Tumor Shrinkage by Metyrapone in Cushing Disease Exhibiting Glucocorticoid-Induced Positive Feedback

Abstract

Context Paradoxical increases in serum cortisol in the dexamethasone suppression test (DST) have been rarely observed in Cushing’s disease (CD). Its pathophysiology and prevalence remain unclear. Case description A 62-year-old woman with suspected CD showed paradoxical increases in cortisol after both 1-mg and 8-mg DST (1.95-fold and 2.52-fold, respectively). The initiation of metyrapone paradoxically decreased plasma ACTH levels and suppressed cortisol levels. Moreover, the pituitary tumor considerably shrank during metyrapone treatment. Ex vivo experiments The resected tumor tissue was enzymatically digested, dispersed, and embedded into Matrigel as 3-D cultured cells. ACTH levels in the media were measured. In this tumor culture, ACTH levels increased 1.3-fold after dexamethasone treatment (p <0.01) while control tumor cultures exhibited no increase in ACTH levels, but rather 20–40% suppression (p <0.05). Clinical study A cross-sectional, retrospective, multicenter study that included 92 patients with CD who underwent both low dose- (LD) and high dose- (HD) DST from 2014 to 2020 was performed. Eight cases (8.7 %) showed an increase in serum cortisol after both LDDST and HDDST. Conclusions This is the first report of a patient with GC-driven positive-feedback CD who showed both ACTH suppression and tumor shrinkage by metyrapone. Our cohort study revealed that 8.7% of patients with CD patients possibly possess GC-driven positive feedback systems, thereby suggesting the presence of a new subtype of CD that is different from the majority of CD cases. The mechanisms exhibiting GC positive-feedback in CD and the therapeutic approach for these patients remain to be investigated.

Organoid models of the pituitary gland in health and disease

“…Another approach cultured primary human pituitary tumor cells in 3D (up to 4 months) in alginate beads ( 119 ). Spheroids were derived from prolactinomas ( 65 ), GH-overproducing somatotropinomas ( 66 ), and ACTH-overproducing corticotropinomas (Cushing’s disease) ( 64 )) ( Table 1 ). The enzymatically dissociated tumor cells were embedded in Matrigel and cultured in DMEM with 10% fetal bovine serum (FBS).…”

“…The enzymatically dissociated tumor cells were embedded in Matrigel and cultured in DMEM with 10% fetal bovine serum (FBS). The following day, drug screening was performed using the formed spheroids, which most likely represent cell aggregates (of which the morphology was not shown in the studies), and effects on PRL, GH, and ACTH secretion were measured ( 64 – 66 ). In all these studies, the obtained pituitary tumor spheroid models do not meet yet the organoid criteria (see above), in particular lacking the demonstration of clonality, expandability, and tumor-phenotype recapitulation through deep characterization ( Table 1 ).…”

Temozolomide and Capecitabine Treatment for an Aggressive Somatotroph Pituitary Tumor: A Case Report and Literature Review

“…To evaluate the direct effect of TMZ on this tumor, we employed an ex vivo three-dimensional (3D) spheroid culture assay of the resected tumor, which is thought to mimic more realistic environment for the tumors than two-dimensional (2D) cultures, as described previously ( 14 , 15 ). In this assay, we measured cell viability using RealTime-Glo MT Cell Viability Assay (Promega).…”

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

“…A real-life study on patients treated with metyrapone did not show tumor enlargement over a mean treatment period of 9 months [ 82 ]. A decrease in tumor volume was instead reported in a patient potentially harboring GC-mediated positive feedback on the adenoma [ 83 ]. Vice versa, the visualization of pituitary adenoma in a previously negative MRI has been reported for both ketoconazole [ 84 ] and mitotane therapy [ 85 ] in a few cases ( Table 2 ).…”