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Original Author(s): Kishan Pankhania
Last updated: 17th July 2023
Revisions: 8

Original Author(s): Kishan Pankhania
Last updated: 17th July 2023
Revisions: 8

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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:

  1. 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
  2. Stimulate lipolysis in adipose tissue
  3. Immunosuppression
  4. Anti-inflammation
  5. Protein and fat metabolism
  6. Bone metabolism – acts on trabecular bone to limit osteoblast activity to make new bone
  7. Regulate calcium absorption from the gastrointestinal tract
  8. Regulate behaviour, mood, and cognition through activity on the 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:

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

Clinical Relevance – Addison’s Disease

This is an autoimmune disease whereby the immune system targets the adrenal glands, resulting in reduced cortisol and aldosterone production. Aldosterone is a mineralocorticoid that regulates sodium and potassium levels in the blood, thereby regulating intravascular volume. It accounts for 80% of cases of hypoadrenalism in the UK.

Patients present with various symptoms, including tiredness, weakness, nausea, and vomiting. Patients also show postural hypotension, which is caused by mineralocorticoid deficiency.

Classically, they demonstrate hyperpigmentation, or ‘bronzing’ in the palmar creases of the hands and flexor surfaces of joints and on the face.

The reason for this is to do with the lack of negative feedback from cortisol to the hypothalamus and pituitary, and the structure of ACTH and its precursors. Firstly, low cortisol stimulates increased ACTH production. Secondly, ACTH and its precursors contain melanocyte-stimulating hormone (MSH)-like peptide sequences, which can mimic MSH and cause hyperpigmentation.

You can test how well the adrenal gland is functioning in terms of cortisol secretion by administering synthetic ACTH. This is commonly referred to as the short synACTHen test. Serum cortisol levels are measured at baseline, after 30 minutes, and after 60 minutes. A normal response would be a significant rise in cortisol levels.

A lack of cortisol rise indicates an adrenal disease such as Addison’s.