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Cushing's Syndrome Summary

Key Definitions

  • Cushing's Syndrome: Pathological hypercortisolism
  • Cushing's Disease: ACTH-secreting pituitary adenoma
  • Most common cause: Exogenous steroids

Clinical Features

  • Moon face & central obesity
  • Purple striae & easy bruising
  • Hypertension & diabetes
  • Proximal myopathy
  • Hirsutism & menstrual irregularity

Diagnostic Tests

  • Late-night salivary cortisol
  • Dexamethasone suppression test
  • 24-hour urinary free cortisol
  • Plasma ACTH level
  • Pituitary MRI

Management

  • Pituitary adenoma: Transsphenoidal surgery
  • Adrenal adenoma: Unilateral adrenalectomy
  • Medical therapy: Steroidogenesis inhibitors
  • Ectopic ACTH: Tumor resection

Causes

  • Pituitary adenoma (Cushing's disease)
  • Adrenal tumors
  • Ectopic ACTH secretion
  • Exogenous corticosteroids

Cushing's Syndrome

Clinical features, diagnosis, and management of pathological hypercortisolism

Cushing's syndrome is the name given to the clinical symptoms and signs induced by pathological hypercortisolism from any cause.

Cushing's disease refers to the specific condition of excess cortisol as a result of an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma.

Causes

This may occur due to:

  1. Excess secretion of ACTH
    • ACTH secreting pituitary adenoma (most common endogenous cause)
    • Ectopic ACTH secreting tumours e.g. bronchogenic or neuroendocrine tumours
  2. Excess adrenal secretion of cortisol
    • Adrenal adenoma
    • Bilateral adrenal hyperplasia
    • Adrenal carcinoma
  3. Exogenous corticosteroid use (most common cause overall)

Clinical Features

Physical Appearance

  • Plethoric moon face
  • Weight gain and central obesity
  • Interscapular fat pad ("buffalo hump")
  • Purple striae
  • Easy bruising
  • Acne

Metabolic & Cardiovascular

  • Impaired glucose tolerance or diabetes
  • Hypertension
  • Ankle oedema
  • Polycythaemia

Musculoskeletal & Endocrine

  • Proximal myopathy
  • Osteoporosis and fragility fractures
  • Menstrual irregularity
  • Decreased libido
  • Hirsutism and frontal alopecia

Other Features

  • Poor wound healing
  • Musculoskeletal aches and pains
  • Unexplained psychiatric symptoms (including depression)

Image: Clinical features of Cushing's syndrome

Moon face, central obesity, purple striae, buffalo hump

CLINICAL FEATURES OF CUSHING'S SYNDROME. (IMAGE BY MIKAEL HÄGGSTRÖM (OWN WORK) [CC0], VIA WIKIMEDIA COMMONS)

Diagnosis

Step 1: Confirm Hypercortisolism

Use one of four high-sensitivity tests (repeat if necessary):

  • Late-night salivary cortisol
  • Overnight 1 mg dexamethasone suppression testing
  • 24-hour urinary free cortisol
  • 48-hour 2 mg dexamethasone suppression testing

Step 2: Determine ACTH Status

Morning plasma ACTH level:

  • Suppressed ACTH: ACTH-independent Cushing syndrome → Adrenal imaging
  • Unsuppressed ACTH: ACTH-dependent Cushing syndrome → Proceed to Step 3

Step 3: Localize ACTH Source

  • Pituitary/sellar MRI for pituitary adenoma
  • If no definitive lesion: Inferior petrosal sinus sampling (IPSS)
  • IPSS gradient >2:1 or 3:1 after CRH stimulation = Cushing's disease
  • No gradient = Investigate for ectopic ACTH secretion (CT chest/abdomen/pelvis)

Management

Treatment should not be undertaken until the diagnosis is firmly established and the source of hypercortisolism is recognised. All patients with moderate to severe hypercortisolism should undergo therapy directed at its underlying cause.

Cause First-line Treatment Alternative Options
Cushing's Disease
(Pituitary adenoma)		 Transsphenoidal resection of pituitary adenoma Pasireotide, steroidogenesis inhibitors, mifepristone
Adrenal Adenoma Unilateral adrenalectomy -
Adrenal Carcinoma Surgical resection (if possible) Chemotherapy, adjunctive therapies
Bilateral Adrenal Disease Bilateral adrenalectomy Steroidogenesis inhibitors, glucocorticoid receptor antagonists
Ectopic ACTH Surgical resection of ACTH-producing tumor Glucocorticoid receptor antagonist, steroidogenesis inhibitors, bilateral adrenalectomy

Medical Therapy Options

  • Steroidogenesis inhibitors: Osilodrostat, ketoconazole, metyrapone, mitotane, etomidate
  • Glucocorticoid receptor antagonist: Mifepristone
  • Somatostatin analogue: Pasireotide

These are used for mild hypercortisolism or short-term for severe hypercortisolism before definitive therapy.