When to measure cortisol levels?

From the Guidelines

Cortisol levels should be drawn in the morning after an overnight 1-mg dexamethasone suppression test (DST), with a serum cortisol level < 1.8 μg/dL (50 nmol/L) at 0800 h considered a normal response. This approach is based on the most recent guideline update on the diagnosis and management of Cushing's disease, published in The Lancet Diabetes and Endocrinology in 2021 1. The overnight 1-mg DST is a widely accepted test for assessing cortisol production, and a negative result strongly predicts the absence of Cushing's syndrome.

• Key considerations when interpreting cortisol levels include:
  • The timing of cortisol measurement, which should be done in the morning after an overnight DST
  • The use of laboratory-specific ranges of expected values to reduce the risk of false-positive results
  • The potential for false-positive results due to factors such as rapid absorption or malabsorption of dexamethasone, concomitant treatment with CYP3A4 inducers, and increased corticosteroid binding globulin (CBG) levels
  • The potential for false-negative results due to factors such as inhibition of dexamethasone metabolism by concomitant medications and decreased CBG and albumin levels. When evaluating cortisol levels, it is essential to consider these factors to ensure accurate interpretation of results and to minimize the risk of false-positive or false-negative results, as highlighted in the guideline update 1.

From the Research

Cortisol Level Assessment

To determine when to draw cortisol levels, it's essential to understand the physiological principles of cortisol synthesis and the diagnosis of Cushing's syndrome.

• Cortisol excess can be diagnosed by exploiting three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH-secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine 2.
• The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system, and understanding its dynamics is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases 3.

Clinical Considerations

When assessing cortisol levels, clinicians should consider the following:

• Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction 3.
• Autonomous cortisol release from the adrenal cortex can be caused by various etiologies, including adrenocortical carcinoma, adenoma, primary pigmented nodular adrenocortical disease, and ACTH-independent macronodular adrenal hyperplasia 4.
• Plasma ACTH levels can be unsuppressed in some cases, especially in adrenocortical carcinoma patients, which can lead to therapeutic misadventures if not interpreted correctly 4.

Diagnostic Approaches

Diagnostic approaches for Cushing's syndrome include:

• Measuring morning cortisol and ACTH levels 5.
• Performing a low-dose ACTH stimulation test to assess the HPA axis 5.
• Imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary to differentiate a pituitary source of excess ACTH from an ectopic source 2.
• Assessing urinary free cortisol levels to diagnose cortisol excess 2.