Synthesis and Transport
- CNS Synthesis: CRH is produced by neurons of the parvocellular nuclei located in the medial region of the hypothalamus.
- Transport: The axons of these neurons project to the median eminence. From there, the neurosecretion is released into the hypophyseal portal system, providing a humoral pathway for signal transmission to the adenohypophysis.
- Additional Sources: During pregnancy, the placenta secretes its own corticotropin-releasing hormone. Furthermore, as the fetus reaches maturity, the fetal hypothalamus also begins to secrete this hormone.
Mechanism of Action and Physiological Effects
The "corticotropin-releasing hormone — adrenocorticotropic hormone — cortisol" cascade ensures survival during stress, illness, physical and emotional strain, and mental stress.
- Effect on the Pituitary: CRH stimulates cells in the adenohypophysis that produce pro-opiomelanocortin (POMC). POMC is cleaved to form adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), $\beta$-endorphin, and other peptides. ACTH, in turn, acts via membrane G protein-coupled receptors and the adenylate cyclase system to stimulate the zona fasciculata of the adrenal cortex to synthesize and secrete glucocorticoids.
- Role in the Nervous System: Within CNS structures, the hormone functions as a neurotransmitter and neuromodulator. It participates in the central regulation of autonomic functions, specifically in activating the sympathetic nervous system.
- Role in Initiation of Labor: In the fetus, hypothalamic CRH secretion stimulates the anterior pituitary, which activates the fetal adrenal glands. The fetal adrenals release cortisol and dehydroepiandrosterone sulfate (DHEA-S). Cortisol activates phospholipase A2 and cyclooxygenase, leading to the synthesis of prostaglandins $\text{PGE}_2$ and $\text{PGF}_{2\alpha}$, while DHEA-S serves as a precursor for placental estriol synthesis. Placental estriol prepares the myometrium, and prostaglandins alongside oxytocin help trigger uterine contractions.
Regulation of CRH Secretion
Regulation occurs via a negative feedback loop.
- Stimulating Factors: Hypothalamic neurosecretory cells are activated by higher CNS structures, primarily the limbic system. This system is stimulated by hypoglycemia, trauma, infection, and stress.
- Inhibiting Factors: Elevated levels of cortisol inhibit the secretion of CRH in the hypothalamus and ACTH in the pituitary.
Clinical Significance and Pathologies
- Secondary (Central) Adrenal Insufficiency: Caused by hypothalamic-pituitary dysfunction. Potential causes include lesions of the hypothalamus and/or pituitary: tumors, ischemia, hemorrhage, or inherited/congenital developmental anomalies. The pathogenetic basis is a deficiency of CRH and/or ACTH.
- Steroid Withdrawal Syndrome: Long-term administration of exogenous glucocorticoids suppresses the endogenous hypothalamic-pituitary-adrenal axis, resulting in profound inhibition of CRH and ACTH synthesis. This leads to atrophy of the adrenal cortex. Upon sudden drug withdrawal, the atrophied adrenal glands cannot rapidly resume cortisol synthesis, leading to acute adrenal crisis characterized by hypotension, hypoglycemia, and shock.