9. Cortisol

Question 1

Which part of the adrenal gland synthesises cortisol?

Answer 1

zona fasiculata

Question 2

what type of adrenal hormone is cortisol?

Answer 2

glucocorticoid

Question 3

describe how the secretion of cortisol is controlled

Answer 3

1. Physical (temp., pain), chemical (hypoglycaemia) and emotional stressors…
2. hypothalamus produces CRH (corticotropin releasing hormone)…
3. stimulates AP corticotropes to release ACTH (adrenocorticotropic hormone)…
4. stimulates zona fasiculara in AGs to release cortisol.

-ve feedback of cortisol on both AP and hypothalamus

Question 4

How is cortisol transported in blood?

Answer 4

lipophilic hormone so requires carrier protein: TRANSCORTIN

small amount bound to serum albumin or free

Question 5

What are the main actions of cortisol?

Answer 5

1. catabolic effects
   - increased protein breakdown in muscle
   - increased lipolysis in fat
2. stress response
   - increased liver gluconeogenesis (increases activity and amount of enzymes)
   - increased BP (increases vessel sensitivity to vasoconstrictors)
3. 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)

Question 6

How does cortisol affect target tissues?

Answer 6

1. crosses plasma membrane of target cell…
2. binds to cytoplasmic Rs…
3. hormone/R complex enters nucleus to interact with specific regions of DNA or transcription factors…
4. changes rate of transcription of specific genes.

Question 7

Why does cortisol cause an increase in liver glycogen stores?

Answer 7

increases gluconeogenesis… increases glucose levels… increases insulin… so increases liver glycogen stores

Question 8

How does cortisol decrease glucose utilisation in muscle?

Answer 8

inhibits insulin-induced GLUT4 translocation in muscle - so prevents glucose uptake (glucose-sparing effect)

Question 9

What is chronic excessive exposure to cortisol called?

Answer 9

cushing’s syndrome

Question 10

What is the most common cause of cushing’s syndrome?

Answer 10

prescribed glucocorticoids

Question 11

Name 3 possible endogenous causes for cushing’s syndrome.

Answer 11

1. benign pituitary adenoma secreting ACTH - CUSHING’S DISEASE
2. adrenal tumour secreting excess cortisol - ADRENAL CUSHING’S
3. non pituitary/adrenal tumours producing ACTH (and/or CRH), e.g. SMALL CELL LUNG CARCINOMA - very rare

Question 12

Which tests should be performed in cases of Cushing’s syndrome?

Answer 12

1. measurement of plasma cortisol and ACTH levels
2. 24hr urinary excretion of cortisol and its breakdown products
3. dynamic function tests, e.g. DEXAMETHASONE suppression test

Question 13

How can one differentiate between the 3 endogenous causes of Cushing’s syndrome?

Answer 13

1. 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)
2. Adrenal cushing’s
   - low plasma ACTH
3. non-pituitary/adrenal tumour
   - high plasma ACTH

Question 14

Why can cortisol, a glucocorticoid, have mineralocorticoid and androgen-like effects when present in high concentrations?

Answer 14

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.

Question 15

Name the signs/symptoms of excess cortisol.

Answer 15

1. weight gain with characteristic body shape and moon-shaped face
2. purple striae (on upper abdomen, upper arms and thighs) and easy bruising
3. thin arms/legs and muscle weakness
4. back pain and rib collapse
5. hyperglycaemia with associated polyuria and polydipsia (“steroid diabetes”)
6. acne

Question 16

Explain the characteristic cushing’s body/face shape.

Answer 16

increased adipose tissue lipolysis… re-distribution of fat in abdomen, supraclavicular fat pads, dorso-cervical fat pad (“buffalo hump”) and face

Question 17

Explain the cushing’s thin arms and legs.

Answer 17

increased muscle proteolysis… wasting of proximal muscles - negative nitrogen balance

Question 18

Explain occurence of hyperglycaemia in cushing’s

Answer 18

increased muscle proteolysis and hepatic gluconeogensis

Question 19

explain the purple striae in cushing’s

Answer 19

catabolic effects of cortisol on proteins, e.g. collagen… weakens skin structure

Question 20

explain the back pain/rib collapse in cushing’s

Answer 20

osteoporosis caused by disturbances in calcium metabolism and loss of bone matrix protein

Question 21

explain the hypertension in cushing’s

Answer 21

mineralocorticoid effects due to sodium and water retention

Question 22

explain the acne in cushing’s

Answer 22

immunosuppressive and anti-inflammatory effects of cortisol - increased susceptibility to bacterial infections

Question 23

name 2 drugs that can cause cushing’s syndrome? what are these used to treat?

Answer 23

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

Question 24

What is important about corticosteroid drugs?

Answer 24

steroid dosage should be reduced gradually and not stopped suddenly!

Question 25

what is addison's disease?

Answer 25

low cortisol in presence of high ACTH

Question 26

what are the causes of addison's disease?

Answer 26

- 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)

Question 27

Describe the signs and symptoms of addison's disease.

Answer 27

1. insidious onset with initial non-specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss and occasional dizziness 2. extreme muscular weakness and dehydration 3. increased skin pigmentation, esp. on exposed areas of body, points of friction, buccal mucosa, scars and palmar creases 4. decreased BP/postural hypotension due to sodium and fluid depletion 5. hypoglycaemic episodes esp. on fasting due to lack of glucocorticoid

Question 28

Why does addison's disease cause increased skin pigmentation?

Answer 28

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.

Question 29

What is an Addisonian crisis?

Answer 29

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

Question 30

What is the treatment for Addisonian crisis?

Answer 30

``` fluid replacement (dextrose in saline) cortisol ```

Question 31

How is Addison's disease diagnosed?

Answer 31

administration of SYNACTHEN intramuscularly (would normally increase plasma cortisol)

Question 32

How does ACTH act at the adrenal glands?

Answer 32

1. hydrophilic peptide hormone that binds to GPCR on surface of cells - MC2 (corticotropin R)... 2. cAMP production... 3. activation of cholesterol esterase: increases conversion of cholesterol esters to free cholesterol also stimulates other steps in cortisol synthesis from cholesterol