E4/5

• Adrenal cortex hormones

  • Corticosteroids- glucocorticoids, mineralocorticoids
  • Androgens
• Adrenal cortex hormones are:

  • Derived from cholesterol
  • Synthesised from acetate (acetyl CoA)
  • Dietary- taken up from circulation
• Synthesis of corticosteroids

  p450 cytochrome enzymes
• Catecholamine synthesis in MEDULLA
• Structure and regulation of StAR

  • Contains a cholesterol transfer domain (StAR related transfer domain – START)
  • It is produced in response to stimulation usually through a cAMP second messenger system
  • Promoted by ACTH, Luteinising hormone
  • Suppressed by Alcohol
• Conversion of cholesterol to pregnenolone

  1. Cytochrome P450scc (Sometimes called side-chain-cleavage or 20,22 Desmolase ) (CYP11A) is located on the inner membrane of the mitochondria and faces the interior

  2. Two Hydroxylase reactions produce 20,22-dihydroxycholesterol

  3. Final stage cleavage of bond between carbon 20 and 22 to produce Pregnenolone
• Glucocorticoids

  • Cortisol (aka hydrocortisone)
  • Corticosterone
• Cortisone

  Synthetic, inactive - converted by body to cortisol
• Glucocorticoid biosynthesis

  • Enzymes
  • Different layers
  • Different intracellular compartments
• Blood transport of cortisol

  • 90%+ bound to plasma protein
  • Transcortin (CBG) – 80+%
  • Albumin – 10%
• ACTH

  • Acts on the adrenal, but is also a prohormone
  • It can be cleaved into α-MSH and CLIP
  • α-MSH regulates melanocytes and CLIP as no known function
• cAMP effects

  1. Immediate: increase cholesterol transport into mitochondria

  2. Subsequent: increase in gene transcription of hydroxylases and increase in LDL receptors

  3. Long term: increase in size and functional complexity of organelles, increase in size and number of cells
• Mechanism of action of glucocorticoids

  • Responsive cells
  • Intracellular receptors (GR)
  • GRE
  • Protein synthesis
• Therapeutic actions of glucocorticoids

  • Anti-inflammatory- in large quantities- may decrease leukocyte action
  • Anti-allergic- decrease histamine synthesis and release
  • Immunosuppression
• Mineralocorticoids

  • Named due to effect on ion levels in plasma
  • Extracellular volume
  • Blood pressure
• Mineralocorticoids

  • Aldosterone
• Biosynthesis of aldosterone- Z. glomerulosa

  1. Progesterone- add 21-hydroxylase

  2. 11-deoxycorticosterone

  3. Add 11-hydroxylase

  4. Corticosterone

  5. 18-hydroxycorticosterone

  6. Add aldosterone synthase

  7. ALDOSTERONE
• Blood transport of aldosterone

  • No specific binding protein
  • Albumin and transcortin (50%)
  • Free in plasma
• Regulation of aldosterone secretion


  • ACTH
  • Plasma K+
  • Plasma Na+
  • Renin-angiotensin system
• What happens when extracellular fluid falls

  1. ECF falls

  2. Renal perfusion press

  3. More juxtaglomerular cells make renin

  4. Produce angiotensinogen and angiotensin 1 and 2

  5. More aldosterone

  6. More renal sodium ion retention

  7. ECF increase
• Mechanism of action of aldosterone

  • Intracellular receptors
  • New protein synthesis- proteins involved in sodium ion handling
• Systemic action of mineralocorticoids

  • Increase sodium reabsorption
  • Less Potassium reabsorption
  • Increased hydrogen loss → metabolic alkalosis
  • Increased H2O reabsorption (increased Na+ reabsorption)
  • Regulation of blood pressure
  • Escape - ECF only by about 15%
  • CHF
• Mineralocorticoids and disease

  • Hyperaldosteronism
  • Primary hyperaldosteronism (Conn's syndrome)
  • Secondary hyperaldosteronism
  • Aldosterone deficiency- Addison's disease
• Adrenal androgens

  • Synthesised in small amounts in zona reticularis
  • DHEA and Androstenedione
  • In females may cause growth of pubic and axillary hair
  • May be responsible for female libido
• Congenital Adreal Hyperplasia

  • Symptoms
  • Treatment- corticosteroid replacement
• CAH (congenital adrenal hyperplasia)

  • E.g. 21 hydroxylase
  • Autosomal recessive; 1 in 10 000 births
  • Decreases glucocorticoid and mineralocorticoid production
  • Less -ve feedback → more ACTH → adrenal hyperplasia
  • Excessive production of adrenal androgens
• The Adrenal Medulla

  • Part of the autonomic nervous system
  • Specialised ganglia supplied by sympathetic preganglionic neurones (ACh as transmitter)
  • Synthesises catecholamines
  • Main site for adrenaline synthesis
  • Not essential for life
• Catecholamine synthesis

  1. Noradrenaline is synthesized in 3 steps from tyrosine

  2. Tyrosine to L-DOPA - Tyrosine hydroxylase catalyses the rate-limiting step

  3. L-DOPA to Dopamine -DOPA decarboxylase, acts on any aromatic acid

  4. Dopamine to Noradrenaline -Dopamine beta-hydroxylase, which is located within the synaptic vesicles

  5. Noradrenaline to Adrenaline – PNMT (phenylethnolamine N-methyl transferase)
• Catecholamine storage and regulation

  • After synthesis, Catecholamine's are transported into synaptic vesicles using a specialised transporter (vesicular monoamine transporter)
  • Vesicles protect hormone from degradation and ensure control can be maintained over how much is released
  • High catecholamine levels within the nerve terminal inhibit rate limiting step (tyrosine hydroxylase; -Ve feedback)
  • High level (rate) of stimulation from nerves stimulates tyrosine hydroxylase
• There is no endocrine negative feedback in the regulation of catecholamine release
• Systemic effects of adrenaline

  • Cardiovascular system
  • Respiratory system
  • Central nervous system
  • Metabolism
• Phaeochromocytoma

  • Excess catecholamines
  • Tumour of chromaffin cells
• Phaeochromocytoma symptoms

  • Episodes of very high BP (250/150 mmHg!!)
  • Sudden, severe headache
  • Palpitations, chest pain
  • Pallor of skin, sweating
  • Anxiousness
• Phaeochromocytoma treatment

  1. Surgery

  2. Alpha blocker (phenoxybenzamine) prevents vasoconstriction

  3. Beta blocker (atenolol) minimises cardiac stimulation

  4. Anti-hypertensive drugs
• Mitochondrial import of cholesterol:

  - Cholesterol transported from the outer mitochondrial membrane to the inner mitochondrial membrane by steroidogenic acute regulatory (StAR) protein

  - Rate limiting step
• Systemic action of glucocorticoids

  1. Metabolism of Carbohydrates: increase plasma glucose, hepatic gluconeogenesis, and Inhibit glucose entry into tissue

  2. Metabolism of proteins in muscles: increase breakdown of protein- produces amino acids, Wasting/growth retardation

  3. Metabolism of proteins in the liver: Increase uptake of amino acids, Protein synthesis, Gluconeogenesis

  4. Metabolism of fat: Increase mobilisation of fatty acids from adipose tissue, Causes Gluconeogenesis, Causes redistribution of extremities- trunk area

  5. Electrolyte balance: Large amounts = mineralocorticoid activity

  6. Bones: Decreased absorption of Ca2+, increased excretion, Inhibition of osteoblasts, Osteoporosis

  7. CNS- Mood/cognition

  8. Immune system: Decrease lymphocytes and eosinophils. Increase neutrophils, RBCs, platelets
• Excess glucocorticoids may lead to

  • Cushings disease/syndrome (tumour)- treat with surgery/radio and metyrapone-11 hydroxylase inhibitor
  • Ectopic ACTH producing tumour
  • Autonomous adrenal adenoma
  • Iatrogenic- long-term immunosuppression with synthetic cortisol analogue
  • Long term psychological stress
  • Truncal obesity, thin arms/legs, striae (stretch marks)
  • Decreased adrenal function
• Decreased adrenal function diseases

  • Primary: Addison's disease- 65% + autoimmune, symptoms include Fatigue, hypoglycaemia, Weight loss, Skin pigmentation, Ion imbalance
  • Secondary: Disease of pituitary (decreased ACTH), stopping long-term glucocorticoid therapy
• Treat Addison's disease with

  Cortisol replacement therapy or mineralocorticoid replacement
• Regulation of aldosterone secretion by

  • Increasing ACTH- this increases secretion
  • Increasing plasma K+ (10%)- this increases secretion
  • Decreasing plasma Na+(10%)- this increases secretion
  • Renin-angiotensin system- an increase in renin will lead to an increase in aldosterone