Thyrotropin-releasing hormone (TRH) is a
hypophysiotropic hormone produced by neurons in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small 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 hypothalamu ...
that stimulates the release of
thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of ...
(TSH) and
prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
from the
anterior pituitary
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
.
TRH has been used clinically for the treatment of
spinocerebellar degeneration and
disturbance of consciousness in humans.
Its
pharmaceutical
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
form is called protirelin (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
) ().
Synthesis and release
![Thyroid system](https://upload.wikimedia.org/wikipedia/commons/d/d1/Thyroid_system.svg)
TRH is synthesized within parvocellular neurons of the
paraventricular nucleus
The paraventricular nucleus (PVN, PVA, or PVH) 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 ...
of the hypothalamus.
It is translated as a 242-amino acid precursor polypeptide that contains 6 copies of the sequence -Gln-His-Pro-Gly-, 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
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
) is converted into
pyroglutamate
Pyroglutamic acid (also known as PCA, 5-oxoproline, pidolic acid) is a ubiquitous but little studied natural amino acid derivative in which the free amino group of glutamic acid or glutamine cyclizes to form a lactam. The names of pyroglutamic ...
(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
The median eminence, part of the inferior boundary of the hypothalamus in the brain, is attached to the infundibulum. The median eminence is a small swelling on the tuber cinereum, posterior to and atop the pituitary stalk; it lies in the area rou ...
, TRH travels to the
anterior pituitary
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
via the
hypophyseal portal system
The hypophyseal portal system is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypo ...
where it binds to the TRH receptor stimulating the release of
thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of ...
from
thyrotrope
Thyrotropes (also called thyrotrophs) are endocrine cells in the anterior pituitary which produce thyroid stimulating hormone (TSH) in response to thyrotropin releasing hormone (TRH).Guyton, A.C. & Hall, J.E. (2006) ''Textbook of Medical Physiology ...
s and
prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
from
lactotropes.
The half-life of TRH in the blood is approximately 6 minutes.
Structure
TRH is a tripeptide, with an amino acid sequence of pyroglutamyl-histidyl-proline amide.
History
The structure of TRH was first determined, and the hormone synthesized, by
Roger Guillemin
Roger Charles Louis Guillemin (born January 11, 1924) is a French-American neuroscientist. He received the National Medal of Science in 1976, and the Nobel prize for medicine in 1977 for his work on neurohormones, sharing the prize that year ...
and
Andrew V. Schally
Andrzej Viktor "Andrew" Schally (born 30 November 1926) is an American endocrinologistAndrew V. Schally"Andrew V. Schally" ''Encyclopædia Britannica''. of Polish ancestry, who was a corecipient, with Roger Guillemin and Rosalyn Sussman Yalow, of ...
in 1969.
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.
Schally and Guillemin shared the 1977
Nobel Prize in Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, according ...
''"for their discoveries concerning the peptide hormone production of the brain."''
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.
Clinical significance
TRH is used clinically by intravenous injection (brand name Relefact TRH) to test the response of the
anterior pituitary gland
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...
; this procedure is known as a
TRH test
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 invo ...
. This is done as diagnostic test of
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
disorders such as secondary
hypothyroidism
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
and in
acromegaly.
TRH has anti-depressant and anti-suicidal properties,
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.
The antidepressant properties of TRH are present when TRH is administered intrathecally, or administration into the spine, and the effects are short-lived.
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.
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.
Side effects
Side effects after intravenous TRH administration are minimal.
Nausea, flushing, urinary urgency, and mild rise in blood pressure have been reported.
After
intrathecal
Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain ma ...
administration, shaking, sweating, shivering, restlessness, and mild rise in blood pressure were observed.
See also
*
thyrotropin-releasing hormone receptor
Thyrotropin-releasing hormone receptor (TRHR) is a G protein-coupled receptor which binds thyrotropin-releasing hormone.
The TRHR is found on the cell membrane of thyrotropes of the anterior pituitary. When the TRHR binds TRH it activates phosp ...
*
thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of ...
*
hypothalamic-pituitary thyroid axis
*
hypothalamic–pituitary–prolactin axis
The hypothalamic–pituitary–prolactin axis (HPP axis), also known as the hypothalamic–pituitary–mammary axis or hypothalamic–pituitary–breast axis, is a hypothalamic–pituitary axis which includes the secretion of prolactin (PRL; lut ...
References
External links
*
{{DEFAULTSORT:Thyrotropin-Releasing Hormone
Galactagogues
Hormones of the hypothalamus
Hormones of the hypothalamus-pituitary-adrenal axis
Hormones of the hypothalamic-pituitary-prolactin axis
Peptide hormones
Thyroid
Tripeptides