Mild Autonomous Cortisol Excess Research Articles

Effect of mild cortisol cosecretion on body composition and metabolic parameters in patients with primary hyperaldosteronism.

To investigate the effects of simultaneous cortisol cosecretion (CCS) on body composition in computed tomography(CT)-imaging and metabolic parameters in patients with primary aldosteronism (PA) with the objective of facilitating early detection. Retrospective cohort study. Forty-sevenpatients with PA and CCS confirmed by 1-mg dexamethasone suppression test (DST) with a cutoff of ≥1.8 µg/dL were compared with PA patients with excluded CCS(non-CCS, n = 47) matched by age and sex. Segmentation of the fat compartments and muscle area at the third lumbar region was performed on non-contrast-enhanced CT images with dedicated segmentation software. Additionally, liver, spleen, pancreas and muscle attenuation were compared between the two groups. Mean cortisol after DST was 1.2 µg/dL (33.1 nmol/L) in the non-CCS group and 3.2 µg/dL (88.3 nmol/L) in the CCS group with mild autonomous cortisol excess (MACE). No difference in total, visceral and subcutaneous fat volumes was observed between the CCS and non-CCS group (p = .7, .6 and .8, respectively). However, a multivariable regression analysis revealed a significant correlation between total serum cholesterol and results of serum cortisol after 1-mg DST (p = .026). Classification of the patients based on visible lesion on CT and PA-lateralization via adrenal venous samplingalso did not show any significant differences in body composition. MACE in PA patients does not translate into body composition changes on CT-imaging. Therefore, early detection of concurrent CCS in PA is currently only attainable through biochemical tests. Further investigation of the long-term clinical adverse effects of MACE in PA is necessary.

Utilizing dehydroepiandrosterone sulfate and its ratio for detecting mild autonomous cortisol excess in patients with adrenal incidentaloma.

Subclinical Cushing syndrome is a condition of mild autonomous cortisol excess (MACE) that lacks typical features of Cushing syndrome but is associated with many complications. It represents a common hormonal dysfunction among patients with adrenal incidentaloma (AI), defined as unexpected masses or lesions found in the adrenal glands during radiological examinations of the chest or abdomen unrelated to adrenal gland assessment. The study evaluated the accuracy of dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone sulfate ratio (calculated by dividing the DHEA-S value by the age and sex-adjusted normal range of DHEA-S) in detecting MACE in AI patients. A cross-sectional study was conducted from April 2021 to July 2022 at the Faiha Specialized Diabetes, Endocrine, and Metabolism Centre (FDEMC) in Basrah, southern Iraq, involving 38 AI patients. Comprehensive laboratory and radiological evaluations were performed, including tests for adrenocorticotropic hormone (ACTH), renin, aldosterone, aldosterone/renin ratio (ARR), metanephrine, normetanephrine, cortisol, DHEA-S, and the 1-mg overnight dexamethasone suppression test (1-mg ONDST). Among the AI patients, 14% had MACE. Both DHEA-S ≤75 µg/dL and a DHEA-S ratio ≤1.7 exhibited a sensitivity of 80% each, with specificities of 73.3% and 76.6%, respectively, in diagnosing MACE in individuals aged ≤65 years. The negative predictive values were 95.7% and 95.8%, respectively. Low DHEA-S and DHEA-S ratio had high sensitivity and specificity in predicting MACE among AI patients aged ≤65 years, with strong negative predictive value.

Primary bilateral macronodular adrenal hyperplasia: clinical and laboratory features

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by bilateral benign adrenocortical lesions, which in some cases lead to Cushing syndrome (CS). Due to the low detection, non-specific, erased clinical picture and slow, long-term progression, it is difficult to assess the true prevalence of PBMAH. This also leads to fairly limited literature data. A detailed analysis of biochemical, imaging parameters, the clinical presentations, in particular, an assessment of the course of comorbidities (arterial hypertension (AH), diabetes (DM), osteoporosis), is necessary to develop an algorithm for managing patients with PBMAH. Analysis of clinical and laboratory characteristics of patients with various forms of PBMAH. A single-center, retrospective, observational, cross-sectional study was carried out. This study included 110 patients with PBMAH who got referred to the National Research Center for Endocrinology in the period from 2013-2023. We carried out comparative and correlation analysis of hormonal (plasma cortisol concentrations after 1 mg dexamethasone (1-mg DST), urinary free cortisol (СКМ), ACTH), biochemical (glycated hemoglobin), radiological data (nodular tissue volume), course of comorbidities (metabolic syndrome, DM, AH, osteoporosis) in three groups of patients: with overt CS, mild autonomous cortisol excess (MACE) and comorbid diseases, and patients with PBMAH without hormonal activity. Among 110 patients 79.1% were women, median age - 60 [51; 68]. The proportion of hormonally inactive forms of PBMAH was 37.3%, the overt CS and MACE was detected in 25.4 and 37.3% consequently. According to the hormonal -examination data: the cortisol level during 1-mg DST was 173.8 nmol/l [86.0; 441.0], ACTH - 3.35 pg/ml [1.00; 8.00], СКМ - 445.5 [249.0; 900.0]. Statistically significant positive moderate correlations were found between the volume of nodular tissue and the level of cortisol after PDT1 (r=0.40, p<0.001), СКМ (r=0.29, p<0.004), as well as a negative moderate correlation between the volume and the level of ACTH (r=-0.40, p<0.001). When analyzing the prevalence and clinical severity of comorbid conditions, DM was diagnosed in 22 (53.7%), AH in 36 (87.8%), obesity and osteoporosis - 23 (56%) and 3 (7.3%) patients. There was no statistically significant difference in the prevalence of CS-associated diseases among the above groups (p=0.56). PBMAH is a heterogeneous pathology with different clinical, hormonal, and imaging characteristics. A correlation was found between the volume of nodular tissue and the degree of hormonal activity of PBMAH. The obtained results emphasize the difficulty in determining clear indications for surgical treatment in the group of patients with MACE. The radicality of proposed surgical procedure should be weighed against its potential complications.

Expression of CYP11B1 and CYP11B2 in adrenal adenoma correlates with clinical characteristics of primary aldosteronism

Primary aldosteronism (PA) shows histological heterogeneity and clinical variability, including the coexistence of hypercortisolemia. Immunohistochemical analyses of steroidogenic enzymes in adrenal tissues have provided new insights into the pathogenesis of PA. However, a comprehensive analysis of the association between enzyme expression and clinical characteristics of PA has rarely been conducted. We aimed to investigate the correlation between clinical characteristics and steroidogenic enzyme expression in PA. A retrospective case-control study. Consecutive patients who underwent unilateral adrenalectomy for PA (n = 180). Patients with adrenal Cushing's syndrome (CS) (n = 29) and nonfunctioning adenoma (n = 6) as comparator groups. A tissue microarray of adrenal adenomas was constructed and immunostained for CYP11B1, CYP11B2 and CYP17A1. The expression of the three enzymes was compared between PA and other adrenal diseases and between PA with and without mild autonomous cortisol excess (MACE). Adrenal adenomas in PA showed lower CYP11B1, higher CYP11B2 and lower CYP17A1 expression than those in adrenal CS (p < .001). Nonfunctioning adenomas showed low expression of the three enzymes. PA with MACE showed higher CYP11B1 expression than PA without MACE. CYP11B1 expression was positively correlated with the severity of hypercortisolemia, and CYP11B2 was positively correlated with that of hyperaldosteronism. The expression of CYP11B1 and CYP11B2 had a negative correlation. Patients with absent clinical improvement after adrenalectomy had lower CYP11B2 expression than those with complete success. Variable expression of steroidogenic enzymes in adrenal adenoma underlies the clinical heterogeneity of PA and is associated with treatment outcomes.

Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism.

An institutional study previously demonstrated that cosyntropin stimulation testing on postoperative day 1 (POD1-CST) identified patients at risk for adrenal insufficiency (AI) following unilateral adrenalectomy (UA) for adrenal-dependent hypercortisolism (HC) and primary aldosteronism (PA), allowing for selective glucocorticoid replacement (GR). This study re-evaluates the need for GR following UA for patients with HC and PA in a larger cohort. A prospective database identified 108 patients who underwent UA for mild autonomous cortisol excess (MACE) (n = 47), overt hypercortisolism (OH) (n = 27), PA (n = 22), and concurrent PA/HC (n = 12) from September 2014 to October 2020; all underwent preoperative evaluation for HC. MACE was defined by the 1 mg dexamethasone suppression test (cortisol >1.8 μg/dL), with ≥5 defined as OH. GR was initiated for basal cortisol ≤5 or stimulated cortisol ≤14 (≤18 prior to April 2017) on POD1-CST. Fifty-one (47%) patients had an abnormal POD1-CST; 54 (50%) were discharged on GR (27 MACE, 20 OH, 1 PA, 6 PA/HC). Median duration of GR was OH: 6.0 months, MACE: 2.1 months, PA: 1 month, PA/HC: 0.8 months. Overall, 26% (n = 7) of patients with OH and 43% (n = 20) of patients with MACE did not require GR. Two (2%) patients with OH had normal POD1-CST but developed AI several weeks postoperatively requiring GR. None experienced life-threatening AI. POD1-CST identifies patients with HC at risk for AI after UA, allowing for selective GR. One-quarter of patients with OH and nearly half of patients with MACE can forgo GR after UA. Patients with PA do not require evaluation for AI if concurrent HC has been excluded preoperatively.

Targeted Mutational Analysis of Cortisol-Producing Adenomas.

Somatic gene mutations have been identified in only about half of cortisol-producing adenomas (CPAs). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1. This work aims to expand our understanding of the prevalence of somatic mutations in CPAs from patients with overt Cushing syndrome (OCS) and "subclinical" mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue. We analyzed FFPE adrenal tissue from 77 patients (n = 12 men, 65 women) with either OCS (n = 32) or MACE (n = 45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPAs (32 OCS CPAs and 46 MACE CPAs). Genomic DNA was isolated from the FFPE CPAs and subjected to targeted amplicon sequencing for identification of somatic mutations. Somatic mutations were identified in 71.8% (56/78) of the CPAs. While PRKACA was the most frequently mutated gene in OCS CPAs (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE CPAs. Most GNAS mutations were observed in MACE CPAs (5/7, 71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored 2 adjacent tumors within the same adrenal gland - one patient had 2 CPAs, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase). A comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPAs. OCS CPAs demonstrated a distinct mutation profile compared to MACE CPAs.

Intratumoral steroid profiling of adrenal cortisol-producing adenomas by liquid chromatography- mass spectrometry

Endogenous Cushing syndrome (CS) is an endocrine disorder marked by excess cortisol production rendering patients susceptible to visceral obesity, dyslipidemia, hypertension, osteoporosis and diabetes mellitus. Adrenal CS is characterized by autonomous production of cortisol from cortisol-producing adenomas (CPA) via adrenocorticotropic hormone-independent mechanisms. A limited number of studies have quantified the steroid profiles in sera from patients with CS. To understand the intratumoral steroid biosynthesis, we quantified 19 steroids by mass spectrometry in optimal cutting temperature compound (OCT)-embedded 24 CPA tissue from patients with overt CS (OCS, n = 10) and mild autonomous cortisol excess (MACE, n = 14). Where available, normal CPA-adjacent adrenal tissue (AdjN) was also collected and used for comparison (n = 8). Immunohistochemistry (IHC) for CYP17A1 and HSD3B2, two steroidogenic enzymes required for cortisol synthesis, was performed on OCT sections to confirm the presence of tumor tissue and guided subsequent steroid extraction from the tumor. LC–MS/MS was used to quantify steroids extracted from CPA and AdjN. Our data indicated that CPA demonstrated increased concentrations of cortisol, cortisone, 11-deoxycortisol, corticosterone, progesterone, 17OH-progesterone and 16OH-progesterone as compared to AdjN (p < 0.05). Compared to OCS, MACE patient CPA tissue displayed higher concentrations of corticosterone, 18OH-corticosterone, 21-deoxycortisol, progesterone, and 17OH-progesterone (p < 0.05). These findings also demonstrate that OCT-embedded tissue can be used to define intra-tissue steroid profiles, which will have application for steroid-producing and steroid-responsive tumors.

Natural history of nonfunctioning adrenal incidentalomas: a 10-year longitudinal follow-up study.

Most data on the natural history of nonfunctioning adrenal incidentalomas (NFAI) are provided by follow-ups up to 5 years. We conducted a 10.5 (9.1–11.9)-year prospective follow-up study of NFAI in 67 participants (20 (29.9%) males, 47 (70.1%) females) of mean age 57.9 (52.3–63.9) years and BMI 27.42 (24.07–30.56) kg/m2). We also evaluated the associations between baseline BMI and changes of NFAIs’ characteristics at follow-up. Progression to mild autonomous cortisol excess (MACE) was observed in 15 (22 %) patients, with 14 of them having post overnight dexamethasone suppression test (ODST) cortisol between 50 and138 nmol/L and only one > 138 nmol/L. The progression rate was significantly higher in overweight and obese than in normal-weight subjects. Patients that developed MACE had a significantly higher baseline mean cortisol after 1 mg ODST. Tumor enlargement ≥10 mm occurred in 8.9% of patients. In comparison with reports of shorter observational periods, we observed a higher growth rate ≥ 10 mm and higher progression rate from NFAI to MACE, particularly in overweight and obese subjects. All tumors had persistent radiological characteristics typical for adrenal adenoma. We concluded that the duration of the follow-up period is an important factor in characterizing the natural history of NFAI. Higher baseline BMI and higher baseline cortisol after ODST might predict the long-term likelihood of progression in hormonal activity. The magnitudes of observed progressions in growth or hormonal activity were clinically insignificant. Our long-term follow-up, therefore, clearly supports the general view that a long-term monitoring of patients with NFAI is not necessary.

Rationale and design of the cardiovascular status in patients with endogenous cortisol excess study (CV-CORT-EX): a prospective non-interventional follow-up study

BackgroundEndogenous Cushing’s syndrome (CS) results in increased cardiovascular (CV) morbidity and mortality. So far, most studies focussed on distinct disease entities rather than the integrity of the CV system. We here describe the design of the Cardiovascular Status in Endogenous Cortisol Excess Study (CV-CORT-EX), a study aiming to comprehensively investigate the health status of patients with endogenous CS (with a particular focus on CV phenotypes, biochemical aspects, quality of life, and psychosocial status).MethodA prospective non-interventional cohort study performed at a German tertiary referral centre. At the time of enrolment, patients will be categorised as: (1) newly diagnosed overt CS, (2) recurrent overt CS, (3) CS in remission, (4) presence of mild autonomous cortisol excess (MACE). The target cohorts will be n = 40 (groups 1 + 2), n = 80 (group 3), and n = 20 (group 4). Patients with overt CS at the time of enrolment will be followed for 12 months after remission (with re-evaluations after 6 and 12 months). At each visit, patients will undergo transthoracic echocardiography, cardiac magnetic resonance imaging, 24-h electrocardiogram, 24-h blood pressure measurement, and indirect evaluation of endothelial function. Furthermore, a standardised clinical investigation, an extensive biochemical workup, and a detailed assessment of quality of life and psychosocial status will be applied. Study results (e.g. cardiac morphology and function according to transthoracic echocardiography and cardiac magnetic resonance imaging; e.g. prevalence of CV risk factors) from patients with CS will be compared with matched controls without CS derived from two German population-based studies.DiscussionCV-CORT-EX is designed to provide a comprehensive overview of the health status of patients with endogenous CS, mainly focussing on CV aspects, and the holistic changes following remission.Trail registrationClinicalTrials.gov (https://clinicaltrials.gov/) NCT03880513, registration date: 19 March 2019 (retrospectively registered). Protocol Date: 28 March 2014, Version 2.

Nonfunctioning Adrenal Incidentalomas are not Clinically Silent: A Longitudinal Cohort Study

The association between nonfunctioning adrenal incidentalomas (NFAIs) and cardiometabolic diseases remains controversial. This retrospective cohort study investigated whether NFAIs are related with prevalent and incident cardiometabolic diseases. This study included 154 patients with biochemically confirmed NFAIs and 1:3 age and sex-matched controls without adrenal incidentalomas (n = 462) among subjects who underwent abdominal computed tomography at a single healthcare center in 2003-2012. Electronic medical records were reviewed for comorbidities at baseline and during a mean follow-up of 7.5 years. The logistic regression analysis for prevalent cardiometabolic diseases and the survival analysis for incident cardiometabolic diseases were performed. The subjects were 55.7±8.8 years of age and predominantly male (73.1%). The NFAI group had a higher body mass index compared to the age and sex-matched control group (25.1±2.8 vs. 24.0±2.8 kg/m2; P<.001). In a cross-sectional design, covariate-adjusted logistic regression showed significantly higher odds ratios (ORs) for diabetes mellitus and hypertension in the NFAI group (adjusted OR [95% confidence interval [CI]], 1.89 [1.17 to 3.06] and 2.26 [1.47 to 3.50], respectively). The NFAI group had a 2-fold higher risk of insulin resistance (adjusted ORs [95% CI], 2.03 [1.06 to 3.90]). Moreover, NFAI subjects with diabetes mellitus had a greater increase in size of adrenal lesions than those without diabetes mellitus (3.4±5.5 vs. 1.4±5.5 mm; P =.048). However, in the survival analysis, the incidence of any cardiometabolic diseases did not differ between the NFAI and control groups. NFAIs are related to prevalent diabetes mellitus or hypertension in our cross-sectional study. However, the presence of NFAIs did not affect the development of cardiometabolic diseases. ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; BMI = body mass index; CI = confidence interval; CT = computed tomography; HbA1c = hemoglobin A1c; HOMA-IR = homeostasis model assessment of insulin resistance; HU = Hounsfield units; MACE = mild autonomous cortisol excess; NFAI = nonfunctioning adrenal incidentaloma; OR = odds ratio.

Genomic classification of benign adrenocortical lesions.

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.

Contralateral adrenal thinning as a distinctive feature of mild autonomous cortisol excess of the adrenal tumors.

To identify radiologic features that correlate with mild autonomous cortisol excess using planar and volumetric analysis. Cross-sectional study. In the study, 64 patients with overt Cushing syndrome (CS), 59 patients with mild autonomous cortisol excess (MACE), and 64 patients with nonfunctioning adrenal tumors (NFAT) with evaluable CT scans were included. Patients with NFAT and MACE were BMI-matched with those with overt CS. Planar and volumetric analyses of CT scans were performed in DICOM images using OsiriX software. The mean age was 56.6 ± 1.01 years, and 123 patients (65.1%) were female. In the order of NFAT, MACE, and overt CS, the diameters and volumes of the adenoma increased, while limb widths and volumes of the contralateral adrenal gland decreased. Patients with MACE or overt CS were more likely to have osteoporosis than those with NFAT (P = 0.006), and patients with overt CS were more likely to experience a fragility fracture than those with NFAT or MACE (P = 0.002). Among radiologic features, the limb width of the contralateral adrenal gland correlated with the cortisol level after overnight dexamethasone suppression test (r = -0.583, P < 0.001). The study showed that the contralateral adrenal limb thinning was a distinctive radiologic feature of autonomous cortisol excess in the planar and volumetric analysis.

Reliability of adrenal computed tomography in predicting the functionality of adrenal incidentaloma.

Adrenal incidentaloma (AI) is an adrenal mass discovered accidentally during abdominal or chest imaging techniques not aimed to adrenal gland assessment. Guidelines suggested confirming the benignity of AI radiologically and excluding hormonal dysfunctions. This study evaluated the reliability of computed tomography (CT) scan radiological parameters in predicting the functionality of AI. A cross-sectional study performed in Faiha Specialized Diabetes, Endocrine and Metabolism Centre from July 2017 to July 2018, involving 38 patients (23 females [60.5%]) harbouring 43 AI referred for evaluation. For all patients, we assessed history, physical examination, radiological parameters of AI by CT scan (native Hounsfield unit [HU]), maximum diameter and absolute percentage washout [APW] and blood investigations (glycated haemoglobin, adrenocorticotropic hormone, aldosterone, renin, aldosterone/renin ratio, normetanephrine, metanephrine, dehydroepiandrosterone sulphate, cortisol and 1 mg overnight dexamethasone suppression test). Native CT adrenal HU ≥18.5 was statistically significant seen in most functional AI (FAI) (P = 0.006), especially in patients with mild autonomous cortisol excess (MACE) and pheochromocytoma (PCC) with P = 0.02 in both. Maximum diameter was significantly high (≥40 mm) in PCC and congenital adrenal hyperplasia (CAH) (P = 0.018 and 0.008, respectively). APW was significantly < 60% only in PCC (P = 0.02). Native HU was the most significant radiological parameter in predicting the functionality of FAI, MACE and PCC, but not in CAH and aldosterone-producing adenoma. The maximum diameter was significant in predicting the PCC and CAH, whereas the APW was significant in predicting PCC only.

Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess: A Systematic Review and Meta-analysis.

Adrenal incidentalomas are mostly benign nonfunctioning adrenal tumors (NFATs) or adenomas causing mild autonomous cortisol excess (MACE), but their natural history is unclear. To summarize the follow-up data of adults with NFAT or MACE to determine the proportions of tumor growth, malignant transformation, and incident changes in hormone function; the prevalence of incident cardiometabolic comorbid conditions; and mortality. MEDLINE, Embase, Cochrane, and Scopus (January 1990 to February 2019) and bibliographies of identified articles, without language restriction. Studies that included 20 or more conservatively managed patients with NFAT or MACE and reported outcomes at baseline and after at least 12 months of follow-up. Pairs of reviewers extracted outcomes and assessed methodological quality. Thirty-two studies reported outcomes of 4121 patients with NFAT or MACE, 61.5% of whom were women; the mean age was 60.2 years, and mean follow-up was 50.2 months. Mean tumor growth was 2 mm over 52.8 months. Clinically significant tumor enlargement (≥10 mm) occurred in 2.5% of patients, and none developed adrenal cancer. Clinically overt hormone excess was unlikely to develop (<0.1%) in patients with NFAT or MACE. Only 4.3% of patients with NFAT developed MACE, and preexisting MACE was unlikely to resolve (<0.1%). Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent (60.0%, 42.0%, 33.7%, and 18.1% of patients, respectively) and were more likely to develop and worsen in MACE than NFAT. New cardiovascular events were more prevalent in MACE (15.5%) than NFAT (6.4%). Mortality was 11.2% and was similar between NFAT and MACE. Evidence was scarce, and definitions of MACE and comorbid conditions were heterogeneous. During follow-up, NFAT and MACE do not show clinically relevant changes in size or hormonal function, but they may carry an increased risk for cardiometabolic comorbid conditions. None.

OR29-2 Mild Autonomous Cortisol Excess (MACE) in Adrenal Incidentalomas - Metabolic Risk Profile and Urinary Steroid Metabolome Analysis in 1208 Prospectively Recruited Patients

BACKGROUND: Adrenal incidentalomas (AI) are frequently associated with mild autonomous cortisol excess (MACE). The 1mg-dexamethasone suppression test (1mg-DST) differentiates MACE into MACE-1 (possible MACE; post-Dex cortisol 50-138 nmol/L) and MACE-2 (definitive MACE; post-Dex cortisol >138 nmol/L). MACE patients do not show clinically overt signs of hypercortisolism but are thought to carry a higher metabolic risk than nonfunctioning (NF) AIs. However, large-scale data about the metabolic impact of MACE are lacking. METHODS: We included 1208 patients with benign AIs and 1mg-DST results prospectively recruited as part of the ENSAT EURINE-ACT study. Clinical information and 24-h urines were available for all patients. Results of mass spectrometry-based urinary steroid profiling were compared to 162 healthy controls and 56 patients with overt adrenal Cushing’s syndrome (CUSH), using a sex- and age-adjusted linear regression model. RESULTS: MACE was found in 48% of adrenal incidentaloma patients (MACE-1 37%, MACE-2 11%), predominantly affecting women (NF 64%, MACE-1 67%, MACE-2 77%). MACE patients were significantly older than those with NF (p<0.001). MACE AIs were larger (median 32mm vs. 22mm in NF) and more often bilateral (31% vs. 17% in NF). The presence and grade of MACE were significantly linked to metabolic risk as assessed by prevalence of hypertension (NF 64%, MACE-1 75%, MACE-2 78%), type 2 diabetes (NF 20%, MACE-1 27%, MACE-2 30%), use of lipid-lowering medications (NF 40%, MACE-1 54%, MACE-2 52%), and osteopenia/osteoporosis (NF 37%, MACE-1 50%, MACE-2 56%) (all p<0.01 by Fisher’s exact test). Patients with MACE and type 2 diabetes more frequently required insulin treatment (31% vs. 15% in NF; p<0.01), and those with hypertension more often needed ≥3 medications (42% vs. 35% in NF; p<0.01). Urinary steroid metabolome analysis of MACE urines revealed a profile characterized by decreased androgen metabolites and increased glucocorticoid metabolites, resembling the profile of CUSH patients, with the latter also showing significantly increased mineralocorticoid precursor excretion (corticosterone and 11- deoxycorticosterone metabolites) (all p<0.001 vs. controls). CONCLUSIONS: MACE is highly prevalent in AIs and associated with an increased burden of metabolic co-morbidities. In addition, the similarities between the MACE and CUSH steroid metabolomes suggests that MACE is both a highly relevant clinical and biochemical entity.

SAT-368 Natural History Of Adrenal Incidentalomas With And Without Mild Autonomous Cortisol Excess; A Systematic Review And Meta-analysis

Background: Adrenal incidentalomas are mostly non-functioning adrenal tumors (NFAT) or adenomas with mild autonomous cortisol excess (MACE), of which the natural history is unclear. We conducted a systematic review and meta-analysis to study the long-term follow-up of NFAT and MACE to determine: (i) proportion of tumor growth and malignant transformation, (ii) incident change of hormone function, and (iii) incident cardio-metabolic comorbidities and mortality. Methods: Literature search of multiple databases including MEDLINE, EMBASE, Cochrane, and Scopus (January 1990 to February 2018). We included studies of adults with NFAT or MACE (as defined by authors), with ≥20 patients undergoing conservative management, and reported outcomes of interest at baseline and after ≥12 months follow-up. Results: We included 31 studies reporting on 4138 patients with incidental NFAT and MACE; 61.9% females, mean age 60.1 years, and mean follow-up 48.9 months. Overall, the data quality was medium-high, but there was significant heterogeneity in MACE and comorbidities definitions. Mean tumor growth in NFAT and MACE was 1.8mm over 60.6 months, which was similar between both groups. Adenomas were less likely to grow when the baseline mean size was ≥2.5cm, compared to smaller adenomas (<2.5 cm); mean size difference 0.8mm and 2.3mm, respectively. While 10% of patients demonstrated tumor enlargement, growth of ≥1cm occurred in only 4.5% over 62.0 months, which was relatively higher in MACE (MACE 4.5% vs. NFAT 2.3%). None of 2690 NFAT and MACE patients developed adrenal malignancy over 42.4 months. Development of overt Cushing’s syndrome and pheochromocytoma was very rare (0.4%). None of 2690 patients developed primary hyperaldosteronism. Of 2088 NFAT patients, 5.6% developed MACE, while pre-existing MACE resolved in 1.9% of 780 patients during 50.6 months. Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent, 59.8%, 46.6%, 34.2%, and 19.3% of patients, respectively, and more likely to develop and worsen in MACE compared to NFAT. Cardiovascular events were twice as common in MACE compared to NFAT, and cardiovascular mortality occurred more in MACE (6.6%) than NFAT (5.0%) during 58.7 months follow-up. Conclusions: Patients with NFAT and MACE do not require radiological or hormonal follow-up. However, they carry an increased risk of cardio-metabolic comorbidities, warranting evaluation and appropriate therapy.

SUN-LB062 The Impact of Autonomous Cortisol Secretion on Body Composition

Objective: Visceral fat and sarcopenia are two independent factors of increased cardiovascular risk. Limited data exist in performance of these markers in patients with adrenal tumors and autonomous cortisol excretion. Methods: Patients were prospectively enrolled from the adrenal clinics between 2014 and 2018. Inclusion criteria were adults discovered with adrenocortical adenoma on abdominal computed tomography (CT) imaging and diagnosed with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol excess (MACE) and Cushing syndrome (CS). Exclusion criteria were malignancy, exogenous steroid use, and BMI<18 kg/m2. MACE was diagnosed based on DST cortisol (cortisol after overnight 1 mg dexamethasone) >1.8 mcg/dl. Age, sex and BMI 1:1 matched healthy controls were recruited from local population. Body composition measurements (visceral adipose tissue [V], subcutaneous adipose tissue [S], visceral/total fat [V/T], and total abdominal muscle mass [M],) were calculated from CT imaging analysis. Results: Of 227 patients with adrenal adenomas, 20 patients were diagnosed with CS, 76 with MACE and 131 with NFAT. Median age of patients was 56 years (range, 18-89), and 67% were women. Median BMI was 31 kg/m2 (range, 18-58). Median size of the adrenal tumour was 2.4 (range, 0.5-13 cm) and median HU 6 (range, -27 to 36). Adrenalectomy was performed in 52 (23%) patients. Prevalence of hypertension, diabetes mellitus type 2, and obesity was similar among patients with CS, MACE and NFAT, however, higher prevalence of osteoporosis and osteopenia was noted in patients with CS compared to MACE and NFAT ( 55% vs 32% vs 16%, P<0.001). No difference in total fat was found in MACE vs NFAT, however, the proportion of visceral fat (V/T) was higher in MACE (0.43 vs 0.37 in NFAT, P=0.005). After adjusting for age, sex and BMI, both mean M (P=0.03) as well as M to total fat ratio (P=0.02) were independently and inversely correlated with DST cortisol in patients with adrenal adenomas. When compared to age, sex and BMI-matched healthy controls, patients with adenomas demonstrated significant differences in muscle mass (30%, 25% and 20% lower in CS, MACE and NFAT when compared to controls, respectively, P<0.0001 for all). Similarly, V/M ratio was 117%, 77% and 51% higher in CS, MACE and NFAT, respectively, when compared to controls (P<0.0001 for all). Conclusion: DST cortisol is positively correlated with visceral fat and negatively correlated with muscle mass. Patients with adenomas present with lower muscle mass and higher proportion of visceral fat when compared to controls, including patients with so called “nonfunctioning” adenomas. Even a subtle abnormality in cortisol secretion, not detectable by current standard of care testing may play a detrimental role in body composition of patients with adenomas. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess; a systematic review and meta-analysis

Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess; a systematic review and meta-analysis

Extensive clinical experience: Hypothalamic-pituitary-adrenal axis recovery after adrenalectomy for corticotropin-independent cortisol excess.

To identify predictors of hypothalamic-pituitary-adrenal (HPA) axis recovery interval and severity of glucocorticoid withdrawal symptoms (GWS) in patients undergoing adrenalectomy for corticotropin-independent cortisol excess. This is a retrospective study of patients with mild autonomous cortisol excess (MACE), moderate and severe Cushing syndrome (CS) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. Adrenalectomy was performed in 81 patients (79% women, median age 52years [IQR 42-62]). HPA axis recovery occurred at a median of 4.3months (IQR 1.6-11.4) after adrenalectomy (severe CS vs moderate CS vs MACE: median 11.4 vs 2.8 vs 2.1months, P<0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1-mg overnight dexamethasone suppression test >10μg/dL or >276nmol/L (9.7 vs 1.3months if cortisol ≤10μg/dL or ≤276nmol/L, P<0.01); body mass index (for every 3kg/m2 decrease, glucocorticoid taper increased by 1month, P<0.05); age <45 (11.4 vs 2.3months if ≥45years, P<0.05); duration of symptoms prior to diagnosis >1year (11.4 vs 2.8months if ≤1year); moon facies (11.4 vs 2.2months if no rounding of the face); and myopathy (13.1 vs 2.7months if no myopathy, P<0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P<0.05) with a median of 1 and 0 events/patient, respectively. The HPA axis recovery interval was the longest for patients with severe CS. Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE. Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS. This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. Retrospective cohort study. Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P<.001) and by 0.3 (P<.001); however, these measurements were decreased by 0.04 (P=.007) and 0.2 (P=.01), respectively, in patients with MACE. Total muscle mass was decreased by -10cm2 (P=.02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28nmol/L cortisol increase there was a 0.008 increase in V/T (P<.001), 0.02 increase in the V/S fat ratio (P<.001) and a 1.2cm2 decrease in mean total muscle mass (P=.002). The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.