Glucocorticoid-Induced Positive Feedback in Cushing Disease: Insights From a Spanish Multicenter Cohort

Cushing disease (CD) is characterized by impaired glucocorticoid negative feedback. In rare cases, patients exhibit glucocorticoid-induced positive feedback (GIPF), which may represent a distinct corticotroph adenoma phenotype. We aimed to investigate the prevalence, clinical and biochemical features, and surgical outcomes of GIPF in a large multicenter cohort.

A retrospective cohort study from the SPAIN-CUSHING registry. We included 139 patients with CD who had a complete overnight 1-mg dexamethasone suppression test. GIPF was defined as higher serum cortisol after dexamethasone compared with baseline. Clinical, biochemical, and radiological characteristics, as well as surgical outcomes, were compared between groups. Recurrence was evaluated in patients undergoing transsphenoidal surgery, with recurrence-free survival assessed by Kaplan-Meier analysis.

Thirteen patients (9.3%) showed GIPF. These patients had lower body mass index (26.4 vs 29.8 kg/m², P = .032), higher urinary free cortisol expressed as the upper limit of normal ratio (4.7 vs 2.8 upper limit of normal, P = .047), and a markedly greater adrenocorticotropin response to desmopressin (525.0 vs 63.1 pg/mL, P = .022). Tumor size, proportion of macroadenomas, and cavernous sinus invasion did not differ. Despite this, after surgery remission was significantly lower in GIPF (28.6% vs 70.2%, P = .036), and Kaplan-Meier analysis showed reduced recurrence-free survival in GIPF patients (log-rank P = .04). Clinical phenotypes and comorbidities were otherwise similar.

GIPF occurs in up to 9% of patients with CD and is associated with poorer surgical outcomes and lower remission rates. This phenotype likely represents a distinct subtype of corticotroph adenoma, highlighting the need for closer follow-up and molecular characterization.