Endocrine System >
Cushing’s Syndrome

“Clinical state caused by chronic glucocorticoid excess with loss of normal feedback mechanisms of the HPA axis and of the circadian rhythm of cortisol secretion”

  • ACTH-independent causes:
    • Iatrogenic: Oral steroids (main cause)
    • Adrenal adenoma/cancer – cortisol not suppressed by dexamethasone as tumour acts autonomously
    • Adrenal nodular hyperplasia
  • ACTH-dependent causes
    • Cushing’s disease – Pituitary adenoma secretes increased ACTH to cause bilateral adrenal hyperplasia
    • Ectopic ACTH production – from small cell lung cancer and carcinoid tumours
    • Ectopic CRH production – some thyroid and prostate cancers (RARE)
  • HPA axis:
    • Hypothalamus secretes CRH (corticotrophin-releasing hormone) which acts on the pituitary
    • Anterior pituitary → releases ACTH → stimulates the adrenal cortex
    • Adrenal cortex produces:
      • Glucocorticoids – carb, lipid and protein metabolism
      • Mineralocorticoids – sodium, potassium and fluid balance
      • Androgens – peripherally converted to testosterone
  • In ACTH-independent causes:
    • Tumour or hyperplasia of the adrenal cortex leads to excess corticosteroid production
    • Excess intake of exogenous steroids can also lead to Cushing syndrome
  • In ACTH-dependent causes:
    • Tumour of pituitary gland leads to excess ACTH production which stimulates excess corticosteroid production from the adrenal cortex
    • Other sources of ACTH include certain types of cancers e.g. carcinoid tumour or small cell lung cancers
Clinical Presentation
  • Symptoms
    • Increased weight
    • Mood change (depression, lethargy, irritability, psychosis)
    • Acne
    • Proximal weakness – test by standing from sitting without using arms
    • Gonadal dysfunction (irregular menses, hirsutism, erectile dysfunction)
    • Recurrent achilles tendon rupture
    • Virilisation (if female)
  • Signs
    • Hyperglycaemia
    • Increased BP
    • Central obesity, buffalo hump, supraclavicular fat distribution
    • Moon face, striae
    • Thinning skin, muscle atrophy
    • Bruises
    • Purple abdominal striae
    • Osteoporosis
    • Infection-prone
    • Poor wound healing
  • Random plasma cortisol levels can mislead (as affected by illness, time of day, stress)
  • Confirm diagnosis with raised plasma cortisol
  • 1st line test: Overnight dexamethasone suppression test
    • Outpatient test
    • Dexamethasone 1mg PO at midnight then do serum cortisol at 8 am
    • Normally cortisol is suppressed to < 50nmol/L
    • No suppression in Cushing’s
    • False positives are seen in depression, obesity, alcohol excess, liver enzyme inducers
  • 2nd line test: 48h dexamethasone suppression test (if first test abnormal)
    • Dexamethasone 0.5mg/6hr POover 48 hours
    • Measure cortisol at 0 and at 48 hours
    • No suppression of cortisol in Cushing’s
  • Localisation test to find a lesion
    • Plasma ACTH – if low then likely to be adrenal-related cause
  • Iatrogenic:
    • Stop steroids if possible
  • Cushing’s disease:
    • Transsphenoidal selective removal of pituitary adenoma
    • Bilateral adrenalectomy (if source unlocatable)
      • Nelson’s syndrome – side effect of adrenalectomy. Elevated ACTH from enlarged pituitary causes skin pigmentation due to loss of negative feedback from adrenalectomy
  • Adrenal adenoma or carcinoma
    • Adrenalectomy – for adenomas
  • Ectopic ACTH
    • Surgery
  • Increased vascular mortality in untreated Cushing’s
  • Despite treatment, conditions such as diabetes, hypertension, obesity, menstrual irregularity, myopathy, subtle mood changes and osteoporosis remain
  • Vascular Problems (eg. CVD)

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