Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...

involved in

stress response The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...

s. It is a

releasing hormone 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 ...

that belongs to

corticotropin-releasing factor family Corticotropin-releasing factor family, CRF family is a Protein family, family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone (also known as CRF), urotensin-II, urotensin-I, urocortin, and sauvagine. ...

. In humans, it is encoded by the ''CRH''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Its main function is the stimulation of the pituitary synthesis of

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

(ACTH), as part of the

hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a ...

(HPA axis). Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 196-amino acid preprohormone. CRH is secreted by 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 ...

(PVN) of 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 ...

in response to

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...

. Increased CRH production has been observed to be associated with Alzheimer's disease and

major depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...

, and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

. In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, such as

T lymphocyte A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

s, and is highly expressed in the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

. In the placenta, CRH is a marker that determines the length of gestation and the timing of

parturition Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...

and delivery. A rapid increase in circulating levels of CRH occurs at the onset of

, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition. A recombinant version for diagnostics is called

corticorelin Corticorelin ( INN, trade name Xerecept) is a diagnostic agent. It is a synthetic form of human corticotropin-releasing hormone (hCRH). Medical uses The corticorelin stimulation test helps to differentiate between the causes for adrenocorticotro ...

(

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 ...

Actions and psychopharmacology

CRH is produced in response to stress, predominantly by

parvocellular neurosecretory cell Parvocellular neurosecretory cells are small neurons within paraventricular nucleus (PVN) of the hypothalamus. The axons of the parvocellular neurosecretory cells of the PVN project to the median eminence, at the base of the brain, where their ne ...

s within the

of the

and is released 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 ...

from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...

, where it stimulates

corticotrope Corticotropes (or corticotrophs) are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). Thes ...

s to secrete

(

ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

) and other biologically-active substances (

β-endorphin ''beta''-Endorphin (β-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced ...

). ACTH stimulates the synthesis of cortisol,

glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

mineralocorticoids Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary min ...

and

DHEA Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functio ...

. In the short term, CRH can suppress appetite, increase subjective feelings of

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, and perform other functions like boosting attention. Abnormally high levels of CRH have been found in people with

, and in the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

of people who have committed suicide. Corticotropin-releasing hormone has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with its receptors corticotropin-releasing hormone receptor 1 (CRFR1) and corticotropin-releasing hormone receptor 2 (CRFR2) in order to induce its effects. Injection of CRF into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors. Sex differences have also been observed with respect to both CRF and the receptors that it interacts with. CRFR1 has been shown to exist at higher levels in the female nucleus accumbens, olfactory tubercle, and rostral anteroventral periventricular nucleus (AVPV) when compared to males, while male voles show increased levels of CRFR2 in the bed nucleus of the stria terminalis compared to females. The CRH-1 receptor antagonist

pexacerfont Pexacerfont (INN, previously known as BMS-562,086) is a drug developed by Bristol-Myers Squibb which acts as a CRF1 antagonist. Corticotropin-releasing factor (CRF), also known as corticotropin-releasing hormone, is an endogenous peptide hormone ...

is currently under investigation for the treatment of

generalized anxiety disorder Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily function ...

. Another CRH-1 antagonist

antalarmin Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist. Corticotropin-releasing hormone (CRH), also known as Corticotropin-releasing factor, is an endogenous peptide hormone released in response to various triggers such as chronic stres ...

has been researched in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out. The activation of the CRH1 receptor has been linked with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist developed by

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...

CP-154,526 CP-154,526 is a potent and selective antagonist of the corticotropin releasing hormone receptor 1 developed by Pfizer. CP-154,526 is under investigation for the potential treatment of alcoholism. See also * Antalarmin Antalarmin (CP-156,181 ...

is under investigation for the potential treatment of

alcoholism Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomi ...

. Increased CRH production has been observed to be associated with Alzheimer's disease. Although one action of CRH is

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...

via the action of cortisol, CRH itself can actually heighten the immune system's

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

response, a process being investigated in multiple sclerosis research. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including

. Alpha-helical CRH-(9–41) acts as a CRH antagonist.

Role in parturition

CRH is synthesized by the

and seems to determine the duration of

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

. Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition: * Increases levels of

dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It fun ...

(DHEA) directly by action on the fetal adrenal gland, and indirectly via the mother's pituitary gland. DHEA has a role in preparing for and stimulating cervical contractions. * Increases prostaglandin availability in uteroplacental tissues. Prostaglandins activate cervical contractions. * Prior to parturition it may have a role inhibiting contractions, through increasing cAMP levels in the myometrium. In culture, trophoblast CRH is inhibited by progesterone, which remains high throughout pregnancy. Its release is stimulated by

and catecholamines, which increase prior to parturition lifting this progesterone block.

Structure

The 41-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

sequence of CRH was first discovered in sheep by Vale ''et al.'' in 1981. Its full sequence is: * SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids. * SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII

Role in non-mammalian vertebrates

In mammals, studies suggest that CRH has no significant thyrotropic effect. However, in representatives of all non-mammalian vertebrates, it has been found that, in addition to its corticotropic function, CRH has a potent thyrotropic function, acting with TRH to control the

hypothalamic–pituitary–thyroid axis The hypothalamic–pituitary–thyroid axis (HPT axis for short, a.k.a. thyroid homeostasis or thyrotropic feedback control) is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress. As its na ...

(TRH has been found to be less potent than CRH in some species).

References

External links

* * {{DEFAULTSORT:Corticotropin-Releasing Hormone Hormones of the hypothalamus Peptide hormones Corticotropin-releasing hormone receptor agonists Hormones of the hypothalamus-pituitary-adrenal axis