Cushing's syndrome is a clinical condition resulting from chronic exposure to excess glucocorticoids, whether from endogenous overproduction or exogenous administration, characterized by central obesity, moon facies, muscle wasting, and metabolic disturbances.

Exam domain	One-glance essentials
Definition / diagnosis	Cushing's syndrome = chronic glucocorticoid excess (exogenous or endogenous); Cushing's disease = specifically pituitary ACTH-secreting adenoma causing the syndrome ^[1]^[2] *First classification step: ACTH-dependent (pituitary/ectopic) vs ACTH-independent (adrenal) vs iatrogenic (most common overall)* ^[3]^[4] Most common cause overall = iatrogenic; most common endogenous cause = Cushing's disease (65–70%); ectopic ACTH ~10–15%; adrenal adenoma/carcinoma ~15–20% ^[5]^[6]
Epidemiology / risks	*Testing indicated for: patients with unusual features for age (osteoporosis/HTN in young), multiple progressive discriminating features, children with ↓ height + ↑ weight, adrenal incidentaloma* ^[3]^[7] Pseudo-Cushing's states — obesity, depression, alcoholism, pregnancy — cause physiological hypercortisolism mimicking Cushing's biochemically; must exclude before diagnosis ^[8]^[9] Iatrogenic sources include prescription steroids, herbal medicines, OTC arthritis drugs, traditional Chinese medicines, and cosmetic creams — always take thorough drug history ^[7]^[6]
Core mechanism	*CRH → ACTH → cortisol axis governed by stress (overrides all), circadian rhythm (peak AM, nadir midnight), and pulsatility; autonomous production loses circadian rhythm and suppressibility* ^[3]^[1] Cortisol excess → gluconeogenesis (DM), protein catabolism (striae/myopathy/bruising), central lipogenesis (truncal obesity), mineralocorticoid spillover (HTN/hypoK), osteoblast inhibition (osteoporosis) ^[6]^[10] *Ectopic ACTH (e.g. SCLC) → rapid severe hypercortisolism → metabolic crisis with hypoK and hyperpigmentation rather than classic Cushingoid habitus* ^[4]^[11] *11β-HSD2 inhibitors (e.g. licorice) prevent cortisol inactivation → cortisol acts on mineralocorticoid receptors → HTN + hypoK mimicking hyperaldosteronism* ^[2]^[9]
Clinical picture	Non-specific features (low PPV): moon face, buffalo hump, central obesity, weight gain, hirsutism; *highly discriminating: purple striae >1 cm, proximal myopathy, easy bruising, thin skin, supraclavicular fat pads, facial plethora* ^[3]^[6] *Clinical clues to cause: hyperpigmentation → ACTH-dependent; severe hypoK → ectopic ACTH; virilisation → adrenal carcinoma; AVN/posterior subcapsular cataracts → iatrogenic* ^[4]^[9] *Low 9 AM cortisol with Cushingoid features = iatrogenic Cushing's — the only cause with suppressed endogenous cortisol* ^[3]^[7] Psychiatric features (depression, psychosis, insomnia) occur in the majority; *in children, ↓ height percentile with ↑ weight is the key presentation* ^[12]^[11]
Investigations	Phase 1 — Exclude iatrogenic: drug history + 9 AM cortisol (low = iatrogenic). Phase 2 — Confirm excess: 1 mg ONDST (suppress to <50 nmol/L), 24h UFC ×2, late-night salivary cortisol ×2; no single best test ^[3]^[13] *Phase 3 — Determine cause: plasma ACTH (<5 pg/mL → ACTH-independent → adrenal CT; >20 pg/mL → ACTH-dependent → HDDST/CRH stimulation + pituitary MRI)* ^[14]^[15] *IPSS: central-to-peripheral ACTH gradient ≥ 2.0 basal or ≥ 3.0 after CRH supports pituitary Cushing disease over ectopic ACTH; insulin-tolerance testing is not recommended to diagnose Cushing syndrome* ^[16]^[13] *Biochemistry before imaging — endocrine principle to avoid chasing incidentalomas. Workup for complications: glucose tolerance, DXA, lipids, other pituitary hormones* ^[3]^[17]
Management	*Surgery is first-line for all endogenous causes; preoperative medical optimisation essential: metyrapone (1st line, 11β-hydroxylase inhibitor) to reduce cortisol, control BP/DM/hypoK* ^[18]^[19] *Cushing disease → expert transsphenoidal surgery; persistent/recurrent disease may require repeat surgery, radiotherapy and/or medical therapy; bilateral adrenalectomy is rescue therapy with Nelson syndrome risk* ^[18]^[20] Perioperative: steroid cover (suppressed HPA axis), prophylactic antibiotics and VTE prophylaxis (LMWH). Post-op: GC replacement until HPA axis recovers (~6–18 months) → Synacthen test before stopping ^[19]^[21] Adrenal adenoma → laparoscopic adrenalectomy (if <6 cm); adrenal carcinoma → open excision + adjuvant mitotane; ectopic ACTH → resect source if possible, otherwise medical therapy ^[18]^[22]
Complications	*Untreated Cushing's is often fatal — CVS (HTN → atherosclerosis → MI/stroke), VTE (hypercoagulable state with risk persisting months post-treatment)* ^[23]^[20] *Metabolic triad (HTN + DM + dyslipidaemia) drives cardiovascular risk and may persist even after biochemical cure; glucocorticoid-induced osteoporosis → always screen with DXA* ^[17]^[23] *Nelson's syndrome post bilateral adrenalectomy: loss of cortisol feedback → aggressive pituitary corticotroph tumour growth + hyperpigmentation; prevent with prophylactic pituitary RT* ^[20]^[21] *Iatrogenic-specific: AVN, posterior subcapsular cataracts, glaucoma; steroid withdrawal must be gradual to avoid adrenal crisis* ^[9]^[6]
Prevention / follow-up	Avoid unnecessary/prolonged exogenous glucocorticoid use; use steroid-sparing agents where possible; always taper steroids gradually — never abrupt cessation after prolonged use ^[7]^[6] Post-TSS: long-term surveillance for recurrence (serial cortisol monitoring); after bilateral adrenalectomy → prophylactic pituitary irradiation to prevent Nelson's syndrome ^[20]^[19] Screen all Cushing's patients for metabolic complications (glucose, lipids, DXA, BP) at diagnosis and during follow-up — these may persist post-cure ^[17]^[23]
Exam traps	*15% of Cushing's disease can still suppress on 1 mg ONDST → negative ONDST does NOT exclude Cushing's if clinical suspicion is high; always use ≥2 test modalities* ^[13]^[15] *ONDST false positives: CYP3A4 inducers (phenytoin, rifampicin) accelerate dexamethasone metabolism; OCP raises CBG → ↑ total cortisol; depression/obesity/alcoholism → pseudo-Cushing's* ^[3]^[9] Do not image before biochemical confirmation — modern imaging finds incidentalomas in 5–10% of adrenal CTs; *always confirm biochemistry before imaging to avoid misattribution* ^[3]^[24] Ectopic ACTH (SCLC) presents with hypoK and metabolic crisis, not classic Cushingoid habitus — do not wait for moon facies; rapid onset + hypoK + hyperpigmentation = ectopic until proven otherwise ^[4]^[11]

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3 Cushing's Syndrome, p.60) ^[2] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Aetiology and Clinical Features sections) ^[3] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Sequence of investigations; Exclusion of iatrogenic Cushing's) ^[4] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Aetiology, Clinical Features, Localisation sections) ^[5] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Aetiology of Cushing's Syndrome section) ^[6] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome, p.97–99) ^[7] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Exclusion of iatrogenic Cushing's) ^[8] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Exclusion of iatrogenic Cushing's section) ^[9] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Cushing's syndrome, p.1621–1626) ^[10] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome, p.62–63) ^[11] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome, p.61) ^[12] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome, p.286–287) ^[13] Senior notes: Ryan Ho Chemical Path.pdf (Diagnostic Function Tests — Diagnosis of Cushing Syndrome, p.29–33) ^[14] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf (Cushing's syndrome workup table, p.4) ^[15] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome diagnostic algorithm, p.99) ^[16] Guideline: Endocrine Society. The Diagnosis of Cushing's Syndrome (2008) ^[17] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf (Workup for complications table, p.4) ^[18] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Treatment of Cushing's Syndrome section) ^[19] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome — Management/Course after therapy, p.100) ^[20] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome — Prognosis and Nelson's syndrome, p.64) ^[21] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome — Management and Prognosis, p.288) ^[22] Senior notes: Maksim Surgery Notes.pdf (Adrenalectomy complications, p.203–204) ^[23] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Complications table, p.1630–1632) ^[24] Senior notes: Block A - Endocrine Data Interpretation.pdf (Approach to adrenal incidentaloma and Cushing's)

Cushing's Syndrome — Definition, Epidemiology, Risk Factors, Anatomy, Etiology, Pathophysiology, Classification, and Clinical Features

Cushing's syndrome is the clinical syndrome resulting from chronic, excessive activation of glucocorticoid receptors by cortisol (or exogenous glucocorticoids) ^[1]^[2]^[3].

Important distinction:

Cushing's syndrome = the clinical phenotype of glucocorticoid excess — it is a syndrome, not a disease, and does not imply aetiology ^[2]. Just like "anaemia," you diagnose it on clinical grounds, then search for the underlying cause.

Cushing's disease = specifically refers to Cushing's syndrome caused by an ACTH-secreting pituitary adenoma (or, rarely, hypothalamic disease driving ACTH excess) ^[1]^[2]^[3].

Think of it this way: Cushing's disease is one particular cause of Cushing's syndrome. Every patient with Cushing's disease has Cushing's syndrome, but not every patient with Cushing's syndrome has Cushing's disease.

GC Lecture High Yield

"Cushing syndrome = excessive secretion of glucocorticoids. Cushing syndrome you can diagnose on PE / spot diagnosis, and should trigger a search for the underlying cause." ^[2]

Cushing's syndrome epidemiology varies dramatically by cause:

Cause	Typical Patient	Sex Ratio	Notes
Iatrogenic (exogenous glucocorticoids)	Any age, either sex	Equal	Most common cause overall ^[1]^[3]
Cushing's disease (pituitary adenoma)	F 25–45 years	F ≫ M (3–8:1)	Accounts for 65–70% of endogenous causes ^[1]^[3]
Ectopic ACTH syndrome	Older men > 50 years	M > F	10–15% of endogenous causes; associated with SCLC, carcinoid tumours ^[1]^[3]
Adrenal adenoma	Bimodal: < 10y and ~50y	F preponderance (4–5×)	~15% of endogenous causes ^[1]^[3]
Adrenal carcinoma	Bimodal	F > M	~5% of endogenous causes ^[3]

Overall incidence of endogenous Cushing's syndrome: approximately 2–5 per million per year. It is uncommon, but iatrogenic Cushing's is extremely common since glucocorticoids are among the most widely prescribed drugs worldwide.

Percentages refer to endogenous Cushing's syndrome only ^[1]^[3].

Risk factors align with the underlying cause:

Chronic exogenous glucocorticoid use (most important risk factor overall):
- Oral prednisolone, dexamethasone, hydrocortisone
- Must rule out any herbal medicine, any "OTC drugs for arthritis" ^[3] — patients may not realise they are taking steroids (some traditional Chinese medicines or "arthritis remedies" contain hidden corticosteroids)
- Inhaled, topical, and intra-articular steroids can also cause Cushing's if used in high doses or with CYP3A4 inhibitors
Female sex — for Cushing's disease and adrenal adenoma
Smoking and male sex > 50y — for ectopic ACTH (SCLC association)
MEN1 syndrome — pituitary adenomas (Cushing's disease), also adrenal adenomas
Carney complex — primary pigmented nodular adrenal disease (PPNAD)
McCune-Albright syndrome — ACTH-independent macronodular adrenal hyperplasia

4. Relevant Anatomy and Physiology (The HPA Axis)

Understanding the hypothalamic–pituitary–adrenal (HPA) axis from first principles is essential because every investigation and classification flows from this axis.

The adrenal cortex has three layers (mnemonic: GFR — from outside in: Glomerulosa, Fasciculata, Reticularis; or "Salt, Sugar, Sex" for their respective hormones):

Zone	Hormone	Regulation	Mnemonic
Zona Glomerulosa	Aldosterone (mineralocorticoid)	Renin-Angiotensin-Aldosterone System (RAAS), K⁺	"Salt"
Zona Fasciculata	Cortisol (glucocorticoid)	ACTH	"Sugar"
Zona Reticularis	Androgens (DHEA, DHEA-S, androstenedione)	ACTH	"Sex"

Cortisol is secreted from the zona fasciculata and zona reticularis, under the influence of ACTH released by the anterior pituitary ^[1]^[2]^[3].

GC Lecture High Yield — HPA Axis Control

"Pituitary releases ACTH under influence of CRF from the hypothalamus. CRF release from the hypothalamus is triggered based on stress, circadian rhythm (highest in morning, lowest at midnight), pulsatility. But stress is the most important factor, can override pulsatility." ^[2]

Physiological Factors Affecting Cortisol Secretion [1][3]:

Circadian rhythm: cortisol is highest in the morning (~6–8 AM) and lowest in the middle of the night (~midnight) ^[1]^[2]^[3]
- This is why we measure 9 AM cortisol as a baseline and midnight salivary cortisol as a screening test (loss of the normal nadir suggests Cushing's)
Stress: cortisol increases dramatically during stress (e.g., infection, inflammation, surgery, trauma) ^[1]^[3]
- Protects key metabolic functions (e.g., glucose supply for the brain during starvation)
- Inhibits potentially damaging inflammatory responses
- Stress can override circadian rhythm and pulsatility ^[2]
Pulsatility: CRH is secreted in a pulsatile manner ^[1]^[3]

4.3 Actions of Cortisol

Cortisol has two major types of receptor activity:

Binds to glucocorticoid receptors → regulates gene transcription ^[1]^[3]
Metabolic effects:
- ↑ Hepatic gluconeogenesis → hyperglycaemia
- ↑ Protein catabolism → muscle wasting, thin skin, striae, easy bruising
- ↑ Lipolysis peripherally but ↑ lipogenesis centrally (paradoxical redistribution) → central/truncal obesity, moon face, buffalo hump
- ↑ Appetite → contributes to weight gain
Anti-inflammatory and immunosuppressive:
- ↓ Cytokine production, ↓ lymphocyte proliferation, ↓ neutrophil migration
- → Increased susceptibility to infection
Bone: Inhibits osteoblasts, ↑ RANKL expression → osteoporosis
CNS: Mood disturbance, insomnia, psychosis
Eye: Posterior subcapsular cataract, raised IOP → glaucoma
Reproductive: Suppresses GnRH → hypogonadism

Cortisol can also bind mineralocorticoid receptors ^[1]^[3]. However, in normal physiology, the enzyme 11β-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) expressed in mineralocorticoid target tissues (distal nephron, sweat glands) inactivates cortisol by converting it to cortisone ^[1]^[3], preventing cortisol from activating these receptors.

Why does this matter clinically?

In severe Cushing's syndrome, the sheer volume of cortisol overwhelms the capacity of 11β-HSD2, leading to cortisol "spillover" onto mineralocorticoid receptors → sodium retention, potassium wasting, hypertension, hypokalaemic alkalosis
This spillover effect is particularly prominent in ectopic ACTH syndrome (where ACTH and cortisol levels are very high)

High Yield Concept — 11β-HSD2

11β-HSD2 inhibitors (e.g., licorice) or deficiency can cause apparent mineralocorticoid excess ^[1]^[3]. This is because cortisol is NOT inactivated, so it acts on mineralocorticoid receptors → hypertension + hypokalaemia, mimicking hyperaldosteronism. This is examined frequently.

ACTH is derived from the precursor molecule pro-opiomelanocortin (POMC). When POMC is cleaved, it produces:

ACTH
α-MSH (melanocyte-stimulating hormone)
β-endorphin
β-lipotropin

This is why hyperpigmentation occurs in ACTH-dependent Cushing's — excess ACTH means excess α-MSH (or ACTH itself acting on melanocortin receptors), stimulating melanocytes ^[4].

The pituitary gland sits in the sella turcica of the sphenoid bone ^[5]. This is relevant because:

Pituitary adenomas causing Cushing's disease are usually microadenomas ( < 10 mm)
They may be difficult to visualise on MRI
The pituitary is adjacent to the optic chiasm — large adenomas can compress it → bitemporal hemianopia (hence the lecture title "I keep bumping into people on my side") ^[6]
Surrounded by the cavernous sinuses containing CN III, IV, V1, V2, VI and the internal carotid artery

5. Aetiology and Classification

GC Lecture High Yield

"The most common cause of Cushing's syndrome is iatrogenic Cushing's" ^[2]^[5]. "Is it ACTH dependent or independent — think one step back the axis, see if it is appropriately low or inappropriately high" ^[2].

When you encounter a patient with Cushingoid features, the very first step is to exclude exogenous steroid use. This includes prescription steroids, herbal medications, "OTC drugs for arthritis," traditional Chinese medicines, and even some cosmetic creams ^[3]^[5].

	ACTH-Dependent (~80% of endogenous)	ACTH-Independent (~20% of endogenous)
Mechanism	Excess ACTH drives adrenal cortisol production	Adrenal gland autonomously produces cortisol; ACTH is suppressed by negative feedback
ACTH level	Normal-high or elevated	Low / undetectable

Detailed Aetiological Classification [1][2][3][4][7]:

Category	Cause	Proportion of Endogenous	Key Features
ACTH-Dependent	Cushing's disease (pituitary adenoma)	65–70%	Usually microadenoma; F 25–45y; ACTH mildly–moderately elevated
	Ectopic ACTH syndrome	10–15%	SCLC, bronchial/thymic carcinoid, MTC (medullary thyroid carcinoma), pancreatic neuroendocrine tumours ^[1]^[3]; very high ACTH & cortisol; often rapid onset with prominent hypokalaemia and hyperpigmentation
	Ectopic CRH syndrome	Exceedingly rare	Tumour secretes CRH → pituitary ACTH release
ACTH-Independent	Adrenal adenoma	~15%	Unilateral; benign; often incidentaloma
	Adrenal carcinoma	~5%	Often large ( > 4 cm); may co-secrete androgens → virilisation in women; poor prognosis
	ACTH-independent macronodular adrenal hyperplasia (AIMAH)	Rare	Bilateral adrenal hyperplasia with aberrant receptor expression
	Primary pigmented nodular adrenal disease (PPNAD)	Rare	Part of Carney complex; bilateral
Exogenous	Iatrogenic (exogenous glucocorticoids)	Most common overall	Oral, inhaled, topical, intra-articular, IV steroids; hidden sources ^[3]
Pseudo-Cushing's	Obesity, alcoholism, depression, pregnancy, stress, CYP3A4 inducers	N/A	Biochemically mimics Cushing's but resolves with treatment of underlying condition ^[4]

5.3 Specific Aetiological Notes

The adenoma is usually a microadenoma ( < 10 mm) — often difficult to find on MRI (~40–50% may not be visible)
The adenoma partially retains negative feedback: cortisol is elevated but ACTH is not maximally suppressed → ACTH is "inappropriately normal" or mildly elevated ^[5]
This is a critical concept: in a normal person, if cortisol is high, ACTH should be suppressed. If ACTH is "normal" in the face of high cortisol, it is inappropriately normal and points to ACTH-dependent Cushing's ^[5]
The adenoma responds to high-dose dexamethasone (partial negative feedback retained) → cortisol suppresses > 50% on HDDST

Causes: SCLC (small cell lung carcinoma), bronchial/thymic carcinoid tumours, medullary thyroid carcinoma (MTC), pancreatic neuroendocrine tumours ^[1]^[3]
ACTH levels are typically very high → cortisol is very high → overwhelms 11β-HSD2 → prominent hypokalaemic metabolic alkalosis and hyperpigmentation
In SCLC: rapid onset, may not have time to develop classic Cushingoid features; patients present with metabolic derangement (hypokalaemia, hyperglycaemia, alkalosis) rather than the typical fat redistribution
In carcinoid: more indolent, can mimic Cushing's disease clinically
Does NOT suppress with high-dose dexamethasone (tumour has no feedback mechanism)

Autonomous cortisol production → negative feedback → ACTH is suppressed (low/undetectable)
Adrenal carcinoma may co-secrete androgens → virilisation (hirsutism, deepening voice, clitoromegaly in women) — this is a red flag for malignancy
On imaging: adenoma is typically small, well-defined, low Hounsfield units (high fat content); carcinoma is typically > 4 cm, irregular, heterogeneous, high Hounsfield units ^[7]

These conditions cause physiological hypercortisolism that can mimic Cushing's biochemically:

Obesity
Alcoholism (alcohol stimulates CRH; also alcohol-related liver disease impairs cortisol metabolism)
Depression (HPA axis hyperactivation)
Pregnancy (physiological rise in cortisol-binding globulin and total cortisol)
Severe stress / critical illness
CYP3A4 inducers (accelerate dexamethasone metabolism → false positive on DST)

Distinguishing pseudo-Cushing's from true Cushing's is one of the most challenging problems in endocrinology. The low-dose dexamethasone suppression test (LDDST) combined with CRH stimulation test (Dex-CRH test) is most useful here.

6. Pathophysiology — How Excess Cortisol Causes the Clinical Features

Understanding the pathophysiology allows you to predict every clinical feature from first principles. Here is a systematic breakdown:

Effect of Excess Cortisol	Mechanism	Clinical Consequence
↑ Hepatic gluconeogenesis + ↑ insulin resistance	Cortisol is a counter-regulatory hormone; it opposes insulin action at multiple levels (↓ GLUT4 translocation, ↑ hepatic glucose output)	Glucose intolerance / diabetes mellitus ^[4]^[8]
↑ Lipolysis (peripheral) + ↑ Lipogenesis (central/visceral) + ↑ Appetite	Cortisol causes paradoxical fat redistribution; central adipocytes have more glucocorticoid receptors and respond with lipogenesis; peripheral fat depots undergo lipolysis	Central/truncal obesity, moon face, buffalo hump (dorsocervical fat pad), enlarged supraclavicular fat pads ^[4]
↑ Protein catabolism + ↓ Collagen synthesis	Cortisol activates proteolytic pathways; inhibits fibroblast collagen production	Thin skin, easy bruising, purple striae (the striae are purple because the thinned dermis reveals the underlying vasculature), proximal myopathy ^[4]

Mechanism	Clinical Consequence
Cortisol overwhelms 11β-HSD2 → acts on mineralocorticoid receptors → ↑ Na⁺/H₂O reabsorption, ↑ K⁺/H⁺ excretion	Hypertension (sodium/water retention + vascular smooth muscle sensitisation to catecholamines), hypokalaemic metabolic alkalosis

Mechanism	Clinical Consequence
↓ Cytokine production, ↓ T-cell function, ↓ neutrophil chemotaxis, ↑ neutrophil demargination	Immunosuppression → increased risk of opportunistic infections (e.g., fungal infections, reactivation TB)
↑ Neutrophil count (demargination from vessel walls)	Apparent leukocytosis on CBP

Mechanism	Clinical Consequence
↓ Osteoblast activity + ↑ RANKL expression → ↑ osteoclast activity + ↓ intestinal Ca²⁺ absorption + ↑ renal Ca²⁺ excretion	Glucocorticoid-induced osteoporosis ^[4] → fragility fractures (vertebral compression fractures are classic)

Mechanism	Clinical Consequence
↑ ACTH → ↑ α-MSH (from POMC cleavage) → melanocyte stimulation	Hyperpigmentation (especially in ectopic ACTH syndrome and Cushing's disease) ^[4]
↑ ACTH → ↑ Adrenal androgen production	Hirsutism, acne (especially in women) ^[4]

Mechanism	Clinical Consequence
Excess cortisol suppresses GnRH pulsatility → ↓ LH/FSH	Menstrual disturbance (oligomenorrhoea/amenorrhoea) in women; impotence/loss of libido in men ^[4]
Excess androgens (from adrenal source)	Contributes to hirsutism and acne in women

Mechanism	Clinical Consequence
Glucocorticoid receptors are highly expressed in hippocampus and limbic system; excess cortisol is neurotoxic to hippocampal neurons	Insomnia, emotional lability, depression, euphoria, psychosis, cognitive impairment ^[4]

Mechanism	Clinical Consequence
Cortisol alters lens protein metabolism → posterior subcapsular opacification	Posterior subcapsular cataract ^[4]
↑ Aqueous humour production + ↑ outflow resistance	Glaucoma ^[4]

7. Clinical Features

Symptom	Pathophysiological Basis
Weight gain (central distribution)	Cortisol stimulates appetite + central lipogenesis with paradoxical peripheral lipolysis
Fatigue, weakness	Proximal myopathy from protein catabolism; may also be from hypokalaemia
Easy bruising	Loss of collagen support for blood vessels (protein catabolism + ↓ collagen synthesis)
Stretch marks (striae) — characteristically purple/violaceous	Rapid central fat deposition stretches thinned skin; thinned dermis reveals subdermal vasculature
Recurrent infections, poor wound healing	Immunosuppression
Polyuria, polydipsia	Hyperglycaemia (glucose intolerance/DM); also cortisol antagonises ADH
Menstrual irregularity (women)	GnRH suppression → ↓ LH/FSH → anovulation
Erectile dysfunction / loss of libido (men)	Hypogonadism from GnRH suppression
Mood changes: depression, anxiety, irritability, insomnia, psychosis	Direct glucocorticoid effects on limbic system and hippocampus
Back pain	Osteoporotic vertebral fractures
Hirsutism, acne (women)	↑ Adrenal androgens (ACTH-driven); also in adrenal carcinoma
Visual field disturbance ("bumping into people on my side")	Only if pituitary macroadenoma compresses optic chiasm → bitemporal hemianopia ^[6]
Headache, sweating, palpitations	Consider concomitant phaeochromocytoma if MEN syndrome; also hypertension

History points to specifically ask ^[2]^[7]:

Exogenous steroid use — "Can be tricky, sometimes even patient doesn't know how they are getting it" ^[2]^[5]

Duration and severity of symptoms

Family history of endocrine tumours (MEN syndromes)

Smoking history (SCLC → ectopic ACTH)

GC Lecture High Yield — Physical Examination

Cushingoid features to look for: moon face, buffalo hump, proximal muscle wasting, central obesity, striae, hirsutism, easy bruising ^[7]

Sign	Pathophysiological Basis
Moon face (round, plethoric face)	Central fat deposition in facial adipose tissue; plethora due to polycythaemia (cortisol stimulates erythropoiesis) and thin skin revealing underlying vasculature
Buffalo hump (dorsocervical fat pad)	Preferential central/truncal fat deposition
Supraclavicular fat pads (filling of supraclavicular fossae)	Central fat deposition
Truncal/central obesity with thin extremities	Central lipogenesis + peripheral lipolysis + limb muscle wasting
Proximal myopathy (difficulty rising from chair, climbing stairs)	Protein catabolism → skeletal muscle wasting (proximal > distal)
Purple/violaceous striae (abdomen, thighs, axillae, breasts)	Stretching of atrophic, thinned skin over rapidly deposited fat; width > 1 cm and purple colour distinguish from normal striae (which are narrow and silvery-white)
Thin, fragile skin	Collagen loss from protein catabolism
Easy bruising (ecchymoses)	↓ Collagen → ↓ vascular support → capillary fragility
Hirsutism (excess terminal hair in androgen-dependent areas in women)	↑ Adrenal androgens
Acne	↑ Adrenal androgens → ↑ sebum production
Hyperpigmentation	↑ ACTH (from POMC) → ↑ α-MSH → melanocyte stimulation. Only in ACTH-dependent causes (especially ectopic ACTH syndrome where ACTH is very high)
Acanthosis nigricans	Insulin resistance (cortisol is a counter-regulatory hormone → ↑ insulin → ↑ IGF-1 receptor activation in skin) ^[4]
Hypertension	Multifactorial: mineralocorticoid effect (Na⁺/H₂O retention), ↑ vascular sensitivity to catecholamines, ↑ angiotensinogen synthesis
Oedema	Na⁺/H₂O retention from mineralocorticoid effect
Kyphosis / loss of height	Osteoporotic vertebral compression fractures
Posterior subcapsular cataract	Altered lens protein metabolism
Bitemporal hemianopia / visual field defect	Pituitary macroadenoma compressing optic chiasm (only in Cushing's disease with large tumour) ^[6]
Hepatomegaly	Hepatic steatosis from metabolic derangement

Feature	Cushing's Disease	Ectopic ACTH	Adrenal Tumour
Onset	Gradual (months–years)	Rapid (weeks–months) in SCLC; indolent in carcinoid	Variable
Cushingoid habitus	Classic	Often absent in SCLC (too rapid); present in carcinoid	Classic
Hyperpigmentation	Mild–moderate	Severe (very high ACTH)	Absent (ACTH suppressed)
Hypokalaemia	Mild or absent	Severe (very high cortisol overwhelms 11β-HSD2)	Mild or absent
Virilisation	Mild	Moderate	Prominent if adrenal carcinoma (co-secretes androgens)
Visual field defect	Possible (if macroadenoma)	No	No
ACTH level	Normal-high / mildly ↑	Very high	Low / undetectable

In ectopic ACTH from SCLC, the presentation is often metabolic rather than Cushingoid:

Profound hypokalaemic metabolic alkalosis
Severe hyperglycaemia
Hyperpigmentation
Muscle weakness
New-onset hypertension
The classic fat redistribution may not have time to develop because the disease progresses so rapidly

These deserve special mention because they are common exam traps:

Condition	Why It Mimics Cushing's
Obesity	Increased cortisol production rate (but also increased clearance; free cortisol may be normal)
Alcoholism	Alcohol stimulates CRH release; impaired hepatic cortisol metabolism
Depression	HPA axis hyperactivation
Pregnancy	↑ CBG (cortisol-binding globulin) → ↑ total cortisol; placental CRH production
Severe stress / critical illness	Physiological HPA activation
CYP3A4 inducers	Accelerate dexamethasone metabolism → false positive DST ^[4]

Important Exam Point

Do NOT diagnose Cushing's syndrome in a critically ill, pregnant, or severely depressed patient based on a single elevated cortisol. Always consider pseudo-Cushing's states and use appropriate confirmatory testing (e.g., Dex-CRH test, LDDST).

Feature	Detail
Definition	Clinical syndrome of chronic glucocorticoid excess
Most common cause overall	Iatrogenic (exogenous steroids)
Most common endogenous cause	Cushing's disease (pituitary ACTH adenoma, 65–70%)
Key classification question	ACTH-dependent vs. ACTH-independent ^[2]
Classic signs	Moon face, buffalo hump, central obesity, purple striae, proximal myopathy, easy bruising, thin skin
Key metabolic derangements	Hyperglycaemia, hypokalaemia (especially ectopic ACTH), hypertension
Key bone complication	Glucocorticoid-induced osteoporosis
Hyperpigmentation	Only in ACTH-dependent causes (POMC → α-MSH)
First step in workup	Exclude exogenous steroid use (including hidden sources)

High Yield Summary

Cushing's syndrome = glucocorticoid excess; Cushing's disease = pituitary ACTH adenoma causing the syndrome
Most common cause overall = iatrogenic; most common endogenous cause = Cushing's disease (65–70%)
First question: Is it exogenous? → If no, is it ACTH-dependent or independent?
9 AM cortisol is the simplest test to exclude iatrogenic Cushing's (exogenous steroids suppress endogenous HPA axis → low morning cortisol)
Cortisol's actions explain every clinical feature: gluconeogenesis → DM; protein catabolism → striae/bruising/myopathy; central lipogenesis → truncal obesity; mineralocorticoid spillover → hypertension/hypokalaemia; immunosuppression → infections; osteoblast inhibition → osteoporosis; ACTH/POMC → hyperpigmentation
Ectopic ACTH (especially SCLC) presents with metabolic crisis (severe hypokalaemia, hyperglycaemia, hyperpigmentation) rather than classic Cushingoid habitus
Pseudo-Cushing's states (obesity, alcoholism, depression, pregnancy) can mimic Cushing's biochemically — must be distinguished with appropriate dynamic testing
Purple striae ( > 1 cm wide), proximal myopathy, easy bruising, and hypokalaemia are the most discriminating clinical features that differentiate true Cushing's from simple obesity

Active Recall - Cushing's Syndrome (Definition to Clinical Features)

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome, p.284) ^[2] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Aetiology of Cushing's Syndrome section) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3 Cushing's Syndrome, p.60) ^[4] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome, p.97) ^[5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Exclusion of iatrogenic Cushing's section) ^[6] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[7] Senior notes: Maksim Surgery Notes.pdf (Adrenal incidentaloma, p.202) ^[8] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf (Cushing's syndrome workup table, p.4)

The differential diagnosis of Cushing's syndrome operates on two distinct levels, and understanding this hierarchy is critical for exams and clinical practice:

Level 1 — "Does this patient actually have Cushing's syndrome, or is something else mimicking it?" (i.e., differential diagnosis of the Cushingoid phenotype)
Level 2 — "If the patient truly has Cushing's syndrome, what is the underlying cause?" (i.e., aetiological differential diagnosis — already covered in the classification section but expanded here with discriminating features)

We will work through both levels systematically.

1. Level 1 — Differential Diagnosis of the Cushingoid Phenotype

A patient presenting with central obesity, moon face, striae, and proximal weakness does not automatically have Cushing's syndrome. Many conditions can mimic its appearance. The key clinical question is: is this true hypercortisolism, or something else?

GC Lecture High Yield — Low Reliability of Clinical Features

"The majority of clinical features are non-specific for Cushing's → PPV of single feature is low. Some common disorders can also be associated with alterations in cortisol secretion (e.g. obesity, depression, alcoholism) → pseudo-Cushing's syndrome." ^[3]^[9]

"More specific features: spontaneous bruising, proximal myopathy, striae, thin skin, supraclavicular fat pads" ^[3]^[9] — these are the features that help you distinguish true Cushing's from mimics.

Condition	Why It Mimics Cushing's	Key Distinguishing Features
Simple (metabolic) obesity	Central fat deposition, glucose intolerance, hypertension, acanthosis nigricans; cortisol production rate may be increased (but clearance also increased, so free cortisol is usually normal)	No thin skin, no proximal myopathy, no spontaneous bruising, no purple striae ( > 1 cm), no supraclavicular fat pads; striae if present are pale/silvery; normal or only mildly abnormal cortisol dynamics
Metabolic syndrome / Type 2 DM	Central obesity, hypertension, glucose intolerance, dyslipidaemia	Insulin resistance features overlap; but lacks catabolic signs (thin skin, bruising, myopathy)
Pseudo-Cushing's states (see below)	Actual mild hypercortisolism but from a physiological or non-neoplastic cause	Resolves when underlying condition is treated
Hypothyroidism	Weight gain, fatigue, depression, menstrual disturbance, myopathy	Fat distribution is generalised (not central); myxoedema; dry skin (not thin); ↓ T4, ↑ TSH
Polycystic ovarian syndrome (PCOS)	Hirsutism, acne, obesity, menstrual irregularity, insulin resistance	No catabolic features; ↑ androgens of ovarian origin; LH/FSH ratio ↑; typically younger women
Congenital adrenal hyperplasia (CAH)	Androgen excess → hirsutism, acne, virilisation; may have mild glucocorticoid excess or deficiency depending on enzyme block	Consider CAH as d/dx if young-onset with prominent androgen excess and primary amenorrhoea ^[3]^[9]; ↑ 17-OHP (21-hydroxylase deficiency)
Drug-induced weight gain	Antipsychotics (olanzapine, clozapine), antidepressants (mirtazapine, TCAs), anticonvulsants (valproate), insulin, sulfonylureas, thiazolidinediones ^[10]	Weight gain is generalised; no catabolic features; drug history is key
Growth hormone deficiency	Central/visceral obesity, fatigue, reduced muscle mass	Preferentially causes increase in abdominal and visceral fat ^[10]; low IGF-1; other pituitary hormone deficiencies may be present
Hypogonadism in males	Central obesity, fatigue, loss of libido, reduced muscle mass	Preferentially causes increase in abdominal and visceral fat ^[10]; low testosterone
Alcoholic pseudo-Cushing's	Moon face, central obesity, hypertension, proximal myopathy, abnormal cortisol dynamics	History of heavy alcohol intake; abnormalities resolve with abstinence
Cushing's syndrome due to exogenous steroids (iatrogenic)	Clinically identical to endogenous Cushing's	Drug history (including hidden sources); iatrogenic Cushing's is more likely a/w AVN, glaucoma, and posterior subcapsular cataracts ^[1]^[3]^[9]

Pseudo-Cushing's describes conditions with genuine mild biochemical hypercortisolism but without a neoplastic or pathological cause. They can cause false-positive screening tests.

GC Lecture High Yield

"Exclusion of physiological hypercortisolism in the absence of Cushing's syndrome" must be done first ^[11]. Two groups:

Clinical features of CS may also be present:

DM (poorly controlled)
Obesity
Pregnancy
Depression
Alcohol dependence
Glucocorticoid resistance

Clinical features of CS unlikely to be present:

Physical stress (hospitalisation/surgery/pain)
Anorexia/malnutrition
Intense chronic exercise
Hypothalamic amenorrhoea
Excess CBG (↑ serum cortisol but not free cortisol) ^[11]

Pseudo-Cushing's State	Mechanism of Hypercortisolism	How to Distinguish from True Cushing's
Obesity	↑ Cortisol production rate (proportional to body mass); but clearance also increased → free cortisol often normal	UFC may be mildly elevated; DST usually suppresses normally; Dex-CRH test is most helpful (cortisol suppresses in pseudo-Cushing's)
Alcoholism	Alcohol stimulates CRH; impaired hepatic cortisol metabolism; also direct toxic effects mimic Cushing's clinically	Resolves with 2–4 weeks of abstinence; repeat testing after abstinence
Depression	HPA axis hyperactivation (limbic system drives CRH); ↑ cortisol secretion	Mood symptoms predominate; cortisol abnormalities resolve with treatment of depression; Dex-CRH test helpful
Pregnancy	↑ CBG → ↑ total cortisol; placental CRH production; loss of dexamethasone suppression	Excess CBG causes ↑ serum cortisol but not free cortisol ^[11]; UFC may be elevated (physiological); late-night salivary cortisol retains some utility
Severe illness / stress	Physiological HPA activation; cortisol is appropriately elevated	Do not test for Cushing's during acute illness; wait until patient is recovered
CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampicin)	Accelerate metabolism of dexamethasone → dexamethasone is cleared faster → appears to not suppress cortisol (false-positive DST)	Use UFC or late-night salivary cortisol instead; drug history is key
Glucocorticoid resistance	Rare genetic condition → ↑ cortisol to compensate for receptor insensitivity; no clinical Cushing's	Very rare; genetic testing

Clinical pearl: The most useful test to distinguish pseudo-Cushing's from true Cushing's is the Dex-CRH test (combined dexamethasone–CRH stimulation test). In pseudo-Cushing's, the HPA axis retains some normal feedback — dexamethasone partially suppresses, and CRH then fails to stimulate significantly. In true Cushing's, cortisol remains elevated. The LDDST is also useful for excluding pseudo-Cushing's ^[4].

This is crucial for clinical exams. Not all features of Cushing's are equally discriminating:

Highly Discriminating (More specific for Cushing's)	Poorly Discriminating (Common in obesity/metabolic syndrome too)
Spontaneous easy bruising	Central obesity
Proximal myopathy	Hypertension
Purple striae ( > 1 cm wide)	Glucose intolerance
Thin, fragile skin	Depression/mood disturbance
Supraclavicular fat pads	Menstrual irregularity
Facial plethora	Hirsutism (common in PCOS)
Osteoporosis (unexpected for age)	Fatigue

High Yield Exam Point

Testing for Cushing's syndrome is indicated for:

Patients with unusual features for age (e.g. osteoporosis, hypertension)
Patients with multiple and progressive features, especially those that are more predictive of CS (e.g. easy bruising, facial plethora, proximal myopathy, striae)
Children with ↓ height percentile and ↑ weight
Patients with adrenal incidentaloma compatible with adenoma ^[12]

2. Level 2 — Aetiological Differential Diagnosis (Determining the Cause of Confirmed Cushing's Syndrome)

Once you have confirmed biochemical hypercortisolism, you need to determine the underlying cause. This is a stepwise process.

GC Lecture High Yield

"The most common cause of Cushing's syndrome is iatrogenic Cushing's — taking of drugs. Quite interesting since some patients may not realize." ^[5]

"9 AM cortisol to exclude iatrogenic Cushing's → MOST SIMPLE TEST. For those patients taking iatrogenic drugs, there will be exogenous suppression of their endogenous HPA axis → so it will be low, don't even have to do other tests." ^[5]

"The patient presents with Cushing's syndrome with a low serum morning cortisol → iatrogenic Cushing's syndrome. The only cause of Cushing syndrome with a low endogenous serum morning cortisol." ^[2]

Finding	Interpretation
Cushingoid features + low 9 AM cortisol + low ACTH	Iatrogenic Cushing's — exogenous steroids suppress the HPA axis; endogenous cortisol is low
Cushingoid features + high cortisol	Endogenous cause → proceed to Step 2

GC Lecture High Yield

"When classifying the causes of Cushing's syndrome, the first question: Is it ACTH dependent or independent? Think one step back the axis, see if it is appropriately low or inappropriately high." ^[2]

ACTH Level	Interpretation	Next Step
ACTH elevated or "inappropriately normal"	ACTH-dependent — the problem is at the pituitary or an ectopic ACTH source	Pituitary MRI + HDDST/CRH stimulation test ± IPSS
ACTH low/suppressed	ACTH-independent — the problem is at the adrenal gland itself	Adrenal CT

Why "inappropriately normal" matters: In a normal person, when cortisol is high, ACTH should be suppressed by negative feedback. If ACTH is "within the normal range" despite elevated cortisol, it is inappropriately normal — this means something is driving ACTH production that is not being appropriately suppressed. This is the hallmark of a pituitary adenoma (Cushing's disease), which retains partial but not complete sensitivity to negative feedback ^[5].

2.3 Step 3: Differentiating Causes Within Each Category

Cause	ACTH Level	Cortisol Response to HDDST	CRH Stimulation Test	IPSS	Key Clinical Clue
Cushing's disease (pituitary adenoma)	Mildly–moderately ↑ (or "inappropriately normal")	Suppresses > 50% (partial feedback retained)	ACTH rises > 50% from baseline (pituitary corticotrophs respond to CRH)	Central-to-peripheral ACTH ratio ≥ 2:1 (basal) or ≥ 3:1 (post-CRH)	Usually microadenoma; F 25–45y; gradual onset
Ectopic ACTH syndrome	Very high (often > 200 pg/mL)	Does NOT suppress (no feedback mechanism in tumour)	No significant ACTH rise (ectopic source not responsive to CRH)	No central ACTH gradient	Rapid onset; usually hypoK instead of classical Cushingoid features; onset usually rapid with cachexia ^[1]^[3]^[9]; hyperpigmentation prominent

GC Lecture High Yield — Ectopic ACTH Clinical Clues

"Malignant tumour with ectopic ACTH: usually hypoK instead of classical Cushingoid features. Onset usually rapid with cachexia → less common to have classical symptoms of Cushing's. Presence of classical Cushingoid features usually indicates a less aggressive tumour (e.g. carcinoids)." ^[1]^[3]^[9]

Ectopic ACTH — Tumour Sources ^[3]^[11]:

Tumour	Approximate % of Ectopic ACTH
Small cell lung carcinoma (SCLC)	~50%
Bronchial carcinoid	~10%
Pancreatic neuroendocrine tumours	~10%
Thymic carcinoid/tumours	~5%
Phaeochromocytoma / Paraganglioma	~2%
GI carcinoids	~2%
Other (prostate, ovarian, breast tumours)	~10%

Cause	ACTH	Cortisol	Imaging	Key Clinical Clue
Adrenal adenoma	Suppressed	Elevated	Unilateral, well-defined, low Hounsfield units ( < 10 HU = lipid-rich), rapid contrast washout ^[7]	Gradual onset; classic Cushingoid features; no virilisation
Adrenal carcinoma	Suppressed	Elevated (often very high)	Large ( > 4 cm), irregular, heterogeneous, high HU, slow washout, possible local invasion ^[7]	Signs suggesting adrenal tumour: palpable abdominal mass, gynecomastia in males, virilisation in females ^[11]; may co-secrete androgens and mineralocorticoids
ACTH-independent macronodular adrenal hyperplasia (AIMAH)	Suppressed	Elevated	Bilateral enlarged adrenals with macronodules	Aberrant receptor expression (e.g. GIP-dependent, β-adrenergic-dependent)
Primary pigmented nodular adrenal disease (PPNAD)	Suppressed	May show paradoxical rise with LDDST	Adrenals may appear normal or mildly nodular on CT	Part of Carney complex (myxomas, lentigines, schwannomas); young patients

GC Lecture High Yield — Clinical Clues to Cause

"Clinical clues to underlying cause:" ^[1]^[3]^[9]

↑ ACTH → hyperpigmentation
Malignant tumour with ectopic ACTH: usually hypoK instead of classical Cushingoid features
Cushing's disease: usually associated with microadenoma → less likely to have hypopituitarism, visual failure, disconnection hyperprolactinaemia
Iatrogenic Cushing's: more likely associated with AVN, glaucoma and posterior subcapsular cataracts

Clinical Finding	Points Towards	Why
Hyperpigmentation	ACTH-dependent (pituitary or ectopic)	↑ ACTH from POMC → ↑ α-MSH → melanocyte stimulation
Severe hypokalaemic alkalosis	Ectopic ACTH	Very high cortisol overwhelms 11β-HSD2 → mineralocorticoid effect at kidney
Rapid onset + cachexia	Ectopic ACTH (especially SCLC)	Aggressive malignancy; too rapid for fat redistribution
Classical Cushingoid habitus + slow onset	Cushing's disease or indolent ectopic (carcinoid)	Gradual cortisol excess allows time for fat redistribution
Virilisation in women (deepening voice, clitoromegaly)	Adrenal carcinoma	Co-secretes androgens
Palpable abdominal mass	Adrenal carcinoma ^[11]	Large tumour
Gynecomastia in males	Adrenal carcinoma ^[11]	May secrete estrogen precursors
Bitemporal hemianopia	Pituitary macroadenoma	Compression of optic chiasm
AVN of hip, glaucoma, posterior subcapsular cataract	Iatrogenic Cushing's ^[1]^[3]^[9]	Exogenous glucocorticoids have stronger association with these complications
Growth retardation (children)	Any cause of Cushing's	Cortisol suppresses GH axis and growth plate activity; stunting of growth is the most prominent S/S in children ^[1]^[3]
Low morning cortisol + Cushingoid features	Iatrogenic	Only cause with low endogenous cortisol ^[2]

Cushing's syndrome itself appears in the differential diagnosis of many other conditions. Recognising these "entry points" is important for exams:

Presenting Complaint	Where Cushing's Sits in the DDx	Ref
Secondary hypertension	Cushing's syndrome alongside Conn's syndrome, pheochromocytoma, renal artery stenosis, coarctation of aorta, OSA ^[13]^[14]	Screen when clinically indicated: overnight 1 mg dexamethasone suppression test ^[13]
Secondary obesity	Cushing's alongside hypothyroidism, hypothalamic tumours, GH deficiency, hypogonadism, PCOS ^[10]
Proximal myopathy / lower limb weakness	Cushing's alongside hypothyroidism, hypokalaemia, dermatomyositis, drug-induced (statins, colchicine), muscular dystrophy ^[15]
Osteoporosis (unexpected for age)	Cushing's alongside other secondary causes (hyperparathyroidism, hypogonadism, coeliac disease, myeloma)
Glucose intolerance / new DM	Cushing's alongside other secondary causes (acromegaly, phaeochromocytoma, pancreatic disease)
Mood disorder / depression	Cushing's and Addison's as secondary causes of depression ^[16]
Dementia workup	RFT, Ca, and Glc for hypercalcaemia, Cushing's or Addison's disease as part of minimum investigations ^[17]
Adrenal incidentaloma	Must determine: Is it functional? Is it malignant? Screen with ONDST + spot ARR + 24h urine metanephrines ^[7]

High Yield Summary

Level 1 — Is it truly Cushing's?

Most Cushingoid features are NON-SPECIFIC → PPV of any single feature is low
Highly discriminating features: purple striae ( > 1 cm), proximal myopathy, easy bruising, thin skin, supraclavicular fat pads, facial plethora
Always consider pseudo-Cushing's (obesity, alcoholism, depression, pregnancy, stress) and other mimics (hypothyroidism, PCOS, CAH, drug-induced weight gain)

Level 2 — What is the cause?

Exclude exogenous steroids FIRST (including hidden sources) → 9 AM cortisol is the simplest test; low cortisol = iatrogenic
ACTH level separates dependent (pituitary/ectopic) from independent (adrenal)
ACTH-dependent: HDDST/CRH stimulation/IPSS separates Cushing's disease from ectopic ACTH
ACTH-independent: Adrenal CT characterises adenoma vs. carcinoma vs. bilateral disease
Key clinical clues: Hyperpigmentation → ACTH-dependent; severe hypoK → ectopic; virilisation → adrenal carcinoma; AVN/cataracts → iatrogenic; low morning cortisol → iatrogenic

Active Recall - Cushing's Syndrome Differential Diagnosis

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome, p.285) ^[2] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Aetiology and Clinical Features sections) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome, p.61) ^[4] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome, p.97–99) ^[5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Exclusion of iatrogenic Cushing's) ^[7] Senior notes: Maksim Surgery Notes.pdf (Adrenal incidentaloma, p.202) ^[9] Senior notes: Ryan Ho Fundamentals.pdf (Cushing's Syndrome, p.435) ^[10] Senior notes: Block A - I am overweight, doctor_ obesity; Hyperlipidaemia.pdf (Conditions associated with obesity) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Cushing's syndrome, p.1621–1626) ^[12] Senior notes: Ryan Ho Chemical Path.pdf (Diagnosis of Cushing Syndrome, p.29) ^[13] Senior notes: Ryan Ho Cardiology.pdf (Secondary causes of hypertension table, p.178) ^[14] Senior notes: Block A - High blood pressure_ hypertension.pdf (Secondary hypertension, p.25) ^[15] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (Differential Diagnosis of Myopathy, p.38) ^[16] Senior notes: Ryan Ho Psychiatry.pdf (Approach to Low Mood, p.140) ^[17] Senior notes: Ryan Ho Neurology.pdf (Dementia workup, p.129)

Before diving into individual tests, it is essential to understand the general principles that govern endocrine investigation. These principles apply to all hormonal workups and are particularly relevant for Cushing's syndrome because of the layered diagnostic algorithm.

GC Lecture High Yield — Sequence of Investigations

"When working up any suspicion of hormonal excess or deficiency, the steps in order are:" ^[5]

History and PE
Baseline blood test → CBC / LRFT
Screening blood biochemistry tests
Confirmatory tests (sometimes dynamic suppression/stimulation tests) → can also workup for complications of the hormone excess/deficiency (biochemistry, ECG, CXR, PSG)
Imaging with MRI / CT
Invasive tests (venous sampling)

"General principle: less invasive before moving on to more invasive. Endocrine is unique in that you need biochemistry before imaging → resolution is too high with our imaging nowadays → so we might find benign lesions which are not related to the condition." ^[5]

This last point is critical: you do NOT start with imaging. If you MRI the pituitary first, you may find a pituitary incidentaloma (present in ~10% of the general population) and incorrectly attribute the Cushing's to it. Similarly, adrenal incidentalomas are found in ~4% of CT scans. High-dose DST is usually done before pituitary MRI to avoid picking up pituitary incidentaloma ^[3]^[1].

GC Lecture High Yield — Diagnostic Function Tests

"Diagnostic (dynamic) function tests (DFTs) involve either stimulating or suppressing a particular hormonal axis. The associated hormonal response is observed." ^[12]

For suspected hormonal excess → use a suppression test (try to suppress the axis — failure to suppress = autonomous production) For suspected hormonal deficiency → use a stimulation test (try to stimulate the axis — failure to stimulate = true deficiency)

In Cushing's, we are dealing with excess, so all screening and confirmatory tests are suppression tests (or tests that demonstrate loss of normal physiology, e.g., loss of circadian rhythm).

2. Diagnostic Criteria — When to Test and What Constitutes a Diagnosis

GC Lecture High Yield — Indications for Testing

Testing for Cushing's syndrome is indicated for: ^[12]

Patients with unusual features for age (e.g., osteoporosis, hypertension)
Patients with multiple and progressive features, especially those that are more predictive of CS (e.g., easy bruising, facial plethora, proximal myopathy, striae)
Children with ↓ height percentile and ↑ weight
Patients with adrenal incidentaloma compatible with adenoma

There is no single "gold standard" test for Cushing's syndrome. Instead, the Endocrine Society guidelines (2008, updated 2025) recommend:

≥ 2 abnormal screening tests → diagnostic of Cushing's syndrome ^[3]^[1]^[9]

If one test is abnormal, perform another confirmatory test or repeat the abnormal test. ^[3]^[9] This is because each individual test has significant false-positive and false-negative rates.

The diagnostic workup proceeds in three phases:

Phase	Goal	Tests Used
Phase 1: Exclude exogenous cause	Rule out iatrogenic Cushing's	Detailed drug history + 9 AM cortisol ^[5]
Phase 2: Confirm endogenous hypercortisolism	Establish that cortisol is autonomously elevated	1 mg ONDST, 24h UFC, late-night salivary cortisol, LDDST ^[8]^[3]^[12]
Phase 3: Determine the cause	Differentiate ACTH-dependent vs. independent; then localise the source	Plasma ACTH, HDDST, CRH stimulation test, imaging (MRI/CT), IPSS ^[3]^[1]^[11]

4. Investigation Modalities — Detailed Breakdown

9 AM Serum Cortisol

GC Lecture High Yield

Aspect	Detail
Principle	Exogenous steroids suppress the HPA axis via negative feedback → endogenous cortisol production is shut down → morning cortisol is low
Procedure	Blood draw at 9 AM (peak of circadian rhythm)
Interpretation	Low cortisol + low ACTH + Cushingoid features = iatrogenic Cushing's
Why this works	In all other causes of Cushing's, cortisol is elevated. Only in iatrogenic Cushing's is the measured (endogenous) cortisol suppressed, because the Cushingoid features are caused by the exogenous steroid which the standard cortisol assay may not detect

Note: Some cortisol assays may cross-react with synthetic glucocorticoids (e.g., prednisolone). Dexamethasone and betamethasone are generally NOT detected by standard cortisol assays, which is why they are used in suppression tests.

4.2 Phase 2: Screening/Confirming Endogenous Hypercortisolism

GC Lecture High Yield — Screening Tests

"Screening and/or confirmatory tests for Cushing's syndrome:" ^[8]

9 AM cortisol and ACTH
1 mg overnight dexamethasone suppression test
24-hour urine for free cortisol
Late-night salivary cortisol
Low-dose dexamethasone suppression test

GC Lecture High Yield

"Initial testing is based on three main modalities:" ^[12]

24-hour urinary free cortisol (UFC) × 2
Late-night salivary cortisol × 2
1 mg overnight dexamethasone suppression test (DST)

"No single best test. If abnormal, should perform another confirmatory test or repeat abnormal test." ^[3]^[9]

This is the most commonly used first-line screening test because it is simple, cheap, and can be done as an outpatient.

"1 mg ONDST preferred to LDDST for diagnosis of Cushing's syndrome (similar Sn and Sp, but easier to perform)" ^[4]

Aspect	Detail
Name breakdown	"Dexamethasone" = a synthetic glucocorticoid ~25× more potent than cortisol; "suppression" = testing whether the HPA axis can be suppressed; "overnight" = done over one night
Principle	Normal: dexamethasone suppresses ACTH secretion → ↓ adrenal cortisol secretion. CS: incomplete suppression ^[12] because the cortisol source is autonomous (tumour) or the set-point is raised (pituitary adenoma)
Procedure	PO 1 mg dexamethasone at 23:00h → Plasma cortisol measured at 09:00h the following morning ^[12]^[3]
Interpretation	Normal: cortisol suppressed to < 50 nmol/L (1.8 μg/dL). CS: cortisol rarely adequately suppressed ^[12]^[3]
Sensitivity	~95% (i.e., very few false negatives — good screening test)
Specificity	~80% (i.e., some false positives — needs confirmation)

Why < 50 nmol/L? This threshold maximises sensitivity. A higher cut-off (e.g., < 138 nmol/L) would increase specificity but miss more cases. For screening, we prioritise sensitivity.

False positives (failed suppression in non-CS): ^[12]

Cause	Mechanism
Enzyme-inducing drugs (anti-epileptics, rifampicin)	↑ Dexamethasone clearance via CYP3A4 induction → less dexamethasone available to suppress ACTH
Women on OC pills or pregnancy	↑ Corticosteroid-binding globulin (CBG) → total cortisol elevated (but free cortisol may be normal)
Severe depression (30–50%)	Physiological HPA axis activation → stress-mediated cortisol elevation
Systemic illness (10–20%)	Same — stress-mediated
Renal failure on dialysis	Altered cortisol and dexamethasone metabolism
Chronic alcohol abuse	Alcohol stimulates CRH; impaired hepatic metabolism
Marked obesity	↑ Cortisol production rate

False negatives (suppression despite CS; very rare < 2%): ^[12]

Cause	Mechanism
Cyclical Cushing's syndrome	Cortisol excess is intermittent; may be in a "normal" phase during test
Slow metabolism of dexamethasone	↑ Drug level → exaggerated suppression

Practical Tip

If clinical suspicion for CS remains high despite normal ONDST, use 24h urinary free cortisol ^[12]. Never rely on a single test to rule out Cushing's if clinical suspicion is high.

Aspect	Detail
Principle	Same as ONDST but more rigorous (longer duration, more dexamethasone exposures) — functions as both screening and confirmation
Procedure	0.5 mg dexamethasone PO Q6H for 2 days (total 48 hours) → cortisol measurement at the end ^[3]^[1]
Interpretation	Normal: cortisol suppressed to < 50 nmol/L. CS: no suppression
Advantages over ONDST	More specific and sensitive ^[12]; better at excluding pseudo-Cushing's
Disadvantages	Requires inpatient stay (for compliance); more complex

"LDDST mainly to exclude pseudo-Cushing's" ^[4] — the extended exposure to dexamethasone gives the normal HPA axis more opportunity to suppress, so pseudo-Cushing's states are more reliably excluded.

Caveat: ^[3]^[1]

Affected by oestrogen level (↑ cortisol-binding globulin) → should stop OCP for ≥ 6 weeks
Metabolised by CYP3A4 → induced by anticonvulsants and rifampicin → use IV route (↓ first-pass metabolism) and check serum dexamethasone level if indicated

Aspect	Detail
Principle	24h urine collection for total free cortisol excretion (removes effect of pulsatile secretion) ^[3]^[9] — captures the entire day's cortisol output rather than a single snapshot
Why "free" cortisol?	Free cortisol is measured because cortisol-binding globulin level may vary in urine ^[12]. Only unbound (free) cortisol is biologically active and filtered by the kidneys
Procedure	Collect all urine over 24 hours; measure total free cortisol
Interpretation	Normal: within reference range. CS: elevated (basal urinary cortisol level > 3× upper limit of normal is highly suggestive) ^[11]
Recommended	× 2 (repeat to confirm, as cortisol can vary) ^[12]

Caveats: ^[3]^[12]

Does not distinguish patients with physiological hypercortisolism (e.g., depression, obesity) — pseudo-Cushing's can give mildly elevated UFC
Practical problems: under-/over-collection, inconvenience, renal diseases ^[12] (impaired renal function → falsely low UFC)
Very high fluid intake ( > 5L/day) → falsely elevated UFC

Aspect	Detail
Principle	CS patients have loss of normal cortisol circadian rhythm → inappropriately elevated late-night salivary cortisol ^[3]^[9]. In normal individuals, cortisol reaches its nadir at ~midnight
Why saliva?	Only free cortisol will be present in saliva due to ultrafiltration ^[12] — not affected by CBG variations (unlike serum cortisol)
Procedure	Patient collects saliva at 23:00–00:00 using a cotton swab (can be done at home)
Interpretation	Cortisol level at 23:00–24:00 ≥ 145 ng/dL (4 nmol/L) → abnormal ^[11]
Recommended	× 2 ^[12]

Caveats: ^[12]

Dependent on diurnal rhythm → not suitable for shift workers
Concentration is usually quite low → sensitive tools (e.g., LC-MS) with limited availability must be used
Contaminated samples (blood in saliva, eating, smoking before collection) → false results

Aspect	Detail
Principle	Not the standard diagnostic test but often done first ^[3]; assessing diurnal variation
Procedure	Blood draw at 9 AM (peak) and midnight (nadir)
Interpretation	Cushing's syndrome: loss of diurnal variation (early morning cortisol may be normal but late-night often raised and similar to morning cortisol). Pseudo-CS: usually intact diurnal variation despite ↑ cortisol secretion ^[3]
Limitation	Requires admission for midnight sample; stress of venepuncture may elevate cortisol; single values less reliable

4.3 Phase 3: Determining the Cause

Once endogenous hypercortisolism is confirmed, the next step is to identify the source.

This is the single most important test for classifying the cause.

GC Lecture High Yield

Aspect	Detail
Principle	ACTH tells you WHERE the problem is. If cortisol is high and ACTH is also high → something is inappropriately driving ACTH (pituitary or ectopic). If cortisol is high and ACTH is suppressed → the adrenal is autonomous
Procedure	Blood draw (EDTA tube, on ice, processed rapidly — ACTH is very fragile)
Timing	Morning sample preferred
Interpretation	< 1.1 pmol/L (< 5 pg/mL) → ACTH-independent CS ^[9]^[11]; > 3.3 pmol/L (> 20 pg/mL) → ACTH-dependent CS ^[9]; values between 1.1–3.3 pmol/L (5–20 pg/mL) are equivocal → repeat or proceed to CRH stimulation

ACTH Result	Cortisol	Diagnosis	Next Step
Low / Suppressed	High	ACTH-independent	Adrenal CT ^[3]
Normal-high / Elevated	High	ACTH-dependent	HDDST / CRH stimulation test + Pituitary MRI ^[3]
Low	Low	Iatrogenic	Drug history confirmation ^[2]

Step 2A (ACTH-Dependent): Differentiating Cushing's Disease from Ectopic ACTH

Aspect	Detail
Principle	A pituitary adenoma (Cushing's disease) retains partial negative feedback sensitivity — it operates at a higher "set point" but can still be partially suppressed by a large dose of dexamethasone. An ectopic ACTH source has no feedback mechanism at all → cannot be suppressed
Procedure	2 mg dexamethasone Q6H for 2 days → measure serum cortisol ^[3]^[1]^[9]
Interpretation	Cushing's disease: cortisol suppresses > 50% of baseline (ACTH responsive to negative feedback). Ectopic ACTH: cortisol NOT suppressed (< 50% suppression) ^[3]^[1]^[9]^[11]
Accuracy	~80% — not perfect; some ectopic carcinoid tumours can partially suppress (they may express CRH receptors)

"High-dose DST is usually done before pituitary MRI to avoid picking up pituitary incidentaloma" ^[3]^[1]

Local Practice Note

"HDDST not performed in PWH (Prince of Wales Hospital — replaced by CRH stimulation test)" ^[4]. In some centres, the CRH stimulation test has largely replaced HDDST for differentiating pituitary from ectopic ACTH.

Aspect	Detail
Principle	CRH (corticotropin-releasing hormone) stimulates pituitary corticotrophs. A pituitary adenoma has CRH receptors and will respond with ACTH release. An ectopic ACTH source does NOT have CRH receptors → no response
Procedure	1 μg/kg CRH IV → serial ACTH and cortisol measurements for 2 hours ^[3]^[1]
Interpretation	Cushing's disease → exaggerated rise in cortisol ( > 20% of baseline) and ACTH ( > 50% of baseline). Ectopic ACTH syndrome → no significant rise ^[3]^[1]^[11]
When to use	Done if high-dose DST is non-diagnostic ^[3]^[9]; increasingly used as first-line differentiating test in some centres

Aspect	Detail
Principle	Combines LDDST with CRH stimulation. After 48h of low-dose dexamethasone, CRH is administered. In pseudo-Cushing's, dexamethasone suppresses cortisol and CRH fails to overcome this. In true Cushing's, cortisol rises above the threshold after CRH
Main use	Distinguishing true Cushing's from pseudo-Cushing's ^[11]
Interpretation	Cortisol > 38 nmol/L (1.4 μg/dL) after CRH → true Cushing's

GC Lecture High Yield

"Insulin tolerance test — indication: differentiation of Cushing's syndrome and pseudo-Cushing's associated with depression and alcoholism" ^[12]

Principle: Insulin administration → hypoglycaemia → stress mechanism activated → ACTH, cortisol and GH released. Interpretation: blunted cortisol response for true Cushing's syndrome (normal: peak cortisol > 550 nmol/L)" ^[12]

In true Cushing's, the HPA axis is already maximally driven → hypoglycaemia fails to further stimulate cortisol (blunted response). In pseudo-Cushing's, the stress response is preserved.

Adrenal CT (preferably contrast CT with adrenal protocol) ^[7] is the imaging of choice.

CT Finding	Suggests	Reason
Unilateral, well-defined, < 4 cm, low Hounsfield units ( < 10 HU)	Adrenal adenoma	70% of adenomas have high lipid content → hypo-attenuated ^[7]; lipid = benign
Size > 4 cm (25% risk of malignancy)	Adrenal carcinoma	Malignant tumours grow large
Irregular shape, heterogeneous, ill-defined border, hypervascularity, central necrosis	Adrenal carcinoma	Features of malignancy ^[7]
Hounsfield units > 10 HU	Worrying for malignancy	The higher the HU, the more worrying; the lower = more fat, less worrying ^[18]
Contrast washout: < 40% relative washout or < 60% absolute washout	Malignancy	Adenoma usually has more washout ^[7] (benign adenomas wash out contrast rapidly)
Bilateral nodularity	AIMAH or PPNAD	Bilateral disease
Growing > 0.5 cm over 6 months	Malignancy	Active growth

Step 3 (ACTH-Dependent, Imaging): Pituitary MRI and IPSS

Aspect	Detail
Modality of choice	MRI, since soft tissue differentiation ^[19]
What to look for	Microadenoma (< 10 mm) or macroadenoma (≥ 10 mm); most Cushing's disease adenomas are microadenomas
Limitation	~40–50% of Cushing's disease microadenomas are NOT visible on MRI; pituitary incidentalomas found in ~10% of population → false positives
Protocol	Gadolinium-enhanced, thin slices through sella

GC Lecture High Yield

"Invasive test for Cushing's syndrome due to Cushing's disease: Inferior petrosal sinus sampling" ^[8]

"Venous sampling of the inferior petrosal sinus for ACTH → especially to help distinguish between pituitary ACTH secretion vs. ectopic ACTH. At the same time, take blood from peripheral vein for simultaneous ACTH level." ^[2]

Aspect	Detail
Principle	The inferior petrosal sinuses drain blood directly from the pituitary gland via the cavernous sinuses. If the ACTH source is the pituitary, ACTH concentration will be much higher in the petrosal sinuses than in peripheral blood. If the source is ectopic, there will be no such gradient
Procedure	Catheters are inserted via jugular or femoral veins into both inferior petrosal veins. ACTH is measured in petrosal and peripheral venous plasma before and within 10 minutes after the injection of CRH ^[11]
Interpretation	Cushing's disease: central-to-peripheral plasma ACTH gradient of ≥ 2.0 before CRH injection or ≥ 3.0 after CRH injection ^[11]
When to use	If imaging is inconclusive (MRI negative or equivocal) ^[3]; the most direct way to measure pituitary ACTH hypersecretion ^[11]
Lateralisation	Can also help lateralise the adenoma within the pituitary (left vs. right) to guide surgery, though this is less reliable
Limitations	Invasive; requires experienced interventional radiologist; risk of venous thrombosis, cranial nerve palsy (rare); false negatives possible with anomalous venous drainage

If ACTH-dependent Cushing's is confirmed but pituitary source is excluded (no MRI lesion, no IPSS gradient):

Investigation	Purpose
CXR	For any obvious CA lung ^[3] — first-line, cheap, fast
CT chest/abdomen/pelvis	Identify bronchial carcinoid, SCLC, thymic tumour, pancreatic NET ^[3]
PET/CT (Ga-68 DOTATATE or FDG)	Localise occult neuroendocrine tumours; Ga-68 DOTATATE PET has high sensitivity for somatostatin receptor-positive tumours (carcinoids)
Stepwise venous sampling	If biochemistry/imaging non-diagnostic ^[3] — selective venous catheterisation sampling for ACTH from various vascular beds
24-hour urine steroid profiling	For adrenal carcinoma ^[18] — abnormal steroid metabolite pattern suggests adrenocortical carcinoma

GC Lecture High Yield

"Workup for complications of Cushing's syndrome due to Cushing's disease: Glucose intolerance, DXA, other pituitary hormones etc." ^[8]

"Workup for complications of Cushing's syndrome due to adrenal adenoma: Glucose intolerance, DXA etc." ^[8]

Investigation	What It Assesses	Why
Fasting glucose / HbA1c / OGTT	Glucose intolerance / DM	Cortisol is a counter-regulatory hormone → insulin resistance
DXA scan	Bone mineral density	Glucocorticoid-induced osteoporosis
Serum electrolytes (K⁺, Na⁺)	Hypokalaemic metabolic alkalosis	Mineralocorticoid effect of cortisol (especially ectopic ACTH)
Lipid profile	Dyslipidaemia	Metabolic syndrome
ECG	LVH, arrhythmias (from hypoK)	Hypertension, electrolyte disturbance
Other pituitary hormones (if pituitary cause)	Hypopituitarism	Mass effect of adenoma; post-surgical deficiency
Ophthalmology review	Visual fields, cataracts, glaucoma	Optic chiasm compression (macroadenoma); steroid effects on eye

	Cushing's Disease	Ectopic ACTH	Adrenal Adenoma/Carcinoma	Iatrogenic CS
Physiology	Loss of circadian rhythm; HPA axis -ve feedback intact but operates at ↑ set-point	Loss of circadian rhythm; -ve feedback of HPA axis is completely lost	Loss of circadian rhythm; due to monoclonal cortisol-secreting tumour	Exogenous steroids → suppression of HPA axis
Cortisol	↑	↑ (often very high)	↑	↓ (endogenous)
LDDST	No suppression	No suppression	No suppression	N/A
ACTH	Normal-high ("inappropriately normal")	Usually high (occasionally normal)	Almost invariably undetectable	Low
HDDST	Usually suppressed ( > 50%)	Usually no suppression	No suppression	N/A
CRH test	Exaggerated rise (ACTH > 50%, cortisol > 20%)	No significant rise above basal	N/A	N/A
Imaging	Pituitary adenoma on MRI ± adrenal hyperplasia on CT	ACTH-secreting tumour on PET/CT	Adrenal tumour on CT abdomen	+ve drug Hx

[Sources: 3, 1, 9, 11]

High Yield — 15% Trap

15% of Cushing's disease can still be able to suppress on low-dose ONDST ^[11]. This means a negative ONDST does NOT completely rule out Cushing's disease if clinical suspicion remains high. Always correlate with clinical picture and use additional tests.

6. Special Diagnostic Scenarios

When an adrenal mass is found incidentally, the two key questions are: "Is it functional?" and "Is it malignant?" ^[7]^[18]

Screening tests for functional tumours: ONDST + spot ARR + 24h urine metanephrines ^[7]

Test	Screens For
1 mg ONDST ( > 50 nmol/L)	Cushing's syndrome (subclinical or overt)
Aldosterone-renin ratio (ARR)	Conn's syndrome
24h urine metanephrines	Phaeochromocytoma

"To diagnose iatrogenic Cushing's syndrome, AM cortisol level and short synacthen test are used (ACTH and cortisol should be suppressed and ACTH is unable to stimulate)" ^[11]

In iatrogenic Cushing's, prolonged HPA axis suppression means the adrenals have atrophied. A 1 μg short synacthen test (administering synthetic ACTH) will fail to produce a normal cortisol rise because the adrenals cannot respond — confirming HPA axis suppression.

High Yield Summary

Phase 1 — Exclude iatrogenic: Drug history + 9 AM cortisol (low = iatrogenic; only cause with low endogenous cortisol)

Phase 2 — Confirm endogenous hypercortisolism: Three screening modalities — 1 mg ONDST (cortisol next AM should suppress to < 50 nmol/L), 24h UFC × 2, late-night salivary cortisol × 2. ≥ 2 abnormal tests = diagnostic. Know false positives of ONDST (CYP3A4 inducers, OCP, depression, obesity, alcoholism). LDDST best for excluding pseudo-Cushing's.

Phase 3 — Determine the cause:

Plasma ACTH: < 5 pg/mL → ACTH-independent (adrenal CT); > 20 pg/mL → ACTH-dependent (HDDST/CRH + pituitary MRI)
HDDST: suppresses > 50% → Cushing's disease; no suppression → ectopic ACTH
CRH stimulation: ACTH rises > 50% → Cushing's disease; no rise → ectopic ACTH
IPSS: central-to-peripheral ACTH gradient ≥ 2.0 (basal) or ≥ 3.0 (post-CRH) → Cushing's disease
Adrenal CT: low HU = likely adenoma; high HU / > 4 cm / irregular = worry malignancy

Biochemistry before imaging — avoid chasing incidentalomas. Always do confirmatory biochemistry first.

Active Recall - Cushing's Syndrome Diagnostic Workup

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome, p.286–287) ^[2] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Aetiology, Clinical Features, Localisation sections) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome, p.62–63) ^[4] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome diagnostic algorithm, p.99) ^[5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Sequence of investigations; Exclusion of iatrogenic Cushing's) ^[7] Senior notes: Maksim Surgery Notes.pdf (Adrenal incidentaloma, p.202) ^[8] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf (Cushing's syndrome workup table, p.4) ^[9] Senior notes: Ryan Ho Fundamentals.pdf (Cushing's Syndrome, p.436–437) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Cushing's syndrome, p.1628–1630) ^[12] Senior notes: Ryan Ho Chemical Path.pdf (Diagnostic Function Tests — Diagnosis of Cushing Syndrome, p.29–33) ^[18] Senior notes: Block A - Endocrine Data Interpretation.pdf (Approach to adrenal incidentaloma and Cushing's) ^[19] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (Radiological Diagnosis of Pituitary Tumours)

The management of Cushing's syndrome is best understood by asking three sequential questions:

What is the cause? — The definitive treatment is entirely determined by the underlying aetiology.
Is the patient fit for surgery? — Surgery is almost always the first-line definitive treatment for endogenous causes.
What needs to happen before, during, and after surgery? — Perioperative optimisation is critical because Cushing's patients have profound metabolic derangements and immunosuppression.

GC Lecture High Yield — Role of Medical and Surgical Treatment

"Surgery indicated for both adrenal and pituitary lesions — adrenal tumours just abdominal surgery from Gen Surg, pituitary tumours require transsphenoidal approach from Neurosurg. But before surgery, essential to use medical treatment to reduce hypercortisolism." ^[2]

GC Lecture High Yield — Perioperative Management

"General perioperative management — control and correct: blood pressure, diabetes, hypokalaemia." ^[2]

"Perioperative management: control and correct HTN, DM, hypoK. Prophylaxis by steroid cover, Abx and for DVT." ^[9]

3. Preoperative (Perioperative) Management — Applicable to ALL Surgical Causes

Before any surgery for Cushing's syndrome, the patient must be medically optimised. This is because:

Hypercortisolism causes immunosuppression → high risk of post-operative infection and poor wound healing
Hypertension, diabetes, hypokalaemia → high perioperative cardiovascular risk
Hypercoagulable state → high risk of venous thromboembolism (VTE)
The normal HPA axis is suppressed → adrenal crisis risk perioperatively when the cortisol source is suddenly removed

GC Lecture High Yield — Perioperative Cautions

"Peri-operative steroid cover: normal HPA axis is usually suppressed." ^[4]^[7]

"Pre-operative antibiotics ± anticoagulation: high risk of infections and thromboembolism." ^[4]^[7]

"Post-operative glucocorticoid ± mineralocorticoid supplement until HPA axis returns (takes around 1 year) → Synacthen test before stopping supplements." ^[4]

Domain	Target	Why
Reduce hypercortisolism	Use medical therapy (see Section 5) to normalise or reduce cortisol before surgery	↓ Infection risk, ↓ metabolic derangement, ↓ wound complications, ↓ VTE risk
Control blood pressure ^[2]^[9]	Antihypertensives as needed (ACEi/ARB, CCB, etc.)	Cortisol causes hypertension via mineralocorticoid effect + ↑ vascular reactivity
Control diabetes ^[2]^[9]	Insulin sliding scale ± oral hypoglycaemics	Cortisol causes insulin resistance → hyperglycaemia worsens infection risk
Correct hypokalaemia ^[2]^[9]	K⁺ supplementation ± spironolactone	Severe hypoK → arrhythmia risk; especially important in ectopic ACTH
VTE prophylaxis	LMWH pre- and post-operatively	Cushing's is a hypercoagulable state (cortisol ↑ clotting factors, ↑ PAI-1, ↓ fibrinolysis)
Antibiotic prophylaxis	Per surgical protocol	Immunosuppression → high SSI risk

This is a concept that students frequently struggle with. Here is the reasoning from first principles:

Why is steroid cover needed? In endogenous Cushing's, the sustained hypercortisolism suppresses the normal HPA axis (the contralateral/remaining adrenal tissue atrophies, and the hypothalamus/pituitary corticotrophs are suppressed). When the cortisol source is surgically removed (adenoma resected, adrenal removed), cortisol levels plummet acutely. The suppressed HPA axis cannot compensate → patient develops acute adrenal insufficiency (Addisonian crisis) unless exogenous glucocorticoids are provided.

Post-op steroid replacement protocol: ^[3]

Immediately post-op: 50–100 mg IV hydrocortisone on-call
Then rapid taper over next 3 days to maintenance
Maintenance: 15–25 mg/day PO hydrocortisone (physiological replacement dose)
Continue until HPA axis recovers — typically ~6–18 months
Check recovery with Synacthen test before stopping ^[4]

4. Definitive (Surgical) Treatment — By Cause

4.1 Cushing's Disease (Pituitary ACTH Adenoma)

GC Lecture High Yield

"Transsphenoidal surgery (1st line): 60–70% curative (i.e. postop cortisol undetectable)" ^[3]^[1]

Aspect	Detail
Name breakdown	"Trans" = through; "sphenoidal" = the sphenoid bone (which houses the sella turcica where the pituitary sits). The surgeon accesses the pituitary through the nose/sphenoid sinus without opening the skull
Procedure	Microadenomectomy if feasible (selective removal of the adenoma, preserving normal pituitary). Otherwise subtotal anterior hypophysectomy if no fertility wish ^[3]^[1]
Cure rate	60–70% ^[3]^[1]; cure defined as post-op cortisol becoming undetectable (because remaining normal corticotrophs are suppressed)
Post-op monitoring	Post-op Day 5: check 9 AM cortisol to see if there is residual tumour → require RT ^[4]. An undetectable cortisol is a good sign — means the tumour is completely removed and the remaining HPA axis is still suppressed
Post-op replacement	May require cortisol replacement due to HPA suppression (may even be lifelong) ^[3]^[1]
Complications	Hypopituitarism (↓ other pituitary hormones), diabetes insipidus (posterior pituitary/stalk damage), CSF rhinorrhoea, post-operative bleeding, meningitis ^[19]

"Monitor all pituitary hormones post-op (T4, LH/FSH, GH, IGF-1, prolactin, reproductive hormones)" ^[4] — because any pituitary surgery risks damaging adjacent hormone-producing cells.

Surgical approach to pituitary: ^[19]

Transsphenoidal → route of choice (transnasal endoscopic / sub-labial)
Transfrontal → for those with very large suprasellar extension, severe chiasmal compression

Indications for pituitary surgery: ^[19]

All tumours that are causing pituitary hyperfunction
All macroadenomas ( > 1 cm)
Vision loss / visual field deficits
Mass effect (headaches, or causing hypopituitarism)
Pituitary apoplexy (emergency)

This follows a stepwise escalation:

Pituitary irradiation: ^[3]^[1]

Insidious effect with maximum effect 6–12 months → can be effective for up to 15 years
Used when surgery fails or is non-resectable, or when fertility is an important concern ^[11] (RT preserves potential fertility better than bilateral adrenalectomy in some settings, though delayed effect is a limitation)
Techniques: conventional external beam RT, stereotactic radiosurgery (Gamma Knife), proton beam therapy
Complication: progressive hypopituitarism (develops over years in 50–80% of patients)

Preop pituitary-acting agents: ^[3]^[1]

Pasireotide (somatostatin analogue) and cabergoline (dopamine agonist) can be used pre-operatively to reduce ACTH secretion from the pituitary adenoma

Aspect	Detail
Indication	Persistent severe hypercortisolism after failed TSS, or desire pregnancy ^[3]
Effect	Removes cortisol source completely → immediate cure of hypercortisolism
Consequence	Lifelong glucocorticoid AND mineralocorticoid replacement therapy required ^[11]^[7]
Major risk: Nelson's syndrome	8–25% in adults, > 50% in children ^[3]^[1]. After bilateral adrenalectomy, there is no cortisol to provide negative feedback → the pituitary corticotroph tumour grows unopposed → enlarging pituitary tumour representing corticotroph tumour progression ^[3]^[1]
Prevention of Nelson's	Need prophylactic pituitary RT to prevent Nelson's syndrome ^[4]
Clinical features of Nelson's	Rapidly growing pituitary mass → visual field defects, headache; very high ACTH → severe hyperpigmentation

High Yield Exam Point

Nelson's syndrome is a classic exam topic. Always mention it when discussing bilateral adrenalectomy for Cushing's disease. The pathogenesis is straightforward: remove both adrenals → no cortisol → no negative feedback on the pituitary → corticotroph adenoma grows aggressively. This is why prophylactic pituitary irradiation is recommended.

4.2 Adrenal Tumours

Aspect	Detail
Treatment	Unilateral adrenalectomy ^[4]^[7]^[9]^[11]
Approach	Laparoscopic transperitoneal approach (lateral decubitus, ipsilateral side up): for mass < 6 cm. Open: preferred if mass > 6 cm or malignant ^[7]
Post-op	Post-operative glucocorticoid therapy is needed because excess cortisol has suppressed CRH and ACTH ^[11] — the contralateral adrenal gland is atrophied from prolonged suppression and cannot produce adequate cortisol immediately. Recovery takes ~6–12 months

Aspect	Detail
Treatment	Surgical excision (open approach preferred given size and malignant potential) ± adjuvant mitotane ^[4]^[9]
Mitotane	"Mito-" = relating to mitochondria; this drug is cytotoxic to adrenal cortical cells → acts as a "medical adrenalectomy" ^[3]^[1]; used as adjuvant therapy to destroy residual/metastatic adrenal cortical tissue
Additional therapies	± Chemotherapy (etoposide + doxorubicin + cisplatin + mitotane = EDP-M regimen for advanced disease) ± RT
Prognosis	Poor; 5-year survival ~35% for advanced disease

Complications of adrenalectomy: ^[7]

Timing	Complication	Detail
Intra-op	Adrenal insufficiency	IV hydrocortisone upon removal of adrenal gland
	Injury to surrounding structures	Right adrenalectomy: IVC, right lobe of liver. Left adrenalectomy: pancreatic tail, spleen
Early post-op	Adrenal insufficiency	PO hydrocortisone post-op
Late	Hypertension (renal artery injury)	Rare

Scenario	Management
Resectable tumour (e.g., bronchial carcinoid)	Surgical excision of tumour — this is the definitive treatment ^[4]
Unresectable / metastatic (e.g., advanced SCLC)	Medical therapy (steroidogenesis inhibitors) as 1st line ^[11]; ± bilateral adrenalectomy for refractory hypercortisolism; treat the underlying malignancy with appropriate chemotherapy/RT
Occult source (cannot locate tumour)	Medical therapy to control cortisol + serial imaging surveillance (CT/PET every 6 months) to find the source

"Steroidogenesis inhibitors are 1st line treatment of ectopic ACTH secretion" ^[11] — because many ectopic ACTH-producing tumours are unresectable or metastatic at presentation.

Aspect	Detail
Principle	Gradual taper of exogenous glucocorticoids; never abruptly stop (risk of adrenal crisis from suppressed HPA axis)
Taper protocol	Reduce dose gradually over weeks to months; rate depends on dose, duration of use, and underlying disease
Monitoring during taper	Monitor for symptoms of adrenal insufficiency (fatigue, hypotension, nausea); check 9 AM cortisol and/or short Synacthen test at physiological replacement doses to assess HPA axis recovery
If taper not possible	Use the lowest effective dose; consider steroid-sparing agents for the underlying condition (e.g., azathioprine, methotrexate for autoimmune disease)

5. Medical Treatment — Detailed Pharmacology

GC Lecture High Yield — Medical Treatment

"Reduction of hypercortisolism — 1st line is Metyrapone: block cortisol synthesis at the final 11β-hydroxylase step. Ketoconazole: inhibit cortisol and androgen secretion." ^[2]

"Medical Tx for preoperative Mx of hypercortisolism → Metyrapone: first-line. Ketoconazole." ^[9]

Medical therapy targets three levels of the HPA axis:

Target Level	Drug Class	Examples	Mechanism
Adrenal gland (steroidogenesis)	Adrenal enzyme inhibitors	Metyrapone, Ketoconazole, Osilodrostat	Block enzymes in cortisol synthesis pathway
	Adrenolytic agents	Mitotane	Cytotoxic destruction of adrenal cortical cells
Pituitary	Pituitary-acting agents	Pasireotide (somatostatin analogue), Cabergoline (dopamine agonist)	↓ ACTH secretion from corticotroph adenoma
Peripheral (receptor)	GC receptor antagonists	Mifepristone	Blocks cortisol from binding its receptor at target tissues

"Indications: pre-op Mx, C/I to surgery, persistent despite surgery, awaiting effect of RT" ^[3]^[1]

More specifically ^[4]^[11]:

Indication	Context
Preoperative	Reduce hypercortisolism and metabolic complications before surgery to reduce surgical risk
Cushing's disease: 2nd line after TSS / RT ^[4]	When surgery fails or is not possible
Control of hypercortisolism before surgery ^[4]	Especially important in ectopic ACTH with severe metabolic derangement
Persistence/recurrence after surgery ^[4]	Residual or recurrent tumour
Ectopic ACTH: unresectable / metastatic / occult malignancy ^[4]	Often first-line definitive medical therapy (as tumour may not be resectable)
Adrenocortical carcinoma: adjuvant therapy to lower cortisol levels ^[4]	Especially mitotane
Awaiting effect after radiotherapy ^[11]	RT takes 6–12 months to work; medical therapy bridges the gap
Severe comorbidities / high surgical risk ^[11]	Patient unfit for surgery
Non-visible tumour / unfavourable resection site ^[11]	Cannot safely resect
Patients with DM or IGT who are NOT surgical candidates ^[11]	Specifically for mifepristone

5.3 Individual Drugs

Aspect	Detail
Name breakdown	"Met-y-rapone" — inhibitor of the final step in cortisol synthesis
Mechanism	CYP11B (11β-hydroxylase) inhibitor → blocks the conversion of 11-deoxycortisol to cortisol → ↓ cortisol synthesis ^[3]^[1]^[2]
Onset	Short-acting, effective within 2 hours ^[3]^[1]
Dosing	Requires BD/TDS dosing due to short duration of action ^[3]^[1]
Advantage	Rapid onset; well-established; can be used in block-and-replace or normalisation strategy
Side effects	Nausea, dizziness; ↑ adrenal androgens (because the block shunts precursors toward androgen pathway) → hirsutism, acne in women; ↑ 11-deoxycorticosterone (weak mineralocorticoid) → hypertension, hypokalaemia
Monitoring	24h UFC or serum cortisol to titrate dose

Aspect	Detail
Name breakdown	"Keto-" = ketone; "-conazole" = azole antifungal class
Mechanism	Originally azole antifungal, but can inhibit cortisol and androgen secretion ^[3]^[1] — inhibits multiple cytochrome P450 enzymes in the steroidogenic pathway (CYP17A1, CYP11A1, CYP11B1)
Advantage	Also reduces androgen levels (useful if hirsutism/virilisation is problematic)
Side effects	Hepatotoxicity (withdrawn from antifungal use as a result) ^[3]^[1]; monitor LFT; ↓ androgen → gynaecomastia, ↓ libido, impotence ^[3]^[1]; GI upset
Contraindication	Pre-existing liver disease; concurrent hepatotoxic drugs

Aspect	Detail
Mechanism	Potent 11β-hydroxylase inhibitor (similar target to metyrapone but more potent and longer-acting)
Advantage	Oral, once or twice daily; high efficacy in normalising UFC
Side effects	Adrenal insufficiency (over-suppression); ↑ adrenal androgens; QTc prolongation; hypokalaemia
Status	Approved by FDA/EMA for Cushing's disease; increasingly used

Aspect	Detail
Name breakdown	"Mito-" = relating to mitochondria; "-tane" = hydrocarbon derivative
Mechanism	Cytotoxic to adrenal cortical cells → adjunct "medical adrenalectomy" ^[3]^[1]; destroys adrenal tissue; also inhibits steroidogenesis
Main use	Adrenocortical carcinoma (adjuvant) ^[4]^[9]; also used for refractory Cushing's disease
Side effects	GI (nausea, vomiting, diarrhoea); neurotoxicity (ataxia, confusion); hepatotoxicity; requires monitoring of drug levels; adrenal insufficiency (expected → need replacement)
Note	Slow onset (weeks to months); fat-soluble so accumulates in adipose tissue; narrow therapeutic window

Aspect	Detail
Name breakdown	"Pasir-" from peptide origin; "-eotide" = somatostatin analogue suffix (cf. octreotide, lanreotide)
Mechanism	Binds to somatostatin receptor subtype 5 (SST5), which is highly expressed on corticotroph adenomas → ↓ ACTH secretion
Main use	Cushing's disease — patients not suitable for surgery, or with persistent disease post-TSS ^[4]^[11]
Side effects	Hyperglycaemia (major — because somatostatin also inhibits insulin secretion); GI (diarrhoea, nausea); gallstones (as with all somatostatin analogues — they inhibit cholecystokinin-mediated gallbladder contraction); bradycardia; QTc prolongation

Aspect	Detail
Mechanism	D2 receptor agonist; some corticotroph adenomas express D2 receptors → ↓ ACTH secretion
Main use	Cushing's disease — mild hypercortisolism; often combined with adrenal enzyme inhibitors
Side effects	Nausea, dizziness, postural hypotension; impulse control disorders; valvular heart disease (at high doses used for Parkinson's — less concerning at lower Cushing's doses)

Aspect	Detail
Name breakdown	Originally developed as an antiprogestogen (RU-486); also blocks glucocorticoid receptors
Mechanism	Competitive antagonist at the glucocorticoid receptor → blocks cortisol action at target tissues; does NOT reduce cortisol levels (in fact, cortisol and ACTH rise due to loss of feedback)
Main use	Patients with DM or IGT who are NOT surgical candidates ^[11]; controls the metabolic consequences of hypercortisolism
Key limitation	Cannot monitor by cortisol levels (they rise paradoxically); must monitor clinical response (glucose, BP, weight)
Side effects	Adrenal insufficiency (if cortisol levels become insufficient relative to receptor blockade); hypokalaemia (cortisol spillover onto unblocked mineralocorticoid receptors); endometrial thickening (antiprogestogen effect → abnormal vaginal bleeding in women)
Contraindication	Pregnancy (potent antiprogestogen → abortifacient)

"Block-and-replace vs. Normalisation" ^[3]^[1]:

Approach	Strategy	When to Use
Block-and-replace	Total ablation of cortisol secretion (high-dose enzyme inhibitors) + addition of replacement steroids (hydrocortisone)	Patients with wide variability in cortisol production and UFC — easier to manage because you completely block everything and replace with a fixed dose
Normalisation	Aim to return cortisol level to normal by titrating enzyme inhibitor dose	Patients with relatively invariable hypercortisolism — dose is adjusted based on UFC/cortisol to keep it in normal range

Cause	1st Line Treatment	2nd Line / Adjuncts	Key Perioperative Points
Iatrogenic	Gradual taper of exogenous steroids	Steroid-sparing agents; lowest effective dose	Taper slowly; monitor for adrenal insufficiency
Cushing's disease	Transsphenoidal surgery (60–70% cure rate) ^[3]^[1]	Repeat TSS → Pituitary RT + medical Tx → Bilateral adrenalectomy (last resort) ^[3]^[1]	Pre-op medical Tx to reduce cortisol; post-op GC replacement; monitor pituitary hormones; risk of Nelson's with bilateral adrenalectomy
Adrenal adenoma	Unilateral adrenalectomy ^[7]^[11]	N/A (curative)	Post-op GC replacement until contralateral adrenal recovers (~6–12 months)
Adrenal carcinoma	Surgical excision + adjuvant mitotane ^[4]^[9]	± EDP-M chemotherapy; ± RT	Post-op GC + MC replacement; poor prognosis
Ectopic ACTH (resectable)	Surgical excision of source tumour	Medical Tx if residual disease	Optimise metabolic derangements pre-op
Ectopic ACTH (unresectable)	Steroidogenesis inhibitors (1st line) ^[11]	± Bilateral adrenalectomy; treat underlying malignancy	Control severe hypoK + hyperglycaemia urgently

"S/S of Cushing's syndrome resolve gradually over a period of 2–12 months. HT, osteoporosis and glucose intolerance improve but may persist." ^[4]

Post-Treatment Phase	Action
Immediate post-op (days)	GC replacement (IV then oral HC); check cortisol Day 5 for Cushing's disease ^[4]; monitor electrolytes, glucose
Short-term (weeks–months)	Taper GC replacement guided by symptoms; monitor for adrenal insufficiency; manage residual HT/DM/osteoporosis
Long-term (months–years)	Synacthen test before stopping GC supplements ^[4]; annual surveillance for recurrence (cortisol, ACTH, imaging); monitor pituitary function (after TSS); DXA for osteoporosis; screen for Nelson's syndrome (after bilateral adrenalectomy)

8. Special Considerations

Pituitary irradiation is preferred (over bilateral adrenalectomy) if fertility is an important concern ^[11] — because bilateral adrenalectomy requires lifelong replacement therapy and carries Nelson's risk, whereas RT can be effective while preserving adrenal function.

However, paradoxically, bilateral adrenalectomy may be chosen if the patient desires pregnancy ^[3] — because medical therapy needs to be stopped in pregnancy (teratogenicity concerns), and bilateral adrenalectomy provides immediate and complete control of hypercortisolism, making pregnancy safer.

In patients with very severe hypercortisolism (e.g., ectopic ACTH from SCLC with life-threatening hypoK, hyperglycaemia, psychosis):

Urgent medical therapy: IV etomidate (anaesthetic agent that inhibits 11β-hydroxylase; used in ICU as continuous infusion for rapid cortisol reduction)
Urgent bilateral adrenalectomy may be considered in extremis

High Yield Summary

Management hierarchy:

Identify and treat the cause — surgery is first-line for all endogenous causes
Preoperative medical optimisation — reduce cortisol (metyrapone 1st line), control BP/DM/hypoK, VTE and antibiotic prophylaxis, perioperative steroid cover
Definitive surgery:
- Cushing's disease → TSS (60–70% cure) → if fail: repeat TSS → pituitary RT + medical Tx → bilateral adrenalectomy (last resort, risk Nelson's 8–25% adults, > 50% children)
- Adrenal adenoma → unilateral adrenalectomy (laparoscopic if < 6 cm)
- Adrenal carcinoma → open excision + adjuvant mitotane
- Ectopic ACTH → resect source if possible; medical therapy if not
Post-op: GC replacement (HPA axis suppressed, recovery ~6–18 months); Synacthen test before stopping; monitor pituitary hormones after TSS; long-term surveillance for recurrence
Medical therapy drugs: Metyrapone (1st line, 11β-hydroxylase inhibitor), Ketoconazole (multiple CYP inhibitor, hepatotoxic), Mitotane (adrenolytic, for carcinoma), Pasireotide (SST analogue, pituitary-acting), Cabergoline (DA agonist, pituitary-acting), Mifepristone (GC receptor blocker, for DM/IGT patients)
Never forget Nelson's syndrome after bilateral adrenalectomy — give prophylactic pituitary RT

Active Recall - Cushing's Syndrome Management

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome, p.288) ^[2] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Treatment of Cushing's Syndrome section) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome — Management, p.64) ^[4] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome — Management, p.100) ^[7] Senior notes: Maksim Surgery Notes.pdf (Adrenalectomy, p.203–204) ^[9] Senior notes: Ryan Ho Fundamentals.pdf (Cushing's Syndrome — Management, p.437) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Treatment, p.1629–1631) ^[19] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (Treatment of pituitary tumours)

Understanding the complications of Cushing's syndrome is straightforward if you think systematically from the pathophysiology of chronic glucocorticoid excess. Every complication traces back to one or more of cortisol's actions: metabolic (gluconeogenesis, protein catabolism, fat redistribution), mineralocorticoid (sodium/water retention, potassium wasting), immunosuppressive, bone-resorptive, and pro-thrombotic. We will cover complications of the disease itself, complications of treatment, and prognostic implications.

1. Complications of the Disease (Untreated / Ongoing Cushing's Syndrome)

GC Lecture High Yield — Complications Table

Complications of Cushing's syndrome by system: ^[11]^[8]

System	Description
CVS	Hypertension, Fluid retention
MSS	Osteoporosis, Proximal muscle weakness
CNS	Irritability, Depression, Psychosis
Haematological	Immunosuppression
Endocrine	Glucose intolerance, Central obesity, Hyperlipidaemia, Hypokalaemia

GC Lecture High Yield — Workup for Complications

"Workup for complications of Cushing's syndrome due to Cushing's disease: Glucose intolerance, DXA, other pituitary hormones etc." ^[8]

"Workup for complications of Cushing's syndrome due to adrenal adenoma: Glucose intolerance, DXA etc." ^[8]

1.2 Detailed Complications with Pathophysiological Basis

Complication	Pathophysiology	Clinical Significance
Hypertension	Multifactorial: (1) Cortisol overwhelms 11β-HSD2 → mineralocorticoid effect → Na⁺/H₂O retention; (2) ↑ vascular smooth muscle sensitivity to catecholamines (cortisol upregulates α1-adrenergic receptors); (3) ↑ hepatic angiotensinogen synthesis; (4) ↓ nitric oxide-mediated vasodilation	Present in ~80% of Cushing's patients; major contributor to cardiovascular morbidity and mortality; may persist after treatment
Fluid retention / oedema	Na⁺/H₂O retention from mineralocorticoid effect of cortisol	Peripheral oedema; contributes to hypertension
Accelerated atherosclerosis	Cortisol promotes dyslipidaemia (↑ LDL, ↑ TG, ↓ HDL), insulin resistance, central obesity, endothelial dysfunction, and a pro-inflammatory vascular milieu	↑ Risk of ischaemic heart disease, stroke, peripheral arterial disease
Left ventricular hypertrophy	Chronic pressure overload from hypertension + direct trophic effects of cortisol on cardiomyocytes	↑ Risk of heart failure, arrhythmias
Cardiomyopathy	Direct glucocorticoid myocardial toxicity at high cortisol levels; particularly relevant in severe ectopic ACTH	Can present with heart failure

Cardiovascular disease is the leading cause of death in untreated Cushing's syndrome. Standardised mortality ratio (SMR) is approximately 2–5× that of the general population, primarily driven by cardiovascular and thromboembolic events.

Complication	Pathophysiology	Clinical Significance
Venous thromboembolism (DVT/PE)	Cortisol increases synthesis of clotting factors (especially factors VIII, IX, von Willebrand factor), increases plasminogen activator inhibitor-1 (PAI-1) → ↓ fibrinolysis; polycythaemia (cortisol stimulates erythropoiesis) → ↑ blood viscosity; central obesity → venous stasis	VTE is a major cause of morbidity and mortality; prophylaxis by steroid cover, Abx and for DVT (hypercoagulable state in CS) ^[1]^[3]
Arterial thrombosis	Same pro-thrombotic milieu + accelerated atherosclerosis	MI, stroke

High Yield Exam Point

"Untreated Cushing's syndrome is often fatal due to cardiovascular and thromboembolic complications" ^[1]^[3]. VTE prophylaxis (LMWH) is essential perioperatively and should be considered in all hospitalised Cushing's patients. Thromboembolic risk remains elevated for months even after successful treatment.

Complication	Pathophysiology	Clinical Significance
Glucose intolerance / Diabetes mellitus	Cortisol is a counter-regulatory hormone: ↑ hepatic gluconeogenesis, ↓ peripheral glucose uptake (↓ GLUT4 translocation), ↑ insulin resistance	~40–45% develop impaired glucose tolerance; ~20–50% develop frank DM. This is "steroid diabetes." May require insulin therapy while Cushing's is active
Central obesity	Cortisol stimulates appetite (via NPY/AgRP pathways), promotes lipogenesis in central/visceral adipocytes (which have more GC receptors), and causes lipolysis peripherally	Contributes to metabolic syndrome; increases cardiovascular risk; may persist even after treatment
Hyperlipidaemia	↑ VLDL synthesis, ↑ lipolysis → ↑ free fatty acids → ↑ TG; ↑ LDL; ↓ HDL	Accelerates atherosclerosis
Hypokalaemic metabolic alkalosis	Cortisol overwhelms 11β-HSD2 → activates mineralocorticoid receptors in renal collecting duct → ↑ ENaC-mediated Na⁺ reabsorption and K⁺/H⁺ excretion	Especially severe in ectopic ACTH syndrome (very high cortisol); can cause muscle weakness, cardiac arrhythmias (U waves, QT prolongation), and contribute to proximal myopathy
± Hypothyroidism	Cortisol suppresses TSH at the pituitary level and inhibits peripheral conversion of T4 → T3 (inhibits deiodinase)	May be subclinical; can compound fatigue, weight gain, and cognitive symptoms

Complication	Pathophysiology	Clinical Significance
Glucocorticoid-induced osteoporosis	Cortisol: (1) directly inhibits osteoblast function and promotes osteoblast apoptosis; (2) ↑ RANKL expression ^[4] → ↑ osteoclast differentiation and activity; (3) ↓ intestinal Ca²⁺ absorption; (4) ↑ renal Ca²⁺ excretion; (5) secondary ↑ PTH (from hypocalcaemia) further drives bone resorption	Vertebral compression fractures are classic; rib fractures; fragility fractures at any site. Osteoporosis may improve but may persist after treatment ^[4]. Workup: DXA scan ^[8]
Proximal myopathy	Protein catabolism → skeletal muscle wasting (type II fibres preferentially affected); hypokalaemia aggravates weakness (↑↑ cortisol can overcome capacity of 11β-HSD2, leading to hypokalaemic alkalosis and aggravated myopathy ^[3])	Difficulty rising from chair, climbing stairs; functional limitation
Avascular necrosis (AVN)	Glucocorticoids cause fat cell hypertrophy within bone marrow → ↑ intraosseous pressure → compromised sinusoidal blood flow → ischaemic necrosis of bone (femoral head most commonly)	Iatrogenic Cushing's is more likely associated with AVN ^[3]; also occurs in endogenous Cushing's
Growth retardation (children)	Cortisol directly inhibits growth hormone secretion and action, suppresses IGF-1, and inhibits chondrocyte proliferation at growth plates	Stunting of growth is the most prominent S/S in children ^[3]^[1]; may not fully recover even after treatment

Complication	Pathophysiology	Clinical Significance
Immunosuppression → ↑ infection risk	Cortisol: ↓ T-cell function (↓ IL-2 production, ↑ T-cell apoptosis), ↓ cytokine production, ↓ neutrophil chemotaxis, ↓ macrophage function; also impaired wound healing (↓ collagen synthesis, ↓ angiogenesis)	Susceptible to opportunistic infections: fungal (Pneumocystis jirovecii, candidiasis, aspergillosis), mycobacterial (reactivation TB), bacterial (UTIs, pneumonia, skin infections); poor wound healing post-surgery; this is why prophylactic antibiotics are needed perioperatively ^[1]^[3]^[7]

Complication	Pathophysiology	Clinical Significance
Depression	Cortisol is neurotoxic to hippocampal neurons (which express high density of GC receptors); chronic exposure causes hippocampal atrophy, HPA axis dysregulation, and altered serotonin/noradrenaline neurotransmission	Present in ~50–80% of Cushing's patients; can be severe; usually improves after treatment but may not fully resolve
Irritability, emotional lability	Limbic system dysregulation by excess glucocorticoids	Common; can significantly impact quality of life
Psychosis	Severe glucocorticoid-induced neurotoxicity; more common at very high cortisol levels	Frank psychosis occurs in ~5–10%; usually steroid-responsive
Cognitive impairment	Hippocampal atrophy → ↓ memory, ↓ attention, ↓ executive function	May be partially reversible after treatment but some deficits persist
Insomnia	Cortisol disrupts the normal circadian sleep-wake cycle; also direct excitatory CNS effects	Very common; contributes to fatigue and psychiatric symptoms

Complication	Pathophysiology	Clinical Significance
Posterior subcapsular cataract	Glucocorticoids alter lens epithelial cell ion transport and protein metabolism → posterior subcapsular opacification	Iatrogenic Cushing's is more likely associated with glaucoma and posterior subcapsular cataracts ^[3]
Glaucoma	Glucocorticoids ↑ aqueous humour production and ↓ trabecular meshwork outflow → ↑ intraocular pressure	Can lead to optic nerve damage if undetected
Visual field defects	Only in Cushing's disease with pituitary macroadenoma compressing the optic chiasm → bitemporal hemianopia	Not a complication of cortisol excess per se, but of the tumour mass effect

Complication	Pathophysiology
Thin, fragile skin	Protein catabolism + ↓ collagen synthesis → dermal atrophy
Easy bruising	Capillary fragility from loss of perivascular collagen support
Poor wound healing	↓ Fibroblast proliferation, ↓ collagen deposition, ↓ angiogenesis, immunosuppression
Fungal skin infections	Immunosuppression + altered skin barrier

Complication	Pathophysiology
Menstrual disturbance / amenorrhoea	Cortisol suppresses GnRH pulsatility → ↓ LH/FSH → anovulation
Infertility	Anovulation (women); ↓ testosterone (men)
Erectile dysfunction / loss of libido (men)	Cortisol suppresses gonadotropins + direct inhibition of Leydig cell testosterone production

2. Complications of Treatment

Timing	Complication	Pathophysiology
Immediate	Post-operative bleeding	Surgical site haemorrhage
	CSF rhinorrhoea	Breach of sellar floor → CSF leak through nose; risk of ascending meningitis ^[19]
Early	Adrenal insufficiency (Addisonian crisis)	Successful removal of ACTH source → cortisol drops acutely while suppressed HPA axis cannot compensate; requires steroid cover (IV hydrocortisone 50–100 mg immediately) ^[1]^[3]
	Diabetes insipidus	Damage to posterior pituitary/pituitary stalk → ↓ ADH → dilute polyuria; often transient (days to weeks) but can be permanent
	SIADH (transient)	Post-surgical inflammation of posterior pituitary → inappropriate ADH release (paradoxically opposite to DI); usually occurs Day 5–10 post-op
Late	Hypopituitarism	Damage to normal anterior pituitary during surgery → ↓ TSH, LH/FSH, GH, prolactin; requires monitoring and lifelong replacement if permanent
	Recurrence	Incomplete tumour removal or regrowth; especially for macroadenomas — rate ~15–30% over 10 years

Complication	Pathophysiology	Prevention / Management
Lifelong adrenal insufficiency	Both adrenals removed → no endogenous cortisol or aldosterone production	Lifelong glucocorticoid AND mineralocorticoid replacement ^[11]^[7]
Nelson's syndrome	Enlarging pituitary tumour representing corticotroph tumour progression ^[3]^[1]; loss of cortisol negative feedback → uninhibited corticotroph adenoma growth; 8–25% adults, > 50% children ^[3]^[1]	Prevention: pituitary irradiation should be done before bilateral adrenalectomy ^[3]; Dx: plasma ACTH > 200 pg/mL + hyperpigmentation ^[3]; Tx: transsphenoidal surgery before tumour becomes a macroadenoma ^[3]
Acute adrenal crisis	Intercurrent illness (infection, trauma, surgery) in a patient on fixed-dose replacement → cortisol demand exceeds supply	Patient education about sick-day rules (double/triple GC dose during illness); MedicAlert bracelet; emergency IM hydrocortisone
Surgical complications	Injury to IVC/right lobe of liver (right adrenalectomy) or pancreatic tail/spleen (left adrenalectomy) ^[7]	Surgical expertise; laparoscopic approach where appropriate

Drug	Key Complications	Why
Metyrapone	↑ Adrenal androgens (hirsutism, acne); hypertension from ↑ 11-deoxycorticosterone; adrenal insufficiency (over-suppression)	Enzymatic block shunts precursors toward androgen and mineralocorticoid pathways
Ketoconazole	Hepatotoxicity ^[3]; gynaecomastia, ↓ libido, impotence	Inhibits hepatic cytochromes; blocks androgen synthesis
Mitotane	GI toxicity; neurotoxicity (ataxia, confusion); adrenal insufficiency	Directly cytotoxic to adrenal cells; fat-soluble → accumulates
Pasireotide	Hyperglycaemia (major); gallstones; QTc prolongation	Somatostatin analogues also inhibit insulin and GLP-1 secretion; inhibit gallbladder contraction
Mifepristone	Adrenal insufficiency; hypokalaemia; endometrial thickening/vaginal bleeding	GC receptor block → loss of feedback → ↑ ACTH → ↑ cortisol spillover onto MC receptors; anti-progestogenic effect on uterus
Pituitary irradiation	Progressive hypopituitarism (50–80% over years); risk of secondary brain tumours (rare, long-term); cognitive effects	Radiation damage to normal pituitary tissue

When tapering exogenous glucocorticoids, two distinct problems can arise:

Complication	Mechanism	Clinical Features
Adrenal crisis (acute adrenal insufficiency)	Prolonged exogenous steroids suppress the HPA axis → adrenal atrophy. Abrupt withdrawal → no endogenous cortisol to meet physiological needs	Hypotension, shock, hypoglycaemia, hyponatraemia, hyperkalaemia, nausea/vomiting, abdominal pain; medical emergency
Steroid withdrawal syndrome	Patients become physiologically "dependent" on supraphysiological cortisol levels. Even gradual tapering to physiological doses → relative cortisol deficiency (tissues have upregulated their cortisol "demand")	Fatigue, malaise, arthralgia, myalgia, mood disturbance, nausea — despite normal cortisol levels. This is distinct from adrenal insufficiency
Flare of underlying disease	The condition for which steroids were prescribed (e.g., SLE, asthma, IBD) reactivates as immunosuppression is reduced	Disease-specific symptoms recur

"Cushingoid features generally resolve by 2–12 months after definitive treatment, but untreated Cushing's syndrome is often fatal due to cardiovascular and thromboembolic complications." ^[1]^[3]

Parameter	Detail
Mortality (untreated)	5-year survival ~50% if untreated; death from cardiovascular disease, thromboembolism, or overwhelming infection
Mortality (treated)	Significantly improved; SMR approaches 1.0 after successful treatment if cortisol normalised, but remains elevated for several years
Features that resolve	Central obesity, moon face, purple striae (fade), proximal myopathy, mood disturbance, immunosuppression — resolve gradually over 2–12 months ^[1]^[3]
Features that may persist	Hypertension, osteoporosis, and glucose intolerance improve but may persist ^[4]; cognitive deficits (hippocampal atrophy partially irreversible); cardiovascular risk remains elevated for years; children may not fully catch up in height
Recurrence	Cushing's disease: ~15–30% recurrence after TSS over 10 years → lifelong surveillance needed

Category	Key Complications	Key Teaching Point
Cardiovascular	Hypertension, atherosclerosis, LVH, cardiomyopathy	Leading cause of death in untreated Cushing's
Thromboembolic	DVT, PE, arterial thrombosis	Hypercoagulable state; always give VTE prophylaxis perioperatively
Metabolic	DM, dyslipidaemia, central obesity, hypokalaemia	Screen with fasting glucose/HbA1c; correct hypoK urgently in ectopic ACTH
Bone	Osteoporosis, fractures, AVN	Screen with DXA; AVN especially with iatrogenic Cushing's
Immune	Opportunistic infections, poor wound healing	Antibiotic prophylaxis perioperatively
Psychiatric	Depression, psychosis, cognitive impairment	Very common; usually improves with treatment
Ophthalmological	Cataract, glaucoma	Especially iatrogenic Cushing's
Post-TSS	Adrenal insufficiency, DI, hypopituitarism, CSF leak	Need steroid cover; monitor pituitary hormones
Post-bilateral adrenalectomy	Nelson's syndrome, lifelong adrenal insufficiency	Prophylactic pituitary RT; lifelong GC + MC replacement

High Yield Summary

Untreated Cushing's is often fatal — primarily from cardiovascular disease (hypertension → atherosclerosis → MI/stroke) and venous thromboembolism (hypercoagulable state)
The metabolic triad (hypertension + diabetes + dyslipidaemia) drives cardiovascular risk and may persist even after cure
Glucocorticoid-induced osteoporosis is mediated by osteoblast inhibition + ↑ RANKL → always screen with DXA
Immunosuppression causes susceptibility to opportunistic infections and poor wound healing — prophylactic antibiotics are essential perioperatively
Psychiatric complications (depression, psychosis, insomnia) occur in the majority of patients and are due to direct glucocorticoid neurotoxicity in the hippocampus and limbic system
Nelson's syndrome (8–25% adults, > 50% children) is a unique complication of bilateral adrenalectomy — the corticotroph tumour grows unchecked without cortisol negative feedback → prevent with prophylactic pituitary RT
Post-treatment: HPA axis takes ~6–18 months to recover → patients need GC replacement and monitoring with Synacthen test; Cushingoid features resolve over 2–12 months but hypertension, osteoporosis, and glucose intolerance may persist
Iatrogenic Cushing's has a specific complication profile: AVN, posterior subcapsular cataracts, and glaucoma are more prominent; steroid withdrawal must be gradual to avoid adrenal crisis

Active Recall - Complications of Cushing's Syndrome

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 8.3.2 Cushing's Syndrome — Management and Prognosis, p.288) ^[2] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours; other endocrine tumours.pdf (Treatment of Cushing's Syndrome section) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 Cushing's Syndrome — Prognosis and Nelson's syndrome, p.64) ^[4] Senior notes: Maksim Medicine Notes.pdf (Cushing's syndrome — Management/Course after therapy, p.100) ^[7] Senior notes: Maksim Surgery Notes.pdf (Adrenalectomy complications, p.203–204) ^[8] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf (Workup for complications table, p.4) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Complications table, p.1630–1632) ^[19] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (Complications of pituitary surgery)

High Yield Summary

Cushing's syndrome = glucocorticoid excess; Cushing's disease = pituitary ACTH adenoma causing the syndrome
Most common cause overall = iatrogenic; most common endogenous cause = Cushing's disease (65–70%)
First question: Is it exogenous? → If no, is it ACTH-dependent or independent?
9 AM cortisol is the simplest test to exclude iatrogenic Cushing's (exogenous steroids suppress endogenous HPA axis → low morning cortisol)
Cortisol's actions explain every clinical feature: gluconeogenesis → DM; protein catabolism → striae/bruising/myopathy; central lipogenesis → truncal obesity; mineralocorticoid spillover → hypertension/hypokalaemia; immunosuppression → infections; osteoblast inhibition → osteoporosis; ACTH/POMC → hyperpigmentation
Ectopic ACTH (especially SCLC) presents with metabolic crisis (severe hypokalaemia, hyperglycaemia, hyperpigmentation) rather than classic Cushingoid habitus
Pseudo-Cushing's states (obesity, alcoholism, depression, pregnancy) can mimic Cushing's biochemically — must be distinguished with appropriate dynamic testing
Purple striae ( > 1 cm wide), proximal myopathy, easy bruising, and hypokalaemia are the most discriminating clinical features that differentiate true Cushing's from simple obesity

High Yield Summary

Level 1 — Is it truly Cushing's?

Most Cushingoid features are NON-SPECIFIC → PPV of any single feature is low
Highly discriminating features: purple striae ( > 1 cm), proximal myopathy, easy bruising, thin skin, supraclavicular fat pads, facial plethora
Always consider pseudo-Cushing's (obesity, alcoholism, depression, pregnancy, stress) and other mimics (hypothyroidism, PCOS, CAH, drug-induced weight gain)

Level 2 — What is the cause?

Exclude exogenous steroids FIRST (including hidden sources) → 9 AM cortisol is the simplest test; low cortisol = iatrogenic
ACTH level separates dependent (pituitary/ectopic) from independent (adrenal)
ACTH-dependent: HDDST/CRH stimulation/IPSS separates Cushing's disease from ectopic ACTH
ACTH-independent: Adrenal CT characterises adenoma vs. carcinoma vs. bilateral disease
Key clinical clues: Hyperpigmentation → ACTH-dependent; severe hypoK → ectopic; virilisation → adrenal carcinoma; AVN/cataracts → iatrogenic; low morning cortisol → iatrogenic

High Yield Summary

Phase 1 — Exclude iatrogenic: Drug history + 9 AM cortisol (low = iatrogenic; only cause with low endogenous cortisol)

Phase 3 — Determine the cause:

Plasma ACTH: < 5 pg/mL → ACTH-independent (adrenal CT); > 20 pg/mL → ACTH-dependent (HDDST/CRH + pituitary MRI)
HDDST: suppresses > 50% → Cushing's disease; no suppression → ectopic ACTH
CRH stimulation: ACTH rises > 50% → Cushing's disease; no rise → ectopic ACTH
IPSS: central-to-peripheral ACTH gradient ≥ 2.0 (basal) or ≥ 3.0 (post-CRH) → Cushing's disease
Adrenal CT: low HU = likely adenoma; high HU / > 4 cm / irregular = worry malignancy

Biochemistry before imaging — avoid chasing incidentalomas. Always do confirmatory biochemistry first.

High Yield Summary

Management hierarchy:

Identify and treat the cause — surgery is first-line for all endogenous causes
Preoperative medical optimisation — reduce cortisol (metyrapone 1st line), control BP/DM/hypoK, VTE and antibiotic prophylaxis, perioperative steroid cover
Definitive surgery:
- Cushing's disease → TSS (60–70% cure) → if fail: repeat TSS → pituitary RT + medical Tx → bilateral adrenalectomy (last resort, risk Nelson's 8–25% adults, > 50% children)
- Adrenal adenoma → unilateral adrenalectomy (laparoscopic if < 6 cm)
- Adrenal carcinoma → open excision + adjuvant mitotane
- Ectopic ACTH → resect source if possible; medical therapy if not
Post-op: GC replacement (HPA axis suppressed, recovery ~6–18 months); Synacthen test before stopping; monitor pituitary hormones after TSS; long-term surveillance for recurrence
Medical therapy drugs: Metyrapone (1st line, 11β-hydroxylase inhibitor), Ketoconazole (multiple CYP inhibitor, hepatotoxic), Mitotane (adrenolytic, for carcinoma), Pasireotide (SST analogue, pituitary-acting), Cabergoline (DA agonist, pituitary-acting), Mifepristone (GC receptor blocker, for DM/IGT patients)
Never forget Nelson's syndrome after bilateral adrenalectomy — give prophylactic pituitary RT

High Yield Summary

Untreated Cushing's is often fatal — primarily from cardiovascular disease (hypertension → atherosclerosis → MI/stroke) and venous thromboembolism (hypercoagulable state)
The metabolic triad (hypertension + diabetes + dyslipidaemia) drives cardiovascular risk and may persist even after cure
Glucocorticoid-induced osteoporosis is mediated by osteoblast inhibition + ↑ RANKL → always screen with DXA
Immunosuppression causes susceptibility to opportunistic infections and poor wound healing — prophylactic antibiotics are essential perioperatively
Psychiatric complications (depression, psychosis, insomnia) occur in the majority of patients and are due to direct glucocorticoid neurotoxicity in the hippocampus and limbic system
Nelson's syndrome (8–25% adults, > 50% children) is a unique complication of bilateral adrenalectomy — the corticotroph tumour grows unchecked without cortisol negative feedback → prevent with prophylactic pituitary RT
Post-treatment: HPA axis takes ~6–18 months to recover → patients need GC replacement and monitoring with Synacthen test; Cushingoid features resolve over 2–12 months but hypertension, osteoporosis, and glucose intolerance may persist
Iatrogenic Cushing's has a specific complication profile: AVN, posterior subcapsular cataracts, and glaucoma are more prominent; steroid withdrawal must be gradual to avoid adrenal crisis

Cushing's Syndrome

References

Cushing's Syndrome — Definition, Epidemiology, Risk Factors, Anatomy, Etiology, Pathophysiology, Classification, and Clinical Features

1. Definition

2. Epidemiology

3. Risk Factors

4. Relevant Anatomy and Physiology (The HPA Axis)

4.1 Adrenal Cortex Zones

4.2 The HPA Axis — Normal Physiology

Physiological Factors Affecting Cortisol Secretion [1][3]:

4.3 Actions of Cortisol

A. Glucocorticoid Action (primary)

B. Mineralocorticoid Action (secondary, ~30–40% of physiological effect) [1][3]

4.4 ACTH (Adrenocorticotropic Hormone)

4.5 Pituitary Anatomy

5. Aetiology and Classification

5.1 The First Question: Exogenous or Endogenous?

5.2 Classification — The Big Picture

Detailed Aetiological Classification [1][2][3][4][7]:

5.3 Specific Aetiological Notes

Cushing's Disease (Pituitary ACTH Adenoma)

Ectopic ACTH Syndrome

Adrenal Adenoma / Carcinoma

Pseudo-Cushing's States [4]

6. Pathophysiology — How Excess Cortisol Causes the Clinical Features

6.1 Metabolic Effects

6.2 Mineralocorticoid Effects

6.3 Immune/Inflammatory Effects

6.4 Bone Effects

6.5 ACTH-Related Effects

6.6 Reproductive Effects

6.7 CNS/Psychiatric Effects

6.8 Ocular Effects

7. Clinical Features

7.1 Symptoms (What the patient tells you)

7.2 Signs (What you find on examination)

7.3 Distinguishing Features by Aetiology

7.4 Ectopic ACTH — Special Consideration

8. Pseudo-Cushing's States

9. Summary Table — Cushing's Syndrome at a Glance

Active Recall - Cushing's Syndrome (Definition to Clinical Features)

References

Differential Diagnosis of Cushing's Syndrome

1. Level 1 — Differential Diagnosis of the Cushingoid Phenotype

1.1 Conditions That Mimic Cushing's Syndrome (Differential of the Cushingoid Phenotype)

1.2 Pseudo-Cushing's States — Detailed Breakdown

1.3 Features That Discriminate True Cushing's from Mimics

2. Level 2 — Aetiological Differential Diagnosis (Determining the Cause of Confirmed Cushing's Syndrome)

2.1 Step 1: Exclude Exogenous Steroid Use

2.2 Step 2: ACTH-Dependent vs. ACTH-Independent

2.3 Step 3: Differentiating Causes Within Each Category

A. ACTH-Dependent Causes

B. ACTH-Independent Causes

2.4 Signs Pointing to the Underlying Cause — Clinical Clues

3. Cushing's Syndrome as a Differential in Other Presentations

4. Diagnostic Approach — Decision Flowchart

5. Summary — Approach to Differential Diagnosis

Active Recall - Cushing's Syndrome Differential Diagnosis

References

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for Cushing's Syndrome

1. Overarching Diagnostic Principles

2. Diagnostic Criteria — When to Test and What Constitutes a Diagnosis

2.1 Who Should Be Tested?

2.2 What Constitutes a Diagnosis?

2.3 The Three-Phase Diagnostic Approach

3. Complete Diagnostic Algorithm

4. Investigation Modalities — Detailed Breakdown

4.1 Phase 1: Excluding Iatrogenic Cushing's

9 AM Serum Cortisol

4.2 Phase 2: Screening/Confirming Endogenous Hypercortisolism

A. 1 mg Overnight Dexamethasone Suppression Test (ONDST)

B. Low-Dose Dexamethasone Suppression Test (LDDST / Liddle's Test)

C. 24-Hour Urinary Free Cortisol (UFC)

D. Late-Night Salivary Cortisol

E. Serum Cortisol (9 AM and Midnight)

4.3 Phase 3: Determining the Cause

Step 1: Plasma ACTH

Step 2A (ACTH-Dependent): Differentiating Cushing's Disease from Ectopic ACTH

High-Dose Dexamethasone Suppression Test (HDDST)

CRH Stimulation Test