Highlight
– Longitudinal changes in cortisol secretion, assessed by repeated 1-mg overnight dexamethasone suppression tests (1-mg DSTs), are common in patients with benign adrenal incidentalomas.
– Patients with persistent mild autonomous cortisol secretion (MACS) exhibit a higher cardiometabolic burden and increased risk for worsening hypertension.
– Although higher cortisol exposure correlates with mortality and cardiovascular events in crude analyses, these associations are not independent of age and baseline cardiovascular risk factors.
– Persistent abnormal cortisol secretion identifies a patient subgroup warranting focused management of modifiable cardiometabolic risks.
Study Background
Adrenal incidentalomas—incidentally detected adrenal masses—are increasingly common due to widespread imaging. Most are benign non-functioning adrenal tumors (NFAT), but a subset exhibits mild autonomous cortisol secretion (MACS), defined biochemically by cortisol concentrations exceeding 50 nmol/L after a 1-mg overnight dexamethasone suppression test (1-mg DST). While outright Cushing’s syndrome is uncommon among incidentaloma patients, MACS is recognized as a subtle but significant hormonal derangement linked to increased cardiometabolic risks such as hypertension, diabetes, and cardiovascular events.
Despite its clinical importance, the prognostic implications of a single 1-mg DST and the value of serial testing remain unclear. Given the potential for dynamic hormonal changes in adrenal incidentalomas over time, investigating temporal cortisol secretion patterns and their relationship with long-term outcomes is critical for optimizing patient management and stratifying risk.
Study Design
This retrospective cohort study analyzed data from 2525 adult patients with benign adrenal incidentalomas diagnosed between 2000 and 2020 across 25 European adrenal centers within the European Network for the Study of Adrenal Tumours consortium. Inclusion criteria required at least two 1-mg DST assessments with a minimum follow-up duration of 36 months. Key exclusion criteria encompassed baseline diagnoses of overt adrenal hormone syndromes (Cushing’s, primary aldosteronism, pheochromocytoma, androgen-secreting tumors), active malignancy near diagnosis, unreliable test results, and use of medications interfering with cortisol metabolism.
Longitudinal cortisol secretion was evaluated by serial post-1-mg DST cortisol levels. Patients were categorized by changes in DST results, focusing on those with persistently normal results (NFAT-to-NFAT), persistently abnormal results (MACS-to-MACS), and those with changing status. The study employed multivariable Cox proportional hazard models to examine associations between cortisol secretion patterns, all-cause mortality, cardiovascular and thrombotic events, and hypertension progression. Cumulative cortisol exposure was estimated from serial DSTs, and restricted mean survival time (RMST) analyses quantified differences in event-free durations.
Key Findings
The median follow-up of patients was 80 months, providing robust longitudinal insight. Notably, 22.3% of patients experienced changes in 1-mg DST status over time, primarily within the first three years post baseline, indicating dynamic hormonal secretion patterns.
Patients with persistently abnormal cortisol secretion (MACS-to-MACS) were older and presented with a greater burden of cardiometabolic risk factors at baseline compared with those maintaining normal cortisol levels (NFAT-to-NFAT). This group exhibited a statistically significant increased hazard for worsening hypertension (adjusted hazard ratio 1.34, 95% CI 1.03–1.73), and their event-free time for hypertension progression was substantially shorter (10-year RMST of 60.4 months versus 86.1 months in NFAT-to-NFAT patients).
In unadjusted analyses, higher baseline post-DST cortisol levels and greater cumulative cortisol exposure correlated with shorter survival and increased cardiovascular and thrombotic event rates. However, these associations lost statistical significance after adjusting for confounders including age and baseline cardiovascular risk factors, suggesting these parameters mediate observed risks.
Importantly, persistent MACS was not independently linked to elevated all-cause mortality or cardiovascular events after adjustment, highlighting multifactorial risk profiles in this population. Nevertheless, persistent autonomous cortisol secretion marks individuals at high cardiometabolic risk, primarily driven by hypertension progression, underscoring a target for clinical intervention.
Expert Commentary
This comprehensive multicenter cohort study is one of the largest to date interrogating temporal cortisol secretion dynamics in adrenal incidentalomas. The findings reinforce the clinical challenge in interpreting 1-mg DST results and stratifying cardiometabolic risks based solely on hormonal testing.
The observation that serial assessment identifies approximately one in five patients with changing cortisol secretion emphasizes the importance of continued biochemical surveillance, at least within the initial years. Persistent mild cortisol excess appears to accelerate hypertension progression, a key modifiable cardiovascular risk factor. These data align with emerging perspectives recommending more nuanced risk stratification beyond binary MACS diagnosis.
Limitations include the retrospective design and potential variability in assay methods or clinical management across centers. Also, exclusion of patients on interfering medications or with overt hormone syndromes may limit generalizability. The study importantly adjusted for confounders, but residual confounding cannot be entirely excluded.
Future prospective studies should validate the clinical utility of repeated 1-mg DST monitoring to refine surveillance protocols and guide therapeutic decisions, including the role of adrenalectomy or medical management in MACS patients with progressive cardiometabolic comorbidities.
Conclusion
This large, multicenter retrospective study elucidates that longitudinal changes in cortisol secretion in benign adrenal incidentalomas are common, with a significant subset of patients demonstrating persistent mild autonomous cortisol secretion associated with worsening hypertension. While cortisol secretion trajectories were not independently predictive of mortality or cardiovascular events after adjusting for confounders, this group represents a population at heightened cardiometabolic risk deserving closer clinical attention.
Routine repeated 1-mg DSTs may provide incremental information for risk stratification and early identification of patients who could benefit from intensified cardiovascular risk modification. Clinicians should emphasize monitoring and managing modifiable risk factors, especially hypertension, in patients with persistently abnormal cortisol secretion. Well-designed prospective trials are warranted to establish consensus guidelines on surveillance and intervention strategies tailored to this heterogeneous patient group.
Funding
This study was supported by the National Institute for Health and Care Research Birmingham Biomedical Research Centre, Horizon Europe 2022, and Deutsche Forschungsgemeinschaft.
References
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3. Morelli V, et al. Mild autonomous cortisol secretion from adrenal incidentalomas: analysis of long-term natural history and outcomes. Endocrine. 2020;68(3):660-667.
4. Terzolo M, et al. Cardiovascular outcomes in patients with adrenal incidentalomas: implications of subclinical hypercortisolism. J Clin Endocrinol Metab. 2013;98(4):1443-1451.