Cyclic Subclinical Hypercortisolism

A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas

Rafael B. Giorgi; Marcelo V. Correa; Flávia A. Costa-Barbosa; Claudio E. Kater


J Endo Soc. 2019;3(3):678-686. 

In This Article

Abstract and Introduction


Purpose: Most adrenal incidentalomas (AIs) are nonfunctioning adenomas (NFAs), but up to 30% may secrete cortisol autonomously without clinical evidence of Cushing syndrome (CS), which nevertheless may increase cardiovascular mortality. This subclinical hypercortisolism (SCH) is confirmed by cortisol resistance to a dexamethasone suppression test (DST). Cyclic cortisol secretion occurs in classic CS but was not reported in SCH.

Objective: Investigate cyclic cortisol production/autonomy in AIs using sequential DSTs.

Methods: A total of 251 patients with AI underwent 487 DSTs over 12 years; patients with at least three DSTs were selected. DSTs were validated by measuring serum dexamethasone. Cyclic SCH was defined when at least two abnormal and two normal DSTs were documented.

Results: A total of 44 patients had three or more DSTs during follow-up: 9 of 44 patients (20.4%) had all negative test results (post-DST cortisol ≤1.8 μg/dL) and were classified as NFA; another nine patients had all positive results (cortisol >1.8 μg/dL) and were classified as sustained SCH. The remaining 26 (59.2%) had discordant responses: 8 of 44 (18.3%) had at least two positive and two negative tests, matching the criterion for cyclic SCH, whereas 18 of 44 (40.9%) had only one discordant test and were classified as possibly cyclic SCH. Eleven of 20 (55%) patients initially classified as NFA did not maintain their cortisol pattern.

Conclusions: Extended follow-up with repeated DSTs uncovered an unusual subset of AIs with cyclic SCH. Recurring production of cortisol may affect determination of AI subtypes if based on just one DST. Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk.


Adrenal incidentalomas (AIs) are recognized as a public health problem, reaching a prevalence of 5% in the general population and 10% in the elderly population. These figures are related to both the improvement in imaging techniques and the widespread access and use of these procedures.[1–3] Although most AIs are nonfunctioning adenomas (NFAs), some may have minor autonomous steroid secretion.[4,5] Subclinical hypercortisolism (SCH) (or autonomic cortisol secretion, as preferred by others[4]), is defined as an autonomous hypersecretion of cortisol with no clear phenotypic manifestations of Cushing syndrome (CS).[4,6] SCH (the term used herein) has emerged in recent years as the most common cause of functioning AI, reaching a prevalence of up to 30% depending on how it is defined.[7] Due to the long-term cortisol overexposure, SCH is associated with metabolic derangements and unfavorable cardiovascular outcomes.[8–11] Although NFA has also been associated with a high prevalence of metabolic abnormalities,[11] a current guideline suggests that no follow-up is necessary when hypercortisolism is ruled out after the initial evaluation.[4] This recommendation has recently been contested.[12]

All forms of clinically overt CS (e.g., Cushing disease, ectopic ACTH syndrome, and adrenal neoplasia) can present with cyclic cortisol secretion.[13] This intriguing wax and wane pattern can mislead the investigation, increasing false-negative scores and the possibility of misdiagnosis.[5,14] There is no consensus to define cortisol cyclicity in CS.[15] Several researchers have identified anomalous cortisol secretion in SCH and a substantial conversion rate to hypercortisolism in patients initially classified as NFA.[5,11,15] However, truly cyclic cortisol secretion has not been documented in AI.

In the current study, we examined whether a cyclic pattern of cortisol secretion may be present in AI, analogous to what is observed in CS. In addition, we compared the prevalence of metabolic abnormalities in the subsets of AI to justify why patients initially classified as NFA may also have a high prevalence of cardiovascular (CV) manifestations.