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.