04. Adrenal Cortex

• the adrenal glands sit on top of the kidneys and have two functional parts - the cortex and the medulla
• the adrenal cortex is where corticosteroids are synthesised, and also weak androgens.

  • corticosteroids = glucocorticoids and mineralocorticoids
• corticosteroids are derived from cholesterol. this is synthesised from acetate (acetyl coA) or taken up from circulation.

  • this is catalysed by P450 cytochrome enzymes.
  • require electron donation for activity.
• the adrenal cortex is split into 3 layers:

  • zona glomerulosa = mineralocorticoids
  • zona fasciculata = glucocorticoids
  • zona reticularis = weak androgens

  the glomerulosa is on the outer layer of the cortex, while the reticularis is closest to the medulla
• catecholamines are synthesised in the medulla
• cholesterol must become prenenolone to enter the pathways to become mineralocorticoids, glucocorticoids or androgens.

  • cholesterol -> pregnenolone occurs in the mitochondria
  • this is the rate limiting step in steroidogenesis
• cholesterol becomes pregnenolone in the mitochondria:

  • moves from the outer membrane to the inner membrane by the StAR protein.
  • StAR produced and regulated in response to cAMP secondary messenger system.
  • related to ACTH.
  • P450scc converts cholesterol to pregnenolone.
• glucocorticoids, e.g. cortisol.

  • 90% of cortisol is bound to plasma protein, mostly transcortin but some albumin.
  • stress is the main driver for cortisol - HPA axis.
  • stress enables hypothalamus to produce CRH.
  • CRH binds to anterior pituitary to produce ACTH.
  • ACTH binds to adrenal gland, enabling cortisol production.
  • negative feedback = cortisol inhibits CRH production
• ACTH is a peptide hormone produced as a pre-pro-hormone.

  • has signal peptide attached which is removed during translation -> pro-hormone called POMC.

  ACTH binds to its receptor which uses cAMP messaging.
• once ACTH binds to its receptor, what happens in the cell depends on how long ACTH has been produced.

  • immediately = increase in cholesterol transport to mitochondria.
  • after = increase gene transcription of hydroxylases needed to make pregnenolone.
  • long term = increase size and number of organelles, leading to hyperplasia. this damages the adrenal gland.
• glucocorticoid mechanism of action:

  binds to intracellular receptor - binds to response elements on DNA which leads to protein synthesis.
• glucocorticoid action:

  • metabolism = increases plasma glucose and breaks down proteins, can lead to muscle wasting.
  • redistributes fat from extremities into trunk area.
  • electrolytes = incorrectly binds to mineralocorticoid receptors, causing electrolyte imbalances.
  • decreased Ca2+ absorption and inhibition of osteoblasts, leads to osteoporosis.
• cushings syndrome is a term for cortisol excess.

  • can be caused by many ways - pituitary tumour (cushings disease), ectopic ACTH producing tumour.
  • latrogenic cushings syndrome = long term immunosuppression with synthetic cortisol analogues.
  • cortisol excess = trunkal obesity, thin legs and arms.
• cushings syndrome treatment:

  • surgery/radiotherapy for a tumour.
  • drugs - metyrapone, inhibits CYP1101 which is involved in cortisol production
• addisons disease is shrinking of the adrenal gland, most cases are due to autoimmunity.

  • fatigue, weight loss and ion imbalance.
  • treated with cortisol replacement therapy

  also can cause aldosterone deficiency
• pituitary disease is a secondary adrenal disorder, stop of ACTH production leads to lack of cortisol action
• mineraolcorticoids effect the ion levels in plasma, leading to a change in blood pressure.

  • main one in humans = aldosterone
• aldosterone regulation

  • high ACTH levels can increase aldosterone levels.
  • low sodium levels lead to aldosterone production
  • high potassium levels lead to aldosterone production.
  • kidney detecting drops in blood pressure leads to renin production leads to angiotensin II production
  • angiotensin II binds to adrenal gland leading to aldosterone production
• both cortisol and aldosterone bind to the mineralocorticoid receptor.

  • then proteins are synthesised that increase sodium reabsorption.
  • increases water reabsorption and increases blood pressure.

  too much aldosterone leads to loss of H+ causing metabolic alkalosis
• hyperaldosteronism (primary):

  • autonomous production of aldosterone
  • e.g. Conns syndrome - enlargement of the cortex.
  • renin levels are normal/low.
  • treated with surgery or spironolactone
• hyperaldosteronism (secondary):

  • high aldosterone due to high renin levels.
  • caused by diuretic therapy or excess liqourice ingestion
• key androgens = DHEA and androstenedione

  • in females may cause growth of pubic and axillary hair - excess causes female virilisation.
• CAH = congenital adrenal hyperplasia

  • symptoms - dehydration, weakness, male genitalia in females and precocious puberty in males
  • 21 hydroxylase deficiency
  • decreased glucocorticoid and mineralocorticoid production - leads to excess ACTH.
  • this leads to excessive production of adrenal androgens
  • as no cholesterol can enter mineralocorticoid or glucocorticoid production pathway