Approximately 1 in 5 patients with adrenal incidentalomas showed changes in cortisol secretion over time, and persistently abnormal results were associated with worsening hypertension, according to new research. The findings suggest that repeat testing may provide clinically relevant information in selected patients, despite current guidelines not recommending routine repeat assessment.

“To our knowledge, this is the largest and most geographically diverse study to date examining longitudinal [cortisol concentration] changes in benign adrenal incidentalomas,” the authors wrote in the paper, published in The Lancet Diabetes & Endocrinology.

“We found that 22.3% of patients had a change in classification [from baseline] over follow-up, most within the first 3 years,” first author Alessandro Prete, MD, PhD, told Medscape Medical News.

“So a baseline-only snapshot misclassifies a meaningful number of patients relative to their longer-term cortisol phenotype,” said Prete, clinical associate professor of endocrinology in the Department of Metabolism and Systems Science at the University of Birmingham and co-lead of the Women’s Metabolic Health Theme at the National Institute for Health and Care Research Biomedical Research Centre, both in Birmingham, England.

Adrenal masses are detected incidentally on imaging performed for unrelated reasons in approximately 3%-7% of adults and are typically benign adrenocortical tumors.

Patients without Cushing syndrome having such tumors are classified as having either nonfunctioning adrenal tumors (NFATs), characterized by cortisol concentrations ≤ 50 nmol/L after a 1-mg overnight dexamethasone suppression test (1-mg DST), or mild autonomous cortical secretion (MACS), characterized by post-DST cortisol concentrations > 50 nmol/L with otherwise normal results on other investigations.

MACS, which accounts for an estimated 19%-50% of adrenal incidentalomas, has been associated with increased mortality and a higher risk for cardiovascular disease, hypertension, type 2 diabetes, and dyslipidemia.

However, the clinical significance of changes in MACS over time has remained unclear. Current guidelines do not recommend routinely repeating the 1-mg DST in patients with adrenal incidentalomas, and management decisions are commonly based on single baseline cortisol measurements.

Multicenter Retrospective Study

To better understand the significance of longitudinal changes, Prete and colleagues retrospectively analyzed 2525 patients at 25 adrenal centers participating in the European Network for the Study of Adrenal Tumours consortium across 14 countries. Participants had benign adrenal incidentalomas diagnosed between January 2000 and December 2020.

All patients underwent at least two 1-mg DSTs during a minimum follow-up of 36 months.

During a median follow-up of 80 months, 22.3% of the patients experienced changes in DST classification from baseline, with most changes occurring within the first 3 years.

Patients with persistently abnormal test results (n = 839) were generally older and had a greater cardiometabolic burden than those with persistently normal results (n = 1103).

After multivariate adjustment, patients with persistently abnormal DST results had a significantly higher risk of worsening hypertension (adjusted hazard ratio, 1.34) and a shorter event-free period for worsening hypertension than patients with NFATs (10-year restricted mean survival time, 60.4 vs 86.1 months).

Patients with a single elevated post-1-mg DST cortisol reading at baseline had a shorter survival and event-free period than those with greater cumulative cortisol exposure and persistently abnormal results. However, these associations were no longer independent of age and baseline cardiometabolic risk factors after adjustment.

Independent predictors of adverse outcomes included smoking, chronic kidney disease, and previous cardiovascular or thrombotic events, “which underscores the importance of proactive management of modifiable risk factors in patients with these risk factors,” the authors wrote.

The results indicate that “a person’s baseline MACS result doesn’t tell you whether they’ll stay in that category,” Prete said.

‘Controlling Away’ Cortisol’s Real Effects?

A key caveat of the study was that several variables included in the multivariable adjustment may not actually be independent of cortisol excess, Prete noted.

“They could plausibly be downstream consequences of longstanding MACS rather than preexisting confounders sitting outside the causal pathway,” he said.

While something like smoking is clearly a genuine confounder, “hypertension and cardiovascular history are far murkier,” he added. “MACS could well be contributing to why those risk factors are present or worse in the first place.”

“If that’s true, adjusting for these [potential cofounders] risks overadjustment by statistically ‘controlling away’ some of cortisol’s real effects rather than isolating a true confounder,” Prete said.

Although the findings make a reasonable case for retesting in selected patients, Prete cautioned that the study was not designed to determine whether repeat testing improves outcomes and that prospective trials will be needed to answer that question.

“That said, there is one clear, practical takeaway that doesn’t need to wait for a trial,” he said. “If a patient has a borderline 1-mg DST result — specifically, cortisol just above the 50-nmol/L cutoff without clearly suppressed adrenocorticotropic hormone or dehydroepiandrosterone sulfate — and adrenalectomy is being considered on the basis of that MACS diagnosis, repeating the test is generally warranted before proceeding.”

Further Studies Needed

Commenting on the study, Alaa Sada, MD, of the Division of Endocrine Surgery in the Department of Surgery at the University of Pittsburgh in Pittsburgh, Pennsylvania, said that the findings support the value of repeat DST testing in selected patients but stop short of demonstrating improved outcomes.

“Repeating DST in some patients can be informative, but whether repeat testing can help change management or improve patient outcomes remains uncertain and requires further studies,” she told Medscape Medical News.

One limitation, she noted, was that only 5.2% of patients underwent adrenalectomy, raising the possibility of selection bias.

“Patients with more severe or unambiguous disease may have gone to surgery earlier before accumulating much longitudinal DST data, limiting how well this cohort captures more severe MACS,” she said.

“As a result, the findings may not be generalizable to all patients with MACS,” she added.

Sada agreed with Prete that several key metabolic morbidities may themselves be consequences of cortisol excess.

“Some studies have shown that when MACS is treated with adrenalectomy and the cortisol autonomy is cured, patients tend to have improvement in these outcomes compared with patients who are not treated with surgery,” she said.

That being said, Sada underscored that the study’s take-home message should be that “the decision to repeat DST should be individualized as it is probably most useful in patients with borderline values or when the result will change management, such as surgical candidacy, rather than as routine surveillance.”

Prete reported having relationships with Neurocrine, Recordati, Esteve, Lundbeck, and Corcept. Sada reported having no relevant disclosures.