Endocrine question bank

C. Start potassium replacement with fluids and delay insulin — Insulin drives potassium into cells. In DKA total body potassium is already depleted by the osmotic diuresis, so insulin is started only once serum potassium is at least 3.5 mmol/L; below that it worsens hypokalemia and risks arrhythmia, cardiac arrest and respiratory-muscle weakness. Glargine is not recommended for DKA, continuous IV insulin is the standard of care rather than subcutaneous rapid analogs, an insulin bolus pushes potassium into cells rather than drawing it out, and starting insulin at 3.1 mmol/L would lower potassium further, not raise it.

A. Residual insulin secretion suppresses ketogenesis — In HHS the β cells still make enough insulin to suppress ketogenesis, so ketonemia and acidemia are minimal despite severe hyperglycemia and hyperosmolality. Counterregulatory hormones — glucagon, growth hormone, cortisol and catecholamines — are released in HHS and drive gluconeogenesis and glycogenolysis, and insulin deficiency still increases lipolysis; the difference is that residual insulin keeps the fatty acids from becoming ketones. His kidneys are not clearing faster: BUN and creatinine are usually raised, reflecting prerenal azotemia. Isotonic fluid comes first, and an early insulin drip is avoided because a rapid fall in glucose risks cerebral edema.

B. β-Blockade blunts adrenergic signs such as tremor and palpitations, while sweating is a cholinergic sign — Hypoglycemia awareness falls with drugs that block the sympathetic nervous system, such as β-blockers, which can reduce or abolish the warning signs. They mask catecholamine-triggered signs such as tremor and palpitations, but sweating — a cholinergic neurogenic sign — remains unmasked and may be the only consistent sign. Brain glucose uptake is insulin-independent (GLUT1, GLUT3), symptoms typically appear at 50–55 mg/dL or below, and in type 1 diabetes autoimmune β-cell destruction leaves no insulin for a drug to release. Long-standing diabetes and neuropathy add to the β-blocker effect rather than replace it.

D. Lipohypertrophy at the old site reduced absorption, so the same dose acted more strongly at a healthy site — Repeated injections into the same area cause lipodystrophy — here lipohypertrophy, a thickening of adipose tissue — which can affect insulin absorption. Injecting into such areas has caused hyperglycemia, and a sudden change to an unaffected site has caused hypoglycemia, so sites are rotated within a region and glucose is monitored closely after a switch. The thigh is not the faster site: abdominal injection gives higher serum levels than thigh injection. A rising requirement or slower absorption would raise glucose, not cause hypoglycemia on the same dose.

C. It is excreted unchanged by the kidneys, mainly by tubular secretion — Metformin is excreted unchanged in the urine: renal clearance is about 3.5 times creatinine clearance, so tubular secretion is the main route, and the risk of accumulation and lactic acidosis rises with the severity of renal impairment. It undergoes no significant hepatic metabolism or biliary excretion, so it has no active metabolite, and it is negligibly bound to plasma proteins. Sepsis adds lactate and can cause prerenal azotemia, so metformin is discontinued.

A. It lowers hepatic glucose output without increasing insulin secretion — Metformin decreases hepatic glucose production, decreases intestinal glucose absorption and improves peripheral glucose uptake, while insulin secretion remains unchanged — so it is unlikely to cause hypoglycemia unless it is combined with insulin or an insulin secretagogue such as a sulfonylurea. Because insulin secretion is unchanged, it does not work by releasing insulin from the β cell; its three actions are on hepatic glucose production, intestinal glucose absorption and peripheral glucose uptake, none of them in the kidney; and it is excreted unchanged, with no significant hepatic metabolism, so it has no active metabolite.

D. Stop it at or before the scan, recheck eGFR 48 hours later, and restart if renal function is stable — Intravascular iodinated contrast has caused an acute decrease in renal function and lactic acidosis in metformin-treated patients. With an eGFR between 30 and 60, the label says to stop metformin at the time of, or before, the study, re-evaluate eGFR 48 hours afterwards and restart if renal function is stable — so it is neither continued through the scan, nor stopped for good, nor held only after the eGFR has already fallen below 30.

B. Inhibition of mitochondrial complex I, so hydrogen ions from ATP hydrolysis are not recycled — Supratherapeutic metformin inhibits complex I of the mitochondrial respiratory chain; mitochondria can then no longer recycle and buffer the hydrogen ions produced by ATP hydrolysis, and these accumulate to produce the metabolic acidosis. Hyperlactatemia is a marker of anaerobic metabolism rather than the direct cause. Metformin impairs, rather than stimulates, gluconeogenesis — reducing hepatic lactate clearance — and the acidosis is an anion-gap acidosis, unlike the non–anion gap acidosis of carbonic anhydrase inhibitors. Treatment is supportive care with prompt hemodialysis.

A. It binds SUR1 and closes the K-ATP channel, depolarizing the β cell — Sulfonylureas bind the SUR1 subunit of the β-cell K-ATP channel and inhibit it: potassium efflux falls, the membrane depolarizes, voltage-gated calcium channels open — they are not blocked — and calcium influx triggers insulin exocytosis. Glyburide lowers glucose acutely by releasing insulin from functioning β cells, and it is the released insulin, not the drug, that acts on muscle receptors. KCNJ11 and ABCC8 encode K-ATP subunits, and glyburide has been studied off-label in these infants with significant falls in HbA1c.

D. Octreotide — Dextrose corrects hypoglycemia but can trigger further insulin secretion from the drug-stimulated β cells, so hypoglycemia recurs. Octreotide, a somatostatin analog, binds somatostatin-2 receptors on β cells and inhibits calcium influx, blocking that secretion and reducing dextrose requirements. Glucagon can itself trigger insulin release and is not used routinely, more dextrose alone feeds the same cycle, and dialysis is unlikely to help because glipizide is highly protein bound.

B. Switch to glipizide — Long-acting sulfonylureas cause severe, prolonged hypoglycemia in older adults, so glyburide is on the Beers list as potentially inappropriate after 65, and geriatric guidance recommends a short-acting sulfonylurea such as glipizide, which has the shortest half-life and is metabolized in the liver to inactive products. Chlorpropamide is also on the Beers list (long-acting, and it can cause SIADH); any glyburide product, micronized or not and whatever the timing, keeps the long-acting drug.

C. Glipizide works only through functioning β cells, which autoimmune destruction has removed — Type 1 diabetes results from autoimmune destruction of pancreatic β cells, causing absolute insulin deficiency, and sulfonylureas lower glucose only by stimulating insulin release from functioning β cells — so type 1 diabetes and diabetic ketoacidosis are contraindications and are treated with insulin. Sulfonylureas release insulin regardless of the glucose level, glipizide itself is the active drug (its metabolites are inactive), and the problem is not insulin resistance but the absence of insulin to release.

B. The incretins it preserves raise insulin only when glucose is normal or high — Sitagliptin inhibits DPP-4, so the patient’s own GLP-1 and GIP stay active longer; they increase insulin release and lower glucagon in a glucose-dependent manner, so they act after meals and little between them — in healthy subjects sitagliptin did not lower glucose or cause hypoglycemia. Its DPP-4 inhibition lasts a full 24 hours, so the protection does not depend on the drug wearing off. It slows incretin inactivation rather than stimulating the GLP-1 receptor itself (direct agonists are on the GLP-1 Agonists page), its half-life is about 12 hours, and it is selective for DPP-4 over DPP-8 and DPP-9.

D. Linagliptin, because it is eliminated mainly through the enterohepatic system — About 80% of linagliptin is eliminated through the enterohepatic system and only about 5% in urine, so no renal dose adjustment is recommended. Sitagliptin is about 79% excreted unchanged in urine and alogliptin 60–71%, so both are dose-adjusted for renal function, and saxagliptin and its active metabolite are cleared partly by the kidney, with a lower dose when eGFR is below 45.

C. Clarithromycin inhibits CYP3A4/5, raising saxagliptin exposure — Saxagliptin’s metabolism is primarily mediated by CYP3A4/5, and strong inhibitors such as clarithromycin significantly increase its exposure — the label limits the saxagliptin dose with them; with a sulfonylurea also on board, the risk of hypoglycemia rises, and a lower sulfonylurea dose may be needed. Clarithromycin is listed among the strong CYP3A4/5 inhibitors, not inducers. The major metabolite, 5-hydroxy saxagliptin, is itself a DPP-4 inhibitor (half as potent), and saxagliptin is eliminated by both hepatic and renal pathways.

C. More patients were hospitalized for heart failure on saxagliptin and alogliptin than on placebo — In SAVOR (saxagliptin) and EXAMINE (alogliptin), heart-failure hospitalizations were more frequent than with placebo, and patients with prior heart failure or renal impairment were at higher risk. The labels advise weighing risks and benefits, monitoring and considering stopping if heart failure develops — a warning, not a contraindication; the sitagliptin and linagliptin labels note heart failure "observed with two other members" of the class.

C. Its attached fatty acid and its resistance to DPP-4 and neutral endopeptidases — Native GLP-1 has a half-life of 1.5 to 2 minutes because DPP-4 and neutral endopeptidases degrade it. Liraglutide carries a C-16 fatty acid (palmitic acid), and self-association that delays absorption, plasma protein binding and stability against both peptidases give it a half-life of 13 hours, suiting once-daily dosing. It is a GLP-1 receptor agonist, not a DPP-4 inhibitor; the Fc-fusion design belongs to dulaglutide; and liraglutide is metabolized like large proteins, without a specific organ as a major route of elimination.

B. Semaglutide, liraglutide, dulaglutide and tirzepatide are all contraindicated in him — All four labels carry the boxed rodent thyroid C-cell tumor warning and contraindicate the drugs with a personal or family history of MTC or with MEN 2 — and inherited MTC is driven by germline RET mutations. A normal calcitonin does not change this; routine calcitonin monitoring is of uncertain value for detecting MTC. The box appears on the semaglutide, dulaglutide and tirzepatide labels as well as liraglutide’s, and the tirzepatide label carries the same contraindication.

A. Food and drink taken with the tablet reduce its absorption from the stomach — Semaglutide tablets rely on the absorption enhancer SNAC, absorption occurs mainly in the stomach, and it is higher after a longer post-dose fast; the tablet is taken on an empty stomach with up to 4 ounces of water, and food, other drinks and other oral medicines wait at least 30 minutes. Even taken correctly, bioavailability is only about 0.4% to 1%, and the tablet is swallowed whole — not split, crushed, chewed or dissolved — with water only.

B. Switch to a non-oral method or add a barrier method for 4 weeks after starting and after each dose escalation — Tirzepatide delays gastric emptying, which may reduce the efficacy of oral hormonal contraceptives; the label advises switching to a non-oral method or adding a barrier method for 4 weeks after initiation and for 4 weeks after each dose escalation. Hormonal contraceptives that are not taken by mouth should not be affected, and the backup period follows every escalation, not just the first week.

A. Increased sodium reabsorption through epithelial sodium channels in the collecting tubule — Pioglitazone stimulates PPAR-γ in the collecting tubules, inducing epithelial sodium channel expression and increasing sodium reabsorption, so fluid is retained; thiazolidinediones cause dose-related fluid retention that may lead to or worsen heart failure — the boxed warning. The heart failure follows from the retained fluid rather than from a direct effect on the heart; pioglitazone’s rare postmarketing hepatic failure is not the mechanism of its edema; and pioglitazone is not an insulin secretagogue, so increased insulin secretion is not the cause.

D. Acarbose blocks the brush-border enzymes that split sucrose into absorbable glucose — Sucrose has to be hydrolyzed to glucose and fructose by intestinal α-glucosidases, which acarbose inhibits, so it is unsuitable for rapid correction; oral glucose (dextrose), whose absorption is not inhibited, is used instead, and severe lows may need IV glucose or glucagon. Sucrose does yield glucose once split, acarbose does not inhibit lactase, and the problem is that sucrose is absorbed too slowly on acarbose, not too fast.

C. Gemfibrozil inhibits CYP2C8 and raises repaglinide exposure, risking severe hypoglycemia — Repaglinide is metabolized by CYP2C8 and CYP3A4; gemfibrozil, a CYP2C8 inhibitor, raised repaglinide exposure about 8-fold, and the combination is contraindicated because of hypoglycemia. Gemfibrozil inhibits — it does not induce — CYP2C8, it is repaglinide’s exposure that rises rather than gemfibrozil’s, and the interaction is metabolic, not albumin displacement causing myopathy.

B. Reducing her mealtime insulin dose when pramlintide is started — Pramlintide used with insulin increases the risk of severe hypoglycemia, particularly in type 1 diabetes, seen within 3 hours of an injection; the label reduces the mealtime insulin dose when pramlintide is started and calls for frequent glucose monitoring. It is injected immediately before major meals, never mixed with insulin (mixing alters both drugs’ pharmacokinetics), and not used with drugs that slow nutrient absorption such as α-glucosidase inhibitors.

D. Gs-coupled receptor → cAMP → PKA → hepatic glycogenolysis and gluconeogenesis — Glucagon binds a Gs-coupled receptor on hepatocytes, raising cAMP and activating protein kinase A, which activates glycogen phosphorylase (glycogenolysis), inactivates glycogen synthase and induces PEPCK (gluconeogenesis), so the liver releases glucose. It acts by activating hepatic glucagon receptors — not insulin receptors, renal transporters or the β-cell K-ATP channel, which is the sulfonylurea target.

B. His hepatic glycogen stores were depleted — Glucagon is effective only if sufficient hepatic glycogen is present; in starvation the stores may be too low, and alcohol inhibits gluconeogenesis but not glycogenolysis, so hypoglycemia follows once glycogen is depleted. Such patients are treated with glucose. Glucagon works intramuscularly — glucose rises within about 10 minutes — and a pheochromocytoma would cause a surge in blood pressure, not a failed glucose response.

A. It may trigger exaggerated insulin release from the tumor and worsen the hypoglycemia — In patients with insulinoma, glucagon may produce an initial rise in glucose but may then, directly or through that rise, stimulate exaggerated insulin release from the insulinoma and cause hypoglycemia; insulinoma is a label contraindication, and glucose is given orally or IV instead. The concern is the tumor’s insulin response, not α-cell loss, lactic acidosis or potassium.

C. A transient rise in pulse and blood pressure, a known glucagon effect in patients on β-blockers — Patients taking β-blockers may have a transient increase in pulse and blood pressure when given glucagon, which may need treatment in coronary artery disease. Glucagon acts on its own G protein–coupled receptors, found in the heart among other tissues, and its positive inotropic effect is mediated through adenylate cyclase rather than β-adrenergic receptors. In overdose, glucagon may lower serum potassium rather than raise it, and anaphylaxis to glucagon presents with hypotension, not hypertension.

E. Propylthiouracil, because methimazole in the first trimester is linked to aplasia cutis and choanal or esophageal atresia — Methimazole taken in the first trimester has been linked to aplasia cutis, choanal atresia and esophageal atresia, so PTU is preferred just before and during the first trimester (with a switch to methimazole later, when PTU’s liver risk matters more). Methimazole crosses the placenta readily because of its low protein binding. Radioactive iodine is contraindicated in pregnancy. Iodide alone fails because the gland escapes the Wolff–Chaikoff effect within 2–4 weeks. Her TSH is already suppressed — Graves glands are driven by TSH-receptor antibodies, so levothyroxine would only add hormone.

C. Start PTU or methimazole first, then give SSKI at least an hour later — In thyroid storm the thionamide is given first to stop new synthesis, and iodine (SSKI) follows at least an hour later to stop release; given first, the iodine load becomes substrate for more hormone. Iodine is part of the sequence precisely because it reduces hormone release, so it is not held back until euthyroidism — it is stopped once his condition improves. Aspirin is avoided because it can raise free hormone by displacing it from binding proteins; acetaminophen and cooling are used instead. A glucocorticoid is also given.

D. Radiation thyroiditis releasing stored thyroid hormone — Radiation thyroiditis typically appears around the third day: the gland becomes tender and swollen, and destroyed follicles release preformed T4 and T3, which can worsen hyperthyroidism or even cause thyroid storm. Jod-Basedow follows a stable-iodine load in an iodine-deficient or nodular gland, weeks later. Marrow suppression from I-131 appears 3–5 weeks after treatment. Hypothyroidism is the later outcome and would not cause palpitations. The HICON label notes that iodide is not considered an allergen; hypersensitivity relates to excipients.

B. Calcium binds levothyroxine in the gut, and the PPI removes the gastric acidity its absorption needs — Calcium carbonate binds levothyroxine in the gut, and gastric acidity is a prerequisite for its absorption, so PPIs reduce it through hypochlorhydria; less T4 is absorbed and the TSH rises. Enzyme induction of T4 metabolism is caused by rifampin, phenobarbital and carbamazepine. Drugs that reduce T4 → T3 conversion include amiodarone, propranolol and glucocorticoids. Reduced protein binding (phenytoin, carbamazepine) usually leaves the TSH normal.

D. IV hydrocortisone, followed by IV levothyroxine — This is myxedema coma. Hydrocortisone is given before thyroid hormone, because levothyroxine increases cortisol metabolism and hypothyroidism can mask adrenal insufficiency; IV levothyroxine follows, since oral thyroid hormone is not recommended for myxedema coma. Rewarming is slow and cautious — rapid rewarming causes vasodilation and worsens hypotension. Hypotonic fluids are avoided in hyponatremia. Liothyronine is added only when there is no response, and high T3 levels have been linked to higher mortality.

E. Suppressed CRH and ACTH leaving atrophic adrenals unable to answer surgical stress — Months of prednisone suppressed CRH and ACTH, and the ACTH-dependent cortex atrophied; stopping abruptly before surgery left her unable to raise cortisol — adrenal crisis. Exogenous glucocorticoids are the most common cause of this central insufficiency, and because aldosterone is regulated by renin–angiotensin rather than ACTH, she has neither hyperkalemia nor hyperpigmentation, which point to primary autoimmune disease. Prednisone has little mineralocorticoid effect, glucocorticoid excess raises glucose rather than lowering it, and Cushing syndrome brings hypertension, not shock. She needs hydrocortisone.

A. Switch to hydrocortisone, adding a mineralocorticoid if needed — In primary adrenal insufficiency aldosterone is lost too, causing volume loss, hyponatremia and hyperkalemia. Dexamethasone has very little, if any, mineralocorticoid activity, so more of it will not correct the potassium; hydrocortisone — the label’s first choice for adrenocortical insufficiency — has roughly equal glucocorticoid and mineralocorticoid effects, and a separate mineralocorticoid is added as needed. Methylprednisolone has minimal mineralocorticoid activity, extra potassium would worsen hyperkalemia, and she still needs glucocorticoid replacement.

D. Induction of lipocortin-1, which inhibits phospholipase A2 — Prednisolone (from prednisone) binds the cytoplasmic glucocorticoid receptor, which moves to the nucleus; transactivation induces lipocortin-1, which decreases phospholipase A2 and so the arachidonic acid that both prostaglandins and leukotrienes come from. Because phospholipase A2 sits upstream of both pathways, blocking a cyclooxygenase would spare leukotrienes, and blocking the leukotriene receptor would act on leukotrienes only. The glucocorticoid receptor is intracellular, not on the cell surface, and transrepression blocks NF-κB rather than increasing it.

E. Neutrophil demargination and longer survival, with eosinophil and lymphocyte apoptosis — Glucocorticoids raise the neutrophil count by demargination, less migration into tissue, inhibited neutrophil apoptosis and release from the marrow, while inducing eosinophil apoptosis and lymphocyte apoptosis. They promote rather than suppress white-cell maturation and release, inhibit T-cell proliferation, and shrink lymphoid tissue; methylprednisolone has minimal mineralocorticoid activity.

C. Glucocorticoid myopathy from muscle protein catabolism — Glucocorticoids are catabolic to muscle, decreasing protein synthesis and increasing breakdown; steroid myopathy is painless proximal weakness with normal CK, and biopsy shows type II fiber atrophy without inflammation. It improves after the steroid is withdrawn. Critical illness myopathy develops over days in ICU patients on large IV doses with neuromuscular blockers, and osteonecrosis presents first with joint pain.

C. Add fludrocortisone, with liberal salt intake — Primary adrenal insufficiency loses aldosterone as well as cortisol; salt craving, orthostatic hypotension and hyperkalemia reflect mineralocorticoid deficiency, and an elevated renin indicates more fludrocortisone is needed, with liberal salt intake. Dexamethasone lacks a mineralocorticoid effect and would need full fludrocortisone replacement, and metyrapone is contraindicated in adrenal cortical insufficiency.

D. Accumulating 11-deoxycorticosterone activating mineralocorticoid receptors — Blocking 11β-hydroxylase raises the cortisol and aldosterone precursors 11-deoxycortisol and 11-deoxycorticosterone; elevated 11-deoxycorticosterone can activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension — the pattern of 11β-hydroxylase-deficient CAH. His cortisol has fallen, not escaped. Significant lowering of cortisol causes hypotension rather than hypertension, and the accumulating androgens cause hirsutism, hypertrichosis and acne.

B. Stop Korlym and give glucocorticoids without delay — On mifepristone, serum cortisol stays elevated or rises because the HPA axis responds to the receptor blockade, so it cannot be used to judge adrenal insufficiency; nausea, fatigue and hypotension are the clinical signs. Korlym is stopped immediately and glucocorticoids are given without delay — high doses may be needed to overcome the blockade. A high cortisol neither rules out insufficiency nor shows inadequate blockade, and adding a drug that lowers cortisol would deepen the insufficiency rather than treat it.

A. A rise in 11-deoxycortisol — Metyrapone blocks 11β-hydroxylation, so cortisol production falls and its feedback is removed; ACTH rises and drives the precursor 11-deoxycortisol up — an intact HPA axis is indicated by an increase in 11-deoxycortisol. Cortisol falls rather than rises, ACTH rises rather than falls, and metyrapone may suppress aldosterone synthesis, causing a mild natriuresis.

A. It suppresses both insulin and glucagon secretion — Octreotide is an even more potent inhibitor of growth hormone, glucagon and insulin than somatostatin; by altering the balance between insulin, glucagon and GH it can cause hypoglycemia or hyperglycemia, so glucose is monitored and antidiabetic doses adjusted. It inhibits rather than stimulates insulin, lowers rather than raises growth hormone, and suppresses TSH, which can cause hypothyroidism.

B. IGF-1 is the marker to follow: GH rises as IGF-1 feedback falls, and pegvisomant cross-reacts in GH assays — Pegvisomant blocks the GH receptor, so IGF-1 falls; GH rises, presumably from diminished inhibition as IGF-1 falls, and because pegvisomant cross-reacts in commercial GH assays, GH appears falsely elevated. IGF-1 is the only biochemical marker used to monitor response, and a normal IGF-1 is the goal of treatment. The GH rise is the expected feedback response, not a sign that the drug stimulates GH or that a new tumor has appeared.

D. D2-receptor blockade removes dopamine’s tonic inhibition of prolactin, and prolactin suppresses GnRH — Prolactin secretion is tonically inhibited by hypothalamic dopamine; neuroleptics such as risperidone raise prolactin through dopamine-receptor antagonism, and risperidone can produce the most significant elevations. Prolactin inhibits GnRH release, lowering LH and FSH, which causes the amenorrhea. Dopamine inhibits rather than stimulates prolactin, and cabergoline is a D2 agonist — one not recommended with D2 antagonists; substitution with an agent that does not raise prolactin is considered instead.

B. Evaluate with an echocardiogram, and stop cabergoline if new valvulopathy is found — Valvular and pericardial fibrosis with cabergoline often present as heart failure; a new murmur, edema or dyspnea calls for an echocardiogram, and cabergoline is stopped for a new diagnosis of valvular regurgitation, restriction or leaflet thickening. Bromocriptine carries the same valvulopathy warning and contraindication, and metoclopramide, a D2 antagonist, is not recommended with cabergoline.

B. It binds bone hydroxyapatite, is released into resorbing osteoclasts and inhibits farnesyl pyrophosphate synthase — Alendronate, a nitrogen-containing bisphosphonate, binds hydroxyapatite at sites of resorption; the resorbing osteoclast releases it and it inhibits farnesyl pyrophosphate synthase, leading to osteoclast apoptosis. Blocking RANKL is how denosumab works. Alendronate reduces resorption with no direct effect on bone formation. Conversion to nonfunctional ATP analogs is the mechanism of the older non-nitrogen-containing agents such as etidronate.

C. With a full glass of plain water, staying upright for at least 30 minutes — Severe esophageal events are more likely when patients lie down after the dose or do not swallow it with a full glass of water, so the tablet is taken with plain water and the patient stays upright for at least 30 minutes. Calcium and other medications are taken at least 30 minutes later because they interfere with absorption. Lying down at bedtime is exactly what raises the esophageal risk, and the tablet is not to be chewed, sucked or crushed.

D. Stop the bisphosphonate and evaluate the opposite femur too — Thigh or groin pain in a patient with long bisphosphonate exposure is evaluated as a possible atypical femur fracture, a stress fracture attributed to oversuppressed bone turnover whose risk increases with the duration of exposure. These fractures may be bilateral, so the other femur is examined, and the bisphosphonate is stopped because continuing it raises the risk in the other leg. Continuing alendronate, raising its dose or switching to another bisphosphonate keeps the same exposure going.

A. IV normal saline first, then IV zoledronic acid, which lowers calcium over 2 to 3 days — Initial treatment of hypercalcemia of malignancy is IV normal saline, with calcitonin and bisphosphonates; zoledronic acid is preferred for its greater potency and shorter infusion, and bisphosphonates begin working in 2 to 3 days. Loop diuretics are not used until the patient is adequately rehydrated. Oral alendronate is only an off-label option, and IV zoledronic acid or pamidronate is recommended. Calcitonin, not a bisphosphonate, acts within 4 to 6 hours.

C. Intermittent PTH-receptor stimulation favors formation, whereas continuous PTH favors resorption — Continuous exposure to PTH, as in hyperparathyroidism, makes bone undergo resorption more than formation, whereas intermittent exposure, as with teriparatide injections, induces formation more than resorption. Teriparatide binds the same PTH receptors as endogenous PTH with the same affinity, and it has the same actions on calcium, raising serum calcium. Blocking RANKL is how denosumab works.

A. Rebound in bone turnover after the reversible RANKL blockade wore off — Denosumab’s effect fades: bone-turnover markers reverse when a dose is missed, and stopping it without a following antiresorptive lets bone turnover rebound — the label reports multiple vertebral fractures after Prolia is discontinued. Atypical femoral fractures are subtrochanteric and diaphyseal femur fractures, not vertebral. Hypocalcemia is a risk during treatment, especially in advanced kidney disease. She started no other treatment, and an antiresorptive such as a bisphosphonate is what prevents the rebound.

C. A past venous thromboembolism is a contraindication — Raloxifene increases the risk of deep vein thrombosis and pulmonary embolism, and active or past venous thromboembolism is a contraindication (boxed warning). It is an estrogen antagonist in breast and uterus — unlike tamoxifen, which is an agonist in the uterus — and an estrogen agonist in bone, where it increases bone mineral density.

B. Increased calcium-sensing receptor sensitivity lowers PTH and serum calcium — Cinacalcet increases the sensitivity of the parathyroid calcium-sensing receptor to calcium, lowering PTH and with it serum calcium; low calcium causes paresthesias and muscle spasms, can prolong the QT interval and lowers the seizure threshold. Cinacalcet acts on the parathyroid gland, not on vitamin D activation; calcitriol excess causes hypercalcemia, not hypocalcemia; and binding RANKL is denosumab’s mechanism.

A. An SGLT2 inhibitor such as empagliflozin or dapagliflozin — Empagliflozin and dapagliflozin are labeled to reduce cardiovascular death and heart-failure hospitalization in heart failure and to slow chronic kidney disease. Pioglitazone carries a boxed warning that it can cause or worsen congestive heart failure, and saxagliptin increased heart-failure hospitalization in its outcome trial. Sulfonylureas carry the UGDP special warning on increased cardiovascular mortality, not a benefit.

D. Glyburide, because it releases insulin regardless of glucose and is long-acting — Sulfonylureas close the β-cell K-ATP channel and release insulin regardless of glucose, so a missed meal can cause severe hypoglycemia; glyburide, a long-acting agent, is on the Beers list for severe prolonged hypoglycemia in older adults. Metformin leaves insulin secretion unchanged and is unlikely to cause hypoglycemia alone, sitagliptin preserves incretins whose action is glucose-dependent, and glucosuria is the SGLT2 inhibitors’ mechanism, not sitagliptin’s.

D. Semaglutide — GLP-1 receptor agonists such as semaglutide delay gastric emptying and increase satiety through the hypothalamus, and the class promotes weight loss compared with placebo; semaglutide reduces body weight. Weight gain is common with sulfonylureas such as glipizide, pioglitazone adds weight by expanding subcutaneous fat and retaining fluid, and weight gain is an adverse effect of insulin therapy.

A. Pramlintide — severe hypoglycemia when used with insulin — Pramlintide used with insulin increases the risk of severe hypoglycemia, particularly in type 1 diabetes, so the mealtime insulin dose is reduced when it is started. Metformin’s boxed warning is lactic acidosis, not thyroid tumors; liraglutide and the other GLP-1 agonists carry the thyroid C-cell tumor warning; and pioglitazone’s boxed warning is that thiazolidinediones cause or worsen congestive heart failure.

C. A saturated solution of potassium iodide (SSKI) or Lugol’s solution — Pharmacologic iodide is the fastest-acting antithyroid drug, working in hours to days by blocking hormone release, and SSKI or Lugol’s solution is given before surgery in Graves disease to reduce gland vascularity and blood loss. Thionamides do not touch stored hormone and take months to restore euthyroidism; radioactive iodine also takes months and destroys the gland rather than preparing it; levothyroxine is T4 replacement, which would add hormone.

B. Methimazole is equally effective, given once daily, with a better safety profile — Methimazole is preferred first-line because it is equally effective, given once daily and safer; propylthiouracil carries a boxed warning for severe liver injury and is reserved for specific situations. Peripheral T4-to-T3 blockade is propylthiouracil’s extra action; agranulocytosis occurs with both, and they cross-react; in the first trimester propylthiouracil may be the treatment of choice, because methimazole is linked to birth defects.

D. Stop methimazole and check a white blood cell count — Agranulocytosis is an idiosyncratic thionamide reaction, usually in the first 3 months; fever or sore throat means stopping the drug and checking a white count. PTU and methimazole cross-react, so switching does not remove the risk, and routine granulocyte monitoring is considered unnecessary — the reaction is caught by symptoms, not scheduled counts.

C. Liothyronine is T3 itself, the active hormone — Liothyronine is T3, which acts within hours with a maximal response in 2 to 3 days; levothyroxine is T4, converted to active T3 by deiodinases, and it has a long half-life (6 to 7 days, against 2 days or less for T3). Conversion runs from T4 to T3, not the reverse, and inhibiting thyroid peroxidase is how the thionamides act.

B. His insufficiency is secondary, and aldosterone, regulated by renin–angiotensin, is preserved — Exogenous glucocorticoids are the most common cause of secondary adrenal insufficiency, which suppresses ACTH but does not affect aldosterone, because aldosterone is regulated by the renin–angiotensin system; so there is no hyperkalemia or hyperpigmentation, and a glucocorticoid alone replaces what is missing. Prednisone has almost no mineralocorticoid effect; fludrocortisone is a very potent mineralocorticoid; and hydrocortisone has roughly equal glucocorticoid and mineralocorticoid effects.

A. Dexamethasone lacks the mineralocorticoid effect that hydrocortisone was providing — Hydrocortisone has a mineralocorticoid effect, but dexamethasone lacks one, so replacing hydrocortisone with dexamethasone requires a full fludrocortisone dose; until that is adjusted, the primary insufficiency’s aldosterone deficit returns as hyperkalemia, volume loss, salt craving and orthostatic hypotension. Dexamethasone is long-acting (36–54 hours); prednisone, not dexamethasone, is the inert prodrug activated in the liver; and dexamethasone does not interfere with cortisol measurement, which is why it is used for suppression testing.

C. A pituitary ACTH-secreting adenoma (Cushing disease) — Failure to suppress on the low-dose test, confirmed by a high urinary free cortisol, establishes Cushing syndrome; a normal or high ACTH means an ACTH-dependent source (pituitary or ectopic), and suppression by high-dose dexamethasone points to Cushing disease, because ectopic tumors do not suppress. An adrenal source would have low or undetectable ACTH, and exogenous corticosteroid use is identified first — she takes none.

A. Switch to eplerenone — Mineralocorticoid antagonists are first-line medical therapy for primary hyperaldosteronism; spironolactone also binds androgen and progesterone receptors, which can cause menstrual irregularity in women, while eplerenone has far lower affinity for those receptors, is favored for primary aldosteronism and is an alternative when spironolactone’s antiandrogen effects are a problem. Fludrocortisone activates the mineralocorticoid receptor, retaining sodium and excreting potassium; cortisol can also activate that receptor; and mifepristone blocks the glucocorticoid receptor, has little mineralocorticoid-receptor affinity and itself causes hypokalemia.

B. Abaloparatide — Abaloparatide, a PTH type 1 receptor agonist given intermittently, stimulates new bone formation — an anabolic effect. Alendronate reduces bone resorption with no direct effect on formation; denosumab blocks RANKL and so suppresses resorption; and raloxifene acts as an estrogen agonist in bone, inhibiting resorption. All three are antiresorptives, and formation falls with resorption because the two are coupled.

A. Severe hypocalcemia, especially with chronic kidney disease–mineral bone disorder — Prolia carries a boxed warning that patients with advanced chronic kidney disease, including dialysis, are at greater risk of severe — sometimes fatal — hypocalcemia, and chronic kidney disease–mineral bone disorder markedly increases the risk. Denosumab undergoes minimal renal filtration and excretion; the acute-phase reaction belongs to IV bisphosphonates; and esophageal ulceration is a risk of oral bisphosphonates.

D. Continue therapy with an antiresorptive, such as a bisphosphonate — Romosozumab is limited to 12 monthly doses; if osteoporosis therapy remains warranted, continued therapy with an antiresorptive agent is considered. Treatment is not simply stopped, and calcitonin is a poor choice for fracture protection because its fracture-reduction efficacy has not been demonstrated.

C. Cinacalcet — Cinacalcet increases the sensitivity of the parathyroid calcium-sensing receptor to calcium, reducing PTH with a concurrent fall in serum calcium. Calcitriol, active vitamin D, raises serum calcium and risks hypercalcemia; teriparatide is a PTH analog that itself increases serum calcium; and romosozumab is a sclerostin inhibitor that acts on bone formation, not on PTH secretion.

A. Prednisone increases gluconeogenesis and opposes insulin, raising postprandial glucose more than fasting glucose — Cortisol increases gluconeogenesis and antagonizes insulin, and systemic glucocorticoids cause a dose-dependent rise in fasting glucose with a larger rise in postprandial values, so glycemic control is harder in diabetes. Displacing a sulfonylurea from its plasma protein binding sites raises the risk of hypoglycemia rather than weakening the drug. Corticosteroids are among the drugs that raise glucose in a patient on glyburide, and when such a drug is withdrawn the patient is watched closely for hypoglycemia, so a permanent dose increase is the wrong plan.

D. Glucocorticoids activate osteoclasts and suppress osteoblasts, and bisphosphonates are labeled for glucocorticoid-induced osteoporosis — Glucocorticoids activate osteoclasts by promoting RANK ligand and reduce the number and function of osteoblasts and osteocytes; trabecular bone is affected first, and its loss can occur within the first 6 to 12 months of therapy. They also inhibit calcium absorption in the gut. Glucocorticoid-induced osteoporosis is among the FDA indications for bisphosphonates, which reduce bone resorption and do not directly stimulate osteoblasts.

E. No; it is not recommended for glycemic control in type 1 diabetes, because it may increase the risk of ketoacidosis — SGLT2 inhibitors are not recommended for glycemic control in type 1 diabetes, where they may increase the risk of diabetic ketoacidosis, and ketoacidosis on these drugs can occur with glucose below 250 mg/dL, so a normal glucose does not exclude it. Their glucose lowering is insulin-independent, through urinary glucose loss. Sulfonylureas are contraindicated in type 1 diabetes, because they work only with residual β-cell function and type 1 diabetes is absolute insulin deficiency. With insulin, an SGLT2 inhibitor raises the risk of hypoglycemia, and a lower insulin dose, not a higher one, may be required.

A. It blocks new hormone synthesis but does not inactivate stored or circulating hormone, so euthyroidism takes months — Thionamides inhibit thyroid peroxidase, blocking iodination and coupling on thyroglobulin, but they do not inactivate stored or circulating hormone, so reaching euthyroidism typically takes several months. Propranolol controls the tachycardia, anxiety and other adrenergic symptoms meanwhile, and at higher doses it also inhibits peripheral conversion of T4 to T3. Blocking hormone release is the action of pharmacologic iodide, and the peripheral conversion block is a property of propylthiouracil, not methimazole.

D. Lower the glimepiride dose — GLP-1 receptor agonists raise the risk of hypoglycemia, including severe hypoglycemia, when used with an insulin secretagogue such as a sulfonylurea, and the sulfonylurea dose may need to be lowered. Dulaglutide’s insulin release is glucose-dependent, metformin is unlikely to cause hypoglycemia on its own, and glyburide has a higher incidence of hypoglycemia than glimepiride.

A. Somatropin inhibits 11β-HSD1, reducing conversion of cortisone to cortisol and unmasking central adrenal insufficiency — GH and somatropin inhibit 11β-hydroxysteroid dehydrogenase type 1, which converts cortisone to active cortisol in liver and fat, so previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. Somatropin lowers rather than raises active cortisol, it causes fluid retention rather than fluid loss, and GH opposes insulin by decreasing insulin sensitivity.

B. Low TSH with a low free T4 — Octreotide suppresses secretion of thyroid-stimulating hormone, which may result in hypothyroidism. TSH drives thyroid hormone synthesis through its Gs-coupled receptor, so less TSH means less T4: the TSH is low rather than high, and the free T4 falls rather than rises.

E. No added fludrocortisone is needed, because high-dose hydrocortisone has significant mineralocorticoid activity — At crisis doses hydrocortisone has significant mineralocorticoid activity, so other mineralocorticoids such as fludrocortisone are unnecessary during the acute phase. Hydrocortisone is the definitive treatment of adrenal crisis, and in known adrenal insufficiency symptoms of a crisis are enough to start it without waiting for results. Fludrocortisone is used only for its mineralocorticoid effects, and dexamethasone lacks a mineralocorticoid effect.

C. Add a mineralocorticoid antagonist such as spironolactone — Hypokalemia was seen in 44% of patients with Cushing syndrome on Korlym, and if it persists despite potassium supplementation, a mineralocorticoid antagonist such as spironolactone or eplerenone is added. Fludrocortisone is a potent mineralocorticoid that increases potassium excretion. Stopping mifepristone and giving glucocorticoids without delay is the response to signs of adrenal insufficiency, such as weakness, nausea, fatigue, hypotension or hypoglycemia, which he does not have. Mifepristone has little affinity for the mineralocorticoid receptor.

B. It acts on glucagon receptors in the heart, and its positive inotropic effect is mediated through adenylate cyclase — Glucagon receptors are present in the heart, and glucagon’s positive inotropic effects, like its other extrahepatic effects, are mediated through adenylate cyclase. For β-blocker overdose a high-dose infusion may be used off-label with β-agonists such as epinephrine, after high-dose insulin euglycemic therapy and catecholamines are optimized. It acts through its own receptor rather than as a β-agonist, its cardiac effect is inotropic rather than through glucose alone, and it is itself a treatment for calcium-channel-blocker overdose.

C. Blocking GH action improved his glucose tolerance, so his diabetes drugs need lower doses — Pegvisomant blocks endogenous GH at its receptor and lowers IGF-1; glucose tolerance may improve, so antidiabetic doses are reduced as necessary to avoid hypoglycemia, which is the most common adverse reaction of insulin. GH can rise on pegvisomant, but GH opposes insulin by decreasing insulin sensitivity; metformin leaves insulin secretion unchanged; and IGF-1 falls rather than rises.

B. Withhold empagliflozin at least 3 days before surgery, and tell the anesthesia team that she takes semaglutide — SGLT2 inhibitors are withheld at least 3 days before surgery or procedures with prolonged fasting and resumed once the patient is stable and eating, and ketoacidosis on them can occur with glucose below 250 mg/dL. GLP-1 receptor agonists have rare postmarketing reports of pulmonary aspiration under general anesthesia or deep sedation from residual gastric contents despite fasting, so the anesthesia team should be told. Semaglutide’s half-life is about a week, so its effect does not wear off overnight.

D. Denosumab carries a boxed warning for severe hypocalcemia in advanced kidney disease, and oral alendronate is not recommended at her creatinine clearance — Patients with advanced chronic kidney disease (eGFR below 30 mL/min/1.73 m², including dialysis) are at greater risk of severe hypocalcemia after denosumab, with hospitalizations and fatal cases reported, and chronic kidney disease–mineral bone disorder markedly increases that risk. Oral alendronate is not recommended when creatinine clearance is below 35 mL/min; it is not metabolized and is excreted mainly in the urine. Denosumab itself undergoes minimal renal excretion and usually needs no renal dose adjustment, and it should not be stopped without a following antiresorptive, because fracture risk, including multiple vertebral fractures, rises after discontinuation.