Temporal changes in cortisol secretion and their association with long-term outcomes in benign adrenal incidentalomas: a retrospective cohort study

Background: Mild autonomous cortisol secretion (MACS), the most common hormonal abnormality in adrenal incidentalomas, is associated with increased cardiometabolic risk. MACS is defined by cortisol concentrations higher than 50 nmol/L after a 1-mg overnight dexamethasone suppression test (1-mg DST). The prognostic value of a single test remains uncertain. We examined longitudinal changes in 1-mg DST results, cumulative cortisol exposure, and their associations with cardiometabolic outcomes and mortality. Methods: In this retrospective cohort study conducted in 25 adrenal centres that are part of the European Network for the Study of Adrenal Tumours consortium across 14 countries with adults (aged ≥18 years) with benign adrenal incidentalomas diagnosed from Jan 1, 2000, to Dec 1, 2020, two or more 1-mg DSTs, and follow-up of at least 36 months, we used multivariable Cox models to assess associations between longitudinal 1-mg DST results and all-cause mortality and cardiovascular and thrombotic events. Patients with Cushing's syndrome, primary aldosteronism, phaeochromocytoma, or androgen-secreting tumour at baseline; active malignancy within 36 months of incidentaloma diagnosis; or suspicion of unreliable 1-mg DST results were excluded, along with patients taking oral glucocorticoids, strong CYP3A4 modulators, adrenal enzyme inhibitors, oral oestrogen, or selective oestrogen receptor modulators. Cumulative cortisol exposure was estimated from serial 1-mg DSTs. Restricted mean survival time (RMST) quantified differences in event-free time. Data were collected from the electronic health records of all eligible patients at each participating centre. Findings: Among 2525 patients (median follow-up 80 months [IQR 49-122]), 563 (22·3%) had changes in 1-mg DST results leading to a change in diagnosis, most within 3 years of their baseline 1-mg DST. Patients with persistently abnormal 1-mg DST results (ie, MACS-to-MACS patients; n=839) were older and had a greater cardiometabolic burden than those with persistently normal results (ie, non-functioning adrenal tumours [NFAT]-to-NFAT patients; n=1103). MACS-to-MACS patients had a higher rate of worsening hypertension (adjusted hazard ratio 1·34 [95% CI 1·03-1·73]) and a shorter event-free time for worsening hypertension (10-year RMST 60·4 months [56·8-75·5] vs 86·1 months [79·1-93·4]) than NFAT-to-NFAT patients. In crude analyses, patients with higher baseline post-1-mg DST cortisol, patients with greater cumulative cortisol exposure, and MACS-to-MACS patients had shorter survival and event-free time; however, these associations were not independent of age and baseline cardiometabolic risk factors after multivariable adjustment. Interpretation: Longitudinal 1-mg DST changes are common. MACS-to-MACS patients had worsening hypertension, but rates of mortality and cardiovascular or thrombotic events were not significantly associated with 1-mg DST trajectories after adjustment for age and cardiovascular risk factors. These findings identify patients with persistently abnormal 1-mg DST results as a group with high cardiometabolic risk that warrants closer attention to modifiable risk factors. Prospective studies are needed to establish the clinical significance of repeated 1-mg DSTs for risk stratification. Funding: National Institute for Health and Care Research Birmingham Biomedical Research Centre, Horizon Europe 2022, and Deutsche Forschungsgemeinschaft.