LAUSR

Incidental adrenal lesions are found during abdominal imaging in 2% to 7% of adults, and determining their cause and potential for malignancy, as well as their levels of excess hormone secretion, presents a challenge for clinicians (1–3). Most frequently, these lesions are benign adrenocortical adenomas without apparent excess steroid production. However, adenomas produce mild cortisol excess without clinical manifestations of Cushing syndrome (CS) in approximately 35% of cases, a condition formerly known as subclinical CS (1–3). Patients with overt adrenal CS are typically diagnosed during investigation of specific symptoms rather than by abdominal imaging for unrelated reasons. In unilateral adenomas causing CS, somatic mutations in PRKACA, CTNNB1, and GNAS genes underlie the adrenocorticotropic hormone (ACTH)–independent activation of cyclic adenosine monophosphate, steroidogenesis-pathway genes, and cortisol excess (4). In patients with incidentally found mild cortisol secretion, adenomas rarely carry such mutations, explaining why fewer than 5% to 10% progress to overt CS (2). In approximately 15% of patients, adrenal incidentalomas are bilateral, frequently secondary to cortisol-secreting primary bilateral macronodular hyperplasia (PBMAH) or bilateral adenomas (1, 2). Although PBMAH is a rare cause (<2%) of adrenal CS, it frequently produces mild cortisol excess at diagnosis, which worsens in up to 40% of cases during follow-up. Previously believed to be sporadic, PBMAH is secondary to genetic causes in at least 25% of cases, with biallelic ARMC5mutations being the most frequent (4). In about 80% of PBMAH cases and 50% of unilateral adenomas, cortisol excess becomes progressively autonomous from pituitary ACTH but is regulated by the aberrant activity of several G-protein–coupled receptors and ligands, including ACTH expressed in PBMAH tissues (5). Recently, inactivating germline KDM1A mutations were found to be responsible for ectopic glucose-dependent insulinotropic polypeptide receptor expression and glucose-dependent insulinotropic polypeptide–dependent PBMAH (6). Thus, “dysregulated cortisol secretion” is more accurate terminology than “autonomous cortisol secretion.” The consequences of overt CS onmortality and cardiovascular, metabolic, bone, immune, and neuropsychiatric morbidity are well established (7). Are there also adverse consequences of mild cortisol excess that indicate a need for medical or surgical therapy? Prete and colleagues (8) report the findings of a cross-sectional study that classified 1305 patients (67% women) according to European Society of Endocrinology (ESE) guidelines (1) based on morning serum cortisol concentrations after the 1-mg overnight dexamethasone-suppression test. Patients with serum cortisol concentrations less than 50 nmol/L were considered to have nonfunctioning adrenal tumors (NFATs) (49%), those with concentrations of 50 to 138 nmol/L were considered to have possible mild autonomous cortisol secretion (MACS-1) (34.6%), and those with concentrations above 138 nmol/L were considered to have definitive mild autonomous cortisol secretion (MACS-2) (10.7%); an additional 5% of participants had CS (8). Thanks to the inclusion of a large number of patients in the study, which was conducted in 14mostly European expert centers, the researchers clearly demonstrate greater prevalence and severity of hypertension in patients with MACS-2 and CS compared with patients with NFATs (adjusted prevalence ratios [aPRs], 1.15 and 1.37, respectively) as well as higher prevalence of requirement for 3 or more antihypertensive medications (aPRs, 1.31 and 2.2, respectively). Type 2 diabetes was more prevalent only in CS compared with NFATs (aPR, 1.62), and insulin therapy was required more frequently in persons with MACS-2 and CS than in those with NFATs (aPRs, 1.89 and 3.06, respectively). Risk for dyslipidemia did not differ between groups. Patients with bilateral adrenal lesions presented with almost double the incidence of MACS and severity of cortisol excess; only patients with bilateral tumors and MACS had an increased metabolic burden. Using multisteroid profiling, increased urinary glucocorticoid excretion progressively suppressed plasma ACTH, serum dehydroepiandrosterone sulfate levels, and urinary androgens. What lessons are offered by this study, the largest to date on adrenal incidentalomas? These data clearly support the ESE guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions, whether unilateral or bilateral (1). The current tool to classify patients has the advantages of availability and ease of application. However, does the tool use optimal cortisol cutoffs? There are potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test, which can be influenced by several factors including alterations in corticosteroid-binding globulin levels, various cortisol assays (immunoassays/liquid chromatography–mass spectrometry) with less precision in low values, and drug interference with dexamethasone metabolism. A retrospective cohort study of 1048 patients with adrenal incidentalomas in Sweden identified increased mortality hazard ratios of 2.30 for patients with post–1-mg dexamethasone cortisol levels of 83 to 137 nmol/L and 3.04 for cortisol levels of 138 nmol/L or more compared with those with cortisol levels less than 50 nmol/L (9). Healthy persons most often suppress cortisol levels much below the cutoff values of 50 nmol/L, and adrenal tissues from NFAT still secrete steroids in dispersed cells in vitro. Even in patients with NFATs, the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable steroid excess (2). Measuring long-term exposure to cortisol excess in scalp hair may be useful, but further study is needed. None of the currently used approaches to measuring cortisol excess consider individual sensitivity to cortisol excess based on polymorphisms of glucocorticoid receptors. Development of markers