12.3 Adrenal & Pituitary Axis Pathology
Key Takeaways
- Screening for Cushing syndrome utilizes 24-hour urinary free cortisol, late-night salivary cortisol, or 1-mg overnight dexamethasone suppression testing.
- Primary adrenal insufficiency presents with hyperkalemia, hyponatremia, hyperpigmentation, and elevated ACTH, whereas secondary adrenal insufficiency retains aldosterone secretion.
- Pheochromocytoma management mandates competitive alpha-adrenergic blockade (phenoxybenzamine) for 7-14 days prior to beta-blocker initiation and surgical resection.
- Dopamine agonists (cabergoline) are the first-line treatment for prolactinomas of any size, with surgery reserved for medication-resistant cases.
- Central Diabetes Insipidus demonstrates a >50% increase in urine osmolality following desmopressin administration, whereas Nephrogenic Diabetes Insipidus exhibits minimal response (<9%).
Adrenal & Pituitary Axis Pathology
Adrenal Cortex Pathology: Hypercortisolism & Cushing Syndrome
Hypercortisolism (Cushing syndrome) results from prolonged exposure to excess glucocorticoids. Etiologies are divided into ACTH-dependent (Cushing disease [pituitary ACTH adenoma], Ectopic ACTH [small cell lung carcinoma]) and ACTH-independent (exogenous steroids, adrenal adenoma/carcinoma, bilateral adrenal hyperplasia).
Diagnostic Workup of Suspected Cushing Syndrome
Screening requires establishing hypercortisolism using at least one of three validated first-line tests: (1) 24-hour Urinary Free Cortisol, (2) Late-Night Salivary Cortisol, or (3) 1-mg Overnight Dexamethasone Suppression Test (DST) (failure to suppress morning cortisol to <1.8 µg/dL).
[ Clinical Features of Hypercortisolism ]
(Central obesity, striae, hypertension)
│
[ Perform Initial Screen ]
(24-hr UFC, Late-Night Salivary, 1-mg DST)
│
[ Cortisol Elevated ]
│
[ Measure Plasma ACTH ]
│
┌──────────────────────────────┴──────────────────────────────┐
[ Low ACTH (<5 pg/mL) ] [ High ACTH (>20 pg/mL) ]
(ACTH-Independent) (ACTH-Dependent)
│ │
[ Abdominal CT/MRI ] [ High-Dose (8-mg) DST ]
│ │
┌─────────────┴─────────────┐ ┌──────────────┴──────────────┐
▼ ▼ ▼ ▼
Adrenal Adenoma / Exogenous Steroids [ Cortisol Suppressed ] [ No Suppression ]
Carcinoma (Clinical History) (Cushing Disease) (Ectopic ACTH)
│ │
▼ ▼
Pituitary MRI Chest CT Scan
Adrenal Insufficiency & Primary Hyperaldosteronism
Adrenal insufficiency (AI) represents deficient adrenocortical hormone production. Primary AI (Addison Disease) is caused by intrinsic destruction of the adrenal cortex (autoimmune adrenalitis in developed nations; tuberculosis worldwide), causing deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens. Secondary AI is caused by pituitary hypofunction or abrupt cessation of long-term glucocorticoids, resulting in deficient ACTH and cortisol while mineralocorticoid production remains intact (regulated by RAAS).
| Clinical/Laboratory Feature | Primary Adrenal Insufficiency (Addison) | Secondary Adrenal Insufficiency |
|---|---|---|
| Plasma Cortisol & ACTH | Low Cortisol, Markedly High ACTH | Low Cortisol, Low/Normal ACTH |
| Aldosterone Secretion | Deficient (Renin is High) | Intact (Renin is Normal) |
| Serum Electrolytes | Hyponatremia, Hyperkalemia, Acidosis | Hyponatremia (Euvolemic), Normal Potassium |
| Skin Hyperpigmentation | Present (POMC cleavage yields MSH) | Absent |
| ACTH Stimulation Test | Peak Cortisol <18 µg/dL (No response) | Subnormal or Delayed Response |
| Treatment | Hydrocortisone + Fludrocortisone | Hydrocortisone alone |
Adrenal Crisis Management
Adrenal crisis is a life-threatening medical emergency presenting with profound shock refractory to vasopressors, fever, confusion, and severe abdominal pain. Treatment must be initiated immediately upon clinical suspicion:
- High-dose IV Hydrocortisone 100 mg bolus, followed by 200 mg/24 hours continuous infusion or 50 mg IV every 6 hours.
- Rapid infusion of 0.9% Normal Saline with 5% Dextrose to restore intravascular volume and correct hypoglycemia.
- Diagnostic testing (cosyntropin stimulation test) should never delay treatment. If testing must be performed during crisis, use Dexamethasone as it does not cross-react with serum cortisol assays.
Primary Hyperaldosteronism (Conn Syndrome)
Autonomous aldosterone hypersecretion by an adrenal adenoma (Conn syndrome, 30%) or bilateral adrenal hyperplasia (70%). Features include resistant hypertension, hypokalemia (often normokalemic early), muscle weakness, and metabolic alkalosis.
- Screening: Morning Plasma Aldosterone Concentration (PAC) to Plasma Renin Activity (PRA) ratio >20 with PAC >15 ng/dL.
- Confirmation: Oral salt loading test or IV saline infusion test (failure to suppress PAC <5 ng/dL).
- Subtype Localization: Abdominal CT followed by Bilateral Adrenal Venous Sampling (AVS) to distinguish unilateral adenoma (cured by laparoscopic adrenalectomy) from bilateral hyperplasia (treated medically with Spironolactone or Eplerenone).
Pheochromocytoma: Preoperative Medical Management
Pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells in the adrenal medulla (or extra-adrenal paraganglioma). It presents with the classic triad of episodic headache, sweating (diaphoresis), and tachycardia, associated with paroxysmal or persistent hypertension.
- Diagnosis: Elevated plasma free metanephrines or 24-hour urinary fractionated metanephrines and catecholamines, followed by abdominal CT or MRI.
- Preoperative Medical Management Protocol:
- Alpha-Adrenergic Blockade FIRST: Administer non-selective, irreversible alpha-blocker Phenoxybenzamine (or selective alpha-1 blocker doxazosin) for 7 to 14 days prior to surgery to expand intravascular volume and control blood pressure.
- Beta-Adrenergic Blockade SECOND: Initiate Propranolol or atenolol only 2 to 3 days prior to surgery to control tachyarrhythmias.
- CRITICAL WARNING: Never start beta-blockers before alpha-blockers. Blockade of vasodilatory beta-2 receptors in the presence of unopposed alpha-1 stimulation triggers catastrophic, fatal hypertensive crises and acute pulmonary edema.
Hypothalamic & Pituitary Pathology
Hyperprolactinemia & Prolactinoma
Prolactin is inhibited tonically by hypothalamic dopamine. Hyperprolactinemia presents with hypogonadism, galactorrhea, amenorrhea, decreased libido, and erectile dysfunction. Macroadenomas (>10 mm) cause mass effect (bitemporal hemianopsia, headache).
- Workup: Exclude pregnancy, primary hypothyroidism (elevated TRH stimulates prolactin), and dopamine-blocking medications (antipsychotics, metoclopramide). Order pituitary MRI.
- Treatment: Dopamine Agonists (Cabergoline preferred over Bromocriptine) are first-line for all prolactinomas (micro- and macroadenomas) to shrink tumor size and restore gonadal function. Transsphenoidal surgery is reserved for tumors resistant or intolerant to dopamine agonists.
Acromegaly
Growth Hormone (GH) hypersecretion by a pituitary somatotroph adenoma. Features include acral tissue overgrowth (increased shoe/glove size), coarse facial features, macroglossia, hypertension, cardiomyopathy, diabetes mellitus, and colonic polyps.
- Screening: Elevated serum Insulin-like Growth Factor 1 (IGF-1).
- Confirmation: Oral Glucose Tolerance Test (OGTT) demonstrating failure of serum GH suppression to <1 ng/mL after 75g oral glucose load.
- Treatment: First-line is Transsphenoidal Surgical Resection. Medical therapy includes Somatostatin Analogs (Octreotide, Lanreotide) or GH receptor antagonists (Pegvisomant).
Diabetes Insipidus (DI) vs. SIADH
| Diagnostic Parameter | Central Diabetes Insipidus | Nephrogenic Diabetes Insipidus | SIADH |
|---|---|---|---|
| Pathophysiology | Lack of ADH secretion from posterior pituitary | Renal V2 receptor resistance to ADH (Lithium, Hypercalcemia) | Unregulated excess ADH secretion (Small cell lung cancer, CNS disease) |
| Serum Sodium / Osmolality | High/Normal (>145 mEq/L) / Hyperosmolar | High/Normal (>145 mEq/L) / Hyperosmolar | Hyponatremia (<135 mEq/L) / Hypoosmolar (<275 mOsm/kg) |
| Urine Osmolality | Dilute (<300 mOsm/kg) | Dilute (<300 mOsm/kg) | Concentrated (>100 mOsm/kg) |
| Water Deprivation Test | Urine Osmolality increases >50% after Desmopressin (dDAVP) | Urine Osmolality increases <9% after Desmopressin | N/A (Euvolemic hyponatremia) |
| First-Line Treatment | Desmopressin (dDAVP) | Discontinue offending drug, Thiazides, Amiloride | Fluid Restriction (800–1000 mL/day), Oral Salt; 3% Hypertonic Saline if severe. |
A 42-year-old man is evaluated for paroxysmal severe headaches, palpitations, and profuse sweating. His blood pressure is 198/112 mmHg, and heart rate is 118/min. Laboratory evaluation reveals a plasma free normetanephrine level of 1,850 pg/mL (normal <148 pg/mL) and metanephrine level of 920 pg/mL (normal <57 pg/mL). Abdominal CT scan shows a 4.2-cm right adrenal mass. Surgical resection is planned. Which of the following is the most appropriate initial medication to initiate?
A 28-year-old man with bipolar disorder treated with lithium carbonate presents with persistent severe thirst and high-volume urination of 5 liters per day. Laboratory studies show a serum sodium of 147 mEq/L, serum osmolality of 302 mOsm/kg, and urine osmolality of 160 mOsm/kg. A water deprivation test is performed, during which urine osmolality remains at 165 mOsm/kg. Desmopressin (dDAVP) is then administered, and urine osmolality measured 2 hours later is 172 mOsm/kg (a 4% increase). Which of the following is the most likely diagnosis?
A 38-year-old woman presents with progressive weight gain, facial fullness, purple abdominal striae, and easy bruising. Physical examination shows central obesity and a dorsocervical fat pad. Initial screening with a 1-mg overnight dexamethasone suppression test reveals a morning serum cortisol of 8.4 µg/dL (normal <1.8 µg/dL). Baseline plasma ACTH level is measured at 84 pg/mL (elevated, normal 10-60 pg/mL). High-dose (8-mg) overnight dexamethasone suppression testing demonstrates a >65% reduction in serum cortisol. Which of the following is the most likely diagnosis?