3. Adrenal Glands

What are the three layers of the adrenal cortex and what do they secrete?

• Zona glomerulosa: Secretes mineralocorticoids (mainly aldosterone)

• Zona fasciculata: Secretes glucocorticoids (mainly cortisol) and sex steroids

• Zona reticularis: Secretes sex steroids and glucocorticoids

How is the release of cortisol controlled?

• Corticotropin-Releasing Hormone (CRH) from the hypothalamus stimulates the release of ACTH from the anterior pituitary.

• ACTH stimulates the adrenal gland to secrete cortisol.

• Negative feedback: High cortisol levels decrease ACTH and CRH secretion, reducing cortisol production.

• Cortisol follows a circadian rhythm:

  • Low levels at night

  • Peak around 8:00 AM

  • Decreases throughout the day.

• Stress (e.g., pain, fear, hypoglycemia) stimulates the release of CRH, ACTH, and cortisol to help cope with stress.

What is the mechanism of action of cortisol (a glucocorticoid)?

• Cortisol diffuses through the cell membrane

• Binds to cytosolic glucocorticoid receptors

• The cortisol–receptor complex enters the nucleus

• Binds to DNA and alters gene transcription

• Leads to protein synthesis → causes a cell response

What are the metabolic actions of glucocorticoids?

• Carbohydrate metabolism:

  • ↑ Liver glucose formation

  • ↑ Liver glycogen synthesis & storage

  • ↓ Insulin action on glucose uptake (muscle & fat)

• Protein metabolism:

  • ↓ Amino acid uptake & protein synthesis (peripheral tissues)

  • ↑ Protein breakdown (muscle, skin, bone)

• Fat metabolism:

  • ↑ Fat breakdown (adipose tissue)

  • ↓ Fat synthesis

What are the anti-inflammatory actions of glucocorticoids?

• In high doses, they inhibit tissue inflammatory processes

• Used to treat chronic inflammatory conditions

• Examples: prednisolone, betamethasone, dexamethasone

What are the anti-allergic effects of glucocorticoids?

• In high doses, inhibit histamine synthesis & release from mast cells

• Used to treat severe asthma & anaphylactic shock

• Examples: beclomethasone, budesonide

What are the immunosuppressive actions of glucocorticoids?

• Affect T-lymphocytes at therapeutic doses

• Used to treat autoimmune diseases

• Prevent tissue rejection after transplants

Why must glucocorticoid treatment not be stopped suddenly?

• Sudden withdrawal can cause adrenal crisis

• Long-term steroid use suppresses adrenal gland function

• Patients need gradual dose reduction unless advised otherwise

• Patients should carry a steroid treatment card or bracelet

• Alerts healthcare providers in emergencies (e.g. car crash)

• Ensures they receive necessary steroids during stress

What are the causes, features & treatment of glucocorticoid hyposecretion?

• Primary adrenocortical insufficiency (Addison’s disease):

  • Cause: adrenal gland dysfunction

  • ↓ cortisol, ↑ ACTH

  • Features: muscle weakness, postural hypotension, dehydration, weight loss, nausea, vomiting, tiredness, ↑ skin pigmentation (due to ACTH acting like MSH)

• Secondary adrenocortical insufficiency:

  • Cause: pituitary dysfunction

  • ↓ cortisol, ↓ ACTH

• Treatment:

  • Hydrocortisone (glucocorticoid)

  • Fludrocortisone (mineralocorticoid)

What are the causes, features & hormone levels in glucocorticoid hypersecretion (Cushing’s syndrome/disease)?

• Causes:

  • Cushing’s disease → pituitary adenoma

  • Cushing’s syndrome → ectopic ACTH-secreting tumour

• Clinical features:

  • Muscle weakness & wasting (thin limbs)

  • Back pain (osteoporosis)

  • Easy bruising, purple striae

  • Fat redistribution (e.g. moon face, buffalo hump)

  • Female virilization (hair growth, acne, amenorrhoea)

  • Hyperglycaemia, polyuria, polydipsia → diabetes tendency

  • Psychological disturbances

• Hormone levels:

  • ↑ plasma cortisol (no diurnal variation)

  • ↓ plasma ACTH

What is the difference between Cushing's Syndrome & Cushing's Disease?

• Cushing’s Syndrome → General term for excess cortisol, from any cause

• Cushing’s Disease → Specific cause of syndrome: pituitary tumour ↑ACTH

• All Cushing’s Disease is Cushing’s Syndrome, but not vice versa

What is the treatment for glucocorticoid hypersecretion (Cushing's syndrome)?

• First line treatment:

  • Trans-sphenoidal surgery + corticosteroid replacement therapy.

• Drug therapy:

  • Inhibition of adrenal steroidogenesis:

    • Metyrapone: 11β-hydroxylase inhibitor.

    • Ketoconazole: Antifungal, P450 enzyme inhibitor, glucocorticoid receptor antagonist.

    • Mitotane: 11β− and 18−hydroxylase inhibitor.

  • Inhibition of ACTH synthesis and secretion:

    • Pasireotide (Signifor): Somatostatin analogue.

  • Inhibition of ACTH secretion from pituitary adenoma:

    • Cabergoline: Dopamine D2 receptor agonist.

  • Inhibition of cortisol receptors:

    • Mifepristone: Progesterone and glucocorticoid receptor antagonist.

What controls the release of the mineralocorticoid aldosterone?

• Regulated by the renal renin-angiotensin system

• Stimulated by a large ↓ in plasma [Na⁺] or a small ↑ in plasma [K⁺]

How does aldosterone exert its effects in the body?

• Aldosterone crosses the membrane & binds to cytosolic mineralocorticoid receptors

• The complex enters the nucleus & binds DNA

• This ↑ synthesis of sodium transport proteins

• Results in:

  • ↑ Na⁺ reabsorption (conservation) &↑ K⁺ & H⁺ excretion

  • Which leads to ↓ water excretion & ↑ blood volume

What are the causes, symptoms & treatment of mineralocorticoid (aldosterone) hyposecretion?

• Causes: Renal disease due to diabetes mellitus or AIDS

• Symptoms:

  • ↑ Na⁺/H₂O excretion

  • ↑ plasma K⁺

  • Hypotension

• Treatment: Replacement therapy

What are the causes, symptoms & treatment of mineralocorticoid (aldosterone) hypersecretion (Conn’s syndrome)?

• Causes:

  • Adrenal hyperplasia (adrenal gland enlargement)

  • Adenoma in zona glomerulosa

• Symptoms:

  • Hypertension (↑ Na⁺ & H₂O retention)

  • ↓ plasma K⁺

  • Alkalosis

  • Muscle weakness, fatigue

  • Cardiac dysrhythmias

  • ↓ plasma renin

• Treatment:

  • Surgery

  • Spironolactone (aldosterone receptor antagonist) 4 weeks before surgery

What is secondary aldosteronism and how is it treated?

• Caused by ↑ renin release = ↑ angiotensin II = ↑ aldosterone

• Triggers: poor renal perfusion, malignant hypertension, renal tumour, diuretics, CHF, hepatic failure

• Treatment: manage underlying cause + spironolactone (aldosterone antagonist)