Medical School · Year 2 · Endocrine · includes a quiz and discussion video

Lecture 7: Adrenal Cortex Anatomy and Physiology

Unit 2.3: Endocrine System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the anatomy and zones of the adrenal cortex
2. Explain glucocorticoid synthesis, regulation, and actions
3. Describe mineralocorticoid synthesis and the renin-angiotensin-aldosterone system
4. Explain adrenal androgen production
5. Describe the hypothalamic-pituitary-adrenal axis
6. Explain steroidogenesis pathways and enzyme deficiencies

Lecture Outline

I. Adrenal Anatomy

The adrenal glands are paired endocrine organs with distinct cortical and medullary regions that arise from different embryologic origins and serve fundamentally different functions. Understanding adrenal anatomy provides the foundation for comprehending adrenal physiology and pathology.

The location and structure of the adrenal glands reflect their relationship to the kidneys and surrounding structures. Each adrenal gland sits atop the superior pole of its respective kidney, within the renal fascia but separated from the kidney by adipose tissue. Each gland weighs approximately 4-5 grams. The right adrenal gland has a pyramidal shape and sits slightly higher than the left, wedged between the liver and the right crus of the diaphragm. The left adrenal gland has a semilunar shape and lies medial to the upper pole of the left kidney, posterior to the stomach and pancreas. Each gland comprises an outer cortex (comprising 80-90% of the gland) and an inner medulla (comprising 10-20%).

The blood supply to the adrenal glands is abundant, reflecting their high metabolic activity. Three arterial sources supply each gland: the superior adrenal artery arising from the inferior phrenic artery, the middle adrenal artery arising directly from the aorta, and the inferior adrenal artery arising from the renal artery. Venous drainage is asymmetric and clinically important: the right adrenal vein drains directly into the inferior vena cava (making it short and difficult to cannulate), while the left adrenal vein drains into the left renal vein (longer and easier to access for adrenal vein sampling).

The cortex and medulla have distinct embryologic origins and functions. The cortex derives from mesoderm (specifically the urogenital ridge) and produces steroid hormones including glucocorticoids, mineralocorticoids, and androgens. The medulla derives from neural crest cells (the same origin as sympathetic ganglia) and produces catecholamines (epinephrine and norepinephrine). While the cortex is regulated primarily by ACTH and angiotensin II, the medulla is regulated by the sympathetic nervous system.

<image>Panel A: Bilateral adrenal glands in situ atop the kidneys showing right pyramidal shape and left semilunar shape with labeled relationships to adjacent structures including liver, IVC, aorta, and kidneys. Panel B: Arterial blood supply diagram showing three sources color-coded as superior adrenal artery from inferior phrenic, middle adrenal artery from aorta, and inferior adrenal artery from renal artery. Panel C: Venous drainage illustration comparing the short right adrenal vein entering IVC directly versus the longer left adrenal vein entering the left renal vein. Panel D: Cross-sectional inset of the adrenal gland showing outer cortex (80-90%) derived from mesoderm and inner medulla (10-20%) derived from neural crest cells.</image>

II. Adrenal Cortex Zones

The adrenal cortex is organized into three distinct zones, each producing specific hormones under distinct regulatory control. The mnemonic "GFR" (from outside to inside) corresponds to "Salt, Sugar, Sex," describing the primary hormone products of each zone.

The zona glomerulosa is the outermost zone of the adrenal cortex. The name derives from the glomerulus-like clustered arrangement of its cells. This zone produces aldosterone, the principal mineralocorticoid. The key enzyme unique to this zone is aldosterone synthase (CYP11B2), which catalyzes the final steps in aldosterone synthesis. Regulation occurs primarily through angiotensin II (via the renin-angiotensin system) and potassium (hyperkalemia directly stimulates aldosterone release). Importantly, the zona glomerulosa lacks 17α-hydroxylase, meaning it cannot synthesize cortisol or androgens—it is dedicated to mineralocorticoid production.

The zona fasciculata is the middle and largest zone of the adrenal cortex. The name reflects the fascicle-like columnar arrangement of its cells. This zone produces cortisol, the principal glucocorticoid. The presence of 17α-hydroxylase enables cortisol synthesis through 17-hydroxylated intermediates. ACTH from the pituitary is the primary regulator, and this zone is highly responsive to ACTH stimulation.

The zona reticularis is the innermost cortical zone. The name reflects the reticular (net-like) arrangement of its cells. This zone produces adrenal androgens, primarily dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S), along with androstenedione. These are weak androgens that serve as precursors for peripheral conversion to testosterone and estrogen. Like the zona fasciculata, this zone is regulated by ACTH.

<image>Panel A: Cross-sectional view of the adrenal gland with three demarcated cortical zones labeled from outside to inside as zona glomerulosa (outermost, clustered cells), zona fasciculata (middle, columnar cells), and zona reticularis (innermost, net-like cells). Panel B: Zone-specific hormone and enzyme summary showing aldosterone with aldosterone synthase in glomerulosa, cortisol with 17-alpha-hydroxylase in fasciculata, and DHEA in reticularis, with the mnemonic GFR equals Salt Sugar Sex. Panel C: Primary regulators for each zone displayed as angiotensin II and potassium for glomerulosa, ACTH for fasciculata, and ACTH for reticularis with feedback loop arrows. Panel D: Histologic inset comparing cellular arrangement patterns with clustered cells in glomerulosa, parallel columnar cells in fasciculata, and net-like reticular cells in reticularis.</image>

III. Steroidogenesis - Overview

Steroidogenesis is the enzymatic process by which cholesterol is converted to various steroid hormones. Understanding the biosynthetic pathways explains how different adrenal zones produce distinct hormones and why specific enzyme deficiencies cause predictable hormonal patterns.

Cholesterol is the universal precursor for all adrenal steroids. Cholesterol for steroidogenesis comes primarily from circulating LDL (low-density lipoprotein) that is taken up by the adrenal cortex, with a smaller contribution from de novo synthesis within adrenal cells. The rate-limiting step in steroidogenesis is the transport of cholesterol from the outer to inner mitochondrial membrane, mediated by the steroidogenic acute regulatory protein (StAR). Mutations in StAR cause lipoid congenital adrenal hyperplasia, the most severe form of adrenal insufficiency.

The key enzymes in steroidogenesis include cytochrome P450 enzymes and hydroxysteroid dehydrogenases. CYP11A1 (also called P450scc for side-chain cleavage) converts cholesterol to pregnenolone in the mitochondria—this reaction occurs in all zones. 3β-hydroxysteroid dehydrogenase (3β-HSD) converts pregnenolone to progesterone and occurs in all zones. CYP17 has dual activities: 17α-hydroxylase activity (converting pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone) and 17,20-lyase activity (converting 17-hydroxypregnenolone to DHEA). CYP17 is present in the zona fasciculata and reticularis but absent from the zona glomerulosa. CYP21 (21-hydroxylase) converts progesterone to deoxycorticosterone (DOC) and 17-hydroxyprogesterone to 11-deoxycortisol. CYP11B1 (11β-hydroxylase) converts 11-deoxycortisol to cortisol in the zona fasciculata. CYP11B2 (aldosterone synthase) converts corticosterone to aldosterone exclusively in the zona glomerulosa.

The pathways specific to each zone reflect the differential enzyme expression. In the zona glomerulosa (lacking CYP17), cholesterol is converted through pregnenolone, progesterone, deoxycorticosterone, and corticosterone to aldosterone. In the zona fasciculata (with CYP17), the pathway proceeds through 17-hydroxylated intermediates to cortisol. In the zona reticularis (with strong lyase activity), DHEA is the primary product, which can be converted to androstenedione.

<image>Panel A: Cholesterol transport into mitochondria via StAR protein as the rate-limiting step in steroidogenesis, with cholesterol structure and outer-to-inner mitochondrial membrane movement illustrated. Panel B: Three branching pathways showing zone-specific products with glomerulosa pathway leading to aldosterone (left), fasciculata pathway leading to cortisol (center), and reticularis pathway leading to DHEA and androstenedione (right), each enzyme labeled with common name and CYP designation. Panel C: Color-coded enzyme distribution map indicating which zones contain each enzyme, with blocked arrows showing where enzyme deficiencies cause accumulation of proximal metabolites. Panel D: Legend showing enzyme colors, mitochondrial versus endoplasmic reticulum location for each reaction, and key regulatory points in the pathway.</image>

IV. Glucocorticoids - Cortisol

Cortisol is the principal glucocorticoid in humans, exerting widespread metabolic, immune, and physiologic effects throughout the body. Understanding cortisol synthesis, transport, metabolism, and actions is essential for comprehending both normal physiology and hypercortisolism or hypocortisolism.

Cortisol synthesis and secretion follow characteristic patterns. Daily cortisol production under basal conditions is approximately 10-20 mg per day (equivalent to about 20-30 mg of hydrocortisone orally, accounting for first-pass metabolism). Cortisol secretion follows a pronounced circadian rhythm, with peak levels occurring in the early morning (6-8 AM, coinciding with awakening) and nadir levels at midnight. Superimposed on this circadian pattern is pulsatile secretion, with ACTH and cortisol released in bursts every 30-120 minutes. Physical and psychological stress can override normal patterns, markedly increasing cortisol production.

Cortisol transport in the blood involves binding to carrier proteins. Cortisol-binding globulin (CBG, also called transcortin) binds 80-90% of circulating cortisol with high affinity. Albumin binds an additional 10% with lower affinity. Only 5-10% of total serum cortisol is unbound (free) and biologically active, able to enter cells and bind glucocorticoid receptors. Conditions affecting CBG levels (pregnancy, estrogen therapy, liver disease) alter total cortisol measurements but generally not free cortisol or clinical status.

Cortisol metabolism occurs primarily in the liver through reduction reactions followed by conjugation with glucuronide or sulfate for renal excretion. Plasma half-life is approximately 60-90 minutes. An important metabolic reaction occurs in the kidney: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts active cortisol to inactive cortisone, protecting the mineralocorticoid receptor from cortisol occupancy (since cortisol and aldosterone have similar affinity for this receptor).

Cortisol exerts diverse actions throughout the body. Metabolically, cortisol promotes gluconeogenesis and hepatic glycogen storage while inhibiting peripheral glucose uptake, raising blood glucose. Cortisol stimulates protein catabolism, particularly in muscle, skin, and connective tissue. Cortisol promotes lipolysis while paradoxically causing central fat redistribution in states of excess. Immunologically, cortisol has potent anti-inflammatory and immunosuppressive effects, inhibiting cytokine production, reducing inflammatory cell migration, and promoting apoptosis of lymphocytes. Cardiovascularly, cortisol is permissive for catecholamine action and maintains vascular tone. In bone, cortisol inhibits osteoblast activity and promotes osteoclast activity, leading to osteoporosis with excess. Cortisol affects the central nervous system, influencing mood, cognition, and the stress response. In excess, cortisol antagonizes growth hormone effects, contributing to growth retardation in children.

<image>Panel A: Circadian rhythm graph showing 24-hour cortisol levels peaking at 6-8 AM and reaching nadir at midnight, with pulsatile secretion pattern overlaid on the diurnal curve. Panel B: Cortisol transport pie chart showing CBG binding (80-90%), albumin binding (10%), and free cortisol (5-10%) with annotation that only the free fraction is biologically active. Panel C: Radial diagram of cortisol actions organized by system including metabolism (gluconeogenesis, protein catabolism, lipolysis), immune (anti-inflammatory, immunosuppression), cardiovascular (permissive for catecholamines), bone (osteoporosis), CNS (mood, cognition), and growth (antagonizes GH). Panel D: Kidney diagram showing 11-beta-HSD2 enzyme converting active cortisol to inactive cortisone to protect mineralocorticoid receptors from cortisol occupancy.</image>

V. Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine system that regulates cortisol secretion. This hierarchical control system integrates circadian rhythms, stress responses, and negative feedback to maintain cortisol homeostasis.

The hierarchy of the HPA axis involves three levels. The hypothalamus (specifically the paraventricular nucleus) produces corticotropin-releasing hormone (CRH). CRH travels through the hypophyseal portal system to the anterior pituitary. The anterior pituitary corticotrophs produce adrenocorticotropic hormone (ACTH). ACTH travels through the systemic circulation to the adrenal cortex. The adrenal cortex (zona fasciculata and reticularis) produces cortisol and androgens in response to ACTH stimulation.

CRH (corticotropin-releasing hormone) is a 41-amino acid peptide produced in the paraventricular nucleus of the hypothalamus. CRH release is pulsatile and follows circadian rhythms, with highest activity in early morning. Various stressors—physical (pain, hypoglycemia, hemorrhage) and psychological (fear, anxiety)—stimulate CRH release. Arginine vasopressin (AVP) is co-secreted with CRH and potentiates its effects on ACTH release.

ACTH (adrenocorticotropic hormone) is a 39-amino acid peptide derived from the precursor protein proopiomelanocortin (POMC). Cleavage of POMC also produces melanocyte-stimulating hormone (MSH, explaining hyperpigmentation in ACTH excess) and β-endorphin (an endogenous opioid). ACTH acts on the adrenal cortex through the melanocortin 2 receptor (MC2R), stimulating cortisol and androgen synthesis. ACTH also has trophic effects, maintaining adrenal cortical mass—ACTH deficiency leads to adrenal atrophy.

Negative feedback is the primary mechanism maintaining cortisol homeostasis. Cortisol inhibits both CRH release from the hypothalamus and ACTH release from the pituitary. This feedback operates at multiple timescales: rapid (minutes, possibly non-genomic), intermediate (hours, genomic), and slow (days, affecting synthesis of CRH and POMC). Exogenous glucocorticoid administration suppresses the HPA axis, and prolonged suppression leads to adrenal atrophy, explaining the need for careful tapering after chronic glucocorticoid therapy.

<image>Panel A: Hierarchical HPA axis cascade showing hypothalamus (paraventricular nucleus) secreting CRH, anterior pituitary (corticotrophs) secreting ACTH, and adrenal cortex producing cortisol, with stimulatory arrows and negative feedback loops from cortisol shown as dashed lines with minus signs. Panel B: Circadian pattern sidebar showing parallel CRH, ACTH, and cortisol peaks in early morning with synchronized pulsatile release patterns across the 24-hour cycle. Panel C: POMC processing inset illustrating cleavage of proopiomelanocortin into ACTH, melanocyte-stimulating hormone (MSH), and beta-endorphin with functional annotations for each product. Panel D: Stress input diagram showing physical and psychological stressors converging on the hypothalamus, with annotation about exogenous glucocorticoid administration causing HPA axis suppression and subsequent adrenal cortical atrophy.</image>

VI. Mineralocorticoids - Aldosterone

Aldosterone is the principal mineralocorticoid, regulating sodium and potassium balance through actions on the renal collecting duct. Understanding aldosterone synthesis, regulation through the renin-angiotensin-aldosterone system (RAAS), and actions is essential for comprehending fluid and electrolyte homeostasis.

Aldosterone synthesis occurs exclusively in the zona glomerulosa. The enzyme aldosterone synthase (CYP11B2) is unique to this zone and catalyzes the final steps converting corticosterone to aldosterone. Daily aldosterone production (approximately 100-200 μg) is much lower than cortisol production.

The renin-angiotensin-aldosterone system (RAAS) is the primary regulator of aldosterone secretion. When renal perfusion decreases (from volume depletion, hypotension, or renal artery stenosis) or distal sodium delivery decreases, the juxtaglomerular cells of the kidney release renin. Renin is a protease that cleaves angiotensinogen (produced by the liver) to form angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE), primarily in the pulmonary vasculature. Angiotensin II has multiple effects: it stimulates aldosterone release from the zona glomerulosa, causes systemic vasoconstriction, stimulates thirst and ADH release, and promotes sodium reabsorption in the proximal tubule. Other stimuli for aldosterone release include hyperkalemia (a direct effect of potassium on the zona glomerulosa) and ACTH (a minor acute stimulant).

Aldosterone actions occur primarily in the renal collecting duct through mineralocorticoid receptors. In principal cells, aldosterone increases activity of the epithelial sodium channel (ENaC), enhancing sodium reabsorption from the tubular lumen. The resulting electronegative tubular lumen drives potassium secretion through potassium channels. In α-intercalated cells, aldosterone promotes hydrogen ion secretion via H+-ATPase. The net effect is volume expansion (from sodium retention), blood pressure increase, hypokalemia, and metabolic alkalosis.

The mineralocorticoid receptor has equal affinity for both aldosterone and cortisol. Since cortisol circulates at concentrations 100-1000 times higher than aldosterone, specificity is conferred by 11β-HSD2, which converts cortisol to inactive cortisone in mineralocorticoid target tissues. When 11β-HSD2 is deficient or inhibited (as by licorice consumption), cortisol activates mineralocorticoid receptors, causing apparent mineralocorticoid excess syndrome with hypertension and hypokalemia.

<image>Panel A: RAAS cascade showing decreased renal perfusion triggering renin release from juxtaglomerular cells, renin cleaving angiotensinogen to angiotensin I, ACE converting to angiotensin II, and angiotensin II stimulating aldosterone release with branch arrows for vasoconstriction, thirst, and ADH effects. Panel B: Aldosterone actions in the collecting duct showing a cross-sectional principal cell with ENaC on apical membrane for sodium reabsorption and ROMK channel for potassium secretion with ion flow arrows. Panel C: Alpha-intercalated cell diagram showing H-plus-ATPase mediating hydrogen ion secretion into the tubular lumen, contributing to metabolic alkalosis in aldosterone excess states. Panel D: Mineralocorticoid receptor specificity illustration showing 11-beta-HSD2 converting cortisol to inactive cortisone in target tissues, with annotation about apparent mineralocorticoid excess syndrome when the enzyme is deficient or inhibited by licorice.</image>

VII. Adrenal Androgens

The adrenal cortex produces androgens that, while weaker than gonadal testosterone, serve important physiologic roles, particularly in women. Understanding adrenal androgen synthesis, regulation, and clinical significance informs evaluation of androgen disorders.

Adrenal androgen synthesis occurs in the zona reticularis. The primary products are dehydroepiandrosterone (DHEA), its sulfated form DHEA-S (which has a much longer half-life due to delayed clearance), and androstenedione. These are "weak" androgens with relatively low affinity for androgen receptors but serve as precursors for peripheral conversion to more potent sex steroids.

Regulation of adrenal androgen production involves ACTH as the primary stimulant. A developmental phenomenon called adrenarche begins around age 6-8 years, when the zona reticularis matures and adrenal androgen production increases. DHEA and DHEA-S levels peak in the third decade of life and then progressively decline with aging—a phenomenon termed adrenopause. This decline may contribute to age-related changes in body composition, bone density, and well-being.

The physiologic role of adrenal androgens relates to their function as precursors for sex steroid production. In peripheral tissues (adipose, skin, and others), adrenal androgens can be converted to testosterone by 17β-hydroxysteroid dehydrogenase and to estrogens by aromatase. In women, adrenal androgens represent the principal source of androgens, contributing to pubic and axillary hair development (adrenarche precedes gonadarche) and maintenance of libido. In men, adrenal androgens make only a minor contribution to total androgen pool since the testes are the dominant source.

Clinical significance of adrenal androgens relates to both deficiency and excess states. In adrenal tumors secreting androgens, DHEA-S is markedly elevated. In adrenal insufficiency, DHEA-S is decreased (though symptoms are primarily from cortisol deficiency). In polycystic ovary syndrome (PCOS), adrenal androgens may be elevated. DHEA-S measurement helps distinguish adrenal from gonadal androgen sources in the evaluation of hyperandrogenism.

<image>Panel A: Zona reticularis location within the adrenal cortex with enzymatic synthesis pathway showing production of DHEA, DHEA-S, and androstenedione with each enzyme step labeled. Panel B: Lifespan timeline graph of adrenal androgen (DHEA-S) levels showing low values in childhood, rising at adrenarche (age 6-8), peaking in the third decade, and declining with aging (adrenopause) with key transitions labeled. Panel C: Peripheral conversion diagram with arrows showing DHEA converted to testosterone by 17-beta-HSD and androstenedione converted to estrogen by aromatase in target tissues including adipose and skin, with annotation that women derive significant androgens from adrenal sources. Panel D: Clinical significance box showing elevated DHEA-S as a marker for adrenal tumors, decreased DHEA-S in adrenal insufficiency, and the role of DHEA-S measurement in distinguishing adrenal from gonadal androgen sources.</image>

VIII. Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders caused by enzyme deficiencies in adrenal steroidogenesis. Understanding the pathophysiology of these conditions explains their clinical manifestations and guides treatment.

The overview of CAH relates to the consequences of impaired cortisol synthesis. When any enzyme required for cortisol production is deficient, cortisol levels fall, eliminating negative feedback on the HPA axis. ACTH levels rise, causing adrenal cortical hyperplasia. Precursors proximal to the enzymatic block accumulate and are shunted into unaffected pathways. The specific clinical features depend on which steroids are deficient and which accumulate.

21-Hydroxylase deficiency (caused by mutations in CYP21A2) accounts for approximately 90-95% of CAH cases. The enzyme normally converts progesterone to deoxycorticosterone (in the mineralocorticoid pathway) and 17-hydroxyprogesterone to 11-deoxycortisol (in the glucocorticoid pathway). When deficient, 17-hydroxyprogesterone (17-OHP) accumulates and is shunted into the androgen pathway, causing androgen excess. Three clinical forms exist based on severity. Classic salt-wasting CAH (complete enzyme deficiency) presents in the newborn period with both cortisol and aldosterone deficiency, causing life-threatening salt-wasting crises with hyponatremia, hyperkalemia, and shock; female infants show virilization with ambiguous genitalia. Classic simple virilizing CAH (severe but partial deficiency) presents with cortisol deficiency and androgen excess but sufficient aldosterone production to prevent salt wasting; females show virilization, and males appear normal at birth but develop precocious puberty. Non-classic (late-onset) CAH (mild deficiency) presents later in life with hyperandrogenic features such as hirsutism, acne, and irregular menses in women.

Other enzyme deficiencies cause distinct clinical patterns. 11β-Hydroxylase deficiency (the second most common) causes cortisol deficiency and androgen excess (similar to 21-hydroxylase deficiency) but differs in that deoxycorticosterone (DOC) accumulates; DOC has mineralocorticoid activity, causing hypertension and hypokalemia. 17α-Hydroxylase deficiency prevents synthesis of cortisol and sex steroids, causing mineralocorticoid excess (hypertension, hypokalemia) and sex steroid deficiency; 46,XY individuals have female phenotype due to lack of testosterone, and 46,XX individuals have sexual infantilism. 3β-Hydroxysteroid dehydrogenase deficiency affects all three zones, causing variable degrees of cortisol, aldosterone, and sex steroid deficiency.

Diagnosis of CAH (particularly 21-hydroxylase deficiency) relies on measurement of 17-hydroxyprogesterone (17-OHP). Basal 17-OHP is elevated in classic forms. ACTH stimulation test (measuring 17-OHP before and after cosyntropin administration) reveals an exaggerated response in non-classic CAH. Electrolytes show hyponatremia and hyperkalemia in salt-wasting forms. Plasma renin activity is elevated in salt-wasters. Genetic testing confirms the diagnosis and guides genetic counseling.

Treatment of CAH aims to replace deficient hormones and suppress excess ACTH (thereby reducing androgen overproduction). Glucocorticoid replacement with hydrocortisone suppresses ACTH and reduces adrenal androgen production. Mineralocorticoid replacement with fludrocortisone is required in salt-wasting forms. Stress dosing with increased glucocorticoid is essential during illness or surgery. Surgical correction of ambiguous genitalia may be considered in virilized females.

<image>Panel A: Steroidogenic pathway with the 21-hydroxylase block highlighted showing accumulation of 17-OHP proximal to the block and shunting into the androgen pathway, with arrows indicating decreased cortisol and aldosterone and increased androgens. Panel B: Comparison table of three forms of 21-hydroxylase deficiency showing classic salt-wasting (severe enzyme deficiency, salt loss crisis, ambiguous genitalia), simple virilizing (moderate deficiency, virilization without salt loss), and non-classic (mild deficiency, later onset hirsutism and acne). Panel C: Clinical presentation illustrations comparing newborn female with virilization (enlarged clitoris, fused labia) versus male (normal at birth with later precocious puberty development). Panel D: 11-beta-hydroxylase deficiency comparison showing accumulation of deoxycorticosterone (DOC) with mineralocorticoid activity causing hypertension and hypokalemia, contrasted with the 21-hydroxylase pattern.</image>

IX. Adrenal Function Testing

Assessment of adrenal function requires understanding the appropriate tests for evaluating both hypercortisolism and hypocortisolism, as well as mineralocorticoid function. The choice of test depends on the clinical question being asked.

Cortisol assessment uses different tests depending on whether excess or deficiency is suspected. Morning cortisol measurement (typically at 8 AM) provides a screening assessment; very low levels (less than 3 μg/dL) suggest adrenal insufficiency, while high levels (greater than 15-18 μg/dL) make insufficiency unlikely. For suspected Cushing syndrome, 24-hour urine free cortisol measures integrated cortisol production, eliminating the confounding effects of CBG variability. Late-night salivary cortisol detects loss of circadian rhythm (normally, cortisol is at its nadir at midnight). The dexamethasone suppression test (DST) evaluates whether exogenous glucocorticoid appropriately suppresses the HPA axis: in the 1 mg overnight DST, dexamethasone given at 11 PM should suppress 8 AM cortisol to less than 1.8 μg/dL; failure to suppress suggests Cushing syndrome.

The ACTH stimulation test (cosyntropin test) is the definitive test for adrenal insufficiency. The standard dose test uses 250 μg of cosyntropin (synthetic ACTH 1-24) given intravenously or intramuscularly. Cortisol is measured at baseline and at 30 and 60 minutes after injection. A normal response is peak cortisol of 18-20 μg/dL or greater, indicating adequate adrenal reserve. A subnormal response indicates adrenal insufficiency. The standard test reliably detects primary adrenal insufficiency but may miss recent or partial secondary adrenal insufficiency (because the adrenal cortex has not yet atrophied enough to fail); in such cases, a low-dose (1 μg) test may be more sensitive.

The CRH stimulation test helps differentiate causes of ACTH-dependent Cushing syndrome. After CRH administration, patients with pituitary Cushing disease show an increase in ACTH and cortisol (indicating a tumor responsive to CRH), while patients with ectopic ACTH secretion typically show no response (indicating an autonomous tumor).

Aldosterone evaluation uses the aldosterone-to-renin ratio as a screening test for primary aldosteronism; a ratio greater than 30 (with aldosterone greater than 15 ng/dL) is suggestive. Confirmatory tests demonstrate non-suppressible aldosterone: oral or intravenous salt loading should suppress aldosterone in normal individuals but fails to do so in primary aldosteronism. Subtype differentiation uses adrenal CT (looking for adenoma versus bilateral hyperplasia) and adrenal vein sampling (the gold standard for lateralization).

Adrenal imaging with CT or MRI evaluates adrenal structure. CT is preferred for most indications, providing excellent anatomic detail. Adrenal incidentaloma evaluation includes assessment of functional status and imaging characteristics suggesting benign versus malignant disease.

<image>Panel A: Cortisol assessment tests organized by clinical question showing screening (morning cortisol), Cushing evaluation (UFC, late-night salivary cortisol, DST), and insufficiency evaluation (ACTH stimulation test) as parallel diagnostic pathways. Panel B: ACTH stimulation test timeline showing cosyntropin 250 mcg injection with cortisol measurements at 0, 30, and 60 minutes and a normal response threshold line at 18 mcg/dL or greater. Panel C: CRH stimulation test interpretation comparing pituitary Cushing disease (ACTH and cortisol rise after CRH) versus ectopic ACTH syndrome (no response to CRH stimulation). Panel D: Aldosterone evaluation algorithm showing screening with aldosterone-to-renin ratio greater than 30, confirmatory salt loading test, and localization with adrenal CT followed by adrenal vein sampling for subtype differentiation.</image>

X. Clinical Applications

Understanding adrenal physiology has direct clinical applications in glucocorticoid therapy, stress dosing, and steroid withdrawal management. These principles guide the safe use of glucocorticoids and prevention of adrenal crisis.

Glucocorticoid therapy is among the most commonly used treatments in medicine, with drugs varying in potency and duration. Glucocorticoid equivalencies are expressed relative to hydrocortisone (cortisol). Hydrocortisone has a relative glucocorticoid potency of 1 and a short duration of action. Prednisone and prednisolone have a relative potency of 4 with intermediate duration. Methylprednisolone has a potency of 5. Dexamethasone has a potency of 25-30 with long duration. Fludrocortisone is used purely for mineralocorticoid replacement (in adrenal insufficiency and orthostatic hypotension) and has minimal glucocorticoid effect.

Stress dosing is required in patients with adrenal insufficiency (primary or secondary) or those taking chronic glucocorticoids who cannot mount an appropriate cortisol response to stress. The dosing reflects the normal physiologic increase in cortisol production during illness or surgery. For minor febrile illness, doubling the usual oral glucocorticoid dose is typically sufficient. For moderate stress (such as minor outpatient surgery), hydrocortisone 50 mg every 8 hours is appropriate. For major surgery or critical illness, hydrocortisone 100 mg IV bolus followed by 50 mg IV every 6-8 hours provides full stress coverage. As the stress resolves, glucocorticoids should be rapidly tapered back to baseline replacement.

Steroid withdrawal requires careful management because chronic glucocorticoid therapy suppresses the HPA axis. Suppression typically occurs after more than 3 weeks of therapy at supraphysiologic doses (more than 7.5 mg prednisone equivalent daily). The degree of suppression varies by dose, duration, and individual factors. Gradual tapering allows the HPA axis time to recover; typical protocols reduce the dose by 10-20% every 1-2 weeks. Before or during tapering, ACTH stimulation testing can assess whether adrenal reserve has recovered. Patients should be warned about symptoms of adrenal insufficiency during withdrawal.

<image>Panel A: Glucocorticoid equivalency table showing hydrocortisone (potency 1), prednisone (potency 4), methylprednisolone (potency 5), and dexamethasone (potency 25-30) with half-life and duration of action information for each. Panel B: Stress dosing protocol displayed as a stepped diagram based on stress severity with minor illness (double oral dose), moderate stress (hydrocortisone 50 mg every 8 hours), and major stress or surgery (100 mg bolus then 50 mg every 6-8 hours). Panel C: Steroid withdrawal timeline showing HPA suppression risk after greater than 3 weeks of supraphysiologic dosing, gradual taper protocol reducing 10-20% every 1-2 weeks, and ACTH stimulation testing to assess adrenal recovery. Panel D: Patient education summary showing warning signs requiring stress dosing (fever, surgery, trauma) and key instructions for safe glucocorticoid management including recognition of insufficiency symptoms.</image>

Summary

The adrenal cortex comprises three zones with distinct functions: zona glomerulosa produces aldosterone (regulated by angiotensin II and potassium), zona fasciculata produces cortisol (regulated by ACTH), and zona reticularis produces adrenal androgens (regulated by ACTH). The mnemonic GFR = Salt, Sugar, Sex captures this organization.

Steroidogenesis begins with cholesterol transport via StAR protein (the rate-limiting step), with subsequent enzyme reactions producing zone-specific hormones. Understanding enzyme locations explains why specific enzyme deficiencies cause predictable patterns of hormone excess and deficiency.

Cortisol is regulated by the HPA axis with circadian rhythm and stress responsiveness, exerting diverse metabolic, immune, and cardiovascular effects. The 11β-HSD2 enzyme protects mineralocorticoid receptors from cortisol occupancy.

Aldosterone is regulated primarily by the RAAS, promoting sodium retention, potassium excretion, and volume expansion in the collecting duct.

Adrenal androgens (DHEA, DHEA-S) peak in the third decade and serve as precursors for peripheral sex steroid production, being the principal androgen source in women.

Congenital adrenal hyperplasia, most commonly from 21-hydroxylase deficiency, demonstrates the consequences of impaired cortisol synthesis: ACTH rises, precursors accumulate, and androgen excess causes virilization.

Testing includes ACTH stimulation for insufficiency, dexamethasone suppression for Cushing, and aldosterone-renin ratio for primary aldosteronism.

Key Terms

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