SAGE IVD recommended including the cortisol (total) test category in the third EDL:
• as a disease-specific IVD for use in clinical laboratories (EDL 3, Section II.b, within a new subsection for endocrine disorders);
• using an immunoassay format;
• to diagnose central (pituitary) or primary (adrenal, Addison’s disease) cortisol deficiency;* and
• to diagnose central (pituitary) or primary (adrenal) hypercortisolism (Cushing’s syndrome).** *Often used with timed collection and stimulation with cosyntropin. ** Often used with timed collection and suppression with dexamethasone. The group further requested the addition of a note to the test category entry in the EDL stating that it is only recommended for use in specialized health care settings.

Adrenal insufficiency and Cushing’s disease are two conditions with high morbidity and mortality. Primary diagnosis of both conditions can usually be done by determining cortisol levels, with very good accuracy. Serum/plasma cortisol concentrations are useful both as a single measurement (morning sample for adrenal insufficiency and midnight cortisol for Cushing’s syndrome) or as a dynamic test (cosyntropin stimulation test for adrenal insufficiency and overnight dexamethasone test for Cushing’s syndrome). Early detection of both conditions can lead to early treatment and reversal. And treatment for adrenal insufficiency is also included in the EML, including corticosteroids and fludrocortisone. Cortisol testing is included in the guidelines of many professional societies and is widely used in clinical practice across the world to both diagnose and follow up adrenal insufficiency and Cushing’s disease. SAGE IVD noted that interpretation of cortisol levels varies depending on whether you are measuring total or free cortisol; and also emphasized that the cost–effectiveness of the test cannot be established based on the data submitted. The group also raised concerns about the potential for misuse of the test if it is introduced in the absence of specialized centres. This is not just about having a specialized laboratory but also about having specialist staff available to interpret results and guide treatment. SAGE IVD also noted that cortisol testing, if positive, may warrant further testing to specify the cause of loss of adrenal function to guide treatment options. The group further noted that different autoanalysers and assays may give different results, although it acknowledged that this is typical of hormone determinations. Importantly, SAGE IVD highlighted a number of interpretive issues with cortisol testing and raised concerns about the potential for it to be inappropriately ordered or inaccurately interpreted without guidance. In particular, the timing of sample collection and the need for cosyntropin stimulation (or dexamethasone suppression) is often critical for cortisol testing to work effectively.

Cortisol levels are directly related to the presence or absence of hypo- or hyper-adrenal function disorders such as Cushing’s syndrome and Addison’s disease. Diagnostic accuracy for these conditions appears to be very good (90% sensitivity and specificity). It should be noted that cortisol testing is a test that, if positive, might warrant further testing to specify the cause of loss of adrenal function that will guide options for treatment. There are no direct comparisons for impact on health outcomes, though it seems likely that early detection of loss of function of the adrenal glands will facilitate early detection, diagnosis and treatment. This is supported by guidelines, as it is not recommended to postpone treatment until cortisol measurement has been performed, but to start immediately and adjust later based on the results. Cost–effectiveness cannot be established based on the current literature. But there is sufficient evidence in the submission to recommend serum cortisol measurement based on the analytic and diagnostic accuracy and likely benefits of early detection and treatment. Diagnostic accuracy measures depend on the indication for the test (intended role of the test) and cut-off points used.

World Health Organization. (‎2021)‎. The selection and use of essential in vitro diagnostics: report of the third meeting of the WHO Strategic Advisory Group of Experts on In Vitro Diagnostics, 2020 (‎including the third WHO model list of essential in vitro diagnostics)‎. World Health Organization. https://iris.who.int/handle/10665/339064