2.5 Adrenal & Pituitary Disorders

Adrenal and pituitary diseases present with complex hormonal excesses and deficiencies. The ABIM examination emphasizes discriminating primary from secondary/ectopic endocrine etiologies, mastering dynamic stimulation and suppression testing, and executing strict preoperative pharmacologic sequences.

1. Adrenal Insufficiency & Acute Adrenal Crisis

Primary vs. Secondary / Tertiary Adrenal Insufficiency

+-------------------------------------------------------------------------------------------------------------+
| FEATURE             | PRIMARY ADRENAL INSUFFICIENCY (Addison)       | SECONDARY / TERTIARY INSUFFICIENCY    |
+---------------------+-----------------------------------------------+---------------------------------------+
| Anatomical Site     | Adrenal Cortex (> 90% destruction)            | Pituitary (ACTH) / Hypothalamus (CRH) |
| Common Etiologies   | Autoimmune adrenalitis (21-hydroxylase Abs),  | Abrupt steroid withdrawal (most common|
|                     | TB, fungal, adrenal hemorrhage (Waterhouse-   | Pituitary adenoma, surgery, apoplexy, |
|                     | Friderichsen, HIT, APS), Checkpoint inhibitors| Sheehan syndrome, infiltrative disease|
| Hormones Deficient  | Glucocorticoid (Cortisol) AND                 | Glucocorticoid (Cortisol) ONLY;       |
|                     | Mineralocorticoid (Aldosterone) + DHEA        | Aldosterone is INTACT (RAAS regulated)|
| Plasma ACTH         | Markedly ELEVATED (> 100-200 pg/mL)           | LOW or Inappropriately Normal         |
| Hyperpigmentation   | PRESENT (buccal mucosa, palmar creases, scars)| ABSENT (Skin is pale / alabaster)     |
| Serum Electrolytes  | Hyponatremia, HYPERKALEMIA, non-anion gap     | Hyponatremia (SIADH-like free water   |
|                     | metabolic acidosis (aldosterone deficiency)   | retention); POTASSIUM IS NORMAL       |
| Daily Replacement   | Hydrocortisone/Prednisone PLUS                | Hydrocortisone or Prednisone ONLY     |
|                     | Fludrocortisone (0.05-0.2 mg/day)             | (Fludrocortisone is NOT needed)       |
+-------------------------------------------------------------------------------------------------------------+

Diagnostic Workup of Adrenal Insufficiency

1. Morning Serum Cortisol & Plasma ACTH (8:00 AM):
   • Serum Cortisol < 3 mcg/dL: Confirms adrenal insufficiency.
   • Serum Cortisol > 18 mcg/dL: Excludes adrenal insufficiency.
   • Serum Cortisol 3–15 mcg/dL: Indeterminate; mandates dynamic stimulation testing.
2. High-Dose Cosyntropin (Synthetic ACTH 1–24) Stimulation Test:
   • Administer 250 mcg Cosyntropin IV or IM; measure serum cortisol at 0, 30, and 60 minutes.
   • Normal Response: Peak serum cortisol >= 18 mcg/dL (500 nmol/L).
   • Primary AI: Subnormal cortisol rise (<18 mcg/dL) with elevated baseline plasma ACTH.
   • Secondary/Tertiary AI: Subnormal cortisol response due to chronic adrenal cortical atrophy (or normal acutely in very recent pituitary injury; evaluate with insulin tolerance test or metyrapone test if acute pituitary injury suspected).

Acute Adrenal Crisis: Emergent Resuscitation

• Clinical Presentation: Refractory distributive and hypovolemic shock unresponsive to vasopressors, high fever, abdominal pain mimicking acute peritonitis, severe vomiting, lethargy, hyponatremia, hyperkalemia, and hypoglycemia.
• Emergency Protocol:
  1. Immediate IV Hydrocortisone: Administer 100 mg IV bolus stat, followed by 50–100 mg IV every 6–8 hours (or continuous infusion of 200 mg/24 hours). Never delay treatment to perform a cosyntropin stimulation test. (If dynamic testing is desired, Dexamethasone 4 mg IV can be given as it does not cross-react with serum cortisol assays).
  2. Aggressive Crystalloid Resuscitation: Rapid infusion of 0.9% Normal Saline + 5% Dextrose (D5NS) to treat volume depletion, hypotension, and hypoglycemia.
  3. Mineralocorticoid Note: High-dose hydrocortisone (>=100 mg/day) saturates mineralocorticoid receptors; fludrocortisone is unnecessary in the acute crisis phase.
• Sick-Day Rules for Chronic AI: During minor febrile illnesses (fever >38°C / 100.4°F), patients must double or triple their oral hydrocortisone dose for 3 days ("3x3 rule"). For severe vomiting/diarrhea or major surgery, administer intramuscular hydrocortisone (100 mg IM) and present to the emergency department.

2. Cushing Syndrome (Hypercortisolism)

Cushing syndrome encompasses the signs and symptoms of prolonged exposure to inappropriately high glucocorticoid levels.

Clinical Features

Central obesity, moon facies, facial plethora, dorsocervical and supraclavicular fat pads ("buffalo hump"), wide violaceous cutaneous striae (>1 cm) on the abdomen and flanks, proximal muscle weakness (difficulty standing from a chair without arms), easy bruising from minimal trauma, severe osteoporosis/vertebral fractures, hypertension, glucose intolerance, and neuropsychiatric changes.

Screening & Diagnostic Algorithm (Rule of 2 Tests)

First-line screening requires at least two concordant abnormal screening tests from the following three validated modalities:

1. 24-Hour Urinary Free Cortisol (UFC): > 3x upper limit of normal.
2. Late-Night Salivary Cortisol (>=2 measurements at 11:00 PM): Elevated (demonstrates loss of normal circadian cortisol nadir).
3. 1 mg Overnight Dexamethasone Suppression Test (DST): Administer 1 mg dexamethasone at 11:00 PM; measure serum cortisol at 8:00 AM. Normal suppression is cortisol < 1.8 mcg/dL (50 nmol/L); failure to suppress (>1.8 mcg/dL) confirms hypercortisolism.

3. Primary Aldosteronism (Conn Syndrome)

Primary aldosteronism (PA) is the most common cause of secondary hypertension, accounting for 5–10% of all hypertensive patients and up to 20% of patients with resistant hypertension.

Clinical Suspicion & Screening

• Indications for Screening: Resistant hypertension (uncontrolled on 3 antihypertensives including a diuretic, or requiring >=4 drugs), hypertension with spontaneous or diuretic-induced hypokalemia, hypertension with adrenal incidentaloma, or hypertension with family history of early-onset stroke (<40 yo).
• Screening Test: Morning, ambulatory Plasma Aldosterone Concentration (PAC in ng/dL) and Plasma Renin Activity (PRA in ng/mL/hr).
  • Positive Screen: PAC / PRA Ratio (ARR) > 20–30 with an absolute PAC >= 15 ng/dL and suppressed renin ($ ext{PRA} < 1.0 ext{ ng/mL/hr}$).
  • Testing Conditions: Correct hypokalemia before testing; discontinue mineralocorticoid antagonists (Spironolactone, Eplerenone) for 4–6 weeks prior to ARR measurement.
• Confirmatory Testing: Oral sodium loading test (24-hour urine aldosterone >12 mcg/24h with urine sodium >200 mEq/24h) or IV Saline Infusion Test (2 L 0.9% NS over 4 hours; post-infusion PAC >10 ng/dL confirms autonomous production).

Subtype Differentiation & Targeted Therapy

• Thin-Section Adrenal CT: Identifies large adrenocortical carcinoma and structural lesions.
• Adrenal Venous Sampling (AVS): Mandatory in surgical candidates before adrenalectomy. Adrenal CT frequently misidentifies non-functional incidentalomas or misses microadenomas. AVS measures cortisol-corrected aldosterone ratios from both adrenal veins.
  • Unilateral Aldosterone-Producing Adenoma (APA) (Lateralization >4:1): Treat with Laparoscopic Unilateral Adrenalectomy (cures hypokalemia in 100%, cures/improves hypertension in >85%).
  • Bilateral Idiopathic Hyperplasia (IHA) (No lateralization): Treat medically with Mineralocorticoid Receptor Antagonists: Spironolactone (first-line, 25–100 mg/day; causes gynecomastia/impotence via anti-androgen effects) or Eplerenone (selective MRA, fewer side effects).

4. Pheochromocytoma & Paraganglioma

Pheochromocytomas are catecholamine-producing neuroendocrine chromaffin cell tumors of the adrenal medulla (paragangliomas arise from extra-adrenal sympathetic/parasympathetic ganglia).

Clinical Presentation & Genetics

• Classic Paroxysmal Triad: Severe episodic headache, profuse diaphoresis, and tachycardia/palpitations in the setting of paroxysmal or sustained hypertension. Other symptoms: tremor, pallor, orthostatic hypotension (from contracted intravascular volume), and hyperglycemia.
• Hereditary Associations (~35–40%): MEN 2A/2B (RET), Von Hippel-Lindau (VHL), Neurofibromatosis Type 1 (NF1), and Succinate Dehydrogenase subunit mutations (SDHB, SDHD).

Diagnostic & Preoperative Protocol

1. Biochemical Diagnosis:
   • High-risk / Inpatient: Plasma Free Fractionated Metanephrines (highest sensitivity: 97–99%).
   • Standard / Outpatient: 24-Hour Urinary Fractionated Metanephrines and Catecholamines (high specificity).
   • Values > 3x upper reference limit confirm diagnosis.
2. Anatomical & Functional Imaging: Contrast-enhanced CT or MRI of abdomen/pelvis (classic hyperintense "lightbulb" sign on T2 MRI); functional imaging with 123-I MIBG or 68-Ga DOTATATE PET/CT for extra-adrenal or metastatic tumors.
3. CRITICAL Preoperative Medical Blockade Sequence:
   • Step 1 (Alpha-Blockade FIRST): Initiate Phenoxybenzamine (non-selective, non-competitive alpha-1/alpha-2 antagonist, 10 mg twice daily, titrating to orthostasis/nasal congestion) or selective alpha-1 blockers (Doxazosin, Terazosin) for 10–14 days preoperatively.
   • Step 2 (Volume Expansion): High-sodium diet and generous oral fluids starting on day 2–3 of alpha-blockade to restore contracted intravascular volume.
   • Step 3 (Beta-Blockade SECOND): Add Propranolol, Atenolol, or Metoprolol 2–3 days prior to surgery to treat reflex tachycardia ONLY AFTER establishing adequate alpha-blockade.
   • LETHAL EXAM TRAP: Never initiate beta-blockade prior to adequate alpha-blockade! Unopposed alpha-1 receptor activation causes catastrophic peripheral vasoconstriction, leading to severe hypertensive crisis, acute pulmonary edema, and intracerebral hemorrhage.

5. Pituitary Disorders & Pituitary Apoplexy

Hyperprolactinemia

• Etiology: Prolactinoma (microadenoma <10 mm, macroadenoma >=10 mm), medications (dopamine antagonists: haloperidol, risperidone, metoclopramide; SSRIs, verapamil), primary hypothyroidism (elevated TRH stimulates prolactin), and pituitary stalk compression ("stalk effect" with prolactin usually <100–150 ng/mL).
• Clinical Manifestations: Women: galactorrhea, oligomenorrhea/amenorrhea, infertility; Men: decreased libido, erectile dysfunction, gynecomastia, mass-effect headaches/bitemporal hemianopsia.
• Treatment: First-line therapy for both micro- and macroadenomas is Dopamine Agonist Therapy: Cabergoline (preferred over Bromocriptine due to higher efficacy, greater tumor shrinkage, and fewer GI side effects). Transsphenoidal surgery is reserved for drug-resistant tumors or acute visual deterioration.

Acromegaly

• Pathophysiology: Autonomous Growth Hormone (GH) hypersecretion from a somatotroph pituitary macroadenoma (>75%), stimulating excessive hepatic production of Insulin-like Growth Factor-1 (IGF-1).
• Clinical Features: Acral enlargement (increase in hat/ring/shoe size), coarse facial features, prognathism, macroglossia, frontal bossing, carpal tunnel syndrome, obstructive sleep apnea, hypertension, cardiomyopathy, glucose intolerance, and increased risk of colorectal adenomas/adenocarcinoma (requires regular colonoscopy surveillance).
• Diagnostic Protocol: Initial screening: Serum IGF-1 level (elevated; reflects integrated 24-hr GH levels). Confirmatory test: Oral Glucose Tolerance Test (OGTT with 75g glucose); normal individuals suppress GH to <1.0 mcg/L (or <0.4 mcg/L on sensitive assays); failure of GH suppression confirms acromegaly. Follow with pituitary MRI.
• Treatment: Transsphenoidal surgery is first-line. Medical therapy for persistent disease: Somatostatin receptor ligands (Octreotide LAR, Lanreotide), GH receptor antagonist (Pegvisomant), or Cabergoline.

Pituitary Apoplexy

• Emergency Presentation: Acute infarction or hemorrhage into a preexisting pituitary adenoma. Characterized by sudden catastrophic severe headache ("thunderclap"), visual acuity loss, bitemporal hemianopsia, ophthalmoplegia (CN III, IV, VI compression in cavernous sinus), and acute panhypopituitarism with life-threatening secondary adrenal collapse.
• Urgent Management: Immediate administration of Stress-Dose Glucocorticoids (Hydrocortisone 100 mg IV stat) to prevent fatal vascular collapse, emergent Pituitary MRI, and Urgent Neurosurgical Transsphenoidal Decompression within 24–48 hours for patients with visual field deficits or altered mental status.