Endocrine Abstracts

Background: Cyclic Cushing Syndrome (CCS) is a condition characterized by at least two episodes hypercortisolism followed by episodes of normocortisolism or hypocortisolism. The clinical features are similar to those of non-cyclic Cushing Syndrome. However, the diagnosis is even more challenging than for its non-cyclic variant; various diagnostic modalities can yield false-negative results when performed during an episode without hypercortisolism. (1)

Objective : An extensive literature search was performed, using databases Embase and Medline in August, 2023. A combination of keywords (cyclic, periodic, intermittent, Cushing syndrome, hypercortisolism) and MeSH terms (Cushing’s syndrome, pituitary ACTH secretion) was used. Relevant articles concerning non-pregnant, adult patients, published after 2003 were retained. Articles with unclear description or lack of cyclicity were excluded.

Results/discussion: Diagnostic tests for Cushing’s Syndrome (CS) include 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and the dexamethasone suppression test (DST). Unlike non-cyclic CS, DST can result in a paradoxical reaction with a significant increase in cortisol. DST is not advised when cyclicity is suspected. Even so, when a notable increase in cortisol is seen, cyclicity should be considered. UFC and LNSC are useful diagnostic tests, but repeated tests are necessary to identify cyclicity. Testing should ideally be conducted during periods of hypercortisolism. (1,2) An underemployed technique for detecting CCS involves measuring cortisol levels in hair, which can reflect cortisol levels over an extended period of time. However, standardized reference values for this method are currently unavailable. (3) The underlying etiology of CCS is similar to that of classic CS, including ACTH-dependent hypercortisolism due to a pituitary adenoma or ectopic ACTH production, and ACTH-independent hypercortisolism. Further differentiation is based on various tests: dynamic testing (CRH, desmopressin, high-dose DST), bilateral inferior petrosal sinus sampling (BIPSS), and imaging (pituitary MRI, FDG-PET, somatostatin analogs PET-CT). (2,4) The main difference from non-cyclic CS is that testing with desmopressin and BIPSS is unreliable during a trough phase. The high-dose dexamethasone test can, as in the DST, result in a paradoxical response. Regarding imaging, there is insufficient data to suggest that imaging in CCS differs from non-cyclic Cushing’s. There is no clarity on the ideal sequence of investigations. In some cases, despite extensive investigations, the underlying etiology remains unclear. (4,5)

Conclusions: We conclude that additional research is necessary to obtain more information on this potentially notso-rare entity, given that there is no clear diagnostical pathway at this moment. Repeated testing is required, with attention to performing the tests at moments of hypercortisolism – given that false negative results are possible in trough phases. Emerging techniques like hair cortisol measurements show promise but need further investigation to develop standardized threshold values.

References: 1. Świątkowska-Stodulska R, Berlińska A, Stefańska K, Kłosowski P, Sworczak K. Cyclic Cushing’s Syndrome – A Diagnostic Challenge. Front Endocrinol (Lausanne). 2021;12(April):1–7. doi:10.3389/fendo.2021.658429.

2. Nowak E, Vogel F, Albani A, et al. Diagnostic challenges in cyclic Cushing’s syndrome: a systematicreview. Lancet Diabetes Endocrinol. 2023;11(8):593–606. doi:10.1016/S2213-8587(23)00150-X.

3. Manenschijn L, Koper JW, Van Den Akker ELT, et al. A novel tool in the diagnosis and follow-up of (cyclic) Cushing’s syndrome: Measurement of long-term cortisol in scalp hair. J Clin Endocrinol Metab. 2012;97(10):1836–43. doi:10.1210/jc.2012-1852.

4. Cai Y, Ren L, Tan S, Liu X, Li C, Gang X, et al. Mechanism, diagnosis, and treatment of cyclic Cushing’ssyndrome: A review. Biomedicine and Pharmacotherapy [Internet]. 2022/06/20. 2022;153(June):113301. Available from: https://www.sciencedirect.com/science/article/pii/S0753332222006904?via%3Dihub.

5. Meinardi JR, Wolffenbuttel BHR, Dullaart RPF. Cyclic Cushing’s syndrome: a clinicalchallenge. Eur J Endocrinol [Internet]. 2007 Sep;157(3):245–54. Available from: https://academic.oup.com/ejendo/article/157/3/245/6695913