Recovery of Hypothalamic‐Pituitary‐Adrenal Axis in Pediatric Cushing Disease

Objectives The postoperative period of Cushing disease (CD) is complicated by a phase of adrenal insufficiency (AI). Factors that influence the duration of AI and its prognostic significance for CD recurrence in children have not been extensively studied. We investigated whether clinical or biochemical factors contribute to the duration of AI, and the correlation of the recovery process with the risk for recurrence. Design Patients with pediatric-onset CD who were followed up for at least 3 months after transsphenoidal surgery (TSS) (n=130) were included in the study. Multivariable Cox proportional hazards analysis was used to assess the association of biochemical and clinical factors with duration of AI. Results Overall, 102 patients recovered adrenal function during their follow-up. Median time to recovery was 12.7 months [95%Confidence Intervals (CI): 12.2-13.4]. On multivariable analysis, clinical (age, gender, disease duration, puberty stage, BMI z-score, tumor size, invasion of the cavernous sinus, year of surgery) and biochemical (midnight cortisol, morning ACTH) factors did not correlate with the time to recovery, except for increase of recovery time noted with increase of urinary free cortisol (UFC) [Hazard Ratio (HR):0.94, 95%CI:0.89-0.99]. Among patients who eventually recovered adrenal function, the risk for CD recurrence was associated with the time to recovery (HR:0.86, 95%CI:0.75-0.99). Conclusions Recovery of adrenal function in patients with CD after TSS may not be associated with most clinical and biochemical factors in the preoperative period except for total cortisol excretion, as evidenced by the correlation with UFC. Earlier recovery is associated with higher risk for recurrence, which has implications for the patients' follow up and counseling.