Basic Sciences in Endocrinology

The prolonged duration of action of insulin degludec is principally due to which property?

Formation of a hexadecanedioic acid-linked multihexamer depot at the subcutaneous injection site.

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Binding to and slow dissociation from serum albumin via a fatty acid side chain.

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Isoelectric precipitation into microcrystals at physiological subcutaneous pH.

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Pegylation increasing hydrodynamic volume and delaying capillary absorption.

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Substitution of proline with aspartic acid at position B28 reducing self-association.

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Parathyroid hormone acting on the PTH1 receptor in renal tubular cells generates which primary second messenger response?

Activation of Gs with adenylyl cyclase-mediated cyclic AMP generation.

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Ligand-activated nuclear receptor binding to hormone response elements.

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Membrane guanylyl cyclase activation producing cyclic GMP.

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Receptor tyrosine kinase autophosphorylation recruiting insulin receptor substrate proteins.

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Signal transducer and activator of transcription phosphorylation via JAK2.

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Which physiological state most commonly causes an elevated total thyroxine concentration with a normal free thyroxine and normal thyroid-stimulating hormone?

Increased thyroxine-binding globulin due to oestrogen excess.

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Familial dysalbuminaemic hyperthyroxinaemia.

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Nephrotic syndrome with urinary binding protein loss.

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Non-thyroidal illness with reduced deiodinase activity.

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Thyroid hormone resistance from a THRB variant.

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What is the physiological principle underlying the 1 mg overnight dexamethasone suppression test?

Glucocorticoid receptor-mediated negative feedback on corticotroph proopiomelanocortin transcription and ACTH release.

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Competitive displacement of cortisol from corticosteroid-binding globulin.

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Direct inhibition of adrenal 11β-hydroxylase by dexamethasone.

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Saturation of hepatic 11β-hydroxysteroid dehydrogenase type 1.

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Stimulation of hypothalamic corticotropin-releasing hormone clearance.

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Deficiency of 21-hydroxylase results in accumulation of which steroid precursor that serves as the principal diagnostic marker?

17-Hydroxyprogesterone.

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11-Deoxycortisol.

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Dehydroepiandrosterone sulfate.

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Deoxycorticosterone.

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Pregnenolone sulfate.

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Which medication class most commonly causes a false-negative aldosterone-to-renin ratio when screening for primary aldosteronism?

Spironolactone

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Amlodipine

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Hydralazine

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Prazosin

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Verapamil

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Why are plasma free metanephrines preferred over plasma catecholamines for the diagnosis of phaeochromocytoma?

Metanephrines are continuously produced within tumour cells by membrane-bound catechol-O-methyltransferase, independent of catecholamine release.

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Metanephrines are exclusively produced in the adrenal medulla and are absent from sympathetic neurones.

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Metanephrines are cleared by monoamine oxidase, giving a longer plasma half-life than catecholamines.

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Metanephrines are not affected by posture or venepuncture stress in any circumstance.

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Metanephrines reflect only extra-adrenal paraganglioma activity.

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Which statement best describes the regulation of circulating insulin-like growth factor 1?

IGF-1 production requires adequate nutritional status and is suppressed in malnutrition and hepatic failure despite elevated growth hormone.

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IGF-1 circulates predominantly unbound, giving it a short plasma half-life.

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IGF-1 is produced mainly by the anterior pituitary under hypothalamic control.

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IGF-1 secretion is pulsatile, mirroring growth hormone pulses over minutes.

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IGF-1 stimulates pituitary growth hormone release through a positive feedback loop.

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Which mechanism explains the elevated prolactin seen with large non-functioning pituitary macroadenomas?

Compression of the hypothalamic–pituitary stalk interrupting dopaminergic inhibition.

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Autonomous prolactin secretion by gonadotroph tumour cells.

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Ectopic production of prolactin-releasing peptide by the tumour.

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Increased prolactin glycosylation prolonging its half-life.

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Loss of oestrogen-mediated suppression of lactotroph proliferation.

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What is the physiological basis for measuring copeptin in the differential diagnosis of the polyuria–polydipsia syndrome?

Copeptin is a stable C-terminal fragment of the vasopressin precursor secreted in equimolar amounts with vasopressin.

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Copeptin is a vasopressin antagonist whose level rises reciprocally with vasopressin secretion.

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Copeptin is derived from the oxytocin precursor and reflects posterior pituitary reserve generally.

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Copeptin is filtered and reabsorbed in the proximal tubule, so levels reflect renal function alone.

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Copeptin is generated within the collecting duct in response to V2 receptor activation.

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What is the principal mechanism by which dual GIP and GLP-1 receptor agonism produces greater weight loss than GLP-1 receptor agonism alone?

Complementary central appetite suppression with GIP receptor-mediated effects on adipose tissue nutrient handling and enhanced tolerability.

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Blockade of gastric ghrelin secretion by GIP receptor antagonism.

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Direct inhibition of pancreatic glucagon secretion by GIP.

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Increased renal sodium excretion producing sustained fluid loss.

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Uncoupling protein 1 activation in brown adipose tissue by GLP-1.

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Which statement best describes the pathophysiology of leptin in common (polygenic) obesity?

Leptin concentrations are proportional to fat mass but hypothalamic resistance impairs the anorexigenic response.

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Leptin concentrations are low, reflecting reduced adipocyte production.

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Leptin deficiency arises from impaired cleavage of the leptin precursor peptide.

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Leptin receptor expression is increased, causing paradoxical hyperphagia.

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Leptin primarily signals through a Gs-coupled receptor to raise cyclic AMP in POMC neurones.

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Which autoantibody has the highest positive predictive value for progression to type 1 diabetes when detected as the first-appearing antibody in early childhood?

Insulin autoantibody.

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Islet antigen-2 (IA-2) antibody.

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Glutamic acid decarboxylase 65 antibody.

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Thyroid peroxidase antibody.

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Zinc transporter 8 antibody.

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The thyroid-stimulating immunoglobulins of Graves disease exert their effect through which mechanism?

Agonist binding to the TSH receptor with constitutive Gs activation and cyclic AMP generation.

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Blockade of thyroid peroxidase-mediated iodine organification.

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Complement-mediated destruction of thyroid follicular cells.

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Cross-reactivity with the sodium–iodide symporter increasing iodine trapping only.

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Inhibition of type 2 deiodinase in peripheral tissues.

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Activation of the calcium-sensing receptor on parathyroid chief cells by extracellular calcium produces which effect?

Gi and Gq coupling with suppression of parathyroid hormone secretion and gene transcription.

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Gs-mediated stimulation of parathyroid hormone secretion.

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Increased parathyroid cell proliferation through beta-catenin signalling.

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Nuclear translocation of the vitamin D receptor with transcriptional activation of PTH.

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Sodium-dependent calcium entry causing membrane depolarisation and hormone release.

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In the biochemical evaluation of male hypogonadism, which factor most commonly causes a low total testosterone with a normal free testosterone?

Reduced sex hormone-binding globulin from obesity and insulin resistance.

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Elevated luteinising hormone from primary testicular failure.

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Hyperprolactinaemia suppressing GnRH pulsatility.

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Increased sex hormone-binding globulin from thyrotoxicosis or ageing.

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Use of an exogenous androgen suppressing endogenous production.

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What is the origin of the elevated serum anti-Müllerian hormone concentration in polycystic ovary syndrome?

Granulosa cells of small antral and pre-antral follicles, which are increased in number.

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Corpus luteum production during the luteal phase.

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Ovarian stromal theca cells under luteinising hormone stimulation.

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Peripheral conversion of androstenedione in adipose tissue.

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Sertoli cell homologue tissue within ovarian hilar remnants.

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During prolonged fasting beyond 72 hours, which adaptation is most important for preserving lean body mass?

Increased whole-body reliance on ketone bodies, reducing the need for gluconeogenesis from amino acids.

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Enhanced hepatic glycogenolysis maintaining euglycaemia.

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Increased skeletal muscle uptake of glucose via GLUT4 translocation.

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Suppression of hormone-sensitive lipase limiting free fatty acid oxidation.

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Upregulation of renal ammoniagenesis to buffer lactic acid.

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Which mechanism of gene dysfunction underlies multiple endocrine neoplasia type 2?

Activating (gain-of-function) mutation of a receptor tyrosine kinase proto-oncogene.

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Biallelic inactivation of a DNA mismatch repair gene.

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Epigenetic silencing of an imprinted locus.

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Inactivating mutation of a tumour suppressor gene requiring a second somatic hit.

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Trinucleotide repeat expansion causing a toxic gain of function.

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Romosozumab increases bone mineral density through which mechanism?

Inhibition of sclerostin, disinhibiting Wnt/beta-catenin signalling in osteoblasts.

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Inhibition of cathepsin K, reducing osteoclast degradation of type I collagen.

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Inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway of osteoclasts.

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Intermittent parathyroid hormone receptor activation favouring osteoblast survival.

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Neutralisation of receptor activator of nuclear factor kappa-B ligand, preventing osteoclast differentiation.

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Basic Sciences in Endocrinology

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