Are Hypercortisolism and Cushing's Syndrome Interchangeable Terms?
No, hypercortisolism and Cushing's syndrome are not interchangeable—hypercortisolism is the broader physiological state of excess cortisol, while Cushing's syndrome specifically refers to pathologic/neoplastic hypercortisolism caused by tumors (ACTH-secreting or adrenal neoplasms). 1, 2
Understanding the Critical Distinction
Hypercortisolism encompasses ALL causes of elevated cortisol, including both pathologic and physiologic etiologies. 1 This broader term describes the biochemical state without implying causation.
Cushing's syndrome is a subset of hypercortisolism that specifically indicates sustained pathologic hypercortisolism from neoplastic sources:
- ACTH-secreting pituitary adenomas (Cushing's disease, 75-80% of cases) 3
- Ectopic ACTH-secreting tumors (approximately 10% of cases) 4
- Autonomous cortisol secretion from benign or malignant adrenal neoplasms (approximately 20% of cases) 4, 1
The Physiologic/Non-Neoplastic Hypercortisolism Category
A critical pitfall is failing to recognize that hypercortisolism can be physiologic/non-neoplastic (formerly called "pseudo-Cushing's syndrome"), which mimics true Cushing's syndrome clinically and biochemically but has no underlying tumor. 1, 2
Common causes of physiologic/non-neoplastic hypercortisolism include:
- Alcohol use disorder (can produce indistinguishable features from neoplastic disease) 1, 2
- Chronic kidney disease (inflammatory activation of HPA axis) 1, 2
- Severe depression and neuropsychiatric disorders (sustained HPA axis activation) 4, 1
- Poorly controlled diabetes mellitus (may cause false-positive screening tests) 3, 1
- Severe obesity (can activate HPA axis and cause false-positive results) 3, 1
Clinical Implications of This Distinction
Using these terms interchangeably leads to diagnostic errors and inappropriate treatment. 1, 2 A patient with alcohol-induced hypercortisolism does not have Cushing's syndrome and should not undergo pituitary surgery or adrenalectomy.
The diagnostic approach must differentiate between these entities:
- Initial screening tests (24-hour urinary free cortisol, 1-mg dexamethasone suppression test, late-night salivary cortisol) detect hypercortisolism of any cause 5, 6, 7
- Normal screening tests exclude hypercortisolism entirely (high sensitivity and negative predictive value) 1
- Abnormal screening tests require clinical correlation to determine if the hypercortisolism is pathologic/neoplastic (true Cushing's syndrome) or physiologic/non-neoplastic 1, 2
Key distinguishing features favoring physiologic/non-neoplastic hypercortisolism:
- History of alcoholism, renal failure, or severe psychiatric disorders should raise immediate suspicion 1
- Mild hypercortisolism with monitoring over 3-6 months may show resolution when underlying condition is treated 5
- Desmopressin stimulation test and dexamethasone-CRH test can help distinguish neoplastic from non-neoplastic causes 1, 2
Proper Terminology in Clinical Practice
When documenting, specify the type of hypercortisolism:
- "Pathologic/neoplastic hypercortisolism (Cushing's syndrome)" for tumor-related cases 1
- "Physiologic/non-neoplastic hypercortisolism" for HPA axis activation without tumor 1, 2
- "Hypercortisolism of uncertain etiology" when initial workup is incomplete 1
The term "Cushing's syndrome" should be reserved for confirmed neoplastic disease to avoid confusion and ensure appropriate treatment pathways. 1, 2