CRH is produced in response to stress, predominantly by
parvocellular neurosecretory cells within the
paraventricular nucleus of the
hypothalamus and is released at the
median eminence 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, where it stimulates
corticotropes to secrete
adrenocorticotropic hormone (
ACTH) and other biologically-active substances (
β-endorphin). ACTH stimulates the synthesis of
cortisol,
glucocorticoids,
mineralocorticoids and
DHEA. In the short term, CRH can suppress
appetite, increase subjective feelings of
anxiety, and perform other functions like boosting
attention. During chronic stress conditions such as
post-traumatic stress disorder (PTSD),
blood serum levels of CRH are decreased in combat veterans with PTSD compared to healthy individuals. It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function. Abnormally high levels of CRH have been found in people with
major depression, Corticotropin-releasing hormone has been shown to
interact with its receptors,
corticotropin-releasing hormone receptor 1 (CRFR1) and
corticotropin-releasing hormone receptor 2 (CRFR2), in order to induce its effects. Injection of CRH 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 CRH 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 is currently under investigation for the treatment of
generalized anxiety disorder. Another CRH-1 antagonist
antalarmin 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,
CP-154,526 is under investigation for the potential treatment of
alcoholism. Increased CRH production has been observed to be associated with
Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including
hypoglycemia.
Role in parturition CRH is synthesized by the
placenta and seems to determine the duration of
pregnancy. Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition: • Increases levels of
dehydroepiandrosterone (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
glucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block. == Structure ==