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Corticotropinomas account for 20% of all aggressive pituitary tumors and pituitary carcinomas and are associated with high mortality. These tumors not only cause neurovascular compromise but can also be fatal due to severe hypercortisolemia itself. Although surgery is considered the primary treatment modality, it is often partially successful or unsuccessful. Moreover, these tumors frequently recur and may be resistant to conventional treatments, including surgery and radiotherapy. Therefore, early multimodal treatment and regular follow-up are necessary. We present a case of aggressive Cushing's disease managed with combined temozolomide therapy and radiotherapy following an unsuccessful transsphenoidal surgery, resulting in significant long-term radiological and biochemical remission. In addition, etomidate infusion was administered to achieve rapid cortisol reduction, highlighting its role as a bridging therapy to other modalities in treating life-threatening and severe hypercortisolemia outside an intensive care setting., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Summary: Cushing's disease (CD) is characterized by distinct syndromic features, often accompanied by obesity and depression. However, considering its gradual onset of symptoms, it is usually associated with diagnostic delays. In rare instances, CD may lead to severe infections due to the observed immunosuppression in affected individuals. We present a rare case of an undiagnosed CD in a 20-year-old male with a medical history of depression and obesity, complicated by severe COVID-19 infection. He presented to the Emergency Room with respiratory distress, hypertensive crisis, and fever, ultimately receiving the diagnosis of SARS-CoV-2 pneumonia. The patient required mechanical ventilation and intensive care unit (ICU) admission due to severe acute respiratory distress syndrome (ARDS). During ICU care, he received remdesivir and dexamethasone, subsequently developing severe hyperglycemia and worsened hypertension, requiring insulin and multiple antihypertensive agents to manage metabolic disruption. Upon physical examination, classic signs of hypercortisolism were noted. Subsequent laboratory tests and pituitary magnetic resonance imaging confirmed the diagnosis of CD. The patient underwent surgical resection with significant improvements in body composition and metabolic parameters postoperatively. After surgery, remission of hypercortisolism was evident, accompanied by notable improvements in mood and overall health. This case underscores the importance of recognizing hypercortisolism in the context of metabolic, physical, and mood changes. Timely diagnosis of CD is crucial to mitigate complications such as severe opportunistic infections and their outcomes., Learning Points: Despite some hallmark features such as proximal myopathy, easy bruising, purple striae, and facial plethora, Cushing's disease (CD) is a challenging diagnosis due to its nonspecific signs and symptoms and gradual onset. The case emphasizes the importance of recognizing subtle signs of CD, such as social isolation, depressive symptoms, and changes in body composition, which may be confounded by external factors like the COVID-19 pandemic. Patients with CD are prone to severe infections due to chronic hypercortisolism-induced immunosuppression. CD diagnostic delays are common, leading to worsening of metabolic and immune dysfunction over time. Heightened clinical suspicion and early intervention are essential to prevent diagnostic delays and optimize patient outcomes.

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.

Purpose: Silent corticotroph adenoma (SCA) exhibits more tumor aggressiveness features than functioning adenomas (FCA). We aimed to investigate PCSK1N expression in CA and examine if ER stress-induced responses affect cell survival in a corticotroph tumor cell model., Methods: Clinical and imaging characteristics were recorded in 33 patients with FCA (20 women, 11 macroadenomas) and 18 SCA (8 women, all macroadenomas). Gene expression of proopiomelanocortin (POMC), T-box transcription factor 19(TBX19)/TPIT, proprotein convertase subtilisin/kexin type 1(PCSK1)/PC1/3, and its inhibitor PCSK1N, was measured by RT-qPCR in adenoma tissue.Mouse pituitary corticotroph tumor (AtT-20) cells were treated with tanespimycin (17-AAG), a HSP90 chaperone inhibitor, to induce ER stress, followed by gene and protein analyses., Results: POMC, TPIT, and PCSK1 expression were higher, whereas PCSK1N was lower in FCA compared to SCA. PCSK1N correlated with POMC (rs= -0.514, p <0.001), TPIT (rs= -0.386, p = 0.005), PCSK1 (rs= -0.3691, p = 0.008), and tumor largest diameter (rs= 0.645, p <0.001), in all CA. Induction of ER stress by 17-AAG in AtT-20 cells led to a decrease of POMC and an increase of PCSK1N gene expression at 24h. Moreover, a downregulation of cell cycle, apoptosis, and senescence pathways, and alterations in cell adhesion and cytoskeleton were observed at the protein level., Conclusions: PCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The aim of this narrative review was to discuss manifestations of endocrine disease other than diabetic foot in the lower extremities. Acromegaly, Addison's disease, Cushing's syndrome, hypo- and hyperthyroidism, hypo- and hyperparathyroidism, autoimmune polyglandular syndrome, hypopituitarism, and glucagonoma are among the endocrine diseases that may present with clinical manifestations in the lower extremities. Clinical signs vary depending on the underlying condition. Clinical suspicion is necessary for early diagnosis. Treatment of the underlying endocrine disease usually results in improvement of lower-extremity manifestations., Competing Interests: Conflicts of interestKleoniki I. Athanasiadou, Christothea A. Tsiridis, and Ioanna A. Paschou have no conflict of interest to declare. Stavroula A. Paschou has participated in clinical trials sponsored by Novo Nordisk, Sanofi, and Eli Lilly, and has received honoraria for advisory board membership or lectures from Novo Nordisk, Sanofi, Bausch Health, and Abbott. Nikolaos Papanas has been an advisory board member of TrigoCare International, Abbott, AstraZeneca, Elpen, MSD, Novartis, Novo Nordisk, Sanofi-Aventis and Takeda; has participated in sponsored studies by Eli Lilly, MSD, Novo Nordisk, Novartis and Sanofi-Aventis; received honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elpen, Galenica, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda and Vianex; and attended conferences sponsored by TrigoCare International, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer and Sanofi-Aventis. Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing’s disease (CD). However, the relative alterations in regional hypercortisolism in the brain remain unclear. Thus, we investigated regional volumetric alterations in CD patients. We also analyzed the associations between these volumetric changes and clinical characteristics. The study participants comprised of active CD (n = 60), short-term-remitted CD (n = 28), and long-term-remitted CD (n = 32) patients as well as healthy control subjects (n = 66). Gray matter volumes (GMVs) were measured via voxel-based morphometry. The GMVs of substructures were defined using the automated anatomical labeling (AAL) atlas. Trends toward normalization in GMV were found in most brain substructures of CD patients. Different trends, including enlarged, irreversible, and unaffected, were observed in the other subregions, such as the a mygdala, thalamus, and caudate. Morphological changes in GMVs after the resolution of hypercortisolism are a complex phenomenon; the characteristics of these changes signifi cantly differ within the brain substructures.

Abstract Background Cushing’s disease (CD) is defined as hypercortisolemia caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (corticotroph PA) that afflicts humans and dogs. In order to map common aberrant genomic features of CD between humans and dogs, we performed genomic sequencing and immunostaining on corticotroph PA. Methods For inclusion, humans and dog were diagnosed with CD. Whole exome sequencing (WES) was conducted on 6 human corticotroph PA. Transcriptome RNA-Seq was performed on 6 human and 7 dog corticotroph PA. Immunohistochemistry (IHC) was complete on 31 human corticotroph PA. Corticotroph PA were compared with normal tissue and between species analysis were also performed. Results Eight genes (MAMLD1, MNX1, RASEF, TBX19, BIRC5, TK1, GLDC, FAM131B) were significantly (P

Abstract Cushing's disease is a rare condition caused by a benign pituitary tumor underlying adrenocorticotropic hormone excess. Medical treatment is implemented when surgical resection is not curative. We present a case of Cushing's disease with recurrence of macroadenoma who developed iatrogenic adrenal insufficiency in the setting of Osilodrostat treatment.

ObjectiveThe first-line treatment for Cushing’s disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%, even in those with real initial remission. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and the treatment response to ketoconazole in Cushing’s disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital.Patients and methodsThis was a retrospective cohort of Cushing’s disease patients with active hypercortisolism who used ketoconazole at any stage of follow-up. Patients who were followed up for less than 7 days, who did not adhere to treatment, or who were lost to follow-up were excluded.ResultsOf the 172 Cushing’s disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, five of whom (15%) had also undergone radiotherapy; seven used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years. A total of 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to nine others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Only four patients had serious adverse effects that warranted discontinuation. There were 20 confirmed episodes of hypokalemia among 10/33 patients (30%).ConclusionKetoconazole effectively controlled hypercortisolism in 66% of Cushing’s disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out. Hypokalemia is a frequent metabolic effect not yet described in other series, which should be monitored during treatment.

ObjectiveTo evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing’s disease (CD) and ectopic Cushing’s syndrome (ECS).MethodsRetrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing’s syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference.Results469 patients were analyzed [78% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94%); ECS, n=26 (6%)] and 237 patients [228 CD (96%), 9 ECS (4%)]. Both tests were performed in 205 patients (44%). The post-CRH %-increase at 30 minutes of both ACTH (cut-off ≥31%, sensitivity 83%, specificity 85%, AUC 0.81) and cortisol (cut-off ≥12%, sensitivity 82%, specificity 89%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the %-suppression during the 8 mg DST was ≥55% (sensitivity 80%, specificity 78%, AUC 0.75).ConclusionThe CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.

(1) Background: Pituicytomas are rare gliomas located in the neurohypophysis or infundibulum. A misdiagnosis of pituicytoma as pituitary adenoma is common because of similar location and occasional endocrine disturbances. (2) Case presentation: We present two cases with the comorbidity of pituicytoma and Cushing's disease (CD). Case 1 is that of a 51-year-old woman, the first reported case of the comorbidity of pituicytoma, CD, and central diabetes insipidus. She received a diagnosis of CD and central diabetes insipidus. After transsphenoidal surgery, histopathology confirmed the diagnosis of pituicytoma and adrenocorticotropin-secreting microadenoma; case 2 is that of a 29-year-old man who received a biochemical diagnosis of CD, but he received a histopathological confirmation of only pituicytoma. Both patients achieved a remission of hypercortisolism without relapse during the follow-up, but they developed hypopituitarism after surgery. We also reviewed all published 18 cases with the comorbidity of pituicytoma and any pituitary adenoma. (3) Conclusions: Pituicytoma might present pituitary hyperfunction disorders such as CD or acromegaly, with or without pathologically confirmed pituitary adenoma. CD is the most common hyperpituitarism occurring concurrently with pituicytomas. The remission rate and hypopituitarism after surgery seem similar or slightly lower in CD than in common pituitary adenomas, but the long-term prognosis is unexplored. [ABSTRACT FROM AUTHOR]

Context: Impaired cognition and altered quality of life (QoL) may persist despite long-term remission of Cushing's disease (CD). Persistent comorbidities and treatment modalities may account for cognitive impairments. Therefore, the role of hypercortisolism per se on cognitive sequelae remains debatable. Objective: To investigate whether memory and QoL are impaired after longterm remission of CD in patients with no confounding comorbidity. Design and Setting: Cross-sectional case-control study in two tertiary referral centers Patients: 25 patients (44.5 ± 2.4 years) in remission from CD for 102.7 ± 19.3 Mo and 25 well-matched controls, without comorbidity or treatment liable to impair cognition. Main Outcome Measure(s): Hippocampus- and prefrontal cortex-dependent memory, including memory flexibility and working memory, were investigated using multiple tests including sensitive locally-developed computerized tasks. Depression and anxiety were evaluated with the MADRS and HADS questionnaires. QoL was evaluated with the SF-36 and CushingQoL questionnaires. The intensity of CD was assessed using mean urinary free cortisol and a score for clinical symptoms. Results: CD patients displayed similar performance to controls in all cognitive tests. In contrast, despite the absence of depression and a minimal residual clinical Cushing score, patients had worse QoL. Most of the SF36 subscales and the CushingQoL score were negatively associated only with the duration of exposure to hypercortisolism (p≤ 0.01 to 0.001). Conclusions: Persistent comorbidities can be a primary cause of long-lasting cognitive impairment and should be actively treated. Persistently altered QoL may reflect irreversible effects of hypercortisolism, highlighting the need to reduce its duration. [ABSTRACT FROM AUTHOR]

Cushing's syndrome is a rare disease with an endogenous cause of excess cortisol secretion. More evidence substantially links cortisol levels to the pachychoroid spectrum diseases. In this systematic review and meta-analysis, we summarize available evidence on pachychoroid spectrum diseases in patients with Cushing's syndrome. We performed a systematic literature search in 11 databases on 21 May 2022. Studies were considered eligible if they performed retinal examination of a consecutive group of patients with Cushing's syndrome using optical coherence tomography (OCT) scans. We extracted data on subfoveal choroidal thickness in patients with Cushing's syndrome compared to matched controls. We also extracted data on the prevalence of pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC), and polypoidal choroidal vasculopathy (PCV). We identified six eligible studies with a total of 159 patients with Cushing's syndrome. On average, patients with Cushing's syndrome have 49.5 µm thicker subfoveal choroidal thickness compared to matched healthy individuals. Pachychoroid spectrum diseases were relatively common in these patients: PPE in 20.8%, CSC in 7.7%, and PCV in 2.8%. We conclude that there should be low threshold to recommend ophthalmic examination to patients with Cushing's syndrome, and that a macular OCT is recommended during this examination. [ABSTRACT FROM AUTHOR]

Cushing's disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing's disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing's disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression. [ABSTRACT FROM AUTHOR]

Transsphenoidal surgery is the first‐line treatment for Cushing's disease to selectively remove the tumor. The rate of postoperative remission is estimated around 70%–80% in expert centers. However, the long‐term remission rate is lower because of recurrence during follow‐up that can be observed in 15% to 25% of the patients depending on the studies and duration of follow‐up. There is no significant predictive factor of recurrence before surgery, but postoperative corticotroph insufficiency and its duration has been found to be a protective factor for recurrence in many studies. The persistence of a positive response to desmopressin after surgery is associated with a higher rate of recurrence. Long term monitoring for recurrence with annual clinical and hormonal investigations after the hypothalamic–pituitary–adrenal axis postoperative recovery is advised. The biological tests used for the diagnosis of Cushing's syndrome (24 h‐urinary‐free cortisol [UFC], late‐night salivary or serum cortisol, 1 mg dexamethasone suppression test) can be used to screen for recurrence. Several studies report that increased late night cortisol and alterations of dynamic testing can be observed before the increased 24 h‐UFC. For this reason it is suggested that late‐night salivary cortisol would be a very sensitive tool to diagnose recurrence, pending the realization of several assays in case of borderline or discrepant result. This review will summarize the knowledge about recurrence of Cushing's disease after pituitary surgery and the current recommendations for its monitoring and diagnosis. [ABSTRACT FROM AUTHOR]

Transsphenoidal surgery (TSS) is the initial treatment modality of first choice in Cushing's disease (CD). With microscopic TSS and endoscopic TSS, two operative techniques with equally favourable remission rates and operative morbidity are available. On average, remission is achieved with primary TSS in 80% of patients with microadenomas and 60% of patients with macroadenomas. The current literature indicates that remission rates in repeat TSS for microadenomas can also exceed 70%. Experience with TSS in CD plays an important role in the success rate and centralization in Pituitary Centres of Excellence has been proposed. Microadenoma stage, imaging‐visible adenoma, confirmation of ACTH‐positive adenoma on histopathology and noninvasiveness are positive predictors for postoperative remission. In postoperative management, a steroid‐sparing protocol with early postoperative assessment of remission status is recommended. Convincing evidence suggests that prolonged postoperative prophylactic antithrombotic measures can significantly reduce the risk of postoperative thromboembolic events in CD. Prevention or successful treatment of cortisol withdrawal syndrome remains an unsolved issue that should be a focus of future research. The further development and broad availability of functional imaging hold promise for improved preoperative detection of microadenomas. Intraoperative identification of microadenomas by specific fluorescent targeting could be a promising future avenue for the treatment of patients with negative imaging. [ABSTRACT FROM AUTHOR]

Pituitary tumors are generally benign, although in rare cases aggressive pituitary tumors (APTs) and carcinomas present important diagnostic and therapeutic challenges and are associated with a high mortality rate. Almost half of these APTs and carcinomas are corticotroph tumors, suggesting a specific prognosis. Clinical, pathological and molecular prognostic markers are limited and do not allow early management of these tumors. Temozolomide remains the first‐line treatment once a diagnosis of aggressive pituitary tumor or carcinoma has been made. Novel alternative treatments exist, including immune checkpoint inhibitors, which can be used in the case of temozolomide treatment failure. The aim of this review is to present the clinical, pathological and molecular characteristics of aggressive corticotroph tumors and carcinomas, and to describe the results obtained with currently available treatments. [ABSTRACT FROM AUTHOR]

Corticotroph tumours are primarily sporadic monoclonal neoplasms and only rarely found in genetic syndromes. Recurrent mutations in the ubiquitin specific protease 8 (USP8) gene are found in around half of cases. Mutations in other genes such as USP48 and NR3C1 are less frequent, found in less than ~20% of cases. TP53 and ATXR mutations are reported in up to one out of four cases, when focusing in USP8 wild type or aggressive corticotroph tumours and carcinomas. At present, USP8 mutations are the primary driver alterations in sporadic corticotroph tumours, TP53 and ATXR mutations may indicate transition to more aggressive tumour phenotype. Next generation sequencing efforts have identified additional genomic alterations, whose role and importance in corticotroph tumorigenesis remains to be elucidated. [ABSTRACT FROM AUTHOR]

Pituitary MRI is essential in the diagnosis of ACTH‐dependent Cushing's syndrome, but its results are inconsistent. The demonstration of a sellar image compatible with the diagnosis of corticotropinoma varies from 40% to 90%, depending on the centre where the imaging is performed. In fact, the expertise of the neuroradiologist, use of a Tesla 3.0 MRI and choice of sequences are fundamental. The T2 and 3D gradient echo sequences after gadolinium injection are the most informative and today allow the detection of macro‐ and microadenomas in almost all cases. The diagnosis of numerous picoadenomas (<3–4 mm) is more challenging. The 2D and 3D spin echo or delayed T1 SE or FLAIR sequences after gadolinium can be used as a complement or to confirm a suspicious image. Characterization of corticotropinomas remains problematic. However, the correct assessment of so‐called incidentalomas by recognizing artifacts, anatomical variants and frequent Rathke's cleft cysts eliminates around 90% of the incidentalomas that mimic pituitary adenomas, as repetitively reported in the literature. For the time being, there is reason to believe that hybrid imaging combining PET and MRI such as 11C‐methionine PET coregistered with volumetric MRI will solve the diagnosis of corticotropinomas in the near future. [ABSTRACT FROM AUTHOR]

This review presents the data on clinical presentation at diagnosis in 1564 patients included in the European Registry on Cushing's syndrome (ERCUSYN), of whom 1045 (67%) had pituitary‐dependent Cushing's syndrome (CS) (PIT‐CS), 385 (25%) had adrenal dependent CS (ADR‐CS) and 89 (5%) had ectopic adrenocorticotropic hormone syndrome (ECT‐CS). The most frequent symptoms in the overall series were weight gain (83%), hypertension (79%), skin alterations (76%) and myopathy (70%). Diabetes mellitus was present in 32% and depression in 35% of patients. Skin alterations, menstrual irregularities and reduced libido were more prevalent in PIT‐CS patients compared to ADR‐CS patients, whereas patients with ECT‐CS more frequently had diabetes mellitus, myopathy, hirsutism and vertebral fractures compared to the other etiologies, consistent with a more severe clinical scenario. Reduced libido and bone fractures were more prevalent in men compared to women. Quality of life was poor at diagnosis, irrespective of the etiology of CS, and also associated with the presence of depression at baseline. A delay of 2 years between the onset of symptoms and diagnosis was also observed, with a high number of specialists consulted, who often missed the correct diagnosis. To develop strategies aimed at shortening the time elapsed to diagnosis, it is important to rapidly start treatment and reduce the burden of the disease on patient psychophysical health and longevity. [ABSTRACT FROM AUTHOR]

Increased multisystem morbidity and mortality in patients with Cushing's syndrome comprise clinical problems and challenges, both at the time of diagnosis and in remission. Relevant comorbidities and clinical problems include hypertension, diabetes, overweight, myopathy and a high risk for acute complications such as infections and venous thrombembolism. Although there are therapy recommendations for most of these comorbidities, there is a lack of large, prospective studies to confirm and optimise them. Mortality is especially high during active disease and within the first year after diagnosis, as a result of cardiovascular events, infections and suicide. All in all, interdisciplinary therapy management is important for reducing morbidity and mortality over the long‐term. [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late‐ night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH‐dependent and non‐ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non‐ACTH dependent forms. Differentiation between the ACTH‐dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100 years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of Cushing’s disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. Methods: RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. The effectiveness of an ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells on Ascl1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays were used to explore downstream pathways. Results: ASCL1 was exclusively overexpressed in USP8-mutant and wild-type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. An ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Conclusion: Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target the treatment of CD. [ABSTRACT FROM AUTHOR]

Objective: Gonadal and sexual disturbances are commonly encountered in patients with Cushing's disease. Nevertheless, the prevalence of hypogonadism in male Cushing's disease, the risk factors as well as the recovery time have been scarcely reported. Therefore, we aimed to explore the prevalence of hypogonadism at baseline and its determinants. In addition, the recovery time of hypogonadism and risk factors for unrecovered gonadal axis in male Cushing's disease with biochemical remission were investigated. Methods: We reviewed medical records of males with Cushing's disease managed between 2010 and 2020. Fifty-two male patients were enrolled according to the criteria. Each case attained biochemical remission after transsphenoidal surgery. Demographic details, clinical features, 24-hour UFC, hormonal profile [serum PRL, FSH, LH, TT, ACTH, cortisol, TT4/FT4, TT3/ FT3, TSH and IGF-1] were measured at baseline and during follow-up. The maximal tumor diameter on MRI was recorded at diagnosis. Results: Hypogonadotropic hypogonadism was observed in thirty-nine patients (75%) at diagnosis. Total testosterone was negatively correlated with ACTH and 24-hour UFC. Midnight serum ACTH level at diagnosis was significantly associated with hypogonadism after adjusting for confounding factors. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months. Seven patients were persistently hypogonadal during the follow-up (≥1 year), mainly due to the hypopituitarism as a complication of the therapies such as surgery. Conclusion: Hypogonadotropic hypogonadism is frequent in male Cushing's disease, but it is reversible in most cases within one-year follow-up after remission. [ABSTRACT FROM AUTHOR]

Nonsurgical medical treatments are often performed for Cushing's disease due to high recurrence rates. However, current medical treatment that targets corticotroph adenomas are limited. To develop a treatment that specifically targets corticotrophs in Cushing's disease, it is necessary to identify corticotroph lineage–specific proteins, which are involved in the Cushing's tumor phenotype. We have previously reported that the expression of E2F transcription factor 1 (E2F1), one of the cell cycle regulatory proteins, was increased in corticotrophs in Cushing's disease model mice and was involved in the regulation of POMC gene expression. Phosphorylation of Ser337 of E2F1 (pS337-E2F1) facilitates its binding to the POMC promoter, which was suggested to contribute to elevated POMC expression in corticotrophs. Here, we report that E2F1 expression is specific to the corticotroph lineage in normal human pituitaries and that the E2F1 protein is localized in the cytosol in normal corticotrophs. We show that pS337-E2F1 is localized in the nucleus specifically in Cushing's tumors, while it is localized in the perinuclear cytoplasm in the normal pituitary. This observation demonstrates that pS337 is a marker for Cushing's tumors and suggests that phosphorylation of E2F1 may be a target for developing a novel pharmacological treatment for tumorigenesis and hormone dysregulation of Cushing's disease. [ABSTRACT FROM AUTHOR]

Background Quantification of salivary cortisol is one of the highly sensitive and specific screening parameters for Cushing's syndrome (CS). However, only late-night salivary cortisol is part of the standard screening procedure. In this study, we aimed to analyze salivary cortisol day profiles in patients with different types of CS to test whether specific patterns might be relevant for diagnosis and subtyping. Material and Methods Among 428 patients including those with confirmed Cushing's syndrome (N=111, of those 75 with Cushing's disease, 27 patients with adrenal CS and nine patients with ectopic CS), autonomous cortisol secretion (N=39) or exclusion of CS (control group, N=278) salivary cortisol was measured five times a day. Results At each of the five time points, salivary cortisol was significantly higher in patients with CS compared to the control group (p≤0.001). Using the entire profile instead of one single salivary cortisol at 11 p.m. improved diagnostic accuracy (85 vs. 91%) slightly. Patients with ACTH-dependent CS had higher salivary cortisol levels than patients with adrenal CS. Also, morning cortisol was significantly higher in patients with ectopic CS than in patients with Cushing's disease (p=0.04). Nevertheless, there was a strong overlap between diurnal profiles, and the diagnostic yield for subtyping was low. Discussion The study results show that using diurnal salivary cortisol profiles for CS diagnosis results in a limited increase in diagnostic accuracy. With significant differences between Cushing subtypes, cortisol profiles are not useful in everyday clinical practice for subtyping of CS. [ABSTRACT FROM AUTHOR]

Objectives: Cushing's disease (CD) is most common endogenous Cushing's syndrome. This study aimed to assess iron alternations in deep grey matter in CD. Design: A cross‐sectional study was performed. Patients: In this study, 48 active CD patients, 39 remitted CD patients and 52 healthy control (HC) subjects underwent magnetic resonance imaging. Measurements: Quantitative susceptibility mapping (QSM). Results: Decreased susceptibility values were found in the bilateral putamen, caudate, red nucleus, subthalamic nucleus and pulvinar nuclei of the thalamus (TL‐PLV) in active and remitted patients with CD compared with HCs. Interestingly, in remitted patients with CD, altered susceptibility values were significantly correlated with altered brain volumes in TL‐PLV, while TL‐PLV may play an essential role as a general regulatory hub for adaptive and flexible cognition. Conclusion: Chronic exposure to hypercortisolism may be related to iron distribution and significantly correlated with altered brain volumes and clinical features in patients with CD. [ABSTRACT FROM AUTHOR]

Introduction: Prolactin (PRL) measurement during inferior petrosal sinus sampling (IPSS) can be helpful to improve the accuracy. We aimed to evaluate the effect of measuring PRL levels as a predictor for the accuracy of IPSS and evaluate its impact on the lateralization of adenomas. Methods: In this retrospective cohort study, we reviewed 51 patients who had undergone IPSS for the investigation of ACTH-dependent hypercortisolism. Results: Forty-nine patients had proven Cushing's disease (CD), one had EAS, and the remaining one patient had adrenal adenoma. Forty-seven patients had an above 2 ACTH IPS/P ratio at baseline, and all the post-corticotropin-releasing hormone (CRH) ACTH IPS/P ratios of patients with proven CD were above 3. In these two patients whose ACTH IPS/P ratio at baseline was below 2, PRL IPS/P ratios were above 1.8 in only the dominant side, which was considered secondary to a prolactin intersinus gradient due to the biological effects of the tumor. PRL-adjusted ACTH IPS/P ratios were > 1.3 in all patients with proven CD; it was 0.7 in the patient with EAS. Surgically confirmed positive lateralization was observed in 55.1% of patients with the ACTH gradient, but when PRL-adjusted ACTH IPS/IPS ratios were used in addition to the ACTH gradient, the ratio increased to 67.3%. Conclusion: Although PRL-adjusted ACTH IPS/P ratios can be helpful to improve the accuracy of results during IPSS procedures, a prolactin intersinus gradient towards the ACTH-dominant side in patients with CD may invalidate PRL as an indicator of pituitary venous outflow. [ABSTRACT FROM AUTHOR]

Numerous studies and reviews agree about the increased cardiovascular risk in Cushing's syn-drome. Therefore, the aim of the paper is to suggest a few common diagnostic and therapeutic cardiologic preferences for the majority of Cushing's syndrome/Cushing's disease (CS/CD) pa-tients which are not yet routine but have the rationale to become standard procedures. This may serve as an initial working document, to be improved by the experts in the field. A narrative review is used to present synthesis and deduction of several approaches in cardiology regarding the actu-al topic. Results are systematized as the risk factors or co-morbidities list (prevalent in CS/CD) coupled with current and adapted cardiologic suggestions for practice. [ABSTRACT FROM AUTHOR]

Context: The long-term somatic and psychiatric consequences of Cushing's syndrome are well-described, but the socioeconomic consequences are largely unknown. Objective: We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing's syndrome in the years before diagnosis and after surgery. Design: Nationwide register-based cohort study. Methods: We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing's syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year -10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression. Results: Compared to the reference population, the patients' employment was permanently reduced from year -6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression. Conclusion: Cushing's syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing's syndrome and, not least, the pervasive health threats of glucocorticoid excess. [ABSTRACT FROM AUTHOR]

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Cushing's disease represents 60–70% of all cases of Cushing's syndrome, presenting with a constellation of clinical features associated with sustained hypercortisolism. Molecular alterations in corticotrope cells lead to the formation of ACTH-secreting adenomas, with subsequent excessive production of endogenous glucocorticoids. In the last few years, many authors have contributed to analyzing the etiopathogenesis and pathophysiology of corticotrope adenomas, which still need to be fully clarified. New molecular modifications such as somatic mutations of USP8 and other genes have been identified, and several case series and case reports have been published, highlighting new molecular alterations that need to be explored. To investigate the current knowledge of the genetics of ACTH-secreting adenomas, we performed a bibliographic search of the recent scientific literature to identify all pertinent articles. This review presents the most recent updates on somatic and germline mutations underlying Cushing's disease. The prognostic implications of these mutations, in terms of clinical outcomes and therapeutic scenarios, are still debated. Further research is needed to define the clinical features associated with the different genotypes and potential pharmacological targets. [ABSTRACT FROM AUTHOR]

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing's disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic–pituitary–adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth. [ABSTRACT FROM AUTHOR]

Background: Cushing's disease (CD) is among the most common etiologies of hypercortisolism. Magnetic resonance imaging (MRI) is often utilized in the diagnosis of CD, however, up to 64% of adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI. We report 15 cases of MRI negative CD who underwent surgical resection utilizing a purely endoscopic endonasal approach. Methods: Endoscopic endonasal transsphenoidal surgery (EETS) was performed on 134 CD cases by a single surgeon. Fifteen cases met inclusion criteria: no conclusive MRI studies and no previous surgical treatment. Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRI. Immunohistochemistry was performed to assess for tumor hormone secretion. Results: Aside from a statistically significant difference (P = 0.001) in histopathological results between patients with negative and positive MRI, there were no statistically significant difference between these two groups in any other demographic or clinical data point. Inferior petrosal sinus sampling (IPSS) with desmopressin (DDAVP®) administration was performed on the 15 patients with inconclusive MRIs to identify the origin of ACTH hypersecretion via a central/peripheral (C/P) ratio. IPSS in seven, five and three patients showed right, left, and central side lateralization, respectively. With a mean follow-up of 5.5 years, among MRI-negative patients, 14 (93%) and 12 patients (80%) achieved early and long-term remission, respectively. In the MRI-positive cohort, over a mean follow-up of 4.8 years, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively. Conclusions: Surgical management of MRI-negative/inconclusive Cushing's disease is challenging scenario requiring a multidisciplinary approach. An experienced neurosurgeon, in collaboration with a dedicated endocrinologist, should identify the most likely location of the adenoma utilizing IPSS findings, followed by careful surgical exploration of the pituitary to identify the adenoma. [ABSTRACT FROM AUTHOR]

Background: Cushing's disease (CD) is rare in pediatric patients. It is characterized by elevated plasma adrenocorticotropic hormone (ACTH) from pituitary adenomas, with damage to multiple systems and development. In recent years, genetic studies have shed light on the etiology and several mutations have been identified in patients with CD. Case presentation: A girl presented at the age of 10 years and 9 months with facial plethora, hirsutism and acne. Her vision and eye movements were impaired. A quick weight gain and slow growth were also observed. Physical examination revealed central obesity, moon face, buffalo hump, supra-clavicular fat pads and bruising. Her plasma ACTH level ranged between 118 and 151 pg/ml, and sella enhanced MRI showed a giant pituitary tumor of 51.8 × 29.3 × 14.0 mm. Transsphenoidal pituitary debulk adenomectomy was performed and immunohistochemical staining confirmed an ACTH-secreting adenoma. Genetic analysis identified a novel germline GPR101 (p.G169R) and a somatic USP8 (p. S719del) mutation. They were hypothesized to impact tumor growth and function, respectively. Conclusions: We reported a rare case of pediatric giant pituitary ACTH adenoma and pointed out that unusual concurrent mutations might contribute to its early onset and large volume. [ABSTRACT FROM AUTHOR]

Introduction: Stress‐related brain disorders can be associated with glucocorticoid disturbance and hippocampal alteration. However, it remains largely unknown how cortisol affects the structure and function of hippocampus. Cushing's disease (CD) provides a unique "hyperexpression model" to explore the effects of excessive cortisol on hippocampus as well as the relation between these effects and neuropsychological deficits. Methods: We acquired high‐resolution T1‐weighted and resting‐state functional magnetic resonance imaging in 47 CD patients and 53 healthy controls. We obtained the volume and functional connectivity of the hippocampal rostral and caudal subregions in both groups. Relationships between hippocampal alterations, neuroendocrine, and neuropsychological assessments were identified. Results: Relative to control subjects, the CD patients had smaller volumes of all four hippocampal subregions. Furthermore, whole brain resting‐state functional connectivity analyses with these four different hippocampal regions as seeds revealed altered hippocampal functional connectivity with high‐order networks, involving the DMN, frontoparietal, and limbic networks in CD patients. The intrinsic hippocampal functional connectivity was associated with the quality of life of the CD patients. Conclusions: Our findings elucidate the cumulative effect of excess cortisol on the morphology and function of hippocampus and reinforce the need for effective interventions in stress‐related brain disease to halt potential hippocampal damage. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the characteristics of Cushing's disease (CD) patients who respond to the desmopressin (DDAVP) test and its underlying mechanisms. Methods: Forty-seven patients with CD who underwent DDAVP testing were included. Patients were divided into two groups: DDAVP test (+) (adrenocorticotropic hormone [ACTH] levels increased by ≥ 1.5-fold during the DDAVP test) and DDAVP test (−) (ACTH levels increased by < 1.5-fold). AVP receptor expression levels in these tumors were quantified using quantitative RT-PCR and immunohistochemistry. AVP receptor promoter activity was analyzed using a dual-luciferase reporter assay system. Results: Females (96.9%) and USP8 mutants (85.7%) were more prevalent in the DDAVP test (+) than in the DDAVP test (−). Indeed, the ACTH and cortisol responsiveness to DDAVP was greater in USP8 mutation positive tumors than that in USP8 wild type tumors (3.0-fold vs. 1.3-fold, 1.6-fold vs. 1.1-fold, respectively). Responsiveness to DDAVP was correlated with the expression levels of AVPR1B, but not with those of AVPR2. Comparably, Avpr1b promoter activity was enhanced by the overexpression of mutant USP8 compared to the wild type. Conclusions: We found that the responsiveness of ACTH to DDAVP in CD was greater in tumors with USP8 mutations. The present data suggest that USP8 mutations upregulate the AVPR1B promoter activity. Additionally, we showed that the DDAVP test can predict the presence of USP8 mutations. [ABSTRACT FROM AUTHOR]

Purpose: Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's Disease (CD). Recurrence rates after a first TSS range between 3 and 22% within 3 years. Management of recurrent or persistent CD may include repeat TSS or stereotactic radiosurgery (SRS). We performed a meta-analysis to explore the overall efficacy of TSS and SRS for patients with CD after an initial surgical intervention. Methods: EMBASE, PubMed, SCOPUS, and Cochrane databases were searched from their dates-of-inception up to December 2021. Inclusion criteria were comprised of patients with an established diagnosis of CD who presented with persistent or biochemically recurrent disease after a first TSS for tumor resection and were treated with a second TSS or SRS. Results: Search criteria yielded 2,116 studies of which 37 articles from 15 countries were included for analysis. Mean age ranged between 29.9 and 47.9 years, and mean follow-up was 11–104 months. TSS was used in 669 (67.7%) patients, while SRS was used in 320 (32.4%) patients, and remission rates for CD were 59% (95%CI 0.49–0.68) and 74% (95%CI 0.54–0.88), respectively. There was no statistically significant difference in the remission rate between TSS and SRS (P = 0.15). The remission rate of patients with recurrent CD undergoing TSS was 53% (95%CI 0.32–0.73), and for persistent CD was 41% (95%CI 0.28–0.56) (P = 0.36). Conclusion: Both TSS and SRS are possible approaches for the treatment of recurrent or persistent CD after a first TSS. Our data show that either TSS or SRS represent viable treatment options to achieve remission for this subset of patients. [ABSTRACT FROM AUTHOR]

Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike first-generation SRLs. Because of the broader binding profile, pasireotide has been suggested to have a greater clinical efficacy in acromegaly than first-generation SRLs and to be efficacious in Cushing's disease. The consequence of this binding profile is the increased blood glucose level in some patients. This results from the inhibition of both insulin secretion and the incretin effect and only a modest suppression of glucagon. A monthly intramuscular formulation of long-acting release pasireotide has been approved for both acromegaly and Cushing's disease treatment. This review presents data on the efficacy and safety of pasireotide treatment mostly in patients with acromegaly and Cushing's disease. Moreover, other possible therapeutic applications of pasireotide are mentioned. [ABSTRACT FROM AUTHOR]

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.

Only a few subacute thyroiditis (SAT) cases secondary to hypocortisolemia developed after successfully treating Cushing's disease (CD) have been reported. In this report, we present an SAT case, which developed immediately after discontinuation of steroid treatment for hypocortisolemia after the successful treatment of CD. A 54-year-old female patient who had recently been diagnosed with type 2 diabetes mellitus was admitted to our center with complaints of proximal myopathy and obesity. Serum cortisol did not suppress adequately after the 1 mg dexamethasone suppression test. Pituitary MRI of the patient with increased basal plasma ACTH level revealed a 6 x 5 mm right-sided adenoma. After successful surgical treatment, the patient was given ten months of steroid therapy due to a suppressed corticotroph axis. Shortly after the steroid treatment was discontinued, the patient was admitted with neck pain, fever, and thyrotoxicosis. The patient was diagnosed with SAT, and methylprednisolone treatment was started again. The underlying pathophysiological mechanisms in SAT cases that develop after the treatment of CD can only be speculated. One possible mechanism could be that the glucocorticoid deficiency develops after effective treatment of hypercortisolism alters the immunological responses or generates self-reactive cells and prepares an appropriate environment for the thyrolytic process. [ABSTRACT FROM AUTHOR]

ContextImpaired cognition and altered quality of life (QoL) may persist despite long-term remission of Cushing’s disease (CD). Persistent comorbidities and treatment modalities may account for cognitive impairments. Therefore, the role of hypercortisolism per se on cognitive sequelae remains debatable.ObjectiveTo investigate whether memory and QoL are impaired after long-term remission of CD in patients with no confounding comorbidity.Design and SettingCross-sectional case-control study in two tertiary referral centersPatients25 patients (44.5 ± 2.4 years) in remission from CD for 102.7 ± 19.3 Mo and 25 well-matched controls, without comorbidity or treatment liable to impair cognition.Main Outcome Measure(s)Hippocampus- and prefrontal cortex-dependent memory, including memory flexibility and working memory, were investigated using multiple tests including sensitive locally-developed computerized tasks. Depression and anxiety were evaluated with the MADRS and HADS questionnaires. QoL was evaluated with the SF-36 and CushingQoL questionnaires. The intensity of CD was assessed using mean urinary free cortisol and a score for clinical symptoms.ResultsCD patients displayed similar performance to controls in all cognitive tests. In contrast, despite the absence of depression and a minimal residual clinical Cushing score, patients had worse QoL. Most of the SF36 subscales and the CushingQoL score were negatively associated only with the duration of exposure to hypercortisolism (p≤ 0.01 to 0.001).ConclusionsPersistent comorbidities can be a primary cause of long-lasting cognitive impairment and should be actively treated. Persistently altered QoL may reflect irreversible effects of hypercortisolism, highlighting the need to reduce its duration.Clinical Trial Registration numberhttps://clinicaltrials.gov, identifier NCT02603653

Introduction Patients with remitted Cushing’s Disease (CD) often present persisting impairments in executive and cognitive functioning domains. Little research has been conducted regarding the functional neural correlates of an important executive functioning skill, namely the ability to plan, in these patients. Objectives To examine visuospatial planning related brain activity in remitted CD patients and matched controls using functional magnetic resonance imaging (fMRI). Methods fMRI scans were made using a 3-Telsa scanner while remitted CD patients (n=21) and age-, gender-, and education matched healthy controls (HCs; n=21) completed a parametric Tower of London (ToL) task. Psychological and cognitive functioning were assessed using validated questionnaires. Clinical severity was assessed retrospectively using the Cushing’s syndrome Severity Index (CSI). Results CD Patients were on average 45.1 (SD=7.1) years old, 81% female, and in remission for mean 10.68 (SD=7.69) years. No differences were found in number of correct trials, response times per ToL trial, or in the region of interest analyses. Exploratory wholebrain analyses found that CD patients showed more activation in several brain regions associated with higher cognitive processes on 2-, 3-, and 5-step trials compared to HCs. Over-recruitment of the right parietal operculum cortex in the patients was significantly negatively associated with the prior active disease state on the CSI (r=-0.519, p=0.02). Conclusions The increased brain activation during the ToL in remitted CD patients versus controls signals over-recruitment of certain brain areas involved in higher cognitive processes. CD may thus result in long-lasting, subtle scarring effects during demanding executive functioning tasks, despite remission. Disclosure No significant relationships.

Abstract Introduction Stress‐related brain disorders can be associated with glucocorticoid disturbance and hippocampal alteration. However, it remains largely unknown how cortisol affects the structure and function of hippocampus. Cushing's disease (CD) provides a unique “hyperexpression model” to explore the effects of excessive cortisol on hippocampus as well as the relation between these effects and neuropsychological deficits. Methods We acquired high‐resolution T1‐weighted and resting‐state functional magnetic resonance imaging in 47 CD patients and 53 healthy controls. We obtained the volume and functional connectivity of the hippocampal rostral and caudal subregions in both groups. Relationships between hippocampal alterations, neuroendocrine, and neuropsychological assessments were identified. Results Relative to control subjects, the CD patients had smaller volumes of all four hippocampal subregions. Furthermore, whole brain resting‐state functional connectivity analyses with these four different hippocampal regions as seeds revealed altered hippocampal functional connectivity with high‐order networks, involving the DMN, frontoparietal, and limbic networks in CD patients. The intrinsic hippocampal functional connectivity was associated with the quality of life of the CD patients. Conclusions Our findings elucidate the cumulative effect of excess cortisol on the morphology and function of hippocampus and reinforce the need for effective interventions in stress‐related brain disease to halt potential hippocampal damage.

Abstract Background Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing’s disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012–February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol