3.11 - Adrenal disorders 2/2 Flashcards
What kind of rhythm does cortisol have?
Diurnal - increase starts from 5am, peaks around 8:30-9am, then decreases again (usually lowest around midnight if asleep)
What is the difference between Cushing’s syndrome and Cushing’s disease?
- Cushing’s syndrome - excess cortisol in body
- Cushing’s disease - type of Cushing’s syndrome where there is a pituitary corticotroph tumour causing excess cortisol
What are the clinical features of Cushing’s syndrome?
- too much cortisol
- centripetal obesity
- moon face and buffalo hump
- proximal myopathy
- hypertension and hypokalaemia (11BHSD inhibited)
- red striae, thin skin, bruising
- osteoporosis, diabetes
How does 11-beta-hydroxysteroid dehydrogenase (11BHSD) protect the mineralocorticoid receptors from cortisol?
- cortisol can bind to either its own receptor (glucocorticoid receptors - GR), or the aldosterone receptors (MR)
- 11BHSD quickly deactivates cortisol into cortisone, protecting the MR and preventing cortisol from having mineralocorticoid effects
What happens to 11-beta-hydroxysteroid dehydrogenase in Cushing’s syndrome and how does this explain the hypertension/hypokalaemia observed?
- excess cortisol means that 11BHSD is overwhelmed and not able to deactivate all the cortisol once secreted
- cortisol has aldosterone-like effects in high concentrations
What are the causes of Cushing’s syndrome?
- taking too many steroids (glucocorticoids)
- pituitary dependent Cushing’s disease
- ectopic ACTH from lung cancer
- adrenal adenoma secreting cortisol
What investigations can be done to determine Cushing’s syndrome?
- 24h urine collection for urinary free cortisol
- blood diurnal cortisol levels (usually highest at 9am and lowest at 12am)
- low dose dexamethasone suppression test
How does the low dose dexamethasone suppression test work?
- dexamethasone = very potent artificial glucocorticoid (steroid)
- give 0.5mg every 6h for 48h
- healthy people will suppress cortisol to zero - pituitary will respond via -ve feedback thinking it is cortisol
- any cause of Cushing’s will fail to suppress cortisol
What types of drugs can be used to deal with high cortisol?
- enzyme inhibitors
- receptor blocking drugs
What specific drugs are used to treat Cushing’s syndrome? (3)
Inhibitors of steroid (cortisol) biosynthesis:
- metyrapone
- ketoconazole
- osilidrostat
What is the mechanism of action of metyrapone?
- inhibition of 11B-hydroxylase
- steroid synthesis in zona fasciculata (and reticularis) is arrested at 11-deoxycortisol stage
- 11-deoxycortisol has no negative feedback on hypothalamus/pituitary
What are the uses of metyrapone?
- control of Cushing’s prior to surgery and/or after radiotherapy (which is slow to take effect)
- adjust oral dose according to cortisol (aim for mean serum cortisol 150-300 nmol/L)
- improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc)
What are some unwanted actions of metyrapone?
- inhibition of 11-hydroxylase causes accumulation of 11-deoxycorticosterone in zona glomerulosa –> aldosterone-like effects –> hypertension and salt retention on long-term administration
- increased adrenal androgen production –> hirsutism (women)
What is the mechanism of action of ketoconazole?
- main use as an antifungal agent - withdrawn in 2013 due to risk of hepatotoxicity
- at higher concentrations, inhibits steroidogenesis = off-label use in Cushing’s syndrome
- mainly blocks 17-alpha hydroxylase, inhibiting cortisol production
What is ketoconazole used for?
- treatment and control of symptoms prior to surgery
- orally active
What is an unwanted side effect of ketoconazole?
Liver damage - possibly fatal (monitor liver function weekly - clinically and biochemically)
What is the mechanism of action for osilidrostat?
- similar to ketoconazole and blocks several enzymes in the steroid synthetic pathway
- mainly blocks 11b and 17a hydroxylase, inhibiting cortisol production
- newer agent - using in UK on named patient basis
What are other treatments of Cushing’s syndrome (other than drugs suppressing cortisol synthesis)? (3)
- pituitary surgery (trans-sphenoidal hypophysectomy)
- bilateral adrenalectomy
- unilateral adrenalectomy for adrenal mass
What is Conn’s syndrome?
- benign adrenal cortical tumour (zona glomerulosa)
- aldosterone in excess
- hypertension and hypokalaemia
Might also see metabolic alkalosis due to excess H+ secretion
What is a summary of the actions of aldosterone?
- increases renal sodium reabsorption
- increases renal potassium excretion
- increases blood pressure (sodium and water retention)
Also increases H+ secretion (so excess –> metabolic alkalosis)
How is Conn’s syndrome diagnosed?
- primary hyperaldosteronism
- renin-angiotensin system should be suppressed (exclude secondary hyperaldosteronism - normal physiological response)
How do we treat Conn’s syndrome?
Mineralocorticoid antagonists - spironolactone, eplerenone
What does spironolactone do?
- competitive antagonist of the MR
- blocks Na+ reabsorption and K+ excretion in the kidney tubules (potassium sparing diuretic)
What is an unwanted side effect of spironolactone?
Gynaecomastia (blocks androgen receptor - anti-androgen drug means reduced testosterone)
