A single hormone test may not capture the long-term health risk faced by some people with benign adrenal tumours. A major international study found that cortisol activity changed over time in more than one in five patients, with most diagnostic shifts occurring during the first three years after the tumour was identified.
The findings challenge the assumption that one normal result permanently establishes an adrenal growth as hormonally inactive. They also suggest that patients with persistently elevated cortisol may deserve closer monitoring for worsening blood pressure and other cardiometabolic problems.
However, the research does not prove that every patient with a benign adrenal tumour needs annual hormone testing. It also did not find that changing cortisol patterns independently predicted heart attacks, strokes or death after researchers accounted for age and existing cardiovascular risk factors. The study instead highlights a more complicated reality: cortisol activity can evolve, and a patient’s broader health may be more informative than one laboratory result taken years earlier.
Benign Adrenal Tumours Are Often Found by Accident
The adrenal glands sit above the kidneys and produce hormones involved in blood pressure, metabolism, immune function and the body’s response to stress. Small growths are frequently discovered during CT or MRI scans performed for unrelated reasons.
These unexpected findings are known as adrenal incidentalomas. Most are benign rather than cancerous, and many initially appear not to produce clinically important amounts of hormones.
A smaller but significant group produces cortisol independently of the body’s normal regulatory system. This condition is called mild autonomous cortisol secretion, or MACS. Unlike overt Cushing’s syndrome, MACS may not produce obvious physical signs, yet it has been associated with hypertension, type 2 diabetes, abnormal cholesterol and other cardiovascular risk factors.
Because symptoms can be subtle or absent, laboratory testing plays a central role in determining whether a tumour is producing excess cortisol.
How the Overnight Dexamethasone Test Works
The standard evaluation is the 1-milligram overnight dexamethasone suppression test.
A patient takes a small dose of dexamethasone, a synthetic glucocorticoid, late in the evening. Blood cortisol is measured the following morning. In a normally regulated system, dexamethasone signals the brain and adrenal glands to reduce cortisol production.
When the morning cortisol level remains elevated, the adrenal tumour may be producing cortisol without responding appropriately to the body’s regulatory signals. In the new study, MACS was defined as a post-test cortisol concentration above 50 nanomoles per litre.
Traditionally, clinicians have often used the initial result to place patients into a stable category: either a nonfunctioning adrenal tumour or a tumour associated with mild autonomous cortisol secretion.
The new evidence suggests that those categories may not remain stable for everyone.
Researchers Followed More Than 2,500 Patients
The retrospective study included 2,525 adults treated at 25 specialist adrenal centres across 14 countries. The centres were part of the European Network for the Study of Adrenal Tumours.
Eligible patients had benign adrenal incidentalomas, at least two overnight dexamethasone suppression tests and a minimum follow-up period of three years. The median follow-up was 80 months, or approximately six years and eight months.
Patients with overt Cushing’s syndrome, primary aldosteronism, pheochromocytoma, androgen-secreting tumours or certain other conditions were excluded. Researchers also excluded situations in which medications or other factors could make the dexamethasone test unreliable.
The team examined how cortisol results changed, estimated cumulative cortisol exposure and compared those patterns with hypertension progression, cardiovascular and thrombotic events, cardiometabolic disease and mortality.
Hormone Status Changed in More Than One in Five Patients
During follow-up, 563 patients—22.3 percent of the study population—had test results that changed enough to alter their diagnostic category.
Some patients initially classified as having nonfunctioning tumours later crossed the threshold for mild autonomous cortisol secretion. Others moved in the opposite direction, from an abnormal result to one within the normal range.
Most of these changes occurred within three years of the first dexamethasone test. This finding indicates that cortisol secretion from benign adrenal tumours can fluctuate rather than remaining biologically fixed from the moment of diagnosis.
A changing test result does not necessarily mean that the tumour suddenly became dangerous. Cortisol measurements can be influenced by medications, illness, sleep, test preparation and laboratory variation. Nevertheless, the frequency of diagnostic change was high enough to question whether one measurement can reliably describe a patient’s cortisol profile for the next decade.
Persistently High Cortisol Was Linked to Worsening Blood Pressure
The clearest clinical difference appeared among patients whose cortisol remained abnormal across repeated tests.
Researchers identified 839 patients with persistent MACS and 1,103 whose results remained normal. The persistent-MACS group was older and already carried a greater cardiometabolic burden at the beginning of follow-up.
After adjustment, patients with consistently abnormal results had a 34 percent higher rate of worsening hypertension than those whose results remained normal. The study defined worsening through outcomes such as a new hypertension diagnosis or the need for more intensive blood-pressure treatment.
Over a ten-year period, the estimated time before hypertension worsened was also shorter in the persistent-MACS group. Researchers calculated approximately 60.4 months free from worsening hypertension, compared with 86.1 months among patients with persistently normal results—a difference of more than two years.
This does not mean every patient with persistent MACS will develop uncontrolled blood pressure. It means the group experienced hypertension progression more frequently and earlier on average.
The Study Did Not Prove a Higher Independent Risk of Heart Attack or Death
The headline finding requires an important qualification.
Before statistical adjustment, higher cortisol measurements and persistent MACS appeared to be associated with shorter survival and less time free from cardiovascular or thrombotic events. Those associations were no longer statistically significant after the researchers accounted for age and baseline cardiometabolic risk factors.
The study therefore does not establish that a changing or persistently abnormal dexamethasone test independently causes heart attacks, strokes, blood clots or earlier death.
Instead, persistent MACS identified a population that was older, had more cardiometabolic problems and experienced greater deterioration in blood-pressure control. Cortisol may contribute to that pattern, but age, existing hypertension, diabetes, obesity, cholesterol and other factors remain critical parts of the risk assessment.
The results support closer attention to cardiovascular health, not a simple claim that one abnormal hormone result predicts a future cardiac event.
Current Guidelines Do Not Recommend Routine Retesting for Everyone
The findings arrive during an ongoing debate over how benign adrenal incidentalomas should be followed.
The 2023 European Society of Endocrinology guideline recommends against repeated hormonal testing when the initial evaluation is normal, unless new signs of hormonal activity appear or associated conditions such as hypertension or type 2 diabetes worsen. The recommendation was designed to avoid unnecessary testing, false-positive results, anxiety and medical procedures in patients whose tumours are unlikely to become clinically important.
The new study does not automatically overturn that guidance. It included only patients who had undergone repeated testing, which may mean they were already considered more likely to need follow-up. As a retrospective analysis, it cannot show whether routinely retesting every patient would improve treatment decisions or prevent cardiovascular events.
The authors therefore called for prospective studies to determine whether repeat dexamethasone testing adds useful information beyond monitoring blood pressure, blood glucose, cholesterol, weight and other established risk factors.
Follow-Up May Need to Focus on the Whole Patient
The practical message is not that every person with an adrenal tumour should demand repeated cortisol tests on a fixed schedule.
A more reasonable implication is that an old normal result should not end the clinical discussion when a patient later develops worsening hypertension, difficult-to-control diabetes, unexpected weight changes or other features potentially associated with cortisol excess.
Patients with persistent MACS may benefit from more active management of modifiable cardiovascular risks. That can include regular blood-pressure assessment, appropriate diabetes and cholesterol treatment, smoking cessation and weight management.
Surgery to remove the affected adrenal gland may be considered for selected patients with MACS and relevant health problems, but it is not automatically recommended for everyone. Decisions depend on age, tumour characteristics, cortisol findings, existing conditions, surgical risk and patient preferences. The University of Birmingham researchers noted that related trial evidence suggests adrenal surgery can improve blood-pressure control in some carefully selected patients with MACS.
One Test Is a Snapshot, Not a Lifetime Forecast
The study’s strongest contribution is showing that cortisol status can change over several years. Among more than 2,500 people with benign adrenal tumours, nearly a quarter moved between diagnostic categories, usually during the first three years.
Persistent cortisol elevation was associated with a heavier cardiometabolic burden and faster worsening of hypertension. Yet repeated hormone results did not independently predict cardiovascular events or mortality after age and existing risks were considered.
One dexamethasone test remains valuable, but it should be interpreted as a snapshot rather than an unchangeable lifetime classification. For patients whose blood pressure, diabetes or other metabolic conditions deteriorate, reassessment by an endocrinologist may reveal information that the original evaluation could not capture.
