What is primary hypercortisolism, also known as Cushing's syndrome?

Primary Hypercortisolism (Cushing's Syndrome)

Primary hypercortisolism, commonly known as Cushing's syndrome, is an endocrine disorder caused by chronic excessive cortisol production from the adrenal glands that is independent of ACTH stimulation—this represents the ACTH-independent form where the adrenal glands autonomously overproduce cortisol without pituitary or ectopic ACTH drive. 1, 2

Pathophysiology

Primary hypercortisolism specifically refers to adrenal-origin cortisol excess where ACTH levels are suppressed or undetectable, distinguishing it from ACTH-dependent forms (pituitary Cushing's disease or ectopic ACTH production). 2, 3

• The adrenal glands produce cortisol autonomously without requiring ACTH stimulation from the pituitary gland 2
• This accounts for approximately 20% of all Cushing's syndrome cases due to endogenous cortisol overproduction 2
• ACTH levels are typically undetectable or suppressed because the excess cortisol provides negative feedback to the pituitary 2

Causes of Primary Hypercortisolism

The adrenal sources include:

• Adrenal adenomas (benign tumors)—the most common cause of primary hypercortisolism 4, 2
• Adrenal carcinomas (malignant tumors)—should be suspected when tumors are larger than 4-5 cm, have irregular margins, are internally heterogeneous, or show local invasion 4
• Bilateral micronodular adrenocortical disease—a rare cause presenting with bilateral adrenal involvement 2
• Macronodular adrenocortical hyperplasia—another uncommon bilateral adrenal pathology 2

Clinical Manifestations

The disorder presents with metabolic, cardiovascular, and psychological disturbances that develop insidiously over time. 1, 3

Classic Signs and Symptoms

• Weight gain with central obesity (face, back of neck, visceral organs) and facial plethora 4, 5
• Skin changes: purple abdominal striae, easy bruising, fragile skin, hirsutism 4
• Dorsal and supraclavicular fat pads ("buffalo hump") 4
• Metabolic complications: hyperglycemia, diabetes mellitus, hypertension 4, 5
• Musculoskeletal effects: muscle weakness, protein catabolism 4, 5
• Psychiatric manifestations: mood disorders, neurocognitive changes 4, 5
• Menstrual irregularities in women 4
• Hypokalemia may occur 6

Pediatric Presentation

• Growth failure with subnormal growth velocity combined with weight gain is the hallmark in children and adolescents 4
• Height standard deviation score (SDS) falls below the mean while BMI SDS rises above the mean for age and sex 4
• Not all children with Cushing's syndrome have obesity, and screening should only be offered to children with unexplained weight gain combined with either growth rate deceleration or height centile decrement 4

Diagnostic Approach

Step 1: Exclude Exogenous Glucocorticoid Use

• Rule out exogenous steroid administration as the most common cause of Cushing's syndrome before proceeding with further testing 5, 3

Step 2: Confirm Hypercortisolism

Three first-line screening tests are recommended, and none has 100% diagnostic accuracy: 4, 5

• 24-hour urinary free cortisol (UFC) measurement 4, 5
• Late-night salivary cortisol or sleeping midnight serum cortisol level 4, 5
• Low-dose dexamethasone suppression test (evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose) 4, 5

Step 3: Determine ACTH-Dependence

Plasma ACTH measurement distinguishes primary (adrenal) from secondary causes: 5, 3

• Suppressed or undetectable ACTH levels indicate ACTH-independent (primary adrenal) hypercortisolism 5, 2
• Mid-normal to elevated ACTH levels suggest ACTH-dependent forms (pituitary or ectopic sources) 5

Step 4: Additional Confirmatory Testing for Primary Hypercortisolism

• High-dose dexamethasone suppression test: Patients with primary adrenal causes do NOT suppress urinary steroid levels 2
• CRH stimulation test: Patients with primary adrenal disease do NOT increase plasma ACTH or cortisol levels after CRH administration 2

Step 5: Localize the Adrenal Pathology

Imaging is pursued only after biochemical confirmation of hypercortisolism: 4

• MRI of the adrenal glands is highly accurate, correctly diagnosing adenomas in 5 of 6 patients and identifying carcinomas and other adrenal pathology 2
• CT imaging characteristics help distinguish benign from malignant lesions:
  • Hounsfield unit (HU) >10 on unenhanced CT suggests possible malignancy 4
  • Enhancement washout <60% at 15 minutes suggests malignancy 4
  • Tumors >4-5 cm with irregular margins or heterogeneous appearance raise suspicion for carcinoma 4
• Petrosal sinus sampling can confirm that ACTH levels in the petrosal sinuses equal peripheral levels, consistent with primary adrenal (not pituitary) disease 2

Treatment

Surgical Management

First-line treatment is surgical removal of the cortisol-producing adrenal tumor: 5, 3, 7

• Laparoscopic adrenalectomy is recommended for benign adrenal adenomas 4
• Open adrenalectomy is recommended for suspected adrenal carcinoma due to rupture risk 4
• Bilateral adrenalectomy is required for bilateral micronodular disease or macronodular hyperplasia 4, 2
• Postoperative corticosteroid supplementation is mandatory until recovery of the hypothalamus-pituitary-adrenal (HPA) axis, which has been suppressed by chronic hypercortisolism 4

Medical Management

Medical therapy is reserved for patients who are not surgical candidates or have unresectable disease: 4, 8

• Ketoconazole (400-1200 mg/day) is most commonly used due to its relatively tolerable toxicity profile 4, 9
• Mitotane is an alternative adrenostatic agent 4, 9
• Mifepristone (glucocorticoid receptor blocker) can be used for symptomatic management, particularly for hyperglycemia and hypertension in Cushing's syndrome 8

Management of Hypertension

Aggressive blood pressure control is essential given the high cardiovascular disease risk: 4

• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are a sensible first-line strategy, as excess cortisol increases renal sodium absorption through mineralocorticoid receptor activation 4
• Hypercortisolism promotes hypertension through multiple additional pathways including renin-angiotensin system activation, vascular sensitization to catecholamines, and impaired nitric oxide bioavailability 4
• Adequate diuretic therapy is likely a cornerstone of successful blood pressure management 4

Monitoring and Prognosis

• Lifelong posttherapy monitoring is required to treat comorbidities and detect recurrence 3
• Patients cured by unilateral or bilateral adrenalectomy typically remain disease-free, though long-term follow-up is essential 2
• Cushing's syndrome is associated with significant multisystem morbidity and mortality if left untreated, including cardiovascular disease, immunosuppression, and metabolic complications 5, 3

Common Pitfalls

• Diagnosis is often delayed by several years due to insidiously progressive course, diverse clinical presentation, and overlap with common conditions like metabolic syndrome 4, 3
• Imaging should never precede biochemical confirmation of hypercortisolism to avoid false-positive findings 4
• In children, only those with unexplained weight gain PLUS growth deceleration warrant screening—obesity alone is insufficient 4
• Malignancy must be suspected in adrenal tumors >4-5 cm, with irregular morphology, or secreting multiple hormones 4