What is the appropriate workup for a young female with mildly elevated serum cortisol levels?

Workup for Mildly Raised Serum Cortisol in a Young Female

Initial Critical Step: Exclude Exogenous Causes

Before proceeding with any biochemical workup, you must first exclude iatrogenic Cushing's syndrome from exogenous glucocorticoid use and rule out estrogen-induced elevation of cortisol-binding globulin (CBG). 1

• In young females, oral contraceptives containing estrogen can cause marked elevations in CBG, leading to extremely high total serum cortisol levels (up to 50-61 mcg/dL) despite normal free cortisol 2
• Estrogen-containing medications increase CBG levels above the normal range (1.7-3.1 mg/dL), which elevates total cortisol measurements without true hypercortisolism 2
• If the patient is on oral contraceptives, consider holding them for 2 months and remeasuring cortisol and CBG levels to determine if this is the cause 2
• Also exclude topical hydrocortisone preparations, inhaled corticosteroids, and other exogenous glucocorticoid sources 1

Confirm True Hypercortisolism with Multiple First-Line Tests

Do not rely on a single elevated serum cortisol measurement—you must perform at least 2-3 of the following screening tests to confirm pathologic hypercortisolism: 3, 1

Late-Night Salivary Cortisol (LNSC)

• Collect at least 2-3 samples at the patient's usual bedtime (not necessarily midnight) 3
• This test has the highest specificity among screening tests and is particularly useful for mild Cushing's syndrome 3, 4
• Critical caveat: Neither a normal LNSC nor normal 24-hour urine free cortisol (UFC) excludes mild Cushing's syndrome—multiple samples are essential 5
• Avoid this test in night-shift workers or those with disrupted sleep-wake cycles 3

24-Hour Urine Free Cortisol (UFC)

• Collect at least 2-3 separate 24-hour urine collections to account for intra-patient variability 3, 1
• UFC measures bioavailable cortisol independent of CBG, making it particularly useful when CBG alterations are suspected 3
• Important limitation: In mild Cushing's syndrome, UFC may be normal or only mildly elevated (<2 times upper limit of normal) 5

Overnight 1-mg Dexamethasone Suppression Test (DST)

• Administer 1 mg dexamethasone between 2300h-midnight, measure serum cortisol at 0800h 3
• Normal suppression is cortisol <1.8 μg/dL (50 nmol/L); values above this indicate abnormal feedback inhibition 3, 6
• Measure dexamethasone levels concomitantly with cortisol to rule out abnormal dexamethasone metabolism and reduce false-positive results 3, 1
• False positives occur with: CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort), rapid gut transit, celiac disease, and elevated CBG from oral estrogens 3

Determine ACTH Dependency Once Hypercortisolism is Confirmed

After confirming true hypercortisolism with multiple positive screening tests, measure morning (0800-0900h) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes: 6, 1

ACTH-Dependent (ACTH >5 ng/L)

• Any detectable ACTH >5 ng/L suggests ACTH-dependent Cushing's syndrome 6
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease 6
• Next step: Obtain high-quality pituitary MRI with thin slices (3T preferred over 1.5T) 6, 1
  • If adenoma ≥10 mm: Presume Cushing's disease 6
  • If adenoma 6-9 mm: Consider CRH stimulation test 6
  • If no adenoma or <6 mm lesion: Proceed to bilateral inferior petrosal sinus sampling (BIPSS) 6, 1

ACTH-Independent (ACTH low or undetectable)

• Low/undetectable ACTH indicates adrenal source 6, 1
• Next step: Obtain adrenal CT or MRI to identify adrenal adenoma, carcinoma, or hyperplasia 6, 1

Special Considerations for Mild/Cyclic Cushing's Syndrome

• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation with sequential LNSC measurements over weeks to months 3, 1
• Patients with mild Cushing's may have LNSC just above the upper limit of normal 3
• In mild cases, multiple samples and multiple different tests (urine, saliva, DST) are needed to establish the diagnosis 5

Common Pitfalls to Avoid

• Do not proceed directly to imaging without biochemical confirmation and ACTH determination—this leads to incidental findings and misdiagnosis 1
• Do not rely on a single test—sensitivity and specificity are insufficient, and false positives/negatives are common 1, 5
• Exclude pseudo-Cushing's states (depression, alcoholism, severe obesity, uncontrolled diabetes) that can cause mild hypercortisolism 6, 1
• Remember that no single test reaches 100% specificity, and results may be discordant in up to one-third of patients 6

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