AVS 372 Exam 3

Lectures 12, 13, 14, 15, and 16

Which specific zone of the adult adrenal cortex is primarily responsible for the synthesis and secretion of mineralocorticoids such as aldosterone?

Zona Glomerulosa! The outermost layer produces mineralocorticoids (aldosterone and deoxycorticosterone) that maintain sodium and potassium balance.

Which protein acts as the rate-limiting step in transporting free cholesterol from the outer mitochondrial membrane into the inner mitochondrial membrane for steroid hormone synthesis?

Steroidogenic Acute Regulatory Protein (StAR)! Upon stimulation by ACTH or cAMP, StAR mediates the rate-limiting transport of free cholesterol into the mitochondria.

In Congenital Adrenal Hyperplasia (CAH) caused by a 21-hydroxylase deficiency, why is there an overproduction of adrenal androgens?

Decreased cortisol and aldosterone lead to compensatory ACTH overproduction, shunting 17-hydroxyprogesterone toward androgens.

Lacking cortisol feedback, ACTH SPIKES, and BLOCKED cortisol/aldosterone pathways cause accumulated precursors (like 17-OH progesterone) to overflow into the androgen pathway.

At the cellular level in the renal distal convoluted tubule and collecting duct, how does aldosterone promote sodium reabsorption?

Enhancing ENaC channel half-life and increasing expression of sodium transport proteins.

Sodium enters principal cells via ENaC channels on the luminal surface (with prolonged short-term half-life and increased long-term protein expression) and is pumped out by Na+/K+ ATPase.

How does Corticosteroid Binding Globulin (CBG/transcortin) bind cortisol compared to aldosterone in the circulation?

CBG has a single binding site with an affinity for cortisol approximately 20-fold higher than for aldosterone.

CBG binds cortisol with an affinity roughly 20 times higher than that of aldosterone.

In a standard 70kg (154lbs) mammal where total body water constitutes roughly 65% of body weight, how is that water primarily distrubuted between intracellular and extracellular compartments?

Intracellular fluid (~65% or 29L) and Extracellular (~35% or 16L)

Of the ~45L of total water, about 29L is intracelluar (65%) and 16L is extracellular (35%), which further subdivides into interstitial, vascular, and transcellular spaces.

Which of the following commonly prescribed blood pressure medications acts specifically as an aldosterone receptor antagonist?

Spironolactone (Aldosterone receptor antagonist)

Spironolactone is a classic mineralocorticoid receptor antagonist used to treat hypertension and hyperaldosteronism.

What is the approximate ratio of epinephrine (adrenaline) to norepinephrine (noradrenaline) secreted by the human adrenal medulla?

10:1 (Ephedrine/Epinephrine is ~80% of total catecholamines)

Epinephrine accounts for roughly 80% of the catecholamines secreted by the human adrenal medulla, yielding a roughly 10:1 E to NE ratio.

Which enzyme catalyzes the rate-limiting step in the biosynthesis of catecholamines (from L-tyrosine to DOPA)?

Tyrosine Hydroxylase (TH)

Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine synthesis, converting L-tyrosine to DOPA.

Beta-1 and Beta-2 adrenergic receptors exert their downstream intracellular effects primarily through which G-protein coupling mechanism?

Gs protein coupling, activating adenylyl cyclase and increasing cyclic AMP

Both beta-1 and beta-2 receptors couple to stimulatory G-proteins (Gs), activating adenylyl cyclase to raise intracellular cyclic AMP.

Activation of alpha-2 and adrenergic receptors typically produces which of the following physiological effects?

Inhibition of norepinephrine release at presynaptic terminals and reduction of cyclic AMP.

Alpha-2 receptors are coupled via Gi to inhibit adenylyl cyclase (decreasing cAMP) and act presynaptically to inhibit further norepinephrine release.

Through which receptor subtype do catecholamines stimulate hepatic glycogenolysis to elevate plasma glucose during the fight or flight response?

Beta-2 receptors (with contributions from alpha-1)

Beta-2 receptors in the liver and skeletal muscle strongly promote glycogenolysis and gluconeogenesis, increasing plasma glucose.

Which phase of the General Adaptation Syndrome (GAS) is characterized as an immediate, autonomic nervous system-directed response where epinephrine is the dominant hormone mobilizing energy reserves?

Alarm phase

The alarm phase is the immediate fight or flight response directed by the autonomic nervous system, with epinephrine as the dominant hormone.

What is a pheochromocytoma?

A catecholamine-secreting tumor arising from chromaffin cells of the adrenal medulla.

A pheochromocytoma (chromaffinoma) is a tumor of the adrenal medulla that secretes excess catecholamines, leading to severe hypertension and sympathetic attacks.

Circulating catecholamines have a very short half-life (less than 2 minutes) and are primarily inactivated by which 2 enzymatic pathways?

Catechol-O-methyltransferases (COMT) and Monoamine oxidases (MAO)

Catecholamines are rapidly degraded via methylation by COMT or deamination by MAO.

A 34-year-old female presents with fatigue, orthostatic hypotension, hyperpigmentation of the gums and palmar creases, and hyperkalemia. Lab testing reveals low morning serum cortisol and markedly elevated plasma ACTH. Which is the most likely diagnosis and underlying pathophysiologic mechanism?

Primary adrenal insufficiency (Addison’s disease) due to autoimmune destruction of the adrenal cortex, resulting in loss of negative feedback and elevated ACTH/MSH precursor cleavage.

Destruction of all 3 zones of the adrenal cortex causes a deficiency of cortisol and aldosterone, prompting compensatory overproduction of proopiomelanocortin (POMC), which cleaves into ACTH and melanocyte-stimulating hormone (MSH), driving hyperpigmentation.

Aldosterone binds to the intracellular mineralocorticoid receptor (MR) in principal cells of the cortical collecting duct. Which best describes the immediate genomic and cellular mechanism of aldosterone action?

Nuclear translocation of the ligand-receptor complex induces transcription of serum and glucocorticoid-regulated kinase 1(SGK1), which upregulates apical ENaC and basolateral Na+/K+-ATPase activity.

Aldosterone acts primarily through genomic pathways: binding the MR initiates transcription of target genes like SGK1, which activates pre-existing and newly synthesized Epithelial Sodium Channels (ENaC) and Na+/K+-pumps.

In human plasma, over 90% of circulating cortisol is bound to corticosteroid-binding globulin (CBG) and albumin, leaving a small unbound “free” fraction. During severe acute systemic inflammation or sepsis, how is this protein-binding dynamic primarily altered?

Leukocyte-derived elastase cleaves CBG, reducing its binding affinity and increasing the proportion of free, biologically active cortisol available to inflamed tissues.

Neutrophil elastase at sites of inflammation cleaves CBG, locally raising the free (active) cortisol fraction to help regulate the immune response.

A patient with hypertension and diabetic nephropathy is prescribed an ACE inhibitor (enalapril). 2 weeks later, follow-up labs show a mild-to-moderate rise in serum creatinine along with hyperkalemia. What is the primary renal hemodynamic explanation for the elevation in serum creatinine?

Vasodilation of the efferent glomerular arteriole reduces intraglomerular capillary hydrostatic pressure and transiently decreases glomerular filtration rate (GFR).

Angiotensin 2 preferentially constricts the efferent arteriole to maintain GFR when renal perfusion pressure drops. Blocking ACE reduces Ang 2, causing efferent dilation, a drop in glomerular hydrostatic pressure, and a slight rise in serum creatinine.

In Hans Selye’s General Adaptation Syndrome (GAS), the progression from the “state of resistance” to the “state of exhaustion” is marked by which fundamental physiological shift?

Depletion of bodily energy reserves (lipids, proteins, glycogen) and failure of the hypothalamic-pituitary-adrenal axis to sustain homeostatic compensation.

In the Stage of Resistance, the body adapts using glucocorticoids and catecholamines; if the stressor persists indefinitely, reserves run out, and the state of exhaustion ensues, leading to organ system compromise.

A 45-year-old patient presents with paroxysmal episodes of throbbing headache, diaphoresis, tachycardia, and severe hypertension. When investigating a suspected pheochromocytoma, genetic testing is often recommended because a significant percentage of cases are familial. Which panel of susceptibility genes is most classically associated with hereditary pheochromocytoma/paragangliomas?

RET, VHL, NF1, and SDH subunits (SDHB, SDHC, SDHD)

Roughly 30-40% of pheochromocytomas are hereditary, driven by germline mutations in RET (MEN 2A/2B), VHL (Von Hippel-Lindau), NF1 (Neurofibromatosis type 1), and SDH complexes.

Epinephrine and norepinephrine are metabolized through sequential actions of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Which specific end products of catecholamine degradation are measured in urine or plasma to screen for pheochromocytoma?

Metanephrines (normetanephrine and metanephrine) and vanillylmandelic acid (VMA).

COMT and MAO convert epinephrine and norepinephrine into metanephrines (noremetanephrine/metanephrine) and eventually VMA, which serve as the standard biochemical markers for diagnosis.

In the juxtaglomerular apparatus, which specific cellular sensor detects changes in luminal NaCl delivery in the thick ascending limb/early distal convoluted tubule to regulate renin release from juxtaglomerular granular cells?

Mecula densa cells via the apical Na+-K+-2Cl- (NKCC2) cotransporter.

Macula densa cells in the distal nephron use NKCC2 to sense luminal NaCl concentration; changes in NaCl flux trigger paracrine signals (like adenosine or prostaglandins) that modulate renin release from neighboring granular cells.

Which pharmacological agent lowers systemic blood pressure primarily by acting as an agonist at central presynaptic alpha-2 adrenergic receptors in the nucleus tractus solitarius (NTS) of the brainstem, thereby reducing sympathetic outflow?

Clonidine (central alpha-2 adrenergic agonist)

Clonidine stimulates central alpha-2 receptors in the brainstem vasomotor center, decreasing sympathetic outflow to the heart, blood vessels, and kidneys.

In classic 21-hydroxylase deficiency (the most common form of congenital adrenal hyperplasia), an enzymatic block prevents the conversion of progesterone and 17-hydroxyprogesterone into aldosterone and cortisol. Consequently, accumulated steroid precursors are shunted predominantly into which alternative pathway?

Androgen synthesis leads to excess DHEA and testosterone production and fetal virilization.

Because 21-hydroxylase is blocked, precursors back up and overflow into the androgen synthesis pathway, causing virilization of female newborns and salt-wasting due to aldosterone/cortisol deficiency.

In primary aldosteronism (Conn’s syndrome), chronic excessive aldosterone leads to sustained renal sodium and water reabsorption, yet patients typically do not develop severe peripheral edema or runaway hypernatremia. What physiological mechanism explains this “aldosterone escape”?

Pressure natriuresis and increased release of atrial natriuretic peptide (ANP) due to initial expansion of extracellular fluid volume override proximal/distal sodium retention.

The initial sodium and water retention expands blood volume and raises arterial pressure. This triggers pressure natriuresis in the renal tubules and the release of ANP from the atria, restoring sodium balance so net positive balance plateaus without runaway edema.

A patient with severe chronic liver cirrhosis exhibits marked hypoalbuminemia and decreased hepatic synthesis of corticosteroid-binding globulin (CBG). How does this affect total versus free (biologically active) plasma cortisol levels?

Total plasma cortisol is abnormally low, while free (unbound) cortisol remains essentially normal due to intact negative feedback regulation of the HPA axis.

Because most circulating cortisol is bound to CBG and albumin, a drop in carrier proteins lowers total measured cortisol. However, the hypothalamic-pituitary-adrenal (HPA) axis senses free cortisol levels and adjusts secretion so that biologically active free cortisol remains normal.

A patient presents with generalized fatigue, hyperkalemia, and orthostatic hypotension. An ACTH stimulation (cosyntropin) test shows a baseline serum cortisol of 3µg/dL with no significant rise 30 minutes post-injection. Which additional diagnostic test is most definitive for distinguishing primary adrenal insufficiency from secondary/tertiary adrenal insufficiency?

Basal plasma ACTH level (markedly elevated in primary, low or inappropriately normal in secondary/tertiary).

In primary adrenal insufficiency (Addison’s disease), the loss of cortisol feedback causes pituitary ACTH to spike. In secondary or tertiary insufficiency, ACTH is low or insufficiently compensated.

A 62-year-old patient with heart failure and resistant hypertension is prescribed a mineralocorticoid receptor antagonist. Comparing spironolactone and eplerenone, what highlights their pharmacological difference?

Eplerenone exhibits higher selectivity for the mineralocorticoid receptor with significantly lower affinity for androgen and progesterone receptors, resulting in a lower incidence of gynecomastia and menstrual irregularities.

In addition to upregulating ENaC and Na+/K+-ATPase in principal cells of the cortical collecting duct, aldosterone directly affects acid-base homeostasis in the distal nephron. What is its specific action on alpha-intercalated cells?

It stimulates apical H+-ATPase pumps and basolateral Cl-/HCO3- exchangers, promoting proton secretion into the lumen and systemic metabolic alkalosis.

Aldosterone stimulates alpha-intercalated cells to pump H+ into the urine via apical H+-ATPase while simultaneously reabsorbing bicarbonate via basolateral anion exchangers, driving metabolic alkalosis.

How do synthetic glucocorticoids (such as dexamethasone and prednisone) fundamentally differ from endogenous cortisol regarding their binding affinity to corticosteroid-binding globulin (CBG)?

Dexamethasone and prednisone possess very low or negligible affinity for CBG, meaning a significantly larger percentage of the circulating drug remains unbound and biologically active.

While endogenous cortisol is ~90% bound to CBG and albumin, synthetic fluorinated or modified glucocorticoids have low affinity for CBG, leaving a high fraction free to diffuse into cells.

A 38-year-old woman presents with chronic fatigue, orthostatic dizziness, progressive weight loss, and hyperpigmentation of the palmar creases and gingiva. Lab evaluation reveals hypoatremia, hyperkalemia, and a low baseline morning cortisol level that fails to rise after an ACTH (cosyntropin) stimulation test. What is the most likely underlying primary defect?

Autoimmune or destructive atrophy of the zona fasciculata and zona glomerulosa.

This clinical picture represents Addison disease (primary adrenal insufficiency). Destruction of the adrenal cortex leads to deficiencies in both glucocorticoids (cortisol) and mineralocorticoids (aldosterone), resulting in salt-wasting hyponatremia, hyperkalemia, and compensatory elevation of ACTH, which drives skin hyperpigmentation.

A 45-year-old man presents with treatment-resistant hypertension, episodic muscle cramping, and paresthesias. Lab studies show mild hypernatremia, severe hypokalemia, and metabolic alkalosis. Plasma renin activity is suppressed, and the aldosterone-to-renin ratio is markedly elevated. What underlying pathology is most characteristic of this condition?

Aldosterone-producing adenoma or bilateral idiopathic adrenal hyperplasia.

Primary aldosteronism is most frequently caused by an aldosterone-producing adenoma (Conn syndrome) or bilateral adrenal hyperplasia, leading to autonomous mineralocorticoid excess, suppressed renin, hypertension, and hyperkalemic alkalosis.

A 52-year-old woman with central obesity, a dorsocervical fat pad, easy bruising, and purple abdominal striae is evaluated for Cushing syndrome. A high-dose dexamethasone suppression test is performed, showing >50% suppression of serum cortisol and low plasma ACTH. What is the most precise anatomical localization of the pathology?

Pituitary ACTH-secreting adenoma (Cushing disease)

Cushing disease is caused by a pituitary corticotroph adenoma. These adenomas usually retain partial feedback sensitivity to high-dose glucocorticoids, causing suppression of ACTH and, subsequently, cortisol.

In the renal principal cell, circulating cortisol and aldosterone have similar binding affinities for the mineralocorticoid receptor (MR). How do renal principal cells maintain specificity so that physiologic concentrations of cortisol do not continuously overactivate the MR?

Co-expression of 11--beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts active cortisol to inactive cortisone.

11beta-HSD2 metabolizes cortisol into cortisone, which has a very low affinity for the mineralocorticoid receptor, leaving the MR free to bind aldosterone.

Following the binding of aldosterone to its cytosolic mineralocorticoid receptor in renal collecting duct principal cells, the delayed genomic response increases net sodium and water reabsorption. Which best describes the coordinated downstream actions?

Increased transcription and translation of apical ENaC subunits, basolateral Na+/K+=ATPase pumps, and mitochondrial ATP synthesis enzymes.

Aldosterone stimulates the gene expression of apical Epithelial Sodium Cannels (ENaC), basolateral Na+/K+-ATPase pumps, and Krebs cycle enzymes to fuel active sodium extrusion and potassium/hydrogen secretion.

A 26-year-old woman in her 2nd trimester of pregnancy has a total serum cortisol concentration that is nearly 3-fold higher than the non-pregnant reference range. However, she exhibits normal blood pressure, normal glucose tolerance, and no signs of Cushing syndrome. Why is her free (biologically active) cortisol level normal?

Estrogen-induced hepatic synthesis of Corticosteroid-Binding Globulin (CBG) raises bound cortisol, while free cortisol remains tightly regulated by negative feedback.

High estrogen during pregnancy upregulates hepatic synthesis of CBG. More cortisol is bound to CBG, increasing the total serum pool, but the free (biologically active) cortisol concentration is tightly regulated by the HPA axis and remains normal.

A 58-year-old hypertensive diabetic patient is prescribed lisinopril. 2 weeks later, he complains of a persistent, annoying dry cough. Which endogenous vasodilator and inflammatory peptide accumulates in the pulmonary circulation due to the inhibition of ACE (kininase 2)?

Bradykinin and substance P

ACE (kininase 2) is responsible for breaking down bradykinin and substance P. ACE inhibitors prevent this degradation, leading to local accumulation of bradykinin and substance P in the respiratory tree, which triggers sensory C-fiber irritation and cough.

What antihypertensive medications selectively block postsynaptic alpha-1-adrenergic receptors on vascular smooth muscle, causing both arterial and venous dilation without causing a significant reflex increase in heart rate?

Prazosin

Prazosin is a competitive alpha-1 adrenergic antagonist that relaxes arteriolar and venous smooth muscle. Unlike direct vasodilators (like hydrazine), it leaves presynaptic alpha-2 receptors intact to inhibit excess norepinephrine release, dampening reflex tachycardia.

During the initial “alarm” stage of Hans Selye’s general adaptation syndrome, the brainstem nucleus that serves as the principal central command center for noradrenergic arousal and sympathetic-adrenomedullary activation is the:

Locus coeruleus in the pontine tegmentum

The locus coeruleus is the principal noradrenergic nucleus in the brainstem, driving heightened vigilance, sympathetic outflow, and HPA-axis activation during the acute Alarm reaction of GAS.

As an organism transitions from the stage of Resistance into the final stage of Exhaustion in Hans Selye’s General Adaptation Syndrome, which physiological failure typically occurs?

Depletion of adrenal steroid and energy reserves, loss of blood pressure regulation, and systemic organ failure.

In the Exhaustion stage, chronic stress depletes adrenal cortisol/catecholamine precursors, exhausts cellular energy stores (ATP), and impairs cardiovascular and immune resilience, leading to tissue damage or collapse.

A 32-year-old man presents with episodic pounding headaches, diaphoresis, and severe tachycardia. Investigations confirm a catecholamine-secreting pheochromocytoma. What pharmacological management steps must be performed prior to surgical resection?

Initiation of alpha-adrenergic receptor antagonism (e.g., phenoxybenzamine) prior to beta-blockade.

Alpha-blockade (e.g., with phenoxybenzamine or doxazosin) must be established first to control blood pressure and expand plasma volume before introducing a beta-blocker to control reflex tachycardia.

A pheochromocytoma is diagnosed in a 28-year-old patient who also presents with medullary thyroid carcinoma and primary hyperparathyroidism. Genetic screening is most likely to identify a germline mutation in which gene?

RET proto-oncogene

This clinical triad defines Multiple Endocrine Neoplasia type 2A (MEN 2A), which is caused by activating germline mutations in the RET proto-oncogene.

Epinephrine and norepinephrine are metabolized by 2 primary enzymes: Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT). What direct intermediate metabolites are formed by the action of COMT on epinephrine and norepinephrine?

Metanephrine and normetanephrine

COMT methylates the meta-hydroxyl group of epinephrine to form metanephrine and norepinephrine to form normetanephrine.

Vanillylmandelic acid (VMA) is frequently measured in 24-hour urine collections to evaluate for catecholamine-secreting tumors. VMA represents the final common oxidative and O-methylated end product produced by the sequential or combined action of which 2 enzymes?

Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT)

VMA is the common end product generated when either epinephrine or norepinephrine undergoes both MAO-mediated oxidative deamination and COMT-mediated O-methylation.