A major new study, published today in The Lancet Diabetes & Endocrinology has shown that cortisol levels in patients with adrenal tumours are far less stable than previously assumed.
The study also identified that those in whom cortisol remains persistently elevated carry a significantly greater risk of worsening high blood pressure and a heavier overall cardiometabolic burden.
Cortisol, often referred to as the "stress hormone", is a steroid hormone produced by the adrenal glands that acts as a master regulator of metabolism, blood pressure, and immune function. When benign tumours form on the adrenal glands (found incidentally in 3-7% of adults) they can cause the body to produce cortisol independently of normal regulatory controls, a condition known as mild autonomous cortisol secretion (MACS). Until now, it was unclear how cortisol levels in these patients change over time, and what that means for their long-term health.
The study of over 2,500 patients was conducted by researchers from 25 specialist adrenal centres across 14 countries as part of the European Network for the Study of Adrenal Tumours ( ENSAT ). It is the largest study of its kind to examine how cortisol patterns evolve over time in patients with benign adrenal tumours and what this means for cardiovascular outcomes.
The study followed 2,525 patients with benign adrenal tumours for an average of nearly 7 years. Each patient underwent repeated hormonal testing using the 1mg overnight dexamethasone suppression test, the standard clinical test used to assess whether the adrenal gland is overproducing cortisol autonomously. Patients were classified based on whether their cortisol levels remained normal, remained elevated (persistent MACS), or changed between categories over time.
The researchers found that cortisol secretion status changed in 22% of patients, far more frequently than previously recognised, with most changes occurring within the first three years after diagnosis. These findings challenge the assumption that a single hormonal test is sufficient to characterise a patient's long-term cortisol profile.
Patients with persistent MACS had the greatest overall cardiovascular burden and faced a 34% higher rate of worsening high blood pressure than those with persistently normal cortisol. Over 10 years, patients with persistent MACS lost an average of 2 years of well-controlled hypertension-free time compared with those whose cortisol remained normal – a clinically meaningful difference in long-term blood pressure control.
Cardiometabolic burden refers to the combined impact of interrelated metabolic and cardiovascular risk factors (including obesity, high blood pressure, type 2 diabetes, and high cholesterol) on overall health, predisposing serious, chronic diseases such as heart failure, heart attack, and stroke.
The study identified patients with persistently abnormal cortisol levels (persistent MACS) as a clinically important, higher-risk group who may benefit from closer monitoring and more proactive management of modifiable risk factors – including blood pressure, cholesterol, weight, and smoking. The results are also consistent with recent randomised trial data, also published in The Lancet Diabetes & Endocrinology , showing that surgery to remove the adrenal tumour can improve blood pressure control in MACS.
Professor Alessandro Prete, Clinical Associate Professor of Endocrinology at the University of Birmingham, Co-lead for the NIHR Birmingham Biomedical Research Centre's Women's Metabolic Health theme, and corresponding author and senior investigator of the study, said: "For many years, the assumption has been that a single hormone test at adrenal tumour diagnosis tells us everything we need to know about a patient's cortisol status.
This study shows that it is simply not the case – cortisol levels change over time in a substantial proportion of patients, and those in whom they remain persistently elevated are at a meaningfully higher risk of developing uncontrolled blood pressure.
These findings should prompt us to think more carefully about which patients need closer follow-up, and whether active treatment to reduce cortisol excess – including surgery in selected cases – could protect their long-term cardiovascular health."
The study also provides important new evidence to inform the ongoing debate around whether, and how often, cortisol testing should be repeated in patients with benign adrenal tumours. Current guidelines recommend repeating the test only in specific clinical circumstances; the authors of the study are calling for prospective studies to determine whether repeated hormonal assessment contributes meaningfully to risk stratification beyond established cardiovascular risk factors.
