Free USMLE Step 1 Reproductive and Endocrine practice questions

Episodic headache, palpitations, and sweating with elevated plasma metanephrines and an adrenal mass indicate a pheochromocytoma. Catecholamine synthesis proceeds tyrosine to L-DOPA (tyrosine hydroxylase, BH4 cofactor), L-DOPA to dopamine (DOPA decarboxylase, pyridoxal phosphate), dopamine to norepinephrine inside the vesicle (dopamine β-hydroxylase, copper and vitamin C), and norepinephrine to epinephrine in chromaffin cells (PNMT, induced by cortisol). Tyrosine hydroxylase is the rate-limiting step, and metyrosine (α-methyl-p-tyrosine) is a competitive inhibitor of it, lowering production of all downstream catecholamines. It is added to α-blockade (always started before any β-blocker) in large or poorly controlled tumors before surgery, or for inoperable disease. Because it also reduces central catecholamine synthesis, sedation is its most common adverse effect; crystalluria and extrapyramidal symptoms can also occur.

B. DOPA decarboxylase is inhibited peripherally by carbidopa, used with levodopa in Parkinson disease, not in pheochromocytoma. C. Dopamine β-hydroxylase acts inside vesicles; its inhibition would lower norepinephrine but raise dopamine and is not the target of metyrosine. D. PNMT converts norepinephrine to epinephrine; inhibiting it would not reduce norepinephrine output. E. COMT inhibition (entacapone) would decrease metanephrine formation and raise catecholamine levels, worsening hypertension.

About 40% of serum calcium is bound to proteins, mainly albumin, about 10% is complexed with anions such as phosphate and citrate, and about 50% is free ionized calcium, the only physiologically active fraction and the one that PTH senses and regulates. When albumin falls, as in cirrhosis, nephrotic syndrome or malnutrition, the protein-bound fraction shrinks and total calcium falls, but ionized calcium stays normal because PTH continues to defend it. This is pseudohypocalcemia, and it fits his absence of symptoms, negative Chvostek and Trousseau signs, normal QT and normal PTH.

The usual estimate is: corrected calcium = measured calcium + 0.8 × (4 minus albumin in g/dL). Here, 7.4 + 0.8 × (4 minus 2.0) = 7.4 + 1.6 = 9.0 mg/dL, which is normal. The formula is only an approximation, and when albumin or pH is abnormal, or in critical illness, ionized calcium should be measured directly.

A. 7.4 mg/dL is the uncorrected measured value and overstates the problem. B. 8.2 mg/dL results from adding 0.8 only once (or from using 0.4 per g/dL), underestimating the correction. D. 9.8 mg/dL would require a correction factor of 1.2 per g/dL. E. 10.6 mg/dL results from adding 0.8 for each 0.5 g/dL rather than for each 1 g/dL of albumin below 4.

A boy who looks normal at birth and then, at 1 to 3 weeks of age, develops vomiting, dehydration, hypotension, hypoglycemia and genital hyperpigmentation has salt-wasting 21-hydroxylase deficiency. Boys are not detected at birth because they have no genital ambiguity, so they present with this adrenal crisis.

Loss of CYP21A2 blocks both branches that need 21-hydroxylation: progesterone cannot become 11-deoxycorticosterone on the way to aldosterone, and 17-hydroxyprogesterone cannot become 11-deoxycortisol on the way to cortisol. Without aldosterone, principal cells of the collecting duct reabsorb less sodium through ENaC and secrete less potassium and hydrogen ion, giving hyponatremia, hyperkalemia and a mild metabolic acidosis. The resulting volume depletion lowers renal perfusion pressure and strongly stimulates the juxtaglomerular cells, so plasma renin activity is high. Cortisol deficiency adds hypoglycemia and hypotension, and the high ACTH (from loss of feedback) stimulates melanocortin-1 receptors, causing hyperpigmentation.

B. Low sodium and high potassium with low renin is hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis), which is driven by low renin rather than by volume depletion. C. High sodium, low potassium and low renin reflect mineralocorticoid excess, as in 11β-hydroxylase deficiency or apparent mineralocorticoid excess, which cause hypertension. D. Hypokalemia with high renin is the pattern of pyloric stenosis, in which vomiting of gastric acid causes hypochloremic, hypokalemic metabolic alkalosis with secondary hyperaldosteronism; it presents somewhat later and without hyperpigmentation or hyperkalemia. E. Hyponatremia with low renin and normal potassium suggests SIADH, a volume-expanded state.

This patient has pituitary apoplexy: sudden hemorrhage into a previously unrecognized macroadenoma, here precipitated by anticoagulation. The thunderclap headache, vomiting, oculomotor palsy from lateral expansion into the cavernous sinus and bitemporal hemianopia from chiasmal compression all reflect abrupt expansion of the sellar contents.

The life-threatening feature is acute ACTH deficiency. Without ACTH, the adrenal fasciculata stops producing cortisol within hours. Cortisol is needed for vascular responsiveness to catecholamines (it upregulates alpha-1 adrenergic receptors and supports vascular tone), so its loss causes vasodilatory shock that resists fluids alone. Cortisol deficiency also explains the hypoglycemia (loss of gluconeogenic support) and contributes to hyponatremia, because cortisol normally suppresses ADH release, so free water is retained. This is why stress-dose hydrocortisone is given first, before imaging-driven decompression and before any thyroid hormone.

A. Aldosterone is wrong because its secretion is driven mainly by angiotensin II and potassium, which still work in secondary (pituitary) adrenal insufficiency; the normal potassium here confirms that the zona glomerulosa is intact.

C. Thyroxine deficiency develops over weeks because T4 has a half-life of about 7 days, and replacing it before cortisol can precipitate adrenal crisis.

D. ADH deficiency would cause diabetes insipidus with hypernatremia, not hyponatremia, and is rare with adenomas because ADH is made in the hypothalamus.

E. Growth hormone loss is common in hypopituitarism but does not cause acute shock.

Hypoglycemia is sensed by glucose-responsive neurons in the hypothalamus and brainstem, which drive a sympathoadrenal discharge. The resulting surge of circulating epinephrine raises glucose (hepatic glycogenolysis and gluconeogenesis) and produces the adrenergic warning symptoms seen here: tremor, palpitations, anxiety and a widened pulse pressure from β1 and β2 effects.

The adrenal medulla is one of the two exceptions to the usual sympathetic wiring. It receives preganglionic fibers from the thoracic splanchnic nerves directly, with no intervening ganglion. Like every preganglionic autonomic neuron, these fibers release acetylcholine onto Nn (neuronal) nicotinic receptors, ligand-gated cation channels. Opening of these channels depolarizes the chromaffin cells, which are neural crest derived, modified postganglionic sympathetic neurons. Calcium entry then triggers exocytosis of granules containing mostly epinephrine (made from norepinephrine by cortisol-induced PNMT). This is why ganglionic blockers such as mecamylamine blunt adrenal epinephrine release.

A and D are wrong because norepinephrine is released by most sympathetic postganglionic fibers onto target organs, not by the fibers that innervate the adrenal medulla, and chromaffin cells are not activated through adrenergic receptors. C is wrong because muscarinic receptors are the targets of parasympathetic postganglionic fibers and of the other sympathetic exception, the cholinergic fibers to eccrine sweat glands. E is wrong because Nm receptors are the muscle-type nicotinic receptors at the neuromuscular junction of skeletal muscle, the site of action of nondepolarizing blockers such as rocuronium, not the receptors on autonomic ganglion cells or chromaffin cells.

This infant has the classic triad of congenital toxoplasmosis: hydrocephalus (rapidly growing head, bulging fontanelle, enlarged ventricles), chorioretinitis (pigmented retinal scars) and diffuse intracranial calcifications. The distribution of calcium is the discriminating clue: Toxoplasma scatters calcifications randomly through the parenchyma, whereas CMV deposits them in a periventricular rim and Zika favors the subcortical junction.

Toxoplasma gondii is an obligate intracellular protozoan whose definitive host is the cat. Humans become infected by ingesting tissue cysts (bradyzoites) in undercooked meat such as pork, lamb or venison, or by ingesting oocysts from cat feces in litter, soil or unwashed produce. When a woman acquires a primary infection during pregnancy, tachyzoites disseminate and cross the placenta. Maternal infection is usually silent, so the diagnosis is often made in the infant. Prevention focuses on cooking meat thoroughly, washing produce and having someone else change the cat litter.

A. Unpasteurized soft cheese transmits Listeria monocytogenes, which causes amnionitis, preterm birth and neonatal sepsis or meningitis rather than this triad.

B. Young children in day care shed CMV in saliva and urine; congenital CMV causes periventricular calcifications, microcephaly and sensorineural hearing loss.

C. Aedes mosquitoes transmit Zika virus, which causes severe microcephaly, not hydrocephalus with macrocephaly.

E. A child with a slapped-cheek rash spreads parvovirus B19, which causes fetal anemia and hydrops.

Oligomenorrhea since menarche, infertility, hirsutism, obesity with acanthosis nigricans and polycystic-appearing ovaries indicate polycystic ovary syndrome. Rapid GnRH pulses favor LH over FSH, so theca cells overproduce androgens, and insulin resistance amplifies theca androgen output and lowers SHBG. The relative FSH deficiency stalls follicle maturation, so ovulation does not occur and no corpus luteum forms. Without a corpus luteum there is no luteal-phase progesterone. Meanwhile estrogen is continuously present, from the ovaries and from aromatization of androgens in adipose tissue. Estrogen drives endometrial proliferation, and progesterone normally converts it to secretory endometrium and then triggers shedding. Unopposed estrogen therefore produces endometrial hyperplasia, irregular heavy breakthrough bleeding and an increased risk of endometrioid endometrial carcinoma. Progestins or combined oral contraceptives protect the endometrium.

A. Androgens are not the main endometrial mitogen; their effect on the endometrium is mainly through aromatization to estrogen.

B. FSH is relatively low in PCOS, and FSH acts on granulosa cells, not on the endometrium.

C. Insulin raises ovarian androgen, not progesterone, production; lack of progesterone is the problem.

E. Estrogen receptors are retained and continuously stimulated; their loss would cause an atrophic endometrium.

Magnesium sulfate is the drug of choice to prevent and treat eclamptic seizures. Magnesium is cleared by the kidney, so when her urine output fell, the serum level climbed into the toxic range.

Magnesium is a physiologic calcium antagonist. At the neuromuscular junction, it competes with Ca2+ at voltage-gated calcium channels of the presynaptic motor nerve terminal. Acetylcholine release by synaptic vesicle exocytosis depends on that Ca2+ influx, so less acetylcholine is released per impulse and the end-plate potential shrinks. Neuromuscular transmission fails progressively: deep tendon reflexes disappear first (around 9 to 12 mg/dL), then respiratory depression follows, then cardiac conduction block and arrest. This fixed order is why reflexes, respiratory rate and urine output are monitored during the infusion. The treatment is to stop the infusion and give calcium gluconate, which overcomes the competitive antagonism at the nerve terminal.

A. Competitive nicotinic receptor blockade is the mechanism of nondepolarizing neuromuscular blockers such as rocuronium; magnesium acts mainly before the synapse.

B. Acetylcholinesterase inhibition increases acetylcholine and would cause fasciculations and cholinergic signs, not flaccid areflexia.

C. Upper motor neuron dysfunction from cerebral edema causes hyperreflexia, the expected finding in preeclampsia before magnesium; areflexia points away from it.

E. Hypokalemia can cause weakness, but magnesium infusion does not lower potassium enough to explain this, and her serum magnesium is clearly toxic.

Clustered, fine, linear and branching microcalcifications on screening mammography in a woman with no mass are the typical presentation of ductal carcinoma in situ. The biopsy shows a malignant proliferation of high-grade, pleomorphic cells that fills and distends ducts. The central necrosis with dystrophic calcification defines the comedo subtype (on cut section, the necrotic cores can be expressed like comedones), and the calcified necrotic debris casts the branching duct pattern seen on mammography. The intact myoepithelial layer and basement membrane around every duct (shown here by continuous p63 staining) and the absence of stromal tumor cells mean the lesion is still in situ. DCIS is a direct precursor of invasive ductal carcinoma, and high-grade comedo lesions carry the highest risk of progression.

A. Lobular carcinoma in situ is usually an incidental finding without calcifications; its cells are small, uniform and discohesive and lack E-cadherin, unlike these pleomorphic cohesive cells with necrosis. B. Invasive ductal carcinoma requires tumor cells beyond the myoepithelial layer and basement membrane in the stroma, which is absent here. D. Sclerosing adenosis produces calcifications that can mimic carcinoma, but it consists of benign, compressed small glands with preserved myoepithelium and no atypia or necrosis. E. Fat necrosis can calcify but shows necrotic fat and foamy macrophages rather than malignant ductal cells.

Pheochromocytoma (episodic hypertension, high metanephrines), medullary thyroid carcinoma (high calcitonin from parafollicular C cells), mucosal neuromas of the lips and tongue, and a marfanoid habitus without hyperparathyroidism define MEN 2B. It is caused by a germline activating mutation of RET, a receptor tyrosine kinase that signals through the RAS and MAP kinase pathway. This is unusual among familial cancer syndromes, most of which are caused by inherited tumor suppressors that need a second hit. Because RET is an oncogene, one mutated allele is enough to drive C-cell and chromaffin cell proliferation, and penetrance of medullary thyroid carcinoma is nearly complete, so carriers undergo prophylactic thyroidectomy, in MEN 2B within the first year of life. The same gene causes MEN 2A and familial medullary thyroid carcinoma, and somatic RET rearrangements occur in papillary thyroid carcinoma.

A. Loss of menin, a nuclear scaffold protein, causes MEN 1 (parathyroid, pituitary, and pancreatic tumors). B. Loss of neurofibromin, a RAS-GAP, causes neurofibromatosis type 1, which can include pheochromocytoma but not medullary thyroid carcinoma or mucosal neuromas. C. Loss of VHL, a substrate-recognition subunit of an E3 ligase, causes pheochromocytoma with renal cell carcinoma and hemangioblastoma. D. Gene amplification, such as N-MYC in neuroblastoma, is a somatic event and is not inherited.