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Original Author(s): Kishan Pankhania
Last updated: 8th February 2024
Revisions: 10

Original Author(s): Kishan Pankhania
Last updated: 8th February 2024
Revisions: 10

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Cortisol is a key hormone in many different physiological processes, including glucose homeostasis, lipolysis, and regulation of mood. It is under the control of adrenocorticotropin hormone, commonly known as ACTH, which is released from the anterior pituitary. Together with the hypothalamic hormone known as corticotrophin-releasing hormone (CRH), they form the hypothalamic-pituitary-adrenal (HPA) axis.

This article will consider the regulation, function, and clinical relevance of ACTH, cortisol, and the HPA axis.

Regulation of the HPA Axis

Hypothalamic Control

A variety of signals, such as stress in a fear-inducing situation, infection, or blood loss, can stimulate the hypothalamus to secrete corticotropin-releasing hormone (CRH). This acts on corticotropes (specialised cells in) the anterior pituitary, which in response secrete ACTH, also known as corticotropin.

Pituitary Control

ACTH is produced in pituitary cells by cleaving prepropriomelanocortin to propriomelanocrotin (POMC), and then to ACTH. In this process, melanocyte stimulating hormone (MSH), endorphins (endogenous opioids), and enkephalins (peptides that regulate pain sensation) are also produced.

ACTH travels in the blood and binds to the melanocortin 2 receptor (MC2r) on cells in the adrenal cortex. It stimulates the synthesis and release of glucocorticoids (steroid hormones) such as cortisol and adrenal androgens from the zona fasciculata and zona reticularis in the outer part of the adrenal cortex.

Fig 1 – The HPA axis in overview, including negative feedback

HPA Axis Functions

Actions of Cortisol

Cortisol exerts its effect on many tissues including the liver, fat, muscle, bone, skin, and others. A summary of the effects of cortisol is listed below:

  • Cortisol increases plasma glucose levels by breaking down proteins into amino acids to be taken to the liver, as well as by stimulating gluconeogenesis in the liver
  • Stimulate lipolysis in adipose tissue
  • Immunosuppression
  • Anti-inflammation
  • Protein and fat metabolism
  • Bone metabolism – acts on trabecular bone to limit osteoblast activity to make new bone
  • Regulate calcium absorption from the gastrointestinal tract
  • Regulate behaviour, mood, and cognition through activity on the central nervous system (CNS)

Cortisol Mechanism of Action

Interestingly, cortisol is hydrophilic enough to travel in plasma, but lipophilic enough to be able to cross the phospholipid plasma membranes of target tissues.

It binds intracellularly to the glucocorticoid receptor (GR) in the cytoplasm, which is a nuclear hormone receptor, causing it to dimerise with another GR.

Without cortisol, the GR is bound to a chaperone and unable to translocate (enter) into the nucleus. When cortisol binds to the GR, the chaperone dissociates, allowing the cortisol-GR complex to move into the nucleus. Here, it associates with glucocorticoid-response elements (GREs) of genes to increase or decrease gene expression.

Negative Feedback of Cortisol

Cortisol has a negative feedback effect by:

  • Inhibiting the production of CRH in the hypothalamus
  • Reducing the sensitivity of the anterior pituitary to CRH, which reduces ACTH release

Clinical Relevance – Addison’s Disease

Addison’s disease is the opposite disease to Cushing’s disease in many ways. Whereas Cushing’s disease is due to an excess of cortisol, Addison’s disease is due to a lack of cortisol, commonly due to autoimmune destruction of the adrenal cortex. This in turn causes hypotension and anorexia, in contrast to hypertension and truncal obesity in Cushing’s disease.

A unique symptom of Addison’s disease is hyperpigmentation, particularly in the creases of the hand and in the mouth. This can be explained via the hypothalamic – pituitary – adrenal (HPA) axis. The decrease in cortisol leads to an increase in ACTH via negative feedback.

ACTH stems from a precursor molecule called pro-opiomelanocortin (POMC). POMC is also a precursor to melanocyte stimulating hormone (MSH), causes darkening of skin. Therefore, an increase in ACTH, leads to an increase in POMC and as a byproduct, an increase in MSH and therefore leads to skin darkening.

A very serious complication of Addison’s disease is an Addisonian crisis. Cortisol is linked to the “fight or flight” response and is released in times of stress to the body. Therefore, in patients suffering from Addison’s disease, they are unable to mount an adequate response to these stresses. This can result in numerous symptoms such as severe hypotension and electrolyte dysfunction.