Corticotropin Releasing Hormone

Corticotropin-releasing hormone (CRH), also known as corticotropin-releasing factor (CRF), corticoliberin, or corticotrophin, is a peptide hormone centrally involved in the regulation of the stress response. It is classified as a releasing hormone within the corticotropin-releasing factor family and plays a pivotal role in coordinating endocrine, autonomic, behavioural, and immune responses to stress. In humans, CRH is encoded by the CRH gene and functions primarily through activation of the hypothalamic–pituitary–adrenal (HPA) axis.

Molecular nature and synthesis

CRH is a 41–amino acid peptide derived from a larger 196–amino acid preprohormone. Post-translational processing of this precursor yields the biologically active hormone. The primary structure of CRH is highly conserved across mammalian species; the human and rat peptides are identical, while differing only slightly from the ovine sequence. This conservation reflects its fundamental physiological importance.
The hormone is synthesised predominantly by parvocellular neurosecretory neurons located in the paraventricular nucleus (PVN) of the hypothalamus. From there, CRH is transported to nerve terminals at the median eminence and released into the hypothalamo–hypophyseal portal circulation.

Role in the hypothalamic–pituitary–adrenal axis

The principal physiological function of CRH is the regulation of the HPA axis, the body’s central stress-response system. Following its release into the portal circulation, CRH acts on corticotroph cells of the anterior pituitary gland, stimulating the synthesis and secretion of adrenocorticotropic hormone (ACTH).
ACTH then acts on the adrenal cortex to promote the production of:

• Glucocorticoids, primarily cortisol
• Mineralocorticoids
• Adrenal androgens, including dehydroepiandrosterone (DHEA)

Cortisol exerts widespread metabolic effects and provides negative feedback inhibition at both pituitary and hypothalamic levels, thereby regulating CRH and ACTH secretion under normal physiological conditions.

Actions in stress and behaviour

CRH is rapidly released in response to physical and psychological stressors. In the short term, it contributes to adaptive responses by:

• Suppressing appetite
• Increasing alertness and attention
• Enhancing anxiety-related behaviours

Beyond its endocrine role, CRH also functions as a neurotransmitter and neuromodulator within the central nervous system. CRH-containing neurons and receptors are distributed in brain regions associated with emotion and motivation, including the amygdala, hippocampus, and cerebral cortex.
Chronic stress leads to sustained activation of the HPA axis, which may alter CRH signalling through enhanced negative feedback mechanisms. In certain conditions, this results in reduced circulating CRH levels and diminished HPA axis responsiveness.

CRH receptors and signal transduction

The biological effects of CRH are mediated primarily through two G-protein-coupled receptors:

• Corticotropin-releasing hormone receptor 1 (CRHR1)
• Corticotropin-releasing hormone receptor 2 (CRHR2)

CRHR1 is widely expressed in the brain and pituitary and is closely associated with anxiety, mood regulation, and stress-related behaviours. CRHR2 has a more restricted distribution and is implicated in modulating stress recovery and autonomic responses.
Binding of CRH to its receptors activates intracellular signalling pathways, notably through cyclic adenosine monophosphate (cAMP), leading to changes in gene expression and neuronal excitability.

Psychopharmacology and mental health relevance

Abnormal CRH activity has been strongly linked with several psychiatric disorders. Elevated CRH levels have been detected in individuals with major depressive disorder and in the cerebrospinal fluid of people who have died by suicide. These findings support the hypothesis of HPA axis hyperactivity in depression.
Conversely, in chronic stress-related conditions such as post-traumatic stress disorder (PTSD), circulating CRH levels may be reduced. This is thought to result from enhanced negative feedback sensitivity to glucocorticoids, leading to overall suppression of HPA axis activity.
Pharmacological modulation of CRH signalling has therefore been a major area of research. CRHR1 antagonists, such as pexacerfont and antalarmin, have been investigated for potential therapeutic roles in anxiety and depression. Although results in humans have been mixed, preclinical studies continue to highlight CRH receptors as important drug targets.

Sex differences in CRH signalling

Significant sex differences have been observed in CRH expression and receptor distribution. In several brain regions, females show higher CRHR1 expression than males, which may contribute to sex-specific vulnerability to stress-related disorders. In contrast, males exhibit increased CRHR2 expression in certain limbic structures. These differences are of particular relevance to understanding sex disparities in anxiety and depressive illnesses.

Peripheral production and immune effects

Although CRH is classically considered a hypothalamic hormone, it is also synthesised in peripheral tissues, including:

• T lymphocytes
• Adrenal glands
• Gastrointestinal tract
• Placenta

CRH has complex immunological actions. While systemic effects mediated by cortisol are generally immunosuppressive, CRH itself can enhance local inflammatory responses. This duality has prompted investigation into its role in inflammatory and autoimmune diseases, such as multiple sclerosis.

Role in pregnancy and parturition

CRH is highly expressed in the human placenta, where it plays a crucial role in determining the length of gestation and the timing of childbirth. Unlike hypothalamic CRH, placental CRH secretion increases progressively throughout pregnancy, with a marked rise just before labour.
Current evidence suggests that CRH contributes to parturition through several mechanisms:

• Increasing fetal and maternal DHEA production, which promotes cervical ripening
• Enhancing prostaglandin availability in uteroplacental tissues, stimulating uterine contractions
• Modulating myometrial activity via cyclic AMP pathways

Placental CRH synthesis is inhibited by progesterone during most of pregnancy, while rising glucocorticoid and catecholamine levels near term relieve this inhibition, facilitating labour onset.

Genetic and clinical disorders

Autosomal recessive hypothalamic corticotropin deficiency, resulting from impaired CRH production, is a rare but serious condition. It leads to deficient ACTH and cortisol secretion and may cause severe metabolic disturbances, including recurrent hypoglycaemia, which can be life-threatening if untreated.
Increased CRH production has also been associated with Alzheimer’s disease, supporting the link between chronic stress, neurodegeneration, and cognitive decline.

Structure and evolutionary aspects

The amino acid sequence of CRH was first identified in sheep in 1981. Structural analysis revealed an alpha-helical configuration critical for receptor binding. Synthetic analogues, such as alpha-helical CRH(9–41), act as CRH antagonists and are widely used in experimental research.
In non-mammalian vertebrates, CRH has a broader endocrine role. In addition to its corticotropic action, it exerts a strong thyrotropic effect, acting alongside thyrotropin-releasing hormone (TRH) to regulate the hypothalamic–pituitary–thyroid axis. In some species, CRH is a more potent stimulator of thyroid-stimulating hormone than TRH, highlighting evolutionary differences in endocrine control mechanisms.