1. [CASE 1 — QUESTION 1]
A 38-year-old woman presents with months of fatigue, weight loss, salt craving, and increasing skin pigmentation, now acutely worse with nausea and dizziness on standing. Vitals show a 30 mmHg systolic postural drop. Laboratory studies reveal sodium 128 mmol/L, potassium 5.7 mmol/L, a low morning cortisol, and a markedly elevated plasma ACTH (adrenocorticotropic hormone). Which diagnosis do these findings most strongly support?
A) Secondary adrenal insufficiency from pituitary failure
B) Tertiary adrenal insufficiency from hypothalamic disease
C) Primary adrenal insufficiency, because elevated ACTH together with hyperkalemia, hyponatremia, postural hypotension, and hyperpigmentation indicates combined glucocorticoid and mineralocorticoid deficiency from adrenal cortical destruction
D) Cushing syndrome from an adrenal adenoma
ANSWER: C
Rationale:
Option C is correct. The combination of low cortisol with markedly elevated ACTH (adrenocorticotropic hormone), plus mineralocorticoid-deficiency features (hyperkalemia, hyponatremia, postural hypotension) and hyperpigmentation, identifies primary adrenal insufficiency from destruction of the adrenal cortex. Loss of cortisol feedback drives ACTH up, and the co-secreted melanocyte-stimulating activity explains the pigmentation.
Option A: Option A is incorrect because secondary adrenal insufficiency produces low or inappropriately normal ACTH and spares the zona glomerulosa, so hyperkalemia and hyperpigmentation would be absent.
Option B: Option B is incorrect because tertiary insufficiency likewise gives low ACTH and preserved aldosterone, inconsistent with the elevated ACTH and hyperkalemia here.
Option D: Option D is incorrect because Cushing syndrome reflects cortisol excess, not the low cortisol with high ACTH and salt-wasting seen in this patient.
2. [CASE 1 — QUESTION 2]
Continuing with the same patient. She becomes profoundly hypotensive and drowsy, unresponsive to an initial intravenous fluid bolus, in the setting of a likely intercurrent infection. Which is the immediate priority?
A) Give intravenous hydrocortisone 100 mg as a bolus together with aggressive intravenous normal saline, without delaying treatment to await cortisol and ACTH results
B) Withhold steroids until a confirmatory short cosyntropin stimulation test is completed
C) Administer oral hydrocortisone and observe over the next several hours
D) Begin fludrocortisone alone to correct the sodium and potassium
ANSWER: A
Rationale:
Option A is correct. This is adrenal crisis. Immediate intravenous hydrocortisone 100 mg as a bolus plus aggressive intravenous normal saline corrects the glucocorticoid deficiency and the sodium and volume deficit. Samples for cortisol and ACTH (adrenocorticotropic hormone) may be drawn before the bolus when feasible, but treatment must never be delayed for results.
Option B: Option B is incorrect because delaying glucocorticoid for confirmatory testing can be fatal in crisis; treatment precedes definitive diagnosis.
Option C: Option C is incorrect because a hypotensive, drowsy patient cannot rely on oral absorption, and observation is unsafe.
Option D: Option D is incorrect because fludrocortisone is oral and slow and does not provide the glucocorticoid stress coverage or volume resuscitation needed; stress-dose hydrocortisone also supplies sufficient acute mineralocorticoid effect.
3. [CASE 1 — QUESTION 3]
Continuing with the same patient. She stabilizes and is transitioned to oral maintenance therapy with hydrocortisone in divided doses. Given her diagnosis, which additional agent is required for complete replacement?
A) An additional glucocorticoid such as prednisolone layered on top of hydrocortisone
B) A mineralocorticoid receptor antagonist to prevent hypertension
C) No additional agent, because hydrocortisone alone fully replaces adrenal output
D) Fludrocortisone, because primary adrenal insufficiency destroys the zona glomerulosa and requires mineralocorticoid replacement in addition to glucocorticoid
ANSWER: D
Rationale:
Option D is correct. Primary adrenal insufficiency destroys all cortical zones, so aldosterone production is lost and fludrocortisone must be added to hydrocortisone. Mineralocorticoid replacement corrects the sodium wasting, hyperkalemia, and postural hypotension that glucocorticoid replacement alone does not fully address.
Option A: Option A is incorrect because adding a second glucocorticoid does not supply mineralocorticoid activity and risks glucocorticoid excess.
Option B: Option B is incorrect because an MR antagonist would worsen the salt wasting and hyperkalemia of primary adrenal insufficiency.
Option C: Option C is incorrect because hydrocortisone alone does not provide adequate mineralocorticoid replacement in primary adrenal insufficiency; fludrocortisone is required.
4. [CASE 1 — QUESTION 4]
Continuing with the same patient. At follow-up the team must adjust her fludrocortisone dose. Which set of parameters best guides mineralocorticoid dose titration?
A) Serum cortisol and plasma ACTH levels
B) Plasma renin activity targeted to the mid-normal range, along with serum sodium and potassium, blood pressure, and absence of postural drop or edema
C) Urinary free cortisol and late-night salivary cortisol
D) Hemoglobin A1c and fasting glucose
ANSWER: B
Rationale:
Option B is correct. Fludrocortisone is titrated to a mid-normal plasma renin activity with normal sodium and potassium, normal blood pressure, and no postural drop or edema. Under-replacement raises renin with hyperkalemia and postural hypotension; over-replacement suppresses renin with hypertension, edema, and hypokalemia.
Option A: Option A is incorrect because cortisol and ACTH (adrenocorticotropic hormone) guide glucocorticoid considerations, not mineralocorticoid dosing.
Option C: Option C is incorrect because urinary free cortisol and late-night salivary cortisol are tests for cortisol excess, irrelevant to fludrocortisone titration.
Option D: Option D is incorrect because glycemic markers do not reflect mineralocorticoid adequacy.
5. [CASE 2 — QUESTION 1]
A 50-year-old man underwent resection of a large nonfunctioning pituitary adenoma two months ago. He reports persistent fatigue and light-headedness. Morning cortisol is low with an inappropriately low plasma ACTH (adrenocorticotropic hormone). Serum sodium and potassium are normal, there is no postural hypotension, and there is no hyperpigmentation. Which condition best fits this picture?
A) Primary adrenal insufficiency from autoimmune adrenalitis
B) Secondary adrenal insufficiency, because low cortisol with inappropriately low ACTH and preserved electrolytes indicates pituitary failure with an intact, renin-responsive zona glomerulosa
C) Apparent mineralocorticoid excess
D) Congenital adrenal hyperplasia presenting in adulthood
ANSWER: B
Rationale:
Option B is correct. Low cortisol with inappropriately low ACTH (adrenocorticotropic hormone) after pituitary surgery, together with normal electrolytes, no postural hypotension, and no hyperpigmentation, indicates secondary adrenal insufficiency. The pituitary fails to drive cortisol, but the zona glomerulosa remains responsive to the renin-angiotensin-aldosterone system, so aldosterone and electrolytes are preserved.
Option A: Option A is incorrect because primary adrenal insufficiency produces elevated ACTH with hyperkalemia, hyponatremia, and hyperpigmentation, none of which are present.
Option C: Option C is incorrect because apparent mineralocorticoid excess causes hypertension and hypokalemia, not cortisol deficiency.
Option D: Option D is incorrect because congenital adrenal hyperplasia involves androgen-precursor excess and is not characterized by post-surgical low ACTH with isolated cortisol deficiency.
6. [CASE 2 — QUESTION 2]
Continuing with the same patient. The team plans hormone replacement. Which regimen is appropriate for his form of adrenal insufficiency?
A) Hydrocortisone plus fludrocortisone, as in primary adrenal insufficiency
B) Fludrocortisone alone
C) Hydrocortisone alone, because the zona glomerulosa remains responsive to the renin-angiotensin-aldosterone system, so mineralocorticoid replacement is unnecessary
D) No replacement, because the low ACTH reflects normal suppression
ANSWER: C
Rationale:
Option C is correct. In secondary adrenal insufficiency, only glucocorticoid replacement is needed. The zona glomerulosa is intact and continues to produce aldosterone under renin-angiotensin-aldosterone system control, so fludrocortisone is not required.
Option A: Option A is incorrect because mineralocorticoid replacement is reserved for primary adrenal insufficiency where the zona glomerulosa is destroyed.
Option B: Option B is incorrect because fludrocortisone does not address the glucocorticoid deficiency causing his symptoms.
Option D: Option D is incorrect because the low cortisol with inappropriately low ACTH (adrenocorticotropic hormone) signals genuine central glucocorticoid deficiency that requires replacement.
7. [CASE 2 — QUESTION 3]
Continuing with the same patient. The team chooses hydrocortisone rather than dexamethasone for maintenance. Which property most justifies this choice?
A) Hydrocortisone is identical to endogenous cortisol with a short half-life, so divided dosing approximates the physiological diurnal rhythm and avoids the prolonged axis suppression of long-acting agents
B) Hydrocortisone has greater mineralocorticoid potency, eliminating any need for fludrocortisone in this patient
C) Hydrocortisone has a longer half-life, permitting once-weekly dosing
Option A is correct. Hydrocortisone is chemically identical to cortisol and has a short half-life of about 1.5 hours, so divided daily dosing can mimic the natural diurnal cortisol curve while avoiding the prolonged hypothalamic-pituitary-adrenal suppression associated with long-acting dexamethasone.
Option B: Option B is incorrect because the choice is based on physiological mimicry and short duration, not on mineralocorticoid potency; in secondary insufficiency no mineralocorticoid is needed regardless.
Option C: Option C is incorrect because hydrocortisone's short half-life precludes infrequent dosing; it requires divided daily administration.
Option D: Option D is incorrect because hydrocortisone is a full glucocorticoid-receptor agonist, which is what provides effective replacement.
8. [CASE 2 — QUESTION 4]
Continuing with the same patient. He is counseled on managing his glucocorticoid during illness. Which instruction is correct?
A) Stop hydrocortisone during fever to avoid masking infection
B) Halve the hydrocortisone dose during illness to limit immune suppression
C) Keep the dose unchanged, since stress does not affect glucocorticoid requirement
D) Double or triple the daily hydrocortisone dose for febrile illness, and use intramuscular or intravenous hydrocortisone 100 mg if vomiting or unable to take oral medication
ANSWER: D
Rationale:
Option D is correct. Physiological stress raises glucocorticoid requirement, so sick-day rules call for doubling or tripling the daily hydrocortisone dose during febrile illness and using parenteral hydrocortisone 100 mg if oral intake is not possible, preventing progression to adrenal crisis.
Option A: Option A is incorrect and dangerous because stopping glucocorticoid during illness precipitates crisis.
Option B: Option B is incorrect because the requirement increases during illness; halving the dose risks crisis.
Option C: Option C is incorrect because intercurrent illness clearly increases glucocorticoid need, so the dose must be raised.
9. [CASE 3 — QUESTION 1]
A 61-year-old man with heart failure with reduced ejection fraction has taken spironolactone for several months as part of guideline-directed therapy. He now reports tender bilateral breast enlargement and reduced libido. Which mechanism best explains these new symptoms?
A) Spironolactone antagonizes the androgen receptor, producing gynecomastia and sexual side effects in addition to its mineralocorticoid receptor blockade
B) Spironolactone directly activates the estrogen receptor in breast tissue
C) Spironolactone inhibits aromatase, raising testosterone and enlarging breast tissue
D) Spironolactone stimulates prolactin secretion through dopamine antagonism
ANSWER: A
Rationale:
Option A is correct. Spironolactone is a steroidal mineralocorticoid receptor antagonist that also antagonizes the androgen receptor and has weak progestogenic activity. The androgen-receptor antagonism causes gynecomastia, decreased libido, and erectile dysfunction, particularly at higher doses.
Option B: Option B is incorrect because spironolactone does not directly activate the estrogen receptor; the feminizing effects come from androgen-receptor blockade and weak progestogenic activity.
Option C: Option C is incorrect because spironolactone does not inhibit aromatase; that mechanism is unrelated to its endocrine side effects.
Option D: Option D is incorrect because spironolactone's sexual and breast effects arise from androgen-receptor antagonism, not dopamine-mediated prolactin elevation.
10. [CASE 3 — QUESTION 2]
Continuing with the same patient. The team wants to preserve mineralocorticoid receptor (MR) blockade without the androgenic side effects. Which switch and tradeoff is correct?
A) Switch to finerenone because it is the steroidal agent most similar to spironolactone
B) Switch to eplerenone, a selective MR antagonist lacking androgen-receptor antagonism, accepting that its lower MR potency generally requires twice-daily dosing and higher cost
C) Switch to fludrocortisone to maintain mineralocorticoid tone without breast effects
D) Increase spironolactone and add testosterone to counter the gynecomastia
ANSWER: B
Rationale:
Option B is correct. Eplerenone is a selective steroidal MR antagonist with negligible androgen-receptor affinity, so it preserves MR blockade without gynecomastia or sexual side effects. The tradeoff is that it is roughly 60-fold less potent at MR than spironolactone, so it is dosed twice daily and costs more.
Option A: Option A is incorrect because finerenone is non-steroidal, not the steroidal agent most like spironolactone, and selecting it on that rationale is wrong.
Option C: Option C is incorrect because fludrocortisone is an MR agonist that would oppose the therapeutic goal and worsen heart failure.
Option D: Option D is incorrect because raising spironolactone worsens androgen-receptor effects, and adding testosterone is inappropriate.
11. [CASE 3 — QUESTION 3]
Continuing with the same patient. He also takes an angiotensin-converting enzyme (ACE) inhibitor, and his estimated glomerular filtration rate (eGFR) is 45 mL per minute per 1.73 m2. Which laboratory value most requires monitoring after starting eplerenone, and why?
A) Serum sodium, because eplerenone causes profound sodium retention
B) Serum calcium, because mineralocorticoid receptor antagonists raise calcium
C) Fasting glucose, because eplerenone suppresses insulin secretion
D) Serum potassium, because reduced eGFR and concurrent renin-angiotensin-aldosterone system (RAAS) blockade compound the potassium-sparing effect of mineralocorticoid receptor antagonism, raising the risk of hyperkalemia
ANSWER: D
Rationale:
Option D is correct. All mineralocorticoid receptor antagonists reduce renal potassium secretion. With reduced eGFR (estimated glomerular filtration rate) and concurrent RAAS (renin-angiotensin-aldosterone system) blockade by an ACE inhibitor, the potassium-retaining effects add together, so serum potassium is the critical monitoring parameter and hyperkalemia the main risk.
Option A: Option A is incorrect because these agents promote natriuresis rather than profound sodium retention.
Option B: Option B is incorrect because mineralocorticoid receptor antagonists do not characteristically raise calcium.
Option C: Option C is incorrect because insulin suppression and hyperglycemia are features of pasireotide, not eplerenone.
12. [CASE 3 — QUESTION 4]
Continuing with the same patient. The team explains that mineralocorticoid receptor (MR) blockade benefits his heart failure beyond its diuretic and blood-pressure effects. Which mechanism accounts for this added benefit?
A) Direct positive inotropic stimulation of cardiac myocytes
B) Blockade of MR confined to the renal collecting duct only
C) Blockade of MR in non-epithelial tissues such as cardiac myocytes and fibroblasts, where MR activation drives fibrosis, inflammation, and adverse remodeling
D) Inhibition of angiotensin-converting enzyme adding to the ACE inhibitor effect
ANSWER: C
Rationale:
Option C is correct. MR is expressed in non-epithelial tissues including cardiac myocytes, fibroblasts, and vascular cells, where its activation promotes fibrosis, inflammation, and oxidative stress. Blocking non-epithelial MR reduces this adverse remodeling, which underlies the mortality benefit of MR antagonists in heart failure beyond diuresis and blood-pressure lowering.
Option A: Option A is incorrect because MR antagonists are not direct inotropes; their benefit is antifibrotic and anti-remodeling.
Option B: Option B is incorrect because limiting the effect to the collecting duct would capture only the diuretic action, not the added cardioprotection.
Option D: Option D is incorrect because MR antagonists do not inhibit angiotensin-converting enzyme; that is a separate drug class.
13. [CASE 4 — QUESTION 1]
A 49-year-old woman with severe Cushing syndrome and marked hypercortisolism is scheduled for surgery, but rapid biochemical control is needed first. Metyrapone is started. Which biochemical change confirms its mechanism of action?
A) A rise in serum cortisol with accumulation of cholesterol
B) A fall in 11-deoxycortisol as cortisol synthesis is restored
C) Accumulation of 11-deoxycortisol, the precursor immediately proximal to the CYP11B1 (11-beta-hydroxylase) step that metyrapone inhibits, while cortisol falls
D) A rise in aldosterone with suppression of renin
ANSWER: C
Rationale:
Option C is correct. Metyrapone inhibits CYP11B1 (11-beta-hydroxylase), the final step converting 11-deoxycortisol to cortisol. The substrate proximal to the block, 11-deoxycortisol, accumulates and serves as a biochemical marker of enzyme inhibition while cortisol falls, often within hours.
Option A: Option A is incorrect because cortisol falls rather than rises, and cholesterol accumulation reflects side-chain cleavage blockade, not metyrapone's action.
Option B: Option B is incorrect because 11-deoxycortisol rises, not falls, since the enzyme converting it to cortisol is blocked.
Option D: Option D is incorrect because metyrapone does not raise aldosterone; precursor shunting raises deoxycorticosterone, a different mineralocorticoid, rather than aldosterone.
14. [CASE 4 — QUESTION 2]
Continuing with the same patient. On high-dose metyrapone her cortisol falls, but she develops worsening hypertension, potassium 3.0 mmol/L, and new acne and hirsutism. Which mechanism accounts for these effects?
A) Metyrapone directly stimulates aldosterone synthase, raising aldosterone
B) Metyrapone blocks the androgen receptor, paradoxically worsening hirsutism
C) Metyrapone inhibits CYP3A4, raising the level of an interacting drug
D) With CYP11B1 blocked and ACTH (adrenocorticotropic hormone) drive persisting, precursors are shunted into deoxycorticosterone (a mineralocorticoid causing hypertension and hypokalemia) and into adrenal androgens (causing acne and hirsutism)
ANSWER: D
Rationale:
Option D is correct. Blocking CYP11B1 while ACTH (adrenocorticotropic hormone) drive continues causes precursors to accumulate and be shunted: into deoxycorticosterone, a mineralocorticoid producing sodium retention, hypertension, and hypokalemia, and into the adrenal androgen pathway, producing acne and hirsutism. A single shunting mechanism explains all the findings even as cortisol falls.
Option A: Option A is incorrect because the mineralocorticoid effect comes from deoxycorticosterone accumulation, not increased aldosterone synthase activity.
Option B: Option B is incorrect because metyrapone does not block the androgen receptor; it increases androgen precursors.
Option C: Option C is incorrect because the effects arise from metyrapone's own precursor shunting, not a CYP3A4 interaction.
15. [CASE 4 — QUESTION 3]
Continuing with the same patient. She deteriorates, is admitted to the ICU, intubated, and can no longer take oral medication, yet still requires rapid, titratable cortisol control. Which agent is best suited?
A) Etomidate by continuous intravenous infusion at sub-anesthetic doses, which inhibits CYP11B1 and is the only parenteral agent providing rapid, titratable cortisol control
B) Oral ketoconazole titrated to liver function
C) Subcutaneous pasireotide twice daily
D) Oral mifepristone once daily
ANSWER: A
Rationale:
Option A is correct. Etomidate, an imidazole anesthetic, inhibits CYP11B1 at sub-anesthetic intravenous infusion doses and is the only parenteral agent for acute hypercortisolism, allowing precise titration in an intubated patient who cannot take oral drugs, with monitoring for sedation and emerging adrenal insufficiency.
Option B: Option B is incorrect because ketoconazole is oral and unsuitable for a patient who cannot take oral medication.
Option C: Option C is incorrect because pasireotide targets pituitary corticotrophs and is not a titratable parenteral agent for acute crisis control.
Option D: Option D is incorrect because mifepristone is oral, blocks the receptor rather than lowering cortisol, and offers no rapid titratable biochemical control.
16. [CASE 4 — QUESTION 4]
Continuing with the same patient. As etomidate lowers her cortisol toward normal, the team must anticipate the predictable consequence of effective steroidogenesis blockade. Which complication should be expected and managed?
A) Hyperkalemia from mineralocorticoid receptor antagonism
B) Adrenal insufficiency from successful cortisol suppression, which should be anticipated and managed with glucocorticoid (hydrocortisone) supplementation when cortisol falls below the target
C) Hyperglycemia from islet somatostatin-receptor activation
D) Gynecomastia from androgen-receptor antagonism
ANSWER: B
Rationale:
Option B is correct. Any effective steroidogenesis inhibitor, including etomidate, can drive cortisol too low and precipitate iatrogenic adrenal insufficiency. This is the expected complication of successful treatment and is managed by anticipating it and supplementing with hydrocortisone when cortisol falls below target, sometimes using a block-and-replace strategy.
Option A: Option A is incorrect because etomidate inhibits cortisol synthesis and does not block the mineralocorticoid receptor, so hyperkalemia from MR antagonism is not the expected issue.
Option C: Option C is incorrect because hyperglycemia from islet somatostatin-receptor activation is a pasireotide effect.
Option D: Option D is incorrect because gynecomastia from androgen-receptor antagonism is a spironolactone effect, not a consequence of etomidate.
17. [CASE 5 — QUESTION 1]
A 57-year-old woman with endogenous Cushing syndrome and poorly controlled type 2 diabetes is not a surgical candidate. Mifepristone is started for her hyperglycemia. Which statement correctly describes its mechanism and an expected biochemical change?
A) It inhibits CYP11B1, lowering cortisol synthesis
B) It is a competitive antagonist at the glucocorticoid receptor (GR), so it blocks cortisol action peripherally while removing feedback, causing plasma cortisol and ACTH (adrenocorticotropic hormone) to rise
C) It is an adrenocorticolytic agent that destroys adrenal tissue
D) It is a somatostatin analog that suppresses ACTH from corticotrophs
ANSWER: B
Rationale:
Option B is correct. Mifepristone is a competitive glucocorticoid-receptor (GR) antagonist; it blocks cortisol action at target tissues rather than reducing synthesis. Because GR also mediates negative feedback, blocking it raises ACTH (adrenocorticotropic hormone) and plasma cortisol.
Option A: Option A is incorrect because mifepristone is not a steroidogenesis inhibitor; cortisol rises rather than falls.
Option C: Option C is incorrect because adrenocorticolytic destruction describes mitotane.
Option D: Option D is incorrect because a somatostatin analog suppressing corticotroph ACTH describes pasireotide.
18. [CASE 5 — QUESTION 2]
Continuing with the same patient. Her urinary free cortisol (UFC) rises after starting mifepristone. How should the team monitor her response to therapy?
A) Use clinical and glycemic endpoints, because mifepristone removes glucocorticoid-receptor feedback so cortisol and UFC rise and cannot track efficacy
B) Titrate the dose to normalize UFC
C) Use late-night salivary cortisol as the primary efficacy marker
D) Stop the drug because rising UFC proves treatment failure
ANSWER: A
Rationale:
Option A is correct. Because mifepristone blocks the glucocorticoid receptor and removes feedback, ACTH (adrenocorticotropic hormone), plasma cortisol, and UFC (urinary free cortisol) all rise; cortisol-based measures therefore cannot gauge response. Clinical and glycemic parameters are the operative endpoints.
Option B: Option B is incorrect because UFC cannot guide dosing on mifepristone, so titrating to normalize it is inappropriate.
Option C: Option C is incorrect because late-night salivary cortisol, another cortisol-based measure, is similarly confounded by the drug-induced cortisol rise.
Option D: Option D is incorrect because a rising UFC is expected with GR blockade and does not indicate failure.
19. [CASE 5 — QUESTION 3]
Continuing with the same patient. She develops potassium 3.0 mmol/L on mifepristone. Which explanation and management is correct?
A) The hypokalemia reflects mineralocorticoid deficiency; add fludrocortisone
B) The hypokalemia is unrelated to mifepristone and requires no action
C) The hypokalemia is due to renal potassium wasting from CYP3A4 induction; reduce the dose
D) Because the glucocorticoid receptor is blocked, the elevated cortisol activates unopposed mineralocorticoid receptors, causing hypokalemia, which is managed with potassium repletion and, if needed, a mineralocorticoid receptor antagonist such as spironolactone or eplerenone
ANSWER: D
Rationale:
Option D is correct. With the glucocorticoid receptor blocked and cortisol elevated, cortisol acts at unopposed mineralocorticoid receptors, producing hypokalemia. Management is potassium repletion and, when needed, a mineralocorticoid receptor antagonist to counter the cortisol-driven mineralocorticoid effect.
Option A: Option A is incorrect because the problem is mineralocorticoid excess from cortisol acting at MR, not deficiency; fludrocortisone would worsen it.
Option B: Option B is incorrect because the hypokalemia is a recognized mifepristone effect that requires management.
Option C: Option C is incorrect because the mechanism is cortisol acting at MR, not CYP3A4-mediated potassium wasting.
20. [CASE 5 — QUESTION 4]
Continuing with the same patient. Her Cushing syndrome is found to be pituitary in origin (Cushing disease), and pasireotide is considered. Which statement about pasireotide is correct?
A) It lowers cortisol by antagonizing the glucocorticoid receptor, like mifepristone
B) It is an adrenocorticolytic agent reserved for adrenocortical carcinoma
C) It activates somatostatin receptor subtype 5 on corticotroph adenoma cells to reduce ACTH (adrenocorticotropic hormone), but commonly causes hyperglycemia because islet somatostatin-receptor activation suppresses insulin and incretin secretion
D) It is a mineralocorticoid receptor antagonist whose main risk is hyperkalemia
ANSWER: C
Rationale:
Option C is correct. Pasireotide is a somatostatin analog that activates somatostatin receptor subtype 5 on corticotroph adenoma cells to lower ACTH (adrenocorticotropic hormone) and cortisol in Cushing disease. Its hallmark adverse effect is hyperglycemia, because the same somatostatin-receptor activation on pancreatic islets suppresses insulin and incretin secretion.
Option A: Option A is incorrect because glucocorticoid-receptor antagonism describes mifepristone, not pasireotide.
Option B: Option B is incorrect because adrenocorticolytic therapy for adrenocortical carcinoma describes mitotane.
Option D: Option D is incorrect because pasireotide is not a mineralocorticoid receptor antagonist; hyperkalemia is the signature of that class.
21. [CASE 6 — QUESTION 1]
A 54-year-old man is diagnosed with adrenocortical carcinoma producing autonomous cortisol. Mitotane is initiated as the primary pharmacological agent. Which description of mitotane is correct?
A) It is an adrenocorticolytic agent that produces selective cytotoxic destruction of adrenocortical cells, used primarily for adrenocortical carcinoma
B) It is a selective CYP11B1 inhibitor approved for Cushing disease
C) It is a glucocorticoid receptor antagonist used for hyperglycemia in Cushing syndrome
D) It is a non-steroidal mineralocorticoid receptor antagonist used in diabetic kidney disease
ANSWER: A
Rationale:
Option A is correct. Mitotane, a derivative related to the insecticide DDT, produces selective cytotoxic destruction of adrenocortical cells (adrenocorticolytic effect) and also inhibits steroidogenic enzymes, providing combined antitumor and cortisol-lowering effects. It is the primary pharmacological agent for adrenocortical carcinoma.
Option B: Option B is incorrect because the selective CYP11B1 inhibitor for Cushing disease is osilodrostat.
Option C: Option C is incorrect because glucocorticoid-receptor antagonism for hyperglycemia describes mifepristone.
Option D: Option D is incorrect because the non-steroidal mineralocorticoid receptor antagonist for diabetic kidney disease is finerenone.
22. [CASE 6 — QUESTION 2]
Continuing with the same patient. He requires glucocorticoid replacement at two to three times the usual physiological dose. Which mechanism explains this elevated requirement?
A) Mitotane antagonizes the glucocorticoid receptor, so higher doses are needed to overcome blockade
B) Mitotane blocks intestinal absorption of glucocorticoids
C) Mitotane raises corticosteroid-binding globulin (lowering the free cortisol fraction) and induces CYP3A4 (accelerating glucocorticoid metabolism), both of which increase the dose needed for adequate free-hormone exposure
D) Mitotane stimulates renal excretion of glucocorticoids
ANSWER: C
Rationale:
Option C is correct. Mitotane increases corticosteroid-binding globulin, which lowers the free cortisol fraction, and induces CYP3A4 (cytochrome P450 3A4), which accelerates glucocorticoid metabolism. Both effects raise the replacement dose required to achieve adequate free-hormone exposure, typically two to three times the usual dose.
Option A: Option A is incorrect because mitotane does not antagonize the glucocorticoid receptor; the high requirement reflects increased binding protein and accelerated metabolism.
Option B: Option B is incorrect because mitotane does not block intestinal absorption of glucocorticoids.
Option D: Option D is incorrect because the dominant mechanisms are increased binding globulin and enzyme induction, not stimulated renal excretion.
23. [CASE 6 — QUESTION 3]
Continuing with the same patient. A separately prescribed medication that is metabolized by CYP3A4 (cytochrome P450 3A4) has become subtherapeutic since mitotane was started. Which mechanism explains this?
A) Mitotane inhibits CYP3A4, raising the other drug's level
B) Mitotane induces CYP3A4, accelerating metabolism of the co-administered substrate and lowering its plasma concentration
C) Mitotane displaces the drug from plasma proteins, increasing its clearance independently of metabolism
D) Mitotane blocks renal reabsorption of the other drug
ANSWER: B
Rationale:
Option B is correct. Mitotane is a CYP3A4 (cytochrome P450 3A4) inducer. Increasing the enzyme's activity accelerates the metabolism of co-administered CYP3A4 substrates, lowering their plasma concentrations and driving them subtherapeutic, which is the same induction effect that raises the patient's glucocorticoid requirement.
Option A: Option A is incorrect because mitotane induces, not inhibits, CYP3A4; inhibition would raise the substrate's level.
Option C: Option C is incorrect because the dominant effect is enzyme induction, not protein-binding displacement.
Option D: Option D is incorrect because the mechanism is hepatic enzyme induction, not altered renal reabsorption.
24. [CASE 6 — QUESTION 4]
Continuing with the same patient. Therapeutic drug monitoring of plasma mitotane is performed. Which statement about mitotane levels and toxicity is correct?
A) Levels are irrelevant because mitotane has no concentration-dependent toxicity
B) Higher levels are always better, so the dose should be maximized regardless of symptoms
C) Toxicity is purely hepatic, mirroring ketoconazole, with no neurological component
D) Mitotane has a therapeutic window: concentrations that are too low reduce antitumor efficacy, while excessive concentrations cause neurological toxicity such as cerebellar ataxia, confusion, and peripheral neuropathy, so levels are monitored to stay within range
ANSWER: D
Rationale:
Option D is correct. Mitotane has a defined therapeutic window. Plasma concentrations below the target are associated with reduced antitumor efficacy, while concentrations above the upper target produce neurological toxicity, including cerebellar ataxia, confusion, and peripheral neuropathy. Therapeutic drug monitoring keeps levels within the effective, tolerable range.
Option A: Option A is incorrect because mitotane toxicity is clearly concentration-dependent, which is why monitoring is done.
Option B: Option B is incorrect because excessive levels cause neurological toxicity, so maximizing the dose is harmful.
Option C: Option C is incorrect because mitotane's dose-limiting toxicity at high levels is prominently neurological, not purely hepatic.
25. [CASE 7 — QUESTION 1]
A neonate is diagnosed with salt-wasting congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21A2) deficiency after presenting with hyponatremia, hyperkalemia, and ambiguous genitalia. Which mechanism explains the androgen excess in this disorder?
A) The enzyme defect directly stimulates gonadal androgen production
B) Loss of cortisol feedback suppresses ACTH, lowering all adrenal steroids
C) The defect activates aromatase, converting cortisol to androgens
D) Impaired cortisol and aldosterone synthesis reduces negative feedback, driving ACTH (adrenocorticotropic hormone) hypersecretion that causes accumulation of precursors proximal to the block, which are shunted into the intact adrenal androgen pathway
ANSWER: D
Rationale:
Option D is correct. In 21-hydroxylase (CYP21A2) deficiency, impaired cortisol and aldosterone synthesis reduces negative feedback, driving ACTH (adrenocorticotropic hormone) hypersecretion and adrenal hyperplasia. Excess ACTH causes accumulation of precursors proximal to the enzymatic block, especially 17-hydroxyprogesterone, which are shunted into the intact androgen-synthesis pathway, producing androgen excess and virilization.
Option A: Option A is incorrect because the androgen excess is adrenal in origin from precursor shunting, not direct gonadal stimulation by the defect.
Option B: Option B inverts the physiology: cortisol deficiency raises ACTH rather than suppressing it, and adrenal androgen output rises.
Option C: Option C is incorrect because aromatase converts androgens to estrogens and is not activated by the defect; cortisol is not an aromatase substrate.
26. [CASE 7 — QUESTION 2]
Continuing with the same patient. Glucocorticoid therapy is started. What is the pharmacological goal of this treatment in CAH?
A) To raise cortisol to supraphysiological levels as the therapeutic target
B) To suppress ACTH (adrenocorticotropic hormone) output using the smallest effective glucocorticoid dose, reducing the drive to overproduce adrenal androgen precursors while preserving growth
C) To stimulate ACTH so that precursor levels normalize
D) To replace mineralocorticoid activity without affecting ACTH
ANSWER: B
Rationale:
Option B is correct. Exogenous glucocorticoid supplies the negative feedback the patient's own cortisol cannot, suppressing pituitary ACTH (adrenocorticotropic hormone) and reducing the drive that overproduces androgen precursors. The aim is the smallest dose that achieves adequate suppression while preserving growth, not full cortisol normalization.
Option A: Option A is incorrect because supraphysiological cortisol impairs growth and causes Cushingoid effects; mild precursor elevation is accepted instead.
Option C: Option C is incorrect because therapy suppresses, rather than stimulates, ACTH; stimulating it would worsen precursor accumulation.
Option D: Option D is incorrect because the glucocorticoid acts specifically by suppressing ACTH; it is not a mineralocorticoid-sparing maneuver.
27. [CASE 7 — QUESTION 3]
Continuing with the same patient, now age 6. Serum 17-hydroxyprogesterone is fully suppressed into the normal range, but growth velocity has fallen below the 25th percentile for height-age. Which adjustment is correct?
A) Increase the glucocorticoid dose to keep 17-hydroxyprogesterone fully normalized
B) Switch to bedtime dexamethasone to improve growth
C) Reduce the glucocorticoid dose, accepting mildly elevated 17-hydroxyprogesterone, because full normalization usually requires growth-impairing glucocorticoid excess and growth velocity must be protected
D) Stop fludrocortisone, which is causing the growth failure
ANSWER: C
Rationale:
Option C is correct. In CAH the dose required to fully normalize 17-hydroxyprogesterone usually entails glucocorticoid excess that impairs linear growth. A declining growth velocity with fully suppressed 17-hydroxyprogesterone signals over-treatment, so the correct action is to reduce the glucocorticoid dose and accept mild precursor elevation to protect growth.
Option A: Option A is incorrect because increasing the dose worsens growth suppression.
Option B: Option B is incorrect because long-acting dexamethasone increases, rather than reduces, the risk of growth impairment in children.
Option D: Option D is incorrect because fludrocortisone, a mineralocorticoid, is not the cause of growth failure; glucocorticoid excess is.
28. [CASE 7 — QUESTION 4]
Continuing with the same patient. Because she has the salt-wasting form, mineralocorticoid management is addressed. Which statement is correct?
A) Fludrocortisone is required, dosed with plasma renin activity, electrolytes, and blood pressure as guides, and sodium chloride supplementation is typically needed in infancy because breast milk and formula provide insufficient sodium to offset renal salt losses
B) Mineralocorticoid replacement is unnecessary because glucocorticoid therapy restores aldosterone
C) Spironolactone is used to control the salt wasting
D) Fludrocortisone requirements steadily increase throughout childhood and never decrease
ANSWER: A
Rationale:
Option A is correct. Salt-wasting CAH requires fludrocortisone, titrated with plasma renin activity, serum electrolytes, and blood pressure. In infancy, sodium chloride supplementation is typically necessary because breast milk and formula do not provide enough sodium to offset renal salt losses despite fludrocortisone.
Option B: Option B is incorrect because glucocorticoid therapy does not restore aldosterone; mineralocorticoid replacement is required in the salt-wasting form.
Option C: Option C is incorrect because spironolactone is a mineralocorticoid receptor antagonist that would worsen salt wasting; a mineralocorticoid agonist is needed.
Option D: Option D is incorrect because fludrocortisone requirements often decrease with age rather than steadily increasing, so the dose must be reassessed over time.
This Web-based pharmacology and disease-based integrated teaching site is based on reference materials that are believed reliable and consistent with standards accepted at the time of development.
Possibility of error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete.
Users should confirm the information contained herein with other sources.
This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site.
Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals.
Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.
Medical or other information thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.