Long-Term Corticotroph Function Following Cure of Cushing’s Syndrome

Introduction: Hyper- and hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in Cushing’s syndrome (CS) and Addison’s disease (AD) is associated with disturbances of classical feedback mechanisms. Time to recovery of adrenal function after CS remission depends on the etiology of CS and is longest after adrenal CS. To date there are no data on the recovery of corticotroph function following CS remission, and the synacthen test is recommended for testing adrenal function in patients with hypopituitarism. Aim Here we aim to test corticotroph function after long-term cure of Cushing’s syndrome following bilateral adrenalectomy (BADx), compared to patients with primary glucocorticoid deficiency due the presence of 21-hydroxylase antibodies or adrenoleucodystrophy, a pathophysiological model of glucocorticoid and mineralocorticoid deficiency. Methods: We retrospectively evaluated data from patients with CS and AD attending our endocrine department between 2000 and 2020, using the following inclusion criteria: BADx performed for pituitary/ectopic/adrenal or occult CS or primary adrenal insufficiency confirmed either by the presence of 21-hydroxylase antibodies or genetically in adrenoleucodystrophy. Results: Full data were available for 93 patients: 43 patients with BADx due to CS (18 patients with pituitary CS, 14 patients with adrenal CS and 11 patients with ectopic/occult CS, F:M 29:14, mean age at BADx 45.4 years age range 13-74 years) and 50 patients with AD (47 cases with positive 21-hydroxylase antibodies, 3 cases with adrenoleucodystrophy, F:M ratio 27:23, mean age at diagnosis 35 years, age range 6-57 years). The observation period was 537.5 patient-years after BADx (mean 12.5 years, range 1-38 years) and 647 patient-years following AD diagnosis (mean 14.2 years, range 1-46 years). At the last visit, there were no differences between the hormone substitution regimes between the groups. ACTH concentrations during the whole observation period and also at the last visit were lowest in patients with adrenal CS (56.5 pg/ml) when compared to patients with AD (487 pg/ml, p<0.001), or with patients with pituitary CS (377.5 pg/mL, p=0.011). ACTH values in patients with AD in long-term follow-up were significantly higher when compared to all patients with CS (141 pg/mL, p<0.001). Conclusion: These data highlight a long-term defective corticotroph function in patients with CS following BADx. Low ACTH concentrations long term after BADx for adrenal CS corroborate that corticotroph function fails to recover after CS cure. In the light of these findings, the utility of the synacthen test for excluding secondary/tertiary adrenal insufficiency following CS remission is disputable and remains to be evaluated in future studies dedicated to CS cohorts.