Journal of the Endocrine Society Journal Article

Tumor Shrinkage by Metyrapone in Cushing Disease

June 14, 2021
 

Yasutaka Tsujimoto, Hiroki Shichi, Hidenori Fukuoka, Masaaki Yamamoto, Itsuko Sato, Takamitsu Imanishi, Tomoaki Nakamura, Naoko Inoshita, Atsushi Ishida, Shozo Yamada, Yutaka Takahashi, Kazuo Chihara
Journal of the Endocrine Society, Volume 5, Issue 6, June 2021, bvab055
https://doi.org/10.1210/jendso/bvab055

Abstract

Context

Paradoxical increases in serum cortisol in the dexamethasone suppression test (DST) have been rarely observed in Cushing 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 adrenocorticotropic hormone (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 3D 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 a 20% to 40% suppression (P < 0.05).

Clinical Study

A cross-sectional, retrospective, multicenter study that included 92 patients with CD who underwent both low-dose and high-dose DST from 2014 to 2020 was performed. Eight cases (8.7%) showed an increase in serum cortisol after both low-dose and high-dose DST.

Conclusion

This is the first report of a patient with glucocorticoid (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.

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