7573 Cyclic Cushing’s Syndrome: Periodicity and Treatment Outcome in an International Multicenter Case Series
Authors: Nowak Elisabeth , Fleseriu Maria , Zhang Qilin , Zhang Shuo , Yuen Kevin Choong Ji , Gilis-Januszewska Aleksandra , Hanzu Felicia Alexandra , Matikainen Niina , Minasyan Mari , Pichler Robert , Araujo-Castro Marta , Arvat Emanuela , Bioletto Fabio , Isand Kristina , Wass John A H , Reincke Martin 
Published: October 2024

Abstract
Disclosure: E. Nowak: None. M. Fleseriu: Consulting Fee; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals. Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals. Q. Zhang: None. S. Zhang: None. K.C. Yuen: Grant Recipient; Self; Corcept, Sparrow. A. Gilis-Januszewska: None. F.A. Hanzu: None. N. Matikainen: None. M. Minasyan: None. R. Pichler: None. M. Araujo-Castro: None. E. Arvat: None. F. Bioletto: None. K. Isand: None. J.A. Wass: None. M. Reincke: Consulting Fee; Self; Recordati Rare Diseases, HRA Pharma, Crinetics, Lundbeck Pharmaceuticals. Grant Recipient; Self; Recordati Rare Diseases, HRA Pharma, Crinetics, Lundbeck Pharmaceuticals.
Background: Cyclic Cushing’s syndrome (cCS) is characterised by variable cortisol secretion periodicity (peaks and throughs); it is marked by diagnostic errors, and possibly poorer overall outcome. Patients and Methods: We investigated cycle characteristics, diagnostic and treatment modalities in patients (pts) with CS from invited expert endocrine centers. cCS was defined as at least 2 clinical and biochemical hypercortisolaemic peaks (high) and 1 spontaneous eu-/or hypocortisolaemic (AI) trough (low) cortisol. Data was extracted from pts charts and transferred into a central database. Ethics approval was obtained centrally and locally. Statistical analysis was conducted with GraphPad Prism 10.1.1. Results: We included 37 pts (70% females) from 12 centers, 20 (54%) with pituitary (pit), 6 (16%) with ectopic, and 11 (30%) with occult tumour origin (suspected 10 ectopic, 1 pit). 24-h urine free cortisol (UFC) was the main diagnostic biomarker used to determine cyclicity; median 14.67 X ULN for peaks (IQR 3.58-45.92) and 0.29 X ULN for troughs (IQR 0.20-0.57). On average, pts experienced 3.11 peaks (± 1.34); 83% occurred at irregular intervals, separated by troughs lasting several months. Pts with suspected/proven ectopic cCS had significantly more peaks (mean 3.75 ± 1.57) vs pit cCS (mean 2.70 ± 0.92; p=0.023) and significantly higher levels of cortisol excess (p&lt;0.05). Twenty-eight (76%) pts had symptoms worsening during peaks. Twelve (32%) pts had spontaneous AI phases. Only 69% of BIPSS were performed during hypercortisolism. In pts with suspected ectopic cCS, imaging was suggestive in 44%. Twenty-four (65%) pts had surgery (19 pit, 5 ectopic), four (11%) had radiation, and 2 (5%) bilateral adrenalectomy. Steroidogenesis inhibitors (SI) were used in 20 (54%) cases; 13 (65%) as titration regimen. After a median follow-up of 42.0 months (IQR 25.50-84.50), 17 (46%) pts achieved therapy-induced remission, 4 (11%) full spontaneous and five (14%) partial remission. Five pts were clinically and biochemically controlled by SI, 5 had persistent overt CS, and 1 (3%) died due to pneumonia pre-therapy. Median time to therapy-induced remission after referral to our centers was 34.0 months (IQR 4.25-58.50). A delayed diagnosis or therapy due to misleading findings was noted in 41% and 38% respectively. Conclusion: Cortisol secretion kinetics is highly variable in CS, with clearly defined cycles of hyper-, eu- and hypocortisolemia in some pts. Here, we show that cCS remains a challenging disease entity even in specialised centers, with less than half of the pts achieving remission at 3.5 years. Despite unpredictable cycle length and amplitude and risk of spontaneous AI, steroidogenesis inhibitors were frequently used in a titration rather than block and replace approach. Better understanding of cortisol secretion kinetics and periodicity may improve diagnostic accuracy and individualised care.
Presentation: 6/1/2024