Thyrotropin-releasing hormone

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thyrotropin-releasing hormone
Thyrotropin-releasing hormone.svg
NCBI gene 7200
HGNC 12298
OMIM 275120
RefSeq NM_007117
UniProt P20396
Other data
Locus Chr. 3 q13.3-q21
Search for
Structures Swiss-model
Domains InterPro
Thyrotropin-releasing hormone
Clinical data
ATC code
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.934 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H22N6O4
Molar mass 362.390 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

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


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

Synthesis and release

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

TRH is synthesized within parvocellular neurons of the paraventricular nucleus of the hypothalamus. [2] 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. [3] The half-life of TRH in the blood is approximately 6 minutes.


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


The structure of TRH was first determined, and the hormone synthesized, by Roger Guillemin and Andrew V. Schally in 1969. [4] [5] 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. [6]

Schally and Guillemin shared the 1977 Nobel Prize in Medicine "for their discoveries concerning the peptide hormone production of the brain." [7] News accounts of their work often focused on their "fierce competition" and use of a very large amount of sheep and pig brains to locate the hormone. [6]

Clinical significance

TRH is used clinically by intravenous injection (brand name Relefact TRH) to test the response of the anterior pituitary gland; this procedure is known as a TRH test. This is done as diagnostic test of thyroid disorders such as secondary hypothyroidism and in acromegaly.

TRH has anti-depressant and anti-suicidal properties, [8] and in 2012 the U.S. Army awarded a research grant to develop a TRH nasal spray in order to prevent suicide amongst its ranks. [9] [10] The antidepressant properties of TRH are present when TRH is administered intrathecally, or administration into the spine, and the effects are short-lived. [8] Some researchers are testing a prodrug approach to administer TRH orally and have TRH reach the brain without being degraded in the stomach or blood. [11]

TRH has been shown in mice to be an anti-aging agent with a broad spectrum of activities that, because of their actions, suggest that TRH has a fundamental role in the regulation of metabolic and hormonal functions. [12]

Side effects

Side effects after intravenous TRH administration are minimal. [13] Nausea, flushing, urinary urgency, and mild rise in blood pressure have been reported. [14] After intrathecal administration, shaking, sweating, shivering, restlessness, and mild rise in blood pressure were observed. [8]

Thyrotropin-releasing hormone (TRH)
Pfam PF05438
InterPro IPR008857
Available protein structures:
Pfam   structures / ECOD  
PDBsum structure summary

See also

Related Research Articles

<span class="mw-page-title-main">Pituitary gland</span> Endocrine gland at the base of the brain

The pituitary gland is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The human pituitary gland is oval shaped, about the size of a chickpea, and weighs 0.5 grams (0.018 oz) on average.

<span class="mw-page-title-main">Hypothalamus</span> Area of the brain below the thalamus

The hypothalamus is a small part of the brain that contains a number of nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. It forms the ventral part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is the size of an almond.

<span class="mw-page-title-main">Tripeptide</span> Peptide consisting of three amino acids joined by peptide bonds

A tripeptide is a peptide derived from three amino acids joined by two or sometimes three peptide bonds. As for proteins, the function of peptides is determined by the constituent amino acids and their sequence. In terms of scientific investigations, the dominant tripeptide is glutathione (γ-L-Glutamyl-L-cysteinylglycine), which serves many roles in many forms of life.

<span class="mw-page-title-main">Posterior pituitary</span> Posterior lobe of the pituitary gland

The posterior pituitary is the posterior lobe of the pituitary gland which is part of the endocrine system. The posterior pituitary is not glandular as is the anterior pituitary. Instead, it is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary, and serve as a site for the secretion of neurohypophysial hormones directly into the blood. The hypothalamic–neurohypophyseal system is composed of the hypothalamus, posterior pituitary, and these axonal projections.

<span class="mw-page-title-main">Paraventricular nucleus of hypothalamus</span>

The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. PVN is thought to mediate many diverse functions through these different hormones, including osmoregulation, appetite, and the response of the body to stress.

<span class="mw-page-title-main">Hypopituitarism</span> Medical condition

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism is used.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Andrew Schally</span> American endocrinologist

Andrzej Viktor "Andrew" Schally is an American endocrinologist of Polish ancestry, who was a corecipient, with Roger Guillemin and Rosalyn Sussman Yalow, of the Nobel Prize in Physiology or Medicine. This award recognized his research in the discovery that the hypothalamus controls hormone production and release by the pituitary gland, which controls the regulation of other hormones in the body. Later in life, Schally utilized his knowledge of hypothalamic hormones to research possible methods for birth control and cancer treatment.

<span class="mw-page-title-main">Median eminence</span>

The median eminence is generally defined as the portion of the ventral hypothalamus from which the portal vessels arise. The median eminence is a small swelling on the tuber cinereum, posterior to and atop the pituitary stalk; it lies in the area roughly bounded on its posterolateral region by the cerebral peduncles, and on its anterolateral region by the optic chiasm.

<span class="mw-page-title-main">Endocrine gland</span> Glands of the endocrine system that secrete hormones to blood

Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testicles, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary glands are neuroendocrine organs.

A neurohormone is any hormone produced and released by neuroendocrine cells into the blood. By definition of being hormones, they are secreted into the circulation for systemic effect, but they can also have a role of neurotransmitter or other roles such as autocrine (self) or paracrine (local) messenger.

Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration. An example of a neuroendocrine cell is a cell of the adrenal medulla, which releases adrenaline to the blood. The adrenal medullary cells are controlled by the sympathetic division of the autonomic nervous system. These cells are modified postganglionic neurons. Autonomic nerve fibers lead directly to them from the central nervous system. The adrenal medullary hormones are kept in vesicles much in the same way neurotransmitters are kept in neuronal vesicles. Hormonal effects can last up to ten times longer than those of neurotransmitters. Sympathetic nerve fiber impulses stimulate the release of adrenal medullary hormones. In this way the sympathetic division of the autonomic nervous system and the medullary secretions function together.

Releasing hormones and inhibiting hormones are hormones whose main purpose is to control the release of other hormones, either by stimulating or inhibiting their release. They are also called liberins and statins (respectively), or releasing factors and inhibiting factors. The principal examples are hypothalamic-pituitary hormones that can be classified from several viewpoints: they are hypothalamic hormones, they are hypophysiotropic hormones, and they are tropic hormones.

Neuroendocrinology is the branch of biology which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Neurophysin II</span>

Neurophysin II is a carrier protein with a size of 19,687.3 Da and is made up of a dimer of two virtually identical chains of amino acids. Neurophysin II is a cleavage product of the AVP gene. It is a neurohypophysial hormone that is transported in vesicles with vasopressin, the other cleavage product, along axons, from magnocellular neurons of the hypothalamus to the posterior lobe of the pituitary. Although it is stored in neurosecretory granules with vasopressin and released with vasopressin into the bloodstream, its biological action is unclear. Neurophysin II is also known as a stimulator of prolactin secretion.

Hypothalamic–pituitary hormones are hormones that are produced by the hypothalamus and pituitary gland. Although the organs in which they are produced are relatively small, the effects of these hormones cascade throughout the body. They can be classified as a hypothalamic–pituitary axis of which the adrenal (HPA), gonadal (HPG), thyroid (HPT), somatotropic (HPS), and prolactin (HPP) axes are branches.

Hypothalamic disease is a disorder presenting primarily in the hypothalamus, which may be caused by damage resulting from malnutrition, including anorexia and bulimia eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury to the hypothalamus. The hypothalamus is the control center for several endocrine functions. Endocrine systems controlled by the hypothalamus are regulated by antidiuretic hormone (ADH), corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, oxytocin, all of which are secreted by the hypothalamus. Damage to the hypothalamus may impact any of these hormones and the related endocrine systems. Many of these hypothalamic hormones act on the pituitary gland. Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland.

Prior to the availability of sensitive TSH assays, thyrotropin releasing hormone or TRH stimulation tests were relied upon for confirming and assessing the degree of suppression in suspected hyperthyroidism. Typically, this stimulation test involves determining basal TSH levels and levels 15 to 30 minutes after an intravenous bolus of TRH. Normally, TSH would rise into the concentration range measurable with less sensitive TSH assays. Third generation TSH assays do not have this limitation and thus TRH stimulation is generally not required when third generation TSH assays are used to assess degree of suppression.

Parvocellular neurosecretory cells are small neurons that produce hypothalamic releasing and inhibiting hormones. The cell bodies of these neurons are located in various nuclei of the hypothalamus or in closely related areas of the basal brain, mainly in the medial zone of the hypothalamus. All or most of the axons of the parvocellular neurosecretory cells project to the median eminence, at the base of the brain, where their nerve terminals release the hypothalamic hormones. These hormones are then immediately absorbed into the blood vessels of the hypothalamo-pituitary portal system, which carry them to the anterior pituitary gland, where they regulate the secretion of hormones into the systemic circulation.


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