Recovery of Hypothalamic-Pituitary-Adrenal Axis in Paediatric Cushing Disease

Christina Tatsi; Megan Neely; Chelsi Flippo; Maria-Eleni Bompou; Meg Keil; Constantine A. Stratakis


Clin Endocrinol. 2021;94(1):40-47. 

In This Article

Abstract and Introduction


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 paediatric-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 the 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, tumour size, invasion of the cavernous sinus and year of surgery) and biochemical (midnight cortisol and morning ACTH) factors did not correlate with the time to recovery, except for increase in recovery time noted with increase in 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. Earlier recovery is associated with higher risk for recurrence, which has implications for the patients' follow-up and counselling.


Cushing disease (CD), caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, is the most common aetiology of Cushing syndrome (CS) in children older than 7 years of age.[1] Successful management of CD is followed by a postoperative period of adrenal insufficiency (AI), which is the result of suppression of the normal hypothalamic-pituitary-adrenal (HPA) axis by endogenous hypercortisolaemia.[2,3] The duration of postoperative AI and the mechanism of HPA axis recovery are not clearly understood, but it is thought that the rate-limiting step lies on the recovery of corticotrophin-releasing hormone (CRH) secretion by hypothalamic cells.[4]

Previous studies, mostly in adults, tried to identify factors that may affect HPA axis recovery. Although it is tempting to hypothesize that the higher or longer the exposure to glucocorticoids, the more severe the suppression, studies have not consistently found that clinical or biochemical factors significantly contribute to the duration of HPA axis suppression.[5–9] Furthermore, the range of the reported median time to recovery varies between various cohorts (ranging from 6 months to more than 2 years). Of note, what has been more commonly reported is the association of early HPA axis recovery with higher risk for CD recurrence.[5,7] However, only one study, from our centre, has previously described the HPA axis recovery in paediatric patients, who may behave differently than adults due to varying sensitivity or maturation of the HPA axis, and this prior study because of its lower numbers did not allow for a meaningful statistical analysis of risk for recurrence.[10]

In the present study, we investigated the association of the time to recovery of HPA axis after successful treatment in a large cohort of paediatric patients with CD with the age of diagnosis and other relevant clinical and biochemical factors. As a secondary aim, we also queried the possible association of recovery time with risk for recurrence that was suggested by our previous inconclusive reports.