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Case Presentation: A 22-year-old female presented to the emergency department with a two-month history of worsening fatigue, unintentional weight gain, and progressive facial swelling. Physical examination findings included hirsutism, moon facies, and abdominal striae. Subsequent brain magnetic resonance imaging revealed the presence of a 2.4-centimeter pituitary macroadenoma, confirming the diagnosis of Cushing’s disease. The patient was then admitted for neurosurgical tumor resection.Discussion: Cushing’s disease is exceedingly rare and often presents with symptoms resembling more prevalent disorders, contributing to delays in diagnosis. Therefore, maintaining a high index of suspicion for this disease is crucial for emergency physicians.

Objective: Cushing syndrome (CS) is the result of chronic exposure to glucocorticoid excess. CS in children is most often caused by the administration of exogenous steroids. Endogenous CS is rare in the paediatric population and is caused mainly by tumours of the pituitary and adrenal glands, with ectopic sources being extraordinarily rare before the age of 18 years. In addition, children and young adults with CS present with different epidemiology, management issues, prognosis and outcomes than older adult patients. This complex disorder needs early diagnosis and management to avoid the significant morbidity and even mortality that can result from chronic untreated CS. Methods: In this review, we present the complex case of a 7‐year‐old boy with CS that highlights the diagnostic and management challenges of paediatric CS patients, including the considerations for genetic predisposition and life‐long consequences of CS in children and young adults. Results: The diagnostic protocols for the evaluation of CS have been devised for adults and tested predominantly on adults. In this review, we discuss necessary modifications so that the testing can be adjusted for use in children. Additionally, pituitary adenomas in children are generally smaller and thus more difficult to recognize on pituitary imaging. Conclusions: The management of the case and its complexities underline the need for children with CS to be managed in a centre with experienced paediatric endocrinologists and skilled neurosurgeons both for their initial diagnosis and treatment as well as for their long‐term follow‐up and management. [ABSTRACT FROM AUTHOR]

People with Cushing's disease (CD) often experience both mood/anxiety disorders and cognitive impairments that persist during long‐term biochemical remission. The relationship between persistent neurocognitive and psychiatric problems in patients with CD is not well understood. Also, mechanisms other than hypercortisolism are poorly understood, and studies comparing CD with nonfunctioning adenomas (NFA) patients postoperatively are scarce. We compared neuropsychological functioning in two groups: individuals with CD in remission (n = 20; 80% female; 61.6 [44.13] months since remission) and individuals with NFAs (n = 20). Evaluation was performed, on average, 4.9 years following pituitary surgery. We used mediation models to evaluate psychiatric dysfunction as a possible mediator of cognitive outcomes and assessed the influence of demographic and medical factors (age at diagnosis, remission duration, and radiation therapy) on neuropsychological outcomes. Neuropsychological outcomes did not differ significantly between groups; however, up to 30% of patients demonstrated mild impairments in attention, processing speed, executive functioning, and visual memory. Time since remission in the CD group was inversely correlated with processing speed; however, this relationship was no longer significant after controlling for the presence of hypertension and diabetes mellitus. Levels of anxiety, depression, or somatization were reported in up to 40% of people with CD. Further, 70% of people with CD and 35% of people with NFA reported continuous depressive symptoms lasting at least 2 years. In conclusion, neuropsychological screening in clinical practice and longitudinal studies in individuals with NFA and CD are needed to identify patients at risk for long‐term neuropsychological dysfunction. Appropriate support and treatment are recommended for persistent cognitive and/or psychiatric dysfunction for both patient groups. [ABSTRACT FROM AUTHOR]

The neurocognitive and psychiatric effects of Cushing's syndrome (CS) are well recognized and negatively impact quality of life. The aim of this systematic review is to compare neurocognitive disease, psychiatric symptoms, and structural brain changes in patients with Cushing's disease (CD)/CS and those with non‐functioning pituitary adenoma (NFPA), both before and after surgical treatment, and in comparison to healthy controls. Possible predictors of persistent neurocognitive symptoms and reduced quality of life in patients with CS are highlighted. We reviewed the English literature published in Medline/Pubmed until 2021 to identify eligible studies. This systematic review was registered on Prospero and reported following the PRISMA statement guidelines. The initial literature search yielded 1772 articles, of which 1096 articles remained after removing duplicates. After excluding case reports, animal studies, narrative reviews, comparative reviews, and articles not in English, 86 papers underwent full‐text review. Studies eligible for inclusion met the following criteria: (1) described patients with CD/CS, (2) reports of psychiatric symptoms, (3) written in English or with available English translation, and (4) published in a peer‐reviewed journal. The full‐text review process identified 40 eligible studies. The 40 studies included a total of 2603 participants with CD or CS, with 45.2% of the total participants having CD. The majority of studies were case–control studies and used validated questionnaires such as the Beck's Depression Index, Trail Making Test, Hospital Anxiety and Depression Scale, and Cushing Quality of Life for screening. Compared to NFPA controls, patients with CD who had greater baseline serum cortisol levels had worse cognitive function, even after surgical remission. This suggests a possible association between greater baseline cortisol levels in patients with CS and persistent cognitive impairment. A longer duration of uncontrolled CS was associated with worse cognitive function; however, there was no association found between the length of remission and memory. Overall brain volume was increased in patients in remission from CD compared to active disease. However, temporal and frontal lobe volumes did not recover to normal volumes. Patients with CS experience neurocognitive dysfunction, psychiatric disorders, and diminished quality of life, and symptoms may persist after curative surgery. We found several factors consistently associated with persistent cognitive and neuropsychiatric symptoms in patients with CS including higher pre‐operatively baseline cortisol production, longer duration of disease, frontal and temporal lobe atrophy, and the presence of cognitive and neuropsychiatric symptoms at baseline. Larger prospective studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the gut microbial signatures and related pathophysiological implications in patients with Cushing's disease (CD). Design and methods Twenty-seven patients with CD and 45 healthy controls were enrolled. Based on obtained metagenomics data, we performed correlation, network study, and genome interaction group (GIG) analysis. Fecal metabolomics and serum enzyme linked immunosorbent assay (ELISA) analysis were conducted in dichotomized CD patients. Caco-2 cells were incubated with gradient concentrations of cortisol for subsequent transepithelial electrical resistance (TEER) measurement, FITC-dextran transwell permeability assay, qPCR, and western blot analysis. Results Gut microbial composition in patients with CD was notably different from that in healthy controls. Network analysis revealed that Eubacterium siraeum might serve as the core specie in the gut microbial system of CD patients. Subsequent GIG analysis identified the positive correlations between GIG9 and UFC. Further serum ELISA and fecal metabolomics uncovered that CD patients with elevated UFC levels were characterized with increased lipopolysaccharide binding protein (LBP). Moreover, remarkable positive association was found between LBP level and relative abundance of E. siraeum. TEER and FITC-dextran transwell assays demonstrated that hypercortisolism induced increased gut permeability. Further qPCR and western blot analysis suggested that dysregulated AhR/Claudin 2 axis might be involved in the development of hypercortisolism-induced defective gut barrier function Conclusions Disease activity associated dysbiosis and defective gut barrier might jointly facilitate the development of systemic inflammation in patients with CD. [ABSTRACT FROM AUTHOR]

Context Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. Objective To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. Design Retrospective study. Setting University hospitals. Patients Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation. Results Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI),.92-.99] in the primary study and.99 [95% CI,.98-1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index.99 [95% CI,.97-1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3-10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value. Conclusion UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms. [ABSTRACT FROM AUTHOR]

Background Cushing's syndrome (CS) can be difficult to diagnose. A timely diagnosis, however, is the cornerstone for targeted treatment, to reduce morbidity and mortality. One reason for the difficulties to identify early on patients with CS might be the presence of a mild phenotype. The aim of the study was to classify the phenotypic landscape of CS. We studied patients with overt CS and mild autonomous cortisol secretion (MACS). Method The study was part of the German Cushing's registry. Patients were prospectively included at time of diagnosis and the number of comorbidities and clinical signs and symptoms were assessed in a standardized fashion. One hundred twenty-nine patients with CS (pituitary CS, n = 85, adrenal CS, n = 32, ectopic CS, n = 12, respectively) and 48 patients with MACS were included. Patients with clinical signs and/or comorbidities typical for CS and at least 2 pathological screening tests were classified as having CS. Patients with a 1 mg low-dose-dexamethasone-suppression test above 1.8 µg/dL without being clinically overt CS were classified as having MACS. Results On average, patients with CS had 2 comorbidities (range 1-3) at time of diagnosis (pituitary CS: 2 [1-3], adrenal CS: 3 [2-4], ectopic CS: 3 [2-4]). Patients with MACS, however, had 3 comorbidities (range 2-3). Hypertension was the most common comorbidity in all subtypes of CS (78%-92%) and in patients with MACS (87%). Of a total of 11 clinical signs, patients with CS had on average 5 with 28% of patients having between 0 and 3 clinical signs, 50% 4-7 signs, and 22% more than 7 clinical signs. Patients with MACS had on average 2 clinical signs (range 1-3) at time of diagnosis. Conclusion The phenotypic landscape of CS is quite variable. The frequency of comorbidities is similar between patients with CS and MACS. A relevant number of patients with overt CS have just a few clinical signs. There is also an overlap in frequency of symptoms and clinical signs between patients with CS and MACS. According to the current guidelines, 96% of our patients with MACS fall into the category "consideration of adrenalectomy". This should be kept in mind when making treatment decisions in the latter group of patients. [ABSTRACT FROM AUTHOR]

Background Pituitary adenomas (PAs)—also now called pituitary neuroendocrine tumours or Pit-NETS—are rare in children and adolescents and exceptional below the age of 10. Most evidence-based high-quality data are derived from larger studies in adult patients. Aims We will review recent knowledge on the epidemiology, clinical features, diagnosis, and treatment modalities of the different types of pituitary adenomas diagnosed in children and adolescents, emphasizing the many reasons why these cases should be discussed within pituitary-specific multidisciplinary teams with experts from both paediatric and adult practice. Conclusions Paediatric PA presents multiple peculiarities that may challenge their adequate management. They are overall proportionally larger and more aggressive than in adults, with potential mass effects including hypopituitarism. Hormonal hypersecretion is frequent, resulting in clinical syndromes affecting normal growth and pubertal development. Prolactinomas represent the most frequent subtype of PA found during childhood, followed by adrenocorticotropin (ACTH) and growth hormone (GH)–secreting adenomas, while clinically non-functioning adenomas are exceptionally diagnosed before the age of 16. The occurrence of a pituitary tumour in a young individual should also prompt genetic testing in each case, searching for either germline mutations in one of the known genes that may drive inherited/familial PA (such as the multiple endocrine neoplasia type 1 or MEN1 gene, or the aryl hydrocarbon receptor interacting protein or AIP gene), or for a mosaic activating mutation of GNAS as found in the McCune-Albright syndrome. [ABSTRACT FROM AUTHOR]

Introduction: In 2011, we reported the overall incidence of Cushing's disease (CD) in Iceland from 1955 through 2009 to be 1.5 cases per million per year with highest incidence in the last decade of the study, a higher incidence then earlier reported. We now present a follow-up study reporting the epidemiology of the disease in Iceland during the 10-year period from 2010 to 2019. Methods: In this nationwide retrospective study, clinical information on patients diagnosed with CD was obtained from electronic medical records, reviewed by consulting endocrinologists. Results: Seventeen patients were diagnosed with CD, 12 women (71%) and 5 men (29%) giving an overall incidence of 5.2 cases per million per year. The mean age at diagnosis was 46 years (range 13–85 years). Biochemical analysis was recorded for all patients and 12 patients (71%) had visible pituitary adenoma on imaging studies. Sixteen patients (94%) were treated with transsphenoidal surgery of which 4 patients (24%) had gamma knife radiosurgery and three (18%) bilateral adrenalectomy after pituitary surgery. Two patients died during the study period. Conclusion: The overall incidence of CD of 5.2 cases per million per year is higher than previously reported, indicating the importance of awareness of CD. As all patients with CD are diagnosed and/or treated at the only University Hospital in Iceland, housing the only department of endocrinology as well as neurosurgery, we are confident that all cases diagnosed during the study period were included in the study. [ABSTRACT FROM AUTHOR]

In veterinary medicine, the significance of high-density lipoprotein (HDL) measurements is not as well documented as it is in humans. The HDL level can be measured in dogs as well and, through referring to the normal range, it is possible to find out what this means in relation to various endocrine diseases and hyperlipidemia diseases. The aim of this study is to measure the HDL levels in dogs with various conditions and to evaluate whether the total cholesterol (TC)-to-HDL ratio is effective as a prognostic indicator in various hyperlipidemia and endocrine diseases, which is significant since it is the first trial in dogs. Through a retrospective study design, sixteen client-owned dogs and cats visiting a local private practice were divided into three groups: five dogs without hyperlipidemia or metabolic disease (Group 1), eight dogs with Cushing’s, hypothyroidism, and gallbladder sludge (Group 2), and three cats, including one with diabetes, one with a urinary disorder, and one healthy cat (Group 3). In two dogs, the TC/HDL values were between 2 and 3; in two dogs, the values were between 3 and 4; and in two dogs, the values were between 4 and 5. In three dogs, the TC/HDL values were between 5 and 6 and in three dogs the ratio values were between 6 and 7. The other value was higher than 8. Except for two dogs that showed lower values than 3, all dogs in Group 1 and Group 2 had concurrent endocrine disease. This means that TC/HDL values can be an excellent indicator of endocrine disease in dogs as well. In cats, although it is a very small batch of samples, a high TC/HDL value of 9 points was shown in the cat that had diabetes mellitus. However, for more statistically significant results, a larger sample group for further investigation is needed.

Objective: Cushing’s syndrome (CS) is associated with an 18-fold greater risk of venous thromboembolism (VTE). We aimed to identify factors which provoke VTE among patients with CS and VTE and to describe the anticoagulant regimen used in these cases. Methods: In this retrospective observational study, patients included in the European Registry on CS (ERCUSYN) in Krakow center, Poland, were followed for the occurrence of VTE and anticoagulant treatment. We identified factors provoking VTE according to the International Society of Thrombosis and Hemostasis (ISTH), along with factors included in the Padua score and CS-VTE score. Results: Of the 128 patients followed for a median of 4.3 years, there were nine patients who experienced ten VTE episodes (prevalence of 7.8% and incidence of 13.4 per 1000 patient-years). All VTEs were classified as provoked according to the ISTH guidance, predominantly due to the transient major and minor (50% and 20%, respectively) factors, while they were less commonly due to persistent (30%) factors. In 2/9 patients, we could not identify any risk factor for VTE according to the Padua score, while in 2/6 patients according to the CS-VTE score. Patients were mostly anticoagulated with vitamin K antagonists (4/8 patients), followed by direct oral anticoagulants (3/8) and low-molecular-weight heparin (1/8). The median duration of anticoagulation was 2.75 years and exceeded beyond the primary treatment in 28% of episodes provoked by transient factors. Conclusion: Further, multicenter studies are required to create a validated thrombotic risk score and guidelines regarding VTE treatment in CS patients.

A 38-year-old Japanese woman with a history of abnormal thyroid function of non-autoimmune origin, pituitary endocrine tumor, and untreated diabetes mellitus was referred to our outpatient clinic when she became pregnant with twins. Physical findings consistent with Cushing’s syndrome (CS) were absent at the time of presentation. Although baseline plasma adrenocorticotropic hormone, serum cortisol, and 24-hour urinary free cortisol excretion levels were above the upper limits of normal non-pregnant reference ranges, we could not exclude a physiological increase associated with pregnancy. No medical or surgical intervention for hypercortisolism was performed during pregnancy. Spontaneous vaginal delivery resulted in the normal delivery of live twins. A diagnosis of Cushing’s disease (CD) was established when papery skin developed postpartum. Transsphenoidal surgery was performed and the hypercortisolism partially resolved post-operatively. The patient’s abnormal thyroid function also resolved. Pregnancy in women with endogenous CS is rare, with less than 300 cases reported. Most reported cases of CS during pregnancy are of adrenal origin. Only two cases of twin pregnancies with CD have been reported. Therefore, we reported the third case of CD in a twin pregnancy and reviewed the diagnostic and therapeutic challenges associated with CD during pregnancy.

Michelantonio De Fano, Alberto Falorni, Massimo Malara, Francesca Porcellati, Carmine Giuseppe Fanelli Department of Medicine and Surgery, Endocrine and Metabolic Sciences Section, University of Perugia, Perugia, ItalyCorrespondence: Michelantonio De Fano; Carmine Giuseppe Fanelli, Email michelantonio.defano@gmail.com; carmine.fanelli@unipg.itAbstract: Patients suffering from acromegaly and Cushing’s Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts’ consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.Keywords: acromegaly, Cushing’s disease, pasireotide, hyperglycemia, diabetes mellitus, cardiovascular risk

Background. Transsphenoidal surgery is the treatment of choice for Cushing's disease. Successful surgery is associated with subnormal postoperative serum cortisol concentrations and cortisoluria levels, which may guide decisions regarding immediate reoperation. Remission is defined as the biochemical reversal of hypercortisolism with the re-emergence of diurnal circadian rhythm. Methods. A single-center prospective cohort study was conducted among thirty-three patients who underwent transsphenoidal pituitary surgery for Cushing's disease. Postoperative surgical outcomes, daily morning cortisolemia, and 24 h urinary-free cortisol from the first to the fifth morning were evaluated. Results. All patients underwent surgery, with a remission rate of 81.2%. Of the 26 patients who achieved early remission, 92% remained in remission. Two patients (7.7%) showed recurrence of Cushing's disease during a mean follow-up of 81.7 months. Early postoperative hypocortisolism suggests complete removal of the tumor, correlating with high rates of remission (p < 0.001). Also, in 12.5% of patients with early cortisol values >138 nmol/L, there was a gradual late remission. Conclusions. In our cohort of patients, the endoscopic transsphenoidal approach was safe and effective in the treatment of Cushing's disease. We demonstrated that serum and urinary cortisol concentrations did not experience significant fluctuations from the first to the fifth day. This constitutes an accurate predictor of durable remission, comprising a distinctive finding in the intermediate term by our team. [ABSTRACT FROM AUTHOR]

The first-line treatment for Cushing's disease is transsphenoidal adenomectomy, which can be curative in a significant number of patients. The second-line options in cases of failed primary pituitary surgery include repeat surgery, medical therapy, and radiation. The role for medical therapy has expanded in the last decade, and options include pituitary-targeting drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. Bilateral adrenalectomy is a more aggressive approach, which may be necessary in cases of persistent hypercortisolism despite surgery, medical treatment, or radiation or when rapid normalization of cortisol is needed. We review the available treatment options for Cushing's disease, focusing on the second-line treatment options to consider after failed primary pituitary surgery. [ABSTRACT FROM AUTHOR]

Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing's syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients. [ABSTRACT FROM AUTHOR]

Cushing’s disease is a rare condition that occurs due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing’s disease in Northern Ireland (NI) from 2000 to 2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing’s disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing’s disease of 1.39–1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤ 50 nmol/L (1.8 µg/dL) and ≤ 138 nmol/L (5 µg/dL), respectively, in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer-term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing’s disease had a significantly higher mortality rate compared to the NI general population (standardised mortality ratio 8.10, 95% CI 3.3–16.7, P < 0.001). Annual incidence of Cushing’s disease in NI is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population. [ABSTRACT FROM AUTHOR]

Background: Endocrine regulation of bone metabolisms is the focus of the "Skeletal Endocrinology" series of meetings. Aims: To report on the outcome of the discussion on the role of vitamin D/PTH axis in endocrine osteopathies held during the 10th Skeletal Endocrinology Meeting which took place in Stresa (Italy) in March 2023. Outcomes: Vitamin D/PTH axis has relevant influence on several outcomes in the general population and in patients affected by endocrinopathies such as hypoparathyroidism and secreting pituitary adenomas. Conclusions: Assessing the status of the vitamin D/PTH axis and using vitamin D and PTH as therapeutic agents is mandatory in several endocrine-related bone metabolic conditions. [ABSTRACT FROM AUTHOR]

Background: Cushing's syndrome (CS) poses diagnostic challenges, particularly in distinguishing pituitary-dependent Cushing's syndrome, Cushing's disease (CD), from the ectopic ACTH syndrome (EAS). This study evaluated the diagnostic value of the desmopressin stimulation test (DST) in patients with ACTH-dependent CS in helping this discrimination. Methods: Twenty-three ACTH-dependent CS patients underwent sequential DST, bilateral inferior petrosal sinus sampling (BIPSS), and transsphenoidal surgery (TSS). Two definitions of a positive DST results were applied. Diagnostic performance was assessed using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios. To avoid bias from predetermined criteria, we generated univariate receiver-operating characteristic (ROC) curves, plotting sensitivity against 1-specificity at various percentage cortisol and ACTH response levels. Results: Against BIPSS, DST demonstrated robust sensitivity (Definition 1: 90.0%, Definition 2: 76.2%) and overall accuracy (Definition 1: 87.0%, Definition 2: 73.9%). PPV was high (Definition 1: 95.0%, Definition 2: 94.1%), but NPV indicated potential false negatives. Compared to TSS, DST showed good sensitivity (Definition 1: 90.9–77.3%) and PPV (100.0%) but limited NPV (16.7%). The likelihood ratios emphasized the diagnostic value of the test. Notably, against TSS, DST showed perfect discriminatory power (AUC 1.000 for percent ACTH, 0.983 for percent cortisol). Conclusion: The desmopressin test shows promise in accurately identifying the underlying cause of ACTH-dependent CS, potentially reducing the reliance on invasive procedures and providing a practical solution for managing complex cases. Further research with larger cohorts is required to validate the utility of the DST in routine clinical practice. [ABSTRACT FROM AUTHOR]

Objective Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. Here, we aimed to assess the cancer risk in patients with CS as compared with individually matched controls. Design A nationwide retrospective matched cohort study of patients with endogenous CS diagnosed between 2000 and 2023 using the database of Clalit Health Services in Israel. Methods Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazard model, with death as a competing event. Results A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0 ± 17.2 years; 2371 (65.4%) women]. The median follow-up was 14.7 years (IQR, 9.9–20.2 years). Patients with CS had an increased cancer risk, with a hazard ratio (HR) of 1.78 (95% CI 1.44–2.20) compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15–2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70–3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies. Conclusion Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population. [ABSTRACT FROM AUTHOR]

Background: Cushing's Disease (CD) is a rare clinical syndrome characterized by excessive secretion of adrenocorticotrophic hormone, leading to significant functional and structural brain alterations as observed in Magnetic Resonance Imaging (MRI). While traditional statistical analysis has been widely employed to investigate these MRI changes in CD, it has lacked the ability to predict individual‐level outcomes. Purpose: To address this problem, this paper has proposed an interpretable machine learning (ML) framework, including model‐level assessment, feature‐level assessment, and biology‐level assessment to ensure a comprehensive analysis based on structural MRI of CD. Methods: The ML framework has effectively identified the changes in brain regions in the stage of model‐level assessment, verified the effectiveness of these altered brain regions to predict CD from normal controls in the stage of feature‐level assessment, and carried out a correlation analysis between altered brain regions and clinical symptoms in the stage of biology‐level assessment. Results: The experimental results of this study have demonstrated that the Insula, Fusiform gyrus, Superior frontal gyrus, Precuneus, and the opercular portion of the Inferior frontal gyrus of CD showed significant alterations in brain regions. Furthermore, our study has revealed significant correlations between clinical symptoms and the frontotemporal lobes, insulin, and olfactory cortex, which also have been confirmed by previous studies. Conclusions: The ML framework proposed in this study exhibits exceptional potential in uncovering the intricate pathophysiological mechanisms underlying CD, with potential applicability in diagnosing other diseases. [ABSTRACT FROM AUTHOR]

Introduction Pituitary neuroendocrine tumors (PitNETs) are rare skull base tumors which can impart significant disability owing to their locally invasive potential. To date, the gamut of PitNET subtypes remains ill-understood at the ligand-receptor (LR) interactome level, potentially limiting therapeutic options. Here, we present findings from in silico analysis of LR complexes formed by PitNETs with clinical presentations of acromegaly, Cushing's disease, high prolactin production, and without symptoms of hormone hypersecretion. Methods Previously published PitNET gene expression data was acquired from ArrayExpress. These data represented all secretion types. LR interactions were analyzed via a crosstalk score approach. Results Cortisol (CORT) ligand was significantly involved in tumor-to-tumor signaling across all PitNET subtypes but prolactinomas, which evidenced active CORT depletion. Likewise, CCL25 ligand was implicated in 20% of the top LR complex interactions along the tumor-to-stroma signaling axis, but silent PitNETs reported unique depletion of the CCL25 ligand. Along the stroma-to-tumor signaling axis, all clinical PitNET subtypes enriched stromal vasoactive intestinal polypeptide ligand interactions with tumor secretin receptor. All clinical PitNET subtypes enriched stromal DEFB103B (human β-defensin 103B) ligand interactions with stromal chemokine receptors along the stroma-to-stroma signaling axis. In PitNETs causing Cushing's disease, immune checkpoint ligand CD274 reported high stromal expression, and prolactinomas reported low stromal expression. Moreover, prolactinomas evidenced distinctly high stromal expression of immune-exhausted T cell response marker IL10RA compared with other clinical subtypes. Conclusion Relative crosstalk score analysis revealed a great diversity of LR complex interactions across clinical PitNET subtypes and between solid tumor compartments. More data are needed to validate these findings and exact clinical importance. [ABSTRACT FROM AUTHOR]

Cushing's disease (CD) is caused by rare pituitary corticotroph tumors that lead to corticotropin (ACTH) excess. Variants in FAF1 , a pro-apoptotic protein involved in FAS-induced cell death, have been implicated in malignant disorders but the involvement of FAF1 in pituitary tumors has not been studied. Genetic data from patients with CD were reviewed for variants in FAF1 gene. Knockout mice (KO) were followed to assess the development of any pituitary disorder or cortisol excess. AtT-20 cells were used to study the effects of the variants of interest on ACTH secretion and cell proliferation. Three variants of interest were identified in 5 unique patients, two of which had rare allele frequency in genomic databases and were predicted to be likely pathogenic. KO mice were followed over time and no difference in their length/weight was noted. Additionally, KO mice did not develop any pituitary lesions and retained similar corticosterone secretion with wild type. AtT-20 cells transfected with FAF1 variants of interest or WT expression plasmids showed no significant difference in cell death or Pomc gene expression. However, in silico prediction models suggested significant differences in secondary structures of the produced proteins. In conclusion, we identified two FAF1 variants in patients diagnosed with CD with a potential pathogenic effect on the protein function and structure. Our in vitro and in vivo studies did not reveal an association of FAF1 defects with pituitary tumorigenesis and further studies may be needed to understand any association. [ABSTRACT FROM AUTHOR]

Introduction: Pituitary apoplexy (PA) in Cushing's disease (CD) is rare with data limited to case reports/series. Methods: We retrospectively reviewed case records of PA in CD managed at our center from 1987 to 2023 and performed a systematic literature review. Results: We identified 58 patients (44 females), including twelve from our center (12/315 CD, yielding a PA prevalence in CD of 3.8%) and forty six from systematic review. The median age at PA diagnosis was 35 years. The most common presentation was type A (79.3%) and symptom was headache (89.6%), with a median Pituitary Apoplexy Score (PAS) of 2. Median cortisol and ACTH levels were 24.9 µg/dl and 94.1 pg/ml, respectively. Apoplexy was the first manifestation of underlying CD in 55.2% of cases, with 31.1% (14/45) presenting with hypocortisolemia (serum cortisol ≤ 5.0 µg/dl), underscoring the importance of recognizing clinical signs/symptoms of hypercortisolism. The median largest tumor dimension was 1.7 cm (53/58 were macroadenomas). PA was managed surgically in 57.8% of cases, with the remainder conservatively managed. All five PA cases in CD with microadenoma achieved remission through conservative management, though two later relapsed. Among treatment-naïve CD patients with macroadenoma, PA-related neuro-deficit improvement was comparable between surgical and conservative groups. However, a greater proportion of surgically managed patients remained in remission longer (70% vs. 38.5%; p = 0.07), for an average of 31 vs. 10.5 months. Conclusion: PA in CD is more commonly associated with macroadenomas, may present with hypocortisolemia, and surgical treatment tends towards higher and longer-lasting remission rates. [ABSTRACT FROM AUTHOR]

Purpose: The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status. Methods: This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter. Results: The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85 years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70 g/dL vs. 13.12 g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20 g/dL and 40.08% in patients with CD and aCS vs. 13.20 g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001). Conclusion: Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cardiovascular comorbidities owing to hormonal excess or deficiency are the main cause of mortality in patients with pituitary disorders. In patients with Cushing's Disease, there is an increased prevalence of cardiovascular diseases and/or risk factors including visceral obesity, insulin resistance, atherosclerosis, arterial hypertension, dyslipidaemia, hypercoagulability as well as structural and functional changes in the heart, like cardiac hypertrophy and left ventricle (LV) dysfunction. Notably, these demonstrate limited reversibility even after remission. Furthermore, patients with acromegaly may manifest insulin resistance but also structural and functional heart changes, also known as "acromegalic cardiomyopathy". Patients with prolactinomas demonstrate an aggravation of metabolic parameters, obesity, dysregulation of glucose and lipid metabolism as well as endothelial dysfunction. Hypopituitarism and conventional hormonal replacement therapy may also contribute to an unhealthy metabolic status, which promotes atherosclerosis and may lead to premature mortality. This review discusses the literature on cardiovascular risk in patients with pituitary disorders to increase physician awareness regarding this aspect of management in patients with pituitary disorders. [ABSTRACT FROM AUTHOR]

Background: Patients with Cushing's disease (CD) often experience slow recovery of bone mineral density (BMD), and the effectiveness of anti-osteoporosis drugs in young CD patients who have achieved biochemical remission after surgery is not well understood. Therefore, we aimed to explore whether bisphosphonates could help accelerate the recovery of osteoporosis in young CD patients with remission. Methods: We retrospectively enrolled 34 young patients with CD who achieved postoperative biochemical remission. All patients suffered from osteoporosis before surgery and were divided into postoperative bisphosphonate treatment group (16 cases) and without bisphosphonate treatment group (18 cases). Clinical data, BMD (Z Value), and bone turnover markers were collected at the time of diagnosis and one year after successful tumor resection. Results: The Z values in the lumbar spine showed slight improvement in both groups at follow-up compared to baseline, but this improvement was not statistically significant. There was no significant difference observed between the two groups at follow-up. One year after operation, bone formation markers (OC and P1NP) were significantly higher than those at baseline in both groups. However, OC and P1NP in the bisphosphonate treatment group were lower than those in control group at one year follow-up. In without bisphosphonate treatment group, β-CTX from follow-up visit was higher than that at baseline, while no significant difference was observed in the bisphosphonate treatment group before and after surgery. Conclusion: Young patients with Cushing's disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission. [ABSTRACT FROM AUTHOR]

No systematic review has holistically analysed the efficacy and safety of levoketoconazole, a novel purified 2S,4R enantiomer of ketoconazole, believed to be 15- to 25-fold more potent than ketoconazole for managing Cushing's syndrome (CS). We undertook this meta-analysis to address this knowledge gap. Electronic databases were searched for studies involving patients with CS receiving levoketoconazole in the intervention arm. The primary outcome was to evaluate changes in mean 24-hour urine-free cortisol (mUFC) levels. Secondary outcomes were to evaluate alterations in cortisol and adverse events. SONICS study showed that normalisation of mUFC was seen in 61%, 55%, and 41% of the patients at the end of 6, 9, and 12 months therapy, respectively. The LOGICs study showed that withdrawal of levoketoconazole was associated with a significant increase in mUFC from 81.3 ± 35.7 to 220.8 ± 333.5 nmol/24h. The late-night salivary-cortisol (LNSC) increase during the drug withdrawal phase was 2.6 nmol/L in the placebo group (PG) compared to 2.2 nmol/L in the levoketoconazole group (LG) (P < 0.05). Re-initiation of levoketoconazole in original LG was associated with a decrease in mUFC from 224.3 ± 341.3 to 135.6 ± 87.3 nmol/24h. Initiation of levoketoconazole in the original PG was associated with a decrease in mUFC from 537.9 ± 346.0 to 141.3 ± 130.3 nmol/24h. Normalisation of mUFC was observed in 50.0% patients in LG compared to 4.5% in the placebo group. The median time for the response was 25 days. The median time to loss of therapeutic response was significantly shorter for PG (24 days) compared to LG (62 days) (P < 0.0001). Levoketoconazole has good efficacy and safety in CS. Bigger and longer studies are warranted to establish its superiority over ketoconazole. [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) is a rare disorder, once exogenous causes have been excluded. However, when diagnosed, the majority of cases are adrenocorticotropic hormone (ACTH)‐dependent, of which a substantial minority are due to a source outside of the pituitary, ectopic ACTH syndrome (EAS). Differentiating among pituitary‐dependent CS, Cushing's disease (CD) and an ectopic source can be problematic. Because non‐invasive tests in the evaluation of CS patients often lack adequate sensitivity and specificity, bilateral inferior petrosal sinus sampling (BIPSS), a minimally invasive procedure performed during the investigation of ACTH‐dependent CS, can be extremely helpful. BIPSS is considered to be the gold standard for differentiating CD from the EAS. Furthermore, although such differentiation may indeed be challenging, BIPSS is itself a complex investigation, especially in recent times due to the widespread withdrawal of corticotrophin‐releasing hormone and its replacement by desmopressin. We review current published data on this investigation and, in the light of this and our own experience, discuss its appropriate use in diagnostic algorithms. [ABSTRACT FROM AUTHOR]

Objective There is increasing evidence that multisystem morbidity in patients with Cushing's disease (CD) is only partially reversible following treatment. We investigated complications from multiple organs in hospitalized patients with CD compared to patients with nonfunctioning pituitary adenoma (NFPA) after pituitary surgery. Design Population-based retrospective cohort study using data from the Swiss Federal Statistical Office between January 2012 and December 2021. Methods Through 1:5 propensity score matching, we compared hospitalized patients undergoing pituitary surgery for CD or NFPA, addressing demographic differences. The primary composite endpoint included all-cause mortality, major adverse cardiac events (ie, myocardial infarction, unstable angina, heart failure, cardiac arrest, and ischemic stroke), hospitalization for psychiatric disorders, sepsis, severe thromboembolic events, and fractures in need of hospitalization. Secondary endpoints comprised individual components of the primary endpoint and surgical reintervention due to disease persistence or recurrence. Results After matching, 116 patients with CD (mean age 45.4 years [SD, 14.4], 75.0% female) and 396 with NFPA (47.3 years [14.3], 69.7% female) were included and followed for a median time of 50.0 months (IQR 23.5, 82.0) after pituitary surgery. Cushing's disease presence was associated with a higher incidence rate of the primary endpoint (40.6 vs 15.7 events per 1000 person-years, hazard ratio [HR] 2.75; 95% CI, 1.54-4.90). Cushing's disease patients also showed increased hospitalization rates for psychiatric disorders (HR 3.27; 95% CI, 1.59-6.71) and a trend for sepsis (HR 3.15; 95% CI,.95-10.40). Conclusions Even after pituitary surgery, CD patients faced a higher hazard of complications, especially psychiatric hospitalizations and sepsis. [ABSTRACT FROM AUTHOR]

Objective: Somatic variants in the ubiquitin‐specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. Design, patients and measurements: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow‐up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. Results: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p =.022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47‐ vs. 24‐year‐olds, p =.033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p =.037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long‐term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence‐free survival presented a tendency to be shorter in USP8‐mutated individuals (76.7 vs. 109.2 months, p =.068). Conclusions: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long‐term follow‐up revealed a tendency toward shorter recurrence‐free survival in USP8‐mutant patients. [ABSTRACT FROM AUTHOR]

Multi-modal histological image registration tasks pose significant challenges due to tissue staining operations causing partial loss and folding of tissue. Convolutional neural network (CNN) and generative adversarial network (GAN) are pivotal in medical image registration. However, existing methods often struggle with severe interference and deformation, as seen in histological images of conditions like Cushing's disease. We argue that the failure of current approaches lies in underutilizing the feature extraction capability of the discriminator in GAN. In this study, we propose a novel multi-modal registration approach GAN-DIRNet based on GAN for deformable histological image registration. To begin with, the discriminators of two GANs are embedded as a new dual parallel feature extraction module into the unsupervised registration networks, characterized by implicitly extracting feature descriptors of specific modalities. Additionally, modal feature description layers and registration layers collaborate in unsupervised optimization, facilitating faster convergence and more precise results. Lastly, experiments and evaluations were conducted on the registration of the Mixed National Institute of Standards and Technology database (MNIST), eight publicly available datasets of histological sections and the Clustering-Registration-Classification-Segmentation (CRCS) dataset on the Cushing's disease. Experimental results demonstrate that our proposed GAN-DIRNet method surpasses existing approaches like DIRNet in terms of both registration accuracy and time efficiency, while also exhibiting robustness across different image types. [ABSTRACT FROM AUTHOR]

Introduction and Purpose: Pituitary neuroendocrine tumors (PitNETs), commonly known as pituitary adenomas, are tumors originating from the adenohypophysis. The purpose of this review was to provide a comprehensive overview of the latest classification, clinical presentation, diagnosis and treatment options for different types of PitNETs. Description of state of knowledge: The World Health Organization (WHO) 2022 guidelines introduced a new classification system for PitNETs, emphasizing the importance of immunohistochemistry in diagnosing these tumors and identifying key transcription factors like PIT1, TPIT, and SF1. Clinical presentation of PitNETs vary widely, with symptoms ranging from mass effect related issues like headaches and visual disturbances to hormone excess syndromes such as hyperprolactinemia, acromegaly, and Cushing’s disease. Magnetic resonance imaging (MRI) is the gold standard for diagnosing adenomas. Treatment approaches depend on tumor type, with dopamine agonists being the first-line treatment for prolactinomas, while endoscopic transsphenoidal surgery (EETS) is the preferred treatment for other PitNETs. EETS achieves high rates of gross total resection and low recurrence. For patients with persistent or recurrent disease, reoperation, medical therapy, or radiotherapy may be required. Conclusions: Pituitary neuroendocrine tumors represent a diverse group of tumors that require an individualized, multidisciplinary approach for accurate diagnosis and effective treatment, aimed at optimizing patient outcomes.

No meta-analysis has holistically analysed and summarized the efficacy and safety of osilodrostat, a novel dual 11β-hydroxylase (cytochrome P450 family 11 subfamily B member 1 [CYP11B1]) and 18-hydroxylase (aldosterone synthase, CYP11B2) inhibitor in managing Cushing’s syndrome (CS). We undertook this meta-analysis to address this knowledge gap. Electronic databases were searched for randomized controlled trials (RCTs) involving patients with CS receiving osilodrostat in the intervention arm. The primary outcome was to evaluate changes in urine free cortisol (UFC) levels. Secondary outcomes were to evaluate alterations in cortisol levels, androgen levels, mineralocorticoid levels, and adverse events. From initially screened 109 articles, data from 2 RCTs involving 144 patients was analysed. After 8–12 weeks of therapy, the odds of achieving a normal 24-hour UFC was higher in patients receiving oslidrostat as compared to placebo. [odds ratio (OR) 21.94 (95% CI: 8.53–56.43); P < 0.00001; I2 = 0%]. The occurrence of adverse events [OR 1.35 (95% CI: 0.52–3.53); P = 0.54; I2 = 0%; low heterogeneity (LH); High certainty of evidence (HCE)], serious adverse events (SAEs) [OR 1.32 (95% CI: 0.30–5.79); P = 0.72; I2 = 0%; LH; HCE], adrenal insufficiency [OR 5.38 (95% CI: 0.91–31.78); P = 0.06; I2 = 0%; LH; HCE], headache [OR 0.98 (95% CI: 0.35–2.76); P = 0.97; I2 = 0%; LH; HCE], hyperandrogenism [OR 3.68 (95% CI: 0.59–22.80); P = 0.16; I2 = 0%; LH; HCE] and deaths [OR 0.32 (95% CI: 0.01–8.00); P = 0.48; I2 = 0%; LH; HCE] was comparable among the groups. The occurrence of nausea [OR 4.25 (95% CI: 1.26–14.30); P = 0.02; I2 = 0%; LH] and arthralgia [OR 6.54 (95% CI: 1.64–26.13); P = 0.008; I2 = 0%; LH; HCE] was significantly higher in the osilodrostat group as compared to placebo. Osilodrostat has good efficacy and safety in CS and was well tolerated over 48 weeks of use.

Abstract Objective Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. Methods Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. Results In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. Conclusion Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

Objective: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. Methods: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. Results: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. Conclusion: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies. [ABSTRACT FROM AUTHOR]

Background: An ACTH-secreting pituitary adenoma is the most common cause of excessive endogenous glucocorticoid production resulting in Cushing's Syndrome. A multidisciplinary approach is paramount. Selective adenomectomy is the treatment of choice. Method: Endoscopic transnasal transsphenoidal approach to the tumour, along with techniques for resection, are demonstrated. Conclusion: Endoscopic transsphenoidal approaches with its magnified view of the pituitary gland allows precise microsurgical dissection during selective adenomectomy. This technique increases the possibility of proving a gross total resection, leading to clinical and biochemical cure in these patients. [ABSTRACT FROM AUTHOR]

Purpose: The success and outcomes of repeat endoscopic transsphenoidal surgery (ETS) for residual or recurrent Cushing's disease (CD) are underreported in the literature. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in these patients. Methods: A retrospective analysis was conducted on 56 patients who underwent a total of 65 repeat ETS performed by a single neurosurgeon between January 2006 and December 2020. Data including demographic, clinical, laboratory, radiological, and operative details were collected from electronic medical records. Logistic regression was utilized to identify potential predictors associated with sustained remission. Results: Among the cases, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had prior endoscopic procedures. Remission was achieved in 47 (83.9%) patients after the first repeat ETS, with an additional 9 (16.1%) achieving remission after the second repeat procedure. During an average follow-up period of 97.25 months, the recurrence rate post repeat surgery was 6.38%. Sustained remission was achieved in 48 patients (85.7%), with 44 after the first repeat ETS and 4 following the second repeat ETS. Complications included transient diabetes insipidus (DI) in 5 (7.6%) patients, permanent (DI) in 2 (3%) patients, and one case (1.5%) of panhypopituitarism. Three patients (4.6%) experienced rhinorrhea necessitating reoperation. A serum cortisol level > 5 µg/dL on postoperative day 1 was associated with a reduced likelihood of sustained remission. Conclusion: Repeat ETS is a safe and effective treatment option for residual or recurrent CD with satisfactory remission rates and low rates of complications. [ABSTRACT FROM AUTHOR]

Background: In patients with Cushing's disease, the preoperative identification of pituitary adenomas is crucial to treatment. However, increasing diagnostic accuracy remains an unresolved issue. Purpose: To evaluate the diagnostic accuracy and the impact of readers' experience regarding high‐resolution contrast‐enhanced magnetic resonance imaging (hrMRI) for identifying pituitary adenomas in comparison with conventional contrast‐enhanced MRI (cMRI) and dynamic contrast‐enhanced MRI (dMRI). Study Type: Retrospective. Population: Sixty‐five patients (median age, 39 years; interquartile range [IQR], 28–53 years; 60% females) with treatment‐naïve Cushing's disease. Field Strength/Sequence: 3‐T, seven fast spin echo sequences. Assessment: The diagnostic accuracies of identifying pituitary adenomas on cMRI, dMRI, combined cMRI and dMRI (cdMRI), and hrMRI were independently evaluated by six readers with three experience levels (high: >20 years, modest: 10–20 years, low: <10 years; two readers for each experience level). Readers were asked to localize the lesion, and measure its diameter on the sequence where identified. The reference standard was postoperative histopathology. The impact of readers' experience and interobserver agreement were assessed. Image quality was assessed using a 5‐point Likert scale, including overall image quality, sharpness, and structural conspicuity. Statistical Tests: McNemar's test, Cochran's test, Wilcoxon signed‐rank test, Mann–Whitney U test, and κ statistics for interobserver agreement. A P‐value <0.05 was considered statistically significant. Results: For identifying pituitary adenomas (median diameter, 5 mm; IQR, 4–5 mm), hrMRI had significantly higher sensitivity (87.7%–93.8%) than cMRI, dMRI, and cdMRI (52.3%–75.4%) for readers with different experience levels. The interobserver agreement was moderate (κ = 0.461–0.523). The sensitivity for hrMRI was comparable between readers with different experience levels (P = 0.371). All image quality scores on hrMRI were significantly higher than cMRI and dMRI (5.0 vs. 4.0). Data Conclusion: For identifying pituitary adenomas in patients with treatment‐naïve Cushing's disease, hrMRI may show high diagnostic accuracy and seems not to be affected by readers' experience. Level of Evidence: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

No meta-analysis has holistically analysed and summarized the efficacy and safety of osilodrostat, a novel dual 11β-hydroxylase (cytochrome P450 family 11 subfamily B member 1 [CYP11B1]) and 18-hydroxylase (aldosterone synthase, CYP11B2) inhibitor in managing Cushing's syndrome (CS). We undertook this meta-analysis to address this knowledge gap. Electronic databases were searched for randomized controlled trials (RCTs) involving patients with CS receiving osilodrostat in the intervention arm. The primary outcome was to evaluate changes in urine free cortisol (UFC) levels. Secondary outcomes were to evaluate alterations in cortisol levels, androgen levels, mineralocorticoid levels, and adverse events. From initially screened 109 articles, data from 2 RCTs involving 144 patients was analysed. After 8–12 weeks of therapy, the odds of achieving a normal 24-hour UFC was higher in patients receiving oslidrostat as compared to placebo. [odds ratio (OR) 21.94 (95% CI: 8.53–56.43); P < 0.00001; I2 = 0%]. The occurrence of adverse events [OR 1.35 (95% CI: 0.52–3.53); P = 0.54; I2 = 0%; low heterogeneity (LH); High certainty of evidence (HCE)], serious adverse events (SAEs) [OR 1.32 (95% CI: 0.30–5.79); P = 0.72; I2 = 0%; LH; HCE], adrenal insufficiency [OR 5.38 (95% CI: 0.91–31.78); P = 0.06; I2 = 0%; LH; HCE], headache [OR 0.98 (95% CI: 0.35–2.76); P = 0.97; I2 = 0%; LH; HCE], hyperandrogenism [OR 3.68 (95% CI: 0.59–22.80); P = 0.16; I2 = 0%; LH; HCE] and deaths [OR 0.32 (95% CI: 0.01–8.00); P = 0.48; I2 = 0%; LH; HCE] was comparable among the groups. The occurrence of nausea [OR 4.25 (95% CI: 1.26–14.30); P = 0.02; I2 = 0%; LH] and arthralgia [OR 6.54 (95% CI: 1.64–26.13); P = 0.008; I2 = 0%; LH; HCE] was significantly higher in the osilodrostat group as compared to placebo. Osilodrostat has good efficacy and safety in CS and was well tolerated over 48 weeks of use. [ABSTRACT FROM AUTHOR]

Pituitary adenomas secreting adrenocorticotropin hormone (ACTH), known as ACTH-secreting pituitary adenomas, cause hypercortisolism by overproducting ACTH and stimulating bilateral adrenal cortical hyperplasia, a condition also known as Cushing’s disease (CD), which is the most common cause of endogenous hypercortisolism. ACTH-secreting pituitary adenomas lead to a series of severe clinical syndromes, including electrolyte disturbances and disorders of glucose and lipid metabolism, affecting multiple organs and systems throughout the body. Transsphenoidal neuroendoscopic surgery is the first-line treatment for ACTH-secreting pituitary adenomas, with a high remission rate, but postoperative recurrence and persistent disease remain unsolved in the treatment of ACTH-secreting pituitary adenomas. The pathological evaluation of ACTH-secreting pituitary adenomas has important value in determining the nature of the lesions, predicting the prognosis, and selecting the drug therapy. This article reviews the advances in the pathologic evaluation of ACTH-secreting pituitary adenomas, including new immunohistochemical markers and microscopic special features. [ABSTRACT FROM AUTHOR]

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 mg subcutaneously twice daily during pre-randomization (=16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment. [ABSTRACT FROM AUTHOR]

Purpose: This study was undertaken to assess the unmet needs within the endogenous Cushing's syndrome (CS) care paradigm from the endocrinologist's perspective, including data abstracted from patient charts. The study evaluated endocrinologists' perceptions on burden of illness and treatment rationale along with the long-term clinical burden of CS, tolerability of CS treatments, and healthcare resource utilization for CS. Methods: Retrospective medical chart data from treated patients with a confirmed diagnosis of CS was abstracted using a cross-sectional survey to collect data from qualified endocrinologists. The survey included a case report form to capture patient medical chart data and a web-enabled questionnaire to capture practitioner-level data pertaining to endocrinologists' perceptions of disease burden, CS treatments, and treatment attributes. Results: Sixty-nine endocrinologists abstracted data from 273 unique medical charts of patients with CS. Mean patient age was 46.5 ± 13.4 years, with a 60:40 (female:male) gender split. The mean duration of endogenous CS amongst patients was 4.1 years. Chart data indicated that patients experienced a high burden of comorbidities and symptoms, including fatigue, weight gain, and muscle weakness despite multi-modal treatment. When evaluating treatments for CS, endocrinologists rated improvement in health-related quality of life (HRQoL) as the most important treatment attribute (mean score = 7.8; on a scale of 1 = Not at all important to 9 = Extremely important). Surgical intervention was the modality endocrinologists were most satisfied with, but they agreed that there was a significant unmet treatment need for patients with CS. Conclusion: Endocrinologists recognized that patients with CS suffered from a debilitating condition with a high symptomatic and HRQoL burden and reported that improvement in HRQoL was the key treatment attribute influencing their treatment choices. This study highlights unmet needs for patients with CS. Patients with CS have a high rate of morbidity and comorbidity, even after treatment. [ABSTRACT FROM AUTHOR]

Objective When transsphenoidal surgery (TSS) does not cure Cushing's disease (CD), 4 treatments are available: drug treatment (DT), second TSS (2nd TSS), bilateral adrenalectomy (BA), and pituitary radiotherapy (PR). DT is attractive but supposes long-term continuation, which we aimed to evaluate. Design and Methods Retrospective study, in a center prioritizing 2nd TSS, of 36 patients, including 19 with TSS failure and 17 with recurrence, out of 119 patients with CD treated by a first TSS, average follow-up 6.1 years (95% confidence interval 5.27-6.91). Control was defined as normalization of urinary free cortisol (UFC) and final treatment (FT) as the treatment allowing control at last follow-up. We also analyzed discontinuation rates of DT in published CD prospective clinical trials. Results Control was achieved in 33/36 patients (92%). DT was initiated in 29/36 patients (81%), allowing at least 1 normal UFC in 23/29 patients (79%) but was discontinued before last follow-up in 18/29 patients (62%). DT was FT in 11/29 patients (38%), all treated with cortisol synthesis inhibitors. Second TSS was FT in 8/16 (50%), BA in 14/14 (100%), and PR in 0/5. In published trials, discontinuation of DT was 11% to 51% at 1 year and 32% to 74% before 5 years. Conclusion DT allowed at least 1 normal UFC in 23/29 patients (79%) but obtained long-term control in only 11/29 (38%), as discontinuation rate was high, although similar to published data. Interestingly, a successful 2nd TSS was the cause for discontinuing efficient and well-tolerated DT in 5 patients. Further studies will show whether different strategies with cortisol synthesis inhibitors may allow for a lower discontinuation rate in patients not candidates for a 2nd TSS so that BA may be avoided in these patients. [ABSTRACT FROM AUTHOR]

Hyperadrenocorticism (HAC) in dogs is routinely treated with trilostane single-dose (CTG) which is reported to cause adverse reactions. The current retrospective study of several dogs with terminal stage of HAC aimed to compare the clinical, hematological, and biochemical effects of trilostane titration-dose treatment (TTG) with the single-dose treatment (CTG). All clinical cases (n=7) were confirmed on HAC by anamnestic, clinical, hematology, biochemistry, and low-dose dexamethasone suppression test findings, indicative for Cushing’s disease. Two cases were treated with CTG (2.2-6.7 mg/kg, single dose daily) and their treatment was discontinued on the second week due to adverse reactions. The TTG cases were treated for up to 12 weeks (0.5 mg/kg once daily for 7 days, and then with 0.5 mg/kg twice daily for 7 days). Blood samples and clinical checks were performed on 0., 4., and 12. weeks of the treatment. Hemoglobin was non-significantly higher in TTG at 12 weeks. Alanine transaminase was significantly lower in the TTG cases on the 12. week of the treatment (78.04±15.37 U/L) compared to the 0-week (137.81±24.03 U/L), and 4-week samples (131.92±23.36 U/L). No significant differences were observed with the CTG cases. Alkaline phosphatase was significantly lower on 12-week samples in TTG (251.02±93.06) compared to the 4-week (567.94±283.93 U/L), and 0-week samples (1,341.84 U/L). In conclusion, TTG has indicated to have significantly higher tendency to decrease alanine transaminase and alkaline phosphatase, alleviating the negative effects on the liver. The clinical findings were more adverse for the CTG.

Background. We report four pediatric subjects with Cushing's disease (CD) diagnosed in the Czech Republic. We focus on initial symptoms of Cushing's syndrome (CS) which can lead to early diagnosis, on typical symptoms of CS in children, their age and sex distribution, the mean length of symptoms prior to diagnosis, indication for examination, post-cure growth, sexual development and pituitary function in our four CD patients after transsphenoidal pituitary surgery (TSS). We describe the diagnostic process leading to confirmation of CD and we emphasize the biochemical and radiological diagnostic difficulties. Conclusions. Pediatric CD has a number of features distinct from adult CD. Our retrospective analysis confirmed the presence of growth retardation and change in facial appearance with development of moon face as the first symptoms of CS. According to our observation, growth retardation is prior to development of moon face. The other typical symptoms frequently seen in pediatric patients are pseudo-precocious puberty in both sexes, hirsutism in pubertal girls due to excessive adrenal androgen secretion and pubertal delay. A corticotropin-releasing hormone (CRH) test and especially bilateral inferior petrosal sinus sampling for ACTH (BIPSS) contribute to confirming the diagnosis of CD and excluding ectopic ACTH syndrome in children with unvisible adenoma on pituitary magnetic resonance imaging (MRI).

Abstract 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