Modeling Postoperative Cortisol Using Normalized Decay Rates in Cushing’s Disease

Background: Cushing’s disease is caused by an ACTH-hypersecreting adenoma of the pituitary gland and is associated with a five-time increased mortality compared with the general population. Only two-thirds of tumors are visible on MRI. Despite an 86% initial postoperative biochemical remission rate, one-quarter of patients recur at 5 years. For other benign brain tumors, extent of resection on imaging predicts survival, but it is the biochemical response that determines surgically induced remission in Cushing’s disease. ACTH and cortisol levels drop immediately after successful surgery, which is due to both removal of ACTH producing adenoma cells and residual normal gland suppression. The considerable temporal variation in nadir cortisol levels after surgery makes single point cortisol level measurements a suboptimal metric for predicting truly definitive remission. In this study, postoperative cortisol levels were modeled using a serum cortisol decay function.

Methods: Cushing’s disease patients from a single institution between 2010 and 2019 were included in the study. Criteria for diagnosis included two of these tests: an elevated 24-hour UFC, elevated midnight salivary cortisol, or a failed 1-mg dexamethasone suppression test. Patients were excluded from the study if they did not have histopathologic confirmation of a corticotroph adenoma. Serum cortisol was sampled every 6 hours after surgery, and steroids were not administered perioperatively unless serum cortisol dropped to <2 μg/dL or <5 μg/dL with symptoms of adrenal insufficiency. Cortisol levels were modeled using the decay function y = Ae ^(-Bx) , where y is the cortisol level and x is the postoperative time. Single patient fitting algorithms were created. Data were normalized by first postoperative cortisol levels and crude data visualized using scatter plots and individual decay rate violin plots to identify potential bimodal conditions for the decay rate.

Results: Patient characteristics for the rapid and gradual decay groups are shown in Table 1. Median follow-up time was 47.4 weeks (interquartile range = 13.5–126). Three patients had persistently elevated cortisol levels after surgery and were excluded. Violin plots of decay rates for the initial remission group (Fig. 1) were bimodal at 0.15, and thus rapid decay was defined as a rate ≥0.15, and gradual decay defined as a rate <0.15. A decay rate of 0.15 means that cortisol will decrease to 36.8% (1/e) of the original value over 6.7 hours. Gender, age, duration of symptoms, revision surgery, tumor size, EGFR, remission status (i.e., steroid dependency), and immunohistochemical staining correlated with decay rate. Crude decay rates were significantly higher in the remission group compared with the recurrence group at last follow-up (Fig. 1; p < 0.05).

Conclusion: Cortisol decay rate is bimodal after removal of corticotroph adenomas in patients with initial remission. Proper decay rate cutoffs and their association with recurrence probability are still unclear, but rapid decay may predict definitive remission after complete resection of the tumor. Further investigation into cortisol decay rates in Cushing’s disease is needed.