Adrenal incidentalomas have increased due to advanced and more sensitive imaging modalities, their increased utilization, and the aging population. Most adrenal incidentalomas are nonfunctional and benign, but a subset of patients has functional and/or malignant tumors. The evaluation of patients with an adrenal incidentaloma involves addressing 2 clinical questions: (1) Is the tumor functional? (2) Is the tumor malignant? A careful history and physical examination focused on signs and symptoms of adrenal functional tumors, biochemical testing, and imaging features are the cornerstone in the evaluation of patients with an adrenal incidentaloma.

BACKGROUND: The impact of abnormal cortisol secretion on cognitive functions in patients with mild autonomous cortisol secretion (MACS) remains uncertain.
OBJECTIVE: To assess cognitive functions, determine serum brain-derived neurotrophic factor (BDNF) concentration in patients with MACS, and association between cognitive subdomains and BDNF.
METHODS: We prospectively recruited 84 participants: 28 patients with MACS, 28 patients with nonfunctional adrenal adenoma (NFAA), and 28 control subjects matched for age, gender, body mass index (BMI), visceral adiposity and educational level. The serum BDNF concentration of participants was measured. DSM-5-focused interviews and Montreal Cognitive Assessments (MoCA) were carried out by an experienced psychiatrist.
RESULTS: Patients with MACS had a higher serum BDNF concentration than the NFAA (p = 0.001), while that of patients with NFAA was lower than the controls (p = 0.044). Linear regression analysis revealed BMI and morning cortisol after overnight 1 mg dexamethasone (DST) were mostly associated with BDNF (p < 0.05). No significant difference was found in MoCA scores between MACS and NFAA groups (p = 0.967), whereas those were lower than the control group (p = 0.004). When the cognitive subdomains were examined seperately, MACS group performed higher memory score than NFAA (p = 0.045), but lower language scores than both the NFAA (p = 0.024) and control groups (p < 0.001). In the whole group, BDNF concentration was positively correlated with memory score (r = 0.337, p = 0.002), whereas DST and language score were negatively correlated (r = -0.355, p = 0.008).
CONCLUSIONS: Low-grade hypercortisolism is associated with elevated BDNF concentrations, which may be a protective factor for memory function in patients with MACS relative to those with NFAA.

BACKGROUND: Once hypercortisolemia is confirmed, differential diagnosis between Cushing\'s syndrome (CS) due to neoplastic endogenous hypercortisolism and non-neoplastic hypercortisolism (NNH, pseudo-Cushing\'s syndrome) is crucial. Due to worldwide corticotropin-releasing hormone (CRH) unavailability, accuracy of alternative tests to dexamethasone (Dex)-CRH, is clearly needed.
OBJECTIVE: Assess the diagnostic accuracy of Dex-CRH test, desmopressin stimulation test, midnight serum cortisol (MSC), and late-night salivary cortisol (LNSC) levels to distinguish CS from NNH.
METHODS: Articles through March 2022 were identified from Scopus, Web of Science, MEDLINE, EMBASE, and PubMed. All steps through the systematic review were performed independently and in duplicate and strictly adhered to the updated PRISMA-DTA checklist.
RESULTS: A total of 24 articles (1900 patients) were included. Dex-CRH had a pooled sensitivity and specificity of 91% (95%CI 87-94%; I2 0%) and 82% (73-88%; I2 50%), desmopressin test 86% (81-90%; I2 28%) and 90% (84-94%; I2 15%), MSC 91% (85-94%; I2 66%) and 81% (70-89%; I2 71%), and LNSC 80% (67-89%; I2 57%) and 90% (84-93%; I2 21%), respectively. Summary receiver operating characteristics areas under the curve were Dex-CRH 0.949, desmopressin test 0.936, MSC 0.942, and LNSC 0.950 without visual or statistical significance. The overall risk of studies bias was moderate.
CONCLUSIONS: Dex-CRH, the desmopressin stimulation test, and MSC have similar diagnostic accuracy, with Dex-CRH and MSC having slightly higher sensitivity, and the desmopressin test being more specific. LNSC was the least accurate, probably due to high heterogeneity, intrinsic variability, different assays, and lack of consistent reported cutoffs. When facing this challenging differential diagnosis, the results presented here should increase clinicians\' confidence when deciding which test to perform.

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and Bilateral Macronodular Adrenocortical Disease (BMAD) are two forms of Adrenocortical Nodular Diseases causing Cushing\'s syndrome, but are two very distinct conditions. PPNAD, affecting mostly young patients with an almost constant severe Cushing\'s syndrome, is characterized by pigmented micronodules, usually less than 1 cm, not always visible on imaging. On the contrary, BMAD is predominantly diagnosed in the fifth and sixth decades, with highly variable degrees of cortisol excess, from mild autonomous cortisol secretion to overt Cushing\'s syndrome. BMAD presents as large bilateral adrenal macronodules, easily observed on imaging. Both diseases are often genetically determined: frequently PPNAD is observed in a multiple neoplasia syndrome, Carney complex (CNC), and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/PKA pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and two predisposing genes are known at present: ARMC5, accounting for around 20% of index cases, and the recently identified KDM1A, causing the rare presentation with food-dependent Cushing\'s syndrome, mediated by the ectopic expression of the Glucose-dependent Insulinotropic Polypeptide receptor (GIPR) in adrenal nodules. GIPR was the first demonstrated receptor to illegitimately regulate cortisol secretion in nodular adrenocortical diseases, and a myriad of other receptors and paracrine signals were discovered afterward. The last 30 years were pivotal in the understanding of the genetics and pathophysiology of Bilateral Adrenocortical Nodular Diseases, leading to a personalized approach of these fascinating conditions.

BACKGROUND: Patients with Cushing\'s syndrome (CS) have higher risk of obesity and diabetes, which are important risk factors of cancers. However, if patients with CS have a higher incidence of cancer remains unknown.
OBJECTIVE: To investigate if endogenous CS is associated with increased cancer incidence.
METHODS: A nationwide cohort study.
METHODS: Analysis of the data retrieved from Taiwan\'s National Health Insurance program in 2006-2017.
METHODS: Between 2006-2017, 1278 patients with newly diagnosed endogenous CS were identified. Among them, 1246 patients without a history of malignancy were enrolled in this study.
METHODS: Endogenous CS.
METHODS: The age- and sex-standardized incidence rate of all-cause cancer and age-sex-calendar year standardized incidence ratio (SIR) of cancer in association with endogenous CS.
RESULTS: The age- and sex-standardized incidences of CS decreased from 4.84 to 3.77 per million person-years between 2006-2017. The age at diagnosis of CS was 45.3 ± 14.8 years, and 80.0% of the patients were female. Cushing\'s disease and adrenal CS accounted for 35.4% and 64.6% of patients with CS, respectively. The incidence rate of cancer in patients with CS was 7.77 (95% Confidence Interval [CI] = 5.84-10.14) per 1000 person-years, with an SIR of 2.08 (95% CI = 1.54-2.75). The three most common cancer types were liver (27.7%), kidney (16.7%), and lung (13.0%).
CONCLUSIONS: Patients with endogenous CS have a higher incidence of cancer.

BACKGROUND: Currently, there is a scarcity of cases and diagnostic data regarding ectopic adrenocortical adenomas, particularly in relation to their impact on gonadal function and localization diagnostic techniques. We report a typical case of ectopic adrenocortical adenomas and the data of treatment follow-up, and review the literature of 31 available cases of ectopic adrenocortical adenomas.
METHODS: A 27-year-old Chinese female patient was admitted to our hospital for hypertension, hyperglycaemia and primary amenorrhea. The patient was functionally diagnosed with ACTH-independent CS and hypogonadotropic hypogonadism. Radiological evaluations, including Computed Tomography (CT) and functional imaging, identified a mass at the left renal hilum. Histological assessments post-surgical excision confirmed the mass to be an ectopic adrenocortical adenoma. A subsequent 3-month follow-up showed no signs of disease recurrence, a swift recovery of the cortisol axis was observed, with a partial recuperation of the gonadal axis.
METHODS: Our literature review shows that the most common ectopic areas of cortisol adenomas are renal hilum and hepatic region. The most positive biomarker is Melan A, and only a few cases have been diagnosed with functional localization.
CONCLUSIONS: Ectopic adrenocortical adenomas may be asymptomatic in the early stage and can impact gonadal function. Physicians who treat hypogonadism must be aware of the need to test cortisol levels and perform functional localization in patients with lumps present.

OBJECTIVE: Thyroid disorders have been reported in hypercortisolism patients. Endogenous Cushing\'s syndrome (CS) potentially complicates its metabolic sequelae. We investigated thyroid function in CS patients to determine this relationship.
METHODS: In this cross-sectional study, we screened CS patients from 2016 to 2019 at our hospital. Patient demographic, medical history, and laboratory data were collected. Additionally, we performed a meta-analysis to demonstrate the prevalence of thyroid dysfunction in patients with CS.
RESULTS: Among 129 CS patients, 48.6% had triiodothyronine (TT3), 27.9% had thyroxine (TT4), 24.6% had free T3 (FT3), 27.7% had free T4 (FT4), and 6.2% had thyroid-stimulating hormone (TSH) levels below the reference values. Those with clinical CS showed more pronounced thyroid suppression than did those with subclinical CS. Cortisol levels were markedly greater in patients with pituitary hypothyroidism (P < 0.001). Serum cortisol levels throughout the day and post low-dose dexamethasone-suppression test (LDDST) results correlated with thyroid hormone levels, particularly in ACTH-independent CS. Correlations varied by thyroid status; FT3 and TSH were linked to cortisol in euthyroid individuals but not in those with low T3 or central hypothyroidism. TSH levels notably halved from the lowest to highest cortisol tertile post-LDDST. Finally, meta-analysis showed 22.7% (95% CI 12.6%-32.9%) central hypothyroidism in 528 CS patients of nine studies.
CONCLUSIONS: Thyroid hormone levels are significantly correlated with cortisol levels and are impaired in patients with CS. However, the physiological adaptation and pathological conditions need further study.

UNASSIGNED: This systematic review and meta-analysis was conducted to compare the benefits of adrenalectomy and conservative treatment for comorbidities associated with mild autonomous cortisol secretion (MACS) in patients diagnosed with MACS.
UNASSIGNED: MACS is the most common benign hormone-secreting functional adrenal incidentaloma. Overproduction of cortisol is observed in MACS patients, resulting in a variety of long-term health issues, including arterial hypertension (HTN), diabetes mellitus (DM), dyslipidemia, obesity, and osteoporosis; however, the classic clinical manifestations of Cushing\'s syndrome (CS) are not present.
UNASSIGNED: A systematic search was conducted using MEDLINE, Embase, Web of Sciences, and Scopus databases on December, 2023. Two reviewers independently extracted data and assessed the quality of the included articles. A meta-analysis was performed to compare the beneficial effects of adrenalectomy versus conservative management for MACS-related comorbidities.
UNASSIGNED: Fifteen articles were included in this study, which evaluated 933 MACS patients (384 Adrenalectomy and 501 Conservative treatment, and 48 excluded due to incomplete follow-up duration). MACS diagnosis criteria were different among the included articles. All studies, however, stated that there must be no overt CS symptoms. Meta-analysis demonstrates the overall advantage of adrenalectomy over conservative treatment for MACS-related comorbidities (Cohen\'s d = -0.49, 95% CI [-0.64, -0.34], p = 0.00). Subgroup analysis indicated that the systolic blood pressure (pooled effect size = -0.81, 95% CI [-1.19, -0.42], p = 0.03), diastolic blood pressure (pooled effect size = -0.63, 95% CI [-1.05, -0.21], p = 0.01), and BMD (pooled effect size = -0.40, 95% CI [-0.73, -0.07], p = 0.02) were significantly in favor of adrenalectomy group rather than conservative treatment but no significant differences between the two treatment groups in other MACS-related comorbidities were reported.
UNASSIGNED: Despite the limited and diverse data, this study demonstrates the advantage of adrenalectomy over conservative treatment for MACS-related comorbidities.

BACKGROUND: Urine free cortisol measurements are routinely performed to evaluate hypercortisolism. Despite their analytical inaccuracy, immunoassay-based methods are frequently used. Advances in liquid chromatography-high-resolution mass spectrometry (LC-HRMS) facilitate the incorporation of powerful diagnostic tools into clinical laboratories. In addition to its high analytical specificity and simultaneous analysis of different metabolites, accurate mass measurement allows for untargeted compound identification, which may help to identify clinically relevant metabolites or drugs.
METHODS: The present study aimed to validate a simple routine LC-HRMS method to quantify cortisol, cortisone, 6β-hydroxycortisol, and 18-hydroxycortisol simultaneously in human urine. Additionally, the study also validated a GC-MS method for the same steroids, evaluated their cross-reactivity with commercial cortisol immunoassays, and quantified the 24 h urine excretion in patients under clinical suspicion or follow-up for hypercortisolism.
RESULTS: The LC-HRMS method involved liquid-liquid extraction using dichloromethane, micro-LC for chromatographic separation and detection using the accurate masses of the steroids, and simultaneous high-resolution full scan acquisition. The method presented acceptable linearity, precision, and accuracy. Significant interference from 6β-hydroxycortisol and cortisone was demonstrated in the cortisol immunoassays, which impacted their reliability in the follow-up of patients with hypercortisolism and significant changes in these cortisol metabolites (i.e., due to drug-induced changes in CYP3A4 activity).
CONCLUSIONS: A rapid and accurate routine LC-HRMS method was validated, which is useful for the evaluation of hypercortisolism and other disorders of glucocorticoid and mineralocorticoid metabolism.

Adrenocortical carcinoma (ACC) is a rare malignant tumor originating in the adrenal cortex and characterized by poor 5-year survival. It occurs with a frequency of 2-4 cases per 2 million in the population. Women are more frequently affected than men and it is mostly detected in the fourth and fifth decades. In the most of cases, the cancerogenesis occurs sporadically because of gene driver mutations in somatic adrenocortical cells, in other cases it can be found as part of a genetically determined syndrome such as Li-Fraumeni syndrome or Wermer\'s syndrome (multiple endocrine adenomatosis type I). ACC most frequently happens occurs without symptoms in the initial stages leading to poor diagnoses. Because of this lack of early detection, the tumor is not considered malignant reducing the benefits of further treatment. Sometimes the fact that the resected tumor is indeed adrenocortical carcinoma becomes clear only after recurrence, or after the appearance of metastases. We present a case of adrenocortical carcinoma in a 46-year-old woman who went to the doctor in 1.5 year after symptoms were manfested. This clinical case illustrates the consequences of late diagnosis of a malignant tumor. We would like to emphasize the importance of timely detection of a neoplasm, using all of the potential of laboratory-instrumental and genomic analysis. Due to low oncological awareness, our patient was slow to seek medical help, which in turn led not only to metastases, but also to complications in the cardiovascular system.
Адренокортикальный рак (АКР) – редкая злокачественная опухоль коры надпочечников c распространенностью 0,5–2 случая на 1 млн населения, характеризующаяся неблагоприятным прогнозом, низкой 5-летней выживаемостью пациентов, поздним сроком выявления и агрессивностью клинического течения. Заболевание чаще встречается среди женщин (1,5:1 или 55–60%), средний возраст на момент постановки диагноза – 40–50 лет. Клинические проявления АКР в большинстве случаев отсутствуют, что является причиной поздней диагностики заболевания. В некоторых случаях АКР диагностируется при рецидиве заболевания после хирургического лечения гормонально-неактивной опухоли надпочечника или на этапе метастазирования. АКР может быть гормонально-активной опухолью, являясь причиной гиперкортицизма/вирильного синдрома и др. Канцерогенез АКР обусловлен как спонтанно возникающими мутациями в соматических клетках коры надпочечников, так и генетическими поломками в рамках того или иного наследственного синдрома, например Ли–Фраумени и Вермера (синдром множественных эндокринных неоплазий 1-го типа). В статье приведен клинический случай, иллюстрирующий последствия поздней диагностики АКР у женщины 46 лет, которая обратилась за медицинской помощью через 1,5 года после развития манифестных симптомов с клиникой вирильного синдрома в сочетании с артериальной гипертензией, инвазией левой почечной вены и распространением опухолевого тромба в просвет нижней полой вены по данным мультиспиральной компьютерной томографии. Данный клинический случай подчеркивает важность онконастороженности и своевременной диагностики АКР с помощью лабораторно-инструментальных и генетических методов.