6.3 Adrenal, Pituitary & Endocrine Syndromes
Key Takeaways
- Primary adrenal insufficiency is confirmed when peak serum cortisol fails to reach > 450–500 nmol/L at 30 minutes following 250 mcg tetracosactide, accompanied by elevated baseline plasma ACTH (> 300 pg/mL).
- Preoperative preparation for pheochromocytoma requires initiating non-selective alpha-blockade (phenoxybenzamine) 10–14 days prior to surgery; beta-blockers must NEVER be started before effective alpha-blockade.
- A high-dose (8 mg) dexamethasone suppression test differentiates pituitary Cushing's disease (> 50% suppression of baseline cortisol) from ectopic ACTH syndrome (no suppression).
- MEN1 presents with the 3 Ps (Parathyroid, Pituitary, Pancreatic NETs), whereas MEN2A/2B (RET proto-oncogene) feature medullary thyroid carcinoma and pheochromocytoma.
6.3 Adrenal, Pituitary & Endocrine Syndromes
Adrenal Insufficiency & Addisonian Crisis
Etiology & Pathophysiology
Primary adrenal insufficiency (Addison's disease) stems from destruction of the adrenal cortex, causing deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens. Autoimmune adrenalitis (anti-21-hydroxylase autoantibodies positive in > 80%) is the predominant cause in western countries. Tuberculosis, bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome), and metastatic disease represent major secondary etiologies. Secondary adrenal insufficiency results from pituitary ACTH deficiency (mineralocorticoid secretion is preserved due to intact renin-angiotensin-aldosterone signaling).
Diagnostic Evaluation
- Short Synacthen (Tetracosactide) Test: The gold-standard diagnostic procedure. Measure plasma cortisol before and 30 minutes following IM/IV injection of 250 mcg tetracosactide.
- Normal Response: Peak serum cortisol > 450–500 nmol/L at 30 minutes.
- Primary AI: Suboptimal peak cortisol (< 450 nmol/L) with elevated baseline plasma ACTH (> 300 pg/mL).
- Secondary AI: Suboptimal peak cortisol with low or inappropriately normal plasma ACTH.
Emergency Management of Addisonian Crisis
Addisonian crisis presents with refractory hypotension, shock, vomiting, severe hyponatremia, hyperkalemia, and hypoglycemia.
Immediate Protocol:
- IV Hydrocortisone: Administer 100 mg IV stat, followed by 200 mg/24h continuous infusion or 50 mg IV 6-hourly. Do NOT delay corticosteroid therapy to perform a Synacthen test if crisis is suspected.
- Intravenous Resuscitation: Rapid infusion of 0.9% NaCl (1 L over 1st hour) with dextrose added for hypoglycemia.
- Maintenance Phase: Transition to oral Hydrocortisone (15–25 mg daily divided: e.g., 10 mg at 07:00, 5 mg at 12:00, 5 mg at 17:00) and Fludrocortisone (50–200 mcg daily for primary AI). Educate patients on Sick Day Rules (double oral hydrocortisone dose during febrile illness).
Cushing's Syndrome: Diagnostic & Localization Pathway
Evaluating suspected Cushing's syndrome follows a strict 3-step diagnostic sequence.
Step 1: Confirmation of Hypercortisolism (Screening)
Require at least two positive screening tests:
- 1 mg Overnight Dexamethasone Suppression Test (ONDST): Serum cortisol > 50 nmol/L at 08:00 following 1 mg dexamethasone at 23:00 is abnormal.
- 24-Hour Urinary Free Cortisol (UFC): > 3-fold upper limit of normal.
- Late-Night Salivary Cortisol (23:00): Elevated on two separate nights.
Step 2: Plasma ACTH Determination
- Plasma ACTH < 10 pg/mL (ACTH-Independent): Indicates adrenal lesion (adenoma, carcinoma, nodular hyperplasia). Perform Adrenal CT.
- Plasma ACTH > 20 pg/mL (ACTH-Dependent): Indicates pituitary or ectopic ACTH hypersecretion. Proceed to localization tests.
Step 3: High-Dose Dexamethasone & Localization Matrix
| Diagnostic Test | Pituitary Cushing's Disease | Ectopic ACTH Syndrome (e.g., SCLC, Carcinoid) |
|---|---|---|
| High-Dose Dexa (8 mg ONDST) | > 50% suppression of baseline cortisol | No suppression (< 50% change) |
| CRH Stimulation Test | Exaggerated ACTH and Cortisol response | Minimal / No response |
| Inferior Petrosal Sinus Sampling (IPSS) | Central-to-peripheral ACTH ratio > 2 (unstimulated) or > 3 (post-CRH) | No gradient (< 2) |
Primary Aldosteronism (Conn's Syndrome)
Characterized by autonomous aldosterone hypersecretion causing hypertension, hypokalemia, and metabolic alkalosis.
- Screening: Plasma Aldosterone-to-Renin Ratio (ARR). An elevated ARR (> 750 pmol/L per ng/mL/h or > 35 in ng/dL units) is screening-positive.
- Subtype Localization: Adrenal CT scan followed by Adrenal Vein Sampling (AVS). AVS is mandatory to distinguish unilateral aldosterone-producing adenoma (cured by laparoscopic adrenalectomy) from bilateral adrenal hyperplasia (managed medically with Spironolactone or Eplerenone).
Pheochromocytoma Management Protocol
Catecholamine-secreting neuroendocrine tumor of adrenal chromaffin cells presenting with episodic headache, diaphoresis, and tachycardia.
Preoperative Medical Blockade Protocol
- Alpha-Adrenergic Blockade FIRST: Initiate non-selective alpha-blocker (Phenoxybenzamine 10 mg BD, titrated up) or selective alpha-1 blocker (Doxazosin) for 10–14 days prior to surgery to control blood pressure and restore intravascular volume.
- Beta-Adrenergic Blockade SECOND: Add Propranolol or Atenolol ONLY AFTER full alpha-blockade is established.
- CRITICAL WARNING: Starting a beta-blocker first causes unopposed alpha-stimulated vasoconstriction, triggering a catastrophic hypertensive emergency.
Pituitary Disorders & Hyperprolactinemia
Pituitary Apoplexy
Acute hemorrhage or infarction of a pituitary adenoma. Patients present with sudden-onset severe headache ("thunderclap"), bitemporal hemianopia, third cranial nerve palsy, acute hypopituitarism, and hemodynamic collapse. Management requires immediate IV Hydrocortisone 100 mg stat and urgent neurosurgical decompression.
Acromegaly
Driven by growth hormone (GH)-secreting pituitary macroadenomas. Features include coarse facial features, macroglossia, acral enlargement, hypertension, diabetes, and bitemporal visual field deficits.
- Screening: Serum IGF-1 (elevated for age and sex).
- Confirmation: Oral Glucose Tolerance Test (75g OGTT). Failure to suppress serum GH to < 1.0 mcg/L (or < 0.4 mcg/L on modern assays) confirms acromegaly.
- Treatment: First-line is transsphenoidal surgical resection. Medical therapy includes Somatostatin Receptor Ligands (Octreotide, Lanreotide) and GH receptor antagonists (Pegvisomant).
Hyperprolactinemia & Prolactinoma
Serum prolactin > 5000 mIU/L strongly indicates a prolactin-secreting pituitary adenoma (prolactinoma). Mild elevations (500–2000 mIU/L) can result from stalk compression, hypothyroidism (elevated TRH stimulates prolactin), or drugs (antipsychotics, metoclopramide).
- First-Line Treatment: Dopamine agonists (Cabergoline 0.25–0.5 mg twice weekly or Bromocriptine) are first-line for both micro- and macro-prolactinomas, producing tumor shrinkage and normalization of prolactin levels in > 80% of cases.
Multiple Endocrine Neoplasia (MEN) Syndromes
| Syndrome | Inheritance & Gene | Clinical Features (The "Ps and Ms") |
|---|---|---|
| MEN 1 | Autosomal Dominant (MEN1 gene encoding Menin) | 3 Ps: Parathyroid (95%), Pituitary (40%), Pancreatic NETs (70% - Gastrinoma, Insulinoma) |
| MEN 2A | Autosomal Dominant (RET proto-oncogene) | 2 Ps, 1 M: Medullary Thyroid Carcinoma (100%), Pheochromocytoma (50%), Parathyroid Hyperplasia (20%) |
| MEN 2B | Autosomal Dominant (RET proto-oncogene M918T) | 1 P, 2 Ms: Medullary Thyroid Carcinoma (100%), Pheochromocytoma (50%), Marfanoid Habitus & Mucosal Neuromas |
A 42-year-old woman is evaluated for a 3-cm left adrenal mass discovered incidentally on CT scanning. Biochemical screening reveals 24-hour urinary normetanephrines at 6 times the upper limit of normal, confirming a pheochromocytoma. She is scheduled for laparoscopic adrenalectomy. Which medical regimen represents the correct preoperative preparation?
A 45-year-old man presents with progressive proximal muscle weakness, central obesity, purple abdominal striae, and hypertension. Screening tests show a 24-hour urinary free cortisol of 420 nmol/24h (elevated) and a failed 1 mg overnight dexamethasone suppression test (08:00 cortisol 280 nmol/L). Baseline plasma ACTH is elevated at 95 pg/mL (normal 10–50 pg/mL). Next, an 8 mg high-dose dexamethasone suppression test is performed, resulting in an 08:00 serum cortisol of 42 nmol/L (an 85% reduction from baseline). What is the underlying cause of hypercortisolism?
A 28-year-old man with a history of vitiligo is brought to the emergency department with severe abdominal pain, vomiting, confusion, and profound hypotension (BP 72/44 mmHg). Examination reveals hyperpigmentation of the palmar creases and buccal mucosa. Laboratory investigations show Na⁺ 124 mmol/L, K⁺ 6.1 mmol/L, glucose 3.1 mmol/L, and urea 14.2 mmol/L. An acute Addisonian crisis is suspected. What is the immediate priority in management?