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Purpose: Adrenal vascular tumors are mainly represented by adrenal cavernous hemangiomas (ACHs) and adrenal cystic lymphangiomas (ACLs). Their radiological features often overlap with malignant tumors, therefore ruling out malignancy becomes mandatory. We analyzed clinical, radiological, and histopathological data to identify specific characteristics of these tumors., Methods: We reviewed 21 patients with ACHs (n = 12), ACLs (n = 8), or adrenal cysts (n = 1) confirmed by histopathology. We selected 82 papers from PubMed to provide a systematic review of the literature., Results: In our cohort, median age at diagnosis was 58 years, with sex evenly distributed. All tumors were unilateral (median size = 44 mm), with 6 cases of increasing tumor size. All tumors exhibited non-contrast CT density > 10 Hounsfield Unit (HU). Calcifications were found in 5 cases. Hormonal studies revealed 11 non-functioning tumors and 2 cortisol-secreting tumors. Elevated urinary metanephrines were found in 2 cases. Immunostaining showed CD31/CD34/factor VIII expression in ACHs (n = 5, 24%) and podoplanin expression in ACLs (n = 6, 29%). The literature review revealed 71 reported cases of ACHs and 104 reported cases of ACLs. Median age at diagnosis was 46 years, with slightly female prevalence (63%). Median tumor size was 48 mm. 84 cases were symptomatic, with life-threatening hemorrhage reported in only 3 patients. Calcifications were found in 23% of cases. Surgical approaches varied, with open and laparoscopic adrenalectomy performed in 55 and 42 patients respectively., Conclusions: ACHs and ACLs represent a diagnostic dilemma in clinical practice due to their rarity and their misleading imaging features., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the local Ethical Committee (CE-AVEC, n. 45/2016/O/Oss EM 82/2017/O). Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s).)

Purpose: whole body scan (WBS) performed following diagnostic or therapeutic administration of I-131 is useful in patients with differentiated thyroid carcinoma. However, it can be falsely positive in various circumstances. We aimed to report a series of pitfalls in a clinical perspective., Methods: A search in the database PubMed utilizing the following terms: "false radioiodine uptake" and "false positive iodine 131 scan" has been made in January 2023. Among the 346 studies screened, 230 were included in this review, with a total of 370 cases collected. Physiological uptakes were excluded. For each patient, sex, age, dose of I-131 administered, region and specific organ of uptake and cause of false uptake were evaluated., Results: 370 cases of false radioiodine uptake were reported, 19.1% in the head-neck region, 34.2% in the chest, 14.8% in the abdomen, 20.8% in the pelvis, and 11.1% in the soft tissues and skeletal system. The origin of false radioiodine uptake was referred to non-tumoral diseases in 205/370 cases (55.1%), benign tumors in 108/370 cases (29.5%), malignant tumors in 25/370 cases (6.7%), and other causes in 32/370 cases (8.7%)., Conclusions: WBS is useful in the follow-up of patients with differentiated thyroid carcinoma, however it can be falsely positive in various circumstances. For this reason, it is critically important to correlate the scintigraphic result with patient's medical history, serum thyroglobulin levels, additional imaging studies and cytologic and/or histologic result., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy., (© 2024. The Author(s).)

Backgrounds: To report the long-term surgical outcomes and the impact on daily life activities of strabismus surgery in patients with Thyroid Associated Orbitopathy (TAO) with and without previous orbital decompression., Methods: Patients who underwent strabismus surgery for TAO were retrospectively reviewed. The primary outcome was to evaluate the influence of orbital decompression on the outcomes of TAO related strabismus surgery. Surgical success was defined by the resolution of diplopia and a post-operative deviation < 10 prism diopters (PD). The secondary outcomes were the clinical features, surgical approaches, and impact on daily life activities., Results: A total of 45 patients were included in the study. The decompression surgery group (DS) included 21 patients (46.7%), whereas the non-decompression surgery group (NDS) patients were 24 (53.3%). The mean follow-up time from the last strabismus surgery was 2,8 years (range 8-200 months). Successful surgical outcome was achieved in 57,1% of patients in the DS, and 75% of patients in the NDS (p = 0,226). DS patients required almost twice the number of surgical interventions for strabismus compared to the NDS (1,95 vs. 1,16 respectively, p = 0,006), a higher number of extraocular muscles recessed in the first surgery (2,67 vs. 1,08 respectively, p < 0.001), and a lower rate of unidirectional surgery compared to NDS (23% vs. 95%, p < 0,001). At the pre-operative assessment, 71.4% of DS patients had eso-hypotropia, while no patients had this type of strabismus in the NDS group (p < 0.001). On the other hand, the hypotropia rate was 79.2% in NDS patients and only 4.8% in DS patients (p < 0.001). Moreover, 21,8% of NDS patients used prism lenses in daily life activities, compared to 42.9% of patients that used prism lenses to reduce the impairment in their daily life activities (p = 0.016)., Conclusions: The results of our study showed that DS patients required almost twice the number of strabismus surgical procedures, a higher number of extraocular muscles recessed in the first surgery, and an increased need for prism lenses to correct the residual deviation compared to the NDS, but with similar long-term surgical outcomes., (© 2024. The Author(s).)

Background: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires., Methods: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis., Results: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores., Conclusions: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making., Materials and Methods: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development., Results: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006)., Conclusions: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The benefits of immunonutrition (IM) in patients who underwent pancreatic surgery are unclear., Methods: A meta-analysis of randomized clinical trials (RCTs) comparing IM with standard nutrition (SN) in pancreatic surgery was carried out. A random-effects trial sequential meta-analysis was made, reporting Risk Ratio (RR), mean difference (MD), and required information size (RIS). If RIS was reached, false negative (type II error) and positive results (type I error) could be excluded. The endpoints were morbidity, mortality, infectious complication, postoperative pancreatic fistula (POPF) rates, and length of stay (LOS)., Results: The meta-analysis includes 6 RCTs and 477 patients. Morbidity (RR 0.77; 0.26 to 2.25), mortality (RR 0.90; 0.76 to 1.07), and POPF rates were similar. The RISs were 17,316, 7,417, and 464,006, suggesting a type II error. Infectious complications were lower in the IM group, with a RR of 0.54 (0.36-0.79; 95 CI). The LOS was shorter in IM (MD -0.3 days; -0.6 to -0.1). For both, the RISs were reached, excluding type I error., Conclusion: The IM can reduce infectious complications and LOS The small differences in mortality, morbidity, and POPF make it impossible to exclude type II error due to large RISs., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autosomal polycystic kidney disease is the most common inherited kidney disease determining 5% of all end-stage kidney disease. The only therapy approved for this condition is Tolvaptan, which, with its aquaretic effect, has a strong effect on patients' daily life. Recently, the literature has been enriched with new works that analyze possible non-pharmacological therapeutic strategies to slow cysts' enlargement and chronic kidney disease progression. Among them, dietary schemes reducing carbohydrate intake and inducing ketoses have been demonstrated to have efficacy in several pre-clinical and clinical studies. A ketogenic diet, calorie restriction, intermittent fasting, and time-restricted feeding can reduce aerobic glycolysis and inhibit the mTOR pathway, producing a reduction in cyst cell proliferation, a reduction in kidney volume, and helping to preserve kidney function. ADPKD's burden of disease has an impact on patients' quality of life, and the possibility to play sports or carry out physical exercise can help people in everyday life. The multisystemic character of the disease, especially cardiovascular involvement, needs to be carefully evaluated to establish the quality and quantity of physical activity that patients can safely carry out.

Introduction: Proteinuria is a major risk factor for the progression of chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated a nephroprotective and antiproteinuric effect in people with type 2 diabetes (T2DM) and proteinuric CKD. We conducted a retrospective study to evaluate clinical and laboratory variables that can help predict proteinuria reduction with SGLT2i therapy., Materials and Methods: Patients affected by T2DM and CKD who started any SGLT2i were included in the study. Patients were stratified into two subgroups, Responder (R) and non-Responder (nR), based upon the response to the therapy with SGLT2i, namely the reduction in a 24 h urine proteins test (uProt) of ≥30% from baseline levels. The aim of the study is to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria reduction. A Kruskal-Wallis test, unpaired t-test and Chi 2 test were used to test the difference in means and the percentage (%) between the two groups. Linear and logistic regressions were utilized to analyse the relationship between proteinuria reduction and basal characteristics., Results: A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. R's patients had a significant higher uProt at baseline (1393 vs. 449 mg/24 h, p = 0.010). There was a significant correlation between baseline uProt and proteinuria reduction with SGLT2i in both univariate (β = -0.43, CI -0.55 to -031; p < 0.001) and multivariate analyses (β = -0.46, CI -0.57 to -0.35, p < 0.001). In the multivariate analysis, there was a significant positive correlation between the estimated glomerular filtration rate (eGFR) and proteinuria reduction (β = -17, CI -31 to -3.3, p = 0.016) and a significant negative correlation with body mass index (BMI) (β = 81, CI 13 to 50, p = 0.021). The multivariate logistic regressions show a positive correlation of being in the R group with diabetic retinopathy at baseline (Odds Ratio (OR) 3.65, CI 0.97 to 13.58, p = 0.054), while the presence of cardiovascular disease (CVD) at baseline is associated with being in the nR group (OR 0.34, CI 0.09 to 1.22, p = 0.1), even if these statements did not reach statistical significance., Conclusions: In this real-life experience, following the administration of SGLT2i, a reduction of more than 30% in proteinuria was observed in more than half of the patients, and these patients had a significantly higher baseline proteinuria value. Variables such as eGFR and BMI are variables that, considered in conjunction with proteinuria, can help predict treatment response before therapy initiation. Different phenotypes of diabetic kidney disease may have an impact on the antiproteinuric response.

Objective: Mild autonomous cortisol secretion (MACS) has been associated with a higher prevalence of osteoporosis, although most data rely on single-center studies with limited sample size. We aimed to assess the prevalence of fragility fractures and contributing factors in a large cohort of patients with adrenal incidentalomas., Design and Methods: Medical records of 1023 patients with adrenal incidentalomas from 1990 to 2019 were reviewed, and 735 patients were selected. Clinically obtained electronic radiological images closest to first endocrine evaluation, such as lateral views of spine X-rays or CT thoraco-abdominal scans, were reviewed to screen for asymptomatic morphometric vertebral fractures. Clinical fragility fractures, hormonal, and dual-energy x-ray absorptiometry (DXA) indices were also recorded., Results: Four hundred seventy-four patients had nonfunctioning (NF) adrenal incidentalomas, 238 had MACS and 23 adrenal Cushing's syndrome (AC). Prevalence of fragility fractures was different (P = .018) between groups, respectively, 24.1% (NF), 34.0% (MACS), and 30.4% (AC), with significant difference between NF and MACS (P = .012). When analyzed separately by sex and menopausal status, this difference remained significant in postmenopausal women (P = .011), with a fracture prevalence of 22.2% (NF) and 34.6% (MACS). Fracture prevalence was similar in males. Women with MACS aged ≥65 years reported a 48.8% prevalence of fractures, as compared with 29.5% in NF (P < .01). In postmenopausal women, fragility fractures were associated with age (odds ratio [OR] 1.1, P < .001), smoking (OR 1.8, P = .048), and 1 mg-dexamethasone suppression test (DST) cortisol (OR 3.1, P = .029), while in men, only age was associated with fragility fractures., Conclusions: A considerable fracture burden was shown in postmenopausal women with adrenal incidentalomas and MACS, with clinical implications for the evaluation and management of bone metabolism., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Preoperative localization of pathological parathyroid glands with imaging is essential for focused unilateral neck exploration and minimally invasive techniques. Recently published studies suggested that contrast-enhanced ultrasonography (CEUS) had high accuracy in the localization of hyperfunctioning parathyroid glands, with a general increase in the sensitivity as compared to conventional sonography. The purpose of this study was to determine the usefulness of CEUS in the localization of parathyroid lesions relating to surgical and histopathological data, in comparison to color Doppler ultrasound (CDUS), in the same series of patients., Methods: Records of 142 patients who underwent parathyroidectomy were retrospectively examined comparing imaging and intraoperative/histopathologic findings., Results: The overall sensitivity of CEUS was 77.6% compared with 74.6% for CDUS, although no significative differences were found (P = .516). Conversely, CDUS has shown higher sensitivity than CEUS in the group of patients with associated thyroid pathology but there was no statistical difference (P = .529). The sensitivity for detection of multiple adenomas was the same for both procedures., Conclusions: We found no significative superior sensitivity of CEUS also in case of concomitant thyroid pathology and multiple glands disease., (© 2022 American Institute of Ultrasound in Medicine.)

Follicular thyroid carcinoma (FTC) represents the second most common malignant thyroid neoplasm after papillary carcinoma (PTC). FTC is characterized by the tendency to metastasize to distant sites such as bone and lung. In the last 20 years, the understanding of the molecular pathology of thyroid tumors has greatly improved. Uncommon BRAF non-V600E mutations have been identified and are generally believed to associate with follicular patterned tumors of low malignant potential, particularly non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (i.e., non-invasive encapsulated follicular variant PTC). We here report for the first time widespread bone metastases from a BRAF K601N mutated follicular tumor., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Many questions concerning Turner syndrome (TS) remain unresolved, such as the long-term complications and, therefore, the optimal care setting for adults. The primary aim of this long-term cohort study was to estimate the incidence of comorbid conditions along the life course., Methods: A total of 160 Italian patients with TS diagnosed from 1967 to 2010 were regularly and structurally monitored from the diagnosis to December 2019 at the University Hospital of Bologna using a structured multidisciplinary monitoring protocol., Results: The study cohort was followed up for a median of 27 years (IQR 12-42). Autoimmune diseases were the comorbid condition with the highest incidence (61.2%), followed by osteoporosis and hypertension (23.8%), type 2 diabetes (16.2%) and tumours (15.1%). Median age of onset ranged from 22 years for autoimmune diseases to 39 years for type 2 diabetes. Malignant tumours were the most prominent type of neoplasm, with a cumulative incidence of 11.9%. Papillary thyroid carcinoma was the most common form of cancer, followed by skin cancer and cancer of the central nervous system. Only one major cardiovascular event (acute aortic dissection) was observed during follow-up. No cases of ischaemic heart disease, heart failure, stroke or death were recorded., Conclusions: This cohort study confirms the need for continuous, structured and multidisciplinary lifelong monitoring of TS, thus ensuring the early diagnosis of important comorbid conditions, including cancer, and their appropriate and timely treatment. In addition, these data highlight the need for the increased surveillance of specific types of cancer in TS, including thyroid carcinoma., (© 2022. The Author(s).)

Objectives: Pheochromocytomas are rare tumors which can present with heterogeneous secretion profiles, clinical manifestations, and radiologic appearance. Under a histopathological point of view, they can be characterized as more or less aggressive with the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score. The aim of this study is to analyze the texture analysis characteristics of pheochromocytoma and identify whether the texture analysis can yield information aiding in the diagnosis and the characterization of those tumors., Methods: Radiological, biochemical, and histopathological data regarding 30 consecutive patients with histologically confirmed pheochromocytoma were analyzed. Images obtained in the unenhanced, late arterial, venous, and delayed phases were used for the texture analysis., Results: Urinary epinephrine and metanephrine levels showed a significant correlation (R 2  = 0.946; R 2  = 699) in the multivariate linear model with texture features, as well as Ki-67 (R 2  = 0.397), PASS score (R 2  = 0.182), GAPP score (R 2  = 0.705), and cellularity showed a significant correlation (R 2  = 0.389). The cluster analysis based on radiomic features resulted in 2 clusters, with significative differences in terms of systolic and diastolic blood pressure values at the time of diagnosis (p = 0.025), GAPP score (4 vs 6, p = 0.05), histological pattern (1-2, p = 0.039), and comedonecrosis (0% vs 50%, p = 0.013)., Conclusion: In conclusion, our study provides the proof of concept for the use of texture analysis on contrast-enhanced CT images as a noninvasive, quantitative tool for helping in the characterization of the clinical, biochemical, and histopathological features of pheochromocytoma., (© 2022. The Author(s).)

Background & Aims: Malnutrition is a well-recognized risk factor for major surgery-related complications, but the impact of preoperative nutritional therapy is still debated due to a lack of high-level evidence. The study aims to evaluate the role of preoperative malnutrition in the postoperative course of patients who underwent pancreatic resection., Methods: This is a retrospective study involving 488 patients who underwent pancreatic resection. An entropy balance was applied to 134 patients at risk for moderate or severe malnutrition (M/S-MAL) to obtain a cohort equal to 354 patients, with the null or low risk of malnutrition (N/L-MAL). The reweighting scheme was made in two steps. In the 1st reweighting, the two cohorts were homogenized for confounding factors not modifiable. In the 2nd reweighting, the two cohorts were matched for modifiable factors by preoperative dietary support. The entropy balance was evaluated with the d-value. The postoperative results were reported as mean differences (MD) or odds ratio (OR) with a confidence interval at 95% (95 CI)., Results: The M/S-MAL included patients with lower values of BMI (d < 0.750), hemoglobin (d = 0.671), serum albumin (d = 0.554), total protein (d = 0.381). The M/S-MAL patients were more frequent ECOG 1-2 (d = 0.418), with jaundice (d = 0.445) or back pain (d = 0.366). The pancreaticoduodenectomy (d = 0.440) and vascular resection (d = 0.620) in the M/S-MAL group were performed more frequently. The pancreatic remnant was more often hard (d = 0.527), and the Wirsung duct dilated (d = 0.459) in the N/L-MAL group. The rate of pancreatic ductal adenocarcinoma was higher in M/S-MAL (d = 0.399). After 1st weighting, M/S-MAL patients have a high comprehensive complication index (CCI) (MD = 5.5; 0.3 to 10.7), were more frequently discharged not at home (OR 2.3; 1.1 to 5.4) with a prolonged mean hospital stay (MD 6.1.1; 0.1 to 12.1, days), After 2nd weighting, the two groups have similar postoperative results., Conclusion: The correction of malnutrition could play an independent role in reducing the severity of complication, length of stay, and type of discharge in patients who underwent pancreatic resection., Competing Interests: Conflict of interest All authors disclosed any actual or potential conflict of interest, including any financial, personal, or other relationships with other people or organisations within that could inappropriately influence (bias) this work. The study was not preregistered., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing)., Methods: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants., Findings: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001)., Interpretation: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma., Funding: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino., Competing Interests: Declaration of interests IB has served as a consultant for Corcept Therapeutics, Sparrow Pharmaceutics, and Spruce Biosciences; was as a member of advisory or data safety monitoring boards for Adrenas Therapeutics, Recordati, and Strongbridge Biopharma (in all cases, institution fees were provided); and reports personal honoraria from Elsevier ClinicalKey. IC reports consulting fees and honoraria from HRA Pharma Rare Diseases and Recordati; was a member of advisory or data safety monitoring boards for HRA Pharma Rare Diseases and Recordati; and has participated in clinical studies from Corcept Therapeutics. ACh reports personal support for attending meetings or travel from Sanofi; personal honoraria from Ipsen; and was a member of advisory or data safety monitoring boards for Ipsen. TDe reports personal consulting fees for being a member of advisory or data safety monitoring boards for HRA Pharma Rare Diseases and Recordati; personal honoraria from Novartis; and has participated in clinical studies from Corcept Therapeutics and HRA Pharma Rare Diseases (for these, institution fees were provided). MF has participated in clinical studies from Corcept Therapeutics and HRA Pharma Rare Diseases (for these, institution fees were provided). LM was a member of the expert panel “Focus Area Adrenal and Cardiovascular Endocrinology” from the European Society of Endocrinology, and led the working group 5 of the project “CA20122—Harmonizing clinical care and research on adrenal tumours in European countries” from the European Cooperation in Science in Technology. JN-P reports grants from Diurnal Group; and has served as a consultant for and received honoraria from HRA Pharma Rare Diseases, Crinetics Pharmaceuticals, and Recordati (in all cases, institution fees were provided). CS reports consulting fees and honoraria from HRA Pharma Rare Diseases and Recordati; was a member of advisory or data safety monitoring boards for HRA Pharma Rare Diseases and Recordati; and has served as coordinator of the Pituitary Club of the Italian Society of Endocrinology. MT reports personal consulting fees (for being a member of advisory or data safety monitoring boards for Corcept Therapeutics and HRA Pharma Rare Diseases); and has participated in clinical studies from HRA Pharma Rare Diseases (for which institution fees were provided). ST reports personal support for attending meetings or travel from Ipsen, Pfizer, and Recordati; personal honoraria from Recordati; and has participated in clinical studies from Crinetics Pharmaceuticals, Novartis, and Strongbridge Biopharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The best approach for minimally invasive adrenalectomy is still under debate., Methods: A systematic search of randomized clinical trials was carried out. A frequentist random-effects network meta-analysis was made reporting the surface under the cumulative ranking (SUCRA). The primary endpoint regarded both in-hospital mortality and morbidity. The secondary endpoints were operative time (OP), blood loss (BL), length of stay (LOS), conversion, incisional hernia, and disease recurrence rate., Results: Eight studies were included, involving 359 patients clustered as follows: 175 (48.7%) in the TPLA arm; 55 (15.3%) in the RPLA arm; 10 (2.8%) in the Ro-TPLA arm; 25 (7%) in the TPAA arm; 20 (5.6%) in the SILS-LA arm; and 74 (20.6%) in the RPA arm. The RPLA had the highest probability of being the safest approach (SUCRA 69.6%), followed by RPA (SUCRA 63.0%). TPAA, Ro-TPLA, SILS-LA, and TPLA have similar probability of being safe (SUCRA values 45.2%, 43.4%, 43.0%, and 38.5%, respectively). Analysis of the secondary endpoints confirmed the superiority of RPA regarding OP, BL, LOS, and incisional hernia rate., Conclusions: The best choice for patients with adrenal masses candidate for minimally invasive surgery seems to be RPA. An alternative could be RPLA. The remaining approaches could have some specific advantages but do not represent the first minimally invasive choice., (© 2022. The Author(s).)

Objective: Patients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency., Methods: We enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed., Results: Aldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism., Conclusion: PTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.

Background: As reported in the literature, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) provides useful qualitative and semi-quantitative data for the prognosis of advanced differentiated thyroid cancer. Instead, there is a lack of data about the real clinical impact of 18F-FDG PET/CT on the choice of the more effective therapeutic approach for advanced differentiated thyroid cancer (DTC) that starts to lose iodine avidity. The primary aim of this retrospective study was to assess how 18F-FDG PET/CT can guide the choice of the best therapeutic approach to RAI-refractory DTC (RAI-R-DTC) in patients with a doubtful iodine uptake/negative 18F-FDG PET/CT I whole-body scan after several radioactive iodine therapies (RAIT). The secondary aim was to assess the prognostic role of clinical and semi-quantitative metabolic 18F-FDG PET/CT parameters in comparison to published data., Materials and Methods: A monocentric retrospective observational study was performed, reviewing the medical records of 53 patients recruited from a database of 208 patients treated at our Institution between 2011 and 2019, with advanced DTC that underwent FDG PET/CT scan for a suspected RAI-R-DTC. Selected patients had to perform a 18F-FDG PET/CT scan after the second RAIT based on a doubtful iodine uptake/negative 131 I whole-body scan and/or persistent elevated thyroglobulin levels. Metabolic response was defined according to positron emission tomography response criteria in solid tumors (PERCIST) guidelines. Standardized uptake value (SUV)max, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The association between metabolic features, clinical parameters and progression free survival (PFS) was assessed applying Kruskal-Wallis, chi-square-Pearson correlation tests, and Cox regression analyses when appropriate., Results: Among our sample of 53 patients (mean age 52.0 ± 19.9 years; 31 women and 22 men), 27 (51.0%) presented a positive 18F-FDG PET/CT scan: 16 (59.0%) underwent watchful waiting, 4 (15.0%) received external-beam radiation therapy (EBRT), 4 (15.0%) underwent surgery, 2 (7.4%) received another course of RAI therapy, and 1 underwent surgery + EBRT. PERCIST response was evaluated in 14/27 patients. Median follow-up was 5.8 ± 3.9 years and median PFS was 38.0 ± 21.8 months. At the last follow-up assessment, 14/53 (26.4%) demonstrated disease progression, 13/53 (24.5) persistence of structural disease, 25/53 (47%) persistence of biochemical disease, and 15/53 (28%) had an excellent response. A significant association was found between therapeutic approach, metabolic response, and final disease response evaluation, as well as a linear correlation between MTV and TLG with thyroglobulin level., Conclusions: Our Institutional experience confirmed the role of 18F-FDG PET/CT as a useful guide in the clinical management of RAI-R-DTC and obviated further unnecessary RAIT.

Background: Laparoscopic adrenalectomy has a well-demonstrated learning curve in the first generation of laparoscopic surgeons. Data about the second generation of laparoscopic surgeons are lacking., Methods: In this retrospective observational study, data from patients undergoing laparoscopic adrenalectomy from 2000 to 2019 in a high-volume center were collected and analyzed. The cumulative sum of procedures of each surgeon and the operating time were evaluated. A multivariate analysis with backward stepwise logistic regression was carried out to define which factors influenced the operative time. Three surgeons performed the analyzed procedures: a senior surgeon who began his laparoscopic activity without receiving specific training or supervision and two young surgeons, who performed their procedures under the guidance of the "senior" experienced surgeon. The first 38 procedures of the three surgeons were then compared., Results: A total of 244 laparoscopic adrenalectomies were performed. Age, clinical diagnosis, side of the lesion, body mass index, comorbidities, Charlson index, American Society of Anaesthesiologists (ASA) score, and lower abdominal surgery were found to have no significant relationship with the operative time (p > 0.05). Gender, symptoms, previous upper abdominal surgery, size of the lesion, and cumulative sum of procedures were independent predictors of operative time. In the comparison between different surgeons, operative time resulted significantly longer for the senior (165 min; 140-180) than for the two junior surgeons (137.5 min; 115-160; p = 0.003 and 130 min; 120-170; p = 0.001)., Conclusions: The presence of a mentor in operative theater and specific training programs could be useful during the learning period. The cumulative sum of procedures related to the operative time represents a good parameter to measure the acquired expertise of a surgeon.

Objective: To investigate the impact of age, obesity and metabolic parameters on 13 circulating steroids in reproductive and menopausal age. To define reference intervals (RIs)., Design: Cross-sectional., Methods: Three hundred and twenty five drug-free, healthy and eumenorrheic women were selected from the general population. Independent relationships of LC-MS/MS-determined steroid levels with age, BMI and metabolic parameters were estimated. Reference sub-cohorts were defined for calculating upper and lower limits in reproductive age, menstrual phases and menopause, and these were compared with limits in dysmetabolic sub-cohorts., Results: Lower androgens, pro-androgens and estrogens, but higher cortisol and metabolites were found in menopausal compared to reproductive age women. Androgens and precursors decreased during reproductive age (P < 0.001-P = 0.002) but not after menopause. 17OH-progesterone decreased with BMI (P = 0.006) and glucocorticoids with waist circumference (P < 0.001P = 0.002) in reproductive age, but increased with triglycerides (P=0.011P=0.038) after menopause. Inverse associations of dihydrotestosterone with BMI (P=0.004) and HDL-cholesterol (P=0.010), estrone with total cholesterol (P=0.033) and estradiol with triglycerides (P=0.011) were found in reproductive age. After menopause, estrone increased with waist circumference (P<0.001) and decreased with insulin resistance (P=0.012). Ovarian steroid RIs were estimated in menstrual phases and menopause. Age- and reproductive status-specific RIs were generated for androgens, precursors and corticosteroids. Lower limits for reproductive age cortisol (P=0.020) and menopausal 11-deoxycortisol (P=0.003) in dysmetabolic sub-cohorts were reduced and increased, respectively, compared to reference limits., Conclusions: Obesity and dysmetabolism differently influence circulating steroids in reproductive and menopausal status. Age, menstrual and menopausal status-specific RIs were provided by LC-MS/MS for a broad steroid panel.

Purpose: Preoperative imaging in patients with primary hyperparathyroidism provides important localization information, allowing the surgeon to perform a focused surgery. However there are no evidence-based guidelines suggesting which preoperative imaging should be used, resulting in a risk of excessive prescription of exams and waste of economic resources. The main purpose of this study was to describe our experience on the performance of various imaging techniques for the preoperative localization of abnormal parathyroid gland/s, with a focus on the sensitivity and specificity of each technique. Secondly, we carried out an analysis of the cost utility of each technique in order to determine the most clinical and cost-effective combination of localization studies., Materials and Methods: Records of 336 patients who underwent parathyroidectomy were retrospectively examined comparing imaging and intraoperative/histopathologic findings to evaluate the accuracy in parathyroid detection of each imaging technique. Costs were determined by regional health system reimbursement., Results: We found that the sensitivity of color Doppler US was significantly higher than SPECT (p 0,023), while the sensitivity of 4D-CT was significantly better than US (p 0,029) and SPECT (p 0,0002)., Conclusions: In experienced hands color Doppler US is a highly sensitive technique especially in patients with no thyroid diseases. In patients with concomitant thyroid pathology, the combination of US and 4D-CT represents a reliable localization technique., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Research into cardiovascular disease (CV) prevention has demonstrated a variety of ultrasound (US) markers predicting risk in the general population but which have been scarcely used for polycystic ovary syndrome (PCOS). Obesity is a major factor contributing to CV disease in the general population, and it is highly prevalent in PCOS. However, it is still unclear how much risk is attributable to hyperandrogenism. This study evaluates the most promising US CV risk markers in PCOS and compares them between different PCOS phenotypes and BMI values., Design: Women fulfilling the Rotterdam criteria for PCOS were recruited from our outpatient clinic for this cross-sectional study., Methods: Participants (n = 102) aged 38.9 ± 7.4 years were stratified into the four PCOS phenotypes and the three BMI classes (normal-weight, overweight, obese). They were assessed for clinical and biochemical parameters together with the following US markers: coronary intima-media thickness (cIMT), flow-mediated vascular dilation (FMD), nitroglycerine-induced dilation (NTG), and epicardial fat thickness (EFT)., Results: There was no statistical difference among the four phenotypes in terms of cIMT, FMD, NTG or EFT, however all the US parameters except NTG showed significant differences among the three BMI classes. Adjusting for confounding factors in multiple regression analyses, EFT retained the greatest direct correlation with BMI and cIMT remained directly correlated but to a lesser degree., Conclusions: This study showed that obesity rather than the hyperandrogenic phenotype negatively impacts precocious US CV risk markers in PCOS. In addition, EFT showed the strongest association with BMI, highlighting its potential for estimating CV risk in PCOS.

Context: DNA methylation has been identified among putative regulatory mechanisms for CYP11B2 expression in primary aldosteronism., Objective: The objective of this work is to investigate DNA methylation and expression of genes encoding steroidogenic enzymes in benign adrenocortical tumors., Design and Setting: This cross-sectional study took place at university hospitals., Patients: We collected fresh-frozen tissues from patients with benign adrenocortical adenomas (n = 48) (nonfunctioning n = 9, autonomous cortisol secretion n = 9, Cushing syndrome n = 17, aldosterone-producing [APA] n = 13) and adrenal cortex adjacent to APA (n = 12). We collected formalin-fixed, paraffin-embedded (FFPE) specimens of paired APA and concurrent aldosterone-producing cell clusters (APCCs) (n = 6)., Intervention: DNA methylation levels were evaluated by quantitative bisulfite next-generation sequencing in fresh-frozen tissues (CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B1, HSD3B2, NR5A1, STAR, and TSPO) and FFPE APA/APCC paired samples (CYP11B2). CYP11B1, CYP11B2, CYP17, CYP21, and STAR gene expressions were examined by quantitative real-time polymerase chain reaction., Main Outcome Measure: The main outcome measure was DNA methylation., Results: CYP11B2 methylation levels were significantly lower in APA than in other adrenal tissues (P < .001). Methylation levels of the remaining genes were comparable among groups. Overall, CYP11B2 expression and DNA methylation were negatively correlated (ρ = -0.379; P = .003). In FFPE-paired APA/APCC samples, CYP11B2 methylation level was significantly lower in APA than in concurrent APCCs (P = .028)., Conclusions: DNA methylation plays a regulatory role for CYP11B2 expression and may contribute to aldosterone hypersecretion in APA. Lower CYP11B2 methylation levels in APA than in APCCs may suggest an APCC-to-APA switch via progressive CYP11B2 demethylation. Conversely, DNA methylation seems not to be relevant in regulating the expression of genes encoding steroidogenic enzymes other than CYP11B2., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We aimed at defining the most effective routine immunoassay- or liquid chromatography-tandem mass spectrometry (LC-MS/MS)-determined steroid biomarkers for identifying non-classic adrenal hyperplasia due to 21-hydroxylase deficiency (21-NCAH) in a PCOS-like population before genotyping., Methods: Seventy PCOS-like patients in reproductive age with immunoassay-determined follicular 17OH-progesterone (17OHP) ≥ 2.00 ng/mL underwent CYP21A2 gene analysis and 1-24 ACTH test. Serum steroids were measured by immunoassays at baseline and 60 min after ACTH stimulation; basal steroid profile was measured by LC-MS/MS., Results: Genotyping revealed 23 21-NCAH, 15 single allele heterozygous CYP21A2 mutations (21-HTZ) and 32 PCOS patients displaying similar clinical and metabolic features. Immunoassays revealed higher baseline 17OHP and testosterone, and after ACTH stimulation, higher 17OHP (17OHP 60 ) and lower cortisol, whereas LC-MS/MS revealed higher 17OHP (17OHP LC-MS/MS ), progesterone and 21-deoxycortisol and lower corticosterone in 21-NCAH compared with both 21-HTZ and PCOS patients. Steroid thresholds best discriminating 21-NCAH from 21-HTZ and PCOS were estimated, and their diagnostic accuracy in identifying 21-NCAH from PCOS was established by ROC analysis. The highest accuracy was observed for 21-deoxycortisol ≥ 0.087 ng/mL, showing 100% sensitivity, while the combination of 17OHP LC-MS/MS  ≥ 1.79 ng/mL and corticosterone ≤ 8.76 ng/mL, as well as the combination of ACTH-stimulated 17OHP ≥ 6.77 ng/mL and cortisol ≤ 240 ng/mL by immunoassay, showed 100% specificity., Conclusions: LC-MS/MS measurement of basal follicular 21-deoxycortisol, 17OHP and corticosterone seems the most convenient method for diagnosing 21-NCAH in a population of PCOS with a positive first level screening, providing high accuracy and reducing the need for ACTH stimulation test.

Background: Adrenal lipid-poor adenomas (LPA) are defined by high unenhanced density (≥ 10 HU), and absolute and relative contrast medium washout > 60% and > 40%, respectively, at computerized tomography (CT). To date, no thorough histopathological characterization has been performed in those frequent lesions (one-third of adrenal adenomas). Our aim was to analyze the histopathological characteristics of adrenal LPA., Methods: Patients with LPA (n = 57) were selected among consecutive subjects referred for an adrenal incidentaloma or ACTH-independent Cushing syndrome. FluoroDeoxyGlucose-Positron Emission Tomography (FDG-PET) was performed in 37 patients. In patients treated by adrenalectomy (n = 17), Weiss score and Lin-Weiss-Bisceglia score (in tumors composed entirely or predominantly of oncocytes) were calculated., Results: Radiological parameters did not differ among patients with ACTH-independent Cushing syndrome (n = 6) and those with adrenal incidentalomas associated with primary aldosteronism (n = 2), autonomous cortisol secretion (n = 14), or non-functioning (n = 35). Patients treated by adrenalectomy had larger tumors (28.9 ± 11.2 vs 17.3 ± 8.4 mm, P < 0.001), higher CT unenhanced density (29.1 ± 11.0 vs 23.1 ± 9.0 HU, P = 0.043), and FDG-PET adrenal uptake (9.0 ± 6.4 vs 4.4 ± 2.3 SUV, P = 0.003) than non-operated ones. Oncocytic features > 75% of the tumor were detected in 12/17 cases (70.6%). Five of those showed borderline-malignant histopathological characteristics by Lin-Weiss-Bisceglia score. Among remaining non-oncocytic tumors, 1/5 had a Weiss score ≥ 3. Overall, 6/17 tumors (35.3%) had borderline-malignant potential. Radiological parameters were similar between patients with benign and borderline-malignant tumors., Conclusions: Adrenal LPA are a heterogeneous group of tumors, mostly composed of oncocytomas. Up to 1/3 of those tumors may have a borderline-malignant potential at histopathology.

Context: Chronic glucocorticoids excess leads to morphological and functional cardiac alterations, a substrate for arrhythmias. Autonomous cortisol secretion (ACS) in adrenal incidentalomas is a model of chronic endogenous hypercortisolism., Objective: To investigate prevalence and incidence of atrial fibrillation (AF) in a large cohort of patients with ACS., Design: Retrospective study., Setting: University hospital., Patients: Patients evaluated between 1990 and 2018 for adrenal incidentalomas (n = 632), without pheochromocytoma, primary aldosteronism, Cushing syndrome, congenital adrenal hyperplasia, and adrenal malignancy. Cortisol after 1-mg dexamethasone suppression test < or > 50 nmol/L defined nonsecreting tumors (NST) (n = 420) and ACS (n = 212), respectively., Intervention: Assessment of AF at baseline (n = 632) and during a median follow-up of 7.7 years retrospectively (NST, n = 249; ACS, n = 108). Comparison with general population., Main Outcome Measure: Prevalence and incidence of AF., Results: AF prevalence was higher in patients with ACS (8.5%) than NST (3.1%, P = 0.003) and the general population (1.7%; P < 0.001 vs ACS, P = 0.034 vs NST). The age-adjusted rate ratio to the general population was 1.0 for NST and 2.6 for ACS. AF was associated with ACS (odds ratio, 2.40; 95% confidence interval [CI], 1.07-5.39; P = 0.035). The proportion of patients with AF at last evaluation was higher in ACS (20.0%) than NST (11.9%; P = 0.026). ACS showed a higher risk of incident AF than NST (hazard ratio, 2.95; 95% CI, 1.27-6.86; P = 0.012), which was associated with post-dexamethasone cortisol (hazard ratio, 1.15; 95% CI, 1.07-1.24; P < 0.001), independently of known contributing factors., Conclusions: Patients with adrenal incidentalomas and ACS are at risk of AF. Electrocardiogram monitoring may be recommended during follow-up., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The diagnosis of primary hyperparathyroidism (PHPT) and chronic hypoparathyroidism (HypoPT) is still challenging, especially in patients asymptomatic or with non-classical phenotypes and for physicians not skilled in calcium-phosphorous (Ca-P) disorders. The serum calcium/phosphorous (Ca/P) ratio has been proposed as accurate index to identify PHPT, while it has never been tested in HypoPT. The aim of this study is to investigate the diagnostic power of the serum Ca/P ratio in the diagnosis of primary parathyroid dysfunctions (both PHPT and HypoPT) in a large series of data., Methods: A multicentric, retrospective, cross-sectional study (ClinicalTrials.gov: NCT03747029) was carried out including 432 PHPT patients and 217 HypoPT patients compared with 389 controls. Serum Ca, P, creatinine, parathyroid hormone and 25OH-vitamin D were collected. Serum Ca and P were expressed in mmol/L. Ca/P diagnostic performance was evaluated by receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy., Results: The Ca/P ratio was significantly higher in PHPT and lower in HypoPT patients than controls (p < 0.0001). At ROC curve analysis, the Ca/P ratio above 2.55 was defined to identify PHPT patients (sensitivity 85.7%, specificity 85.3%) and below 1.78 to identify HypoPT patients (sensitivity 88.2%, specificity 87.9%)., Conclusions: The Ca/P ratio is a highly accurate index to identify PHPT when Ca/P is above 2.55 and HypoPT when it is below 1.78. These results demonstrate the reliability of this index to rule in/out primary parathyroid dysfunctions and remark the importance of measuring serum P in clinical practice.

Objective: To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men., Design: Cross-sectional study., Methods: Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts., Results: We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (-0.34 nmol/L, P = 0.045), cortisol (-87 nmol/L, P = 0.045-0.002) and corticosterone (-10.1 nmol/L, P = 0.048-0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively., Conclusions: Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.

Context: Steroid profiling by mass spectrometry has shown implications for diagnosis and subtyping of adrenal tumors., Objectives: To investigate steroid profiles and their cardiovascular correlates in a large cohort of patients with nonsecreting (NS) adrenal incidentalomas and autonomous cortisol secretion (ACS)., Design: Cohort study., Setting: University hospital., Patients: Patients (n = 302) with incidentally discovered adrenal masses, divided into unilateral adenoma and hyperplasia with ACS (n = 46 and n = 52, respectively) and NS (n = 120 and n = 84, respectively). Post-dexamethasone suppression test (DST) cortisol <50 or >50 nmol/L defined NS and ACS, respectively., Intervention: Analysis of 10-steroid panel by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and clinical data (mean follow-up 39 months)., Main Outcome Measures: Difference in baseline and post-DST steroid profiles between groups. Correlation with cardiovascular profile., Results: Patients with unilateral adenomas and ACS showed higher cortisol, 11-deoxycortisol, and corticosterone and lower dehydroepiandrosterone than those with NS adenomas. Patients with ACS hyperplasia showed higher cortisol and lower androgens in women than those with NS. Patients with ACS had reduced suppression of post-DST cortisol, 11-deoxycortisol, and corticosterone, irrespective of adrenal morphology. Post-DST cortisol and corticosterone were associated with higher prevalence of severe/resistant hypertension. Patients with ACS unilateral adenomas showed higher incidence of worsening of hypertensive disease and novel cardiovascular events than those with NS, with post-DST cortisol [hazard ratio (HR) 1.02; 95% CI, 1.01 to 1.03; P < 0.001] and baseline corticosterone (HR 1.06; 95% CI, 1.01 to 1.12; P = 0.031) among the main predictors., Conclusions: Patients with adrenal incidentalomas showed different steroid profiles, depending on functional status and adrenal morphology, with implications for their cardiovascular status., (Copyright © 2019 Endocrine Society.)

The finding of an indeterminate adrenal mass at radiological investigations is a challenge for physicians. Complex diagnostic work-up, periodic follow-up, or surgical intervention are therefore needed to rule out malignant lesions. Tertiary care hospitals are provided with 18 F-fludeoxyglucose ( 18 F-FDG) positron emission tomography (PET) and 18 F-dihydroxyphenylalanine ( 18 F-DOPA) PET, which aid in the characterization of indeterminate adrenal masses. Nevertheless, the histopathological examination may be required to exclude malignancy or rare etiologies. A 54-year-old woman presented to our clinic 6 months after a cerebral hemorrhage. She was hypertensive and had recently discovered a left adrenal mass of 15 mm during an abdominal ultrasound. Contrast-enhanced CT, following adrenal protocol, revealed a 14-mm adrenal mass without characteristics suggestive of an adrenal adenoma. Tumor markers were negative. Functional tests excluded hormone hypersecretion. An 18 F-DOPA PET was negative. An 18 F-FDG PET showed mild uptake of both the adrenal glands, with a more circumscribed pattern in the left one (maximum standardized uptake value = 4). As the clinical diagnosis was still indeterminate, we performed laparoscopic left adrenalectomy. The histopathological examination described a sclerosing angiomatoid nodular transformation (SANT) of the adrenal gland, a benign lesion already described as a rare occurrence only in the spleen. IgG4 levels were reduced. In conclusion, this is a report of a SANT of the adrenal gland, a novel entity that should be taken into consideration in the differential diagnosis of indeterminate adrenal masses at CT scan.

Background: Stimulated thyroglobulin levels measured at the time of remnant ablation (A-hTg) and BRAF V600E mutation had shown prognostic value in predicting persistent disease in differentiated thyroid cancer (DTC). The aim of this study was to evaluate the prognostic role of A-hTg combined with the BRAF V600E status in association with the revised American Thyroid Association (ATA) risk stratification., Material and Methods: 620 patients treated for a DTC were included in this study with a median follow-up duration of 6.1 years. All patients underwent total thyroidectomy followed by radioiodine ablation. Patients with positive anti-thyroglobulin antibodies were excluded. The predictive value of A-hTg was calculated by receiver operating characteristic curve (ROC curve) analysis. The Cox proportional hazard regression model, including the BRAF status, A-hTg, and ATA classification system, was assessed to evaluate the existing persistent disease risk., Results: Taken together, the BRAF status and A-hTg levels improve the ATA risk classification in all categories. In particular, in the low-risk ATA classification, only the combination of BRAF V600E +A-hTg > 8.9ng/ml was associated with persistent disease ( P = 0.001, HR 60.2, CI 95% 5.28-687). In the intermediate-risk ATA classification, BRAF WT +A-hTg > 8.9ng/ml was associated with persistent disease ( P = 0.029, HR 2.71, CI 95% 1.106-6.670) and BRAF V600E +A-hTg > 8.9ng/ml was also associated with persistent disease ( P < 0.001, HR 5.001, CI 95% 2.318-10.790). In the high-risk ATA classification, both BRAF V600E +A-hTg < 8.9ng/ml and BRAF V600E +A-hTg > 8.9 ng/ml were associated with persistent disease ( P = 0.042, HR 5.963, CI 95% 1.069-33.255 and P = 0.002, HR 11.564, CI 95% 2.543-52.576, respectively)., Conclusions: The BRAF status and stimulated thyroglobulin levels at ablation time improve the ATA risk stratification of differentiated thyroid cancer; therefore, even A-hTg could be included in risk classification factors.

Objective: Primary aldosteronism is associated with higher cardiovascular morbidity as compared with essential hypertension. Vascular complications encompass myocardial infarction and cerebrovascular events. Aortic damage in primary aldosteronism has never been explored, although a few cases of ascending aorta aneurisms have been reported., Design and Methods: We consecutively enrolled patients affected by primary aldosteronism (n = 45) and compared them with patients affected by essential hypertension (n = 47), on an outpatient setting. Echocardiographic data of patients with primary aldosteronism were collected during a mean follow-up of 3 years, in subjects who underwent adrenal surgery (n = 12) and those on mineralocorticoid receptor antagonists (n = 33)., Results and Conclusion: We found that patients with primary aldosteronism had larger ascending aorta diameters than those with essential hypertension before starting any specific treatment. Patients with primary aldosteronism did not show significant changes in the size of ascending aorta during a mean of 3 years of follow-up, irrespective of the type of treatment (medical vs. surgical treatment). A longer follow-up will better clarify if worsening of the aortic damage may be better prevented by surgery rather than by mineralocorticoid receptor antagonists.

Similarities in neural activation patterns in obese and substance-dependent subjects led to the food addiction concept, but studies exploiting this issue for obesity stratification are missing. We assessed brain activation in response to food cues using 18 F-2-fluoro-2-deoxy-glucose-PET in 36 overweight women, stratified by low or high food addiction groups according to the Yale Food Addiction Scale (YFAS). Assessments were repeated after a 3-month diet. We found greater activation in thalamus, hypothalamus, midbrain, putamen, and occipital cortex (reward), but not in prefrontal and orbitofrontal cortices (control/reward receipt) in the high-YFAS versus low-YFAS group. In high-YFAS subjects, orbitofrontal responsiveness was inversely related to YFAS severity and hunger rating, and positive associations were observed between regional brain activation and lipid intake. A 3-month diet abolished group differences in brain activation. Our data suggest that food addiction distinguishes an overweight phenotype that can be reversed by diet, opening to personalized strategies in obesity treatment., (© 2018 John Wiley & Sons, Ltd and Eating Disorders Association.)

Background: Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic., Methods: Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic., Results: About 50% of PCCs examined had somatic mutations on the known susceptibility VHL , NF1 , and RET genes. In addition to these driver events, mutations on SYNE1 , ABCC10 , and RAD54B genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes., Conclusions: Additional somatic passenger mutations can be associated with known susceptibility VHL , NF1 , and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.

Objective: N-acylethanolamines play different roles in energy balance; anandamide (AEA) stimulates energy intake and storage, N-palmitoylethanolamide (PEA) counters inflammation, and N-oleoylethanolamide (OEA) mediates anorectic signals and lipid oxidation. Inconsistencies in the association of plasma N-acylethanolamines with human obesity and cardiometabolic risk have emerged among previous studies, possibly caused by heterogeneous cohorts and designs, and by unstandardized N-acylethanolamine measurements. We aimed to characterize changes in the plasma profile, including N-acylethanolamine levels and ratios associated with obesity, menopause in women, and ageing in men, and to define the significance of such a profile as a biomarker for metabolic imbalance., Methods: Adult, drug-free women (n = 103 premenopausal and n = 81 menopausal) and men (n = 144) were stratified according to the body mass index (BMI) into normal weight (NW; BMI: 18.5-24.9 kg/m 2 ), overweight (OW; BMI: 25.0-29.9 kg/m 2 ), and obese (OB; BMI ≥30.0 kg/m 2 ). Anthropometric and metabolic parameters were determined. Validated blood processing and analytical procedures for N-acylethanolamine measurements were used. We investigated the effect of BMI and menopause in women, and BMI and age in men, as well as the BMI-independent influence of metabolic parameters on the N-acylethanolamine profile., Results: BMI and waist circumference directly associated with AEA in women and men, and with PEA in premenopausal women and in men, while BMI directly associated with OEA in premenopausal women and in men. BMI, in both genders, and waist circumference, in women only, inversely associated with PEA/AEA and OEA/AEA. Menopause increased N-acylethanolamine levels, whereas ageing resulted in increasing OEA relative abundance in men. AEA and OEA abundances in premenopausal, and PEA and OEA abundances in lean menopausal women, were directly associated with hypertension. Conversely, PEA and OEA abundances lowered with hypertension in elderly men. Insulin resistance was associated with changes in N-acylethanolamine ratios specific for premenopausal (reduced PEA/AEA and OEA/AEA), menopausal (reduced OEA/AEA) women and men (reduced OEA/AEA and OEA/PEA). PEA and OEA levels increased with total cholesterol, and OEA abundance specifically increased with HDL-cholesterol. Elevated triglyceride levels were associated with increased N-acylethanolamine levels only in menopausal women., Conclusions: Obesity-related N-acylethanolamine hypertone is characterized by imbalanced N-acylethanolamine ratios. The profile given by a combination of N-acylethanolamine absolute levels and ratios enables imbalances to be identified in relationship with different metabolic parameters, with specific relevance according to gender, menopause and age, representing a useful means for monitoring metabolic health. Finally, N-acylethanolamine system appears a promising target for intervention strategies., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Purpose: Aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion are reported in an increasing number of patients. Five aldosterone-producing adenomas from patients with primary aldosteronism and subclinical hypercortisolism were examined., The Aims of Our Study Were: (1) to analyze pathological features and immunohistochemical expression of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) in these tumors; (2) to investigate somatic mutations involved in adrenal steroid hypersecretion and/or tumor growth., Methods: Archival micro-dissected paraffin-embedded slides from tumor specimens were used for histological and molecular studies. Immunohistochemistry was performed using monoclonal anti-CYP11B1 and anti-CYP11B2 antibodies. Cellular composition was determined by examining for known features of zona fasciculata and zona glomerulosa, and immunoreactivity for CYP11B1 and CYP11B2 by McCarty H-score. Spot regions for mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, PRKACA, and CTNNB1 gene sequences were evaluated., Results: Four APAs showed a predominant (≥50%) zona fasciculata-like cell pattern: one tumor had CYP11B1 H-score = 150, no detectable CYP11B2 expression, and harbored a PRKACA p.Leu206Arg mutation (that we have reported previously elsewhere), one had no CYP11B1 expression, CYP11B2 H-score = 40, and no mutations; the remaining two adenomas had high CYP11B1 H-score (160 and 240, respectively) and low CYP11B2 H-score (30 and 15, respectively), with the latter harboring a CTNNB1 p.Ser45Phe activating mutation. One of five aldosterone-producing adenomas had a predominant zona glomerulosa-like pattern, CYP11B1 H-score = 15, CYP11B2 H-score = 180, and no mutations., Conclusions: The majority of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion were composed mainly of zona fasciculata-like cells, while CYP11B1 and CYP11B2 immunostaining demonstrated clear heterogeneity. In a subset of cases, different somatic mutations may be involved in hormone excess and tumor formation.

Background: Salivary androgen testing represents a valuable source of biological information. However, the proper measurement of such low levels is challenging for direct immunoassays, lacking adequate accuracy. In the last few years, many conflicting findings reporting low correlation with the serum counterparts have hampered the clinical application of salivary androgen testing. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) makes it possible to overcome previous analytical limits, providing new insights in endocrinology practice., Methods: Salivary testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA) and 17OHprogesterone (17OHP) were extracted from 500µL of saliva, separated in 9.5 min LC-gradient and detected by positive electrospray ionization - multiple reaction monitoring. The diurnal variation of salivary and serum androgens was described by a four paired collection protocol (8 am, 12 am, 4 pm and 8 pm) in 19 healthy subjects., Results: The assay allowed the quantitation of T, A, DHEA and 17OHP down to 3.40, 6.81, 271.0 and 23.7 pmol/L, respectively, with accuracy between 83.0 and 106.1% for all analytes. A parallel diurnal rhythm in saliva and serum was observed for all androgens, with values decreasing from the morning to the evening time points. Salivary androgen levels revealed a high linear correlation with serum counterparts in both sexes (T: R>0.85; A: R>0.90; DHEA: R>0.73 and 17OHP: R>0.89; p<0.0001 for all)., Conclusions: Our LC-MS/MS method allowed a sensitive evaluation of androgen salivary levels and represents an optimal technique to explore the relevance of a comprehensive androgen profile as measured in saliva for the study of androgen secretion modulation and activity in physiologic and pathologic states.

Objective: The aim of this study is to determine whether any correlation between CT findings and functional parameters exists to predict subclinical glucocorticoid secretion., Materials and Methods: This is a retrospective database study of 55 patients with incidentally discovered adenomas, investigated through CT with an adrenal protocol, assessing diameters and attenuation values on the unenhanced and contrast-enhanced phases. Patients underwent blood cortisol and corticotropin evaluation and overnight dexamethasone suppression test (DST), in accordance with clinical recommendations. Cortisol levels higher than 50 nmol/L after DST identified subclinical cortisol secretion. We identified 28 subjects with lipid-rich nonsecreting adenomas, nine with lipid-rich secreting adenomas, 11 with lipid-poor nonsecreting adenomas, and seven with lipid-poor secreting adenoma., Results: Cortisol levels after DST were significantly and positively related to mass diameters. At univariate analysis, maximum and minimum diameters and attenuation in the delayed phase were significantly related to the presence of secreting or nonsecreting adenoma; at multivariate analysis, only the minimum diameter and the attenuation in the venous phase entered the stepwise logistic regression. Similarly, minimum diameter and attenuation in the venous phase emerged also at the multivariate stepwise regression between radiologic parameters and cortisol levels after DST. The formula of the radiologic score computed by using the coefficients of the multivariate regression was as follows: (0.1914 × minimum diameter) + (0.0308 × enhanced attenuation). The diagnostic accuracy of this discriminatory score in differentiating secreting from nonsecreting adenomas was 84.9%, the sensitivity was 81.3%, and the specificity was 87.2%. Adenomas with scores greater than 7.59 were considered as secreting adenomas, and adenomas with scores less than 7.36 were considered as nonsecreting adenomas., Conclusion: This study shows that imaging parameters can predict subclinical cortisol hypersecretion in patients with adrenal adenomas.

Objective: The endocannabinoid system hypertonicity features obesity. Excess circulating 2-arachidonoylglycerol was variously associated with obesity-related metabolic impairment; however, unstandardized experimental and analytical settings have clouded its usefulness as a dysmetabolism biomarker. We aimed at assessing the influence of body mass index (BMI), menopause in women, and aging in men on 2-arachidonoylglycerol relationship with metabolic parameters., Methods: Adult, unmedicated women (premenopausal (preMW): n = 103; menopausal (MW): n = 81) and men (n = 144) were stratified in normal weight (NW; BMI: 18.5-24.9 kg/m 2 ), overweight (OW; BMI: 25.0-29.9 kg/m 2 ), and obese (OB; BMI ≥ 30.0 kg/m 2 ) classes. Anthropometric and metabolic parameters were determined. Plasma 2-arachidonoylglycerol was measured by a validated liquid chromatography-mass spectrometry assay., Results: 2-arachidonoylglycerol level was raised by menopause (P < 0.001) and by obesity in preMW (P < 0.001) and in men (P = 0.019). In the overall cohorts, 2-arachidonoylglycerol displayed BMI-independent relationships with dyslipidemia (preMW, MW and men), insulin resistance (MW and men), and hypertension (men), but not with waist circumference. Within preMW BMI classes, 2-arachidonoylglycerol correlations were found with triglycerides (P = 0.020) and total cholesterol (TC; P = 0.040) in OB women. In MW, 2-arachidonoylglycerol correlation with triglycerides was found in NW (P = 0.001) and OW (P = 0.034), but not in OB class. Moreover, we found 2-arachidonoylglycerol correlations with TC (P = 0.003), glucose (P < 0.001), and HOMA-IR (P = 0.035) specific for NW MW class. In men, 2-arachidonoylglycerol correlated with triglycerides in NW, OW (both P < 0.001), and OB (P = 0.029), with SBP (P = 0.023) and diastolic BP (DBP; P = 0.048) in OB, and with TC (P < 0.001) in OW class. In NW class 2-arachidonoylglycerol correlations were found with insulin (P = 0.003) and HOMA-IR (P = 0.001), both enhanced by aging (both P = 0.004), and with glucose (P = 0.015) and HDL (P = 0.004)., Conclusions: Plasma 2AG is a biomarker of clustering metabolic dysfunctions, especially in lean men and menopausal women, and could be of help in identifying subjects with elevated cardiometabolic risk despite a healthy anthropometric appearance.

Salivary steroid testing represents a valuable source of biological information; however, the proper measurement of low salivary levels is challenging for direct immunoassays, lacking adequate sensitivity and specificity and causing poor inter-laboratory reproducibility. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has overcome previous analytical limits, often providing results deviating from previous knowledge. Nowadays, LC-MS/MS is being introduced in clinical laboratories for salivary cortisol testing; however, so far only a few studies have reported thorough biological validation based on LC-MS/MS data. In this study, we provide a thorough analytical, pre-analytical and biological validation of an LC-MS/MS method for the measurement of salivary cortisol (F) and of its inactive metabolite cortisone (E). Analytes were extracted from 50μl of saliva, were then separated in 7.5min LC-gradient and detected by negative electrospray ionization-multiple reaction monitoring. The reliability of a widely diffused collection device, Salivette(®), was assessed and the overall procedure was validated. The diurnal cortisol and cortisone fluctuation in saliva and serum was described by a four paired collection protocol (8 am, 12 am, 4 pm and 8 pm) in 19 healthy subjects. The assay allowed the quantitation of F and E down to 39.1 and 78.1pg/ml, with an imprecision range of 5.5-9.5%, 3.9-14.1% and 2.6-14.4%, and an accuracy range of 105.5-113.1%, 88.5-98.7% and 90.7-96.7% for both analytes at low, medium and high levels, respectively. Salivette(®) provided comparable results and better precision (CV<1.0%) as referred to direct spitting (CV<13.0%). A parallel diurnal rhythm in saliva and serum was observed for cortisol and cortisone, with values lowering from the morning to the evening time points (P<0.0001). While salivary E linearly correlated to total serum F (R(2)=0.854, P<0.001), salivary F showed an exponential relationship (R(2)=0.903, P<0.001) with serum F reflecting the free circulating fraction. A non linear association between E and F was observed in saliva (R(2)=0.941, p<0.001) consistent with the type II 11β-HSD activity. We concluded that our LC-MS/MS method allowed a sensitive evaluation of salivary levels of cortisol and cortisone. The simultaneous determination of both hormones in saliva allowed the differential estimation of the active and of the total glucocorticoid exposure over the daytime. The assay could provide further insight into the comprehension of normal and dysfunctional glucocorticoid circadian rhythm., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Primary hyperaldosteronism (PA) has recently been demonstrated to be strictly associated to metabolic syndrome as compared with essential hypertension (EH). Besides, the characteristics of metabolic syndrome are different in PA compared to EH, as high fasting glucose is more frequent in the former condition. The adverse effect of excess aldosterone on insulin metabolic signaling has generated increasing interest in the role of hyperaldosteronism in the pathogenesis of insulin resistance and resistant hypertension. Moreover, aldosterone receptor antagonist therapy in diabetic and cardiopathic patients improved coronary flow. The aim of this review is to present recent knowledge about the relationship between aldosterone, insulin resistance and diabetes.

Context: Long-term follow-up studies revealed that patients with subclinical hypercortisolism (SH) due to adrenocortical adenomas have an increased incidence of cardiovascular diseases and mortality. No studies have yet investigated the steroid profile and its implications in patients with SH., Objective: The objective of the study was to analyze the steroid profile by liquid chromatography-tandem mass spectrometry in sera from patients with unilateral adrenocortical adenomas., Design: This was a cross-sectional study., Setting: The study was conducted at an outpatient clinic., Participants: Patients with adrenocortical adenomas (nonsecreting, n = 66; SH, n = 28) and 188 age- and sex-matched controls drawn from the general population participated in the study., Main Outcome Measures: Cortisol, 21-deoxycortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, T, progesterone, 11-deoxycorticosterone, and corticosterone in the basal condition and after a 1-24 ACTH test, and clinical data were measured., Results: Patients with SH showed lower basal and 1-24 ACTH-stimulated levels of dehydroepiandrosterone and androstenedione than those with nonsecreting adenomas and controls. T was also lower in SH females. Receiver-operating characteristic curves showed that androgens had good accuracy in predicting SH (sensitivity and specificity were 71% and 76% for dehydroepiandrosterone and 69% and 61% for androstenedione, respectively). Increased cortisol and reduced dehydroepiandrosterone levels were independently associated with increased waist circumference. Cortisol was also independently associated with increased number of cardiovascular risk factors in SH patients. After 1-24 ACTH stimulation, the SH patients also showed increased production of 21-deoxycortisol and 11-deoxycorticosterone., Conclusions: Liquid chromatography-tandem mass spectrometry steroid profile performed for the first time in sera from patients with adrenocortical adenomas showed impaired secretion of several steroids in SH patients. This fingerprint can help in better characterizing the functional status of these tumors.

Epidemiological studies have shown that overweight and cancer are closely related, even though obesity alone does not apparently heighten cancer risk by the same amount. Given the low overall risk of all cancers with obesity, it is unlikely that obesity alone causes cancer, but should instead be considered as a tumor promoter. There are three main hypotheses that could explain how obesity might contribute to cancer development and growth: the inflammatory cytokines from adipose tissue hypothesis, the insulin resistance and hyperinsulinemia hypothesis, and the unopposed estrogen cancer hypothesis. The link between obesity and cancer is that adipocytes constitute a major component of the tumor microenvironment for breast and abdominally metastasizing cancers, promoting tumor growth. This review will mainly focus attention on the relationship between adipose tissue, estrogens, and cancer risk.

Background: Incidental discovery of adrenal masses has increased over the past few years. Mild alterations in cortisol secretion without clinical signs of overt hypercortisolism (subclinical Cushing's syndrome) are a common finding in patients with these tumours. Although metabolic alterations and increased cardiovascular risk have been noted in patients with subclinical Cushing's syndrome, incidence of cardiovascular events and mortality in the long term have not been assessed. We aimed to ascertain the frequency of new cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas, tumours of intermediate phenotype, or those causing subclinical Cushing's syndrome., Methods: From January, 1995, to September, 2010, consecutive outpatients with adrenal incidentalomas who were referred to the endocrinology unit of S Orsola-Malpighi Hospital, Bologna, Italy, were enrolled into our study. Individuals were assessed every 18-30 months for the first 5 years (mean follow-up 7·5 [SD 3·2] years, range 26 months to 15 years). Cortisol concentrations after the 1 mg dexamethasone suppression test (DST) were used to define non-secreting (+50 nmol/L) and intermediate phenotype (50-138 nmol/L) adrenal incidentalomas and subclinical Cushing's syndrome (+138 nmol/L). At the end of follow-up, patients were reclassified as having either unchanged or worsened secreting patterns from baseline., Findings: 198 outpatients were assessed; at the end of follow-up, 114 patients had stable non-secreting adrenal incidentalomas, 61 had either a stable intermediate phenotype or subclinical Cushing's syndrome, and 23 had a pattern of secretion that had worsened. By comparison with patients with stable non-secreting adrenal incidentalomas, the incidence of cardiovascular events was higher in individuals with a stable intermediate phenotype or subclinical Cushing's syndrome (6·7% vs 16·7%; p=0·04) and in those with worsened secreting patterns (6·7% vs 28·4%; p=0·02). Cardiovascular events were associated independently with a change (from baseline to the end of follow-up) in cortisol concentrations post DST (hazard ratio 1·13, 95% CI 1·05-1·21; p=0·001). Survival rates for all-cause mortality were lower in patients with either stable intermediate phenotype adrenal incidentalomas or subclinical Cushing's syndrome compared with those with stable non-secreting masses (57·0% vs 91·2%; p=0·005). Factors associated with mortality were age (hazard ratio 1·06, 95% CI 1·01-1·12; p=0·03) and mean concentrations of cortisol post DST (1·10, 1·01-1·19; p=0·04). Compared with patients with stable non-secreting adrenal incidentalomas, unadjusted survival for cardiovascular-specific mortality was lower in patients with either a stable intermediate phenotype or subclinical Cushing's syndrome (97·5% vs 78·4%; p=0·02) and in those with worsened secreting patterns (97·5% vs 60·0%; p=0·01). Cancer mortality did not differ between groups., Interpretation: Even when clinical signs of overt hypercortisolism are not present, patients with adrenal incidentalomas and mild hypercortisolism have an increased risk of cardiovascular events and mortality., Funding: None., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In addition to its roles in providing insulation and mechanical support, adipose tissue (AT) has been recognised as the major site for storage of surplus fuel. Since leptin was discovered, white AT (WAT) has been recognised as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines. The metabolic and endocrine activities of AT are under the control of several hormones: a particular role has been played by glucocorticoids (GC), which able to participate, along with other hormones, both in recruitment of progenitor cells and in differentiation and secretive activities. AT is also able to generate cortisol from cortisone through 11β-hydroxysteroid-dehydrogenase (11β-HSD). There are controversial reports in the literature, showing a hyperactivity of 11β-HSD in obesity. It has been postulated that obesity, particularly the visceral body fat distribution (V-BFD), may be considered a maladaptation to stress exposure, thus leading to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and higher-than-normal cortisol levels. In this review, we will examine the cross-talk between the HPA axis and AT, their relationship under stressful events, depending on steroid hormones and different adipokine secretions.

Nowadays pharmacological therapy to limit obesity has reached a critical stage: not only have Authorities limited the use of antiobesity drugs due to their proven inefficacy and dangerous side effects, but bariatric surgery has delivered better results. At present, when the number of obese subjects is growing exponentially worldwide and more and more pathological mechanisms inducing fat accumulation have been discovered, no drugs are available to help patients and physicians to limit one the most dreadful causes of death. Following the failures of promising drugs as sibutramine and rimonabant, many companies stopped to invest in the field of obesity pharmacotherapy. At the same time, leading Authorities have started to require more solid evidence before providing authorization for these drugs to enter the market. This review aims at revising the failed promises of antiobesity drugs and describing the few potential future candidates in order to shed some light in the still uncertain field of antiobesity drugs. It also provides a critical contribution to the ongoing debate among scientists, clinicians, patients and Authorities on the possibility to treat obesity with pharmacological drugs.