Search Results (17)

Background. Glucocorticoid-induced osteoporosis represents a well-known type of secondary osteoporosis (SOp). While the most prevalent sub-category includes corticotherapy, another important contributor is represented by Cushing’s syndrome. In this traditional landscape, adrenal incidentalomas do not involve a standard cause of SOp, since most of them are non-functioning adrenal tumours (NFATs). Yet, 30–40% of them are not entirely “non-functioning”, due to mild autonomous cortisol secretion (MACS). Despite not being a guideline-based diagnosis, a lower ACTH might point to various NFATs/MACS complications. Objective. This study aimed to determine the relationship between the bone health status of post-menopausal women with NFATs/MACS and their baseline morning ACTH level. The bone health indicators were DXA, FRAX, and bone remodelling markers. Methods. This was a retrospective, real-life, transversal study in adult females who were hospitalized in a single tertiary centre of endocrinology. They were all anti-osteoporotic drug-naïve. The subjects underwent CT and DXA scanning and a 1 mg dexamethasone suppression test (DST). Results. The cohort (sample size of N = 84 patients, 61.49 ± 7.86 years) had a type 2 diabetes rate of 18%, arterial hypertension rate of 75%, and a dyslipidemia rate of 78%. Median ACTH was 11.89 pg/mL. The prevalence of MACS was 30.95%. The mean largest tumour diameter (LTD) was 2.25 ± 0.99 cm. ACTH correlated with second-day cortisol after the 1 mg DST (r = −0.301, p = 0.024), and LTD (r = −0.434, p < 0.001). ROC analysis for the bone resorption marker CrossLaps showed an AUC of 0.647 (p = 0.05), with the highest Youden index for the cut-off at 0.32 ng/mL (sensitivity 87.50%, specificity 39.50%). Bone impairment (osteoporosis + osteopenia) was found in 65% of patients, with an osteoporotic fracture prevalence of 4.76%. The lowest mean T-score (−1.12 ± 1.00) showed osteopenia, and the median trabecular bone score pointed a partially degraded microarchitecture [median (interquartile interval): 1.320 (1.230, 1.392)]. FRAX and FRAXplus estimations correlated with bone mineral density (BMD) at all three central DXA sites, regardless of the ACTH cut-off. Patients with a low ACTH (<10 pg/mL) displayed similar bone/adrenal features when compared to those with normal ACTH, except forbut they had a higher MACS rate (45.45% versus 21.57%, p = 0.021) and a larger LTD (2.67 ± 0.98 versus 1.98 ± 0.92 cm, p = 0.003). Fracture estimation showed that only in patients with a low ACTH, the 10-year fracture risk for major osteoporotic fractures (MOF) adjusted for lumbar BMD was lower than the risk for MOF adjusted for diabetes (p = 0.036), and the 10-year hip fracture risk was lower when adjusted for lumbar BMD (p = 0.007). ACTH correlated with lumbar BMD (r = 0.591, p = 0.002) only in the group with an ACTH < 10 pg/mL, suggesting its potential usefulness as a bone biomarker in these cases. On the other hand, MACS-negative subjects with a low ACTH versus those with a normal ACTH showed higher CrossLaps (0.60 ± 0.27 versus 0.42 ± 0.21 ng/mL, p = 0.022), indicating an elevated bone resorption even in patients with tumours that are regarded as true non-secretors. Conclusions. A subgroup of patients diagnosed with NFATs/MACS might be prone to skeletal damage, and biomarkers such as ACTH (specifically, suppressed ACTH) might serve as a surrogate pointer to help refine this higher risk in daily practice. Further research to address other ACTH cut-offs will place ACTH assays in the overall bone status evaluation in these patients, most probably not as a single biomarker, but in addition to other assays. Full article

Background/Objectives: Cushing’s syndrome (CS) is a rare endocrine disorder caused by chronic glucocorticoid excess. With the increasing recognition of mild autonomous cortisol secretion (MACS), clinical and biochemical differentiation between overt and mild forms has become more challenging. This study evaluated the clinical significance of the hemoglobin–albumin–lymphocyte–platelet (HALP) score in patients with Cushing’s disease (CD), adrenal Cushing’s syndrome (ACS), MACS, and nonfunctioning adrenal adenoma (NFA), focusing on its potential role in the preoperative evaluation and postoperative follow-up of hypercortisolism. Methods: We retrospectively analyzed 361 patients evaluated for cortisol excess between February 2019 and June 2025. Patients were categorized into four groups: CD, ACS, MACS, and NFA. Demographic, clinical, and hormonal parameters, as well as surgical outcomes, were recorded, and the HALP score was compared between the four groups. The diagnostic performance of the HALP score in differentiating overt Cushing’s syndrome (CD + ACS) from MACS/NFA was assessed using receiver operating characteristic (ROC) curve analysis. Postoperative changes in the HALP score were analyzed in surgically treated patients. Results: HALP scores were significantly lower in overt CS than in MACS and NFA. Using a threshold value of 40, the HALP score demonstrated 51.9% sensitivity and 90.4% specificity in differentiating CD/ACS from MACS/NFA. Among 68 operated patients, postoperative HALP data were available for 49 patients, for whom HALP scores significantly increased in both CD and ACS groups (p = 0.001 for each). Conclusions: The HALP score serves as a simple, cost-effective biomarker that reflects the combined hematologic and metabolic impact of cortisol excess. Significant postoperative improvement in the HALP score suggests its potential utility as a complementary tool in the preoperative assessment of hypercortisolism. Full article

Introduction/Background: Most adrenal incidentalomas (AIs) are non-functioning adrenal tumors (NFATs) without clinically overt hormonal hypersecretion; one-third show subtle endocrine over-activity and mild autonomous cortisol secretion (MACS). One out of ten NFATs involves not a unilateral (UTs), but bilateral tumors (BTs). Bone health, as opposed to cardio-metabolic complications, is less studied in NFAs/MACS, particularly in BTs. Hence, we aimed to analyze (blood) mineral metabolism assays (MMAs), including bone turnover markers (BTMs), central Dual-Energy X-ray Absorptiometry (DXA), and 10-year fracture risk estimation (FRAX/FRAXplus) in menopausal patients with UTs vs. BTs. Methods: This was a retrospective, single-center study. The inclusion criteria were women aged ≥50 y and CT-based AI detection. The exclusion criteria were medication against osteoporosis, malignancies, bone metabolic disorders, and cs-1mg-DST >5 µg/dL. Results: The cohort [N = 129; mean age: 62.39 ± 7.9 y; and y since menopause (YSM): 13.7 ± 8] included UT (62.22%) and BT (31.78%) groups with a similar age, YSM, type 2 diabetes rate (35.23% vs. 36.59%), arterial hypertension (73.6% vs. 75.5%), BMI, fasting glycemia, and glycated hemoglobin A1c (p > 0.5 for each). The borderline significance for morning cortisol was higher in UTs vs. BTs [median (interquartile interval): 13.9 (11.16, 15.00) vs. 10.10 (8.88, 12.95) µg/dL; p = 0.05] and the MACS-positive rate (24.45% vs. 36.59%; p = 0.051). The largest tumor diameter was similar (2.26 ± 0.97 vs. 2.51 ± 0.87 cm; p = 0.175), as was cs-1mg-DST [1.27 (1.01, 1.95) vs. 1.52 (0.92, 2.78) µg/dL; p = 0.357]. MMAs, BTMs, and DXA-BMD/T scores were similar in the UT vs. BT groups. The most prevalent DXA categories were osteopenia (50.82%) and normal (41.38%). The rate of DXA bone impairment (osteoporosis + osteopenia) was 72.13% vs. 58.62%. A generally low prevalence of fragility fractures was found (3.88%; N = 5, 3/2 between the groups). Out of the 25.58% (N = 33) females who were found to be MACS-positive, 54.55% were in the UT group and 45.45% were in the BT group. Age, YSM, the rate of analyzed comorbidities, BMI, biochemical parameters, DXA/BMDs, and FRAX/FRAXplus (lumbar BMD adjustment)-based probabilities were similar between the UT and BT groups, regarding MACS-positive vs. MACS-negative groups. Diabetic patients were all MACS-positive. A higher PTH level in the MACS-positive UT vs. MACS-positive BT groups (36.32 ± 9.21 vs. 51.65 ± 9.58 pg/mL; p = 0.01) was found, with the mean 25-hydroxyvitamin D showing mild deficiency (24.21 ± 12.73 vs. 26.16 ± 9.89 ng/mL; p = 0.694). In UTs, the largest tumor diameter statistically significantly correlated with baseline ACTH (r = −0.391; p < 0.001) and cs-1mg-DST (r = 0.306; p < 0.001), while in BTs, the largest diameter of the two tumors showed a positive correlation with cs-1mg-DST (r = 0.309; p = 0.012). Conclusions: The findings from this real-life setting (similar age, YSM, and diabetes and MACS-positive rates) could help us to better understand the bone features in UTs vs. BTs, noting that ACTH/cs-1mg-DST measurements showed no difference. The study population was associated with a generally low fracture prevalence and 10-year fracture risk probabilities, which might act as a bias in this distinct clinical exploration. Whether a multifactorial algorithm is needed to provide a 360-degree perspective of the bone health assessment in these patients remains an open matter. So far, starting from the current guidelines, a patient-centered approach is mandatory. To our best knowledge, this study adds to the limited number of prior studies regarding bone impairment in bilateral tumors. Full article

Over the last few decades, due to improvement in imaging techniques, the increased detection of adrenal incidentalomas is observed. Non-aldosterone producing adrenal adenomas (NAPACAs) often co-exist with second benign or malignant lesions. In the present study, we aimed to assess the presence of second neoplasms, both benign and malignant, in patients with NAPACAs, and to investigate possible correlations with clinical parameters, hormonal characteristics and the emergence of comorbidities. A total of 130 NAPACA patients were included in this single-center retrospective study. In this cohort, 35.4% of NAPACA patients carried any second neoplasm (either benign or malignant) whereas, 26.9% had a second malignant neoplasm. Cortisol levels after 1 mg overnight dexamethasone suppression test (F-ODS) were significantly higher in patients without a second neoplasm (p = 0.02), and this finding was consistent even when categorizing patients with and without malignancies (p = 0.02). In line with this observation, ACTH/F-ODS levels were significantly higher in patients with second malignancies (p < 0.05). Interestingly, the presence of mild autonomous cortisol secretion tended to be lower in patients with second malignancies (p = 0.08). No remarkable differences in the comorbidities of NAPACA patients with and without a second neoplasm were documented. Further prospective studies will be needed to elucidate the role of mild hypercortisolemia on the development of these second tumors in NAPACA patients. Full article

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. Full article

Background/Objective: One third of “non-functioning adrenal tumours” (NFAs) have mild autonomous cortisol secretion (MACS). An updated analysis of the hormonal biomarkers profile, including risk factors and the rate of post-surgery adrenal insufficiency (PSAI), the duration of restoring the normal adrenocortical function in MACS/NFA and potential impacts on clinical comorbidities. Methods: Comprehensive review based on PubMed search (January 2020–January 2025). Results: The studies (n = 14) included 2623 patients (N = 1158 underwent unilateral adrenalectomy), aged 18–93 (mean = 57.49 years), with a female-to-male ratio = 1.54. Post-adrenalectomy (n = 9, N = 753) analysis: the PSAI risk correlated with the severity of baseline hypercortisolism. PSAI incidence: 50% of MAC. The rate after 4–6 weeks follow-up was 71.9% (adrenal Cushing’s syndrome) vs. 50% (MACS) vs. 14.4% (NFA). PSAI duration was up to 35 months. Early PSAI diagnosis was reflected by post-operative cortisol assay on day 1 (cut-off ≤ 5 µg/dL) and an ACTH (Cosyntropin) stimulation test (CST) (cortisol cut-off ≤ 14 µg/dL). Pre-operatory PSAI predictors: higher serum cortisol-DST (1 mg dexamethasone testing) and lower baseline plasma ACTH (not all studies agreed). Conclusions: A stratified strategy is encouraged following a unilateral adrenalectomy in MACS; PSAI is expected in almost half of patients, with a potential improvement of hypertension. Serum cortisol assays serve as most useful biomarker as pre-operatory PSAI predictor (after DST) and, potentially, in addition with baseline ACTH. Post-surgery basal cortisol measurement (± CST) helps the decision of glucocorticoids replacement since first post-operative day and during follow-up, serial testing at 3 months is a useful tool. Full article

Background: Adrenal incidentalomas are detected in various medical and surgical healthcare departments, including primary healthcare. One up to three out of ten individuals confirmed with nonfunctioning adrenal incidentalomas (NFAs) actually present a mild autonomous cortisol secretion (MACS), which is distinct from Cushing’s syndrome. Objective: We aimed to assess the cortisol secretion in newly detected adrenal incidentalomas in patients who were referred by their primary healthcare physician upon accidental detection of an adrenal tumor at abdominal computed tomography (CT) scan that was performed for unrelated (non-endocrine) purposes. Methods: This retrospective study included adults diagnosed with an adrenal incidentaloma via CT during the previous 3 months. Inclusion criteria: age ≥ 40 years (y). A triple stratification of exclusion criteria involved: (1) Clinical aspects and medical records such as active malignancies or malignancies under surveillance protocols, subjects under exogenous glucocorticoid exposure (current or during the previous year), or suggestive endocrine phenotypes for any hormonal ailment; (2) Radiological appearance of suspected/confirmed (primary or secondary) adrenal malignancy, adrenal cysts, or myelolipomas; (3) Endocrine assays consistent with active endocrine tumors. Protocol of assessment included baseline ACTH, morning plasma cortisol (C-B), cortisol at 6 p.m. (C-6 pm), and after 1 mg dexamethasone suppression testing (C-1 mg-DST), 24-h urinary free cortisol (UFC), and a second opinion for all CT scans. MACS were defined based on C-1 mg-DST ≥ 1.8 and <5 µg/dL (non-MACS: C-1 mg-DST < 1.8 µg/dL). Results: The cohort (N = 60, 78.33% female; 60.72 ± 10.62 y) associated high blood pressure (HBP) in 66.67%, respectively, type 2 diabetes (T2D) in 28.37% of the patients. Females were statistically significantly older than males (62.40 ± 10.47 vs. 54.62 ± 9.11 y, p = 0.018), while subjects with unilateral vs. bilateral tumors (affecting 26.67% of the individuals) and those with MACS-positive vs. MACS-negative profile had a similar age. Body mass index (BMI) was similar between patients with unilateral vs. bilateral incidentalomas, regardless of MACS. Patients were divided into five age groups (decades); most of them were found between 60 and 69 years (40%). Left-gland involvement was found in 43.33% of all cases. The mean largest tumor diameter was 26.08 ± 8.78 mm. The highest rate of bilateral tumors was 46.67% in the 50–59 y decade. The rate of unilateral/bilateral and tumor diameters was similar in females vs. males. The MACS-positive rate was similar in females vs. males (23.40% vs. 23.08%). A statistically significant negative correlation (N = 60) was found between BMI and C-B (r = −0.193, p = 0.03) and BMI and UFC (r = −0.185, p = 0.038), and a positive correlation was found between C-B and C-6 pm (r = 0.32, p < 0.001), C-B and UFC (r = 0.226, p = 0.011), and C-6 pm and C-1 mg-DST (r = 0.229, p = 0.010), and the largest tumor diameter and C-1 mg-DST (r = 0.241, p = 0.007). Conclusions: Adrenal incidentalomas belong to a complex scenario of detection in the modern medical era, requiring a multidisciplinary collaboration since the patients might be initially detected in different departments (as seen in the current study) and then referred to primary healthcare for further decision. In these consecutive patients, we found a higher female prevalence, a MACS rate of 23.33%, regardless of uni/bilateral involvement or gender distribution, and a relatively high rate (than expected from general data) of bilateral involvement of 26.67%. The MACS-positive profile adds to the disease burden and might require additional assessments during follow-up and a protocol of surveillance, including a tailored decision of tumor removal. The identification of an adrenal incidentaloma at CT and its hormonal characterization needs to be integrated into the panel of various chronic disorders of one patient. The collaboration between endocrinologists and primary healthcare physicians might improve the overall long-term outcomes. Full article

Background/Objective: Osteoporotic fractures may be prevalent, as expected, in patients with primary osteoporosis such as menopause-related or age-related bone loss, but a supplementary contribution to the risk may be added by less than common conditions, including a non-functioning adrenal tumor with or without mild autonomous cortisol secretion (MACS). Many of the standard fracture risk-related elements are captured by the FRAX model; yet, novel insights are brought by an improved algorithm, namely, FRAXplus. Our objective was to analyze the fracture risk in menopausal females diagnosed with low bone mineral density (BMD) and MACS-negative adrenal incidentalomas using FRAXplus (lumbar BMD adjustment). Methods: This as a retrospective, multi-center study of 66 menopausal women, where 50% of them had non-MACS adrenal tumors (group A), and 33 were controls (group B). They were put into four sub-groups, either group A1 (N = 14/33 subjects with normal DXA), or A2 (19/33 subjects with lowest T-score < −1), or group B1 (14/33) where subjects had normal DXA, or group B2 (19/33) for subjects with low BMD. Results: The sub-groups were matched on age, body mass index, and years since menopause, as well BMD matched (A versus B, A1 versus B1, A2 versus B2). FRAX analysis showed similar results for 10-year probability between groups A and B, and A2 and B2, while lumbar BMD adjustment showed statistically significant lower risk in group A1 versus B1 (p = 0.013), but not for hip fracture (p = 0.064). Conclusions: we introduced a pilot study in the FRAXplus model regarding adrenal tumors diagnosed in menopausal females with or without low BMD at central DXA assessment, a pilot study that to the best of our knowledge represents the first of this kind due to the novelty of using this fracture risk calculator with lumbar BMD adjustment. FRAXplus algorithm might be a better discriminator for fracture risk in these patients since we found that in age-, BMI-, and years since menopause-matched sub-groups, patients with normal DXA and MACS-free adrenal incidentalomas display a lower 10-year probability of major osteoporotic fractures than controls upon lumbar BMD adjustment. Full article

Background/Objectives: Mild autonomous cortisol secretion (MACS) can coexist with primary aldosteronism (PA). The purpose of our study was to evaluate whether (MACS) influences parameters analyzed during adrenal venous sampling (AVS) in patients with PA. Methods: Patients with PA from the SPAIN-ALDO Registry and the German Conn’s Registry with available 1 mg-dexamethasone suppression test (DST) and AVS were included. MACS was defined as a post-DST cortisol > 1.8 µg/dL in the absence of specific signs and symptoms of Cushing’s syndrome. Results: Two-hundred and twenty-five patients were included, 98 (43.6%) of whom had concomitant MACS. The mean age was 54 ± 10 years and 37.3% were women. AVS was performed by simultaneous catheterization of both adrenal veins and analysis of basal samples in 157 patients (69.8%), with both basal and post-ACTH samples in 15 patients (6.7%), and during continuous ACTH infusion in 53 patients (23.6%). AVS was considered technically unsuccessful in 40 cases (17.8%), suggesting unilateral secretion in 106 (47.1%) and bilateral secretion in 79 (35.1%). We did not find significant differences in the percentage of unilateral and bilateral results, cortisol, corrected aldosterone, or selectivity indices in the dominant and non-dominant veins, nor in the lateralization index or the contralateral suppression index between patients with and without MACS. They also had similar rates of surgical treatment and biochemical and clinical response. Conclusions: Although pathophysiological reasoning suggests that MACS could hinder AVS identification of unilateral forms of PA, our data suggest that such interference, if it exists, is of moderate clinical relevance. Full article

Background: Increased cardiovascular risk has been described in individuals with adrenal incidentalomas. The aim of the present study is to assess the effect of remnant cholesterol (RC) on the cardiovascular risk and mortality of patients with adrenal incidentalomas. Methods: A retrospective cohort study was conducted with patients with adrenal incidentalomas between 2001 and 2024. One hundred thirty-seven patients (mean age of 61.2 ± 11.5 years; 56.6% women) with non-functioning adrenal incidentalomas and with mild autonomous cortisol secretion (MACS) (cortisol post-dexamethasone suppression test ≥1.8 µg/mL) were included. The patients were divided into two groups using 30 mg/dL as the cut-off for RC. Logistic regression models were used to study the impact of RC on major adverse cardiovascular events and mortality (MACEs). Results: Patients with RC ≥ 30 mg/dL exhibited a higher prevalence of type 2 diabetes mellitus (T2D) (p < 0.001), lower HDL-C (p < 0.001) and LDL-C (p = 0.025) levels, a higher frequency of treatment with statins (p = 0.032), and a higher rate of non-fatal major cardiovascular events (p = 0.038) and MACEs (p = 0.038). Patients with MACS showed no differences in RC or complications during the follow-up. The relative risk of high RC was 2.65 (1.04–6.77) for cardiovascular events and 2.27 (1.05–4.92) for MACEs, with p < 0.05 in both cases. The only variables independently affecting MACEs were age ([odds ratio] OR = 1.13 [p = 0.004]), female sex (OR = 0.20; p = 0.016), LDL-C (OR = 1.02; p = 0.029), and RC (OR = 1.06; p = 0.014). T2D and HDL-C were not independently associated with MACEs. Conclusions: RC ≥30 mg/dL in patients with adrenal incidentalomas was associated with a higher prevalence of T2D, lower HDL-C levels, and a higher risk of MACEs. MACS was not associated with RC or MACEs during the follow-up. Full article

Background: Adrenal tumors are a common finding in clinical practice, and only detailed evaluation may reveal secretory and metabolic abnormalities or their malignant character. We aimed to highlight epidemiological data, rates of malignancy, clinical or secretory characteristics, and the cardiometabolic implications of adrenal masses. Methods: We conducted a retrospective analysis using data from the medical files of 474 patients with adrenal pathology hospitalized between January 2007 and January 2020, before the COVID-19 pandemic, using the ICD-10 codes. After applying inclusion and exclusion criteria, a total of 264 patients with adrenal tumors were enrolled in the study. Patients underwent clinical examination, abdominal imaging, and hormonal evaluation, and some of them underwent a pathological exam after adrenalectomy. Results: Median age at diagnosis was 56 (17) years, with 81.06% of patients being female. The median follow-up period was 41.5 (70) months, ranging from 6 months to 13 years. Adrenal tumors were most frequently seen in older female patients, with 83.47% of them being over 40 years old. The malignancy rate was 4.54%. Hormonally nonfunctioning tumors (71.95%) predominated, and overt hypercortisolism was present in 10.61% of patients, as was mild autonomous cortisol secretion in 5.31% of patients, primary hyperaldosteronism in 8.71% of patients, and adrenal paraganglioma in 3.41% of patients. Cardiometabolic comorbid conditions were similar in patients with functioning and nonfunctioning tumors. Conclusions: All patients with adrenal tumors should receive a complete hormonal workup and detailed malignancy risk assessment. Even though a hormonally active tumor predisposes to cardiometabolic comorbid conditions, a nonfunctioning lesion may also be associated with such disorders and needs thorough assessment. Full article

We studied the application of CT texture analysis in adrenal incidentalomas with baseline characteristics of benignity that are highly suggestive of adenoma to find whether there is a correlation between the extracted features and clinical data. Patients with hormonal hypersecretion may require medical attention, even if it does not cause any symptoms. A total of 206 patients affected by adrenal incidentaloma were retrospectively enrolled and divided into non-functioning adrenal adenomas (NFAIs, n = 115) and mild autonomous cortisol secretion (MACS, n = 91). A total of 136 texture parameters were extracted in the unenhanced phase for each volume of interest (VOI). Random Forest was used in the training and validation cohorts to test the accuracy of CT textural features and cortisol-related comorbidities in identifying MACS patients. Twelve parameters were retained in the Random Forest radiomic model, and in the validation cohort, a high specificity (81%) and positive predictive value (74%) were achieved. Notably, if the clinical data were added to the model, the results did not differ. Radiomic analysis of adrenal incidentalomas, in unenhanced CT scans, could screen with a good specificity those patients who will need a further endocrinological evaluation for mild autonomous cortisol secretion, regardless of the clinical information about the cortisol-related comorbidities. Full article

The number of adrenal incidentaloma (AI) cases has increased in the last few years due to the widespread use of imaging diagnostics. Management requires evaluation of the malignant nature and hormonal activity. The aim of the present study is to assess possible clinical abnormalities in 132 AI patients both at baseline and during follow-up (mean 48.6 ± 12.5 months). In all patients, demographic, anthropometric data, biochemical, metabolic and hormonal data, and 24-h ambulatory blood pressure monitoring were assessed. Mild autonomous cortisol secretions (MACS) were diagnosed in patients without signs and symptoms of overt Cushing’s syndrome and post dexamethasone (DXM) plasma cortisol concentration > 50 nmol/L (>1.8 μg/dL). Patients with overnight DXM-1 mg test positive showed higher values of diastolic blood pressure, glycemia and uric acid levels compared to patients with negative DXM test at baseline. During follow-up, the potential development of MACS in patients with nonfunctional AI showed a prevalence of 29%, though the cardiovascular and metabolic alterations were less pronounced compared to those diagnosed with MACS at baseline. Therefore, follow-ups with AI patients are useful for observing changes in clinical features. Full article

Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing’s syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to highlight the most recent data concerning the glucose profile, particularly, type 2 diabetes mellitus (T2DM) in NFAIs with/without mild autonomous cortisol secretion (MACS). This was a comprehensive review of the literature; the search was conducted according to various combinations of key terms. We included English-published, original studies across a 5-year window of publication time (from January 2020 until 1 April 2024) on PubMed. We excluded case reports, reviews, studies on T1DM or secondary diabetes, and experimental data. We identified 37 studies of various designs (14 retrospective studies as well 13 cross-sectional, 4 cohorts, 3 prospective, and 2 case–control studies) that analysed 17,391 individuals, with a female-to-male ratio of 1.47 (aged between 14 and 96 years). T2DM prevalence in MACS (affecting 10 to 30% of NFAIs) ranged from 12% to 44%. The highest T2DM prevalence in NFAI was 45.2% in one study. MACS versus (non-MACS) NFAIs (n = 16) showed an increased risk of T2DM and even of prediabetes or higher fasting plasma glucose or HbA1c (no unanimous results). T2DM prevalence was analysed in NFAI (N = 1243, female-to-male ratio of 1.11, mean age of 60.42) versus (non-tumour) controls (N = 1548, female-to-male ratio of 0.91, average age of 60.22) amid four studies, and two of them were confirmatory with respect to a higher rate in NFAIs. Four studies included a sub-group of CS compared to NFAI/MACS, and two of them did not confirm an increased rate of glucose profile anomalies in CS versus NFAIs/ACS. The longest period of follow-up with concern to the glycaemic profile was 10.5 years, and one cohort showed a significant increase in the T2DM rate at 17.9% compared to the baseline value of 0.03%. Additionally, inconsistent data from six studies enrolling 1039 individuals that underwent adrenalectomy (N = 674) and conservative management (N = 365) pinpointed the impact of the surgery in NFAIs. The regulation of the glucose metabolism after adrenalectomy versus baseline versus conservative management (n = 3) was improved. To our knowledge, this comprehensive review included one of the largest recent analyses in the field of glucose profile amid the confirmation of MACS/NFAI. In light of the rising incidence of NFAI/AIs due to easier access to imagery scans and endocrine evaluation across the spectrum of modern medicine, it is critical to assess if these patients have an increased frequency of cardio-metabolic disorders that worsen their overall comorbidity and mortality profile, including via the confirmation of T2DM. Full article

Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS. Full article