9. Cortisol Flashcards
Which part of the adrenal gland synthesises cortisol?
zona fasiculata
what type of adrenal hormone is cortisol?
glucocorticoid
describe how the secretion of cortisol is controlled
- Physical (temp., pain), chemical (hypoglycaemia) and emotional stressors…
- hypothalamus produces CRH (corticotropin releasing hormone)…
- stimulates AP corticotropes to release ACTH (adrenocorticotropic hormone)…
- stimulates zona fasiculara in AGs to release cortisol.
-ve feedback of cortisol on both AP and hypothalamus
How is cortisol transported in blood?
lipophilic hormone so requires carrier protein: TRANSCORTIN
small amount bound to serum albumin or free
What are the main actions of cortisol?
- catabolic effects
- increased protein breakdown in muscle
- increased lipolysis in fat - stress response
- increased liver gluconeogenesis (increases activity and amount of enzymes)
- increased BP (increases vessel sensitivity to vasoconstrictors) - anti-inflammatory effects and depression of immune response (prescribed to organ transplant patients)
- inhibits macrophage activity
- inhibits mast cell degranulation (useful medication for allergic reactions)
How does cortisol affect target tissues?
- crosses plasma membrane of target cell…
- binds to cytoplasmic Rs…
- hormone/R complex enters nucleus to interact with specific regions of DNA or transcription factors…
- changes rate of transcription of specific genes.
Why does cortisol cause an increase in liver glycogen stores?
increases gluconeogenesis… increases glucose levels… increases insulin… so increases liver glycogen stores
How does cortisol decrease glucose utilisation in muscle?
inhibits insulin-induced GLUT4 translocation in muscle - so prevents glucose uptake (glucose-sparing effect)
What is chronic excessive exposure to cortisol called?
cushing’s syndrome
What is the most common cause of cushing’s syndrome?
prescribed glucocorticoids
Name 3 possible endogenous causes for cushing’s syndrome.
- benign pituitary adenoma secreting ACTH - CUSHING’S DISEASE
- adrenal tumour secreting excess cortisol - ADRENAL CUSHING’S
- non pituitary/adrenal tumours producing ACTH (and/or CRH), e.g. SMALL CELL LUNG CARCINOMA - very rare
Which tests should be performed in cases of Cushing’s syndrome?
- measurement of plasma cortisol and ACTH levels
- 24hr urinary excretion of cortisol and its breakdown products
- dynamic function tests, e.g. DEXAMETHASONE suppression test
How can one differentiate between the 3 endogenous causes of Cushing’s syndrome?
- Cushing’s disease
- high plasma ACTH
- +ve dextromethasone suppression test (suppression of plasma cortisol by >50% because diseased pituitary retains some sensitivity to potent synthetic steroids) - Adrenal cushing’s
- low plasma ACTH - non-pituitary/adrenal tumour
- high plasma ACTH
Why can cortisol, a glucocorticoid, have mineralocorticoid and androgen-like effects when present in high concentrations?
All steroid hormone Rs have similar basic structure with hormone and DNA binding domains. Hormone-binding domains of mineralocorticoid/androgen Rs and glucocorticoid Rs have >60% sequence homology. So cortisol can bind to these to a limited extent, causing their partial activation.
Name the signs/symptoms of excess cortisol.
- weight gain with characteristic body shape and moon-shaped face
- purple striae (on upper abdomen, upper arms and thighs) and easy bruising
- thin arms/legs and muscle weakness
- back pain and rib collapse
- hyperglycaemia with associated polyuria and polydipsia (“steroid diabetes”)
- acne
Explain the characteristic cushing’s body/face shape.
increased adipose tissue lipolysis… re-distribution of fat in abdomen, supraclavicular fat pads, dorso-cervical fat pad (“buffalo hump”) and face
Explain the cushing’s thin arms and legs.
increased muscle proteolysis… wasting of proximal muscles - negative nitrogen balance
Explain occurence of hyperglycaemia in cushing’s
increased muscle proteolysis and hepatic gluconeogensis
explain the purple striae in cushing’s
catabolic effects of cortisol on proteins, e.g. collagen… weakens skin structure
explain the back pain/rib collapse in cushing’s
osteoporosis caused by disturbances in calcium metabolism and loss of bone matrix protein
explain the hypertension in cushing’s
mineralocorticoid effects due to sodium and water retention
explain the acne in cushing’s
immunosuppressive and anti-inflammatory effects of cortisol - increased susceptibility to bacterial infections
name 2 drugs that can cause cushing’s syndrome? what are these used to treat?
PREDNISOLONE and DEXAMETHASONE
- used to treat inflammatory disorders, e.g. asthma, inflammatory bowel disease, RA and other auto-immune conditions
- suppress immune reaction to organ transplantation
What is important about corticosteroid drugs?
steroid dosage should be reduced gradually and not stopped suddenly!
what is addison’s disease?
low cortisol in presence of high ACTH
what are the causes of addison’s disease?
- main cause: auto-immune atrophy of adrenal gland (affects more women than men)
- pituitary/hypothalamus disorder leading to decreased ACTH/CRF secretion
- much rarer causes: fungal infection, adrenal cancer and adrenal haemorrhage (e.g. following trauma)
Describe the signs and symptoms of addison’s disease.
- insidious onset with initial non-specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss and occasional dizziness
- extreme muscular weakness and dehydration
- increased skin pigmentation, esp. on exposed areas of body, points of friction, buccal mucosa, scars and palmar creases
- decreased BP/postural hypotension due to sodium and fluid depletion
- hypoglycaemic episodes esp. on fasting due to lack of glucocorticoid
Why does addison’s disease cause increased skin pigmentation?
Decreased cortisol… reduced negative feedback on AP… more POMC required to synthesise ACTH - also produces MSH… a- and y-MSH stimulate melanin synthesis by melanocytes.
ACTH itself can also activate melanocortin Rs on melanocytes so will also contribute to hyperpigmentation.
What is an Addisonian crisis?
Life threatening emergency due to adrenal insufficiency precipitated by: severe stress, salt depravation, infection, trauma, cold exposure, over exertion, abrupt steroid drug withdrawal…
Symptoms: nausea, vomiting, pyrexia, hypotension and vascular collapse
What is the treatment for Addisonian crisis?
fluid replacement (dextrose in saline) cortisol
How is Addison’s disease diagnosed?
administration of SYNACTHEN intramuscularly (would normally increase plasma cortisol)
How does ACTH act at the adrenal glands?
- hydrophilic peptide hormone that binds to GPCR on surface of cells - MC2 (corticotropin R)…
- cAMP production…
- activation of cholesterol esterase: increases conversion of cholesterol esters to free cholesterol
also stimulates other steps in cortisol synthesis from cholesterol
