Adrenal Cortex Physiology

The adrenal (suprarenal) gland is a high-yield endocrine topic that fuses Physiology, Biochemistry, and Medicine. The cortex (outer 80–90%) is mesodermal and makes steroids; the medulla (inner 10–20%) is neural-crest derived and makes catecholamines. For NEET PG, the cortex is examined through three lenses: (1) which zone makes which hormone and what regulates it, (2) the steroidogenesis enzyme pathway and its block-points (congenital adrenal hyperplasia, CAH), and (3) clinical correlation — Cushing, Addison, Conn, and CAH. Get the zone-hormone-regulator triad and the enzyme map straight, and the clinical scenarios become deductions rather than memory.

Functional anatomy and zonation

The cortex has three concentric zones, classically remembered by "GFR — Salt, Sugar, Sex" (Glomerulosa → mineralocorticoids/salt; Fasciculata → glucocorticoids/sugar; Reticularis → androgens/sex). The corresponding tropic control reads outward-in as "The deeper you go, the sweeter it gets" (renin-angiotensin → ACTH → ACTH).

Zone	Position	Major product	Primary regulator	Key enzyme present/absent
Zona glomerulosa	Outermost	Aldosterone (mineralocorticoid)	Angiotensin II, serum K⁺ (ACTH minor)	Has aldosterone synthase (CYP11B2); lacks 17α-hydroxylase
Zona fasciculata	Middle (largest)	Cortisol (glucocorticoid)	ACTH	Has 17α-hydroxylase, 11β-hydroxylase
Zona reticularis	Innermost	DHEA, DHEA-S, androstenedione	ACTH	Has 17,20-lyase activity

High-yield: Only the glomerulosa expresses aldosterone synthase (CYP11B2), and only it lacks 17α-hydroxylase — that is why it cannot make cortisol or androgens. The medulla's PNMT (converts noradrenaline → adrenaline) is induced by the high local cortisol arriving via the cortico-medullary portal venous system, linking cortex and medulla.

Embryology and blood supply (quick recall): The cortex arises from coelomic mesoderm near the gonadal ridge, whereas the medulla is neural-crest (sympathetic chromaffin tissue) — hence ectopic adrenal cortical rests can occur along the path of gonadal descent. Arterial supply is from three sources (superior — inferior phrenic; middle — directly from aorta; inferior — renal artery), draining via a single central vein (right adrenal vein into IVC, left into the left renal vein) — relevant to adrenal vein sampling in Conn syndrome. The foetal adrenal has a large transient foetal zone that makes DHEA-S (precursor for placental oestriol) and involutes after birth, leaving the permanent cortex; the three definitive zones are not fully differentiated until ~3 years of age.

Steroidogenesis — the master pathway

All steroids derive from cholesterol. The committed, rate-limiting step is cholesterol transport across the mitochondrial membrane by StAR (Steroidogenic Acute Regulatory) protein, followed by side-chain cleavage by CYP11A1 (desmolase / 20,22-desmolase) to form pregnenolone. ACTH acts via Gs → cAMP → PKA to upregulate StAR and desmolase (acute) and the downstream enzymes (chronic).

Key enzyme branch-points to memorise:

• 3β-hydroxysteroid dehydrogenase (3β-HSD): converts Δ5 (pregnenolone, 17-OH-pregnenolone, DHEA) to Δ4 steroids (progesterone, 17-OH-progesterone, androstenedione).
• 17α-hydroxylase (CYP17): needed for cortisol and sex steroids; its 17,20-lyase activity makes androgens.
• 21-hydroxylase (CYP21A2): needed for both aldosterone and cortisol (the mineralocorticoid + glucocorticoid arms).
• 11β-hydroxylase (CYP11B1): final step to cortisol (11-deoxycortisol → cortisol).
• Aldosterone synthase (CYP11B2): corticosterone → aldosterone, glomerulosa only.

Enzyme deficient	Cortisol	Aldosterone/mineralocorticoid	Androgens	Hallmark
21-hydroxylase (~90% of CAH)	↓	↓ (salt-wasting)	↑	Ambiguous genitalia (XX), salt-wasting crisis, ↑17-OHP
11β-hydroxylase	↓	↑ (11-deoxycorticosterone)	↑	Virilisation + hypertension
17α-hydroxylase	↓	↑ (DOC)	↓	Hypertension + hypogonadism, ambiguous/female-phenotype XY
3β-HSD	↓	↓	↑ DHEA (weak)	Salt-wasting, ambiguous in both sexes

High-yield: The two CAH variants with hypertension are 11β-hydroxylase and 17α-hydroxylase deficiency (excess mineralocorticoid precursor DOC). The two with virilisation/↑androgens are 21-hydroxylase and 11β-hydroxylase. So 11β-hydroxylase = hypertension + virilisation (the overlap). 17α-hydroxylase = hypertension WITHOUT virilisation (low sex steroids).

Regulation — the HPA axis and RAAS

Cortisol (glucocorticoid) — HPA axis: Hypothalamus releases CRH → anterior pituitary releases ACTH (from POMC) → zona fasciculata releases cortisol → cortisol exerts negative feedback on both CRH and ACTH.

ACTH is cleaved from pro-opiomelanocortin (POMC), which also yields MSH — explaining the hyperpigmentation of primary adrenal failure (high ACTH/MSH). Cortisol shows a diurnal rhythm: peak around 6–8 AM, nadir around midnight. CRH/ACTH are pulsatile; stress (surgery, hypoglycaemia, sepsis) overrides feedback.

Aldosterone — RAAS and potassium: ↓Renal perfusion / ↓Na⁺ → juxtaglomerular cells release renin → angiotensinogen → angiotensin I → (ACE, lung) angiotensin II → stimulates glomerulosa → aldosterone → Na⁺/water retention + K⁺ and H⁺ excretion. Hyperkalaemia is a direct, potent stimulus for aldosterone independent of renin.

High-yield: Aldosterone is regulated chiefly by angiotensin II and serum K⁺, NOT primarily by ACTH. This is why in panhypopituitarism (low ACTH) aldosterone is largely preserved, and patients do not get severe salt-wasting — distinguishing secondary from primary adrenal insufficiency.

How aldosterone actually works at the nephron: It binds the cytoplasmic mineralocorticoid receptor in principal cells of the cortical collecting duct, then translocates to the nucleus and upregulates ENaC (epithelial Na⁺ channels) on the luminal membrane and the Na⁺/K⁺-ATPase on the basolateral membrane. The result is Na⁺ reabsorption with an electronegative lumen that drives K⁺ and H⁺ secretion — hence the classic Conn picture of hypertension, hypokalaemia, and metabolic alkalosis. Aldosterone also acts on the colon, salivary, and sweat glands; the elevated sweat Na⁺ in aldosterone deficiency contributes to salt craving in Addison disease. Atrial natriuretic peptide (ANP), released on atrial stretch, opposes the whole axis by inhibiting renin and aldosterone and promoting natriuresis — a frequently tested counter-regulator.

Actions of cortisol (the "stress steroid")

Cortisol acts via cytoplasmic glucocorticoid receptors → altered gene transcription. Mnemonic for catabolic, anti-insulin actions: it raises glucose by every route.

• Metabolic: ↑gluconeogenesis, ↑glycogenolysis, peripheral insulin antagonism (→ hyperglycaemia, "steroid diabetes"); ↑proteolysis (muscle wasting, thin skin, striae); permissive lipolysis but central fat redistribution (moon face, buffalo hump, truncal obesity).
• Immune/anti-inflammatory: ↓phospholipase A2 (via lipocortin/annexin-1) → ↓prostaglandins/leukotrienes; stabilises lysosomes; causes demargination → neutrophilia but lymphopenia, eosinopenia, monocytopenia; suppresses T-cells.
• Permissive on catecholamines: upregulates α1/β-adrenergic receptors → maintains vascular tone and BP; deficiency → hypotension.
• Mineralocorticoid-like at high doses: cortisol can bind the mineralocorticoid receptor; normally 11β-HSD2 in the kidney inactivates cortisol to cortisone, protecting the receptor. Loss/inhibition (liquorice, apparent mineralocorticoid excess) → hypertension, hypokalaemia.
• Other: ↑gastric acid (ulcer risk), bone resorption + ↓Ca absorption (osteoporosis), ↓fibroblast activity (poor wound healing), CNS mood effects, foetal lung surfactant maturation.

High-yield: Cortisol's protection from the mineralocorticoid receptor by 11β-HSD2 is a favourite — its deficiency or inhibition causes "apparent mineralocorticoid excess" with low renin AND low aldosterone but hypertension/hypokalaemia.

Stress response, in order: Within seconds the sympatho-adrenal medullary axis releases catecholamines; over minutes-to-hours CRH-ACTH-cortisol mounts the slower, sustained response that mobilises fuel and restrains over-exuberant inflammation. This is why stress-dose steroids are given perioperatively to patients on chronic glucocorticoids or with adrenal insufficiency — the suppressed or destroyed adrenal cannot mount the surge, and unprotected patients can collapse into crisis. The same logic explains why etomidate (a 11β-hydroxylase inhibitor) is avoided as an infusion in the critically ill, and why ketoconazole, metyrapone, and osilodrostat are used therapeutically to lower cortisol in Cushing syndrome by blocking specific steroidogenic enzymes.

Adrenal androgens

Zona reticularis (and to a degree fasciculata) secretes DHEA, DHEA-sulfate (DHEA-S), and androstenedione — weak androgens converted peripherally to testosterone/oestrogen. DHEA-S is the marker of adrenal androgen production (high in adrenal tumours/CAH; near-normal in PCOS where ovarian androgens dominate) because it is almost exclusively adrenal in origin and has a long half-life. In women these contribute meaningfully to libido and pubic/axillary hair (adrenarche, the rise in adrenal androgens around age 6–8, which is distinct from gonadarche). Cortisol carriage is also testable: ~90% of plasma cortisol is bound to corticosteroid-binding globulin (CBG/transcortin), some to albumin, and only the small free fraction is biologically active. Oestrogen (pregnancy, OCP) raises CBG, so total cortisol rises while free cortisol stays normal — a trap when interpreting cortisol assays in pregnancy.

Clinical correlation — disorders of cortisol

Cushing syndrome (cortisol EXCESS)

Features: central obesity, moon facies, buffalo hump, purple striae >1 cm, proximal myopathy, hypertension, glucose intolerance, osteoporosis, easy bruising, hirsutism, psychiatric changes.

Stepwise approach: Confirm hypercortisolism → 24-h urinary free cortisol / late-night salivary cortisol / low-dose (1 mg overnight) dexamethasone suppression test → measure ACTH → high-dose dexamethasone + imaging to localise.

Cause	ACTH	High-dose dexamethasone	Notes
Pituitary adenoma (Cushing disease)	↑/normal	Suppresses (>50%)	Commonest endogenous cause; MRI pituitary
Ectopic ACTH (e.g., small-cell lung CA)	↑↑	Does NOT suppress	Severe hypokalaemia, rapid onset, pigmentation
Adrenal adenoma/carcinoma	↓ (suppressed)	Not applicable	CT adrenals
Exogenous steroids	↓	—	Commonest overall cause

Addison disease (primary adrenal insufficiency, cortisol + aldosterone deficiency)

Causes in India: historically tuberculosis; worldwide autoimmune adrenalitis is commonest. Features: fatigue, weight loss, hyperpigmentation (high ACTH/MSH, palmar creases/buccal mucosa), hypotension, salt craving, hyponatraemia + hyperkalaemia, hypoglycaemia.

• Investigation of choice: Short ACTH (cosyntropin/Synacthen) stimulation test — failure of cortisol to rise confirms adrenal failure. Baseline 8 AM cortisol + ACTH levels help (high ACTH = primary; low/normal = secondary).
• Drug of choice: Hydrocortisone (glucocorticoid) + fludrocortisone (mineralocorticoid) for primary disease. In adrenal (Addisonian) crisis — hypotension, shock: IV hydrocortisone 100 mg stat + aggressive IV normal saline + dextrose.

High-yield: Secondary insufficiency (pituitary cause, low ACTH) → no hyperpigmentation, aldosterone preserved (so K⁺ usually normal, no salt-wasting); only glucocorticoid replacement needed. Primary (Addison) → hyperpigmentation + hyperkalaemia + needs fludrocortisone.

Conn syndrome (primary hyperaldosteronism)

Hypertension + hypokalaemia + metabolic alkalosis with low renin, high aldosterone (high aldosterone-to-renin ratio = screening test of choice). Confirm with saline suppression. Cause: adrenal adenoma or bilateral hyperplasia. Drug of choice (medical/hyperplasia): spironolactone/eplerenone; unilateral adenoma → adrenalectomy.

Differentials and distinguishing pearls

• Hypertension + hypokalaemia, low renin: Conn (high aldosterone) vs 11β-/17α-CAH or Liddle/AME (low aldosterone).
• Hyperpigmentation: Addison (↑ACTH) vs haemochromatosis vs Peutz-Jeghers — Addison has buccal/palmar crease pigmentation + electrolyte changes.
• Hirsutism/virilisation in a young woman: late-onset 21-hydroxylase CAH (↑17-OHP) vs PCOS (↑LH:FSH, ovarian) vs androgen-secreting tumour (very high DHEA-S/testosterone).
• Cushingoid + ↓ACTH: adrenal tumour or exogenous steroids, not pituitary.
• Pseudo-Cushing: alcoholism, severe depression, and uncontrolled diabetes can mildly raise cortisol and blunt suppression; the dexamethasone-CRH test and clinical context separate these from true Cushing.
• Incidentaloma: an adrenal mass found on imaging needs hormonal screening (1 mg dexamethasone, metanephrines, and aldosterone-renin ratio if hypertensive) to exclude subclinical Cushing, phaeochromocytoma, and Conn before deciding on surgery.

Complications

• Untreated Cushing: cardiovascular disease, diabetes, vertebral fractures, infections, thromboembolism, psychosis.
• Addisonian crisis: life-threatening hypotensive shock, hyperkalaemic arrhythmia, hypoglycaemia, death if steroids delayed — give steroids before confirmatory tests in suspected crisis.
• CAH salt-wasting (21-OH): neonatal vomiting, dehydration, shock, hyperkalaemia in first 1–2 weeks.
• Chronic exogenous steroid use: HPA axis suppression → adrenal atrophy → must taper, never stop abruptly (risk of crisis). Suppression can persist for 6–12 months after stopping long courses, so cover intercurrent illness and surgery with stress doses.
• Adrenal haemorrhage: bilateral haemorrhagic destruction in meningococcaemia (Waterhouse-Friderichsen syndrome) precipitates acute primary adrenal failure — a classic eponym to know.
• CAH long term: if under-treated, persistent ACTH drive causes adrenal hyperplasia, precocious puberty, short final height (early epiphyseal fusion), and testicular adrenal rest tumours in males; over-treatment with glucocorticoid causes iatrogenic Cushing and growth suppression — management is a tightrope.

Recently asked / exam angle

• Which zone is independent of ACTH / regulated by angiotensin II and K⁺ → zona glomerulosa (aldosterone).
• Rate-limiting step of steroidogenesis → StAR-mediated cholesterol transport (desmolase / CYP11A1 is the first enzymatic step).
• CAH variant with hypertension + virilisation → 11β-hydroxylase; hypertension + sexual infantilism → 17α-hydroxylase; commonest CAH → 21-hydroxylase (↑17-OHP, salt-wasting).
• Enzyme protecting mineralocorticoid receptor from cortisol → 11β-HSD2; its inhibition (liquorice) → apparent mineralocorticoid excess.
• Best screening test for Conn → plasma aldosterone-to-renin ratio; for Cushing → late-night salivary cortisol / overnight 1 mg dexamethasone; for Addison → short ACTH stimulation test.
• High-dose dexamethasone suppresses pituitary Cushing but not ectopic ACTH/adrenal tumour.
• Cortisol causes neutrophilia with lymphopenia and eosinopenia (classic CBC pattern in steroid use/stress).
• Marker of adrenal androgen excess → DHEA-S.

Rapid revision

• GFR makes Salt, Sugar, Sex; control = RAAS, ACTH, ACTH (deeper = sweeter).
• Glomerulosa: aldosterone, driven by angiotensin II + K⁺, lacks 17α-hydroxylase.
• Rate-limiting step = StAR protein moving cholesterol into mitochondria; first enzyme = desmolase (CYP11A1).
• 21-hydroxylase deficiency = commonest CAH = ↓cortisol + ↓aldosterone + ↑androgens + ↑17-OHP (salt-wasting, virilisation).
• 11β-hydroxylase = hypertension + virilisation; 17α-hydroxylase = hypertension + no sex steroids.
• HPA axis: CRH → ACTH (from POMC) → cortisol → negative feedback; diurnal peak at ~8 AM.
• Cortisol = anti-insulin, immunosuppressive, permissive on catecholamines; neutrophilia + lymphopenia + eosinopenia.
• 11β-HSD2 inactivates cortisol in kidney; its loss → apparent mineralocorticoid excess (HTN + hypokalaemia, low renin/aldosterone).
• Cushing workup: confirm cortisol excess → measure ACTH → high-dose dex distinguishes pituitary (suppresses) from ectopic/adrenal (no suppression).
• Addison: autoimmune (world) / TB (India), hyperpigmentation + hyperkalaemia + hyponatraemia; test = short ACTH stim; Rx = hydrocortisone + fludrocortisone.
• Adrenal crisis = IV hydrocortisone 100 mg + saline + dextrose, before confirmatory tests.
• Conn: HTN + hypokalaemia + low renin/high aldosterone; screen with aldosterone-renin ratio; Rx spironolactone or adrenalectomy.