The Adrenal Cortex and Corticosteroids

The adrenal gland has two embryologically and functionally separate parts: an inner medulla, derived from neural crest, which secretes catecholamines as part of the sympathetic nervous system, and an outer cortex, derived from mesoderm, which secretes steroid hormones. This article concerns the cortex. Histologically the cortex is organized into three concentric layers, from outermost to innermost:

All three hormone classes are steroids, synthesized from cholesterol through a shared initial step and then diverging based on which enzymes each zone expresses. Because steroids are lipophilic, they are not stored in secretory granules the way peptide hormones are; instead, the cortex synthesizes and releases them essentially on demand, meaning the rate-limiting step of hormone production is enzymatic conversion of cholesterol, not vesicle exocytosis. Corticosteroids act on intracellular receptors — glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) — that reside in the cytoplasm bound to chaperone proteins until hormone binding triggers translocation to the nucleus. There the hormone-receptor complex functions as a transcription factor, binding hormone response elements in DNA and altering gene expression. This mechanism, contrasted with the fast membrane-receptor signaling covered under Hormone Receptors and Signal Transduction, explains why steroid effects have an onset of roughly 30 minutes to several hours and last far longer than peptide hormone effects — they work by making new proteins, not by flipping an existing switch.

Step 1 — Cholesterol delivery and the rate-limiting step. Adrenocortical cells take up cholesterol mainly from circulating LDL via LDL receptors, supplemented by de novo synthesis. Free cholesterol is transported from the outer to inner mitochondrial membrane by StAR (steroidogenic acute regulatory protein). This translocation step is rate-limiting for the entire pathway and is acutely stimulated by ACTH (in fasciculata/reticularis) or angiotensin II (in glomerulosa) within minutes via cAMP-PKA or calcium-calmodulin signaling respectively.

Step 2 — The common committed step. Inside the mitochondrion, the cholesterol side-chain cleavage enzyme (P450scc, encoded by CYP11A1) converts cholesterol to pregnenolone. This is the single shared, irreversible entry point for every corticosteroid and gonadal steroid in the body.

Step 3 — Zone-specific enzymatic branching. Pregnenolone then shuttles between mitochondria and smooth endoplasmic reticulum, and which enzymes a given zone expresses determines the final product:

• Zona glomerulosa uniquely expresses aldosterone synthase (CYP11B2), which performs three sequential oxidations converting corticosterone to aldosterone. Crucially, this zone lacks 17α-hydroxylase (CYP17A1), so it cannot make cortisol or androgens — it is committed to the mineralocorticoid pathway.
• Zona fasciculata expresses 17α-hydroxylase (diverting pregnenolone/progesterone toward 17-hydroxy intermediates) and 11β-hydroxylase (CYP11B1), culminating in cortisol. It lacks aldosterone synthase, so it cannot make aldosterone.
• Zona reticularis expresses high 17,20-lyase activity (a second function of CYP17A1, favored here by the cofactor cytochrome b5), cleaving the side chain to produce DHEA and androstenedione, weak androgens that are later converted to testosterone and estrogens in peripheral tissues (skin, adipose, gonads).

Step 4 — Control loops operate on different timescales and triggers. Aldosterone control: Falling blood pressure or blood volume triggers renin release from juxtaglomerular cells of the kidney; renin cleaves angiotensinogen to angiotensin I, converted by ACE (mainly in lung capillaries) to angiotensin II, which binds glomerulosa cell receptors, raising intracellular Ca²⁺ and stimulating aldosterone synthase. Independently, a rise in plasma K⁺ of even 1 mEq/L directly depolarizes glomerulosa cells and stimulates aldosterone secretion — a direct ionic feedback loop bypassing the brain entirely. ACTH has only a minor, permissive, short-term effect on aldosterone. Cortisol control: This is the classic HPA axis. Stress, hypoglycemia, and a circadian pacemaker in the suprachiasmatic nucleus drive the hypothalamus to secrete corticotropin-releasing hormone (CRH) into hypophyseal portal blood, which stimulates the anterior pituitary corticotrophs to secrete ACTH. ACTH binds melanocortin-2 receptors (MC2R) on fasciculata cells, raising cAMP and stimulating both StAR and the whole cortisol-synthesizing enzyme cascade. Cortisol then feeds back negatively on both hypothalamus and pituitary, closing the loop. Cortisol secretion follows a strong circadian rhythm, peaking shortly before waking and reaching its nadir near midnight. Androgen control: Reticularis output tracks ACTH like the fasciculata, but its relative contribution to circulating androgens is modest in adult males (testicular testosterone dominates) and more physiologically significant in females and in both sexes' peripheral tissue conversion pathways.

Step 5 — Target actions. Cortisol raises blood glucose by stimulating hepatic gluconeogenesis, inhibiting peripheral glucose uptake in muscle and fat (an anti-insulin, "diabetogenic" effect), promoting lipolysis, and driving protein catabolism in muscle to supply gluconeogenic amino acid precursors. It suppresses immune and inflammatory responses by inhibiting phospholipase A2 (reducing prostaglandin and leukotriene synthesis), reducing cytokine transcription, and decreasing capillary permeability. It also permits full vascular responsiveness to catecholamines — a "permissive" action explaining why cortisol deficiency causes hypotension. Aldosterone acts on the principal cells of the renal cortical collecting duct, upregulating epithelial Na⁺ channels (ENaC) and the Na⁺/K⁺-ATPase, increasing Na⁺ reabsorption and K⁺ secretion; the water that follows sodium osmotically. Net effect: expanded extracellular fluid volume, raised blood pressure, and lowered plasma K⁺. Adrenal androgens contribute to pubic and axillary hair growth (adrenarche) and, especially in females, are a significant source of circulating androgen and estrogen precursor after peripheral conversion.

Establishing that the cortex, not the medulla, is essential for life. In the 1920s and 1930s, physiologists including Wilburt Davison and later Frank Hartman, and separately George Oliver and Edward Schafer's earlier catecholamine work, distinguished cortex from medulla function. The definitive demonstration came from adrenalectomy studies: animals with the adrenal cortex removed die within days from circulatory collapse, hyperkalemia, and hypoglycemia, whereas animals whose medulla alone is destroyed (but cortex spared) survive essentially normally, because sympathetic nerves elsewhere can substitute for adrenal catecholamines. This asymmetry proved the cortex, not the medulla, is the life-sustaining component — reversing the earlier assumption (based on medullary catecholamine research) that the adrenal's key output was epinephrine.

Extraction and identification of cortical hormones (Kendall, Reichstein, Hench, 1930s–1949). Edward Kendall at the Mayo Clinic and Tadeusz Reichstein in Basel independently isolated multiple crystalline steroid compounds from adrenal cortex extract, labeling them alphabetically (Compound A through Compound U). Kendall's "Compound E" was later identified as cortisone. The proof that this compound was physiologically central came when Philip Hench, a Mayo rheumatologist, administered Compound E to a patient with severe rheumatoid arthritis in 1948; the patient, previously wheelchair-bound, walked normally within days. This dramatic clinical reversal — reported to a stunned academic audience — demonstrated the potent anti-inflammatory action of glucocorticoids and earned Kendall, Reichstein, and Hench the 1950 Nobel Prize in Physiology or Medicine. It also proved that a single adrenal-derived molecule could suppress inflammation across an entire organ system, establishing pharmacological glucocorticoid therapy.

Distinguishing mineralocorticoid from glucocorticoid function — the replacement experiments. Adrenalectomized animals die primarily of a mineralocorticoid deficiency: unchecked renal Na⁺ loss and K⁺ retention causes fatal hyperkalemic cardiac arrhythmia within days, well before glucocorticoid deficiency alone would be lethal. This was proven directly: adrenalectomized animals given only a glucocorticoid survive metabolic stress but still die of salt-wasting, whereas replacement with a mineralocorticoid (or simply feeding excess saline) rescues survival even without any glucocorticoid, and combined replacement of both restores near-normal physiology. This dissection — showing that saline alone can substitute for the missing mineralocorticoid — was decisive evidence that the "life or death" hormone of the adrenal cortex is aldosterone's Na⁺-retaining action, while cortisol governs the animal's capacity to withstand stress rather than baseline survival.

Mapping zonal specificity (mid-20th century histochemistry and later molecular cloning). Selective ACTH suppression (via glucocorticoid feedback or hypophysectomy) was shown to atrophy the fasciculata and reticularis while sparing the glomerulosa, whose aldosterone output persisted — direct evidence that glomerulosa function is largely ACTH-independent and instead depends on the renin-angiotensin system. Conversely, sodium-restricted diets (activating renin-angiotensin) selectively hypertrophy the glomerulosa without affecting fasciculata size. Molecular cloning of CYP11B2 (aldosterone synthase) in the 1980s–90s confirmed it is expressed exclusively in glomerulosa cells, providing the definitive molecular explanation for why only that zone can synthesize aldosterone.

Example 1 — Reasoning through a clinical presentation. A 34-year-old woman presents with fatigue, weight loss, hyperpigmentation of the skin creases and gums, salt craving, hypotension (88/56 mmHg), hyponatremia (128 mEq/L, normal ~140), and hyperkalemia (5.9 mEq/L, normal ~4.0). Lab work shows morning cortisol low, and plasma ACTH markedly elevated. Reasoning: Low cortisol plus low aldosterone-type findings (hyponatremia, hyperkalemia, hypotension, salt craving) indicate global adrenal cortex failure, not an isolated zone problem — this is primary adrenal insufficiency (Addison's disease), where the cortex itself is destroyed (commonly autoimmune). Because cortisol is low, the pituitary loses its negative feedback and ACTH rises; ACTH shares a precursor (proopiomelanocortin, POMC) with melanocyte-stimulating hormone, explaining the hyperpigmentation — a classic sign present only in primary (not secondary/pituitary) adrenal insufficiency, since in secondary failure ACTH is low, not high. This distinguishes primary adrenal disease from a pituitary-based (secondary) cortisol deficiency, where skin pigmentation would be normal or pale, and where aldosterone is typically preserved because it is largely renin-angiotensin-driven rather than ACTH-driven.

Example 2 — Quantitative reasoning on aldosterone and sodium balance. Suppose a healthy adult ingests a very low-sodium diet, dropping plasma volume slightly, and plasma renin activity rises threefold. Estimate the physiological consequence chain and approximate net effect on urinary sodium excretion. Reasoning, step by step: 1. ↓Plasma volume → ↓renal perfusion pressure → juxtaglomerular cells release more renin (here, threefold). 2. Renin cleaves angiotensinogen → angiotensin I → ACE (mainly pulmonary endothelium) → angiotensin II. 3. Angiotensin II acts on zona glomerulosa: raises intracellular Ca²⁺, stimulates StAR and aldosterone synthase (CYP11B2), increasing aldosterone secretion (typically several-fold above baseline under sustained sodium restriction). 4. Aldosterone reaches renal principal cells within roughly 30–90 minutes (genomic, receptor-mediated action), upregulating ENaC and Na⁺/K⁺-ATPase. 5. Result: fractional Na⁺ reabsorption in the collecting duct rises, so urinary Na⁺ excretion falls toward near-zero (under maximal stimulation, the kidney can approach less than 1% of filtered Na⁺ excreted, versus its normal ~1%, and go even lower), restoring extracellular volume over 1–3 days. 6. As a side effect, K⁺ secretion also increases (since ENaC-driven Na⁺ reabsorption creates a lumen-negative potential favoring K⁺ secretion), so plasma K⁺ tends to fall slightly — this is why chronic diuretic-induced volume depletion (mimicking this scenario) classically causes hypokalemia via secondary hyperaldosteronism. This illustrates the physiological logic: the aldosterone axis defends extracellular volume, using Na⁺ retention as its lever, with K⁺ handling as a mechanistic byproduct rather than the primary controlled variable — the reverse priority of the direct K⁺-sensing pathway described earlier.

Edward Calvin Kendall spent nearly three decades at the Mayo Clinic pursuing what he suspected was a life-sustaining cortical hormone, working with almost industrial-scale extraction of animal adrenal glands — reportedly processing tons of cattle adrenal cortex to isolate mere grams of crystalline steroid. His painstaking biochemical purification produced a library of related compounds (labeled A–U) whose biological activities were unknown until rheumatologist Philip Hench, struck by the clinical observation that rheumatoid arthritis symptoms sometimes remitted during pregnancy or jaundice (both states of altered steroid metabolism), hypothesized that an adrenal-derived "substance X" was anti-inflammatory. Hench persuaded Kendall's collaborators to synthesize enough Compound E for a human trial. Tadeusz Reichstein in Switzerland, working in parallel and largely independently, achieved comparable structural characterization of adrenal steroids, and his laboratory's synthetic route later proved essential for industrial-scale cortisone production.

Endocrinology and emergency medicine. Addison's disease and adrenal crisis remain treated exactly along the physiological logic above: glucocorticoid (hydrocortisone) plus mineralocorticoid (fludrocortisone) replacement, with stress-dose glucocorticoid escalation during illness or surgery because the normal HPA axis cannot mount its own cortisol surge.

Rheumatology and immunology. Synthetic glucocorticoids (prednisone, dexamethasone, betamethasone) are frontline anti-inflammatory and immunosuppressive drugs for asthma, rheumatoid arthritis, inflammatory bowel disease, organ transplantation, and severe allergic reactions — direct descendants of Hench's original cortisone trial.

Critical care. Dexamethasone reduced mortality in severe COVID-19 respiratory failure, one of the largest global demonstrations of glucocorticoid pharmacology in modern history (RECOVERY trial, 2020), by dampening the cytokine-driven inflammatory lung injury.

Cardiology and nephrology. Mineralocorticoid receptor antagonists (spironolactone, eplerenone, and newer nonsteroidal agents like finerenone) block aldosterone's renal and cardiac fibrotic actions, used in resistant hypertension, heart failure, and diabetic kidney disease — a direct pharmacological exploitation of the aldosterone-ENaC pathway.

Diagnostics. The dexamethasone suppression test and ACTH stimulation (cosyntropin) test exploit the HPA feedback loop and zonal enzymology directly to diagnose Cushing syndrome, adrenal insufficiency, and congenital adrenal hyperplasia (enzyme defects such as 21-hydroxylase deficiency, which block cortisol/aldosterone synthesis and shunt precursors toward androgen overproduction).

Reproductive endocrinology and dermatology. Adrenal androgen excess (as in congenital adrenal hyperplasia or adrenal tumors) explains virilization syndromes, guiding both diagnosis and hormone-blocking therapy.

Veterinary and agricultural science. Aldosterone and cortisol assays are used to monitor stress physiology in livestock management and wildlife conservation, connecting directly to the broader themes of Stress and the HPA Axis.

Ask the tutor: How does chronic psychological stress remodel the HPA axis differently from a single acute stressor?