15.3 Adrenal Disorders & Steroid Pharmacology

15.3 Adrenal Disorders & Steroid Pharmacology

Quick Answer: GFR—glomerulosa aldosterone, fasciculata cortisol, reticularis androgens; medulla catecholamines. Sort Cushing by ACTH and suppressibility; Addison by high ACTH, low cortisol/aldosterone, hyperpigmentation. CAH: 21-OH salt-waste + virilization; 11-OH HTN + virilization; 17-OH HTN + hypogonadism. Chronic steroids suppress HPA—taper.

Adrenal questions integrate steroid synthesis pathways, volume/potassium physiology, and pharmacology. Draw the cortex zones once, then use ACTH, renin, and androgen signals as compass headings for every vignette.

Adrenal Anatomy and Products

The adrenal cortex is mesodermal; the medulla is neural crest (chromaffin cells).

Cholesterol → pregnenolone (rate-limiting side-chain cleavage, ACTH-stimulated StAR activity conceptually) feeds all cortical steroids. Enzymatic "traffic" down mineralocorticoid, glucocorticoid, or androgen pathways is the foundation of congenital adrenal hyperplasia (CAH) patterns.

Cushing Syndrome: Causes and Dexamethasone Logic

Cushing syndrome = clinical hypercortisolism from any cause. Cushing disease = pituitary ACTH-secreting adenoma specifically.

Major causes:

1. Exogenous glucocorticoids (most common overall clinically)—suppressed ACTH and adrenal atrophy of fasciculata/reticularis.
2. Cushing disease (pituitary ACTH adenoma) — high ACTH, bilateral adrenal hyperplasia; often partial suppression with high-dose dexamethasone; CRH stimulation may raise ACTH/cortisol.
3. Ectopic ACTH (e.g., small cell lung cancer) — very high ACTH, marked hypercortisolism/hyperpigmentation possible, usually not suppressed by high-dose dexamethasone; mineralocorticoid-like effects can be severe (hypokalemia).
4. Adrenal adenoma/carcinoma secreting cortisol — suppressed ACTH, contralateral adrenal atrophy; no dexamethasone suppression of cortisol.

Screening concepts: late-night salivary cortisol, 24-h urinary free cortisol, low-dose overnight dexamethasone suppression. Interpretation on CBSE is qualitative: failure to suppress suggests endogenous Cushing; then ACTH level splits ACTH-dependent vs independent; imaging follows the biochemistry (pituitary vs chest/abdomen).

Clinical features: central obesity, moon facies, buffalo hump, purple striae, easy bruising, proximal myopathy, hyperglycemia/insulin resistance, hypertension, osteoporosis, immunosuppression, psychiatric changes, menstrual irregularities.

Primary Adrenal Insufficiency and Crisis

Addison disease (primary adrenal insufficiency): destruction of the entire cortex (autoimmune most common in developed settings; TB historically/global; metastasis, infection, hemorrhage). Loss of cortisol and aldosterone (androgens). High ACTH and POMC peptides → hyperpigmentation (buccal, palmar creases). Labs: hyponatremia, hyperkalemia, mild metabolic acidosis, prerenal azotemia, eosinophilia sometimes, low morning cortisol with high ACTH, low aldosterone, high renin.

Secondary adrenal insufficiency (pituitary ACTH loss or chronic exogenous steroids): low cortisol but aldosterone relatively preserved (Ang II/K+ still drive glomerulosa) → less hyperkalemia; no hyperpigmentation (ACTH low).

Waterhouse–Friderichsen syndrome: acute bilateral adrenal hemorrhage, classically with meningococcemia (Neisseria meningitidis) and purpura fulminans → acute adrenal failure, septic shock. Recognize the association even when full management detail is not asked.

Adrenal crisis: refractory hypotension, abdominal pain, fever—needs glucocorticoids and volume, with mineralocorticoid replacement in primary disease chronically (fludrocortisone).

Congenital Adrenal Hyperplasia (Enzyme Blocks)

CAH is autosomal recessive impaired cortisol synthesis → loss of negative feedback → high ACTH → adrenal hyperplasia and shunting into pathways proximal to the block.

Memory hooks:

• Only 21-OH among these three causes salt wasting (true aldosterone deficiency without DOC backup).
• 11-OH and 17-OH cause hypertension via DOC.
• 21-OH and 11-OH increase androgens (virilization).
• 17-OH decreases sex steroids (opposite sexual phenotype problem).

Newborn screening uses elevated 17-hydroxyprogesterone for 21-OH deficiency. Treatment concepts: replace glucocorticoids (and mineralocorticoids if salt-wasting) to suppress ACTH drive and provide missing hormones.

Pheochromocytoma and Primary Hyperaldosteronism

Pheochromocytoma: catecholamine-secreting chromaffin tumor (rule of 10s historically: 10% extra-adrenal, bilateral, malignant, children, familial—numbers approximate). Episodic headache, palpitations, diaphoresis, paroxysmal hypertension. Associations: MEN2A/2B, VHL, NF1, succinate dehydrogenase mutations. Diagnose with plasma/urine metanephrines conceptually; α-blockade before β-blockade preoperatively is the classic pharmacologic order (avoid unopposed α-constriction).

Primary hyperaldosteronism (Conn syndrome and bilateral hyperplasia): autonomous aldosterone → HTN, hypokalemia, metabolic alkalosis, suppressed renin. Distinguish from secondary hyperaldosteronism (renovascular disease, edematous states) where renin is high. Spironolactone/eplerenone antagonize the mineralocorticoid receptor.

Glucocorticoid vs Mineralocorticoid Effects and HPA Suppression

Glucocorticoid receptor effects (cortisol, synthetic GCs):

• ↑ hepatic gluconeogenesis and glycogen storage; anti-insulin peripheral effects → hyperglycemia
• Protein catabolism (skin thinning, myopathy)
• Lipolysis/redistribution
• Anti-inflammatory/immunosuppressive (↓ NF-κB, leukocyte trafficking)
• Osteoporosis (↓ formation, ↑ resorption, ↓ Ca absorption)
• Mood changes, insomnia; peptic ulcer risk with NSAIDs; avascular necrosis association with high-dose use

Mineralocorticoid receptor effects (aldosterone, fludrocortisone; cortisol can activate MR if not inactivated by 11β-HSD2 in kidney):

• Principal-cell ENaC and Na/K-ATPase upregulation → Na+ retention, K+ and H+ wasting

Relative receptor profiles (conceptual): dexamethasone is potent glucocorticoid with negligible mineralocorticoid activity (used in suppression tests). Fludrocortisone is potent mineralocorticoid. Cortisol and prednisone have mixed activity; 11β-HSD2 converts cortisol → cortisone in the kidney to protect the MR—licorice inhibits 11β-HSD2 → apparent mineralocorticoid excess.

Steroid Taper and HPA Axis Suppression

Chronic exogenous glucocorticoids suppress CRH and ACTH → fasciculata/reticularis atrophy. Stopping abruptly risks secondary adrenal insufficiency (cortisol deficiency under stress) even though mineralocorticoid function is largely intact. Exams emphasize: do not stop chronic steroids suddenly; taper; stress-dose coverage for illness/surgery in suppressed patients. Recovery of the HPA axis can take weeks to months.

Clinical Integration

Moon facies after long prednisone is exogenous Cushing with low ACTH. Purple striae plus high ACTH and a lung mass suggest ectopic ACTH. Hyponatremia, hyperkalemia, and bronze skin suggest Addison. A virilized infant girl with salt wasting is 21-OH CAH until proven otherwise; a virilized hypertensive child suggests 11-OH; a hypertensive phenotypic female lacking secondary sex characteristics may be 17-OH. Spells of headache, palpitations, and diaphoresis with MEN2 family history point to pheo. Resistant hypertension with spontaneous hypokalemia and low renin points to primary aldosteronism.

Zone → product → secretagogue → feedback → enzyme shunt is the complete adrenal algorithm for CBSE success.