Corticotropin-releasing hormone

Actions and psychopharmacology

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, and in the cerebrospinal fluid of people who have committed suicide.

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.

Although one action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten the immune system's inflammation response, a process being investigated in multiple sclerosis research.

Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.

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

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

The 41-amino acid 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 (TRH has been found to be less potent than CRH in some species).

References

References

1. (September 1995). "Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression". The American Journal of Psychiatry.
2. (2008). "The central corticotropin releasing factor system during development and adulthood". European Journal of Pharmacology.
3. (1987). "Corticotropin-releasing factor as a transmitter in the human olivocerebellar pathway". Brain Research.
4. "Entrez Gene: CRH corticotropin releasing hormone".
5. "Corticotrophin-releasing hormone". Society for Endocrinology.
6. (November 2019). "Neurobiological links between stress and anxiety". Neurobiology of Stress.
7. (2021). "CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans". Psychiatric Research and Clinical Practice.
8. (October 2015). "Post-traumatic stress disorder". Nature Reviews. Disease Primers.
9. (April 2014). "Corticotropin releasing factor: a key role in the neurobiology of addiction". Frontiers in Neuroendocrinology.
10. (June 2017). "Altered Pituitary Gland Structure and Function in Posttraumatic Stress Disorder". Journal of the Endocrine Society.
11. (March 2002). "Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test". Biological Psychiatry.
12. (February 1989). "Elevated CSF CRF in suicide victims". Biological Psychiatry.
13. (December 1999). "A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes". Molecular Endocrinology.
14. (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology.
15. (March 2017). "Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress". Nature Neuroscience.
16. (2004-02-10). "CRF and CRF receptors: role in stress responsivity and other behaviors". Annual Review of Pharmacology and Toxicology.
17. (July 2008). "Corticotropin-releasing factor binding protein within the ventral tegmental area is expressed in a subset of dopaminergic neurons". The Journal of Comparative Neurology.
18. (June 2019). "A sexually dimorphic distribution of corticotropin-releasing factor receptor 1 in the paraventricular hypothalamus". Neuroscience.
19. (2008-08-01). "Study of Pexacerfont (BMS-562086) in the Treatment of Outpatients With Generalized Anxiety Disorder". ClinicalTrials.gov.
20. (2008-08-02). "Drug Has Potential To Prevent Alcoholics From Relapsing". ScienceDaily.
21. (July 2008). "Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: a urocortin1-independent mechanism". Proceedings of the National Academy of Sciences of the United States of America.
22. (September 1993). "Infectious diseases and the immune system". Scientific American.
23. (August 1999). "Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat". The American Journal of Physiology.
24. (November 1972). "The hormones of the hypothalamus". Scientific American.
25. (2001). "Fetal growth and development". Cambridge University Press.
26. (April 1989). "Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta". The Journal of Clinical Endocrinology and Metabolism.
27. (September 1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin". Science.
28. (March 1985). "NIH conference. Clinical applications of corticotropin-releasing factor". Annals of Internal Medicine.
29. (October 2002). "Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals". The Journal of Endocrinology.
30. (March 2006). "Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates". General and Comparative Endocrinology.