Treatment for essential tremor (ET) and cortical myoclonus (CM) differs. As their clinical distinction can be difficult, with large inter- and intra-observer variability, there is a need for additional diagnostic tools.

We aim to develop a machine learning based approach using accelerometry data to support clinicians in their diagnosis of ET versus CM.

We recorded the upper body movements of 19 ET and 19 CM patients performing 21 tasks using eight accelerometry sensors. The phenotype was classified by applying an explainable machine learning method called generalized matrix learning vector quantization (GMLVQ) to the power spectrum derived from the accelerometry recordings. In addition to the general classification performance, GMLVQ provides context for the decisions made. This includes the relevance of frequencies and thus the identification of distinct patterns in the phenotypes.

For all postures and dynamic tasks, excellent classification results were reached with AUROC approaching 1,0. For the classification, GMLVQ considers the overall shape of the power spectrum, whereby the frequencies 5-7 Hz as well as 3-4 and 9-10 Hz are of particular importance. These frequencies correspond to the tremor peak and local minima that are also observed as characteristics in the literature.

The excellent classification results provide a proof of concept for the discrimination of ET and CM by applying a GMLVQ machine learning analysis to power spectra derived from accelerometry recordings. Such a system could support clinicians to improve the diagnostic accuracy.

Adrenal lesions are common and require appropriate management when clinically relevant. The approach to the evaluation of an adrenal lesion is to exclude malignancy and hormone excess as these are associated with significant morbidity and mortality. Imaging of adrenal lesions primarily aims to identify features indicating benignity. Non-contrast CT is recommended as first-line imaging for adrenal lesions. Indeterminate lesions that require further characterization may proceed to adrenal protocol CT (with contrast) or MRI, with a trend in recent years towards increasing use of MRI. PET-CT may also be used to assess adrenal lesions in certain clinical scenarios. Clinical guidelines recommend that all adrenal incidentalomas require further dedicated imaging unless they are clearly benign on imaging. The imaging strategy of adrenal lesions depends upon a number of factors including patient history, nature of detection, imaging characteristics (size, heterogeneity, presence of intracellular lipid), and the presence or absence of hormone excess. Special considerations are given to pregnant patients, young patients < 40 years, and those with a history of an extra-adrenal malignancy. This review outlines the role of imaging for adrenal lesions, describes the various imaging options and investigation strategies, and highlights relevant imaging findings.

To evaluate the potential of Photon counting CT (PCCT) -derived iodine densities and Virtual-Non-Contrast (VNC) reconstructions for the differentiation between adrenal adenomas and adrenal metastases.

This retrospective study enrolled 53 PCCT scans of patients with adrenal lesions (29 adenomas, 24 metastases) including early-arterial (ea) and portal-venous (pv) contrast phase. Iodine maps and VNC reconstructions were calculated from the acquired sequences. Using the measured values, several parameters such as relative enhancement (RE), normalized iodine density (NID), and iodine to VNC ratio (IVR) were calculated. In the acquired image series, iodine maps and VNC reconstructions density values were evaluated (adrenal lesion, ipsilateral adrenal tissue, contralateral adrenal tissue, portal vein, descending aorta, inferior vena cava, subcutaneous adipose tissue, in the first lumbar vertebral body, surrounding air, and in the psoas muscle) and compared.

In total, the measured structures showed significant variation in density values due to different contrast phases and reconstructions. VNC reconstructions of portal-venous contrast phase showed significant differences in measured density mean values between adrenal adenomas and adrenal metastases (21.64 HU vs. 28.26 HU, p: 0.027, AUC: 0.68). No significant differences between metastases and adenomas were observed in iodine concentration, RE of ea, NID of ea and pv, as IVR of ea. Significant alterations were observed in RE of pv (p: 0.023, AUC: 0.7) and IVR of pv (pv: 0.029, AUC: 0.69).

The recent study shows that PCCT derived VNC reconstructions of portal venous contrast phase can be used for reliable differentiation of adrenal adenomas and adrenal metastases and underlines the value of PCCT in oncological imaging.

11-Oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11β-hydroxyandrostenedione to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity.

To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches.

Cross-sectional observational study of patients with CKD (n = 85) and healthy controls (n = 46) measuring serum and urinary concentrations of glucocorticoids, and classic and 11-oxygenated androgens by liquid chromatography tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant.

HSD11B2 activity declined with estimated glomerular filtration rate (eGFR), evidenced by higher cortisol/cortisone (E) ratios in patients with CKD than in controls (P < .0001). Serum concentrations of E, 11KA4, 11KT, and 11β-hydroxytestosterone were lower in patients with CKD than in controls (P < .0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2, and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR.

This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.

To summarize the epidemiology and clinical implications of adrenal incidentalomas, as well as the recommended hormonal and radiological evaluation, treatment and follow-up that should be carried out in patients with adrenal incidentalomas.

The prevalence of adrenal incidentalomas has increased in the last decades due to advanced and more sensitive imaging modalities, their increased utilization, and the aging population. The evaluation of patients with adrenal incidentalomas should be focused on addressing two questions: Is the tumor functional, and is the tumor malignant? In relation to functionality, although most adrenal incidentalomas are clinically nonfunctioning, a significant proportion of patients have mild autonomous cortisol secretion and a lower proportion over functional adrenal syndromes. The differentiation between malignant and benign lesions is usually based on the radiological appearance of the lesion in CT and/or MRI. Adrenalectomy is considered the first-line treatment for malignant and functioning tumors. Radiological follow-up is not necessary for lesions classified as benign, but for indeterminate lesions, CT/MRI should be repeated in 6-12 months.

Adrenal incidentalomas are a common clinical problem, and their assessment should be focused on ruling out hormonal hypersecretion and malignancy. In general, adrenalectomy is considered the treatment of choice for malignant and functioning adrenal tumors.

Androgen excess is common in women and refers to clinical or biochemical evidence of elevated androgenic steroids such as testosterone. It is associated with underlying polycystic ovary syndrome in the majority of cases. However severe androgen excess is less common and may indicate the presence of underlying adrenal or ovarian neoplasms, genetic disorders or severe insulin resistance syndromes. Currently there are few consensus guidelines to assist clinicians with a standardised management approach to the patient with severe androgen excess.

Clinical practice guideline.

This guideline has been developed with expertise from colleagues in endocrinology, gynaecology, clinical biochemistry and nursing, and furthermore provides a unique patient perspective to guide clinicians.

The Society for Endocrinology commissioned this new guideline to collate multi-disciplinary guidance for clinical practitioners in the investigation of severe androgen excess. Recommendations have been made in the areas of clinical assessment, biochemical work up, dynamic testing and imaging, informed where possible by the best available evidence.

This guideline will provide guidance for clinicians in their approach to patients with severe androgen excess.

Pediatric adrenocortical carcinoma (pACC) is an exceptionally rare and aggressive malignancy, accounting for only 0.2-0.3% of childhood cancers. Characterized by significant endocrine activity and often associated with genetic syndromes such as Li-Fraumeni syndrome, pACC exhibits distinct clinical and molecular profiles compared to adult adrenocortical carcinoma (ACC). Current treatment approaches, largely adapted from adult protocols, center on surgery and chemotherapy, including mitotane. However, the lack of pediatric-specific data and major clinical trials underscores a pressing need for tailored therapeutic strategies. Advances in molecular profiling have unveiled actionable targets, such as alterations in the Wnt/β-catenin and MAP/ERK pathways, overexpression of IGF2, and epigenetic dysregulation. Emerging therapies, including immune checkpoint inhibitors, CAR T-cell therapy, and radiopharmaceuticals, hold promise but remain largely untested in pediatric populations. Targeting metabolic vulnerabilities, such as steroidogenesis and lipid metabolism, offers additional avenues for therapeutic innovation. Furthermore, improved diagnostic tools like liquid biopsy and steroid profiling may enhance disease monitoring and early detection. Despite progress in understanding pACC biology, significant challenges remain in translating these insights into effective treatments. Collaborative efforts, such as the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), and the development of pediatric-specific clinical trials are vital for advancing the field. Multidisciplinary care and international research initiatives will be pivotal in addressing the unmet needs of pACC patients. By leveraging molecular insights and fostering global collaboration, the field can move toward personalized medicine, improving outcomes and quality of life for children with this challenging disease. Expanding clinical trials, refining diagnostic tools, and integrating novel therapies into treatment regimens will be critical in bridging the gap between pediatric and adult ACC treatment success.

Production of adrenal androgens begins with cholesterol, and through a series of enzymatic steps catalyzed by the cytochrome p450 superfamily, forms several 19-carbon sex hormones. Benign disorders of adrenal androgen hypersecretion include adrenal variants of polycystic ovarian syndrome, congenital adrenal hyperplasia, and nonmalignant tumors. Adrenocortical carcinomas can also oversecrete adrenal androgens. Primary adrenal hypoandrogenism is not generally accepted as a stand-alone diagnosis in women. Blockade of adrenal androgens has emerged as contemporary treatment of men with metastatic prostate cancer. Here, we explore the history of the adrenal gland, its biosynthetic pathway, and common disorders of adrenal androgen hypersecretion and blockade.

Adrenal function testing is recommended in all adrenal nodules 1 cm or larger with evaluation for pheochromocytoma, hyperaldosteronism, cortisol production, and androgen production as 40% of adrenal nodules are functional. Additional testing can be performed in patients with suspicious nodules by imaging. A multidisciplinary approach to evaluation and treatment of adrenal nodules is mandatory to consider the nuances involved in laboratory screening, confirmatory testing, and localization procedures.

Adrenal incidentalomas are adrenal masses ≥ 1 cm discovered on imaging studies for unrelated clinical conditions. The prevalence of adrenal incidentalomas has increased as a byproduct of the widespread use of cross-sectional imaging, particularly in older adults. The clinical significance of adrenal incidentalomas varies based on tumor size, hormonal activity, and imaging characteristics. While most adrenal incidentalomas are benign and asymptomatic, a significant minority are hormonally active or malignant, necessitating careful evaluation and management. Adrenal hormone secretion can have significant clinical implications. Biochemical testing is crucial to assess for hormone excess, including steroid hormones (mineralocorticoids, glucocorticoids, and androgens), which are made in the adrenal cortex, as well as catecholamines, which are made in the adrenal medulla. Non-contrast computed tomography (CT) is the preferred modality for evaluating adrenal nodules as it allows for assessment of tissue density in Hounsfield units (HU). Benign lesions typically have an homogeneous appearance with HU ≤ 10. Contrast-enhanced CT with delayed washout can help differentiate benign tumors from malignant tumors. Tumors ≥ 4 cm, or those with indeterminate features may require further imaging, such as magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT. The management of adrenal incidentalomas is determined by hormonal secretion and imaging characteristics. Surgical resection is recommended for functional tumors and those that are suspicious for malignancy, including tumors ≥ 4 cm in size and those with rapid growth. Non-functional tumors < 4 cm may undergo imaging surveillance. The goal of this review is to summarize the contemporary literature and guidelines on adrenal incidentalomas, and to describe the key principles regarding evaluation and management.

Urinary steroid profiling after hydrolysis of conjugates is an emerging tool to differentiate aggressive adrenocortical carcinomas (ACC) from benign adrenocortical adenomas (ACA). However, the shortcomings of deconjugation are the lack of standardized and fully validated hydrolysis protocols and the loss of information about the originally conjugated form of the steroids. This study aimed to evaluate the quality of the deconjugation process and investigate novel diagnostic biomarkers in urine without enzymatic hydrolysis.

24 h urine samples from 40 patients with ACC and 40 patients with ACA were analyzed by untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry both unmodified and after hydrolysis with arylsulfatase/glucuronidase from Helix pomatia. Both approaches were compared regarding the differentiation of ACC vs. ACA via ROC analyses and to evaluate the hydrolyzation efficiency of steroid conjugates.

Steroid glucuronides were fully deconjugated, while some disulfates and all monosulfates were still largely detectable after enzymatic hydrolysis, suggesting incomplete and variable deconjugation. In unhydrolyzed urine, steroid monosulfates showed the best differentiation between ACC and ACA (highest AUC=0.983 for C21H32O6S, followed by its isomer and two isomers with the molecular formula C21H32O7S). Moreover, several disulfates were highly abundant and increased in ACC compared to ACA.

This work highlights the limitations of hydrolyzing steroid conjugates before analysis and shows a possible superiority of a direct analysis approach compared to a hydrolysis approach from a methodological point of view and regarding diagnostic accuracy. Several steroid conjugates were found as promising diagnostic biomarkers for differentiation between ACC and ACA.

Primary aldosteronism is the most common cause of secondary hypertension, yet most cases remain unrecognized and left without optimal treatment. The diagnostic inertia may be attributed to the lack of specific symptoms, insufficient awareness among physicians, still conflicting indications for screening for primary aldosteronism and first and foremost challenging diagnostics. This review describes the current challenges of biochemical diagnostics of primary aldosteronism, including screening, case confirmation and subtyping. It also discusses immunoassays widely used in assessment of suspected autonomous aldosterone secretion - recent advances in the field and limitations of the method in comparison to the gold standard - liquid chromatography -tandem mass spectrometry. The review focuses on the application of novel "omics" strategies in the diagnostics of primary aldosteronism. Steroidomics and proteomics offer a possibility to simultaneously assess steroids and protein/peptides on a large scale. This multianalyte approach in comparison to the selective quantification of a chosen compound has been proved useful in the diagnostics of primary aldosteronism. It also offers a unique insight into the individual characteristics, underlying mechanisms and even reflects the genetic alterations of primary aldosteronism cases. The "omics" techniques are associated with large amounts of generated data, the interpretation of which may be troublesome and often necessitates the use of artificial intelligence. The novel advances in the biochemical diagnostics of primary aldosteronism, including "omics" techniques, presented in this review may help to address the most emerging problems, increase the number of diagnosed patients and facilitate the choice of an optimal treatment.

This document presents the findings of the American Association of Clinical Endocrinology (AACE) on the diagnosis, management, and surveillance of patients with multiple endocrine neoplasia type 1 (MEN1) and associated tumors. The task force included a diverse group of experts in endocrinology, oncology, genetics, surgery, and patient representation. A comprehensive literature review was conducted to address key issues related to the evaluation, surveillance, and treatment of MEN1-related tumors.

The task force, comprised of 9 members with expertise in endocrinology, surgery, medical oncology, genetics, and patient advocacy, collaborated to develop guidance for the evaluation, surveillance, and management of MEN1-associated tumors. Consensus was defined as ≤1 dissenting vote and significant majority as ≥75%. Relevant studies were identified through a literature review process, and consensus statements were based on the available evidence.

The task force deliberated on the surveillance, evaluation, and management of MEN1-related tumors including parathyroid, pituitary, and gastroenteropancreatic neuroendocrine tumors and other tumors of relevance. The document also addresses the indications for MEN1 genetic testing.

This consensus statement aims to offer evidence-informed guidance for health care providers involved in the care of patients with MEN1 and associated tumors. It provides guidance on diagnostic tools, genetic testing criteria, imaging techniques, surgical interventions, and posttreatment monitoring. The practical, patient-centered approach outlined in this document is intended to improve outcomes for individuals with MEN1 and other high-risk endocrine tumors.

Guidelines suggest performing urine steroid profiling in patients with indeterminate adrenal tumors to make a noninvasive diagnosis of adrenocortical carcinoma (ACC). However, urine steroid profiling is not widely available.

To determine the accuracy of clinically available serum 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone in diagnosing ACC.

We conducted a prospective single-center cohort study of patients with adrenal masses evaluated between 2015 and 2023. Serum was analyzed by liquid chromatography-mass spectrometry for 17OH-pregnenolone, 17OH-progesterone, and 11-deoxycortisol. Reference standard for adrenal mass included histopathology, imaging characteristics, imaging follow up of 2 years, or clinical follow up of 5 years. Localized Generalized Matrix Learning Vector Quantization analysis was used to develop serum steroid score and assessed with area under receiver operating curve.

Of 263 patients with adrenal masses, 44 (16.7%) were diagnosed with ACC, 161 (61%) with adrenocortical adenomas (ACAs), 27 (10%) with other adrenal malignancies, and 31 (12%) with other. Hounsfield unit ≥ 20 was demonstrated in all ACCs, in all but 1 other adrenal malignancy, and in 58 (31%) ACAs. All 3 steroids were higher in patients with ACCs vs non-ACCs, including when comparing ACCs with functioning ACAs, and with ACAs with Hounsfield unit ≥ 20 (P < .0001 for all). Localized Generalized Matrix Learning Vector Quantization analysis yielded a serum steroid score that discriminated between ACC and non-ACC groups with a mean threshold fixed area under receiver operating curve of 0.823.

We showed that measurements of 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone could be valuable in diagnosing ACC. After appropriate validation, serum steroid score could be integrated in clinical practice.

The management of rare tumors at reference centers with specialized multidisciplinary tumor boards (MTBs) improves patient survival. No international standardized diagnostic and treatment recommendations for pediatric patients with adrenocortical carcinoma (ACC) exist so far. The aim of this case-based study is to determine how congruent treatment recommendations are in different specialized institutions in different countries.

In this cross-sectional, case-based survey study, five anonymized patient cases, including imaging data of pediatric adrenocortical carcinomas (pACCs), were distributed to seven international specialized centers located in Brazil, Germany, India, Italy, Poland, Turkey, and the USA. The centers were tasked with providing recommendations regarding the treatment sequence and modalities, as well as indicating the level of consensus on these decisions within their MTBs. For each case, the treatment approach recommended by the highest number of centers was recorded to calculate an agreement percentage relative to all treatment recommendations made. The consensus level for each case was determined on a scale of 1 to 10, with higher scores indicating greater agreement among MTB members.

A total of five patient cases were discussed across seven MTBs, yielding a total of 34 treatment recommendations. The agreement percentages for the primary therapeutic approach for each case were as follows: primary therapeutic approach: 88.6%; surgical approaches: 51.8%; and systemic chemotherapy recommendations: 53%.

This study represents the first case-based analysis of international inter-center agreement on pediatric ACC management. Inter-center agreement regarding treatment allocation and sequencing was low, while the level of consensus within each MTB was high. These findings point to potentially significant and clinically relevant differences in treatment standards across centers, highlighting the need for international collaboration and standardized diagnostic and therapeutic recommendations, especially for rare tumors. Increased case-based exchanges between centers are essential to reduce the substantial discrepancies observed here and to further standardize the management of pediatric patients with ACC.

An adrenal mass discovered incidentally during imaging for unrelated clinical reasons is termed an "adrenal incidentaloma" (AI). AIs can be categorized as primary or metastatic, functioning or non-functioning, and benign or malignant. The primary goal of radiological evaluation is to exclude malignancy by differentiating between benign and malignant lesions. Most AIs are benign, with adenomas and macronodular bilateral adrenal hyperplasia being the most common types. Less common benign lesions include myelolipomas, pheochromocytomas, cysts, and hematomas. Malignant adrenal masses account for less than 10% of cases and often include metastases from other cancers or primary adrenal diseases, such as adrenocortical carcinoma and pheochromocytoma. Computed Tomography (CT) remains the gold standard for diagnosing adrenal incidentalomas, while Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) are utilized for indeterminate cases. Additionally, innovative imaging techniques such as texture analysis are gaining importance, as they can assess quantitative parameters that are not visible to the human eye. This review aims to provide an updated overview of malignant adrenal lesions on CT and MRI, emphasizing key imaging features suspicious for malignancy to aid in distinguishing between benign and malignant lesions. Furthermore, it highlights the growing role of radiomics as a supportive tool for radiologists.

This study aimed to focus on the role of radiologists in the diagnosis and management of adrenal lesions, particularly primary aldosteronism (PA) and secondary hypertension. As hypertension affects more than one-third of the population in Japan, identifying secondary causes such as PA and adrenal lesions is crucial. Establishing a radiological differential diagnosis of adrenal lesions using advanced imaging techniques, such as computed tomography and magnetic resonance imaging, is crucial. Knowledge of the imaging findings of various benign and malignant adrenal lesions, such as adrenocortical adenomas, cortisol-producing lesions, pheochromocytomas, adrenocortical carcinoma, malignant lymphoma, and metastatic tumors, is necessary. Adrenal venous sampling (AVS) plays a crucial role in accurately localizing aldosterone hypersecretion in PA, especially when imaging fails to provide a clear diagnosis. This paper details the technical aspects of AVS, emphasizing catheterization techniques, anatomical considerations, and the importance of preprocedural imaging for successful sampling. Furthermore, we explore segmental adrenal venous sampling (SAVS), a more refined technique that samples specific adrenal tributary veins, offering enhanced diagnostic accuracy, particularly for microadenomas or challenging cases that may be missed with conventional AVS. The methodology for performing SAVS, along with the interpretation criteria for successful sampling and lateralization, is also outlined. Furthermore, radiologists have initiated treatments for unilateral PA, such as radiofrequency ablation, and play an integral role in the management of adrenal lesions. Collaborative approaches across clinical departments are required to enhance patient management in medical care involving the adrenal gland.

Exogenous Cushing's syndrome is the result of long-term exposure to glucocorticoids, while endogenous Cushing's syndrome occurs due to excessive production of glucocorticoids within the body. Cushing's syndrome remains a diagnostic challenge for the treating physician.Mass spectrometry, with its better resolution, detectability, and specificity, paved the way to understanding the cellular and molecular mechanisms involved in several diseases that facilitated the evolution of biomarkers and personalized medicine, which can be applicable to manage Cushing's syndrome as well.

There are only a few reports of mass spectrometry-based metabolomic approaches to endogenous Cushing's syndrome of certain etiologies. However, the application of this approach in the diagnosis of exogenous Cushing has not been explored much. This review attempts to discuss the application of the mass spectrometry-based metabolomic approach in the evaluation of Cushing's syndrome.

Global metabolomics has the potential to discover altered metabolites and associated signaling and metabolic pathways, which may serve as potential biomarkers that would help in developing tools to accelerate precision medicine. Multi-omics approaches will provide innovative solutions to develop molecular tests for multi-molecule panel assays.

Mild autonomous cortisol secretion (MACS) is diagnosed based on postdexamethasone cortisol >1.8 µg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS.

To characterize 24-hour (h) urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS vs referent subjects.

Cross-sectional study, 2018-2023, at a referral center. Patients with MACS and age-, sex-, body mass index-, and menopausal status-matched referent subjects were included. Urine was collected over a 24 hour period as separate daytime and nighttime collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects was admitted for serum measurements of free and total cortisol every 2 hours. Outcomes were steroids, steroid sums, and ratios.

Patients with MACS (n = 72) had lower µg/24 hour median androgens (2084 vs 3283, P < .001), higher glucocorticoids (15 754 vs 12936, P < .001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P < .001) than referent subjects. Patients also had lower steroid day/night ratios than referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour areas under the curve for total and free serum cortisol were similar. However, evening mean total (5.3 vs 4.0 µg/dL, P = .056) and free (0.2 vs 0.1 µg/dL, P = .035) cortisol was higher in patients vs referent subjects.

Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production.

Necrosis in postoperative histology has been reported as being specific for adrenocortical carcinoma (ACC) compared to adenoma. We therefore retrospectively analyzed the diagnostic accuracy of the finding of necrosis in preoperative cross-sectional imaging and postoperative histology as a marker for ACC in our patient cohort. Among the 411 adrenalectomies in 396 patients performed between 2008 and April 2022, 30 cases of ACC (7.6%) were identified, with one tumor measuring less than 40 mm excluded. All 45 benign adrenocortical tumors of at least 40 mm in diameter, including Cushing, Conn, and hormonally inactive adenomas, served as controls. Preoperative imaging was available for 40 benign and 27 malignant adrenocortical tumors. In total, 10 of 40 (25%) benign adrenocortical tumors and 22 of 27 (81%) ACCs showed signs of possible necrosis in preoperative imaging. Pathologic examination confirmed necrosis in 1 of 40 (2.5%) benign tumors and in 26 out of 27 (96%) malignant tumors. The specificities of possible necrosis in preoperative imaging and necrosis in histology for diagnosing ACC were 75% and 97.5%, respectively, whereas the sensitivities were 81% and 96%, respectively. Signs of possible necrosis in radiologic imaging and tumor necrosis in histology proved to be very good predictive markers for the diagnosis of malignant adrenocortical tumors.

Data regarding [18F]FDG-PET/CT for the characterization of adrenal lesions are limited. Most of the studies proposed the tumor-to-liver maximum standardized uptake values (SUVratio) > 1.5 as the best cut off to predict malignancy. The aim of the study was to calculate the optimum cut off in a heterogeneous population with adrenal lesions and evaluate the diagnostic performance SUVratio >1.5.

Retrospective analysis of adrenal lesions undergoing [18F]FDG-PET/CT (2013-2022) for different reasons (atypical adrenal incidentalomas, extra adrenal tumor staging). The diagnosis of benignity was assessed by: (i) histology; (ii) stability or minimal diameter increase (<20%/<5 mm) on 12-months follow-up for non-operated patients. The optimal SUVratio and performance of SUVratio >1.5 were calculated by ROC curves.

Forty-two consecutive lesions (diameter 36.1 ± 20.3 mm, 6 bilateral) underwent [18F]FDG-PET/CT (19F, age 61.2 ± 11.7 years). Twenty-nine lesions were benign, 11 malignant [8 metastases (2 bilateral) and 1 adrenocortical carcinoma (ACC)] and 2 pheochromocytomas. The SUVratio cut-off in our population was 1.55 (Sn 100%, Sp 73.7%, AUC 0.868), with similar values excluding pheochromocytomas and metastases (SUVratio cut-off 1.49, Sn 100%, Sp 96.3%, AUC 0.988). The SUVratio cut-off of 1.5 showed 100% Sn, 87% Sp, 73% PPV, and 100% NPV.

[18F]FDG-PET/CT could help in decision making process avoiding unnecessary surgery. The SUVratio cut-off of 1.5 has a good performance in a heterogenous population.

Differentiating pheochromocytomas from other adrenal masses based on computed tomography (CT) characteristics remains challenging, particularly in lipid-poor lesions with variable washout patterns. This study evaluated CT features for distinguishing pheochromocytomas in good and poor washout subcohorts.

We prospectively analyzed 72 patients with unilateral lipid-poor adrenal masses. CT protocol included basal, bolus-tracked arterial, early venous (45 seconds postarterial), and delayed (15 minutes postarterial) phases. Masses were categorized into good and poor washout groups. Histopathology provided the final diagnosis. CT characteristics and calculated indices were compared between pheochromocytomas and other masses in each washout category.

The cohort included pheochromocytomas (n = 35), adrenocortical carcinoma (ACC; n = 15), lipid-poor adenomas (n = 13), and metastatic infiltration/infection (n = 9). In the good washout group, pheochromocytomas (n = 15) showed larger diameters (6.00 vs 3.45 cm, P = .001), higher necrosis frequency (73.3% vs 30%, P = .049), and greater arterial attenuation (173.2 vs 74.5 HU, P < .001) compared to adenomas (n = 9). Arterial attenuation provided a high discriminatory value [area under the curve (AUC): 0.967], with 100% sensitivity at 87.6 Hounsfield unit (HU) and 100% specificity at 139.9 HU. In the poor washout group, pheochromocytomas (n = 20) exhibited higher arterial attenuation (99.2 vs 59.2 HU, P < .001; AUC: 0.844) compared to ACC (n = 14), metastatic infiltration (n = 9), and adenomas (n = 4), with 85% sensitivity and 78% specificity at 73.3 HU. Normetanephrine-secreting/nonsecretory pheochromocytomas showed higher arterial enhancement than metanephrine-secreting ones (132.0 vs 90.5 HU, P = .020) within the poor washout group.

Arterial phase attenuation on CT has good diagnostic accuracy for differentiating pheochromocytomas from other adrenal masses in both good and poor washout categories, potentially guiding hormonal workup.

The analysis of steroids for endocrine disorders is in transition from immunoassay of individual steroids to more specific chromatographic and mass spectrometric methods with simultaneous determination of several steroids. Gas chromatography (GC) and liquid chromatography (LC) coupled with mass spectrometry (MS) offer unrivalled analytical capability for steroid analysis. These specialist techniques were often judged to be valuable only in a research laboratory but this is no longer the case. In a urinary steroid profile up to 30 steroids are identified with concentrations and excretion rates reported in a number of ways. The assays must accommodate the wide range in steroid concentrations in biological fluids from micromolar for dehydroepiandrosterone sulphate (DHEAS) to picomolar for oestradiol and aldosterone. For plasma concentrations, panels of 5-20 steroids are reported. The profile results are complex and interpretation is a real challenge in order to inform clinicians of likely implications. Although artificial intelligence and machine learning will in time generate reports from the analysis this is a way off being adopted into clinical practice. This review offers guidance on current interpretation of the data from steroid determinations in clinical practice. Using this approach more laboratories can use the techniques to answer clinical questions and offer broader interpretation of the results so that the clinician can understand the conclusion for the steroid defect, and can be advised to program further tests if necessary and instigate treatment. The biochemistry is part of the patient workup and a clinician led multidisciplinary team discussion of the results will be required for challenging patients. The laboratory will have to consider cost implications, bearing in mind that staff costs are the highest component. GC-MS and LC-MS/MS analysis of steroids are the choices. Steroid profiling has enormous potential to improve diagnosis of adrenal disorders and should be adopted in more laboratories in favour of the cheap, non-specific immunological methods.

Adrenal masses are found in up to 5%-7% of adults. The 2016 European guidelines on the management of adrenal incidentalomas have standardised the workup of these patients, but evidence of their impact on clinical practice is lacking.

Retrospective review of clinical presentation, radiological characteristics, and final diagnosis of a large cohort of patients with adrenal masses referred to a tertiary care centre 1998-2022. Sub-analysis compares outcomes before and after implementing the 2016 guidelines.

A total of 1397 patients (55.7% women; median age 60 years [interquartile range {IQR}, 49-70]) were included. Incidental discovery was the most frequent mode of presentation (63.7%) and 30.6% of patients had masses ≥ 4 cm (median 2.9 cm [IQR, 1.9-4.7]). Unenhanced computed tomography Hounsfield units (HU) were available for 763 patients; of these, 32.9% had heterogeneous masses or >20 HU. The most common diagnoses were adrenocortical adenoma (56.0%), phaeochromocytoma (12.7%), adrenocortical carcinoma (10.6%), and metastases (5.7%). At multivariable analysis, significant predictors of malignancy included >20 HU or heterogeneous density (odds ratio [OR] 28.40), androgen excess (OR 27.67), detection during cancer surveillance (OR 11.34), size ≥ 4 cm (OR 6.11), and male sex (OR 3.06). After implementing the 2016 guidelines, the number of adrenalectomies decreased (6.1% pre-2016 vs 4.5% post-2016) and the number of patients discharged increased (4.4% pre-2016 vs 25.3% post-2016) for benign non-functioning adrenal masses.

Implementing the 2016 guidelines positively impacted clinical practice, reducing unnecessary surgeries and increasing the discharge rate for benign adrenal masses, thereby preserving healthcare resources and patient burden.

Mild autonomous cortisol secretion (MACS) accounts for a significant proportion of adrenal incidentaloma. Current endocrinological screening tests for MACS are complex, particularly in areas with limited medical resources. This study aimed to develop a diagnostic tool based on leukocyte-related parameters to differentiate between MACS and non-functioning adrenal adenoma (NFA).

Inthis retrospective case-control study, propensity score-matching was used to select 567 patients from a cohort of 1108 patients (201 MACS, 907 NFA). External validation cohort included 52MACS and 48 NFA from two hospitals, which did not overlap with the modeling cohort patients. Leukocyte-related parameters were evaluated, and the diagnostic efficacy of each parameter was assessed by calculating Youden's J index (J) and the area under the curve (AUC). The study population was divided into training and testing samples using a 10-fold cross-validation method. Machine learning (ML) and classification and regression tree (CART) model were established.

After propensity score matching, 567 patients were enrolled, including 197 MACS and 370 NFA. With the exception of basophil percentage, all other parameters differed significantly between the two groups. Lymphocyte count, lymphocyte percentage, eosinophils count, eosinophils percentage, and basophil percentage were lower in the MACS group compared to the NFA group. Eosinophils percentage demonstrated the highest AUC (0.650), with a sensitivity of 51.3% and specificity of 73.2%. The ML model, based on multiple parameters,exhibited better performance in diagnosing MACS (sensitivity 76%, specificity 77.4%, and AUC 0.818). A clinically usable CART model achieved an AUC of 0.872, with a sensitivity of 95% and a specificity of 75.7%.  In the validation cohort, the prediction accuracy of the ML model and the CART model were 0.784 and 0.798, respectively.

TheCART diagnostic model, constructed based on leukocyte-related parameters, could assist clinicians in distinguishing between MACS and NFA.

This white paper provides practical guidance for clinicians encountering bilateral adrenal masses.

A case-based approach to the evaluation and management of bilateral adrenal masses. Specific clinical scenarios presented here include cases of bilateral adrenal adenomas, hemorrhage, pheochromocytomas, metastatic disease, myelolipomas, as well as primary bilateral macronodular adrenal hyperplasia.

Bilateral adrenal masses represent approximately 10% to 20% of incidentally discovered adrenal masses. The general approach to the evaluation and management of bilateral adrenal masses follows the same protocol as the evaluation of unilateral adrenal masses, determined based on the patient's clinical history and examination as well as the imaging characteristics of each lesion, whether the lesions could represent a malignancy, demonstrate hormone excess, or possibly represent a familial syndrome. Furthermore, there are features unique to bilateral adrenal masses that must be considered, including the differential diagnosis, the evaluation, and the management depending on the etiology. Therefore, considerations for the optimal imaging modality, treatment (medical vs surgical therapy), and surveillance are included. These recommendations were developed through careful examination of existing published studies as well as expert clinical opinion consensus.

The evaluation and management of bilateral adrenal masses require a comprehensive systematic approach which includes the assessment and interpretation of the patient's clinical history, physical examination, dynamic hormone evaluation, and imaging modalities to determine the key radiographic features of each adrenal nodule. In addition, familial syndromes should be considered. Any final treatment options and approaches should always be considered individually.

The purpose of this study was to evaluate the capabilities of multiparametric magnetic resonance imaging (MRI) in differentiating between lipid-poor adrenal adenoma (LPAA) and adrenocortical carcinoma (ACC).

Patients of two centers who underwent surgical resection of LPAA or ACC after multiparametric MRI were retrospectively included. A training cohort was used to build a diagnostic algorithm obtained through recursive partitioning based on multiparametric MRI variables, including apparent diffusion coefficient and chemical shift signal ratio (i.e., tumor signal intensity index). The diagnostic performances of the multiparametric MRI-based algorithm were evaluated using a validation cohort, alone first and then in association with adrenal tumor size using a cut-off of 4 cm. Performances of the diagnostic algorithm for the diagnosis of ACC vs. LPAA were calculated using pathology as the reference standard.

Fifty-four patients (27 with LPAA and 27 with ACC; 37 women; mean age, 48.5 ± 13.3 [standard deviation (SD)] years) were used as the training cohort and 61 patients (24 with LPAA and 37 with ACC; 47 women; mean age, 49 ± 11.7 [SD] years) were used as the validation cohort. In the validation cohort, the diagnostic algorithm yielded best accuracy for the diagnosis of ACC vs. LPAA (75%; 46/61; 95% CI: 55-88) when used without lesion size. Best sensitivity was obtained with the association of the diagnostic algorithm with tumor size (96%; 23/24; 95% CI: 80-99). Best specificity was obtained with the diagnostic algorithm used alone (76%; 28/37; 95% CI: 60-87).

A multiparametric MRI-based diagnostic algorithm that includes apparent diffusion coefficient and tumor signal intensity index helps discriminate between ACC and LPAA with high degrees of specificity and accuracy. The association of the multiparametric MRI-based diagnostic algorithm with adrenal lesion size helps maximize the sensitivity of multiparametric MRI for the diagnosis of ACC.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied.

We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents.

Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess.

We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

Adrenal incidentalomas, including nonfunctioning adrenal incidentalomas (NFAI), are associated with a high prevalence of diabetes mellitus (DM). While NFAI is diagnosed by exclusion when no hormone excess exists, subtle cortisol secretion may exist and contribute to DM development. However, it alone cannot explain the increased risk, and whether other steroid metabolites are involved remains unclear.

To investigate steroid metabolites associated with DM in patients with NFAI using plasma steroid profiles.

Using liquid chromatography-tandem mass spectrometry, 22 plasma steroid metabolites were measured in 68 patients with NFAI (31 men and 37 women). Data were adjusted for age before normalization.

Discriminant analysis showed that plasma steroid profiles discriminated between patients with and without DM in men (n = 10 and = 21, respectively) but not women: 11β-hydroxytestosterone, an adrenal-derived 11-oxygenated androgen, contributed most to this discrimination and was higher in patients with DM than in those without DM (false discovery rate = .002). 11β-hydroxytestosterone was correlated positively with fasting plasma glucose (r = .507) and hemoglobin A1c (HbA1c) (r = .553) but negatively with homeostatic model assessment of β-cell function (HOMA2-B) (r = -.410). These correlations remained significant after adjusting for confounders, including serum cortisol after the 1-mg dexamethasone suppression test. Bayesian kernel machine regression analysis verified the association of 11β-hydroxytestosterone with HbA1c and HOMA2-B in men.

Plasma steroid profiles differed between those with and without DM in men with NFAI. 11β-hydroxytestosterone was associated with hyperglycemia and indicators related to pancreatic β-cell dysfunction, independently of cortisol.

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.

Bilateral adrenal masses, increasingly encountered in clinical practice, manifest across diverse contexts, including incidental discovery, malignancy staging, and targeted imaging after hormonal diagnosis of adrenal disorders. The spectrum encompasses various pathologies, such as cortical adenomas, macronodular adrenal disease, pheochromocytomas, myelolipomas, infiltrative disorders, and primary and secondary malignancies. Notably, not all masses in both adrenal glands necessarily share the same etiology, often exhibiting diverse causes. Recently, the European Society of Endocrinology and the European Network for the Study of Adrenal Tumors updated guidelines, introduced a 4-option schema based on imaging, aiding in targeted hormonal testing and management. This "Approach to the Patient" review delves into the latest advancements in imaging, biochemical, and genetic approaches for the diagnostic and management nuances of bilateral adrenal masses. It provides insights and a contemporary framework for navigating the complexities associated with this clinical entity.