Adrenal structure and function

Question 1

Where are the adrenal glands found?

Answer 1

Above the kidneys on the posteromedial surface

Question 2

Mneumonic to remember the different zones of the adrenal cortex

Answer 2

GFR (outer to inner)

Salt, sweet and sex (for their functions respectively)

Question 3

What do mineralocorticoids (aldosterone) do and what controls their release?

Answer 3

Their function is salt retention

Their release is controlled by renin

Question 4

What do glucocorticoids (cortisol) do and what controls their release?

Answer 4

They are involved in controlling how our cells use sugar, fat and curbing inflammation

Their release is controlled by ACTH

Question 5

What do sex steroids do and what controls their release?

Answer 5

• They are involved in increasing bone density, decreasing body fat, improve sexual function and correct some hormonal problems
• Their release is controlled by ACTH

Question 6

What do adrenaline and noradrenaline do and what controls their release?

Answer 6

• They are involved in the fight or flight response

- Their release is controlled by the sympathetic nervous system

Question 7

What is the common structure of all steroid hormones?

Answer 7

Three cyclohexane rings and a single cyclopentane ring

Question 8

The increased pigmentation seen in Addison’s disease is due to what?

Answer 8

Activation of the melanocortin receptor by ACTH

Question 9

What is the main precursor for all steroid hormones?

Answer 9

CHOLESTEROL

Question 10

The production of glucocorticoids and adrenal androgens is under the control of what?

Answer 10

The hypothalamic-pituitary axis (HPA)

Question 11

The production of mineralocorticoids is under the control of what?

Answer 11

RAAS

- Specifically angiotensin 2

Question 12

Explain the HPA axis

Answer 12

1. The hypothalamus releases CRH
2. CRH acts on the ACTH cells in the pituitary gland (anterior), causing them to release ACTH
3. ACTH acts on the adrenal cortex, releasing cortisol into the circulation which inhibits (NEG FEEDBACK LOOP) the ACTH and CRH

Question 13

Give an example of a factor which causes activation of the HPA axis by activating CRH in the hypothalamus?

Answer 13

Stress

Question 14

ACTH and cortisol follow which pattern of secretion?

Answer 14

A diurnal pattern!

• Highest in the morning, fall throughout the day but spike after your meals. Lowest levels are seen around midnight
• A diurnal cycle is any pattern that recurs every 24 hours as a result of one full rotation of the planet Earth around its axis

Question 15

Why is it important to recognise the circadian pattern of ACTH and cortisol secretion in practice?

Answer 15

When treating those with adrenal insufficiency:
1) replacement dose you give tries to mimic the normal circadian pattern

2) In Cushing’s syndrome (xs cortisol secretion), the diurnal pattern is disrupted (this is why we use midnight salivary cortisol reading to diagnose Cushing’s syndrome)

Question 16

Glucocorticoids vs mineralocorticoids vs adrenal androgens, which ones are secreted in the highest amounts per day?

Answer 16

1. Glucocorticoids = HIGH amounts
2. Mineralocorticoids = LOW amounts
3. Adrenal androgens = Most abundant

Question 17

What is the consequence of the structural similarities between the glucocorticoids/corticosteroids, cortisol and cortisone, and the mineralocorticoid aldosterone?

Answer 17

The glucocorticoids can bind to the mineralocorticoid receptor and have mineralocorticoid activity which is Na & H2O retention and K+ excretion

Question 18

Since glucocorticoids are secreted in HIGH amounts every day, what mechanism does the body put in place to stop them from activating the mineralocorticoid receptors?

Answer 18

The body deactivates the active steroids (cortisol, corticosterone, prednisolone) by the enzyme 11-betahydroxysteroid-dehydrogenase type 2 which converts them into inert steroids

Question 18

What is adrenal insufficiency?

Answer 18

Adrenal insufficiency is a condition where there is deficiency or impairment in cortisol secretion

Question 19

What can adrenal insufficiency be divided into?

Answer 19

Primary, secondary and tertiary adrenal insufficiency

Question 20

What is primary adrenal insufficiency also known as?

Answer 20

Addison’s disease

Question 21

What is Addison’s disease?

Answer 21

A condition in which there is destruction of the adrenal glands
- Most commonly autoimmune but it can have other causes

Question 22

What is secondary adrenal insufficiency?

Answer 22

Adrenal glands are intact but there is a lack of cortisol secretion due to lack of ACTH (pit) or CRH (hypothalamus)

Question 23

What is the most common cause of Addison’s disease in developed countries vs worldwide?

Answer 23

Auto-immune adenalitis (80% cases)

• Up to 75% have positive antibodies (so the remaining 25% can have the disease without the antibodies)
• 50% or more may have other auto-immune conditions
• WORLDWIDE = Tuberculosis-induced adrenocortical deficiency

Question 24

Clinical features of Addison's disease

Answer 24

- Skin hyperpigmentation - Low blood pressure - Weakness - Weight loss - Nausea - Diarrhoea - Vomiting - Constipation - Abdominal pain - Vitiligo - Buccal pigmentation

Question 25

Clinical features of Addison's disease (adrenal) crisis

Answer 25

1. Fever 2. Syncope 3. Convulsions 4. Hypoglycaemia 5. Hyponatraemia 6. Severe vomiting and diarrhoea

Question 26

Causes for Addison's disease

Answer 26

- Auto-immune - Infection: TB, fungal, CMV - Infiltration: metastases, lymphoma, amyloidosis - Infarction: thrombophilia - Haemorrhage: meningococcal septicaemia, anticoagulants - Adrenoleukodystrophy: condition which is inherited and seen in younger children

Question 27

Diagnosis for Addison's disease

Answer 27

1. Random cortisol: check cortisol at any point of the day 2. 9am cortisol: this is when cortisol level is supposed to be greatest (<100nmol confirms adrenal insufficiency) 3. Short synacthen/ACTH stimulation test (definitive test)

Question 28

What is the short synacthen test?

Answer 28

1. We take a basic cortisol sample from patient 2. Inject synthetic ACTH (intramuscular or intravenous) 3. Check cortisol levels 30 mins later - Normal response is 30 min cortisol > 540 nmol/L

Question 29

What is primary adrenal insufficiency and its effect on CRH and ACTH?

Answer 29

Addison's disease - Main pathology is at the adrenal gland level, destruction of glands - In an effort to increase cortisol levels, there is an increase in CRH and ACTH levels

Question 30

What is secondary adrenal insufficiency and its effect on CRH and ACTH?

Answer 30

- The defect is at the pituitary level - ACTH is either normal or low because the defect is at the pituitary level - CRH is high

Question 31

What is tertiary adrenal insufficiency and its effect on CRH and ACTH?

Answer 31

- The defect is at the hypothalamus level | - CRH is low and ACTH is low or normal

Question 32

Causes for secondary adrenal insufficiency

Answer 32

- Structural lesions | - Radiotherapy-related damage to the pituitary or hypothalamus

Question 33

What is the major hormonal factor precipitating adrenal crisis?

Answer 33

Mineralocorticoid | - NOT glucocorticoid deficiency

Question 34

What is the predominant manifestation of adrenal crisis?

Answer 34

Hypotensive shock | - Rarely hypoglycaemia is seen

Question 35

Total loss of adrenocortical function causes death within what time period?

Answer 35

3 days to 2 weeks

Question 36

How do you manage an Addisonian crisis?

Answer 36

- Fluid replacement: 1-3L of saline in first 12-24hrs - Hypoglycaemia: IV dextrose - Prompt IV hydrocortisone replacement - Precipitating cause should be treated

Question 37

Long term treatment for Addisonian patient no longer in crisis

Answer 37

1. Hydrocortisone - 10mg morning - 5mg lunch - 5mg evening 2. Fludrocortisone (aldosterone agonist) 3. Androgen replacement: DHEA daily 4. HPA axis suppression: reduce dose gradually to prevent crisis

Question 38

What are the sick day rules?

Answer 38

1. Never stop steroids 2. Double dose during illness/infection 3. If unable to take PO hydrocortisone, need IM/IV hydrocortisone 4. Carry steroid card / MedicAlert bracelet

Question 39

What is the most common cause of secondary adrenal insufficiency?

Answer 39

- HPA axis suppression due long term steroid use - Pituitary/hypothalamic disease - Structural lesions of pituitary or hypothalamus (less common)

Question 40

Clinical presentation of secondary adrenal insufficiency

Answer 40

Similar to primary insufficiency except: 1. No hyperpigmentation: since ACTH levels are normal or low 2. No dehydration or hyperkalaemia: because aldosterone secretion is intact, which is mediated by RAAS 3. Hypoglycaemia more common 4. Clinical manifestations of pituitary or hypothalamic tumour if this is the underlying cause (visual disturbances, headaches, cranial nerve palsies)

Question 41

What is Cushing's syndrome?

Answer 41

Associated with prolonged exposure to elevated levels of glucocorticoids

Question 42

What is the most common cause of Cushing's syndrome?

Answer 42

Exogenous corticosteroid use (IATROGENIC) | - Causes suppression of the HPA axis which can last as long as a year

Question 43

Clinical features of Cushing's syndrome

Answer 43

1. Thinning and bruising of the skin 2. Skin ulcers (poor wound healing) 3. Central obesity 4. Buffalo hump: deposition of fat at the back of the neck 5. Moon face 6. Osteoporosis: due to high cortisol level 7. Cardiac hypertrophy 8. Hirsutism/Dark facial hair (in women) 9. Muscle wasting in extremities 10. Abdominal striae (purple) 11. Amenorrhea (in women) 12. Erectile dysfunction (men)

Question 44

Difference between Cushing's disease and Cushing's syndrome

Answer 44

Cushing's disease = condition due to an ACTH-producing pituitary adenoma causing hypercortisolaemia Cushing's syndrome = resulting from ANY cause of hypercortisolism

Question 45

How can Cushing's syndrome be sub-classed?

Answer 45

1. ACTH dependent - This is where the Cushing's syndrome is driven by >ACTH levels (most common cause of Cushing's) - Pituitary adenoma = 60-70% of these cases - Ectopic ACTH production = less common cause of ACTH-dependent Cushing's 2. ACTH independent - Due to Xs cortisol secretion at the level of the adrenal glands - Majority caused by exogenous steroids = 80-90%. Distinguishing feature is that ACTH levels are suppressed - Adrenal adenomas/carcinomas = 10-20%

Question 46

Differential diagnoses for Cushing's syndrome

Answer 46

- Alcoholism - Depression - Obesity - Anorexia - Bulimia

Question 47

Screening tests for Cushing's syndrome

Answer 47

1. 24 hour urine free cortisol 2. 1mg overnight dexamethasone suppression test 3. Midnight serum cortisol 4. Late night salivary cortisol

Question 48

Associated laboratory abnormalities with Cushing's syndrome

Answer 48

1. Raised WBC 2. Hyperglycaemia 3. Hypokalaemic metabolic alkalosis

Question 49

How is the overnight dexamethasone suppression test carried out?

Answer 49

1. Take 1mg dexamethasone at 11pm 2. Check 9am cortisol 3. Timing is crucial 4. In normal individuals, 9am cortisol is <50nmol/L - Sensitivity 98% for Cushing's - False positive results, due to: decreased absorption, increased dex clearance (anti-convulsants), increase in CBG (oestrogen), pseudo-cushing's states

Question 50

What is the treatment for ACTH-dependent Cushing's?

Answer 50

- The primary treatment for ACTH-dependent Cushing's is removal of the cortisol producing adenoma - Other treatment includes: Adrenalectomy

Question 51

Gold standard treatment for Cushing's

Answer 51

Transsphenoidal surgery, with either: 1. Microadenomectomy: where an identifiable adenoma is found this can be resected leaving residual tissue of the anterior pituitary 2. Subtotal resection of the anterior pituitary: used where no identifiable adenoma and no desire for fertility after counselling the patient. There is a risk of hypopituitarism.