Discussion: Hormonal Workup - Cortisol

Written By Marshall Strother

When is testing necessary?

  • There is strong consensus amongst guidelines that all patients with adrenal incidentaloma >1cm require testing for hypercortisolism regardless of the presence of any relevant clinical signs or symptoms.(1–4)

Which screening tests should be performed?

  • There is strong consensus amongst guidelines that the 1mg overnight dexamethasone suppression test (1ODST) is the screening test of choice for hypercortisolism in the setting of adrenal adenoma.(1–5) 

  • There is also broad acknowledgement that there have not been head-to-head comparisons establishing the superiority of the 1ODST over other well-studied tests,(2,3) including measuring late-night salivary cortisol (LNSC) and urinary free cortisol (UFC). The preference for the 1ODST is thus based on perceived simplicity of performance and the presence of relatively well-accepted guidelines for interpretation.(2)

How should the test be performed?

  • The patient takes 1 mg of dexamethasone by mouth at 11pm and then a serum cortisol level is drawn 9 hours later at 8am.(3,5) 

How should the test be interpreted?

  • Broad consensus exists on the following cutoffs for interpretation of serum cortisol during a 1ODST in the setting of incidentaloma(1–5)

    • <1.8μg/dL (50nmol/L) rules out excess cortisol secretion

    • 1.9 - 4.9μg/dL (51-138 nmol/L) is considered equivocal 

    • > 5.0 μg/dL (139 nmol/L) is considered generally diagnostic of cortisol excess

  • These cutoff values do not take into account the following possible sources of false positive and false negative tests(3,5)

    • Possible causes of false negative tests

      • CYP3A4-inhibiting medications

        • CYP3A4 metabolizes dexamethasone, so medications that inhibit this enzyme may increase dexamethasone levels, leading to more vigorous suppression of cortisol levels

      • Low cortisol binding globulin (e.g. nephrotic syndrome) 

    • Possible causes of false positive tests

      • CYP4A4 inducing medications (see above) (e.g. phenobarbital, phenytoin, rifampicin, St. John’s Wort)

      • Patient did not take dexamethasone

      • Patient did not absorb dexamethasone (e.g. due to chronic diarrheal disease) 

      • Oral contraceptive pills: increased estrogen leads to increased cortisol binding globulin which increases total serum cortisol levels. One small study from 1989 reported a 50% false positive rate in women taking oral contraceptives(6), a number which has been quoted in at least two sets of guidelines.(3,7)

      • Hepatitis (same mechanism as oral contraceptives)

  • Measuring dexamethasone levels at the same time as serum cortisol can be helpful as a way to identify false positive tests caused by patients not taking, failing to absorb, or excessively metabolizing the dexamethasone.(5) Dexamethasone levels less than 4.5 nmol/L (0.18μg/dL) have been proposed to be inadequate for the 1ODST according to the the most study to examine this question,(5,8) though an older cutoff of or 5.6 nmol/L (0.22μg/dL) still appears in older guidelines.(7)

  • There is disagreement in the guidelines regarding whether the 1ODST is reliable in night shift workers, whose circadian variation in cortisol levels has been altered.(3,5) Depression and critical illness have also been mentioned as possibly decreasing the reliability of the 1ODST.(3)


What additional testing is required if cortisol excess is suspected?

  • If cortisol excess is ruled out, no further testing is required.

  • Morning ACTH levels should be measured outside of the context of a dexamethasone suppression test. These should be low or low-normal in patients with cortisol excess from an adrenal lesion.(2,3,5)

  • The European Society of Endocrinology recommends screening for hypertension, diabetes, and asymptomatic vertebral fractures (with x-ray if the spine is incompletely evaluated on the CT showing the adrenal lesion)(2)

  • There is no consensus on how to best adjudicate equivocal results. The presence of symptoms, results of repeat 1ODST testing in 3-12 months, and the results of late-night salivary cortisol tests or 24 hour urinary free cortisol tests may all be helpful.(2,5) While guidelines state that the sensitivity and specificity of these last two tests have been shown to be excellent, cutoffs used to produce the results vary by study.(2,5,7) 

  • Low DHEA-S (<40mcg/dL) may be helpful (84% sensitivity and 81% positive predictive)l in confirming autonomous cortisol secretion from adrenal adenomas, although this has not yet been incorporated into any clinical guidelines. The combination of low DHEA-S and low ACTH provides good accuracy and positive predictive value.(9)

There is no consensus on the management of “mild autonomous cortisol secretion” (ACTH-independent hypercortisolism diagnosed on biochemical testing in the absence of overt symptoms of Cushing syndrome) caused by adrenal adenomas. For example, the American Association of Endocrine Surgeons recommends resection of all adrenal adenomas causing cortisol excess, even in the absence of signs/symptoms of excess, citing data that such cortisol excess may be dangerous in the long term.(1)  Canadian, Korean, and European guidelines recommend that the decision of whether to resect or monitor be made on a case-by-case basis utilizing shared decision making.(2–4)

1. Yip L, Duh QY, Wachtel H, Jimenez C, Sturgeon C, Lee C, et al. American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg. 2022 Oct 1;157(10):870–7.

2. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug 1;175(2):G1–34.

3. Rowe NE, Kumar RM, Schieda N, Siddiqi F, McGregor T, McAlpine K, et al. Canadian Urological Association guideline: Diagnosis, management, and followup of the incidentally discovered adrenal mass. Can Urol Assoc J. 2023 Jan 26;17(2):12–24.

4. Lee JM, Kim MK, Ko SH, Koh JM, Kim BY, Kim SW, et al. Clinical Guidelines for the Management of Adrenal Incidentaloma. Endocrinol Metab Seoul Korea. 2017 Jun 1;32(2):200–18.

5. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on Diagnosis and Management of Cushing’s Disease: A Guideline Update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847–75.

6. Nickelsen T, Lissner W, Schöffling K. The dexamethasone suppression test and long-term contraceptive treatment: measurement of ACTH or salivary cortisol does not improve the reliability of the test. Exp Clin Endocrinol. 1989;94(3):275–80.

7. Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May 1;93(5):1526–40.

8. Ceccato F, Artusi C, Barbot M, Lizzul L, Pinelli S, Costantini G, et al. Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation. J Endocrinol Invest. 2020 Aug 1;43(8):1105–13.

9.Carafone LE, Zhang CD, Li D, Lazik N, Hamidi O, Hurtado MD, et al. Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion. Biomedicines. 2021 Jul;9(7):741.

Last updated 6/16/24 by Marshall Strother and Julie Hallanger-Johnson

Marshall Strother
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