Cushing's syndrome

Overview

Causes of Cushing's syndrome

Feature	Cushing's disease (pituitary adenoma)	Adrenal adenoma	Ectopic ACTH
ACTH level	High (normal or elevated)	Low / suppressed	Very high
High-dose DST: ACTH	Suppressed	Already suppressed	NOT suppressed
High-dose DST: cortisol	Suppressed	NOT suppressed	NOT suppressed
Hyperpigmentation	Mild	Absent	Prominent
Key association	Bitemporal hemianopia if macroadenoma	Autonomous adrenal cortisol secretion	Small cell lung cancer / pulmonary carcinoid

🎯

Cushing's disease = ACTH-secreting pituitary adenoma (specific cause). Cushing's syndrome = any cause of glucocorticoid excess (umbrella term). Exogenous (iatrogenic) = most common cause overall; both ACTH and cortisol are low.

Presentation

•Central obesity ('lemon on a stick') - fat redistribution to visceral/truncal depots with thin limbs

•Moon face and buffalo hump - fat redistribution to face and dorsocervical region

•Proximal myopathy - cortisol catabolises skeletal muscle; difficulty rising from chair / climbing stairs

•Purple striae (>1 cm, abdominal) - impaired collagen synthesis

•Easy bruising and thin skin

•Hypertension - mineralocorticoid activity, sodium and water retention

•Hirsutism, acne, amenorrhoea - excess ACTH drives adrenal androgen production (ACTH-dependent disease)

•Hyperpigmentation - high ACTH states only (ACTH shares homology with MSH); prominent in ectopic ACTH

•Impaired glucose tolerance / diabetes - cortisol promotes gluconeogenesis and insulin resistance

•Bitemporal hemianopia - pituitary macroadenoma compressing optic chiasm

🚨

In children: weight gain WITH falling height centiles is the red flag for Cushing's syndrome. Simple exogenous obesity is associated with normal or accelerated growth - this reversal is the key discriminator.

Investigations

•Screening (confirm cortisol excess):

•Overnight 1 mg dexamethasone suppression test (DST) - 1 mg at 11 pm; cortisol at 9 am; normal suppression <50 nmol/L

•24-hour urinary free cortisol - integrates cortisol over full day, avoids moment-to-moment variability

•Late-night salivary cortisol - exploits loss of diurnal rhythm; cortisol remains elevated at midnight in disease

•Localisation (identify source): plasma ACTH level is the first step - low ACTH = ACTH-independent (adrenal); high/normal ACTH = ACTH-dependent (pituitary or ectopic)

•High-dose DST - distinguishes pituitary adenoma (both suppressed) from ectopic ACTH (neither suppressed) and adrenal adenoma (ACTH already low, cortisol not suppressed)

•CT adrenal glands - next investigation when ACTH-independent disease confirmed; non-invasive, identifies adrenal adenoma

💡

Adrenal vein sampling can confirm unilateral vs bilateral adrenal cortisol excess but CT adrenals is the appropriate first imaging step in ACTH-independent disease.

Management

•Exogenous Cushing's syndrome: gradual reduction of glucocorticoid dose under specialist supervision - abrupt withdrawal risks adrenal crisis

•Cushing's disease (pituitary adenoma): transsphenoidal adenomectomy - first-line; cure rates ~70-90%

•Adrenal adenoma: laparoscopic adrenalectomy; post-operative adrenal insufficiency expected - contralateral gland suppressed, requires temporary glucocorticoid replacement

•Ectopic ACTH syndrome: treat underlying tumour; bridge with metyrapone or ketoconazole to control cortisol

🥈 Second-line

•pituitary radiotherapy for recurrent Cushing's disease; metyrapone or ketoconazole as bridging/medical therapy

🥉 Third-line

•bilateral adrenalectomy for refractory ACTH-dependent disease - causes permanent adrenal insufficiency and risks Nelson's syndrome (pituitary tumour enlargement due to loss of cortisol feedback, presenting with hyperpigmentation and visual field defects)

⚠️

Children and pregnant women with suspected endogenous Cushing's syndrome must be referred urgently to specialist endocrinology - do not delay for screening tests in primary care.