Section 9.3: Adrenal & Pituitary Disorders

Adrenal & Pituitary Disorders (Cushing's, Addison's, Pheochromocytoma)

PANCE High-Yield Focus: Differentiating adrenal and pituitary disorders requires understanding endocrine feedback loops. Focus on Cushing's syndrome screening algorithms (24-hour urine cortisol and low-dose dexamethasone suppression), Addison's disease diagnosis (cosyntropin stimulation test) and steroid replacement rules, and the strict preoperative alpha-before-beta blockade requirement for pheochromocytoma.

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Cushing's Syndrome: Cortisol Excess

Pathophysiology

Cushing's syndrome is the clinical state resulting from chronic exposure to excess glucocorticoids.

• Exogenous (Iatrogenic): The most common cause overall, due to long-term high-dose steroid therapy.
• Endogenous Causes:
  • Cushing's Disease: An ACTH-secreting pituitary adenoma (70% of endogenous cases).
  • Adrenal Cushing's: A cortisol-secreting adrenal adenoma or carcinoma.
  • Ectopic ACTH Syndrome: An ACTH-secreting neuroendocrine tumor (e.g., small cell lung cancer).

Clinical Presentation

Classic features include truncal obesity, moon facies (rounded face), a dorsocervical fat pad (buffalo hump), supraclavicular fat pads, and wide (> 1 cm), purple skin striae on the abdomen or thighs. Other signs include proximal muscle weakness, hypertension, impaired glucose tolerance, easy bruising, osteopenia, and hirsutism.

Diagnostic Workup Flow

1. Screening (Requires at least 2 abnormal tests):
   • 24-hour Urinary Free Cortisol: Measures integrated free cortisol excretion; elevated in Cushing's.
   • 1-mg Overnight Dexamethasone Suppression Test (DST): Administer dexamethasone at 11:00 PM and measure cortisol at 8:00 AM. In normal individuals, cortisol suppresses to < 1.8 mcg/dL. Failure to suppress indicates Cushing's.
   • Late-Night Salivary Cortisol: Elevated; normal patients have a physiological nadir at night.
2. Determining ACTH Dependency (Measure Plasma ACTH):
   • Low ACTH (< 5 pg/mL): ACTH-independent. Indicates an adrenal tumor or exogenous steroid use. Perform CT of the abdomen.
   • High ACTH (> 20 pg/mL): ACTH-dependent. Indicates pituitary or ectopic ACTH.
3. High-Dose (8-mg) Dexamethasone Suppression Test:
   • Cushing's Disease (Pituitary): Cortisol suppresses (> 50% reduction in baseline) because pituitary cells retain some feedback sensitivity.
   • Ectopic ACTH: Cortisol does not suppress because secretion is completely autonomous.

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Addison's Disease: Adrenal Insufficiency

Pathophysiology

Adrenal insufficiency is characterized by deficient production of adrenal cortex hormones.

• Primary Adrenal Insufficiency (Addison's Disease): Autoimmune destruction of all three zones of the adrenal cortex (autoimmune adrenalitis). It results in a deficiency of both cortisol and aldosterone.
• Secondary Adrenal Insufficiency: Pituitary dysfunction leading to deficient ACTH. The most common cause is the abrupt cessation of chronic glucocorticoid therapy. Aldosterone levels remain normal because aldosterone is regulated by the renin-angiotensin-aldosterone system (RAAS), not ACTH.

Clinical Presentation

Common symptoms include chronic fatigue, muscle weakness, weight loss, anorexia, nausea, and orthostatic hypotension.

• Addison's-Specific Signs (Primary Only):
  • Hyperpigmentation: High ACTH levels cross-react with melanocortin-1 receptors, causing hyperpigmentation of palmar creases, buccal mucosa, and scars.
  • Electrolyte Abnormalities: Aldosterone deficiency leads to renal sodium wasting and potassium retention, causing hyponatremia, hyperkalemia, and non-gap metabolic acidosis.

Diagnostics

1. Screening: Low morning cortisol (< 3 mcg/dL).
2. Confirmatory Test: Cosyntropin (ACTH) Stimulation Test. Cortisol is measured before and 30/60 minutes after synthetic ACTH injection.
   • Primary (Addison's): Cortisol fails to rise (remains < 18 mcg/dL) and ACTH is elevated.
   • Secondary: Cortisol fails to rise or rises subnormally (due to adrenal atrophy), but ACTH is low or normal.

Management

• Maintenance:
  • Addison's: Lifetime replacement of both glucocorticoids (Hydrocortisone) and mineralocorticoids (Fludrocortisone).
  • Secondary: Glucocorticoid replacement only.
• Stress-Dosing Rules: Patients must double or triple oral doses during minor illnesses. IV Hydrocortisone (100 mg) is required for major surgical or medical stress.
• Adrenal Crisis: A life-threatening emergency presenting with refractory hypotension/shock, vomiting, abdominal pain, fever, hyponatremia, and hyperkalemia. Treat immediately with intravenous Hydrocortisone (100 mg bolus) and aggressive intravenous normal saline with dextrose. Do not delay treatment to wait for labs.

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Pheochromocytoma: Adrenal Medulla Tumor

Pathophysiology

A rare, catecholamine-secreting tumor arising from chromaffin cells of the adrenal medulla. It is associated with genetic syndromes: MEN 2A/2B, Von Hippel-Lindau (VHL), and Neurofibromatosis Type 1 (NF-1).

Clinical Presentation

Presents with paroxysmal (episodic) hypertension and the classic triad:

1. Episodic, severe headache
2. Diaphoresis (sweating)
3. Palpitations

Diagnostics

• Initial screening: 24-hour urine fractionated metanephrines and catecholamines (highest sensitivity) or plasma free metanephrines.
• Localization: CT or MRI of the abdomen/pelvis.

Preoperative Management Rule

Definitive treatment is surgical resection. However, patients require strict medical preparation:

1. Alpha-blockade FIRST: Initiate an irreversible alpha-blocker (e.g., Phenoxybenzamine) or selective alpha-1 blocker (e.g., Doxazosin) for 7–14 days to control blood pressure and expand intravascular volume.
2. Beta-blockade SECOND: Introduce a beta-blocker (e.g., Propranolol) only after adequate alpha-blockade has been established to control tachycardia.

• CRITICAL PANCE TRAP: Initiating a beta-blocker first is contraindicated. It blocks beta-2-mediated vasodilation, leaving alpha-1 receptors unopposed to bind circulating catecholamines. This causes profound, life-threatening vasoconstriction and a hypertensive crisis.

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Pituitary Disorders: Prolactinoma & Diabetes Insipidus

Prolactinoma

Prolactinomas are the most common functioning pituitary adenomas. Females present with amenorrhea, galactorrhea, and infertility. Males present with erectile dysfunction, decreased libido, and gynecomastia. Large macroadenomas (>10 mm) compress the optic chiasm, causing bitemporal hemianopsia and headaches. Diagnosis is established by elevated serum prolactin (> 200 ng/mL) and a brain MRI. First-line therapy is dopamine agonists (e.g., Cabergoline or Bromocriptine), which suppress hormone release and shrink the tumor; transsphenoidal surgery is reserved for refractory cases.

Diabetes Insipidus (DI)

DI is characterized by polyuria and polydipsia due to deficient ADH action. Central DI is caused by deficient ADH secretion (e.g., brain trauma, surgery), while Nephrogenic DI is caused by renal resistance (e.g., lithium toxicity, hypercalcemia). Diagnosis involves a water deprivation test followed by desmopressin challenge: in Central DI, urine osmolality increases by >50%, while in Nephrogenic DI, it remains low. Central DI is treated with Desmopressin, and Nephrogenic DI with thiazide diuretics and stopping lithium.

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Acromegaly and Gigantism

Acromegaly is caused by excessive growth hormone (GH) in adulthood; gigantism is the same excess occurring before epiphyseal plate closure. It is a pituitary blueprint topic.

• Pathophysiology: A benign pituitary somatotroph adenoma secretes excess GH. GH stimulates hepatic insulin-like growth factor 1 (IGF-1) production, which drives tissue growth.
• Clinical Presentation (Adults): Coarse facial features (macrognathia, frontal bossing, widened spaces between teeth), enlargement of hands and feet (ring/shoe size increasing), prognathism, macroglossia, headache, bitemporal hemianopsia (from suprasellar extension compressing the optic chiasm), carpal tunnel syndrome, hypertension, insulin resistance/ type 2 diabetes mellitus, and cardiomegaly.
• Diagnostic Workup:
  1. Serum IGF-1 — best initial screening test. Elevated IGF-1 suggests acromegaly.
  2. Oral Glucose Tolerance Test — confirmatory. In normal physiology, glucose suppresses GH. In acromegaly, GH fails to suppress below 1 ng/mL after 75 g oral glucose load (paradoxical elevation may even occur).
  3. Pituitary MRI — localize the adenoma.
• Management:
  1. Transsphenoidal surgical resection — first-line therapy for most pituitary adenomas.
  2. Somatostatin analogs (Octreotide, Lanreotide) — for patients who are not surgical candidates or have persistent disease postoperatively; suppress GH secretion.
  3. Dopamine agonist (Cabergoline) — useful in mild cases; less effective than somatostatin analogs for GH-secreting adenomas.
  4. Pegvisomant — a GH receptor antagonist used when somatostatin analogs fail; lowers IGF-1 but does not shrink the tumor.

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Diagnostic Differentiation of Adrenal Disorders