Adrenal Glands

• 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
• Adrenal Gland Regions


  • Cortex (Outer Region)
  • Medulla (Inner Region)
• Adrenal Cortex


  • 80-90% of adrenal gland
  • Derived from mesoderm
  • 3 regions (zona)
• Adrenal Medulla


  • 10-20% of adrenal gland
  • Derived from ectoderm
  • Modified post-ganglionic neurons
  • Intimately connected to sympathetic nervous system
• Adrenal Cortex Zones


  • Zona Glomerulosa
  • Zona Fasciculata
  • Zona Reticularis
• Zona Glomerulosa


  • Abundant smooth ER, lipid droplets
  • Mineralocorticoids (aldosterone) - affect mineral homeostasis
• Zona Fasciculata


  • Abundant smooth ER, lipid droplets
  • Glucocorticoids (cortisol) - affect glucose homeostasis
• Zona Reticularis


  Androgens (DHEA) - have masculinising/virilising effects
• Steroids


  • Derivatives of perhydrocyclopentanophenanthrene ring - 4-ring structure, Carbons numbered
  • Derived from Cholesterol - natural precursor of all steroid hormones - Comes from LDL in blood
• Glucocorticoid Receptor - MOA

  1. Bind to the hormone (lipophilic)

  2. Dimerise to form a homodimer

  3. Migrate from cytosol to nucleus

  4. Bind to glucocorticoid response elements (GRE) in promoter of specific genes

  5. Activate/repress expression of certain genes
• Glucocorticoid receptor


  Zinc-finger transcription factor
• Cortisol


  • Essential glucocorticoid for life
  • Produced in zona fasciculata and reticularis
  • In plasma, 75% bound to corticoisteroid-binding globulin (CBG)
  • Only unbound is biologically active
• Cortisol


  Resistance to stress - makes nutrients available for ATP production
• Cortisol


  • Stimulates liver cells to synthesise glucose from non-carbohydrates & thereby blood glucose concentrations - (gluconeogenesis)
  • Inhibits synthesis of fat and protein in tissues
  • Promotes use of fatty acids (lipolysis) as energy source for gluconeogenesis, decreasing the use of glucose
• Cortisol


  • Raises blood pressure by vasoconstriction
  • Also has mineralocorticoid activity (less than aldosterone)
• Cortisol


  • Reduces release of histamine from mast cells & basophils
  • Decreases capillary permeability
  • Depresses phagocytosis
• Cortisol


  • Reduces lymphocyte numbers
  • Reduced antibody production
• Cortisol Regulation


  1. Emotion, stress, trauma stimulates corticotropin-releasing hormone (CRH) from hypothalamus

  2. CRH regulates adrenocorticotrophic hormone (ACTH) from anterior pituitary

  3. ACTH stimulates cortisol production from adrenal

  4. Cortisol inhibits ACTH from pituitary
• Cortisol Secretion


  • Cortisol secretion pattern episodic and variable
  • Rhythm over 24h-period, independent of environmental variables - Also called diurnal rhythms
  • Main clock in suprachiasmatic nucleus in hypothalamus - operates via clock and per genes switched on & off
  • Affects CRH, ACTH levels
  • Rhythm upset by time shifting (eg. jetlag)
  • Some diseases get no rhythm e.g. Cushing's or stress
• Cortisol episodes


  • Burst in early am (an hour after awakening)
  • Rest of day brief bursts (7-15 episodes)
  • Increased release with coffee consumption
  • Increased during sleep stage when protein is being recycled
  • Increases with increased exercise time & intensity
• Causes of Hypercortisolism


  • Primary disorder of adrenal (e.g. tumour) - "Cushing's syndrome"
  • Secondary overactivity due to overproduction of ACTH from pituitary (e.g. tumour) -"Cushing's disease"
  • Patient hormone treatment - "iatrogenic" (physician-caused) hypercortisolism
• Treatment of Hypercortisolism


  • Remove tumour
  • Metyrapone, aminoglutethimide, Trilostane, ketoconazole - Interfere with steroid biosynthesis
• Symptoms of Addison's Disease

  • Lethargy
  • Weakness
  • Weight loss
  • Serum K+, Na+
  • Decreased blood pressure
  • Impaired elimination of water
  • Increased pigmentation
  • Vague abdominal pains
  • Vomiting
  • Anaemia
  • Feeble heart action
  • Irritable stomach
  • Hypoglycaemia
• Causes of Addison's Disease

  • Adrenocortical failure - Deficiency of both cortisone and aldosterone
  • Main cause is autoimmunity
• Treatment of Addison's Disease

  • Replacement therapy with oral: hydrocortisone, fludrocortisone (synthetic mineralocorticoid)
• Clinical Uses of Glucocorticoids


  • Replacement therapy for adrenal failure e.g. Addison's disease and adrenalectomy
  • Anti-inflammatory & immunosuppressive therapy - reverse all types/stages of inflammation arthritis, asthma, allergies, transplants, dermatological disorders, shock
  • Neoplastic disease (specific cancers) e.g. Hodgkin's disease, acute lymphoblastic leukaemia, brain tumours (oedema reduction)
• Adverse Side Effects of Glucocorticoid Therapy

  • 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
• Strategies 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
• Aldosterone


  • Potent mineralocorticoid
  • Produced exclusively in zona glomerulosa
  • In plasma, 60% bound to corticoisteroid-binding globulin (CBG)
• Aldosterone


  • Increases Na+ reabsorption by kidney tubules
  • Increased excretion of K+ and H+
  • Raises blood pressure, plasma volume
  • Low Na+, dehydration, haemorrhage : aldosterone secretion
  • and opposite
• Overproduction of Aldosterone


  • Na+ and H2O retention
  • Volume of extracellular fluid
  • Hypertension
  • Hypokalaemia
  • Alkalosis
• Causes of Aldosterone Overproduction


  • Primary hyperaldosteronism - Conn's syndrome, Benign tumour
  • Secondary hyperaldosteronism - Excessive RAS action, Kidney disease, Liver cirrhosis, Congestive heart failure
• Treatment of Aldosterone Overproduction

  • Remove tumour or adrenals, or drug therapy
• Anti-Mineralocorticoids


  Spironolactone, Eplerenone - Competitive inhibitors of aldosterone
• Uses of Anti-Mineralocorticoids


  • K+ sparing diuretic (weak diuretic, give with other diuretic, thiazide or loop diuretic) & anti-androgen
  • Poorly absorbed by GI tract; max effect only after 3 days therapy
  • Use to treat: hepatic cirrhosis, malignant ascites, nephrotic syndrome, primary aldosteronism & congestive heart failure
• Adrenal Sex Hormones


  • Male sex hormone (androgens) - from zona reticularis
  • Small quantities produced
• DHEA


  • Primary precursor of natural oestrogens
  • Mostly secreted in the sulphated form, DHEAS
  • Highly circulating but low affinity for androgen receptors
  • thus considered weak androgens
  • Over-the-counter drug in USA
  • Purported to improve memory, work in anti-ageing; unproven value
• Androstenedione


  Converted metabolically to testosterone
• Diseases of Adrenal Cortex - Overproduction of Sex Hormones

  • Excess Androgens - Due to tumours or enzyme defects, Cause excessive masculinisation in males & females (adrenogenital syndrome)
  • Excess Oestrogens - Due to tumours, Cause feminisation
• Adrenal Medulla


  • Chromaffin Cells - Electron dense granules with catecholamines: Adrenaline (80%) / Noradrenaline (20%)
  • Adrenal medullary cells are modified postganglionic neurons - Each chromaffin cell receives direct innervation from preganglionic cholinergic nerve fibres ie. sympathetic ganglion
  • Hormones are "sympathomimetic": - effects mimic those of sympathetic branch of ANS, cause "fight-flight" behavior