Evaluation of adrenal incidentalomas: Current approaches, caveats, and unexplored issues

Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are non-functioning adrenocortical adenomas, but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system and updated systematic reviews on four predefined clinical questions crucial for the management of incidentalomas: A) How to assess risk of malignancy? ; B) How to define and manage mild autonomous cortisol secretion? ; C) Who should have surgical treatment and how should it be performed? ; D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected Recommendations: 1) Each adrenal mass requires dedicated adrenal imaging. Recent advances now allow discrimination between risk categories: Homogeneous lesions with HU ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size. All other patients should be discussed in a multidisciplinary expert meeting, but only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice. 2) Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines and a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/l (≤1.8 µg/dl)). Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/l (>1.8 µg/dl) harbor increased risk of morbidity and mortality. For this condition, we propose the term 'mild autonomous cortisol secretion' (MACS). 3) All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (e.g. hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated. 4) In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach. 5) The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. 6) Surgery is not usually indicated in patients with an asymptomatic, non-functioning unilateral adrenal mass and obvious benign features on imaging studies. Furthermore, we offer recommendations for the follow-up of non-operated patients, management of patients with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses, and for young and elderly patients with adrenal incidentalomas. Finally, we suggest ten important research questions for the future.

Disclosure: R. Sagar: None. A. Saadulla: None. A. Abbas: None. Background: Mild autonomous cortisol secretion (MACS) is common in patients presenting with adrenal incidentalomas (AI) and has been associated with cardiovascular and metabolic co-morbidities. Whilst there is growing evidence to support the increased risk of cardiometabolic co-morbidity in this cohort, the bone health effects are less well characterised. Our study evaluated the prevalence of fragility fracture and fracture risk in patients with AI and MACS compared with a cohort of patients with benign, non-functional AI. Methods: Retrospective observational data were collected on 391 patients with MACS and an AI along with 626 patients with a benign, non-functional AI. Demographic, biochemical, radiological and bone health data were recorded. FRAX, a validated fracture risk stratifying tool, was used to calculated risk scores for all patients aged between 40 and 90 and risk category according to national guidance were also recorded. Results: MACS cohort (mean age 69±10 and 53% female) had a mean cortisol on overnight dexamethasone suppression test of 76.6±21nmol/l. Benign, non-functional patients had a mean age 61.4±12 and 57% female. Both cohorts had predominantly unilateral lesions (76% in MACS versus 84%). Patients with MACS had a significantly higher prevalence of all fragility fractures, 15.9% compared with 6.7% in the benign, non-functional group, p<0.0001. Patients with MACS had a significantly higher 10-year risk of major osteoporotic fracture (10.6±3.8% versus 7.1±5.4%, p<0.0001) and also hip fracture (7.2±4.1% versus 1.9±2.7%, p<0.0001). 17% of MACS cohort were classed as either high or very high fracture risk, with a further 28% classed as intermediate risk requiring further assessment of bone health compared with 3% high/very high risk in the non-functional group. Despite this only 31% of the MACS group had undergone DEXA scan to assess bone mineral density compared to 13% of the non-MACS group. Only 5% of MACS patients were on osteoporosis treatment (3% in non-MACS cohort). Conclusions: Patients with MACS make up a large proportion of those presenting with adrenal incidentaloma. Our study suggests an increased prevalence of fragility fractures along with increased fracture risk in patients with MACS compared to those with non-functional AI. However, we also demonstrate an unmet need, with less than 1/3 of patients with MACS undergoing formal bone health assessment and just 5% of the total cohort on treatment for osteoporosis despite a significant proportion meeting intervention thresholds. Presentation: 6/1/2024

Prevalence of Mild Autonomous Cortisol Secretion in Adrenal Incidentalomas and the Significance of Subcentimeter Adrenal Nodules: A Single-Center Cohort Study.

ContextThe risk of vertebral fractures (VFx) in patients with adrenal incidentalomas (AI) and mild autonomous cortisol secretion (MACS) is debated.ObjectiveTo evaluate the VFx prevalence and incidence in patients with AI and MACS.MethodsThis cross-sectional and longitudinal study using retrospective data from 4 Italian endocrinology units included 444 patients (cross-sectional arm) and 126 patients (longitudinal arm, 24.9 ± 5.3 months follow-up) to evaluate prevalent and incident VFx, respectively, in patients with MACS (MACS-yes) and without MACS (MACS-no). The main outcome measures were serum cortisol after a 1-mg dexamethasone test (F-1mgDST), bone mineral density (BMD) by dual-energy x-ray absorptiometry at spine (LS) and femur (FN), and VFx presence by x-ray.ResultsCross-sectional arm: 214 and 230 patients were MACS-yes and MACS-no, respectively, based on F-1mgDST >1.8 µg/dL (50 nmol/L). Patients with MACS had higher VFx prevalence (62.6%) than those without MACS (22.9%, P < .001); MACS was associated with prevalent VFx (odds ratio, 5.203; 95% CI, 3.361-8.055; P < .001; relative risk [RR] 2.07), regardless of age, body mass index, gender distribution, LS-BMD, and presence of type 2 diabetes mellitus (T2D). Longitudinal arm: 66 and 60 patients were MACS-no and MACS-yes, respectively. Patients without MACS showed higher number of incident VFx (36.4%) than patients without MACS (10.0%, P < .001); MACS was associated with the presence of an incident VFx (RR 4.561; 95% CI, 1.600-13.003; P = .005) regardless of age, LS-BMD, gender distribution, presence of prevalent VFx, and T2D. Results were confirmed in women and men when separately evaluated.ConclusionWomen and men with AI and MACS are at higher risk of VFx.

The prevalence of adrenal incidentalomas is increasing substantially with cross-sectional imaging, with reported prevalence from 1% to 5% on computed tomography and up to 8.7% at autopsy. While the majority of incidentalomas are benign nonfunctional adenomas, clinicians face the critical challenge of identifying the rare adrenocortical carcinoma (0.5-2 per million annually), which carries an extremely poor prognosis with 5-year survival of only 50% and <15% if metastatic. Functioning adrenal tumors occur in 27.5% of incidentalomas, including mild autonomous cortisol secretion (MACS) in 5%-30%, primary aldosteronism in 5%-6%, and pheochromocytomas in 4%-8%. Comprehensive literature review of current evidence on adrenal incidentaloma management incorporating a systematic three-pillar diagnostic framework is presented: (1) imaging assessment based on Hounsfield unit attenuation and contrast washout, (2) comprehensive hormonal testing for cortisol excess, aldosterone excess, and pheochromocytoma, and (3) growth assessment over time. A three-pillar diagnostic approach effectively stratifies adrenal incidentaloma management. lesions with Hounsfield units <10 are benign (0% malignancy risk), 10-20 are indeterminate (0.5% risk), and >20 are suspicious (6.3% risk), both warranting comprehensive evaluation. Hormonal evaluation: MACS is diagnosed by a positive 1-mg dexamethasone suppression test for cortisol without clinical Cushing features; overt Cushing presents with markedly elevated cortisol, suppressed ACTH, and characteristic clinical stigmata. Primary aldosteronism with an aldosterone-to-renin ratio of >30 requires confirmatory testing. Pheochromocytoma diagnosis requires plasma-free metanephrines. A growth rate of >0.8 cm/year predicts malignancy. Comprehensive evaluation incorporating imaging characterization, hormonal testing, and growth surveillance provides an evidence-based framework for safe management of adrenal incidentalomas. Recent randomized controlled trials support expanded surgical indications in carefully selected MACS patients, particularly those with documented comorbidities, demonstrating superior cardiovascular and metabolic outcomes compared with medical management alone. The paradigm has shifted from treating secondary comorbidities medically to addressing the underlying autonomous cortisol production surgically. Minimally invasive adrenalectomy remains the gold standard surgical approach in experienced hands.

Background/Introduction The overnight 1 mg dexamethasone suppression test (ONDST) is currently the only method to distinguish non-functioning adrenal incidentalomas (NFAI) from those with MACS. Biomarkers for better characterization of MACS are still under investigation. In Cushing’s syndrome, cortisol excess activates renal mineralocorticoid receptors, causing sodium retention and volume expansion, which suppress aldosterone and renin levels. In MACS, with slightly elevated cortisol and urinary free cortisol (UFC), a partial suppression of the renin- angiotensin-aldosterone system (RAAS) is hypothesized. Consequently, ratios such as aldosterone/cortisol, aldosterone/UFC, and cortisol/renin may be reduced in MACS, potentially serving as useful discriminative biomarkers. Purpose To evaluate the diagnostic accuracy of the ratios of aldosterone/cortisol, renin/cortisol, and aldosterone/UFC in differentiating MACS from NFAI. Additionally, to investigate the effects of MACS on the RAAS. Methods A retrospective study was conducted on 149 patients with adrenal incidentalomas: 69 MACS and 80 NFAI, per 2023 ESE-ENSAT guidelines. Blood levels of cortisol(C), ACTH, aldosterone(A), renin(R), UFC, and related ratios (A/C, C/R, A/UFC) were measured. Comparisons were made both overall and after wash-out from interfering therapies affecting the RAAS. Results 69 MACS (mean age 69; F/M 40/29) and 80 NFAI (mean age 61 [49-70]; F/M 36/44) were initially compared without pharmacological wash-out. Aldosterone levels were significantly lower in MACS compared to NFAI (p&amp;lt;0.001), while cortisol levels were higher(p=0.015). Renin showed no significant difference (p=0.179). The A/C ratio was significantly lower in MACS than in NFAI (p&amp;lt;0.001), as was the A/UFC ratio (p&amp;lt;0.001). ROC analysis of the A/C ratio yielded an AUC of 0.736 (95%CI 0.655-0.817, p&amp;lt;0.001), with a cut-off &amp;lt;6.52 for MACS (sensitivity 65.2%, specificity 74.7%). This accuracy improved after wash-out (35 MACS vs 61 NFAI), reaching an AUC of 0.813 (95%CI 0.724-0.903, p&amp;lt;0.001), with a cutoff &amp;lt;6.13 for MACS diagnosis (sensitivity 74.3%, specificity 73.8%). Other ratios showed similar trends, maintaining statistical significance (p&amp;lt;0.001) but lower accuracy. Conclusions This pilot study suggests that the Aldosterone/Cortisol ratio could be a simple, effective biomarker to distinguish MACS from NFAI before the dexamethasone test, especially with proper wash-out. The findings also support that even mild hypercortisolism may suppress the RAAS.

Simple SummaryThis article reflects a comprehensive analysis between cortisol secretion and the presence of other endocrine-related adenomas (specifically thyroid, parathyroid and pituitary). Cortisol has anti-inflammatory properties but has also been related to impaired cell proliferation and function. Specifically, its role in the presence of other benign lesions has not been described. For these reasons, we analyzed the prevalence of these other endocrine-related benign lesions in patients with nonfunctioning adrenal incidentalomas and with mild autonomous cortisol secretion. We observed that mild autonomous hypercortisolism does not affect the prevalence of other endocrine-related adenomas but is associated with increased metabolic comorbidities and mortality in these patients.Background: Adrenal incidentalomas (AI) are frequent findings in clinical practice. About 40% of AIs are associated with hypercortisolism of variable severity. Although mild autonomous cortisol secretion (MACS) has been associated with the impaired clinical outcome of several diseases, its effect on the development of benign neoplasms is unknown. Aim: To compare the prevalence of adenomas (thyroid, parathyroid, pituitary and other locations) in patients with nonfunctioning AIs (NFAIs) and MACS. Methods: A multicenter, retrospective study of patients with AIs evaluated in four tertiary hospitals was performed. Results: A total of 923 patients were included. Most patients were male (53.6%), with a mean age at diagnosis of 62.4 ± 11.13 years; 21.7% presented with bilateral AIs. MACS was observed in 29.9% (n = 276) of patients, while 69.9% (n = 647) were NFAIs. Adenomas in locations other than the adrenal gland were observed in 36% of the studied population, with a similar distribution in patients with MACS and NFAIs (33% vs. 32%; p > 0.05). There were no statistically significant differences in the prevalence of pituitary, thyroid, parathyroid or other endocrine-related adenomas between both groups, but the prevalence of metabolic comorbidities and mortality was increased in patients with MACS, specifically in patients with thyroid and other endocrine-related adenomas (p < 0.05). Conclusions: Adenomas in locations other than the adrenal glands occur in one third of patients with AIs. Mild autonomous hypercortisolism does not affect the prevalence of other endocrine-related adenomas but is associated with increased metabolic comorbidities and mortality, especially in patients with thyroid adenomas and adenomas in other locations.

Mild autonomous cortisol secretion (MACS) is a frequent finding in adrenal incidentalomas (AI), yet its diagnosis remains challenging. We aimed to compare clinical and biochemical profiles between MACS and non-functioning AIs and to identify reliable biomarkers, alternative to the 1 mg dexamethasone suppression test (DST), that can support the diagnosis of MACS. We retrospectively analyzed 171 patients with AIs (70 MACS, 101 non-functioning AI) evaluated between 2005 and 2025. MACS was defined by DST cortisol >1.8 μg/dL without overt Cushing's syndrome. Patients with MACS showed a higher prevalence of dyslipidemia (68.1% vs 52.0%; P = .037) and anxiety-depressive disorders (25.0% vs 11.0%; P = .018). Biochemically, they showed lower adrenocorticotropic hormone (11.1 pg/mL vs 16.8 pg/mL; P = .014), dehydroepiandrosterone-sulfate (0.3 μg/mL vs 0.9 μg/mL; P < .001), and testosterone levels in male (3.56 ng/ml vs 5.41 ng/ml, P = .04), with higher post-DST cortisol (2.8 μg/dL vs 1.2 μg/dL; P < .001), 24-hour urinary-free cortisol (67.2 μg/24h vs 44.8 μg/24h; P < .001), and late-night serum cortisol (8.2 μg/dL vs 3.6 μg/dL, P < .001). Adrenocorticotropic hormone <15 pg/mL (P = .029) and dehydroepiandrosterone-sulfate <0.5 μg/mL (P = .009) independently predicted MACS (area under the curve: 0.78) and were combined into a 2-point diagnostic score with 89.5% sensitivity and 97.5% negative predictive value. Late-night cortisol ≥5.1 μg/dL showed good accuracy (area under the curve: 0.83) for identifying patients with MACS and correlated with the number of MACS-related comorbidities (P = .0178). MACS is associated with neuropsychiatric and gonadal dysfunction. A simple and easily applicable biochemical score, together with late-night cortisol, may support diagnosis, particularly when the DST is inconclusive or in hospitalized patients.

Background/Objective: The overnight 1-mg dexamethasone suppression test (DST) represents the conventional/standard tool for endogenous hypercortisolemia screening, typically in relationship with adrenal and pituitary masses. Nevertheless, an associated spectrum of challenges and pitfalls is found in daily practice. This analysis aimed to evaluate: (I.) the diagnosis relevance of 1-mg DST in patients with adrenal incidentalomas (AIs) with/without mild autonomous cortisol secretion (MACS) exploring different cutoffs of the second-day plasma cortisol after dexamethasone administration (cs-DST) with respect to cardio-metabolic outcomes; (II.) the potential utility of adding other biomarkers to DST [plasma morning adrenocorticotropic hormone (ACTH), 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), dehydroepiandrosterone sulfate (DHEAS)]; and (III.) DST variability in time. Methods: This narrative analysis was based on searching full-text, English articles in PubMed (between January 2023 and April 2025) via using different term combinations: "dexamethasone suppression test" (n = 239), "diagnosis test for autonomous cortisol secretion" (n = 22), "diagnosis test for mild autonomous cortisol secretion" (n = 13) and "diagnosis test for Cushing Syndrome" (n = 61). We manually checked the title and abstract and finally included only the studies that provided hormonal testing results in adults with non-functional adenomas (NFAs) ± MACS. We excluded: reviews, meta-analyses, editorials, conference abstracts, case reports, and case series; non-human research; studies that did not provide clear criteria for distinguishing between Cushing syndrome and MACS; primary aldosteronism. Results: The sample-focused analysis (n = 13 studies) involved various designs: cross-sectional (n = 4), prospective (n = 1), retrospective (n = 7), and cohort (n = 1); a total of 4203 patients (female-to-male ratio = 1.45), mean age of 59.92 years. I. Cs-DST cutoffs varied among the studies (n = 6), specifically, 0.87, 0.9, 1.2, and 1.4 µg/dL in relationship with the cardio-metabolic outcomes. After adjusting for age (n = 1), only the prevalence of cardiovascular disease remained significantly higher in >0.9 µg/dL vs. ≤0.9 group (OR = 2.23). Multivariate analysis (n = 1) found cs-DST between 1.2 and 1.79 µg/dL was independently associated with hypertension (OR = 1.55, 95%CI: 1.08-2.23, p = 0.018), diabetes (OR = 1.60, 95%CI: 1.01-2.57, p = 0.045), and their combination (OR = 1.96, 95%CI:1.12-3.41, p = 0.018) after adjusting for age, gender, obesity, and dyslipidemia. A higher cs-DST was associated with a lower estimated glomerular filtration rate (eGFR), independently of traditional cardiovascular risk factors. Post-adrenalectomy eGFR improvement was more pronounced in younger individuals, those with lower eGFR before surgery, and with a longer post-operative follow-up. Cs-DST (n = 1) was strongly associated with AIs size and weakly associated with age, body mass index and eGFR. Cortisol level increased by 9% (95% CI: 6-11%) for each 10 mL/min/1.73 m2 decrease in eGFR. A lower cs-DST was associated with a faster post-adrenalectomy function recovery; the co-diagnosis of diabetes reduced the likelihood of this recovery (OR = 24.55, p = 0.036). II. Additional biomarkers assays (n = 5) showed effectiveness only for lower DHEAS to pinpoint MACS amid AIs (n = 2, cutoffs of <49.31 µg/dL, respectively, <75 µg/dL), and lower ACTH (n = 1, <12.6 pmol/L). III. Longitudinal analysis of DST's results (n = 3): 22% of NFAS switch to MACS after a median of 35.7 months (n = 1), respectively, 29% (n = 1) after 48.6 ± 12.5 months, 11.8% (n = 1) after 40.4 ± 51.17 months. A multifactorial model of prediction showed the lowest risk of switch (2.4%) in individuals < 50 years with unilateral tumor and cs-DST < 0.45 µg/dL. In the subgroup of subjects without cardio-metabolic comorbidities at presentation, 25.6% developed ≥1 comorbidities during surveillance. Conclusions: The importance of exploring the domain of AIs/NFAs/MACS relates to an increasing detection in aging population, hence, the importance of their optimum hormonal characterization and identifying/forestalling cardio-metabolic consequences. The spectrum of additional biomarkers in MACS (other than DST) remains heterogeneous and still controversial, noting the importance of their cost-effectiveness, and availability in daily practice. Cs-DST serves as an independent predictor of cardio-metabolic outcomes, kidney dysfunction, while adrenalectomy may correct them in both MACS and NFAs, especially in younger population. Moreover, it serves as a predictor of switching the NFA into MACS category during surveillance. Changing the hormonal behavior over time implies awareness, since it increases the overall disease burden.

BackgroundLimited data describe cognitive deficits in patients with Cushing syndrome (CS). The impact of mild autonomous cortisol secretion (MACS) on cognition is unknown.ObjectiveTo determine the impact of MACS on cognitive function.MethodsSingle-center cross-sectional study of adults with MACS and age and sex-matched volunteers. MACS was defined as cortisol >1.8 mcg/dL following the dexamethasone suppression test (DST) in patients with an adrenal incidentaloma and no features of CS. We measured cognitive function through the NIH toolbox cognition battery (7 standardized tests of attention, episodic and working memory, language, executive function, and processing speed). T-scores corrected for age, sex, education, and race were used for analysis. All patients completed the SF-36 questionnaire. The frailty index was calculated as previously reported (Singh S. JCEM 2020).ResultsParticipants included 50 patients with MACS (median age 61, range 54-68) and 50 volunteers (median age 60 years, range 54-68), with 60% women in both groups. In patients with MACS, median post-DST morning cortisol was 3.6 (range, 2.4-6.2), and median corticotropin was 8.5 (range, 5.9-13) pg/mL (normal 6-60). Patients with MACS had a higher median frailty index (median of 0.26 vs. 0. 05 in volunteers, p<0. 001) and lower quality of life scores on the SF-36 survey (median of 47 vs. 91, p<0. 001). Compared to volunteers, patients with MACS performed worse in the domains of attention and executive function (effective allocation of one's limited capabilities in an abundance of stimuli) (median T-score of 50 vs. 46, p=0. 03), cognitive flexibility (tested as the capacity to plan and monitor goal-directed activities) (median T-score of 61 vs. 55, p=0. 01). The fluid composite score (includes executive function, episodic memory, working memory, and processing speed) was lower in patients with MACS (mean of 53.2 vs. 48.9, p=0. 03). The total composite score was lower in patients with MACS when compared to volunteers (median T score of 50 vs. 54, p=0. 06). The total composite cognitive scores in patients of MACS were associated with the Frailty Index (R2 = 0.13, p = 0. 025) and SF-36 scores (R2 = 0. 08, p = 0. 05), but not post-DST cortisol.ConclusionCompared to volunteers, patients with MACS demonstrate cognitive impairment, particularly in the executive domain, which closely mimics changes observed with aging. These deficits do not correlate with the degree of cortisol excess.Presentation: No date and time listed

Plasma Steroid Profiling Combined With Machine Learning for the Differential Diagnosis in Mild Autonomous Cortisol Secretion From Nonfunctioning Adenoma in Patients With Adrenal Incidentalomas

Predictive Model for Mild Autonomous Cortisol Secretion in Patients Evaluated in Artificial Intelligence-Driven Adrenal Incidentaloma Clinic.

This study investigates the link between mild autonomous cortisol secretion (MACS) in adrenal incidentaloma (AI) patients and the occurrence and severity of cardiovascular and metabolic comorbidities. It aims to provide a detailed overview of this relationship, highlight gaps in current research, and propose directions for future studies. We conducted a retrospective analysis at Ankara City Hospital's Endocrine Department outpatient clinic, reviewing 627 AI patients from February 2019 to May 2021. The study involved a detailed analysis of clinical records, hormonal evaluations, and imaging, focusing on differentiating MACS from non-functioning adrenal incidentalomas (NFAI) and examining the impact of MACS on associated health conditions. The study found that MACS patients had a statistically higher incidence of diabetes mellitus (35% vs. 20%), hypertension (60% vs. 45%), hyperlipidaemia (40% vs. 25%), and coronary artery disease (30% vs. 15%) compared to the NFAI group. Independent predictors of MACS included the presence of bilateral adrenal masses, larger adrenal mass diameter (with a cutoff value of ≥ 18.5 mm, showing 83% sensitivity and 56% specificity for predicting MACS, and lower dehydroepiandrosterone sulphate (DHEAS) levels (≤ 49.31 μg/dL predicting MACS, with 61% sensitivity and 73% specificity). This research underscores the critical clinical implications of detecting MACS in AI patients, particularly its association with increased cardiovascular and metabolic risks. It calls for vigilant screening and a comprehensive management approach for affected patients. Additionally, the findings highlight the need for further studies to improve patient care and outcomes in this population.

Many adrenal adenomas exhibit mild autonomous cortisol secretion (MACS). Although MACS is associated with increased cardiovascular mortality, the underlying mechanisms are not fully defined. To investigate mechanisms that may link MACS and cardiovascular mortality in adults with adrenal adenoma. Cross-sectional study. Twenty adults with adrenal adenoma and MACS and 20 controls with nonfunctioning adrenal adenoma. Reactive hyperemia index (RHI) was measured by peripheral artery tonometry and 24-hour ambulatory blood pressure monitoring (24h AMBP) was performed. Indices of insulin secretion and sensitivity were estimated by measuring glucose and insulin fasting and following a mixed meal. The primary outcome was the difference in RHI between participants with MACS vs nonfunctioning adrenal adenoma. The average cortisol after 1-mg dexamethasone and urinary free cortisol were higher in patients with MACS. There was no significant difference in fasting RHI (2.0 [interquartile range (IQR) 1.6-2.4] vs 2.0 [IQR 1.7-2.2, P = .72), but postprandial RHI was higher in patients with MACS (2.2 [1.8-2.7] vs 1.8 [1.5-2.2], P = .04). 24-hour ambulatory blood pressure monitoring and Matsuda index were not significantly different in the groups. Fasting glucose and glucose area under the curve after the mixed meal were higher and insulinogenic index was lower in participants with MACS. Adults with adrenal adenoma and MACS do not have fasting endothelial dysfunction and postprandial endothelial function may be better. These patients have fasting and postprandial hyperglycemia with lower insulin secretion, which may underlie the association between MACS and increased cardiovascular mortality.

&lt;p dir="ltr"&gt;&lt;b&gt;Background&lt;/b&gt;: Adrenal incidentalomas (AIs) are increasingly detected through modern imaging. Most are nonfunctional adrenal tumors (NFATs) in which physiological cortisol secretion is assumed, whereas 20-50% have mild autonomous cortisol secretion (MACS), a subtle cortisol excess without clinical signs of Cushing syndrome. MACS has been associated with increased mortality and a higher prevalence of cardiometabolic comorbidities, whereas NFATs have traditionally been regarded as clinically harmless. However, emerging evidence indicates that NFATs may also be linked to adverse cardiometabolic outcomes and related health risk.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Aims&lt;/b&gt;: To evaluate long-term health risks associated with AIs. &lt;b&gt;Study I&lt;/b&gt;: To examine mortality by cortisol secretion status in patients with AIs in a single center. &lt;b&gt;Study II-IV&lt;/b&gt;: To characterize major clinical outcomes in patients with Als without overt hormonal secretion (presumed NFATs) compared with matched controls using a nationwide cohort. Specifically, &lt;b&gt;Study II&lt;/b&gt; aims to quantify all-cause and cause- specific mortality, &lt;b&gt;Study III&lt;/b&gt; to determine overall and site-specific cancer incidence, and &lt;b&gt;Study IV&lt;/b&gt; to evaluate fracture prevalence and incidence, including the effects of adrenalectomy.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Methods and Results: Study I&lt;/b&gt;: Single-center 13-year follow-up of 365 patients with AIs showed highest mortality in patients with MACS (18.2%) vs. patients with NFATs (7.8%), mainly from non-adrenal cancers. Higher cortisol concentrations, age, and tumor size predicted mortality.&lt;b&gt; Study II&lt;/b&gt;: Nationwide case-control study (17,726 patients with presumed NFATs; 124,366 controls) found increased all-cause mortality (aHR 1.21), particularly cardiovascular (aHR 1.21) and cancer-related (aHR 1.54), with stronger effects in individuals &lt;65 years. &lt;b&gt;Study III&lt;/b&gt;: Presumed NFATs were linked to higher cancer incidence (aHR 1.31), including thyroid, lung, gastrointestinal, kidney, bladder, pancreatic and breast cancers. &lt;b&gt;Study IV&lt;/b&gt;: In 20,390 patients with presumed NFATs, fracture prevalence (aOR 1.27) and incidence (aHR 1.27) were higher, especially vertebral fractures (aHR 1.83) and in younger men. Adrenalectomy eliminated the excess risk of fracture.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Conclusions&lt;/b&gt;: Both MACS and AIs presumed to be NFATs are associated with adverse long-term outcomes, particularly in younger individuals and men. These entities are better understood as part of a continuum within eucortisolemic individuals, suggesting that even cortisol activity within the normal range may contribute to chronic disease risk.&lt;/p&gt;&lt;h3&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Patrova J,&lt;/b&gt; Kjellman M, Wahrenberg H, Falhammar H. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine 2017 58(2):267-275. &lt;a href="https://doi.org/10.1007/s12020-017-1400-8" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1007/s12020-017-1400-8&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;II. &lt;b&gt;Patrova J,&lt;/b&gt; Mannheimer B, Lindh J. D, Falhammar H. Mortality in patients with nonfunctional adrenal tumors. JAMA Intern Med 2023;183(8):832-838. &lt;a href="https://doi.org/10.1001/jamainternmed.2023.2442" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1001/jamainternmed.2023.2442&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Patrova J,&lt;/b&gt; Mannheimer B, Larsson M, Lindh J. D, Falhammar H. The incidence of cancers in patients with nonfunctional adrenal tumors: a Swedish population-based national cohort study. J Endocr Soc. 2024;8(10):bvae154. &lt;a href="https://doi.org/10.1210/jendso/bvae154" target="_blank"&gt;https://doi.org/10.1210/jendso/bvae154&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;IV. Lindh J. D, &lt;b&gt;Patrova J,&lt;/b&gt; Mannheimer B, Falhammar H. Prevalence and incidence of fractures in patients with nonfunctional adrenal tumors. JAMA Netw Open. 2024;7(4):e246453. &lt;a href="https://doi.org/10.1001/jamanetworkopen.2024.6453" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1001/jamanetworkopen.2024.6453&lt;/a&gt;&lt;/p&gt;