Hypothalamus → CRH (corticotropin-releasing hormone)
      ↓
Anterior pituitary (corticotrophs) → ACTH (adrenocorticotropic hormone)
      ↓
Adrenal cortex (zona fasciculata) → Cortisol
      ↓
Cortisol → NEGATIVE FEEDBACK on hypothalamus and pituitary

• CRH is secreted in a pulsatile manner ^[1][2].
• ACTH stimulates cortisol synthesis and secretion from the adrenal cortex ^[1][2].
• Cortisol then feeds back to suppress both CRH and ACTH release (negative feedback).

1. Circadian rhythm: Cortisol is highest in the early morning (~0600–0800h) and lowest around midnight. This is driven by the suprachiasmatic nucleus in the hypothalamus.

   • Clinical relevance: In Cushing's syndrome, this diurnal variation is lost — cortisol remains inappropriately elevated at night. This is why late-night salivary cortisol is a screening test ^[2][3].

2. Stress response: Cortisol rises dramatically during physiological stress (infection, surgery, trauma, inflammation).

   • Why? Cortisol mobilises glucose for the brain, suppresses excessive inflammatory responses, and supports cardiovascular function — these are survival mechanisms ^[1][2].
   • Clinical relevance: "Pseudo-Cushing's" states (physiological hypercortisolism) can occur in severe illness, depression, alcoholism, and obesity, making diagnosis challenging.

3. Pulsatility: CRH (and hence ACTH and cortisol) is secreted in pulses, not continuously. This is why a single random cortisol level is unreliable — you need integrated measures like 24h urinary free cortisol ^[2][3].

Cortisol acts by binding intracellular glucocorticoid receptors (GR), which are nuclear transcription factors — they regulate gene expression ^[1][2]. This explains why cortisol effects are broad and take time to manifest (unlike catecholamine actions which are immediate).

This is a critical concept:

• Cortisol has ~30–40% affinity for mineralocorticoid receptors (MR) in addition to its glucocorticoid receptor (GR) effects ^[1][2].
• Normally, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in mineralocorticoid-responsive tissues (kidney, colon) inactivates cortisol → cortisone (which cannot bind MR). This "shields" the MR from cortisol.
• In Cushing's syndrome: the sheer excess of cortisol overwhelms the capacity of 11β-HSD2, causing spillover cortisol to activate MR → resulting in hypokalemic alkalosis (mimicking hyperaldosteronism) ^[1][2][3].

Why does this matter? This explains why severe Cushing's syndrome (especially ectopic ACTH with very high cortisol levels) causes profound hypokalaemia. In adrenal Cushing's, cortisol levels are typically lower than ectopic ACTH syndromes, so hypokalaemia is less prominent but can still occur.

• A benign monoclonal neoplasm of the zona fasciculata that autonomously secretes cortisol, independent of ACTH regulation.
• The excess cortisol feeds back on the hypothalamus/pituitary → suppressed ACTH → the contralateral adrenal gland (and the normal tissue of the ipsilateral gland) atrophies due to lack of ACTH trophic support.
• This is critically important surgically: after unilateral adrenalectomy, the remaining (atrophied) adrenal gland cannot produce adequate cortisol immediately → temporary secondary adrenal insufficiency until the HPA axis recovers (typically 6–18 months) ^[4].

• Usually unilateral, solitary, small (< 3–4 cm)
• Well-circumscribed, encapsulated, homogeneous
• Lipid-rich (because steroidogenic cells store cholesterol as lipid droplets) → appears as low attenuation on unenhanced CT (< 10 Hounsfield units — radiologically characteristic of a benign adenoma) ^[3]
• Typically produces cortisol alone (pure glucocorticoid excess)
• May be found as an adrenal incidentaloma — up to 6% of incidentalomas are subclinical Cushing's syndrome ^[4]

• Somatic activating mutations in:
  • PRKACA (catalytic subunit of protein kinase A) — most common (~40% of cortisol-producing adenomas). PKA is the main effector of cAMP signalling downstream of ACTH receptor (MC2R). An activating mutation means constitutive PKA activity → autonomous cortisol production regardless of ACTH levels.
  • CTNNB1 (β-catenin, Wnt pathway) — less common.
  • GNAS (Gsα, the stimulatory G-protein) — same protein mutated in McCune–Albright syndrome.

• A rare, aggressive malignancy arising from adrenal cortical cells.
• Typically produces multiple steroids (cortisol + androgens ± oestrogens ± mineralocorticoids) because the tumour is less differentiated and does not restrict itself to one steroidogenic pathway. This "mixed secretion" pattern is an important clinical clue — e.g. a woman presenting with Cushing's features AND virilisation (hirsutism, deepened voice, clitoromegaly) should raise alarm for ACC.
• Often large at presentation (> 6 cm), because it grows rapidly and may not cause symptoms until locally advanced or metastatic.
• Metastasises to liver, lungs, lymph nodes, bone.

• Unilateral (usually), large (often > 6 cm), heterogeneous (areas of necrosis, haemorrhage, calcification)
• High attenuation on CT (> 10 HU unenhanced), delayed contrast washout (retains > 50% contrast at 15 minutes — unlike benign adenomas which wash out quickly)
• Functionally: ~60% are functional (cortisol ± androgens most commonly); ~40% are non-functional
• Poor prognosis: 5-year survival ~20–35% overall

• TP53 mutations (Li–Fraumeni syndrome — autosomal dominant, germline TP53 mutation)
  • In southern Brazil, there is a founder TP53 R337H mutation causing very high rates of childhood ACC.
• IGF-2 overexpression (via loss of imprinting at 11p15 locus — Beckwith–Wiedemann syndrome region)
• Wnt/β-catenin pathway activation
• mTOR pathway alterations

• Weight gain, particularly central/truncal obesity
  • Why? Cortisol promotes visceral (central) fat deposition via upregulation of lipogenic enzymes and redistribution of fat from peripheral to central depots. Cortisol also increases appetite (stimulates NPY in hypothalamus). The limbs remain thin due to peripheral fat lipolysis and muscle wasting → the classic "lemon on sticks" appearance ^[3].

• Easy bruising (ecchymoses) — spontaneous, without significant trauma
  • Why? Cortisol inhibits collagen synthesis and causes capillary fragility by thinning the supportive connective tissue around blood vessels → minimal shear forces rupture capillaries.
• Skin changes: thinning, poor wound healing
  • Why? Cortisol is catabolic to connective tissue — it degrades collagen and inhibits fibroblast proliferation. Wounds heal slowly because fibroblast migration and collagen deposition are impaired.
• Purple/violaceous striae (typically > 1 cm wide, on abdomen, thighs, breasts, upper arms)
  • Why? Rapid central fat deposition stretches already thinned skin → the underlying blood vessels show through the atrophied dermis, giving the purple colour. This distinguishes them from the common pale/white striae of simple obesity or pregnancy.
• Acne
  • Why? Cortisol excess (and adrenal androgens, especially if ACC or adrenal hyperplasia) stimulates sebaceous glands.
• Hirsutism (women)
  • Why? Adrenal androgen co-secretion (DHEA, androstenedione). This is particularly prominent in ACC, which often co-secretes androgens.

• Proximal muscle weakness (proximal myopathy)
  • Why? Cortisol is profoundly catabolic to skeletal muscle — it accelerates protein breakdown and inhibits protein synthesis, especially in proximal (type II fast-twitch) muscle fibres. Patients have difficulty rising from a chair, climbing stairs, or raising arms above the head. Additionally, hypokalaemia (from mineralocorticoid effect of cortisol overflow) further exacerbates muscle weakness ^[3].
• Back pain / bone pain
  • Why? Osteoporosis from cortisol-mediated suppression of osteoblast function, enhanced osteoclast activity, decreased intestinal calcium absorption, and increased renal calcium excretion. Vertebral compression fractures are common.

• Psychiatric disturbances: depression (most common), emotional lability, irritability, insomnia, euphoria, anxiety, cognitive impairment, and rarely frank psychosis ^[3]
  • Why? Cortisol modulates neurotransmitter systems (serotonin, norepinephrine, GABA) and has direct neurotoxic effects on the hippocampus (glucocorticoid receptor–mediated neuronal apoptosis and dendritic remodelling). The hippocampus has the highest density of GR in the brain.
• Insomnia
  • Why? Loss of the normal cortisol circadian rhythm — cortisol remains elevated at night, disrupting sleep architecture.

• Oligo- or amenorrhoea (females)
  • Why? Cortisol suppresses GnRH pulsatility → ↓LH and FSH → anovulation. Additionally, adrenal androgens (especially in ACC) can directly disrupt the menstrual cycle.
• Impotence and decreased libido (males)
  • Why? Same mechanism — cortisol suppresses the HPG axis.
• Infertility

• Polyuria, polydipsia (symptoms of DM)
  • Why? Cortisol-induced insulin resistance → hyperglycaemia → osmotic diuresis.

• Recurrent infections (skin, urinary, respiratory, opportunistic)
  • Why? Cortisol is immunosuppressive — reduces T-cell function, cytokine production, neutrophil migration to sites of infection (though neutrophil count rises due to demargination).

• Rapid onset of symptoms (weeks to months rather than months to years)
• Virilisation in women (deepening of voice, clitoromegaly, male-pattern baldness, severe hirsutism) — due to androgen co-secretion
• Feminisation in men (gynaecomastia) — due to oestrogen co-secretion (rare)
• Abdominal/flank pain or mass — due to large tumour size, local invasion
• Weight loss (paradoxical — from malignancy-related cachexia despite Cushingoid fat redistribution)

• "Lemon on sticks" body habitus: truncal obesity with thin limbs ^[3]
• Moon face (lunula facies): rounded, plethoric face due to central fat deposition and thin facial skin with visible superficial blood vessels
  • Why? Fat redistribution to the face + cortisol-induced polycythaemia (stimulates erythropoietin) + capillary fragility → facial plethora.
• Buffalo hump: dorsocervical fat pad (fat accumulation in the posterior neck)
  • Why? Selective lipogenesis in the dorsocervical region.
• Supraclavicular fat pads: fat deposition above the clavicles (relatively specific for Cushing's — rare in simple obesity)

• Thin, fragile skin (can see veins through it; "tissue paper" skin)
• Wide (> 1 cm) purple/violaceous striae — classically on the abdomen, flanks, thighs, breasts, upper arms
• Spontaneous ecchymoses (bruises without significant trauma)
• Acne
• Hirsutism (females) — excess terminal hair in androgen-dependent areas (upper lip, chin, chest, linea alba)
• Hyperpigmentation: only if ACTH is elevated (i.e., ACTH-dependent causes). In adrenal Cushing's, ACTH is suppressed → NO hyperpigmentation ^[2][3]. This is an important differentiating sign.
  • Why? ACTH is cleaved from the same precursor molecule (pro-opiomelanocortin, POMC) as α-MSH (melanocyte-stimulating hormone). When ACTH is high, α-MSH is also high → stimulates melanocortin-1 receptors on melanocytes → hyperpigmentation.

• Proximal myopathy: weakness of shoulder girdle and hip flexors. Test by asking the patient to stand from a squatting position without using hands, or to raise arms above head against resistance.
• Kyphosis (from vertebral compression fractures due to osteoporosis)

• Hypertension (found in ~80% of CS patients)
  • Why? Multiple mechanisms:
    1. Cortisol overwhelms 11β-HSD2 → activates MR → Na⁺ and water retention
    2. Cortisol ↑sensitivity to catecholamines and angiotensin II (permissive effect)
    3. Cortisol ↑hepatic synthesis of angiotensinogen
    4. Cortisol ↓NO and prostacyclin production → ↑vasoconstriction

• Central obesity (measure waist circumference)
• Abdominal mass — if large adrenal tumour (especially ACC, which can be > 10 cm)
• Purple striae on abdominal wall

• Hirsutism, acne (female)
• Virilisation signs in ACC: clitoromegaly, temporal balding, deepened voice
• Gynaecomastia (male, if oestrogen-secreting ACC — rare)

• Exophthalmos may rarely occur in severe Cushing's (retro-orbital fat deposition — distinct from Graves' disease)
• Raised IOP / central serous retinopathy — cortisol effect

• Decreased height percentile with increasing weight percentile — this is a crucial distinguishing feature from simple obesity, where children are typically tall for their age (obesity → increased IGF-1 → increased linear growth) ^[3].
  • Why? Cortisol directly suppresses the growth plate and inhibits GH secretion and IGF-1 action.

This is the most commonly used first-line screening test, especially in outpatient settings ^[5][7].

Principle (from first principles):

• Dexamethasone ("dexa" = a potent synthetic glucocorticoid) is given exogenously.
• In a normal person: dexamethasone activates glucocorticoid receptors in the hypothalamus and pituitary → suppresses CRH and ACTH → the adrenal glands stop making cortisol → morning cortisol falls to very low levels.
• In Cushing's syndrome: the cortisol production is autonomous (whether from adrenal tumour, pituitary adenoma, or ectopic source). The source does NOT respond to the normal negative feedback of this low dose of dexamethasone → cortisol remains elevated.

Procedure ^{[1][2][3][5][7]}:

• Basal cortisol at 0900h
• 1 mg dexamethasone orally at 2300h (midnight)
• Cortisol measurement again at 0900h the following morning

Interpretation ^[4][5][7]:

• Normal: cortisol suppressed to < 50 nmol/L (1.8 µg/dL) ^[4][5][7]
• Cushing's syndrome: cortisol > 50 nmol/L (failure to suppress) ^[4][5][7]
• Sensitivity ~95–98% (high — good for screening)
• Specificity ~80% (moderate — false positives are common)

False positives (failed suppression in non-CS) ^[7]:

False negatives (suppression despite CS; very rare, < 2%) ^[7]:

• Cyclical Cushing's syndrome (cortisol secretion is intermittent — tested during a "trough")
• Slow metabolism of dexamethasone → drug levels accumulate → excessive suppression

Variant — Standard Low-Dose DST (Liddle's Test) ^[1][2][3][7]:

• 0.5 mg dexamethasone PO Q6H for 2 days (total 4 mg over 48h) → cortisol measurement at the end
• More specific and sensitive than overnight DST ^[7]
• Used as an inpatient confirmatory test
• Same interpretation: failure to suppress cortisol to < 50 nmol/L = CS

Method: 24-hour urine collection for total free cortisol excretion ^[1][2][3][5]

Principle:

• Cortisol in blood is ~90% protein-bound (to CBG and albumin) and ~10% free. Only free cortisol is biologically active and is filtered by the kidneys.
• By collecting urine over 24 hours, you get an integrated measure of free cortisol production, removing the effect of pulsatile secretion ^[1][2][3]. This avoids the problem of a single random cortisol level being misleadingly high or low due to CRH pulsatility.
• Free cortisol is measured because cortisol-binding globulin level may vary — by measuring free cortisol specifically, you eliminate this variable ^[5].

Interpretation:

• Normal range varies by laboratory (typically < 250 nmol/24h or < 90 µg/24h by HPLC/LC-MS/MS)
• Elevated UFC = hypercortisolism
• UFC > 3–4× ULN → virtually diagnostic of Cushing's syndrome ^[4] — pseudo-Cushing's very rarely causes this degree of elevation
• Should be collected ×2 (or ×3) because of day-to-day variability ^[4][5]

Caveats ^[1][2][3][5]:

• Does not distinguish patients with physiological hypercortisolism (e.g., depression, obesity) — both true CS and pseudo-CS can have mildly elevated UFC
• Under-collection or over-collection errors → check urine creatinine to validate completeness
• Not reliable in renal impairment (GFR < 30 mL/min → reduced cortisol filtration → falsely low UFC)
• High fluid intake can falsely elevate UFC (↑GFR → ↑cortisol filtration)

Additional value: the 24h urine steroid profile can be measured simultaneously — this allows detection of synthetic steroids (indicates iatrogenic Cushing's) and fetal-origin steroid metabolites (suggests adrenocortical carcinoma) ^[2].

Principle: CS patients have loss of normal cortisol circadian rhythm ^[1][2][3][5]

From first principles:

• In a normal person, cortisol follows a circadian rhythm: highest at ~0600–0800h, lowest at ~2300–0000h (midnight).
• In Cushing's syndrome, this rhythm is abolished — cortisol remains inappropriately elevated throughout the 24-hour cycle, including at midnight.
• Only free cortisol will be present in saliva due to ultrafiltration ^[5] — salivary cortisol reflects the biologically active free cortisol fraction, unaffected by CBG levels. This is a major advantage over serum cortisol.

Procedure:

• Patient collects saliva at 2300h (using a cotton swab/collection device, e.g., Salivette)
• Should be collected ×2 on separate nights ^[5]
• Must avoid eating, drinking (especially alcohol), smoking, or brushing teeth 30 min before collection (to avoid blood contamination)

Interpretation:

• Cut-off varies by assay; typically > 2.0 nmol/L (by LC-MS/MS) is considered elevated
• Sensitivity ~93–100%, Specificity ~93–100% (excellent for screening)

Caveats:

• Not readily available — requires sensitive analytical tools like LC-MS/MS ^[5]
• Not suitable for shift workers — their circadian rhythm is disrupted physiologically ^[5]
• Smoking, oral lesions → blood contamination → falsely elevated

Serum cortisol is not a standard diagnostic test but is often done first ×2 at early AM + late night ^[1][2]:

• Cushing's syndrome: often with loss of diurnal variation (early morning cortisol may be normal, but late-night cortisol is often raised and similar to morning cortisol) ^[1][2]
• Pseudo-CS: usually intact diurnal variation despite ↑cortisol secretion ^[1][2]
• Random cortisol is unreliable due to pulsatile secretion and stress response — this is why paired AM + late-night cortisol is more informative

• Open surgical approach preferred — typically > 6 cm, concern for malignancy. Laparoscopic approach risks capsular breach and tumour spillage/seeding, which worsens prognosis.
• En bloc resection: complete resection with negative margins (R0 resection) is the single most important prognostic factor. This may include en bloc nephrectomy, splenectomy (left-sided), or partial hepatectomy (right-sided) if there is local invasion.
• Lymph node dissection: regional lymphadenectomy if suspicious nodes present.
• Avoid tumour rupture: capsular breach → peritoneal carcinomatosis → dramatically worsens prognosis.

These drugs block specific enzymes in the cortisol biosynthetic pathway:

(i) Metyrapone ^[1][2][3]:

• First-line medical therapy for Cushing's syndrome ^[1][2][3]
• Mechanism: CYP11B (11β-hydroxylase) inhibitor → ↓cortisol synthesis ^[1][2]
  • 11β-hydroxylase catalyses the final step in cortisol synthesis (11-deoxycortisol → cortisol). Blocking this step effectively halts cortisol production.
  • "Mety-rapone" → think "meter-rapid-one": it rapidly meters (controls) cortisol.
• Effect: short-acting, effective within 2 hours but requires BD/TDS dosing ^[1][2]
• Dose: typically 250–750 mg TDS, titrated to cortisol levels (target UFC normalisation)
• Side effects:
  • Accumulation of cortisol precursors (11-deoxycortisol, 11-deoxycorticosterone) → some of these have mineralocorticoid activity → can worsen HTN, hypokalaemia, oedema
  • Accumulation of adrenal androgens (due to shunting of precursors) → hirsutism, acne in women
  • Nausea, dizziness, headache
  • Adrenal insufficiency if over-dosed (monitor UFC)

(ii) Ketoconazole ^[1][2][3]:

• Originally an azole antifungal, but can inhibit cortisol and androgen secretion ^[1][2]
• Mechanism: inhibits multiple CYP enzymes in the steroidogenic pathway (CYP17, CYP11A1, CYP11B1) → broadly reduces cortisol, aldosterone, and androgen synthesis
• Also has a direct inhibitory effect on ACTH secretion at the pituitary level
• Side effects: hepatotoxicity (withdrawn from antifungal use as a result), ↓androgen (gynaecomastia, ↓libido, impotence in males) ^[1][2]
  • Liver function tests must be monitored regularly (weekly initially, then monthly)
  • FDA black box warning for hepatotoxicity (rare fulminant hepatic failure)
• Dose: 200–400 mg BD–TDS
• Advantage in women: anti-androgen effect may be beneficial (↓hirsutism)
• Disadvantage in men: anti-androgen side effects limiting

(iii) Osilodrostat (newer agent, approved 2020):

• Mechanism: potent CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) inhibitor
• More specific than ketoconazole; effective oral agent
• Approved for Cushing's disease and being used off-label for adrenal causes
• Side effects: adrenal insufficiency, hypokalaemia (aldosterone reduction), QTc prolongation, hirsutism/acne (androgen precursor accumulation)

(iv) Levoketoconazole (approved 2021):

• The 2S,4R enantiomer of ketoconazole with improved cortisol-lowering efficacy and potentially better hepatic safety profile
• Same mechanism as ketoconazole but more potent against steroidogenic CYP enzymes

(i) Mitotane ^[1][2]:

• Cytotoxic to adrenal cortical cells → adjunct "medical adrenalectomy" for CA adrenal ^[1][2]
• Mechanism: accumulates in adrenal mitochondria → disrupts mitochondrial function → direct cytotoxic destruction of adrenal cortical cells (zona fasciculata and reticularis preferentially). Also inhibits CYP11A1 (side-chain cleavage enzyme).
• Indications:
  • Adjuvant therapy after ACC resection (reduces recurrence)
  • First-line for unresectable/metastatic ACC
  • Severe Cushing's not controlled by enzyme inhibitors
• Dosing: 1–6 g/day orally; requires therapeutic drug monitoring (target trough 14–20 mg/L). Onset of action is slow (weeks to months).
• Side effects: GI (nausea, vomiting, diarrhoea — very common), neurological (ataxia, confusion, lethargy), hepatotoxicity, ↑sex hormone-binding globulin (→ ↓free testosterone), adrenal insufficiency (ALL patients need glucocorticoid replacement)
• Critical: mitotane increases cortisol-binding globulin → total cortisol may appear elevated despite adequate treatment. Must monitor free cortisol or use clinical assessment.

(i) Mifepristone (RU-486):

• Mechanism: competitive antagonist at the glucocorticoid receptor (GR) — blocks cortisol's action at the receptor level without reducing cortisol production
• "Mifepristone" → "mifi" = against, "prestone" = progesterone/cortisol; originally developed as an anti-progesterone (abortifacient), but also has potent GR antagonism
• Indication: hyperglycaemia secondary to Cushing's syndrome in patients who are not candidates for surgery
• Key limitation: because it blocks the GR, you cannot monitor cortisol levels to assess efficacy (cortisol will actually RISE due to loss of negative feedback). Must monitor clinical parameters (glucose, weight, blood pressure) instead.
• Side effects: hypokalaemia (cortisol rises → mineralocorticoid receptor activation → hypoK), adrenal insufficiency (difficult to detect), endometrial thickening (anti-progesterone effect → vaginal bleeding)
• Contraindication: pregnancy (abortifacient)

Pituitary-acting agents: e.g., pasireotide (somatostatin analogue), cabergoline (DA agonist) ^[1][2]

These are primarily used for Cushing's disease (pituitary source), NOT for primary adrenal causes. However, mentioned for completeness:

• Pasireotide: binds somatostatin receptor subtype 5 (SST5) on corticotroph cells → ↓ACTH secretion. S/E: hyperglycaemia (inhibits insulin secretion), GI symptoms, cholelithiasis.
• Cabergoline: dopamine D2 agonist → some corticotroph adenomas express D2 receptors → ↓ACTH. Off-label use.

Post-op glucocorticoid ± mineralocorticoid supplement until HPA axis recovers ~1 year later ^[4]

Rationale: The contralateral adrenal is atrophied from chronic ACTH suppression. Recovery of the HPA axis takes 6–18 months (up to 2 years in some patients). During this period, the patient is functionally adrenal-insufficient and requires exogenous glucocorticoid replacement.

Monitoring HPA axis recovery:

• Periodic morning cortisol levels (drawn before the daily hydrocortisone dose)
• Once morning cortisol > 200–300 nmol/L, attempt tapering hydrocortisone
• Short synacthen test (SST) can be performed when morning cortisol is rising: peak cortisol > 550 nmol/L confirms adequate adrenal reserve → can discontinue glucocorticoid
• Patient must carry a steroid emergency card and wear a MedicAlert bracelet during the replacement period

• Usually NOT needed after unilateral adrenalectomy for adenoma (the contralateral adrenal's zona glomerulosa recovers faster because aldosterone secretion is primarily regulated by RAAS, not ACTH)
• Needed after bilateral adrenalectomy (BMAH, PPNAD) — lifelong fludrocortisone 50–200 µg/day

Patients on glucocorticoid replacement must be educated:

• Double the oral hydrocortisone dose during minor illness (fever, infections)
• Triple or use IM/IV hydrocortisone during severe illness, vomiting, or if unable to take oral medication
• Emergency IM hydrocortisone (100 mg) at home for vomiting/diarrhoea
• Seek medical attention if unable to keep oral steroids down

• Prevalence: ~80% of CS patients
• Pathophysiology (multiple mechanisms acting together):
  1. Cortisol overwhelms 11β-HSD2 → activates MR in kidney → Na⁺ retention, volume expansion
  2. Cortisol has permissive effect on catecholamine vasoconstrictive action (upregulates adrenergic receptors)
  3. Cortisol stimulates hepatic synthesis of angiotensinogen (RAAS substrate) → ↑angiotensin II
  4. Cortisol inhibits nitric oxide (NO) and prostacyclin synthesis → loss of vasodilatory tone
• Consequence: left ventricular hypertrophy (LVH), heart failure, accelerated atherosclerosis
• May persist even after biochemical cure if longstanding (structural vascular remodelling)

• Cortisol excess promotes atherogenesis via:
  • Dyslipidaemia: ↑LDL, ↑triglycerides, ↓HDL (cortisol increases hepatic VLDL synthesis and inhibits lipoprotein lipase)
  • Insulin resistance → hyperglycaemia → endothelial dysfunction
  • Direct cortisol-mediated endothelial injury
  • Chronic hypertension → arterial wall damage
• Consequences: ischaemic heart disease, myocardial infarction, stroke, peripheral arterial disease

• Cortisol excess → myocardial fibrosis, LVH (from pressure overload + direct GR-mediated cardiac remodelling)
• May develop HFpEF or overt heart failure
• Partially reversible after cure, but may not fully normalise

• Prevalence: ~40–50% develop frank DM; an additional 20–30% have impaired glucose tolerance (IGT)
• Pathophysiology:
  • Cortisol ↑hepatic gluconeogenesis (upregulates PEPCK and glucose-6-phosphatase)
  • Cortisol ↓peripheral glucose uptake by antagonising insulin signalling at the post-receptor level (↓GLUT4 translocation)
  • Cortisol ↑glucagon secretion and ↓insulin sensitivity → insulin resistance
  • Together: ↑glucose production + ↓glucose utilisation = hyperglycaemia
• May require insulin therapy (oral hypoglycaemics often insufficient)
• May persist after cure if pancreatic β-cell exhaustion has occurred (but often improves significantly)

• ↑LDL, ↑triglycerides, ↓HDL
• Contributes to accelerated atherosclerosis
• Mechanism: cortisol increases hepatic VLDL production, promotes visceral adiposity (visceral fat is more metabolically active → releases free fatty acids → hepatic lipogenesis), and inhibits lipoprotein lipase

• More prominent in ectopic ACTH syndrome (very high cortisol), but can occur in any cause
• Why? ↑↑Cortisol overwhelms 11β-HSD2 → MR activation in renal collecting duct → Na⁺ reabsorption, K⁺ secretion, H⁺ secretion → hypokalaemia + metabolic alkalosis ^[2][3]
• ↑↑Cortisol can overcome capacity of inactivating effects of 11β-HSD2, leading to hypokalaemic alkalosis and aggravates myopathy ^[2][3]
• Consequences: muscle weakness (exacerbates myopathy), cardiac arrhythmias (U waves, flattened T waves, risk of Torsades de Pointes), nephrogenic diabetes insipidus (polyuria)

• Prevalence: ~30–50% of CS patients have osteoporosis; up to 70% have reduced BMD
• Pathophysiology:
  • Cortisol directly suppresses osteoblast function and promotes osteoblast/osteocyte apoptosis
  • Cortisol ↑RANKL expression → enhanced osteoclastogenesis → ↑bone resorption
  • ↓Intestinal calcium absorption (antagonises vitamin D action)
  • ↑Renal calcium excretion (↓tubular calcium reabsorption)
  • ↓Gonadal hormones (GnRH suppression) → loss of protective oestrogen/testosterone effects on bone
• Consequences: vertebral compression fractures (most common — often asymptomatic), rib fractures, kyphosis, height loss, chronic back pain
• Partially reversible after cure (BMD improves over 1–3 years), but established fractures do not reverse

• Iatrogenic Cushing's: more likely associated with AVN, glaucoma and posterior subcapsular cataracts ^[1][2]
• Why? Cortisol causes intra-osseous fat cell hypertrophy → raised intraosseous pressure → impaired blood flow to subchondral bone → ischaemic necrosis. Most commonly affects femoral head, humeral head.
• Presents with hip or shoulder pain; diagnosed by MRI
• May require joint replacement

• Proximal myopathy is one of the more specific features of Cushing's syndrome ^[2][3]
• Why? Cortisol is catabolic to type II (fast-twitch) muscle fibres → protein breakdown > synthesis → muscle wasting and weakness. Hypokalaemia from mineralocorticoid overflow further exacerbates this.
• Leads to functional impairment: difficulty rising from chairs, climbing stairs, lifting arms above head
• Reversible with treatment (improves over weeks to months), but may need physiotherapy