Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas

Abstract

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.

Adrenalectomy in Japanese patients with subclinical Cushing syndrome: 1‐mg dexamethasone suppression test to predict the surgical benefit

“…Focusing on patients with cortisol secretion <1.8 in the 1‐mg DST, who were excluded from a diagnosis of SCS in the new Japanese criteria or European and American guidelines, a number of patients showed improvements of clinical variables and reduction of drug usage. It has been reported in several studies that in patients who did not fulfill the diagnostic criteria of SCS, a certain number (~14%) of those were later diagnosed with SCS by follow‐up tests 21–23 . These latent patients might be included in this population, suggesting that it is recommended, as previous studies reported, to follow patients who were once diagnosed with non‐functional adrenal tumors and to repeatedly carry out 1‐mg DSTs or other hormonal tests.…”

“…It has been reported in several studies that in patients who did not fulfill the diagnostic criteria of SCS, a certain number (~14%) of those were later diagnosed with SCS by follow-up tests. [21][22][23] These latent patients might be included in this population, suggesting that it is recommended, as previous studies reported, to follow patients who were once diagnosed with non-functional adrenal tumors and to repeatedly carry out 1-mg DSTs or other hormonal tests.…”

Cyclic Cushing’s Syndrome – A Diagnostic Challenge

“…Cyclic Cushing's syndrome (also known as intermittent or periodic) is a disease characterized by periods of transient hypercortisolemia shifting into periods of normo-and/or hypocortisolemia. Just as classic Cushing's syndrome, cyclic hypercortisolemia may arise from hormonal activity of corticotropinoma (approximately 80% of all cases), ectopic adrenocorticotropic hormone (ACTH; corticotropin) release, or ACTH-independent causes (1)(2)(3)(4)(5)(6)(7)(8)(9). Retrospective analysis of 201 patients with Cushing's syndrome showed that 15% of them met the diagnostic criteria of intermittent hypercortisolemia and up to 70% showed evidence of cyclicity before the diagnosis (10).…”

“…Giorgi et al demonstrated periodic nature of subclinical hypercortisolemia in 18% patients with hormonally active adrenal incidentalomas (3). The fluctuation of observed abnormalities may explain the difficulties in diagnostics of periodic hypercortisolemia and often ambiguous results (3,11). These dilemmas seem to be especially pronounced in ACTH-dependent cases (6,7,12).…”

Defining Nonfunctioning Adrenal Adenomas on the Basis of the Occurrence of Hypocortisolism after Adrenalectomy

“…The unexpected finding of increased cardiovascular risk even in NFAI patients was suggested to be due to an exaggerated cortisol response to stress [ 11 ], increased secretion of steroid precursors [ 14-16 ], cyclic cortisol secretion [ 17 ], and to variations in individual cortisol sensitivity [ 18 ]. Alternatively, it has been proposed that these tumors have subtle cortisol (hyper)secretion [ 19 , 20 ], which cannot be disclosed by the currently used parameters of hypothalamic–pituitary–adrenal (HPA) axis activity.…”