Adrenal Gland
Composite endocrine organ of two embryologically distinct tissues sitting atop each kidney. Cortex (mesodermal, 80–90%): three concentric zones each producing distinct steroid hormones via cytochrome P450 enzymes from cholesterol — zona glomerulosa (aldosterone, CYP11B2), zona fasciculata (cortisol, CYP11B1), zona reticularis (DHEA/DHEAS, CYP17A1 17,20-lyase). Medulla (neuroectodermal, 10–20%): chromaffin cells (modified sympathetic postganglionic neurons) secrete epinephrine (80%) and norepinephrine (20%) via the tyrosine → L-DOPA → dopamine → NE → Epi pathway (PNMT induced by intra-adrenal portal cortisol). The gland is the principal interface between the neuroendocrine and autonomic stress response systems.
Overview
The adrenal (suprarenal) glands are paired endocrine organs sitting atop each kidney in the retroperitoneal space — the right gland is pyramidal, the left crescentic. Each weighs approximately 4–6 g and measures 3–5 cm × 3 cm, yet these compact structures regulate critical physiological processes: acute and chronic stress response, blood pressure and electrolyte homeostasis, immune modulation, carbohydrate and lipid metabolism, and androgen precursor supply for peripheral sex hormone synthesis.
The adrenal gland is developmentally and functionally a composite organ of two entirely distinct tissues: (1) Cortex (outer 80–90%): mesodermal origin; synthesises steroid hormones from cholesterol via P450 enzymes; three concentric zones. (2) Medulla (inner 10–20%): neuroectodermal origin (modified sympathetic ganglion cells); chromaffin cells secrete catecholamines directly into the bloodstream. High cortisol concentrations from the cortex are delivered via an intraglandular portal system to the medulla — inducing PNMT expression, enabling NE → Epi conversion. The adrenal gland is thus the principal interface between the neuroendocrine and autonomic stress response systems.
Anatomy and Zones
Vascular supply (three-source, stress-proof): Superior adrenal arteries (inferior phrenic artery), middle adrenal arteries (aorta), inferior adrenal arteries (renal arteries). Venous drainage: right adrenal vein → IVC directly (short, surgically challenging); left adrenal vein → left renal vein. Intraglandular portal circulation carries cortisol-rich blood from cortex to medulla.
| Zone | Proportion | Product | Regulator | Rate-limiting step |
|---|---|---|---|---|
| Zona glomerulosa (ZG) | ~15% | Aldosterone | Angiotensin II, ↑K⁺ (primary); ACTH (permissive) | CYP11B2 (aldosterone synthase) — expressed only in ZG |
| Zona fasciculata (ZF) | ~75% | Cortisol | ACTH (HPA axis) — circadian + stress | StAR (mitochondrial cholesterol import, phosphorylated by PKA) |
| Zona reticularis (ZR) | ~10% | DHEA, DHEAS, androstenedione | ACTH; unknown ZR-specific factors | CYP17A1 (17,20-lyase activity, activated by cytochrome b5) |
| Medulla | ~10–20% | Epinephrine (~80%), norepinephrine (~20%) | Preganglionic sympathetic (splanchnic nerve → ACh → nAChR) | Tyrosine hydroxylase (TH) — rate-limiting; PNMT for Epi synthesis |
Common steroidogenic pathway (all zones): Cholesterol → (StAR, mitochondrial import, rate-limiting) → CYP11A1 (P450scc, side-chain cleavage) → Pregnenolone → zone-specific P450 enzymes. All zones share CYP21A2 (21-hydroxylase) — its deficiency causes the commonest form of congenital adrenal hyperplasia.
Function
CORTEX — Three Zones Steroidogenesis
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Cholesterol (from LDL/HDL, stored as cholesterol esters)
│ StAR (Steroidogenic Acute Regulatory protein)
│ → mitochondrial cholesterol import (rate-limiting, ACTH/AngII → PKA → StAR phosphorylation)
▼
CYP11A1 (P450scc) → Pregnenolone
│
├─ ZG PATHWAY ─── CYP17A1 (absent in ZG) ✗
│ Pregnenolone → progesterone → (CYP21A2/21-hydroxylase) → 11-deoxycorticosterone
│ → (CYP11B2/aldosterone synthase, ZG only) → Aldosterone
│ Action: MR in collecting duct → ↑ENaC, ↑ROMK, ↑Na⁺/K⁺-ATPase → ↑Na⁺ reabsorption, ↑K⁺ secretion
│
├─ ZF PATHWAY ─── CYP17A1 (17α-hydroxylase)
│ Pregnenolone → 17-OH-pregnenolone → 17-OH-progesterone
│ → (CYP21A2) → 11-deoxycortisol
│ → (CYP11B1/11β-hydroxylase) → Cortisol
│ HPA axis: Stress/circadian → PVN CRH → anterior pituitary ACTH → MC2R → Gs → cAMP → PKA → StAR/CYP11B1
│ Negative feedback: Cortisol → GR in hypothalamus (↓CRH) + pituitary (↓ACTH)
│
└─ ZR PATHWAY ─── CYP17A1 (17,20-lyase, activated by cytochrome b5)
17-OH-pregnenolone → DHEA → (SULT2A1) → DHEAS (most abundant circulating steroid)
DHEA → androstenedione (peripheral conversion → testosterone, DHT, oestrogens)
MEDULLA — Catecholamine Synthesis and Secretion
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Tyrosine → (TH + tetrahydrobiopterin, rate-limiting) → L-DOPA
→ (AADC/DOPA decarboxylase) → Dopamine
→ (DBH in chromaffin granule) → Norepinephrine
→ (PNMT, cytosolic, cortisol-induced) → Epinephrine
Splanchnic nerve (preganglionic) → ACh → nAChR on chromaffin cell
→ depolarisation → Ca²⁺ influx → exocytosis of chromaffin granules
→ Epi/NE + chromogranin A + enkephalin + ATP released into bloodstream
FIGHT-OR-FLIGHT CARDIOVASCULAR EFFECTS:
Epinephrine β₁ → ↑HR + ↑contractility + ↑AV conduction
Epinephrine β₂ → vasodilation (skeletal muscle, coronary arteries)
Norepinephrine α₁ >> β → generalised vasoconstriction → ↑MAP
Net: ↑cardiac output + ↑MAP → ↑organ perfusion under stress
METABOLIC EFFECTS:
β₂ → ↑hepatic glycogenolysis → ↑glucose; ↑lipolysis → ↑FFA
β₂ → ↑glucagon, ↓insulin → ↑hepatic glucose output
β₂ → bronchial smooth muscle relaxation → bronchodilation
Cortisol — Metabolic and Immune Actions
Metabolic effects: Liver: ↑PEPCK + ↑G6Pase → ↑gluconeogenesis; ↑glycogen synthesis (insulin-permissive). Muscle: ↑ubiquitin-proteasome protein catabolism → amino acids → gluconeogenic substrates. Adipose: ↑lipolysis (↑HSL) → FFA release; chronic excess → central/visceral adiposity. Bone: ↓osteoblast (↓Wnt, ↓IGF-1) + ↑osteoclast (indirect) → osteoporosis; ↓intestinal Ca²⁺ absorption (↓VDR) + ↑renal Ca²⁺ excretion → hypercalciuria.
Immune effects: Activated glucocorticoid receptor (GR) → ↓NF-κB (binds p65/RelA, blocks DNA binding) + ↓AP-1 → ↓IL-1β, IL-2, IL-6, TNF-α, COX-2, iNOS gene transcription. Annexin-1 (lipocortin-1) induction → ↓phospholipase A2 → ↓arachidonic acid → ↓prostaglandins + leukotrienes. ↑Anti-inflammatory IL-10 (Th2 shift at high doses). Lymphocyte redistribution from blood to lymphoid tissues → transient lymphocytopenia and eosinopenia. ↓T cell IL-2 → ↓T cell proliferation (basis for therapeutic immunosuppression in organ transplantation + autoimmune disease).
Circadian pattern: ~15–25 mg/day secreted in pulsatile circadian pattern (peak ~8:00 am, nadir at midnight). Free cortisol (~5%) is active; ~95% bound (cortisol-binding globulin 75%, albumin 20%). Cortisol circadian disruption (shift work, Cushing's disease) has downstream metabolic and immune consequences.
Pathology
Primary Adrenal Insufficiency (Addison's Disease)
Destruction of >90% of adrenal cortex → combined cortisol + aldosterone deficiency. Autoimmune (70%: anti-CYP21A2 antibodies → APS-1 or APS-2), TB (bilateral caseating granulomata), metastatic cancer, Waterhouse-Friderichsen syndrome (meningococcal bilateral adrenal haemorrhage), CMV (HIV), adrenoleucodystrophy (X-linked ABCD1 mutation). Clinical: fatigue, weight loss, postural hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia, hyperpigmentation (↑ACTH/α-MSH). Addisonian crisis (acute): life-threatening hypotension → IV hydrocortisone 100 mg bolus + fluid resuscitation. Long-term: hydrocortisone 15–25 mg/day + fludrocortisone 50–200 µg/day.
Cushing Syndrome (Hypercortisolism)
Most common overall cause: exogenous glucocorticoids. Endogenous: Cushing's disease (~70%, pituitary ACTH-secreting adenoma), ectopic ACTH (SCLC, carcinoid, ~15%), adrenal adenoma/carcinoma (~15%). Clinical features: central obesity, moon face, buffalo hump, wide purple striae, proximal myopathy, osteoporosis, diabetes, hypertension, psychiatric disturbance, impaired wound healing, ↑infection risk. Diagnosis: 24h urinary free cortisol, midnight salivary cortisol, 1 mg overnight dexamethasone suppression test (fails to suppress → Cushing's). Localisation: ACTH level + pituitary MRI + inferior petrosal sinus sampling (IPSS).
Phaeochromocytoma / Paraganglioma
Catecholamine-secreting tumour of adrenal chromaffin cells (phaeochromocytoma) or extra-adrenal sympathetic ganglia (paraganglioma). ~30–40% hereditary (VHL, MEN-2A/2B with RET mutations, NF1, SDH subunit mutations). Classical triad: episodic hypertension + headache + diaphoresis + palpitations. Can cause Takotsubo-like cardiomyopathy. Diagnosis: plasma free metanephrines/normetanephrines (99% sensitivity); imaging CT/MRI + ⁶⁸Ga-DOTATATE PET. Treatment: α-blockade first (phenoxybenzamine or doxazosin) → then β-blockade (never β first → risk of unopposed α crisis) → laparoscopic adrenalectomy.
Primary Hyperaldosteronism (Conn Syndrome)
Autonomous aldosterone secretion (independent of RAAS) → hypokalaemia, hypertension, ↑aldosterone, ↓renin (suppressed). Most common cause: bilateral idiopathic hyperplasia (60–65%, spironolactone/eplerenone); aldosterone-producing adenoma (30–35%, KCNJ5 somatic mutation, surgical cure after adrenal venous sampling lateralisation). Prevalence ~10% of hypertensive patients — systematically underdiagnosed. Screen with aldosterone:renin ratio (ARR) in resistant hypertension, hypokalaemic hypertension, adrenal incidentaloma.
Congenital Adrenal Hyperplasia (CAH)
21-hydroxylase deficiency (CYP21A2, 95% of CAH): ↓cortisol + ↓aldosterone + ↑17-OH-progesterone + ↑androgens → salt-wasting crisis (neonates), virilisation of females (ambiguous genitalia), simple virilising (partial enzyme activity), or non-classical (mild, late-onset). Neonatal screening: heel-prick 17-OHP. Treatment: hydrocortisone (suppresses ACTH → reduces androgen excess) ± fludrocortisone.
Cross-Atlas Connections
References
- Hall JE, Hall ME. Guyton and Hall Textbook of Medical Physiology. 14th ed. Elsevier; 2021. elsevier.com
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 9th ed. W.H. Freeman; 2019. macmillanlearning.com
- Nieman LK. Diagnosis of Cushing's syndrome in the modern era. Endocrinol Metab Clin North Am. 2018;47(2):259–73. doi:10.1016/j.ecl.2018.02.001
- Lenders JW, Duh QY, Eisenhofer G, et al. Phaeochromocytoma and paraganglioma: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. doi:10.1210/jc.2014-1498