pathways and, in some contexts, signaling, which can transiently upregulate TRH expression to support metabolic demands. In contrast, generally suppresses TRH release through reduced signaling, though initial adaptive responses may involve catecholamine-mediated adjustments before suppression dominates. Inhibitory factors also fine-tune TRH secretion. Somatostatin, released from periventricular hypothalamic neurons, directly suppresses TRH release from hypothalamic tissue, contributing to the restraint of thyroid axis activity during non-stressful conditions. Dopamine, acting via tuberoinfundibular pathways, inhibits TRH release in the , further modulating basal secretion levels. Circulating hormones influence TRH dynamics in response to nutritional status. Leptin, secreted from , enhances TRH gene expression and release in the PVN by recruiting STAT3 transcription factors to the TRH promoter, thereby supporting function during fed states. Ghrelin, an orexigenic peptide from the , exerts an inhibitory effect on the hypothalamic-pituitary- axis, including reduction of TRH secretion in animal models and suppression of TSH in humans, though its role can vary with metabolic context. In pathophysiological states like primary hypothyroidism, diminished thyroid hormone levels impair , resulting in elevated TRH secretion from the PVN as the system attempts to compensate for low T3 and T4. This dysregulation underscores the sensitivity of TRH release to endocrine feedback loops.

Peripheral Effects on Endocrine System

Thyrotropin-releasing hormone (TRH) primarily exerts its peripheral effects on the endocrine system through the hypothalamic-pituitary-thyroid (HPT) axis, where it binds to thyrotropin-releasing hormone receptor 1 (TRHR1) on thyrotroph cells. TRHR1 is a Gq-coupled that, upon TRH binding, activates (PLC), leading to the production of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This signaling cascade mobilizes intracellular calcium stores, increasing cytosolic calcium levels and activating (PKC), which ultimately stimulates the synthesis and release of (TSH) from thyrotrophs. In addition to TSH, TRH stimulates (PRL) secretion from pituitary lactotroph cells via the same /PLC-IP3-calcium pathway, as TRHR1 is also expressed on these cells. This effect is particularly notable in conditions like , where hyperprolactinemia occurs in 20-57% of cases due to elevated TRH drive. The released TSH then acts on follicular cells, binding to TSH receptors to promote uptake, synthesis, and the production and secretion of (T3) and thyroxine (T4), thereby completing the HPT axis feedback loop with negative regulation by T3 and T4 on both TRH and TSH. The dose-response profile for TRH's stimulation of TSH release is well-characterized in clinical settings, with intravenous administration of 200-500 μg typically eliciting a peak TSH response within 30 minutes in healthy individuals, often doubling or more from baseline levels. This response is dose-dependent, with lower thresholds around 10-50 μg sufficient for detectable TSH elevation in sensitive assays, though supraphysiologic doses are used diagnostically to assess pituitary reserve. Beyond the HPT axis, TRH has minor extrathyroidal effects on other endocrine targets; for instance, it can provoke paradoxical (GH) release in 70-80% of patients via TRHR1 on somatotrophs, and preproTRH fragments may inhibit (ACTH) secretion in animal models, though these roles are not primary.

Central Nervous System Roles

Neuromodulatory Functions

Thyrotropin-releasing hormone (TRH) and its receptors (TRHRs) are widely distributed throughout the (CNS), enabling diverse neuromodulatory roles beyond endocrine regulation. TRH neurons and TRH mRNA expression are prominent in hypothalamic regions such as the paraventricular nucleus (PVN), as well as in extrahypothalamic areas including the , telencephalon, mesencephalon, (e.g., and rhinal cortex), brainstem nuclei, and . TRHRs, particularly TRHR1 and TRHR2, show complementary distributions, with high densities in the , , limbic structures like the , motor and cranial nerve nuclei, , and spinal lamina I, supporting TRH's influence on neural circuits involved in emotion, , and . TRH modulates monoaminergic systems in the , enhancing the turnover and release of serotonin (5-HT) and norepinephrine (NE), which contributes to its potential effects in preclinical models of depression. Administration of TRH or its analogs increases cerebral noradrenaline turnover and stimulates NE and release in various regions, while also promoting 5-HT release, particularly in models where monoamine deficits mimic depressive states. These actions occur independently of peripheral thyroid hormone effects, as evidenced by rapid behavioral improvements in depression models following central TRH application. In the of the , TRH contributes to and by altering the thermoregulatory set point and promoting . Microinjections of TRH into the preoptic/anterior lower the body temperature set point in hibernating species, facilitating adaptive thermogenic responses, while broader CNS TRH signaling enhances and suppresses , as seen in studies of TRH's wake-promoting effects. TRH interacts with other neuropeptides to fine-tune neuronal excitability, such as by modulating the effects of (SP) in respiratory and sensory circuits. In the brainstem and , TRH co-localizes with SP in certain neurons and enhances SP-mediated excitation of motoneurons, potentiating respiratory rhythm and sensory transmission through shared G-protein-coupled receptor pathways. Genetic studies using TRH or TRHR knockout mice reveal links between TRH deficiency and altered emotional and behaviors. TRH-deficient mice exhibit disruptions in sleep architecture, reduced , and increased susceptibility to anxiety- and depression-like phenotypes, while TRHR1 s show heightened anxiety and depressive behaviors, underscoring TRH's role in limbic modulation independent of function.

Neurotransmitter Activity

Thyrotropin-releasing hormone (TRH) functions as a through its co-localization with classical neurotransmitters in specific neuronal populations, notably in serotonergic neurons of the medullary . In these neurons, TRH is stored and released alongside serotonin (5-HT) and , contributing to the modulation of respiratory control circuits by enhancing excitatory drive to respiratory rhythm-generating neurons in the and retrotrapezoid nucleus. Presynaptic release of TRH from terminals occurs in a calcium-dependent manner at synapses within the , where it binds to postsynaptic type 2 thyrotropin-releasing hormone receptors (TRHR2) to initiate signaling cascades leading to neuronal . of TRHR2, which is prominently expressed in spinal motoneurons and certain nuclei, triggers C-mediated increases in intracellular calcium and inhibition of conductances, resulting in membrane and enhanced neuronal excitability. In spinal motor function, TRH enhances motoneuron excitability by directly exciting alpha-motoneurons through axodendritic synapses, facilitating locomotor patterns and supporting recovery after . Application of TRH or its analogs depolarizes motoneurons and potentiates persistent inward currents, promoting rhythmic motor output in neonatal models of locomotion and aiding functional restoration in injured spinal circuits by counteracting post-injury hypoexcitability. Electrophysiological studies in hippocampal slices demonstrate TRH's role in direct synaptic transmission, where it induces excitatory postsynaptic potentials (EPSPs) by enhancing NMDA receptor-mediated currents in CA1 pyramidal neurons. Bath application of TRH amplifies Schaffer collateral-evoked EPSPs without altering presynaptic release, indicating a postsynaptic mechanism that strengthens signaling and contributes to hippocampal network activity. Species differences in TRH's neurotransmitter activity are evident, with more prominent direct excitatory effects in amphibians compared to mammals for certain neural circuits. In frog spinal motoneurons, TRH elicits large, voltage-dependent enhancements of EPSPs and synaptic currents, driving robust behavioral responses like locomotion, whereas in mammals, these effects are subtler and often integrated with other neuromodulators in respiratory and motor pathways.

Clinical and Therapeutic Aspects

Diagnostic Applications

The thyrotropin-releasing hormone (TRH) stimulation is a diagnostic procedure used to evaluate hypothalamic-pituitary dysfunction by assessing the pituitary gland's capacity to release (TSH) in response to TRH administration. In this , 200-500 μg of TRH is administered intravenously as a bolus, typically after an overnight fast. Blood samples are drawn at baseline (0 minutes), 20 minutes, and 60 minutes post-injection to measure TSH levels, allowing for the calculation of the peak TSH response or fold increase. This protocol helps differentiate between primary and secondary , as well as identify pituitary lesions. Interpretation of the TRH stimulation test relies on the magnitude of the TSH response. A blunted TSH rise (typically <2-5-fold increase or peak <5-10 μIU/mL) in patients with low or low-normal free thyroxine (T4) levels indicates secondary (pituitary) or tertiary (hypothalamic) due to impaired TSH secretion. Conversely, an exaggerated TSH response (>20-30 μIU/mL peak) suggests primary , where the pituitary compensates for low thyroid hormone levels. As an adjunct, the test evaluates response, which is often blunted in patients with prolactinomas or other pituitary lesions, aiding in the detection of such tumors when basal is elevated but inconclusive. Although historically valuable, the is now rarely used in routine practice due to the availability of highly sensitive TSH assays that reliably diagnose most disorders through basal measurements alone. (MRI) has further reduced its necessity by directly visualizing hypothalamic-pituitary abnormalities in equivocal cases. It remains occasionally employed in complex scenarios, such as borderline TSH levels with suspected central or to confirm pituitary reserve when other tests are nondiagnostic.

Therapeutic Potential and Uses

Thyrotropin-releasing hormone (TRH) has limited approved therapeutic applications, primarily through its synthetic analog protirelin, which has been used adjunctively to adjust hormone dosage in patients with primary . However, protirelin's therapeutic role remains restricted, and it was withdrawn from markets in several regions, including the , in 2002 due to the availability of more convenient diagnostic alternatives like immunoassays. A key approved use of a TRH analog is taltirelin, which received marketing approval in in for the treatment of spinocerebellar degeneration, particularly to alleviate symptoms in . As of 2024, taltirelin remains approved and available in for this indication, with recent studies reaffirming its efficacy in improving symptoms. Clinical trials supporting this approval demonstrated improvements in motor function, with a double-blind, randomized controlled study showing significant benefits in ataxia scores compared to . Investigational applications of TRH and its analogs have focused on psychiatric disorders, including depression and , leveraging TRH's neuromodulatory effects in the . In depression, intravenous administration of TRH has shown rapid effects, with improvements in mood observed within hours in treatment-resistant patients. TRH analogs like montirelin and CG-3703 have exhibited significant activity in preclinical and early clinical studies, enhancing response rates without substantially altering hormone levels. For , trials with the TRH analog DN-1417 reported reductions in positive symptoms, such as hallucinations, correlating with behavioral rating scale improvements. The short plasma of TRH, approximately 6.5 minutes following intravenous injection, poses significant delivery challenges, necessitating the development of stable analogs or alternative administration routes to sustain therapeutic effects. Analogs such as taltirelin overcome this by resisting enzymatic degradation, allowing oral and prolonged central action. Intranasal formulations, including nanoparticle-encapsulated TRH, are under preclinical investigation to enhance penetration and bypass systemic clearance. Efficacy data from clinical studies indicate modest effects with TRH at doses of 1-10 mg, particularly in augmenting standard treatments, though results vary and larger trials are needed for broader validation.

Adverse Effects and Safety

The administration of thyrotropin-releasing hormone (TRH), also known as protirelin, is generally associated with mild and transient side effects, primarily due to its actions. Common adverse effects include , a sensation of flushing or warmth, urinary urgency, , a metallic or bad taste in the mouth, abdominal discomfort, and dry mouth, occurring in approximately 50% of patients receiving intravenous doses. These symptoms typically onset within minutes of injection and resolve within 15-30 minutes without intervention. Serious risks are less frequent but can include bronchospasm, particularly in patients with or obstructive airway disease, as well as or leading to syncope. Contraindications encompass known hypersensitivity to TRH, and caution is advised in individuals with , , or myocardial ischemia, where it may lower the or exacerbate fluctuations. Convulsions have been reported rarely in patients with predisposing conditions such as or brain lesions. In animal models, dose-dependent manifests at high intravenous doses exceeding 3 mg/kg, where TRH can activate electroclinical seizures lasting 25-45 minutes in some . Long-term safety data indicate no evidence of carcinogenicity or mutagenicity based on available , though comprehensive assessments are limited. Analogs such as taltirelin exhibit improved safety profiles with reduced gastrointestinal effects like , while maintaining similar efficacy and showing no significant adverse impacts on or development in preclinical evaluations. During TRH administration, particularly in diagnostic tests, monitoring of is essential before and for at least 15 minutes post-injection, with patients positioned to mitigate hypotensive risks; electrocardiogram (ECG) monitoring may be warranted in those with cardiovascular concerns. TRH is classified as C, with use recommended only if potential benefits outweigh risks due to limited human data.

Historical Development

Discovery and Isolation

The quest to identify the hypothalamic factor responsible for stimulating thyrotropin (TSH) secretion from the gland culminated in its isolation in 1969 by two independent research teams led by Andrew V. Schally at the Veterans Administration Hospital in New Orleans and at in . Both groups employed bioassays measuring TSH release to guide the purification process from acid extracts of animal hypothalami, marking a breakthrough in understanding neurohumoral control of the endocrine system. Schally's team isolated the factor from porcine hypothalami, while Guillemin's group worked with ovine tissue, demonstrating the substance's potency at nanomolar concentrations despite its low abundance in neural tissue. The purification efforts were monumental, requiring the processing of vast quantities of starting material due to the hormone's scarcity and instability. Schally's laboratory extracted and fractionated material from over 100,000 porcine hypothalami to yield approximately 2.8 mg of purified substance by 1966, with further refinements leading to the final isolation in 1969; similar scale-up was necessary for Guillemin's team, which handled millions of ovine hypothalamic fragments to obtain sufficient material for . These challenges highlighted the technical hurdles of early isolation, including the development of sensitive bioassays and countercurrent distribution techniques to separate the active component from thousands of contaminants. Initially termed thyrotropin-releasing factor (TRF) based on its functional role, the substance's complete chemical identity was elucidated later that year through enzymatic digestion, analysis, and , confirming it as a small . The structural determination in 1969 paved the way for total , which verified the molecule's activity and enabled its renaming as thyrotropin-releasing (TRH) in 1970 upon publication of confirmatory studies. This discovery not only validated the long-hypothesized existence of hypothalamic releasing factors but also opened avenues for synthesizing analogs and studying pituitary regulation. In recognition of their pioneering work on peptide hormones of the , including TRH and subsequent factors like luteinizing hormone-releasing hormone, Schally and Guillemin shared half of the 1977 in Physiology or Medicine with Rosalyn Yalow, whose techniques complemented these isolation efforts.

Key Milestones in Research

In the 1980s, molecular cloning efforts advanced the understanding of TRH biosynthesis, with the isolation of the rat prepro-TRH cDNA in 1986 revealing that the precursor polypeptide contains multiple copies of the TRH tripeptide sequence (up to six in rodents), enabling the identification of diverse TRH forms and processing pathways in the brain. This discovery highlighted the complexity of TRH production beyond simple endocrine regulation, laying the groundwork for exploring its neuromodulatory potential. By the early 1990s, the TRH receptor (TRHR1) was cloned from rat pituitary cells, confirming it as a seven-transmembrane G protein-coupled receptor linked to the Gq/11 pathway, which activates phospholipase C and inositol phosphate signaling upon TRH binding. The human TRHR was subsequently cloned in 1993, facilitating studies on receptor structure-function relationships and tissue distribution. During the 1990s, synthetic protirelin (TRH itself) gained traction for clinical applications, initially as a diagnostic tool but increasingly in therapeutic trials for psychiatric conditions; early studies demonstrated rapid effects in refractory depression, with intravenous administration improving mood and reducing suicidality in small cohorts of patients. Intrathecal delivery of protirelin in 1997 further showed short-term behavioral improvements in , shifting interest toward TRH's (CNS) actions. These findings marked a pivot from TRH's traditional endocrine role to its potential in mood disorders. The 2000s brought the discovery of the TRHR2 isoform in 1998, a second Gq-coupled receptor subtype with distinct tissue expression, particularly in the CNS and , broadening TRH signaling mechanisms. This isoform's identification supported emerging evidence of TRH's non-endocrine functions, including roles in , , and ; for instance, TRH neurons in the contribute to osmotic balance by modulating release and renal water excretion in vertebrates. From the 2010s onward, research emphasized TRH analogs for CNS therapeutics, particularly in neurodegenerative diseases, reflecting a broader shift from endocrine-focused studies to neuroprotective applications. Analogs like taltirelin, a stable TRH mimetic approved in Japan in 2009 for spinocerebellar degeneration, demonstrated neuroprotection in Parkinson's disease models by preserving dopaminergic neurons and improving motor function via enhanced mitochondrial activity and reduced oxidative stress. A 2023 review integrated preclinical and clinical data, underscoring TRH analogs' potential to mitigate amyloid-beta toxicity in Alzheimer's disease and motor deficits in amyotrophic lateral sclerosis through anti-apoptotic and neurotrophic effects. Recent investigations, including 2022 analyses of endocrine disruptions in post-COVID-19 fatigue, have linked alterations in endocrine function, including thyroid pathways, to persistent symptoms like exhaustion. This evolution underscores TRH's transition to a multifaceted CNS modulator, with analogs offering improved stability and reduced peripheral side effects for conditions like neurodegeneration.

References

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  2. https://www.ncbi.nlm.nih.gov/books/NBK500006/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC2849853/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC372555/
  5. https://pubmed.ncbi.nlm.nih.gov/18418668/
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC6535279/
  7. https://pubmed.ncbi.nlm.nih.gov/24199031/
  8. https://www.nature.com/articles/s41422-022-00646-6
  9. https://www.jbc.org/article/S0021-9258%2818%2947446-7/pdf
  10. https://www.genscript.com/peptide/RP10112-Thyrotropin_Releasing_Hormone_TRH_.html
  11. https://www.ncbi.nlm.nih.gov/books/NBK279070/
  12. https://academic.oup.com/edrv/article/20/5/599/2530835
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