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Abstract: A 34-year-old woman who presented with severe psychosis and clinical features of Cushing syndrome underwent 18 F-FDG PET/CT that revealed hypermetabolic lung lesion along with predominantly increased metabolism of bilateral basal ganglia, a scintigraphic correlate of acute psychosis. The lesion was surgically excised and histopathologically proven to be adrenocorticotropic hormone-producing lung carcinoid. Posttreatment 18 F-FDG PET scan showed restoration of normal brain metabolism with complete reversal of psychosis. Even though rare, one should be aware of psychosis as an initial presentation of Cushing syndrome and use of 18 F-FDG PET/CT for mapping brain metabolism as shown in this case., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Minimally invasive surgery for paediatric adrenal tumours has evolved, but robot-assisted laparoscopic adrenalectomy (RALA) in children remains poorly studied. The current prospective study aims to demonstrate the safety and efficacy of RALA in treating children with adrenal tumours., Methods: A prospective institutional analysis of children presenting with neuroblastic and endocrine tumours treated with RALA was undertaken over a six year-period. For each child, clinical parameters were collected relating to diagnosis, surgery and outcomes., Results: A total 50 RALA were performed; 23 for unilateral neuroblastic tumours (87 % neuroblastomas) and 27 for endocrine tumours. Eight neuroblastic tumours (35 %) had image-defined risk factors (all due to tumour invading the renal pedicle). Median length of stay was two days. Resection margins were macroscopically clear in all cases. After median follow-up of 2.9 years (1.6-3.9), two children are under treatment for metastatic relapse (high-risk disease) and three died due to refractory disease. Sixteen children had endocrine tumours: pheochromocytoma (n = 13), or bilateral nodular adrenocortical hyperplasia with Cushing's syndrome (n = 14). One child required non-emergent conversion, and one complication occurred (grade IIIb) after median follow-up of 3.3 years (1.0-5.7)., Conclusions: The current study is the largest reported experience in the literature and confirms the safety and effectiveness of RALA in carefully selected children with adrenal tumours. Through an iterative process and in the setting of a dedicated paediatric robotic surgical team indications have been clarified and extended. The current study confirms RALA has particularly utility in patients with severe disease (IDRF + metastatic neuroblastomas) or genetic predisposition syndromes., Competing Interests: Declaration of competing interest TB is an official proctor for Intuitive Surgical. None of the other authors have any disclosures., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Thymic neuroendocrine tumor as a cause of Cushing syndrome is extremely rare in children., Case Presentation: We report a case of a 10-year-old girl who presented with typical symptoms and signs of hypercortisolemia, including bone fractures, growth retardation, and kidney stones. The patient was managed with oral ketoconazole, during which she experienced adrenal insufficiency, possibly due to either cyclic adrenocorticotropic hormone (ACTH) secretion or concurrent COVID-19 infection. The patient underwent a diagnostic work-up which indicated the possibility of an ACTH-secreting pituitary neuroendocrine tumor. However, after a transsphenoidal surgery, the diagnosis was not confirmed on histopathological examination. Subsequent bilateral inferior petrosal sinus sampling showed strong indications of the presence of ectopic ACTH syndrome. Detailed rereading of functional imaging studies, including 18 F-FDG PET/MRI and 68 Ga DOTATOC PET/CT, ultimately identified a small lesion in the thymus. The patient underwent videothoracoscopic thymectomy that confirmed a neuroendocrine tumor with ACTH positivity on histopathological examination., Conclusion: This case presents some unique challenges related to the diagnosis, management, and treatment of thymic neuroendocrine tumor in a child. We can conclude that ketoconazole treatment was effective in managing hypercortisolemia in our patient. Further, a combination of functional imaging studies can be a useful tool in locating the source of ectopic ACTH secretion. Lastly, in cases of discrepancy in the results of stimulation tests, bilateral inferior petrosal sinus sampling is highly recommended to differentiate between Cushing disease and ectopic ACTH syndrome., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Signed informed consent was obtained from the patient and the patient´s parents for the publication of this case report and accompanying images. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Prolonged glucocorticoid overexposure leads to Cushing's syndrome (CS). It is characterised by diverse metabolic, cardiovascular and bone mineral manifestations. A middle-aged woman presented for a preoperative evaluation of a pathological fracture of the left neck of the femur. She had a history of a hip fracture on the opposite side 3 years back. She exhibited several features specific to CS and was subsequently diagnosed with Cushing's disease. She underwent transsphenoidal adenoma resection and achieved remission. Glucocorticoids primarily affect the trabecular bone compared with cortical bones, and vertebral fractures are common in CS. The femoral neck consists of both trabecular and cortical bone and can be involved in CS. Our patient was not diagnosed as CS at the first pathological fracture and was subsequently diagnosed only after the second fracture. This case report underscores the importance of a diligent search for a possible endocrinological aetiology in any case of pathological fractures., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Adrenal incidentalomas (AIs) are relatively uncommon neoplasms in 2% of apparently healthy individuals requiring evaluation for functionality and malignancy., Aim: We aimed to study the clinical, biochemical, and radiological profiles of patients presenting with AI and histopathological outcomes of those undergoing adrenalectomy. Materials and Methods: This retrospective study enrolled 62 AI patients attending a tertiary care center in South India between January 2016 and October 2023. Demographic details, radiological features, functionality, and histopathological data were analyzed., Results: Out of 62 patients, total masses evaluated were 65 indicating bilaterality in 3 patients. The female: male ratio was 1.69, with a median age of 55 years (interquartile range: 44-64 years). 45.1% of individuals were >60 years. The most common indication for imaging was pain abdomen in 43 (69.4%). The median size was 3.2 cm. Fifty-five (88.7%) were assessed for functionality and 27 (49.1%) were functional. Among the 62 individuals, 14 (20.2%) had hypercortisolism, 11 (15.9%) had pheochromocytoma, 5 (7.24%) had primary hyperaldosteronism (PA), and 4 (5.7%) had hyperandrogenism including plurihormonal in 7. A mass size of 3.2 cm was of great value in distinguishing functional tumors with a sensitivity of 72% and specificity of 66% with an area under the curve of 0.682. A total of 34 (54.8%) patients underwent adrenalectomy. On histopathological examination, Adenoma (44.1%) was the most common followed pheochromocytoma (26.5%), adrenal cysts (8.8%), and Myelolipoma (5.9%). Two (5.9%) incidentalomas were adrenocortical carcinoma (ACC). Eight (53.3%) adenomas were functional with 6 having hypercortisolism (including 1 with hyperandrogenism) and 2 with PA., Conclusion: In our experience, the incidence of pheochromocytoma was second most common after adenoma. Since most functional tumors (60%) and all ACCs were ≥4 cm, a thorough biochemical evaluation for hormonal excess and evaluation for malignancy followed by surgery should be considered for lesions, especially ≥4 cm. Thus, we report the baseline demographic and clinical characteristics of patients with AI from a single center in South India., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Background: Secondary adrenal insufficiency (SAI) may occur in patients after unilateral adrenalectomy for adrenal-dependent hypercortisolism (HC) or primary aldosteronism (PA). This study aimed to assess whether postoperative day (POD) 1 basal cortisol was predictive of an abnormal cosyntropin stimulation test (CST) result and the need for glucocorticoid replacement (GR)., Methods: A retrospective review of consecutive patients who underwent unilateral adrenalectomy for HC, PA, or both between September 2014 and September 2022 was performed. On POD1, CST was performed for all the patients with HC, and before 2021 for all the patients with PA. The patients with an abnormal CST result were deemed at risk of SAI and discharged with GR. Receiver operating characteristic (ROC) curves were generated to evaluate the sensitivity (SN) and specificity (SP) of basal cortisol thresholds to predict an abnormal CST result., Results: The patients underwent unilateral adrenalectomy for overt hypercortisolism (OH; n = 42), mild autonomous cortisol excess (MACE; n = 70), mixed PA/HC (n = 22), or PA (n = 73). On POD1, CST was performed for 152 patients (93% OH, 96% MACE,73% PA/HC, 41% PA), and 80 patients (53%) had SAI (67% OH, 55% MACE, 44% PA/HC, 33% PA). The SN and SP of a basal cortisol level of 10 µg/dL or lower to predict an abnormal CST were respectively 92% and 77% for OH, 94% and 73% for MACE, 100% and 85% for PA, and 100% and 67% for PA/HC. The optimal basal cortisol level for predicting an abnormal CST for patients with PA or PA/HC was 5 µg/dL or lower (SN/SP, 100%)., Conclusions: After unilateral adrenalectomy for HC, PA, or mixed PA/HC, POD1 CST improved identification of patients at risk for SAI compared with basal cortisol levels alone. The authors recommend that POD1 CST be performed to determine the risk for SAI and the need for postoperative GR after unilateral adrenalectomy for patients with HC., (© 2024. Society of Surgical Oncology.)

Background: Several cases of autoimmune disease onset after treatment for Cushing's syndrome have been reported., Case Presentation: Herein, we report a case of myasthenia gravis crisis in a 51-year-old woman 2 months after adrenalectomy for adrenal Cushing's syndrome accompanied by takotsubo cardiomyopathy. The resolution of excessive endogenous cortisol after adrenalectomy may have triggered the onset of previously latent myasthenia gravis., Conclusions: Observing the similarities in symptoms between myasthenia gravis and adrenal crisis, which can sometimes be challenging to differentiate, is essential. Moreover, the presence of takotsubo cardiomyopathy as a non-motor manifestation of myasthenic crisis must be noted., (© 2024. The Author(s).)

Objective: Metabolic syndrome (MetS) affects about one-fourth of the global adult population and is characterized by hyperglycemia, abdominal obesity, low HDL (high-density lipoprotein cholesterol) cholesterol, and high triglycerides and blood pressure. Its emergence in developed nations is linked to energy intake imbalances and sedentary lifestyles. There is a parallel between MetS and conditions marked by glucocorticoid excess, such as Cushing's syndrome (CS), sharing features like central obesity, hypertension, dyslipidemia, and insulin resistance. This study aimed to investigate the association between retroperitoneal fat area (RFA) and MetS components in patients undergoing laparoscopic lateral transabdominal adrenalectomy. While intra-abdominal visceral fat's role in MetS has been studied, the significance of RFA needs further exploration., Patients and Methods: The research involved 88 patients categorized into three groups: adrenal-dependent CS, subclinical CS (SCS), and nonfunctional adrenal incidentaloma (NFA). Parameters, including body mass index (BMI), RFA, waist circumference, blood pressure, lipid profile, and fasting glucose levels, were measured. The study used hormonal hypersecretion assessments, criteria for SCS diagnosis, and biochemical analyses. MetS components were determined based on established criteria, and RFA quantification used advanced imaging software on computed tomography (CT) scans. Previous studies on intra-abdominal fat and MetS were reviewed to contextualize the findings., Results: Patients with MetS had significantly higher BMI, waist circumference, and RFA compared to those without MetS. Positive correlations were observed between BMI, RFA, central obesity, and MetS. ROC curve analysis showed a significant relationship between RFA and MetS, with a cutoff value of 36.6 cm² predicting MetS accurately in 95% of cases. The results were compared with existing literature on visceral fat's impact on MetS., Conclusions: The study findings underscore the associations between anthropometric parameters, specifically RFA and MetS. RFA is a valuable tool for assessing metabolic risk, with implications for refining criteria for adrenalectomy in individuals with adrenal incidentalomas.

Adrenal gland-induced hypertension results from underlying adrenal gland disorders including Conn's syndrome, Cushing's syndrome, and Pheochromocytoma. These adrenal disorders are a risk for cardiovascular and renal morbidity and mortality. Clinically, treatment for adrenal gland-induced hypertension involves a pharmaceutical or surgical approach. The former presents very significant side effects whereas the latter can be ineffective in cases where the adrenal disorder reoccurs in the remaining contralateral adrenal gland. Due to the limitations of existing treatment methods, minimally invasive treatment options like microwave ablation (MWA) have received significant attention for treating adrenal gland disorders. A precise comprehension of the dielectric properties of human adrenal glands will help to tailor energy delivery for MWA therapy, thus offering the potential to optimise treatments and minimise damage to surrounding tissues. This study reports the ex vivo dielectric properties of human adrenal glands, including the cortex, medulla, capsule, and tumours, based on the data obtained from four patients (diagnosed with Conn's syndrome, Cushing's syndrome, and Pheochromocytoma) who underwent unilateral adrenalectomy at the University Hospital Galway, Ireland. An open-ended coaxial probe measurement technique was used to measure the dielectric properties for a frequency range of 0.5-8.5 GHz. The dielectric properties were fitted using a two-pole Debye model, and a weighted least squares method was employed to optimise the model parameters. Moreover, the dielectric properties of adrenal tissues and tumours were compared across frequencies commonly used in MWA, including 915 MHz, 2.45 GHz, and 5.8 GHz. The study found that the dielectric properties of adrenal tumours were influenced by the presence of lipid-rich adenomas, and the dielectric properties of Cushing's syndrome tumour were lowest in comparison to the tumours in patients diagnosed with Conn's syndrome and Pheochromocytoma. Furthermore, a notable difference was observed in the dielectric properties of the medulla and cortex among patients diagnosed with Conn's syndrome, Cushing's syndrome, and Pheochromocytoma. These findings have significant implications for the diagnosis and treatment of adrenal tumours, including the optimisation of MWA therapy for precise ablation of adrenal masses., (© 2024. The Author(s).)

Purpose: Surgical therapy represents the first-line treatment for endogenous Cushing's syndrome (CS). While postoperative glucocorticoid replacement is mandatory after surgical remission, the role of perioperative glucocorticoid therapy is unclear., Methods: We recruited patients with central or adrenal CS in whom curative surgery was planned and patients who underwent pituitary surgery for other reasons than CS as a control group. Patients did not receive any perioperative glucocorticoids until the morning of the first postoperative day. We performed blood samplings in the morning of surgery, immediately after surgery, in the evening of the day of surgery, and in the morning of the first and third postoperative day before any morning glucocorticoid intake. We continued clinical and biochemical monitoring during the following outpatient care., Results: We recruited 12 patients with CS (seven with central CS, five with adrenal CS) and six patients without CS. In patients with CS, serum cortisol concentrations <5.0 µg/dL (<138 nmol/L) were detected in the morning of the first and third postoperative day in four (33%) and six (50%) patients, respectively. Morning serum cortisol concentrations on the third postoperative day were significantly lower when compared to preoperative measurements (8.5 ± 7.6 µg/dL vs. 19.9 ± 8.9 µg/dL [235 ± 210 nmol/L vs. 549 ± 246 nmol/L], p = 0.023). No patient developed clinical or biochemical signs associated with hypocortisolism. During follow-up, we first observed serum cortisol concentrations >5.0 µg/dL (>138 nmol/L) after 129 ± 97 days and glucocorticoids were discontinued after 402 ± 243 days. Patients without CS did not require glucocorticoid replacement at any time., Conclusion: Perioperative glucocorticoid replacement may be unnecessary in patients with central or adrenal CS undergoing curative surgery as first-line treatment., (© 2024. The Author(s).)

Context: Few studies have directly compared the cognitive characteristics of patients with mild autonomous cortisol secretion (MACS) and Cushing's syndrome (CS). The effect of surgical or conservative treatment on cognitive function in patients with MACS is still unclear., Objective: To compare the differences in cognitive function between patients with MACS and CS and evaluate the effect of surgery or conservative treatment on cognitive function., Methods: We prospectively recruited 59 patients with nonfunctional adrenal adenoma (NFA), 36 patients with MACS, and 20 patients with adrenal CS who completed the global cognition and cognitive subdomains assessments. Seventeen MACS patients were re-evaluated for cognitive function after a 12-month follow-up period; of these, eleven underwent laparoscopic adrenalectomy and six received conservative treatment., Results: Patients with MACS and CS performed worse in the global cognition and multiple cognitive domains than those with NFA (all P<0.05). No statistical difference was found in cognitive functions between patients with MACS and CS. Logistic regression analysis showed that patients with MACS (odds ratio [OR]=3.738, 95% confidence intervals [CI]: 1.329-10.515, P=0.012) and CS (OR=6.026, 95% CI: 1.411-25.730, P=0.015) were associated with an increased risk of immediate memory impairment. Visuospatial/constructional, immediate and delayed memory scores of MACS patients were significantly improved at 12 months compared with pre-operation in the surgical treatment group (all P<0.05), whereas there was no improvement in the conservative treatment group., Conclusion: Patients with MACS have comparable cognitive impairment as patients with CS. Cognitive function was partially improved in patients with MACS after adrenalectomy. The current data support the inclusion of cognitive function assessment in the clinical management of patients with MACS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Zhao, Zhang, Tian, Zhang, Lou, Zhang, Yang, Zhu and Li.)

Introduction: The management of Mild Autonomous Cortisol Secretion (MACS) remains a topic of debate among clinicians, with differing opinions on the effectiveness of surgical intervention compared to conservative treatment methods. This meta-analysis provides a comprehensive assessment of available literature to determine the most effective approach for treating this condition., Methods: On December 1, 2023, an exhaustive literature search of English databases Embase, PubMed, the Cochrane Library, Scopus, Web of Science, as well as the Chinese databases China HowNet, Wanfang Database, SinoMed Database, and Weipu Database using the keywords "Mild Autonomous Cortisol Secretion", "Subclinical Cushing's Syndrome", "Subclinical Hypercortisolism", "Mild Cortisol Autonomous Secretion", "Adrenal Incidentaloma", "Surgical Treatment" and "Adrenalectomy". The data were statistically analyzed using STATA version 15.0., Results: In this comprehensive analysis involving 629 patients with MACS, the therapeutic efficacy of adrenalectomy was evident. The meta-analysis results indicate that compared to conservative treatment, surgical intervention more effectively improves obesity indicators in patients: waist circumference (SMD=-0.62, 95% CI: -1.06 to -0.18), BMI (SMD=-0.41, 95% CI: -0.62 to -0.20), enhances glycemic control: fasting blood glucose (SMD=-0.47, 95% CI: -0.68 to -0.26), glycated hemoglobin (SMD=-0.66, 95% CI: -0.95 to -0.38), improves lipid metabolism: triglycerides (SMD=-0.45, 95% CI: -0.73 to -0.16), lowers blood pressure: systolic blood pressure (SMD=-1.04, 95% CI: -1.25 to -0.83), diastolic blood pressure (SMD=-0.89, 95% CI: -1.12 to -0.65), and ameliorates hormonal metabolic disorder: 24h urinary free cortisol (SMD=-1.10, 95% CI: -1.33 to -0.87), ACTH (SMD=2.30, 95% CI: 1.63 to 2.97). All these differences are statistically significant., Conclusion: This meta-analysis shows that, compared to conservative treatment, surgical treatment is more effective in improving obesity indicators, glycemic control, lipid metabolism, reducing blood pressure, and ameliorating hormonal metabolic disorders in patients with MACS. These statistically significant results highlight the importance of considering surgical intervention in the management of patients with MACS., Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023492527., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ren, Nan and Zhang.)

Purpose: This study aimed to determine the effect of adrenal mass functionality and different hormone subtypes synthesized by the adrenal masses on laparoscopic adrenalectomy (LA) outcomes., Materials and Methods: The study included 298 patients, 154 of whom were diagnosed with nonfunctional masses. In the functional group, 33, 62, and 59 patients had Conn syndrome, Cushing's syndrome, and pheochromocytoma, respectively. The variables were analyzed between the functional and nonfunctional groups and then compared among functional masses through subgroup analysis., Results: The incidence of diabetes mellitus, hypertension, and obesity, blood loss, and length of hospital stay (LOH) were significantly higher in the functional group than in the nonfunctional group. In the subgroup analysis, patients with pheochromocytoma had significantly lower body mass index but significantly higher mass size, blood loss, and LOH than the other two groups. A positive correlation was found between mass size and blood loss in patients with pheochromocytoma (p ≤ 0.001, r = 0.761). However, no significant difference in complications was found among the groups., Conclusions: In this study, patients with functional adrenal masses had higher comorbidity rates and American Society of Anesthesiologists scores. Moreover, blood loss and LOH were longer on patients with functional adrenal masses who underwent LA. Mass size, blood loss, and LOH in patients with pheochromocytoma were significantly longer than those in patients with other functional adrenal masses. Thus, mass functionality did not increase the complications., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The aim of this study is to assess whether clinical and imaging characteristics are associated with the hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACAs)., Design: This is a single-center cohort study., Methods: Consecutive adult patients with incidental ACA were diagnosed between 2000 and 2016., Results: Of the 1516 patients with incidental ACA (median age 59 years, 62% women), 699 (46%) had nonfunctioning adenomas (NFAs), 482 (31%) had mild autonomous cortisol secretion (MACS), 62 (4%) had primary aldosteronism (PA), 39 (3%) had Cushing syndrome, 18 (1%) had PA and MACS, and 226 (15%) had incomplete work-up. Age, sex, tumor size, and tumor laterality, but not unenhanced computed tomography Hounsfield units (HU), were associated with hormonal subtypes. In a multivariable analysis, ≥1 cm growth was associated with younger age (odds ratio [OR] = 0.8 per 5-year increase, P = .0047) and longer imaging follow-up (OR = 1.2 per year, P < .0001). Adrenalectomy was performed in 355 (23%) patients, including 38% of MACS and 15% of NFA. Adrenalectomy for NFA and MACS was more common in younger patients (OR = 0.79 per 5-year increase, P = .002), larger initial tumor size (OR = 2.3 per 1 cm increase, P < .0001), ≥1 cm growth (OR = 15.3, P < .0001), and higher postdexamethasone cortisol (OR = 6.6 for >5 vs <1.8 μg/dL, P = .002)., Conclusions: Age, sex, tumor size, and laterality were associated with ACA hormonal subtype and can guide diagnosis and management. Tumor growth was more common with younger age and longer follow-up. Unenhanced HU did not predict hormonal subtype or growth. Adrenalectomy for MACS and NFA was mainly performed in younger patients with larger tumor size, growth, and elevated postdexamethasone cortisol., Competing Interests: Conflict of interest: I.B. reports consulting or advisory board participation with Corcept Therapeutics, HRA Pharma, Sparrow Pharmaceuticals, Recordati Rare Diseases, Neurocrine Biosciences, Diurnal, Sparrow, Novo Nordisk, AstraZeneca, Xeris, and Adrenas outside the submitted work and reports funding from Recordati and HRA Pharma outside this work. I.B. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as coauthor. O.H. reports advisory board participation with Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Xeris, Lantheus, and Neurocrine Biosciences outside the submitted work. D.L. is currently an employee of BridgeBio Pharma, which is unrelated to the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD., Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles., Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations ( PRKAR1A , PDE11A , PRKACA , CTNNB1 , PDE8B , and ARMC5 ) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD ( p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period., Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC., Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Ding, He, Fu, Li, Feng, Dong and Liao.)

Objective: This systematic review and meta-analysis was conducted to compare the benefits of adrenalectomy and conservative treatment for comorbidities associated with mild autonomous cortisol secretion (MACS) in patients diagnosed with MACS., Background: MACS is the most common benign hormone-secreting functional adrenal incidentaloma. Overproduction of cortisol is observed in MACS patients, resulting in a variety of long-term health issues, including arterial hypertension (HTN), diabetes mellitus (DM), dyslipidemia, obesity, and osteoporosis; however, the classic clinical manifestations of Cushing's syndrome (CS) are not present., Methods: A systematic search was conducted using MEDLINE, Embase, Web of Sciences, and Scopus databases on December, 2023. Two reviewers independently extracted data and assessed the quality of the included articles. A meta-analysis was performed to compare the beneficial effects of adrenalectomy versus conservative management for MACS-related comorbidities., Results: Fifteen articles were included in this study, which evaluated 933 MACS patients (384 Adrenalectomy and 501 Conservative treatment, and 48 excluded due to incomplete follow-up duration). MACS diagnosis criteria were different among the included articles. All studies, however, stated that there must be no overt CS symptoms. Meta-analysis demonstrates the overall advantage of adrenalectomy over conservative treatment for MACS-related comorbidities (Cohen's d = -0.49, 95% CI [-0.64, -0.34], p = 0.00). Subgroup analysis indicated that the systolic blood pressure (pooled effect size = -0.81, 95% CI [-1.19, -0.42], p = 0.03), diastolic blood pressure (pooled effect size = -0.63, 95% CI [-1.05, -0.21], p = 0.01), and BMD (pooled effect size = -0.40, 95% CI [-0.73, -0.07], p = 0.02) were significantly in favor of adrenalectomy group rather than conservative treatment but no significant differences between the two treatment groups in other MACS-related comorbidities were reported., Conclusion: Despite the limited and diverse data, this study demonstrates the advantage of adrenalectomy over conservative treatment for MACS-related comorbidities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Khadembashiri, Mohseni, Harandi, Pejman Sani, Khadembashiri, Atlasi, SeyedAlinaghi, Mohajeri- Tehrani and Larijani.)

Objective: Onset and exacerbation of autoimmune, inflammatory or steroid-responsive conditions have been reported following the remission of Cushing syndrome, leading to challenges in distinguishing a new condition versus expected symptomatology following remission. We describe a case of a 42-year-old man presenting with new-onset sarcoidosis diagnosed 12 months following the surgical cure of Cushing syndrome and synthesise existing literature reporting on de novo conditions presenting after Cushing syndrome remission., Methods: A scoping review was conducted in Medline, Epub, Ovid and PubMed. Case reports and case series detailing adult patients presenting with new-onset conditions following Cushing syndrome remission were included., Results: In total, 1641 articles were screened, 138 full-text studies were assessed for eligibility, and 43 studies were included, of which 84 cases (including our case) were identified. Most patients were female (85.7%), and the median reported age was 39.5 years old (IQR = 13). Thyroid diseases were the most commonly reported conditions (48.8%), followed by sarcoidosis (15.5%). Psoriasis, lymphocytic hypophysitis, idiopathic intracranial hypertension, multiple sclerosis, rheumatoid arthritis, lupus and seronegative arthritis were reported in more than one case. The median duration between Cushing remission and de novo condition diagnosis was 4.1 months (IQR = 3.75). Of those patients, 59.5% were receiving corticosteroid therapy at the time of onset., Conclusion: Our scoping review identified several cases of de novo conditions emerging following the remission of Cushing syndrome. They occurred mostly in women and within the year following remission. Clinicians should remain aware that new symptoms, particularly in the first year following the treatment of Cushing syndrome, may be manifestations of a wide range of conditions aside from adrenal insufficiency or glucocorticoid withdrawal syndrome., (© 2024 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: Laparoscopic adrenalectomy is widely performed for a number of hormone-producing tumors and postoperative management depends on the hormones produced. In the present study, we conducted a retrospective analysis to clarify the risk factors for postoperative complications, particularly postoperative fever after laparoscopic adrenalectomy., Methods: We analyzed 406 patients who underwent laparoscopic adrenalectomy at our hospital between 2003 and 2019. Postoperative fever was defined as a fever of 38 °C or higher within 72 h after surgery. We investigated the risk factors for postoperative fever after laparoscopic adrenalectomy., Results: There were 188 males (46%) and 218 females (54%) with a median age of 52 years. Among these patients, tumor pathologies included 188 primary aldosteronism (46%), 75 Cushing syndrome (18%), and 80 pheochromocytoma (20%). Postoperative fever developed in 124 of all patients (31%), 30% of those with primary aldosteronism, 53% of those with pheochromocytoma, and 8% of those with Cushing syndrome. A multivariate logistic regression analysis identified pheochromocytoma and non-Cushing syndrome as independent predictors of postoperative fever. Postoperative fever was observed in 42 out of 80 cases of pheochromocytoma (53%), which was significantly higher than in cases of non-pheochromocytoma (82/326, 25%, p < 0.01). In contrast, postoperative fever developed in 6 out of 75 cases of Cushing syndrome (8%), which was significantly lower than in cases of non-Cushing syndrome (118/331, 35.6%, p < 0.01)., Conclusion: Since postoperative fever after laparoscopic adrenalectomy is markedly affected by the hormone produced by pheochromocytoma and Cushing syndrome, it is important to carefully consider the need for treatment., (© 2024. The Author(s).)

Glucocorticoid withdrawal syndrome is a challenging clinical phenomenon that can complicate the postsurgical recovery of Cushing syndrome. It is characterized by physical tolerance and dependence to supraphysiologic glucocorticoid exposure during active Cushing syndrome followed by the abrupt decline in cortisol levels after surgical treatment. The symptoms of glucocorticoid withdrawal often overlap with those of postoperative adrenal insufficiency and can be difficult for patients to cope with and for clinicians to treat. This mini review will discuss the clinical characteristics, pathophysiology, and management of glucocorticoid withdrawal syndrome while highlighting recent data in the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang and Ioachimescu.)

Purpose: Cushing syndrome (CS) is a well-known risk factor for cardiovascular morbidities. We aimed to evaluate endothelial and cardiovascular functions, endothelial mediators and pro-inflammatory cytokines in patients with CS before and after remission., Methods: Adult patients with newly diagnosed endogenous CS were included. Metabolic [body mass index (BMI), glucose, and lipid values] and cardiovascular evaluation studies [24-h ambulatory blood pressure monitoring, carotid intima-media thickness (CIMT), flow-mediated dilation (FMD), and echocardiography] were performed, and endothelial mediators [asymmetric dimethyl arginine (ADMA) and endothelin-1 (ET-1)] and pro-inflammatory cytokines [interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α)] were measured. Control group was matched in terms of age, gender, and BMIs., Results: Twenty-five patients, mean age 40.60 ± 14.04 years, completed the study. Compared to controls (n = 20) mean arterial pressure (MAP) and CIMT were higher (p < 0.005 and p = 0.012, respectively), and FMD (p < 0.001) and mitral E/A ratio (p = 0.007) lower in the patients during active disease. Baseline serum ADMA, ET-1, and IL-1β were similar between the groups, while TNF-α was lower in the patients (p = 0.030). All patients were in complete remission 1 year following surgery. BMI, LDL cholesterol, serum total cholesterol, fasting plasma glucose, MAPs, and CIMT significantly decreased (p < 0.005), while there was no improvement in FMD (p = 0.11) following remission. There was no significant change in ADMA, IL-1β, and TNF-α levels, but ET-1 increased (p = 0.011)., Conclusions: Remission in CS improves some cardiovascular parameters. ADMA and ET-1 are not reliable markers for endothelial dysfunction in CS. Metabolic improvements may not directly reflect on serum concentrations of TNF-α and IL-1β following remission of CS., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Purpose: Primary bilateral adrenal hyperplasia (PBMAH) is associated with hypercortisolism and a heterogeneous clinical expression in terms of cortisol secretion and related comorbidities. Historically, treatment of choice was bilateral adrenalectomy (B-Adx); however, recent data suggest that unilateral adrenalectomy (U-Adx) may be an effective alternative. For the latter, factors predicting the postsurgical outcome (e.g., biochemical control) have not been identified yet., Methods: PBMAH patients undergoing U-Adx for overt Cushing's syndrome (CS) in two tertiary care centers were retrospectively analysed. Remission was defined as a normalization of urinary free cortisol (UFC) without the need for medical treatment. The potential of hCRH test as a predictor of U-Adx outcome was evaluated in a subgroup., Results: 23 patients were evaluated (69% females, mean age 55 years). Remission rate after U-Adx was 74% at last follow up (median 115 months from UAdx). Before U-Adx, a positive ACTH response to hCRH (Δ%ACTH increase > 50% from baseline) was associated with higher remission rates., Conclusions: Three of four patients with PBMAH are surgically cured with U-Adx. Pre-operative hCRH testing can be useful to predict long-term remission rates., (© 2023. The Author(s).)

The clinical characteristics of Cushing's syndrome (CS) vary with etiology, and few studies have investigated the risk factors affecting CS recurrence after surgery. This retrospective study involved 202 patients diagnosed with CS between December 2012 and December 2022. The patients were divided into three groups according to etiology: Cushing's disease (CD), adrenocortical adenoma (ACA), and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Of the patients with CS, 41.9% had hypokalemia and 15.0% had hypophosphatemia. The cortisol levels were negatively correlated with blood potassium, blood chlorine, and blood phosphorus. Moreover, 22.4% of patients had an abnormal heart structure, 11.2% had centripetal remodeling, 5.6% had centripetal hypertrophy, and 5.6% had centrifugal hypertrophy. The overall recurrence rate of CS caused by pituitary tumors and adrenal adenoma was 25.7%. The recurrence times were longer in the ACA group versus the CD group, in patients < 50 years of age versus in patients ≥ 50 years old group, and in patients with CD with tumors ≥ 1 cm versus tumors < 1 cm. Age, preoperative cortisol level, postoperative cortisol level, and absolute neutrophil value were closely related to postoperative recurrence, and etiology was an independent predictor of tumor recurrence in patients with CS. The results of this study showed that CS caused by different etiologies showed different clinical manifestations, blood electrolyte characteristics, and that CS could affect patient cardiac structure and function. Etiology is an independent predictor of tumor recurrence in patients with CS., (© 2024. The Author(s).)

Objective: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE., Design: A retrospective observational cohort study., Methods: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database., Results: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely., Conclusion: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: We analyze the long-term outcome of surgery for Cushing's syndrome (CS) and the influence of the extent of surgical resection on the duration of postoperative cortisone substitution., Methods: One-hundred forty-one patients (129 female, 12 males; mean age: 45.7 ± 12.8 years) operated between January 2000 to June 2020 were included in the analysis. Patients suffered from manifest (124) or subclinical (17) CS due to benign unilateral adrenal neoplasia. All tumors were removed by the posterior retroperitoneoscopic approach. 105 patients had total (TA) and 36 partial (PA) adrenalectomies. All patients were discharged with ongoing corticosteroid supplementation therapy., Results: Follow-up data could be obtained for 83 patients. Twenty-four (1 male, 23 females; mean age 42.3 years) underwent PA and 59 TA (6 males, 53 females; mean age 44.6 years). Mean follow-up time was 107 ± 68 months (range: 6-243 months). The median duration of postoperative corticosteroid therapy was 9.5 months after PA and 11 months after TA (p = 0.1). Significantly, more patients after total adrenalectomy required corticosteroid therapy for more than 24 months (25% vs. 4%; p = 0.03). Recurrent ipsilateral disease occurred in one case after partial adrenalectomy and was treated by completion adrenalectomy. A case of contralateral recurrence associated with subclinical Cushing's syndrome was observed after total adrenalectomy., Conclusions: The risk of local recurrence after partial adrenalectomy in CS is low. Cortical-sparing surgery may shorten corticosteroid supplementation therapy after surgery., (© 2023 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Severe uncontrolled Cushing's syndrome (CS) is an acute life-threatening condition. As it is often not responsive to medical therapy, emergency bilateral adrenalectomy (BA) may present the only therapeutic option. Moreover, multiple bone fractures, representing one of the clinical consequences of hypercortisolism, may not permit both prone and lateral patient's positioning during surgery, thus making minimally invasive approaches nonfeasible. We report our preliminary experience with an alternative approach in this selected patients' category. Among 613 patients who underwent endoscopic adrenalectomy at our centre (34-5.6% BA) between January 1997 and October 2021, 3 patients were scheduled for laparoscopic transabdominal anterior bilateral adrenalectomy (La-TABA). Surgery was performed with patient in supine position, with fastened arms and legs to allow Trendelenburg and anti-Trendelenburg movements and lateral rotations. The procedure consisted in a synchronous bilateral adrenalectomy. A modern multi-articulated operative table provided rotations on the right and left side to perform left and right adrenalectomy, respectively. One male and two female patients with a mean age of 34 ± 3.1 years underwent La-TABA. Mean operative time was 200 ± 138.3 min. No perioperative complications were registered. Mean postoperative hospital stay was 8 ± 4.4 days. In very severe ACTH-dependent CS, BA should be performed as soon as possible. La-TABA may represent the most appropriate therapeutic option, as this patients' category is not able to tolerate prone and lateral positioning required during the conventional surgery. Despite the higher technical complexity of the procedure compared with the other endoscopic approaches to adrenalectomy, it retains the benefits of minimally invasive surgery in terms of postoperative complications and recovery., (© 2023. Italian Society of Surgery (SIC).)

Background: Cushing's syndrome (CS) is a disorder characterized by exposure to supraphysiologic levels of glucocorticoids. The purpose of this study was to evaluate the association between CS and postoperative complication rates following total joint arthroplasty (TJA)., Methods: Patients diagnosed with CS undergoing TJA for degenerative etiologies were identified from a large national database and matched 1:5 to a control cohort using propensity scoring. Propensity score matching resulted in 1,059 total hip arthroplasty (THA) patients with CS matched to 5,295 control THA patients and 1,561 total knee arthroplasty (TKA) patients with CS matched to 7,805 control TKA patients. Rates of medical complications occurring within 90 days of TJA and surgical-related complications occurring within 1 year of TJA were compared using odds ratios (ORs)., Results: The THA patients with CS had higher incidences of pulmonary embolism (OR 2.21, P = .0026), urinary tract infection (UTI) (OR 1.29, P = .0417), pneumonia (OR 1.58, P = .0071), sepsis (OR 1.89, P = .0134), periprosthetic joint infection (OR 1.45, P = .0109), and all-cause revision surgery (OR 1.54, P = .0036). The TKA patients with CS had significantly higher incidences of UTI (OR 1.34, P = .0044), pneumonia (OR 1.62, P = .0042), and dislocation (OR 2.43, P = .0049) and a lower incidence of manipulation under anesthesia (MUA) (OR 0.63, P = .0027)., Conclusion: CS is associated with early medical- and surgical-related complications following TJA and a reduced incidence of MUA following TKA., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets., Methodology: Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1)., Results: Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes - FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively., Outcome: This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Vetrivel, Tamburello, Oßwald, Zhang, Khan, Jung, Baker, Rainey, Nowak, Altieri, Detomas, Watts, Williams, Wielockx, Beuschlein, Reincke, Sbiera and Riester.)

Objective: To explore the value of catheter-based adrenal ablation in treating Cushing's syndrome (CS)-associated hypertension. Methods: A clinical study was conducted in patients with CS, who received catheter-based adrenal ablation between March 2018 and July 2023 in Daping Hospital. Parameters monitored were blood pressure (outpatient and 24-hour ambulatory), body weight, clinical characteristics, serum cortisol and adrenocorticotropic hormone (ACTH) at 8 am, 24-hour urinary free cortisol (24 h UFC), fasting blood glucose and postoperative complications. Procedure effectiveness was defined as blood pressure returning to normal levels (systolic blood pressure<140 mmHg (1 mmHg=0.133 kPa) and diastolic blood pressure<90 mmHg), cortisol and 24 h UFC returning to normal and improvement of clinical characteristics. The parameters were monitored during follow up in the outpatient department at 1, 3, 6, and 12 months after catheter-based adrenal ablation. Results: A total of 12 patients (aged (40.0±13.2) years) were reviewed. There were 5 males, with 5 cases of adenoma and 7 with hyperplasia from imaging studies. Catheter-based adrenal ablation was successful in all without interruption or surgical conversion. No postoperative complication including bleeding, puncture site infection, adrenal artery rupture or adrenal bleeding was observed. The mean follow up was 28 months. Compared to baseline values, body weight declined to (59.48±11.65) kg from (64.81±10.75) kg ( P= 0.008), fasting blood glucose declined to (4.54±0.83) mmol from (5.53±0.99) mmol ( P= 0.044), outpatient systolic blood pressure declined to (128±21) mmHg from (140±19) mmHg ( P= 0.005), diastolic blood pressure declined to (78±10) mmHg from (86±11) mmHg ( P= 0.041), and the mean ambulatory daytime diastolic blood pressure declined to (79±12) mmHg from (89±8) mmHg ( P= 0.034). Catheter-based adrenal ablation in 8 patients was defined as effective with their 24 h UFC significantly reduced after the procedure (1 338.41±448.06) mmol/L from (633.66±315.94) mmol/L, P= 0.011). The change of 24 h UFC between the effective treatment group and ineffective group was statistically significant ( P =0.020). The postoperative systolic blood pressure in the treated adenoma group was significantly lower than those of hyperplasia group (112±13) mmHg vs. (139±20) mmHg, P =0.026). Conclusions: For patients with CS-associated hypertension who are unwilling or unable to undergo surgical treatment, catheter-based adrenal ablation could improve the blood pressure and cortisol level. Catheter-based adrenal ablation could be a safe, effective, and minimally invasive therapy. However, our results still need to be validated in further large-scale studies.

Purpose: ACTH-secreting pheochromocytoma is a rare cause of ectopic Cushing's syndrome, posing a clinical challenge for the severity of its clinical presentation, the difficulty in the prevention and the management of surgical complications. Sparse data are currently available about the optimal preoperative management of the severe symptoms due to both hypercortisolism and catecholamine excess, especially regarding the role and timing of medical therapies., Methods: We present a series of three patients with ACTH-secreting pheochromocytoma. A brief review of the available literature evidence on the preoperative management of this rare clinical condition is also conducted., Discussion: Patients with ACTH-secreting pheochromocytoma show peculiarities as compared to other forms of ACTH-dependent Cushing's syndrome, in terms of clinical presentation, preoperative management, and peri- and post-surgical short-term outcome. Pheochromocytoma should be ruled out in patient with ectopic CS of unknown origin because of the high anesthesiologic risk of proceeding to surgery with an undiagnosed pheochromocytoma. Proper preoperative recognition of complications of both hypercortisolism and catecholamines excess is the key to prevent the morbidity and mortality of an ACTH-producing pheochromocytoma. In these patients the absolute priority is to control excessive cortisol secretion since the rapid correction of the hypercortisolism is the most effective treatment of all the related comorbidities and it is mandatory to prevent severe complications during surgery, opting if necessary for a "block-and-replace" regimen., Conclusion: Our additional cases and this literature review could provide a better understanding of the complications to be evaluated at diagnosis and some suggestions on their management during the preoperative period., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: Functional adrenal tumors (FATs) are rare and if left untreated, there is a substantial risk of morbidity and mortality due to uncontrolled excess hormone secretion. The three most common FATs are cortisone-producing tumors (hypercortisolism), aldosterone-producing tumors (hyperaldosteronism), and catecholamines-producing tumors (pheochromocytomas). The study aims to evaluate demographic characteristics and 30-day outcomes after laparoscopic adrenalectomy of FATs., Methods: Patients who underwent laparoscopic adrenalectomy for FATs were selected from the ACS-NSQIP database (2015-2017), and divided into three groups (hyperaldosteronism, hypercortisolism, and pheochromocytoma). Preoperative demographics, medical comorbidities, and 30-day postoperative outcomes among the three groups were analyzed using the chi-squared test, analysis of variance (ANOVA) and Kruskal-Wallis one-way analysis of variance. Multivariable logistic regression was performed to assess the effects independent variables on the likelihood of increased overall morbidity., Results: Of a total of 2410 patients who underwent laparoscopic adrenalectomy, 345 (14.3%) patients with FATs were included. Patients in the hypercortisolism group were younger, had higher proportion of females, had higher BMI, had a higher proportion of White ethnicity and had a higher proportion of diabetes. The hyperaldosteronism group had a higher proportion of Black ethnicity and a higher proportion of hypertension (HTN) requiring medication. Thirty day postoperative outcomes showed that the pheochromocytoma group had a higher rate of serious morbidity, overall morbidity, and highest readmission rates. There were three deaths, 1 in the pheochromocytoma and 2 in the hypercortisolism groups. Operative time (in minutes) was longer in the hypercortisolism group. Median length of stay was higher in hypercortisolism (2 days) and pheochromocytoma (1.5 day) groups., Conclusion: Functional adrenal tumors show distinct variations in patient demographics and postoperative outcomes. It is essential to use this information during the preoperative period to optimize patients prior to intervention and counsel patients about potential postoperative outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The major adrenal tumors with endocrine activity are primary aldosteronism, Cushing's syndrome/mild autonomous cortisol secretion, and pheochromocytoma/paraganglioma. Excessive aldosterone secretion in primary aldosteronism causes cardiovascular, renal, and other organ damage in addition to hypertension and hypokalemia. Cortisol hypersecretion in Cushing's syndrome/mild autonomous cortisol secretion causes obesity, hypertension, impaired glucose tolerance, and cardiometabolic syndrome. Massive secretion of catecholamines in pheochromocytoma/paraganglioma causes hypertension and cerebrocardiovascular disease due to rapid blood pressure fluctuation. Moreover, pheochromocytoma multi-system crisis is a feared and possibly fatal presentation of pheochromocytoma/paraganglioma. Thus, adrenal tumors with endocrine activity are considered an indication for adrenalectomy, and perioperative management is very important. They have a risk of perioperative complications, either due to direct hemodynamic effects of the hormone hypersecretion or due to hormone-related comorbidities. In the last decades, deliberate preoperative evaluation and advanced perioperative management have significantly reduced complications and improved outcomes. Furthermore, improvements in anesthesia and surgical techniques with the feasibility of laparoscopic adrenalectomy have contributed to reduced morbidity and mortality. However, there are still several challenges to be considered in the perioperative care of these patients. There are very few data available prospectively to guide clinical management, due to the rarity of adrenal tumors with endocrine activity. Therefore, most guidelines are based on retrospective data analyses or small case series. In this review, the latest knowledge is summarized, and practical pathways to reduce perioperative complications and improve outcomes in adrenal tumors with endocrine activity are presented., (© 2023 The Japanese Urological Association.)

Background: Primary bilateral macronodular adrenal hyperplasia (PMAH) combined with infection by an opportunistic pathogen is complicated. Clinical evidence on managing PMAH patients with infections by opportunistic pathogens is insufficient., Case Presentation: A 66-year-old male was admitted with bilateral adrenal masses and was diagnosed with PMAH. Fever and disturbance of consciousness appeared after laparoscopic left adrenalectomy. Cryptococcal meningitis was confirmed by cerebrospinal fluid (CSF) culture. The exacerbation of his medical condition was suspected to result from immune reconstitution inflammatory syndrome (IRIS), and he had been treated with antifungal therapy and glucocorticoid replacement, but he responded poorly and eventually died of multiorgan failure. We summarized the clinical observations of 12 Cushing's syndrome (CS) patients infected by Cryptococcus. Seven out of nine patients who were treated for cryptococcus infection before receiving CS survived, while three patients treated for cryptococcus infection after CS treatment developed signs of IRIS and eventually died., Conclusion: Cushing's syndrome, complicated with cryptococcal infection, has a high mortality rate, mainly when IRIS emerges. Carefully identifying the presence of the suspected infection, and controlling cryptococcal infection before removing the culprit adrenals could be the rational choice., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Context: Cortisol-lowering drugs may not restore a normal cortisol secretion in Cushing disease (CD)., Objective: This work aimed to assess the long-term cortisol exposure in medically treated CD patients using hair-cortisol (HF) and hair-cortisone (HE) measurement., Methods: This multicenter prospective study included 3 groups of female patients: CushMed = 16 treated with a stable cortisol-lowering drug dosage and normal urinary free cortisol (UFC); CushSurg = 13 cured by pituitary surgery; CushBla = 15 receiving stable recommended doses of hydrocortisone following bilateral adrenalectomy. Patients were evaluated for 3 months with their usual treatments. Two late-night saliva and 24-hour urine samples were collected monthly in CushMed, and at study end in CushSurg and CushBla patients. A 3-cm hair sample was collected at study end from all patients. Main outcome measures included clinical score and centralized measurement of UFC, late-night salivary cortisol (LNSF), late-night salivary cortisone (LNSE), HE, HF., Results: Despite having almost all UFCs normalized, CushMed patients exhibited increased HE as compared to CushSurg controls (P = .003). CushMed patients also had increased clinical score (P = .001), UFC (P = .03), LNSF, LNSE (P = .0001), and variability in the latter parameters (P = .004). CushBla patients had increased HF and HE, contrasting with LNSEs similar to CushSurg patients. Six of 15 CushMed patients exhibited increased HE concentrations and had increased antihypertensive drug dosage compared to CushMed patients with normal HE (P = .05)., Conclusion: Despite normalized UFCs, a subset of medically treated CD patients displays an altered circadian rhythm of serum cortisol. A single HE measurement identifies chronic mild persistent hypercortisolism and could replace multiple saliva analyzes to monitor medical treatments in CD patients once UFC is normalized., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adrenal incidentalomas represent an increasingly common clinical conundrum with significant implications for patients. The revised 2023 European Society of Endocrinology (ESE) guideline incorporates cutting-edge evidence for managing adrenal incidentalomas. This paper provides a concise review of the updated contents of the revised guideline. In the 2023 guideline, in patients without signs and symptoms of overt Cushing's syndrome, a post-dexamethasone cortisol level above 50 nmol/L (>1.8 μg/dL) should be considered as mild autonomous cortisol secretion. Regarding the criteria of benign adrenal adenomas, a homogeneous adrenal mass with ≤10 Hounsfield units on non-contrast computed tomography requires no further follow-up, irrespective of its size. The updated guideline also discusses steroid metabolomics using tandem mass spectrometry to discriminate malignancy. It underscores the importance of high-volume surgeons performing adrenalectomy and emphasizes the pivotal role of a multidisciplinary team approach in deciding the treatment plan for indeterminate adrenal masses. The guideline advocates for more proactive surgical treatment for indeterminate adrenal masses in young patients (<40 years) and pregnant women. This review of the 2023 ESE guideline underscores the ongoing evolution of the adrenal incidentaloma management landscape, emphasizing the need for further research and adaptation of diagnostic and therapeutic strategies.

Objective: To map inflammatory biomarkers in patients with autonomous cortisol secretion (ACS) and overt Cushing syndrome (CS)., Method: Observational study including serum from prospectively included patients with ACS (n = 63), adrenal CS (n = 2), pituitary CS (n = 8), and healthy subjects (n = 120). Serum samples were analysed for 92 inflammatory biomarkers using proximity extension assay (OLINK)., Results: Combined, the ACS and CS patients displayed significant differences in levels of 49/92 inflammatory biomarkers (46 increased/3 decreased) compared with healthy controls. No differences in biomarker levels were found between ACS and overt CS, and none of the biomarkers correlated with the degree of hypercortisolism. Postoperative samples were available for 17 patients, median 24 months (range 6-40) after surgery and biochemical curation. There was no significant normalization of the biomarkers postoperatively., Conclusion: There was a systemic rise in inflammatory biomarkers in patients with ACS and CS, not correlated to the degree of hypercortisolism. These biomarkers were not normalized following biochemical cure., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Objective: Glucocorticoid withdrawal syndrome (GWS) is a scarcely studied phenomenon that complicates the recovery following surgical remission of hypercortisolism. We aimed to characterize the presence and trajectory of glucocorticoid withdrawal symptoms in the postoperative period and to determine presurgical predictors of GWS severity., Design: Longitudinal observational study., Methods: Glucocorticoid withdrawal symptoms were prospectively evaluated weekly for the first 12 weeks following surgical remission of hypercortisolism. Quality of life (CushingQoL and Short-Form-36) and muscle function (hand grip strength and sit-to-stand test) were assessed at the baseline and at 12 weeks after surgery., Results: Prevalent symptoms were myalgias and arthralgias (50%), fatigue (45%), weakness (34%), sleep disturbance (29%), and mood changes (19%). Most symptoms persisted, while myalgias, arthralgias, and weakness worsened during weeks 5-12 postoperatively. At 12 weeks after surgery, normative hand grip strength was weaker than at baseline (mean Z-score delta -0.37, P = .009), while normative sit-to-stand test performance improved (mean Z-score delta 0.50, P = .013). Short-Form-36 Physical Component Summary score worsened (mean delta -2.6, P = .015), but CushingQoL score improved (mean delta 7.8, P < .001) at 12 weeks compared to baseline. Cushing syndrome (CS) clinical severity was predictive of postoperative GWS symptomology., Conclusion: Glucocorticoid withdrawal symptoms are prevalent and persistent following surgical remission of hypercortisolism with baseline CS clinical severity predictive of postoperative GWS symptom burden. Differential changes observed in muscle function and quality of life in the early postoperative period may reflect the competing influences of GWS and recovery from hypercortisolism., Competing Interests: Conflicts of interest: I.B. serves on the editorial board of the European Journal of Endocrinology. She was not involved in the review or editorial process for this paper, for which she is listed as an author. I.B. also reports advisory board participation/consulting (fees to institution) with HRA Pharma, Corcept, Recordati, Sparrow Pharmaceutics, Neurocrine, Spruce, and Diurnal outside the submitted work, and data monitoring and safety board participation for Adrenas. W.F.Y. reports consulting fees and drug safety monitoring board participation for Bayer AG and scientific advisory board participation for Crinetics Pharma. C.D.Z. reports advisory board participation/consulting (fees to institution) with Corcept. D.L. is currently an employee of BridgeBio, which is unrelated to the submitted work. The remaining authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Ectopic ACTH-producing pituitary adenoma (EAPA) of the clivus region is extraordinarily infrequent condition and merely a few reports have been reported to date., Patient Concerns: The patient was a 53-year-old woman who presented with Cushing-like appearances and a soft tissue mass in the clivus region., Diagnoses: The final diagnosis of clivus region EAPA was established by clinical, radiological and histopathological findings., Interventions: The patient underwent gross total clivus tumor resection via transsphenoidal endoscopy., Outcomes: Half a year after surgery, the patient Cushing-like clinical manifestations improved significantly, and urinary free cortisol and serum adrenocorticotropin (ACTH) returned to normal., Lessons: Given the extreme scarcity of these tumors and their unique clinical presentations, it may be possible to misdiagnose and delayed treatment. Accordingly, it is especially crucial to summarize such lesions through our present case and review the literature for their precise diagnosis and the selection of optimal treatment strategies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bilateral macronodular adrenocortical disease (BMAD) is characterized by the development of adrenal macronodules resulting in a pituitary-ACTH independent Cushing's syndrome. Although there are important similarities observed between the rare microscopic descriptions of this disease, the small series published are not representative of the molecular and genetic heterogenicity recently described in BMAD. We analyzed the pathological features in a series of BMAD and determined if there is correlation between these criteria and the characteristics of the patients. Two pathologists reviewed the slides of 35 patients who underwent surgery for suspicion of BMAD in our center between 1998 and 2021. An unsupervised multiple factor analysis based on microscopic characteristics divided the cases into 4 subtypes according to the architecture of the macronodules (containing or not round fibrous septa) and the proportion of the different cell types: clear, eosinophilic compact, and oncocytic cells. The correlation study with genetic revealed subtype 1 and subtype 2 are associated with the presence of ARMC5 and KDM1A pathogenic variants, respectively. By immunohistochemistry, all cell types expressed CYP11B1 and HSD3B1. HSD3B2 staining was predominantly expressed by clear cells whereas CYP17A1 staining was predominant on compact eosinophilic cells. This partial expression of steroidogenic enzymes may explain the low efficiency of cortisol production in BMAD. In subtype 1, trabeculae of eosinophilic cylindrical cells expressed DAB2 but not CYP11B2. In subtype 2, KDM1A expression was weaker in nodule cells than in normal adrenal cells; alpha inhibin expression was strong in compact cells. This first microscopic description of a series of 35 BMAD reveals the existence of 4 histopathological subtypes, 2 of which are strongly correlated with the presence of known germline genetic alterations. This classification emphasizes that BMAD has heterogeneous pathological characteristics that correlate with some genetic alterations identified in patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Central venous sampling (CVS) with corticotropin-releasing hormone (CRH) stimulation is a crucial technique in evaluating adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS). We evaluated central venous sampling (CVS) and magnetic resonance imaging (MRI) findings in predicting the localization and lateralization of pituitary microadenomas., Methods: We analyzed 29 patients with CS who underwent CVS with CRH stimulation and examined with MRI retrospectively. Catheterization to central sinuses was successfully performed in 26 patients. Three patients with variant anatomy or inability to cannulate were diagnosed with CD after examination of pathology., Results: After CVS, among 26 patients, 23 patients were determined to have CD (88.4%) and 2 (7.7%) patients were diagnosed with ectopic ACTH syndrome. One patient was diagnosed with CD postoperatively. While the sensitivity of the CVS was 95.6%, sensitivity of the preoperative pituitary MRI was lower (69.5%). Also, the negative predictive value ratio was higher in CVS than in MRI (66% versus 22%). Diagnostic accuracy in the lateralization of the tumor was high as in CVS as in MRI (76.4% versus 73.9%)., Conclusion: Central venous sampling with higher sensitivity in the localization of pituitary microadenoma, also has approximately similar diagnostic accuracy in lateralizing the tumor with MRI.

A wide range of clinical presentations for Cushing's syndrome has been described in the literature. Avascular necrosis of femur is a well-recognized complication of excessive glucocorticoid administration, but its occurrence due to endogenous hypercortisolism is rare. We present the case of a 47-year-old male who presented to us with severe low backache, hypertension, uncontrolled diabetes, and other signs and symptoms of Cushing's syndrome. Hormonal evaluation confirmed hypercortisolism, and a contrast-enhanced computed tomography of the abdomen localized the lesion in the left adrenal gland. Assessment of the severe low back ache-the main symptom for which the patient came to us-by magnetic resonance imaging of the spine and pelvis revealed avascular necrosis of bilateral femoral heads. Resection of the left adrenal gland revealed an adrenocortical carcinoma. To the best of our knowledge, this is only the second case where an adrenocortical cancer leading to hypercortisolism is the cause of avascular necrosis of hip.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) accounts for <2% of cases of Cushing's syndrome. The majority of patients present with no obvious steroid excess it means with autonomous cortisol secretion (ACS). The classic treatment for patients with overt Cushing's syndrome is bilateral adrenalectomy, but unilateral resection of the larger adrenal gland can result in clinical and/or biochemical remission in >90% of cases, especially in cases of ACS. In this article, a series of 32 cases with PBMAH is described. Most of the cases of PBMAH had ACS, except for one case with overt Cushing's syndrome. A study of aberrant receptors was performed in six patients, being negative in three cases, positive in the metoclopramide test in two cases and positive in the metoclopramide test and in the mixed meal test in another patient. The patient with overt Cushing's syndrome was treated with adrenostatic therapy achieving biochemical control, while two patients with ACS underwent unilateral adrenalectomy with resection of the largest adrenal gland, demonstrating hypercortisolism remission and improvement of cardiovascular risk factors after surgery. This article describes a series of 32 cases of PBMAH and offers a comprehensive review of PBMAH., (Copyright © 2023 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Surgical diseases of the adrenal gland include pheochromocytoma/paraganglioma, primary hyperaldosteronism, Cushing syndrome, and adrenocortical carcinoma. These conditions may be associated with familial syndromes, and genetic testing is available and recommended in most. For adrenal surgeons to be familiar with these syndromes and know when to consider referral for genetic counseling and genetic testing is important. Identification of patients with familial syndromes allows for the detection and screening of associated syndromic neoplasms, guides surgical planning and operative approach, influences recurrence and malignancy risk assessment, aids in the development of a postoperative surveillance plan, and determines the need for screening family members., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Nearly half of the adult population in the United States has been diagnosed with hypertension. Adrenal hormonal hypersecretion is a leading cause of secondary hypertension. Adrenal vein sampling (AVS) may assist in differentiating between unilateral and bilateral adrenal hormonal hypersecretion to identify patients who are candidates for adrenalectomy. We reviewed the use of AVS at our institution along with associated outcomes after adrenalectomy. Materials and Methods: A retrospective chart review was conducted of patients with a diagnosis of primary hyperaldosteronism (PA) or adrenocorticotropic hormone-independent Cushing syndrome (AICS) and who underwent adrenalectomy between January 1, 2010, and December 1, 2021. Patient data of baseline characteristics, preoperative workup, including AVS, and postoperative outcomes were collected and analyzed. Results: Seventy-one patients were identified in the study period (48 PA and 23 AICS). Computed tomography scan identified unilateral adrenal nodules in 52 patients (29 left; and 23 right), bilateral nodules in 13 patients, and no nodules in 6 patients. AVS was performed in 45 patients with PA (93%) and 5 patients with AICS (21%). After surgery, the number of PA patients with hypokalemia or requiring potassium supplementation significantly decreased after adrenalectomy (before surgery: 33 [68.7%]; and after surgery: 5 [10.4%], P  < .01). The number of medications required for hypertension in AICS patients also significantly decreased. No major adverse events were noted. Conclusions : Our long-term experience demonstrates the ongoing use of AVS during workup of patients with primary hyperaldosteronism and for select patients with adrenocorticotropic hormone-independent Cushing syndrome. However, a low level of discordance between imaging and AVS findings in PA patients suggests that there may be a subset of patients in whom preoperative AVS is not necessary.

Aim: To evaluate frequency of heart failure syndrome in patients with endogenous hypercortisolism and to establish relationship between effective treatment for hypercortisolism and regression of heart failure with particular emphasis on the observation of NT-proBNP and ST2 levels., Materials and Methods: 56 patients with endogenous hypercortisolism (45 female, mean age 47 years [36; 55] hospitalized with endogenous hypercortisolism to National Medical Research Center for Endocrinology were enrolled in the study. All patients underwent comprehensive clinical investigation including expert echocardiography with speckle tracking and evaluation of NT-proBNP and ST2 cardiac biomarkers at baseline and 6 months after surgical treatment., Results: According to clinical data and elevated biomarkers of cardiac stress 28 out of 56 patients (50%) at baseline met the criteria for heart failure. 20 patients were included in the final analysis. Follow-up investigation with focus on changes in NT-proBNP and ST2 levels demonstrated that surgical correction of endogenous hypercortisolism resulted in resolution of heart failure syndrome in 11 patients (55%)., Conclusion: These preliminary data suggest that signs and symptoms of heart failure are observed in patients with endogenous hypercortisolism in about half the cases. Surgical correction results in resolution of heart failure in approximately two thirds of the cases. Prospective evaluation NT-proBNP and ST2 levels may provide important diagnostic and prognostic information in patients with endogenous hypercortisolism.

Iatrogenic Cushing's syndrome is a life-threatening condition which requires an early diagnosis multidisciplinary approach. Despite reports of iatrogenic Cushing's syndrome following nasal or inhaled steroids, its development after topical betamethasone eye drops for a short duration is a less frequently reported or anticipated condition. We describe a 6-week-old infant who developed exogenous Cushing's syndrome following topical steroids after bilateral goniotomy for newborn glaucoma. The child was kept under observation and managed with a physiological dose of hydrocortisone. Parental counselling regarding the proper method of eye drop instillation and signs of steroid toxicity is of vital importance in all cases of pediatric ocular surgeries, especially where bilateral surgeries are undertaken., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Not required for Clinical Vignette.

Robotic assisted surgery is the most rapidly developing field of minimally invasive surgery. Its wide diffusion has led to the development and standardization of robotic-assisted approaches also for adrenalectomy. In this study, we present the first five robotic-assisted lateral transabdominal adrenalectomies performed with the new Hugo RAS™ system (Medtronic, Minneapolis, MN, USA). After an official training course of the surgical team, five consecutive patients scheduled for unilateral adrenalectomy, underwent robotic-assisted operations in our institution. Patients that were candidates for partial adrenalectomy were excluded. A description of the operating theatre, robotic arms and docking setup is provided. Four female and one male patient underwent lateral transabdominal adrenalectomy, three for lesions on the left side and two on the right. Median lesion size was 3.9 cm (range: 30-90) and preoperative diagnosis was Cushing's syndrome in three patients, an adrenal cystic lesion and a pheochromocytoma. The median docking time was 5 min (range: 5-8) and the median console time was 55 min (range: 29-108). Procedures were performed without intraoperative complications and no conversions or additional ports were needed. System's function and docking were uneventful. Based on our initial experience, adrenalectomy with the Hugo™ system is feasible. This study provides technical notes for other centres that wish to perform robotic-assisted adrenalectomies with the Hugo™ RAS as well as general information and our preliminary insights on this new platform., (© 2022. The Author(s).)