Adrenal Hormone Synthesis & Action Step 1 Practice Exam

A — 21-hydroxylase deficiency (~90% of CAH). Lose 21-hydroxylase and the axis cannot make cortisol OR aldosterone — hence the salt-wasting crisis (hyponatremia, hyperkalemia, hypotension) in the first 2 weeks of life. Precursors upstream of the block accumulate — 17-OH progesterone is pathognomonically elevated — and get shunted into the still-intact androgen pathway, virilizing 46,XX infants. 11β (B) = hypertension + virilization. 17α (C) = hypertension + NO virilization. Desmolase (E) is incompatible with life beyond a few days.

B — 11β-hydroxylase deficiency. Unique combo: hypertension + virilization. Why? 11β-hydroxylase converts 11-deoxycortisol → cortisol AND 11-deoxycorticosterone (DOC) → corticosterone. Lose it and DOC — a weak mineralocorticoid that accumulates to strong levels — drives hypertension and hypokalemia. Cortisol is low → loss of negative feedback → ACTH drives androgen pathway → virilization. Renin is SUPPRESSED (not activated like in a volume-depleted state) because DOC causes volume expansion. Compare/contrast with 21-OH (salt-wasting hypotension + virilization) and 17α (hypertension without virilization).

C — 17α-hydroxylase deficiency. The "odd one out" — hypertension WITHOUT virilization. CYP17 is needed for both cortisol (via 17α-hydroxylation) AND all sex steroids (via 17,20-lyase). Lose it, and: cortisol ↓ (→ ACTH ↑ → drives corticosterone/DOC pathway → HTN and hypokalemia), androgens ↓ (→ phenotypic females regardless of karyotype — 46,XY presents as undervirilized female with absent breast development because estrogen also can't be made), aldosterone synthase is intact but suppressed by volume expansion from DOC. Mnemonic: "17 has NO sex" — no androgens, no estrogens.

A. Cortisol pathway step-by-step: cholesterol → pregnenolone (desmolase / CYP11A1, rate-limiting, mitochondrial) → pregnenolone → progesterone (3β-HSD) → 17-OH progesterone (17α-hydroxylase / CYP17) → 17-OH prog → 11-deoxycortisol (21-hydroxylase / CYP21) → 11-deoxycortisol → cortisol (11β-hydroxylase / CYP11B1, mitochondrial). The 21-hydroxylase deficiency from Question 1 blocks at the third-to-last step, explaining why 17-OHP accumulates. Memorize: "17, 21, 11 — cortisol is done."

B. Canonical ZF signaling: ACTH binds MC2R (the ACTH receptor, a Gs-coupled GPCR specific to the adrenal cortex) → adenylyl cyclase → cAMP → PKA → phosphorylates StAR → increased cholesterol shuttling from outer to inner mitochondrial membrane → more desmolase substrate → acute cortisol burst. Chronically, ACTH ALSO upregulates transcription of every steroidogenic enzyme — but the acute (minutes) response is StAR-mediated. MC1R is on melanocytes; MC3R/MC4R in hypothalamus handle appetite.

B. Free hormone hypothesis applied to cortisol (LO 5). Cortisol-binding globulin (CBG / transcortin) carries ~90% of circulating cortisol. Estrogen upregulates hepatic CBG synthesis, so pregnancy and combined OCP use raise TOTAL cortisol without raising FREE cortisol — the clinically active fraction. Patients are eucortisolemic despite the high total number. Same principle applies to TBG and total T4. Clinical pearl: when screening for Cushing in a woman on OCP/pregnant, use 24-hr urinary free cortisol or salivary cortisol rather than total serum cortisol.

A — 11β-HSD2 inhibition (apparent mineralocorticoid excess). Cortisol and aldosterone bind the mineralocorticoid receptor (MR) with EQUAL affinity. Kidney principal cells protect MR from cortisol (which circulates at ~1,000× higher concentration than aldosterone) by expressing 11β-HSD2, which rapidly inactivates cortisol → cortisone. Glycyrrhetinic acid (the active licorice component) inhibits 11β-HSD2 → cortisol accumulates locally → over-activates MR → aldosterone-like effects (HTN, hypokalemia, alkalosis) — but with SUPPRESSED aldosterone (because the real RAAS sees volume-expanded state). Urinary cortisol:cortisone ratio is the giveaway. Same biochemistry underlies the syndrome of apparent mineralocorticoid excess (AME).

B. LO 6 textbook steroid-hormone mechanism. Aldosterone is lipophilic → crosses the plasma membrane → binds the cytoplasmic mineralocorticoid receptor (MR) held in an HSP90 complex. Hormone-MR complex translocates to nucleus → binds hormone response elements → drives transcription of SGK1, ENaC subunits, and Na⁺/K⁺-ATPase. SGK1 phosphorylates Nedd4-2 → prevents ENaC ubiquitination → more ENaC on apical membrane. Net effect: Na⁺ reabsorption (with K⁺ and H⁺ secretion). Steroid actions are characteristically delayed (~30 min to hours) compared to peptide hormones because they require gene transcription.

B. Cortisol binds the cytoplasmic glucocorticoid receptor (GR) / HSP90 chaperone complex. Hormone binding releases HSP90, dimerized GR translocates into the nucleus and performs TWO distinct genomic actions: (1) Trans-activation at glucocorticoid response elements — induces PEPCK, glucose-6-phosphatase, tyrosine aminotransferase (gluconeogenesis); lipocortin/annexin A1 (anti-inflammatory); and (2) Trans-repression of NF-κB and AP-1 — blocks cytokines, COX-2, adhesion molecules. Chronic over-dosing → all the features listed: diabetogenic, myopathic, osteoporotic, centripetal obesity — all explained by activated GR transcription programs.

B. Combined LO 5 (half-life) + LO 6 (mechanism). Dexamethasone is a synthetic glucocorticoid with: (1) long half-life (~36-54 h; cortisol ~90 min) → single evening dose suppresses the morning ACTH surge; (2) very high GR affinity (~25× cortisol) → tiny dose suffices to exert negative feedback; (3) critically, it does NOT cross-react with standard cortisol immunoassays → the measured 8 AM cortisol is genuine endogenous cortisol. In normals, DEX suppresses ACTH → cortisol falls below 1.8 µg/dL. In Cushing (any cause), autonomous cortisol secretion is not suppressed. High-dose dex (8 mg) later distinguishes pituitary-dependent Cushing disease (suppresses) from ectopic ACTH (does not).

C — Zona fasciculata. LO 3 map: ZF secretes cortisol, which has anti-inflammatory and immunosuppressive effects. ZR secretes androgens (DHEA, androstenedione). ZG secretes aldosterone. Adrenal medulla secretes catecholamines. Remember GFR = "Salt, Sugar, Sex" corresponding to glomerulosa → fasciculata → reticularis.

E — All of the above. DHEA and androstenedione are the major adrenal androgens. In females, the adrenal gland is the ONLY significant source of circulating androgens, so adrenal androgens drive libido, sebaceous gland hypertrophy/acne, and pubic + axillary hair development (adrenarche). Contrast with males, who primarily rely on testicular testosterone. Adrenal androgens also provide substrate for peripheral aromatization to estrogens, especially in adipose tissue — important in postmenopausal women.

B. Classic 21-hydroxylase deficiency: enzyme deficit blocks both the aldosterone path (ZG) and the cortisol path (ZF). Aldosterone ↓ → salt wasting (hyponatremia + hyperkalemia + hypotension). Cortisol ↓ → hypoglycemia, and loss of feedback → ACTH ↑. Excess ACTH produces MSH from POMC → hyperpigmentation. Precursors shunt into androgens → penile enlargement. Stress/hypoglycemia → GH ↑ (counter-regulatory). Insulin ↓ from hypoglycemia. Corticosterone requires 21-OH too so it drops.

D — Anti-17α-hydroxylase (blocking). Block 17α-OH (CYP17) → low cortisol → ACTH ↑ → hyperpigmentation + drive into the intact mineralocorticoid pathway (→ DOC, corticosterone excess → hypernatremia, hypokalemia, HTN). CYP17 also provides 17,20-lyase for sex steroid production; losing it blocks all gonadal/adrenal androgen output → primary amenorrhea and absent sexual development. The key distinguishing pattern from 21-OH is "HTN + LOW androgens" (vs salt-wasting + HIGH androgens in 21-OH).

C — Enzyme deficiency (non-classic CAH). The combination of high ACTH + low cortisol + virilization is a shortcut for adrenal cortical enzyme deficiency. Low cortisol disinhibits ACTH, and ACTH stimulates the intact androgen branch → virilization. A POMC-producing pituitary tumor (A) would produce high ACTH but ALSO high cortisol (Cushing). Adrenal medulla (B) makes catecholamines, not sex steroids. CRH mutation (D) would give LOW ACTH. Insulinoma (E) causes hypoglycemia, not this picture. This is how non-classic CAH (mild 21-OH deficiency) often presents in adult women.

C — Cortisol. ACTH is the PRIMARY regulator of cortisol (and, to a lesser extent, adrenal androgen) release from zona fasciculata. Although ACTH is required for synthesis of ALL adrenal steroids (desmolase is ACTH-sensitive), aldosterone and androgens are primarily controlled by OTHER mechanisms: aldosterone by the renin-angiotensin system and serum K⁺, catecholamines (medulla) by the sympathetic nervous system. A tumor that overproduces ACTH (Cushing disease) predominantly raises cortisol.

C — Angiotensin II. The primary stimuli for aldosterone release from ZG are hyperkalemia (NOT hypokalemia) and angiotensin II. ACTH plays a permissive (not primary) role. ANP INHIBITS aldosterone (opposes Na retention). High plasma Na⁺ would inhibit renin → less AT-II → LESS aldosterone, not more. Mechanism: hyperkalemia depolarizes ZG cells opening voltage-gated Ca²⁺ channels; AT-II binds AT1 GPCR → PLC → IP3/DAG → Ca²⁺ → aldosterone synthase.

B — Both low. Autonomous aldosterone production from a ZG adenoma (Conn syndrome) causes Na retention + volume expansion → high BP sensed by juxtaglomerular apparatus → renin suppression. With renin suppressed, angiotensin II is also low (renin and AT-II almost always move together because renin is the rate-limiting enzyme). The diagnostic criterion is a high aldosterone:renin ratio. Secondary hyperaldosteronism (e.g., renal artery stenosis) would have both renin and AT-II HIGH.

C — Cushing's DISEASE (pituitary). Classic hypercortisolism picture + ACTH that is elevated AND responds to CRH = CRH-responsive pituitary ACTH adenoma = Cushing disease. Distinctions to nail: Cushing SYNDROME = any cause of hypercortisolism; Cushing DISEASE = ACTH-producing pituitary adenoma specifically. Exogenous glucocorticoid therapy (D) would have LOW ACTH (suppressed by feedback). Ectopic ACTH from a lung carcinoid would have HIGH ACTH but would NOT respond appropriately to CRH stimulation. High-dose dexamethasone suppression: pituitary Cushing suppresses, ectopic does not.

B — Inverted circadian rhythm. LO 3/regulation detail: normal cortisol/ACTH peaks at 6-8 AM and nadirs near midnight. This patient shows evening peak > morning peak, the reverse of physiology — typical of night-shift workers or disrupted sleep-wake cycles. All values fall in the reference range, so there is no adrenal insufficiency (D,E). Pulsatility (A) is normal every 30-60 min — not what's abnormal here. Circadian regulation is hypothalamic (SCN) → CRH → ACTH → cortisol.

D — Potassium. Hyperkalemia depolarizes zona glomerulosa cells → opens L-type voltage-gated Ca²⁺ channels → Ca²⁺ influx → triggers vesicle fusion and direct aldosterone release. This is a very tight feedback loop — small rises in serum K⁺ acutely drive aldosterone to enhance K⁺ excretion. Angiotensin II is the other primary stimulus (independent of K⁺). Na⁺, Ca²⁺, Cl⁻, and Mg²⁺ have no direct clinically-relevant effect on ZG cells.

A — Adrenal insufficiency (Addison disease). LO 6 synthesis: this is the FULL flipside of every cortisol + aldosterone action. No cortisol → hypoglycemia + fatigue + hypotension; no aldosterone → salt wasting → hyponatremia + hyperkalemia + salt craving + orthostasis. High ACTH (from loss of feedback) drives POMC → α-MSH → bronze hyperpigmentation. This is PRIMARY adrenal insufficiency (vs SECONDARY = pituitary, which would NOT hyperpigment and would leave aldosterone intact because RAAS, not ACTH, drives aldosterone). Autoimmune adrenalitis is the #1 cause in the developed world.