adrenal

• Adrenal glands


  Located superior to the kidneys (suprarenal), each 9cm3, 4-6g, well supplied with blood from aorta, renal & phrenic arteries, highest rate of blood flow in the body
• Structure of adrenal gland

  • Cortex (outer region, 80-90%, derived from mesoderm) with 3 regions (zona glomerulosa, zona fasciculata, zona reticularis)
  • Medulla (inner, 10-20%, derived from ectoderm, modified post-ganglionic neurons, intimately connected to sympathetic nervous system)
• Zona glomerulosa


  Abundant smooth ER, lipid droplets, produces mineralocorticoids (aldosterone) that affect mineral homeostasis
• Zona fasciculata


  Abundant smooth ER, lipid droplets, produces glucocorticoids (cortisol) that affect glucose homeostasis
• Zona reticularis


  Produces androgens (DHEA) that have masculinising/virilising effects
• Adrenal cortex - "Salt, stress and sex" - the three S's of the adrenal
• Steroid hormones


  Derived from cholesterol, a natural precursor of all steroid hormones, come from LDL in blood, have a 4-ring perhydrocyclopentanophenanthrene structure with a fatty acid chain
• Hormone synthesis in the cortex

  1. In mitochondrion

  2. In smooth ER
• Glucocorticoid receptor


  A zinc-finger transcription factor that must bind to the hormone, dimerise, migrate to the nucleus, bind to glucocorticoid response elements in promoters, and activate/repress gene expression to modify inflammatory/metabolic/immune response
• Cortisol


  Essential glucocorticoid for life, produced in zona fasciculata and reticularis, 75% bound to corticosteroid-binding globulin in plasma, only unbound is biologically active, provides resistance to stress by making nutrients available for ATP production, affects glucose/protein/fat metabolism, raises blood pressure, has anti-inflammatory and immunosuppressive effects
• Cortisol regulation


  1. Emotion, stress, trauma stimulates CRH from hypothalamus

  2. CRH regulates ACTH from anterior pituitary

  3. ACTH stimulates cortisol production from adrenal

  4. Cortisol inhibits ACTH from pituitary (negative feedback)
• Cortisol secretion - circadian pattern

  Episodic and variable, with a rhythm over 24h-period independent of environmental variables, controlled by the suprachiasmatic nucleus in the hypothalamus, with a burst in the early morning and brief bursts throughout the day, increased with coffee, sleep, exercise, disrupted by jet lag and some diseases
• Diseases of adrenal cortex - hypercortisolism (overproduction)


  • Cushing's syndrome (primary adrenal disorder or secondary ACTH overproduction)
  • Iatrogenic (physician-caused) hypercortisolism
• Diseases of adrenal cortex - hypocortisolism (deficiency)


  • Addison's disease (adrenocortical failure, mainly autoimmune)
• Treatment for Addison's disease

  Replacement therapy with oral hydrocortisone and fludrocortisone (synthetic mineralocorticoid), to reduce overproduction of ACTH
• Clinical uses of glucocorticoids


  • Replacement therapy for adrenal failure
  • Anti-inflammatory & immunosuppressive therapy
  • Neoplastic disease treatment
• Glucocorticoid compounds


  • Hydrocortisone (cortisol)
  • Cortisone
  • Prednisolone
  • Prednisone
  • Dexamethasone
  • Betamethasone
  • Fludrocortisone
  • Aldosterone
• Glucocorticoid therapy: adverse side effects


  Depend on dose, frequency, route, duration, age, clinical condition. Include cardiovascular, renal, musculoskeletal, skin, bone, CNS, ophthalmic, immune system, GI tract, and endocrine effects
• Glucocorticoids: side effect reduction


  Give in the morning, use short-acting, reduce doses, alternate day therapy, use topical/inhaled, target steroid-receptor complex, target transcriptional mechanisms
• Glucocorticoid therapy: adverse side effects

  Depend on dose, frequency, route of administration, therapy duration, age & clinical condition
• Glucocorticoid side effects


  • Cardiovascular & renal effects: hypertension & oedema
  • Musculoskeletal & skin & bone effects: obesity, thin skin, osteoporosis, growth suppression in children, moon face, buffalo hump, myopathy, prolonged wound healing, hairiness
  • CNS effects: psychoses, dependence, headaches, increased appetite
  • Ophthalmic problems: glaucoma
  • Immune system: increase risk of infection
  • GI tract: peptic ulcers
  • Endocrine system: suppression of hypothalamic-pituitary axis, diabetes risk, menstrual problems
• Glucocorticoid side effect reduction

  • Side effects greatest: parenteral>oral>topical/inhaled
  • Duration of exposure main factor involved
• Ways to reduce glucocorticoid side effects

  • Give AM not PM
  • Use short acting glucocorticoids
  • Reducing doses
  • Alternate day therapy
  • Use topical or inhalation therapy
  • Target steroid-receptor complex
  • Target transcriptional mechanisms
• "Holy Grail": a glucocorticoid with the potent anti-inflammatory effects but WITHOUT the unwanted metabolic/other effects
• Mineralocorticoids


  Produced in the zona glomerulosa of the adrenal cortex
• Hormone synthesis in the adrenal cortex

  1. In mitochondrion

  2. In smooth ER
• Aldosterone

  • Potent mineralocorticoid
  • Produced exclusively in zona glomerulosa
  • In plasma, 60% bound to corticoisteroid-binding globulin (CBG)
  • Increases Na+ reabsorption by kidney tubules
  • Increased excretion of K+ and H+
  • Raises blood pressure, plasma volume
  • Low Na+, dehydration, haemorrhage: ⇑ aldosterone secretion
  • Linked to renin-angiotensin system (RAS) of kidney
• Renin-angiotensin system (RAS)

  Juxtaglomerular cells release renin - renin converts angiotensinogen to Ang I - ACE converts Ang I to Ang II - Ang II stimulates adrenal gland to release aldosterone - aldosterone acts on kidney
• High plasma K+

  Low plasma Na+
• Glucocorticoid compounds


  • Hydrocortisone (cortisol)
  • Cortisone
  • Prednisolone
  • Prednisone
  • Dexamethasone
  • Betamethasone
  • Fludrocortisone
  • Aldosterone