What is the purpose of cortisol (adrenocorticotropic hormone, ACTH) testing?

From the Guidelines

Cortisol testing should be performed using a 1 mg dexamethasone suppression test, with a serum cortisol level of 1.8 μg/dL (50 nmol/L) or below indicating a normal response, as recommended by the most recent guideline update 1. When interpreting cortisol test results, it is essential to consider the clinical context and potential factors that may influence the outcome, such as concomitant medications or underlying medical conditions 1.

Key Considerations for Cortisol Testing

• The test should be performed in the morning, between 7-9 AM, when cortisol levels are naturally highest, to provide the most accurate baseline measurement.
• Patients should avoid strenuous exercise, alcohol, and stress 24 hours before testing, and should not eat, drink (except water), or take medications that might affect cortisol levels (like steroids) for 8-12 hours prior to the test unless directed otherwise by their doctor.
• Normal morning cortisol levels generally range from 5-23 mcg/dL (138-635 nmol/L), though reference ranges vary by laboratory.
• Abnormal results may indicate conditions like Cushing's syndrome (elevated cortisol) or Addison's disease (low cortisol), requiring follow-up testing such as dexamethasone suppression tests or ACTH stimulation tests for confirmation.

Follow-up Testing and Management

• If the initial screening test is abnormal, additional testing should be performed to evaluate for Cushing's syndrome, as recommended by various guidelines 1.
• Adrenalectomy should be considered on an individual patient basis, depending on the patient's overall health, symptoms, and cortisol-induced comorbidities 1.
• Patients with cortisol-secreting adenomas should undergo medical screening for comorbid conditions, including hypertension, type 2 diabetes, and asymptomatic vertebral fractures, as recommended by some guidelines 1.

From the FDA Drug Label

Metopirone is indicated, in combination with other diagnostic tests, for the diagnosis of adrenal insufficiency in adult and pediatric patients.

This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone.

Approximately 8 hours after administration of Metopirone, evaluate the values of ACTH and 11-desoxycortisol Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact HPA axis function is generally indicated by an increase in 11‑desoxycortisol to over 70 mcg/L.

Cortisol testing using metyrapone (Metopirone) involves assessing the ability of the adrenals to respond to the drug by measuring 11-desoxycortisol and ACTH levels.

• The test is typically performed on an outpatient basis, with a single dose of Metopirone administered at midnight, and blood samples taken the following morning.
• An increase in 11-desoxycortisol to over 70 mcg/L indicates an intact HPA axis function.
• The ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency due to overlap between normal and abnormal responses 2.

From the Research

Cortisol Testing Methods

• The overnight dexamethasone suppression test is a commonly used method to screen for Cushing's syndrome, but its sensitivity is limited in patients with mild and/or episodic hypercortisolism 3.
• The dexamethasone suppression test (DST) explores the pituitary feedback to glucocorticoids and is recommended for Cushing's Syndrome (CS) diagnosis, but its diagnostic accuracy can be affected by dexamethasone bioavailability 4.
• Quantification of serum dexamethasone in DST samples may improve test performance and increase the specificity of serum cortisol levels 4, 5.

Dexamethasone Thresholds

• A dexamethasone threshold of 4.5 nmol/L was calculated as the lower 2.5th percentile of dexamethasone distribution in non-CS patients with cortisol ≤ 50 nmol/L after 1-mg DST 4.
• A method-specific cortisol cutoff of 2.4 µg/dL (66 nmol/L) was applied to samples with suspected CS, increasing the clinical specificity for CS from 67.5% to 92.4% while preserving 100% clinical sensitivity 5.
• The lower limit of normal (LLN) for dexamethasone was considered to be 1.8 ng/mL (4.6 nmol/L) 5.

Combined Dexamethasone-CRH Test

• The combined dexamethasone-CRH test was developed to distinguish Cushing's syndrome from pseudo-Cushing's states, achieving greater accuracy in diagnosis than individual tests 6, 7.
• A plasma cortisol concentration greater than 38 nmol/L measured 15 minutes after CRH administration correctly identified all cases of Cushing's syndrome and all cases of pseudo-Cushing's states 6.
• The dexamethasone-suppressed CRH test (Dex-CRH test) differentiates patients with Cushing's syndrome from those with normal physiology, with cortisol measurements obtained during the Dex-CRH test being suppressed in normal volunteers below those found in mild Cushing's disease 7.