What causes elevated cortisol levels?

Causes of Elevated Cortisol Levels

Elevated cortisol results from either exogenous corticosteroid administration or endogenous overproduction, with exogenous steroid use being the most common cause overall, followed by ACTH-dependent sources (pituitary tumors in 60-70% of endogenous cases, ectopic ACTH-secreting tumors) and ACTH-independent adrenal pathology (adenomas, carcinomas, bilateral hyperplasia). 1

Exogenous Causes

The most frequent cause of Cushing syndrome is exogenous corticosteroid therapy. 1 This includes:

• Chronic prednisone, prednisolone, or other glucocorticoid administration for inflammatory, autoimmune, or allergic conditions, which suppresses the hypothalamic-pituitary-adrenal (HPA) axis and can produce full Cushingoid features when used long-term at pharmacologic doses 2
• Prolonged therapy creates adrenal suppression that may persist for up to 12 months after discontinuation, with the diurnal rhythm of the HPA axis lost during chronic use 2

Endogenous ACTH-Dependent Causes

When ACTH levels are mid-normal to elevated, cortisol excess originates from ACTH-producing sources 1:

Pituitary Sources (Cushing Disease)

• Benign pituitary adenomas account for approximately 60-70% of endogenous Cushing syndrome cases 1
• These corticotroph adenomas autonomously secrete ACTH, driving bilateral adrenal cortisol production 3

Ectopic ACTH Production

• Ectopic tumors in the lung, thyroid, pancreas, or bowel produce ACTH independently of pituitary control 3
• Elevated ACTH with suppressed or absent pituitary adenoma on imaging suggests ectopic source 3

Endogenous ACTH-Independent Causes

When ACTH is suppressed, the adrenal glands autonomously produce excess cortisol 3:

Adrenal Adenomas

• Benign adrenal tumors produce cortisol without ACTH stimulation 3
• Typically removed via laparoscopic adrenalectomy when causing clinical hypercortisolism 3

Adrenal Carcinomas

• Malignant adrenal tumors should be suspected when tumors exceed 5 cm, have irregular margins, are internally heterogeneous, or show local invasion 3
• These aggressive tumors often present with markedly elevated cortisol and rapid symptom progression 3

Bilateral Adrenal Hyperplasia

• ACTH-independent bilateral multinodular hyperplasia rarely causes symmetric cortisol overproduction from both adrenal glands 3
• Adrenal vein sampling determines lateralization of cortisol production to guide surgical approach 3

Physiological Hypercortisolism (Pseudo-Cushing Syndrome)

Non-neoplastic activation of the HPA axis produces mild cortisol elevation without true Cushing syndrome 3:

Obesity

• Visceral adiposity in young females drives physiological hypercortisolism strongly linked to cardiovascular risk, with elevated cortisol correlating with abdominal fat distribution 4
• Urinary glucocorticoid excretion links directly to metabolic syndrome components including blood pressure, fasting glucose, and waist circumference 4

Polycystic Ovary Syndrome (PCOS)

• PCOS affects 8-13% of young women and presents with hyperandrogenism, obesity, insulin resistance, and hypertension—all associated with elevated cortisol 4

Psychiatric Disorders

• Depression, anxiety, and chronic psychological stress activate the HPA axis, producing cortisol elevation that can be severe 3, 4
• Severe mental depression can cause incomplete dexamethasone suppression, mimicking true Cushing syndrome 4
• Psychosocial stress correlates with myocardial infarction risk through cortisol-mediated mechanisms 4

Alcohol Use Disorder

• Chronic alcoholism activates the HPA axis and produces positive screening tests for hypercortisolism 3

Other Physiological States

• Pregnancy increases corticosteroid-binding globulin (CBG), elevating total cortisol levels 3
• Oral estrogen therapy similarly increases CBG and total cortisol measurements 3
• Chronic active hepatitis raises CBG levels 3

Important Caveats

UFC in pseudo-Cushing syndrome is almost always within 3-fold of normal, whereas true Cushing syndrome typically shows higher elevations 3. However, distinguishing between the two can be challenging, particularly when:

• Obesity, psychiatric disorders, and PCOS coexist, creating overlapping clinical features with true Cushing syndrome 3, 4
• Medications interfere with testing: CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) cause false-positive dexamethasone suppression tests, while CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) cause false-negative results 3
• Circadian rhythm disruption from shift work or irregular sleep schedules affects late-night salivary cortisol testing 3

The loss of normal circadian rhythm is characteristic of true Cushing syndrome, with failure to achieve the normal cortisol nadir at night 3, 2. In contrast, physiological hypercortisolism often preserves some circadian variation 5.