Hypothalamus-Pituitary-Adrenal axis (HPA axis)

Author: Paolo Carfora
Date: 19/02/2012


How stress can interfere with regular corticosteroid levels and their effects on aging.
Our body is programmed to adapt to acute stressful events, one of the mechanisms to carry out this function is the HPA axis. Chronic stress can lead to a constant activation of this system of balancing with serious health consequences.

HPA axis regulation

The activation of HPA axis involves the release of Corticotropin Releasing Hormone (CRH) by CRH neurons, located in hypotalamic paraventricular nucleus, into the pituitary portal cyrculation. The 50% of these neurons express vasopressin (VP) gene: VP works as co-factor for the release of ACTH by pituitary cells. When CRH reaches the anterior pituitary, it binds CRHR1 receptors while VP binds to Vb1 receptors. Several studies have shown that the number of receptors, both CRHR1 and V1b exposed on the cells of anterior pituitary, increases in case of prolonged stress, resulting in a rise of plasma ACTH and consequent secretion of corticosteroids by the adrenal.
In normal conditions, HPA-axis activity follows a circadian rhythm, which leads to high levels of cortisol shortly before waking, then the secretion is kept constant throughout the day (with slight increases after a meal) and finally decreases during the evening with a minimum by night.

Circadian levels of melatonin secreted by the pineal, follow an opposite course instead.


Corticotropin Releasing Hormone is a 41-amino acid peptide, is the pirncipal member of a family of neuropeptides wich include urocortin 1,2 and 3. CRH neurons are located not only in the paraventricular nucleus but also in several other areas of the nervous system:

The green dots represent the CRH neurons: as shown in the figure, they are concentrated in the paraventricular nucleus of the hypothalamus. Although can be found close to the catecholaminergic neurons in the brain stem, in the frontal cortex, in the core of the amygdala, and other limbic areas too. This evidence shows that CRH, in addition to being a factor for ACTH secretion, works as a stimulant for the secretion of further CRH, by neurons of the paraventricular nucleus. Furthermore CRH-secreting neurons in the paraventricular nucleus are under the direct influence of ascending noradrenergic pathways from the brainstem. The secretion of serotonin, norepinephrine and acetylcholine affect the production of CRH. CRH neurons in paraventricular nucleus (PVN) also receive afferents from glutamatergic interneurons in the paraventricular area. Finally glutamatergic (activation) or GABAergic (inhibition) afferences coming from the central nucleus of the amygdala and from the base of the stria terminalis stimulate or inhibit transcription. CRH peptide has been identified also in non-nervous structures, such as gastrointestinal tract and cells of the immune response. At last CRH seems to have a major role in modulating the behavioral and emotional response to stress: several studies have shown that depressed patients have higher levels of CRH trascription and secretion

CRH trascription

The primary mechanism of modulation of HPA axis, occurs due to regulation of CRH trascription in CRH neurons of the paraventricular nucleus.

  • Activation of transcription

To activate the transcription, is necessary that the transcription factor CREB binds to the CRE sequence of the promoter of CRH-gene inside the nucleus. For this to occur, it is necessary that CREB is phosphorylated into pCREB: this can be done in 4 different ways

  • G protein activation: subunit alpha-q activates phospholipase c, this in turn produces inositol 3 P (IP3) and diacylglycerol (DG). IP3 increases the levels of citoplasmatic calcium, activating the calcium-dependent protein kinase (CaMK) which phosphorylates CREB. DG activates the protein kinase C (PKC) instead, wich phosphorylates CREB too.
  • RAS pathway: RAS activates RAF, which in turn activates MEK. This lead to the activation of myogenic activated protein kinase (MAPK), it also able to phosphorylate CREB.
  • cAMP pathway: the activation of other Gs proteins leads to an increase of adenylate cyclase activity and consequently to a boost in cAMP levels: this activates the phosphokinase A which phosphorylates CREB.
  • voltage-gated channels: this pathway starts with the opening of voltage-gated channels, wich allows calcium to enter in citoplasm. A rise in the concentration of calcium activates other CaMK, leading to CREB phosphorylation.

CREB, however, is not sufficient to start the transcription, it is necessary a second transcription factor: TORC.

TORC is normally found in cytoplasm, phosphorylated and bound to a scaffolding protein (14-3-3): this condition is kept constant thanks to SIK (salt inducible kinase), wich keeps TORK phosphorylated. SIK is activated by protein kinase C (PKC). When transcription begins, G proteins activates adenylate cyclase wich increases citoplasmatic levels of cAMP. cAMP activates PKA, wich phosphorylates SIK in pSIK ,its inactive form. Then the opening of voltage-gated Ca2 + channels, allows the activation of phosphatase PPP3, wich phosphorylates TORC. pTORC is now detached from 14-3-3 and enters the nucleus activating trascription.
The molecular physiology of CRH neurons 2011

  • Inibition of transcription

Mechanisms of feedback exerted by glucocorticoids have been demonstrated experimentally, but is not yet clear exactly how this happens. As regards, the mechanism of intracellular inhibition, a repressor of cAMP has been identified: ICER (inducible cyclic AMP early repressor) wich fits on the CRE site, thus preventing the interaction with CREB of this and consequently the production of further CRH . Signs of ICER appear after 1 hour from the stressful stimulus reaching a peak after 3 hours.

Effect of CRH on anterior pituitary

CRH released into the pituitary portal circulation, reaches the anterior pituitary cells, stimulating the secretion and production of ACTH .

Experiments on mice and rats have shown that the action of CRH occurs by binding a particular receptor that stimulates a rise of cAMP levels in the cell: this leads to the closure of TREK-1 channels with subsequent depolarization and opening of VGCC channels, with a rise of cytoplasmic Ca2 +. This causes exocytosis of ACTH containing vesicles (rapid response): in this way ACTH is secreted into circulation and can be effectively detected by the adrenal.
Ca2+ signaling and exocytosis in pituitary corticotropes 2012

Corticosteroids and aging

High levels of corticosteroids have been associated with disturbances in circadian rhythms and cognitive deficits typical of elderly. Aging is associated with high levels of circulating corticosteroids, although the levels of plasma ACTH are not always high.
It has been demonstrated that the secretion of corticosteroids in response to acute stress in elderly can be either reduced or increased and longer lasting than young subjects: advancing age, in 40% of those observed there is an increase of the average levels of plasma cortisol while a moderate increase was found in a similar proportion of subjects. The remainder, about 20%, presents lower cortisol levels by old rather then by young. These different reports indicate a particular genetic variation.
In addiction to plasma concentration, the effects of glucocorticoids on a given tissue depend also on the amount of receptors expressed by that tissue. Glucocorticoids are able to cross plasma membrane and tie the glucocorticoid receptor (GR) found in cytoplasm. Then the steroid-receptor complex migrates into the nucleus, where binds promoters related components of genes activated by glucocorticoid. Glucocorticoids bind with even higher affinity mineralocorticoid receptor, and these can bind the same glucocorticoid promoter inside the nucleus.
Another element which characterizes the sensitivity of a tissue to glucocorticoids is the concentration of 11 beta hydroxy steroid dehydrogenase (11-beta-HSD) in that tissue: these enzymes are able to convert corticosteroids in their inactive form (11-beta-HSD-2), cortisone; or carry out the opposite task (11-beta-HSD-1), converting cortisone into its active form (cortisol). The transcription of 11-beta-HSD-1 increases with age, both in brain and peripheral tissues. This leads the tissue to an increased sensitivity to corticosteroids in elderly.
HPA axis responsiveness to stress: Implications for healthy aging 2010

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