1. A 58-year-old man with heart failure with reduced ejection fraction has been taking spironolactone for nine months. He now reports painful bilateral breast enlargement and reduced libido, and his serum potassium is 5.1 mmol/L. His ejection fraction has improved and the team wants to preserve mineralocorticoid receptor (MR) blockade. Which change is most appropriate?
A) Discontinue all MR blockade permanently, as the gynecomastia indicates an allergic reaction
B) Increase the spironolactone dose to overcome the side effects
C) Add an androgen supplement while continuing spironolactone unchanged
D) Switch to eplerenone, a selective MR antagonist that lacks the androgen-receptor antagonism causing his gynecomastia, and continue monitoring serum potassium
E) Switch to fludrocortisone to maintain mineralocorticoid tone
ANSWER: D
Rationale:
Option D is correct. The gynecomastia and reduced libido reflect spironolactone's off-target androgen-receptor antagonism. Eplerenone is a selective steroidal MR antagonist with negligible androgen-receptor affinity, so it preserves the cardioprotective MR blockade without the endocrine effects. Because all MR antagonists raise potassium, serum potassium must continue to be monitored, especially given his current level of 5.1 mmol/L.
Option A: Option A is incorrect because gynecomastia is a predictable androgen-receptor effect, not an allergic reaction, and abandoning MR blockade would forfeit a mortality benefit in heart failure with reduced ejection fraction.
Option B: Option B is incorrect because spironolactone's anti-androgen effects worsen with higher doses.
Option C: Option C is incorrect because adding androgen does not address the receptor blockade and is inappropriate; switching to a selective agent is the correct solution.
Option E: Option E is incorrect because fludrocortisone is an MR agonist; it would oppose the therapeutic goal and cause sodium retention and worsening heart failure.
2. A 34-year-old woman with Addison disease (primary adrenal insufficiency) on stable hydrocortisone and fludrocortisone presents during a prolonged heat wave with light-headedness on standing, a 25 mmHg systolic postural drop, serum sodium 132 mmol/L, potassium 5.4 mmol/L, and an elevated plasma renin activity. Her glucocorticoid dosing has not changed. Which adjustment is most appropriate?
A) Reduce the fludrocortisone dose, since these findings indicate over-replacement
B) Increase the fludrocortisone dose, since postural hypotension, hyponatremia, hyperkalemia, and elevated renin indicate mineralocorticoid under-replacement worsened by sweat sodium losses
C) Stop fludrocortisone and rely on hydrocortisone alone
D) Increase only the hydrocortisone dose, since the findings reflect glucocorticoid deficiency
E) Make no change, as these values are expected and require no action
ANSWER: B
Rationale:
Option B is correct. Postural hypotension, hyponatremia, hyperkalemia, and an elevated plasma renin activity together indicate mineralocorticoid under-replacement. Fludrocortisone requirements rise in hot weather because sodium is lost in sweat, so a temporary dose increase, guided by renin and electrolytes toward the mid-normal range, is appropriate.
Option A: Option A is incorrect because over-replacement produces the opposite pattern, hypertension, edema, hypokalemia, and suppressed renin.
Option C: Option C is incorrect because stopping fludrocortisone in primary adrenal insufficiency removes essential mineralocorticoid replacement and would worsen the salt wasting.
Option D: Option D is incorrect because the electrolyte and renin pattern is mineralocorticoid, not glucocorticoid, deficiency; raising hydrocortisone alone does not correct it.
Option E: Option E is incorrect because the abnormal electrolytes, postural drop, and elevated renin specifically signal inadequate mineralocorticoid replacement requiring action.
3. A 47-year-old woman is recovering from resection of a nonfunctioning pituitary macroadenoma. She has fatigue and a low morning cortisol with an inappropriately low plasma ACTH (adrenocorticotropic hormone). Her serum sodium and potassium are normal, blood pressure is normal without postural change, and there is no hyperpigmentation. Which replacement strategy is correct?
A) Hydrocortisone replacement alone, because this is secondary adrenal insufficiency in which the renin-responsive zona glomerulosa preserves aldosterone, so mineralocorticoid replacement is unnecessary
B) Hydrocortisone plus fludrocortisone, because all adrenal insufficiency requires both
C) Fludrocortisone alone, because aldosterone is the deficient hormone
D) High-dose dexamethasone alone, because it provides both glucocorticoid and mineralocorticoid coverage
E) No replacement, because a low ACTH indicates adequate adrenal function
ANSWER: A
Rationale:
Option A is correct. The low cortisol with inappropriately low ACTH (adrenocorticotropic hormone) and the absence of mineralocorticoid-deficiency features (normal sodium and potassium, no postural hypotension, no hyperpigmentation) identify secondary adrenal insufficiency from pituitary failure. The zona glomerulosa remains responsive to the renin-angiotensin-aldosterone system, so aldosterone is preserved and only glucocorticoid replacement with hydrocortisone is required.
Option B: Option B is incorrect because mineralocorticoid replacement is needed only in primary adrenal insufficiency; the zona glomerulosa is intact here.
Option C: Option C is incorrect because aldosterone production is preserved in secondary insufficiency, and fludrocortisone does not address the glucocorticoid deficiency causing her symptoms.
Option D: Option D is incorrect because dexamethasone lacks meaningful mineralocorticoid activity and, with its long half-life, is a poor choice for routine replacement.
Option E: Option E is incorrect because the low cortisol with inappropriately low ACTH confirms central glucocorticoid deficiency that requires replacement.
4. A 41-year-old man with known primary adrenal insufficiency is brought in with fever, repeated vomiting, profound hypotension unresponsive to intravenous fluids, drowsiness, sodium 126 mmol/L, and potassium 6.0 mmol/L during an acute infection. Which action is the immediate priority?
A) Obtain a random cortisol and ACTH and withhold steroids until results return
B) Administer oral hydrocortisone and reassess in several hours
C) Give immediate intravenous hydrocortisone 100 mg as a bolus together with aggressive intravenous normal saline, without delaying treatment for laboratory confirmation
D) Give fludrocortisone alone to correct the sodium and potassium
E) Start a potassium-lowering protocol and defer corticosteroids
ANSWER: C
Rationale:
Option C is correct. This is adrenal crisis. The immediate priority is intravenous hydrocortisone 100 mg as a bolus (followed by ongoing hydrocortisone) plus aggressive intravenous normal saline to correct the volume and sodium deficit. A cortisol and ACTH may be drawn before the bolus when feasible, but treatment must never be delayed for results.
Option A: Option A is incorrect because withholding glucocorticoid to await laboratory confirmation can be fatal in crisis.
Option B: Option B is incorrect because a vomiting, hypotensive, drowsy patient cannot rely on oral absorption, and watchful waiting 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 the crisis demands; stress-dose hydrocortisone also supplies sufficient mineralocorticoid effect acutely.
Option E: Option E is incorrect because the hyperkalemia will respond to glucocorticoid and volume replacement; deferring corticosteroids to treat potassium alone is dangerous.
5. A 52-year-old woman with severe Cushing syndrome is started on high-dose metyrapone to achieve rapid cortisol control before surgery. Over two weeks her cortisol falls, but she develops worsening hypertension, potassium 3.1 mmol/L, and new acne and facial hair. Which mechanism best explains these new findings?
A) Metyrapone is failing to lower cortisol, and these are signs of persistent hypercortisolism
B) Metyrapone is causing adrenal insufficiency, and the findings are an unrelated rebound
C) Metyrapone is blocking the androgen receptor, paradoxically increasing hair growth
D) Metyrapone is inhibiting CYP3A4 and raising the level of an interacting antihypertensive
E) By inhibiting CYP11B1, metyrapone shunts accumulating precursors into deoxycorticosterone (a mineralocorticoid causing hypertension and hypokalemia) and into adrenal androgens (causing acne and hirsutism)
ANSWER: E
Rationale:
Option E is correct. Metyrapone inhibits CYP11B1, the final step of cortisol synthesis. With cortisol synthesis blocked and ACTH (adrenocorticotropic hormone) drive continuing, precursors accumulate and are shunted: into deoxycorticosterone, a mineralocorticoid that causes sodium retention, hypertension, and hypokalemia, and into the adrenal androgen pathway, producing acne and hirsutism. This precursor shunting explains all the new findings even as cortisol falls.
Option A: Option A is incorrect because cortisol is falling; the new problems arise from precursor shunting, not persistent hypercortisolism.
Option B: Option B is incorrect because the hypertension, hypokalemia, and androgenic features are directly explained by precursor shunting, not an unrelated rebound, and adrenal insufficiency would not cause hypertension.
Option C: Option C is incorrect because metyrapone does not block the androgen receptor; it increases androgen precursors.
Option D: Option D is incorrect because the picture is driven by metyrapone's own steroidogenic shunting, not a CYP3A4 interaction.
6. A critically ill patient in the ICU has florid ectopic ACTH (adrenocorticotropic hormone) syndrome with severe hypercortisolism. The patient is intubated, cannot take oral medication, and requires rapid, titratable reduction of cortisol while awaiting definitive treatment. Which agent is best suited to this situation?
A) Oral ketoconazole titrated against liver function tests
B) Etomidate by continuous intravenous infusion at sub-anesthetic doses, which inhibits CYP11B1 and is the only parenteral agent providing rapid, titratable cortisol control
C) Oral metyrapone increased over several days
D) Subcutaneous pasireotide twice daily
E) Oral mifepristone once daily
ANSWER: B
Rationale:
Option B is correct. Etomidate, an imidazole anesthetic, inhibits CYP11B1 (11-beta-hydroxylase) at sub-anesthetic intravenous infusion doses and is the only parenterally available agent for acute hypercortisolism. Its rapid onset and offset allow precise titration in an intubated patient who cannot take oral drugs, with monitoring for sedation and emerging adrenal insufficiency.
Option A: Option A is incorrect because ketoconazole is oral and cannot be given to a patient who cannot take oral medication, and it lacks the immediate parenteral titratability required.
Option C: Option C is incorrect because metyrapone is oral and unsuitable here despite its speed.
Option D: Option D is incorrect because pasireotide targets pituitary corticotrophs in Cushing disease and is not a titratable parenteral agent for an acute ectopic ACTH crisis.
Option E: Option E is incorrect because mifepristone is oral, blocks the receptor rather than lowering cortisol, and offers no rapid titratable biochemical control.
7. A 60-year-old man with endogenous Cushing syndrome and poorly controlled type 2 diabetes is treated with mifepristone. His glycemic control improves, but his urinary free cortisol (UFC) rises and he develops potassium 3.0 mmol/L. The team asks how to interpret the rising UFC and manage the hypokalemia. Which response is correct?
A) The rising UFC means treatment failure; mifepristone should be stopped
B) The rising UFC means the dose is too high; mifepristone should be reduced until UFC normalizes
C) The hypokalemia means mineralocorticoid deficiency; fludrocortisone should be added
D) Because mifepristone antagonizes the glucocorticoid receptor (GR), cortisol and UFC rise as feedback is removed (so UFC cannot track response and glycemic and clinical endpoints are used instead), and the elevated cortisol activates unopposed mineralocorticoid receptors, causing hypokalemia that is managed with potassium repletion and, if needed, an MR antagonist
E) The hypokalemia and rising UFC indicate the patient does not have Cushing syndrome
ANSWER: D
Rationale:
Option D is correct. Mifepristone blocks the glucocorticoid receptor (GR) rather than lowering cortisol synthesis. Removing GR-mediated feedback raises ACTH (adrenocorticotropic hormone), plasma cortisol, and UFC (urinary free cortisol), so UFC cannot be used to gauge response; clinical and glycemic parameters are tracked instead. The elevated cortisol is unopposed at the mineralocorticoid receptor, producing hypokalemia, which is managed with potassium repletion and, when needed, a mineralocorticoid-receptor antagonist.
Option A: Option A is incorrect because a rising UFC is expected with GR blockade and does not indicate failure; the improving glycemic control reflects efficacy.
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 the hypokalemia results from cortisol activating mineralocorticoid receptors, not from mineralocorticoid deficiency; adding fludrocortisone would worsen it.
Option E: Option E is incorrect because these findings are the expected pharmacodynamic consequences of mifepristone, not evidence against the diagnosis.
8. A 45-year-old woman with Cushing disease who is not a surgical candidate is started on pasireotide. Over six weeks her urinary free cortisol declines toward normal, but her fasting glucose rises from 95 to 180 mg/dL. Which is the most appropriate interpretation and next step?
A) The hyperglycemia is an expected on-target effect of pasireotide, which suppresses insulin and incretin secretion through islet somatostatin receptors; continue the drug for its cortisol benefit and initiate glucose monitoring and antidiabetic therapy
B) The hyperglycemia indicates worsening hypercortisolism, so the pasireotide dose should be increased
C) The hyperglycemia is an allergic reaction, so pasireotide should be stopped immediately
D) The hyperglycemia indicates the drug is not working and should be replaced with mifepristone, which never affects glucose
E) The hyperglycemia is unrelated to pasireotide and requires no specific attention
ANSWER: A
Rationale:
Option A is correct. Pasireotide lowers ACTH (adrenocorticotropic hormone) and cortisol by activating somatostatin receptors on corticotroph adenoma cells, but the same somatostatin-receptor activation on pancreatic islets suppresses insulin and incretin secretion, causing hyperglycemia in a majority of patients. Because the cortisol response is favorable, the correct approach is to continue pasireotide while monitoring glucose and initiating antidiabetic therapy.
Option B: Option B is incorrect because the falling urinary free cortisol shows the drug is working; the hyperglycemia is a direct islet effect, and raising the dose would worsen it.
Option C: Option C is incorrect because the hyperglycemia is a predictable mechanistic effect, not an allergic reaction.
Option D: Option D is incorrect because the drug is effective against cortisol, and mifepristone is used for hyperglycemia in Cushing syndrome rather than being free of glucose effects; the claim that it never affects glucose is wrong.
Option E: Option E is incorrect because the marked glucose rise is a known pasireotide effect that requires active management.
9. A 7-year-old child with salt-wasting congenital adrenal hyperplasia (CAH) is maintained on hydrocortisone and fludrocortisone. Serum 17-hydroxyprogesterone is fully suppressed into the normal range, but the child's growth velocity has fallen below the 25th percentile for height-age over the past year. Which adjustment best reflects correct management?
A) Increase the hydrocortisone dose further to keep 17-hydroxyprogesterone fully normalized
B) Switch the child to bedtime dexamethasone to improve growth
C) Reduce the glucocorticoid dose, accepting mildly elevated 17-hydroxyprogesterone, because full normalization usually requires glucocorticoid excess that impairs linear growth, and growth velocity must be protected
D) Stop fludrocortisone, since it is responsible for the growth failure
E) Make no change, because normalized 17-hydroxyprogesterone confirms optimal therapy regardless of growth
ANSWER: C
Rationale:
Option C is correct. In CAH the goal is the smallest glucocorticoid dose that adequately suppresses androgen precursors while preserving growth. Full normalization of 17-hydroxyprogesterone typically requires glucocorticoid excess, which impairs linear growth; a falling growth velocity in the setting of fully suppressed 17-hydroxyprogesterone signals over-treatment. The correct response 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, the opposite of what is needed.
Option B: Option B is incorrect because long-acting dexamethasone carries a higher, not lower, risk of growth impairment in children.
Option D: Option D is incorrect because fludrocortisone, a mineralocorticoid, is not the cause of growth failure; the glucocorticoid excess is.
Option E: Option E is incorrect because growth velocity is a primary monitoring target, and a declining velocity warrants dose reduction even when 17-hydroxyprogesterone looks optimal.
10. A 55-year-old man with adrenocortical carcinoma is on mitotane with hydrocortisone replacement. He requires escalating hydrocortisone doses to feel well, and a separately prescribed medication cleared by CYP3A4 (cytochrome P450 3A4) has drifted to subtherapeutic levels. Which explanation accounts for both problems?
A) Mitotane inhibits CYP3A4, raising the other drug's levels, and lowers corticosteroid-binding globulin
B) Mitotane antagonizes the glucocorticoid receptor, so more hydrocortisone is needed, and it does not interact with other drugs
C) Mitotane blocks renal hydrocortisone excretion while slowing metabolism of the other drug
D) Mitotane stimulates cortisol synthesis, lowering replacement needs, while accelerating the other drug's metabolism
E) Mitotane increases corticosteroid-binding globulin (lowering free cortisol) and induces CYP3A4 (accelerating metabolism of hydrocortisone and of the co-administered CYP3A4 substrate), so higher glucocorticoid doses are needed and the other drug becomes subtherapeutic
ANSWER: E
Rationale:
Option E is correct. Mitotane raises corticosteroid-binding globulin, lowering the free cortisol fraction, and induces CYP3A4 (cytochrome P450 3A4), accelerating glucocorticoid metabolism; both effects increase the glucocorticoid dose required, which is why replacement is typically two to three times the usual dose. The same CYP3A4 induction speeds metabolism of co-administered CYP3A4 substrates, driving them subtherapeutic. One induction-plus-binding mechanism explains both observations.
Option A: Option A is incorrect because mitotane induces rather than inhibits CYP3A4 and raises rather than lowers corticosteroid-binding globulin.
Option B: Option B is incorrect because mitotane does not antagonize the glucocorticoid receptor and clearly does interact with CYP3A4 substrates.
Option C: Option C is incorrect because the mechanism is enzyme induction and increased binding protein, not blocked renal excretion or slowed metabolism.
Option D: Option D is incorrect because mitotane is adrenocorticolytic and lowers cortisol, raising replacement needs, and it induces rather than is unrelated to the other drug's metabolism.
11. A 63-year-old man with type 2 diabetes and diabetic kidney disease has persistent albuminuria despite a maximally tolerated angiotensin-receptor blocker. His estimated glomerular filtration rate (eGFR) is 48 mL per minute per 1.73 m2 and serum potassium is 4.8 mmol/L. Which addition is most appropriate to reduce his cardiorenal risk, and what is the key precaution?
A) Add spironolactone, accepting that gynecomastia is the principal concern in this setting
B) Add finerenone, a non-steroidal mineralocorticoid receptor antagonist shown to reduce cardiorenal events in diabetic kidney disease, while monitoring serum potassium closely because his reduced eGFR and concurrent renin-angiotensin-aldosterone system (RAAS) blockade raise hyperkalemia risk
C) Add fludrocortisone to improve renal perfusion
D) Stop the angiotensin-receptor blocker and start high-dose dexamethasone
E) Add an additional RAAS blocker for dual angiotensin inhibition
ANSWER: B
Rationale:
Option B is correct. Finerenone is a non-steroidal mineralocorticoid receptor antagonist that reduces composite cardiorenal endpoints in patients with type 2 diabetes and diabetic kidney disease with albuminuria already on maximally tolerated RAAS (renin-angiotensin-aldosterone system) blockade. The essential precaution is close potassium monitoring, because his reduced eGFR (estimated glomerular filtration rate) and concurrent RAAS blockade increase the risk of hyperkalemia; his current potassium of 4.8 mmol/L is acceptable to begin but must be followed.
Option A: Option A is incorrect because the dominant safety concern when adding mineralocorticoid-receptor blockade in this setting is hyperkalemia, and finerenone has the specific cardiorenal-outcome evidence in diabetic kidney disease that spironolactone lacks.
Option C: Option C is incorrect because fludrocortisone is a mineralocorticoid agonist that would worsen sodium retention and proteinuric kidney disease.
Option D: Option D is incorrect because stopping the angiotensin-receptor blocker removes proven renoprotection, and dexamethasone has no role here.
Option E: Option E is incorrect because dual RAAS blockade increases hyperkalemia and acute kidney injury risk without improving outcomes and is not recommended.
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