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Background and Objective: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated., Methods: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses., Results: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm 3 vs 0.49 ± 1.17 cm 3 , P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis., Conclusion: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Objective: In this study on patients with Cushing disease, post-transsphenoidal surgery (TSS), we attempt to predict the probability of remaining in remission, at least for a year and relapse after that, using Bayes' theorem and the equation of conditional probability. The number of parameters, as well as the weightage of each, is incorporated in this equation., Design and Methods: The study design was a single-centre ambispective study. Ten clinical, biochemical, radiological and histopathological parameters capable of predicting Cushing disease remission were identified. The presence or absence of each parameter was entered as binary numbers. Bayes' theorem was applied, and each patient's probability of remission and relapse was calculated., Results: A total of 145 patients were included in the study. ROC plot showed a cut-off value of the probability of 0.68, with a sensitivity of 82% (range 73-89%) and a specificity of 94% (range 83-99%) to predict the probability of remission. Eighty-one patients who were in remission at 1 year were followed up for relapse and 23 patients developed relapse of the disease. The Bayes' equation was able to predict relapse in only 3 out of 23 patients., Conclusions: Using various parameters, remission of Cushing disease can be predicted by applying Bayes' theorem of conditional probability with a sensitivity and a specificity of 82% and 94%, respectively. This study provided an objective way of predicting remission after TSS and relapse in patients with Cushing disease giving a weightage advantage to every parameter., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

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.

Background: The dopaminergic agonist cabergoline (CAB) has been used in the pharmacological treatment of Cushing's disease (CD). The effect is attributed to the frequent expression of the dopamine receptor subtype 2 in corticotroph tumors. However, in-vivo studies have demonstrated the normalization of 24-h urinary cortisol (24-h UC) in approximately 30-40% of patients over the long term, mainly after surgical failure. The aim was to evaluate the effect of CAB as monotherapy in the early preoperative period and on the recurrence of CD., Methods: A single-center retrospective study was conducted in a tertiary referral center. Twenty-one patients with confirmed CD were included. The median age was 32 years (13-70), 86% were female, 10 had microadenomas, and 11 had macroadenomas. They were diagnosed from 1986 to 2016 and used CAB as monotherapy either in the preoperative period (N.=7, CABi) or upon recurrence before any other treatment (N.=14, CABr). A "complete response" was considered 24-h UC normalization and a "partial response" was considered a 24-h UC reduction of >50%. UC was obtained at the last follow-up evaluation. The normalization of late-night salivary cortisol (LNSC) after CAB use was evaluated in most patients, as well as the tumor diameter by pituitary MRI, before and after CAB treatment., Results: Complete response was achieved in 29% (6/21) of subjects after 14.9±16.4 months of treatment, with an average dose of 2.2±1.0 mg/week. Partial response occurred in 9.5% (2/21). LNSC normalized in 35% (6/17) of patients, and no variation in tumor diameter before and after CAB use was observed (N.=13): 6.8±6.8 vs. 7.2±7.1 mm. There was no normalization of 24-h-UC in the CABi subgroup at the end of the treatment, whereas 43% (6/14) of patients in the CABr subgroup reached complete response. The CABi subgroup was treated for 4.7±1.9 months, and the CABr subgroup was treated for 20.1±18.1 months. Both groups were administered similar doses of CAB (CABi 2.1±0.9 and CABr 2.3±1.1 mg/week). Interestingly, the difference between the subgroups' complete response was evident early on in the three months of treatment: no patients in the CABi subgroup vs. 6/10 (60%) in the CABr subgroup (P=0.035), despite a lower dose in the CABr subgroup (1.1 vs. 1.6; P=0.008). The normalization of LNSC occurred in 20% of the CABi subgroup and in 42% of the CABr subgroup., Conclusions: The normalization of 24-h UC and LNSC occurred in approximately 30% of all patients, mainly in those who used CAB for the recurrence of CD. Despite the small number of subjects in the CABi subgroup, the absence of hormone control in this subgroup discourages the use of this medication as primary therapy or as a preoperative treatment option.

Purpose: The endoscopic endonasal approach (EEA) has become the preferred treatment for pituitary tumors, with minimal sinonasal morbidity. However, patients with Cushing's disease (CD) may represent a subgroup with prolonged impairment of sinonasal quality of life (QOL)., Methods: We retrospectively identified patients with CD who underwent EEA at our institution. Control patients with non-functional tumors were matched by age, gender, and extent of EEA. The primary outcome was post-operative 22-item Sino-Nasal Outcome Test (SNOT-22) scores., Results: Ten patients with CD met the selection criteria and 20 controls were selected for comparison. Nine of the CD patients achieved persistent endocrinologic remission post-operatively. Comparing the CD and control groups, there was no difference in post-operative SNOT-22 score at 1 or 3 months. At 6 months, SNOT-22 scores were significantly worse in the CD group (27.4 ± 21.6 vs. 2.8 ± 2.3, P  = .039). SNOT-22 scores improved to normal from 1 to 6 months in the control cohort ( P  = .007), but not in the Cushing's group ( P  = .726). Morbidity was present across all SNOT-22 domains, but was highest in the sleep domain ( P  = .023). Only morbidity in the facial domain improved over time ( P  = .032)., Conclusions: Patients with CD have significantly prolonged postoperative sinonasal QOL impairment following EEA compared to patients with non-functioning tumors, who normalize within 6 months. In CD patients, only morbidity in the facial domain, likely related to post-operative pain and nasal packing, improved over time, while the sleep domain was the most affected., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CHS: Consultant/Ownership in SpiWay, LLC; PAG: Consultant/Ownership in Spiway, LLC, and consultant for Stryker Corporation.

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies., Methods: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission., Results: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years., Conclusion: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

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.

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Hypercortisolism frequently induces trabecular bone loss, more pronounced at the lumbar spine, resulting in osteoporosis, and thus an increase in fracture risk. Several studies have shown bone mass recovery in patients with Cushing's disease (CD) after treatment., Objective: To examine treatment effects on TBS (trabecular bone score) in addition to aBMD (areal bone mineral density) in a cohort of patients with CD., Design and Setting: Single-center retrospective longitudinal study in patients diagnosed with CD and successfully treated following surgery and/or medical treatment., Patients: We included 31 patients with median age and BMI (body mass index) of 37.7 [28.4;43.3] years old and 27.7 [25.8;30.4] kg/m 2 , respectively. Median 24 h urinary cortisol before treatment was 213.4 [168.5;478.5] μg/24 h. All subjects were completely biochemically controlled or cured after treatment., Main Outcome Measures: aBMD and TBS were evaluated at AP Spine (L1-L4) with DXA prodigy (GE-Lunar), QDR 4500 (Hologic), and TBS iNsight® (Med-Imaps) before and after treatment., Results: Absolute TBS and aBMD gains following cure of CD were significant (p < 0.0001, and p < 0.001, respectively). aBMD and TBS increased by +3.9 and 8.2 % respectively after cure of CD. aBMD and TBS were not correlated before (p = 0.43) and after treatment (p = 0.53). Linear regression analyses showed that TBS gain was independent of baseline BMI and that low TBS at baseline was predictive of TBS gain after treatment., Conclusion: The more significant improvement of microarchitecture assessed by TBS than aBMD and the absence of correlation between TBS and aBMD suggest that TBS may be an adequate marker of bone restoration after cure of CD. To support this conclusion, future studies with larger sample sizes and longer follow-up periods should be carried out., Competing Interests: Declaration of competing interest Renaud Winzenrieth – Former senior scientist at Med-Imaps. Elina Tan, Laurence Guignat, Azeddine Dellal, Catherine Cormier, Eugénie Koumakis - None., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Endonasal endoscopic transsphenoidal surgery (TSS) and resection of pituitary adenomas are considered the gold standard treatment for Cushing disease (CD). Even with various recent advances in management, disease persistence and recurrence are common in these patients. The remission rate in the global population after surgery has been reported to vary widely from 64% to 93%. This study aims to determine the various clinical, biochemical, radiological, and histological factors that correlate with persistence and recurrence in patients with CD. This study also aims to understand the clinicopathological significance of EGFR-MAPK, NF-κB, and SHH pathway activation and to study the protein expression of activation markers of these pathways (i.e., c-Fos, c-Jun, GLI-1, pMEK, NR4A1, and p44) in functioning corticotroph pituitary adenomas., Methods: From January 2009 to September 2022, the clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD with a median follow-up of 8.1 years (range, 1-13.29 years) were ambispectively analyzed. The preoperative clinical, biochemical, and radiological features, operative findings, postoperative clinical and biochemical data, and histopathological and molecular profiles were retrieved from the electronic medical records. The patients were followed up to assess their remission status., Results: Among the 174 surgeries performed, 140 were primary surgeries, 22 were revision surgeries, 24 surgeries were for pediatric patients, and 12 surgeries were for patients with Nelson syndrome. In the primary surgery cohort, 74.3% were female, and the average age was 28.73 ± 10.15 years. Of the primary surgery cohort, 75% of the patients experienced remission compared with 47.4% after revision surgery. The remission rate for the pediatric patients was 55.5%. The postoperative day 1 plasma cortisol (P < 0.001; area under the curve, 0.8894; range, 0.8087-0.9701) and adrenocorticotropic hormone (P < 0.001; area under the curve, 0.9; range, 0.7386-1) levels were seen to be strong independent predictors of remission in the primary surgery cohort. The remission rate after endoscopic TSS was greater than that after microscopic TSS in patients undergoing primary surgery (81.08% vs. 57.14%; P = 0.008). The presence of adenoma on histopathological examination (HPE) was also a strong predictor of disease remission (P = 0.020). On stratifying by surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of nonremission (odds ratio, 38.1; 95% confidence interval, 4.2-348.3) compared with endoscopically operated patients with adenoma found on HPE. A lower immunoreactivity score for NR4A1 was found to correlate with higher remission rates (P = 0.074). However, none of the molecular markers studied (i.e., c-Fos, c-Jun, GLI-1, pMEK, and p44) showed a significant correlation with the preoperative cortisol values., Conclusions: The remission rate after primary surgery is higher than that after revision surgery and is lower for pediatric patients than for adults. The postoperative day 1 plasma cortisol and adrenocorticotropic hormone levels are strong independent predictors of remission in the primary surgery cohort. An endoscopic approach with histopathological evidence of adenoma is associated with a higher remission rate; thus, endoscopy should be the approach of choice for these patients with the goal of identification of an adenoma on HPE., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Sun, Ye and Zhang.)

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., (© 2024. Crown.)

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., (© 2024. The Author(s).)

Objectives: Cushing's disease (CD) is a diagnostic and therapeutic challenge, especially in pediatric patients. CD, primarily caused by adrenocorticotropic hormone-secreting pituitary adenomas, manifests typically with growth retardation and weight gain. There are no published guidelines for pediatric patients., Case Presentation: We report three pediatric patients diagnosed with CD in a Portuguese tertiary hospital. All patients presented with hypercortisolism features. All patients underwent transsphenoidal pituitary surgery (TSS) as a first-choice treatment; however, it was unsuccessful in one patient and the other patients experienced recurrence. Patients were submitted to different approaches so basal serum cortisol levels could be achieved. Two of three patients achieved remission., Conclusions: TSS remains the first-line treatment yet challenging due to microadenomas and technical complexities. Medical therapy with agents like metyrapone or ketoconazole, pituitary radiotherapy, or bilateral adrenalectomy are, usually, second-line interventions, unless there is a contraindication to surgery. Our findings support the finding that a shorter hypothalamic-pituitary-adrenal axis recovery time increases the risk of recurrence of CD. Our cases illustrate the intricate management and variable outcomes of pediatric CD, underscoring the importance of multidisciplinary care and continuous surveillance., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described., Objective: To determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission., Design: Retrospective matched cohort analysis., Setting: Academic medical center/pituitary center., Patients: Patients with CD with surgical remission and surgically treated NFPA., Measurements: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests., Results: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%)., Limitation: The small sample of patients with autoimmune disease limited identification of independent risk factors., Conclusion: Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger., Primary Funding Source: Recordati Rare Diseases Inc., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2024.

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

Objective: To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing disease., Methods: The presented study was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data regarding patient demographics, IPSS tumor lateralization, and postoperative endocrinologic outcomes were abstracted and pooled with random effects meta-analysis models. Additional meta-regression models were used to examine the association between the accuracy of IPSS tumor lateralization and postoperative outcomes (recurrence/persistence or remission/cure). Statistical analyses were performed using the Comprehensive Meta-Analysis software (significance of P < 0.05)., Results: Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59 months), the rate of correct IPSS tumor lateralization was 69% [95% confidence interval: 61%, 76%], and the rate of postoperative remission/cure was 78% [67%, 86%]. Preoperative IPSS tumor lateralization was concordant with magnetic resonance imaging lateralization for 53% of patients [40%, 66%]. There was no significant association between the rate of correct IPSS tumor lateralization and postoperative remission/cure among study-level data (P = 0.735). Additionally, there was no association among subgroup analyses for studies using stimulatory agents during IPSS (corticotropin-releasing hormone or desmopressin, P = 0.635), nor among subgroup analyses for adult (P = 0.363) and pediatric (P = 0.931) patients., Conclusions: Limited data suggest that the rate of correct IPSS tumor lateralization may not be positively associated with postoperative remission or cure in patients with Cushing disease. These findings bring into question the utility of IPSS tumor lateralization in the context of preoperative planning and surgical approach rather than confirming a pituitary source., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cushing's disease is a rare severe neuroendocrine disorder caused by chronic overproduction of adrenocorticotropic hormone by a pituitary tumor. Supraphysiological concentrations of cortisol in endogenous hypercortisolism have an immunosuppressive and anti-inflammatory effect similar to therapy with systemic glucocorticosteroids. This may reduce the activity of the patient's concomitant autoimmune inflammatory diseases. On the other hand, a decrease in cortisol levels during treatment for Cushing's disease may be associated with a reactivation of the immune system that pose a risk of onset or recurrence of an autoimmune disorder. We present our own clinical case demonstrating the development of sarcoidosis after surgical treatment of Cushing's disease.

Paediatric Cushing's disease (CD) is characterized by excess ACTH secretion from a pituitary adenoma, leading to hypercortisolism. It has approximately 5% of the incidence of adult CD and is a rare disorder in the paediatric age range. The four most specific presenting features of hypercortisolism are: change in facial appearance, weight gain, decreased linear growth and virilisation shown by advanced pubic hair for the stage of breast development or testicular volume. The main diagnostic priority is the demonstration of hypercortisolism followed by distinction between its ACTH-dependent and ACTH-independent origin, thus leading to identification of aetiology. All treatment options aim to resolve or control hypercortisolism. Consensus favours transsphenoidal (TSS) pituitary surgery with selective removal of the corticotroph adenoma. TSS in children with CD is now well established and induces remission in 70-100% of cases. External pituitary radiotherapy and bilateral adrenalectomy are second-line therapeutic approaches in subjects not responding to TSS. Long-term medical treatment is less frequently adopted. Recurrence in paediatric CD cases is low with factors predicting relapse being higher post-TSS cortisol and ACTH levels and rapid recovery of the hypothalamic-pituitary-adrenal axis after TSS. In summary, complete excision of the microadenoma with histological and biochemical evidence for this, predicts a low rate of recurrence of CD. Due to the need for rapid diagnosis and management to avoid the burden of prolonged exposure to hypercortisolism, tertiary university centres comprising both paediatric and adult endocrinology specialists together with experienced pituitary surgery and, eventually, radiotherapy units are recommended for referral of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Savage and Ferrigno.)

Objective: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases., Design: National, multicenter and retrospective study., Patients: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017., Measurements: Diagnostic tests of CD and tumour size., Results: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure., Conclusions: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery., (© 2023 John Wiley & Sons Ltd.)

Introduction: Chronic exposure to excessive endogenous cortisol leads to brain changes in Cushing's disease (CD). However, it remains unclear how CD affects large-scale functional networks (FNs) and whether these effects are reversible after treatment. This study aimed to investigate functional network changes of CD patients and their reversibility in a longitudinal cohort., Methods: Active CD patients (N = 37) were treated by transsphenoidal pituitary surgery and reexamined 3 months later. FNs were computed from resting-state fMRI data of the CD patients and matched normal controls (NCs, N = 37). A pattern classifier was built on the FNs to distinguish active CD patients from controls and applied to FNs of the CD patients at the 3-month follow-up. Two subgroups of endocrine-remitted CD patients were identified according to their classification scores, referred to as image-based phenotypically (IBP) recovered and unrecovered CD patients, respectively. The informative FNs identified by the classification model were compared between NCs, active CD patients, and endocrine-remitted patients as well as between IBP recovered and unrecovered CD patients to explore their functional network reversibility., Results: All 37 CD patients reached endocrine remission after treatment. The classification model identified three informative FNs, including cerebellar network (CerebN), fronto-parietal network (FPN), and default mode network. Among them, CerebN and FPN partially recovered toward normal at 3 months after treatment. Moreover, the informative FNs were correlated with 24-h urinary-free cortisol and emotion scales in CD patients., Conclusion: These findings suggest that CD patients have aberrant FNs that are partially reversible toward normal after treatment., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Cushing's disease (CD) poses significant challenges in its treatment due to the lack of reliable biomarkers for predicting tumor localization or postoperative clinical outcomes. Sphingosine-1-phosphate (S1P) has been shown to increase cortisol biosynthesis and is regulated by adrenocorticotropic hormone (ACTH)., Methods: We employed bilateral inferior petrosal sinus sampling (BIPSS), which is considered the gold standard for diagnosing pituitary sources of CD, to obtain blood samples and explore the clinical predictive value of the S1P concentration ratio in determining tumor laterality and postoperative remission. We evaluated 50 samples from 25 patients who underwent BIPSS to measure S1P levels in the inferior petrosal sinuses bilaterally., Results: Serum S1P levels in patients with CD were significantly higher on the adenoma side of the inferior petrosal sinus than on the nonadenoma side (397.7 ± 15.4 vs . 261.9 ± 14.88; P < 0.05). The accuracy of diagnosing tumor laterality with the interpetrosal S1P and ACTH ratios and the combination of the two was 64%, 56% and 73%, respectively. The receiver operating characteristic curve analysis revealed that the combination of interpetrosal S1P and ACTH ratios, as a predictor of tumor laterality, exhibited a sensitivity of 81.82% and a specificity of 75%, with an area under the curve value of 84.09%. Moreover, we observed that a high interpetrosal S1P ratio was associated with nonremission after surgery. Correlation analyses demonstrated that the interpetrosal S1P ratio was associated with preoperative follicle-stimulating hormone (FSH), luteinizing hormone (LH), and postoperative ACTH 8 am levels (P < 0.05)., Conclusion: Our study demonstrated a significant association between the interpetrosal S1P ratio and tumor laterality, as well as postoperative remission in CD, suggesting that the interpetrosal S1P ratio could serve as a valuable biomarker in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Wu, Hu and Xiao.)

Context: Single ACTH measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions., Objective: To investigate the changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD and help establish ACTH cutoffs for targeted clinical trials in CD., Design: Retrospective analysis of CD patients who underwent TSS from 2005 to -2019., Setting: Referral center., Patients: CD patients (n = 253) with ACTH measurements before and after TSS., Interventions: TSS for CD., Main Outcome Measures: Remission after TSS., Results: Remission was observed in 223 patients after TSS. Those in remission had higher ACTH variability at AM (P = .02) and PM (P < .001) time points compared to nonremission. The nonremission group had a significantly narrower diurnal range compared to the remission group (P = <.0001). A decrease in plasma ACTH of ≥50% from mean preoperative levels predicted CD remission after TSS, especially when using PM values. The absolute plasma ACTH concentration and ratio of preoperative to postoperative values were significantly associated with nonremission after multivariable logistic regression (adj P < .001 and .001, respectively)., Conclusions: Our findings suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. These insights could guide clinicians in developing rational outcome measures for interventions targeting CD adenomas., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)

Purpose: Patients with Cushing's disease (CD) experienced transient central adrenal insufficiency (CAI) after successful surgery. However, the reported recovery time of hypothalamic-pituitary-adrenal (HPA) axis varied and the related factors which could affect recovery time of HPA axis had not been extensively studied. This study aimed to analyze the duration of CAI and explore the factors affecting HPA axis recovery in post-operative CD patients with biochemical remission., Methods: Medical records of diagnosis with CD in Huashan Hospital were reviewed between 2014 and 2020. 140 patients with biochemical remission and regular follow-up after surgery were enrolled in this retrospective cohort study according to the criteria. Demographic details, clinical and biochemical information at baseline and each follow-up (within 2 years) were collected and analyzed., Results: Overall, 103 patients (73.6%) recovered from transient CAI within 2 years follow-up and the median recovery time was 12 months [95% confidence intervals (CI): 10-14]. The age was younger and midnight ACTH at baseline was significantly lower, while the TT3 and FT3 levels were significantly higher in patients with recovered HPA compared to patients with persistent CAI at 2-year follow-up (p < 0.05). In persistent CAI group, more patients underwent partial hypophysectomy. TT3 at diagnosis was an independent related factor of the recovery of HPA axis, even after adjusting for gender, age, duration, surgical history, maximum tumor diameter, surgical strategy, and postoperative nadir serum cortisol level (p = 0.04, OR: 6.03, 95% CI: 1.085, 22.508). Among patients with unrecovered HPA axis at 2-year follow-up, 23 CAI patients (62%) were accompanied by multiple pituitary axis dysfunction besides HPA axis, including hypothyroidism, hypogonadism, or central diabetes insipidus., Conclusion: HPA axis recovered in 73.6% of CD patients within 2 years after successful surgery, and the median recovery time was 12 months. TT3 level at diagnosis was an independent related factor of postoperative recovery of HPA axis in CD patients. Moreover, patients coexisted with other hypopituitarism at 2-year follow-up had a high probability of unrecovered HPA axis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Corticotroph adenoma delineation in Cushing's disease (CD) patients with previous surgery can be challenging. This study investigated the outcome of whole-sellar gamma knife radiosurgery (GKRS) in MRI-negative, but hormone-active CD patients with prior failed treatment attempts., Methods: We retrospectively analyzed data of nine CD cases who underwent whole-sellar GKRS between April 2008 and April 2020 at a single center. Remission was determined as normal morning serum cortisol, normal 24-hour urinary free cortisol (UFC) or extended postoperative requirement for hydrocortisone replacement., Results: Median age was 35.0 years, and most of the cases were female (89%). All subjects had undergone previous surgery. The mean pre-GKRS morning serum cortisol and 24-hour UFC were 27.5 μg/dL and 408.0 μg, respectively. Target volume varied from 0.6 to 1.8 cc, and the median margin dose was 28 Gy. The median duration of endocrine follow-up was 105 months, and initial endocrine remission was achieved in eight subjects (89%) at a median time of 22 months. The actuarial initial remission was 44% at two years, 67% at four years, and 89% at six years. The mean recurrence-free survival was 128 months. Age and pre-GKRS morning serum cortisol was found to be predictors for initial and durable endocrine remissions. New-onset hypopituitarism was observed in two of five patients (40%). None of the patients developed new neurological deficits and had GKRS-related adverse events during the follow-up., Conclusions: Whole-sellar GKRS is a safe and efficient method to manage MRI-negative CD and provides similar GKRS outcome rates as in MRI-positive CD.

Cushing's disease (CD) is characterized by endogenous hypercortisolism that is associated with increased mortality and morbidity. Due to high recurrence rates in CD, the determination of high-risk patients is of paramount importance. In this study, we aimed to determine recurrence rates and clinical, laboratory, and histological predictors of recurrence in a high volume single-center. This retrospective study included 273 CD patients operated in a single pituitary center between 1997 and 2020. The patients with early postoperative remission were further grouped according to recurrence status (recurrent and sustained remission groups). Demographic, radiologic, laboratory, pathologic, and follow-up clinical data of the patients were analyzed and compared between groups. The recurrence rate was 9.6% in the first 5 years; however, the overall recurrence rate was 14.2% in this study. Higher preoperative basal ACTH levels were significantly correlated with CD recurrence even with ACTH levels adjusted for tumor size, Ki-67 levels, and tumoral invasion. Recurrence rates were significantly higher in patients with ACTH levels higher than 55 pg/ml, tumor diameter>9.5 mm, and if adrenal axis recovery was before 6 months. The severity of hypercortisolism, morbidities, and demographic factors except age were not predictive factors of recurrence. Based on our study data, younger age at diagnosis, a diagnosis of osteoporosis, higher preoperative ACTH levels, larger tumor size, invasive behavior, higher Ki 67 index, and early recovery of the adrenal axis during the postoperative period attracted attention as potential predictors of recurrent disease., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objective: Adrenocorticotrophic hormone excessive secretion in pituitary-dependent Cushing disease (CD) patients may lead to anatomic variations of the nasal-sphenoidal corridor as a result of hormone-induced abnormal soft tissue change. However, there is still a lack of data on anatomic dimensions in CD patients. In this study, magnetic resonance images were analyzed to determine the anatomic variations of the nasal cavity and sphenoid sinus in CD patients., Methods: A retrospective radiographic analysis was conducted on CD patients undergoing endonasal transsphenoidal surgery as primary treatment between January 2013 and December 2017. A total of 97 CD patients and 100 controls were included. The nasal and sphenoidal anatomic dimensions of CD patients were compared with the control group., Results: Both sides of nasal cavity height, middle nasal meatus width, and inferior nasal meatus width in CD patients were narrower than that of controls. When compared with controls, the ratio of the middle turbinate to middle nasal meatus and the ratio of inferior turbinate to inferior nasal meatus was found to increase on both sides in CD patients. Intercarotid distance of CD patients was shorter than that of controls. The most prevalent pneumatization pattern of CD patients was postsellar, followed by sellar, presellar, and conchal., Conclusions: Cushing disease patients have nasal and sphenoidal anatomic variations affecting the endonasal transsphenoidal surgical corridor, especially the shorter intercarotid distance. The neurosurgeon should be aware of these anatomic variations, and adapt surgical techniques and optimal approaches to reach the sella safely., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Objective: Diagnosis and accurate localization of recurrent tumors in Cushing's disease (CD) are challenging, especially after multiple transsphenoidal surgeries (TSSs) or radiosurgery. Even experts face difficulties in detecting these recurrent tumors, and a favorable surgical outcome is not guaranteed. In this report, the authors aimed to determine the usefulness of 11C-methionine positron emission tomography (MET-PET) for evaluating patients with recurrent CD with inconclusive magnetic resonance imaging (MRI) lesions and to develop a treatment protocol for these cases., Methods: In this retrospective study of patients with recurrent CD in the period between April 2018 and December 2022, the authors assessed the usefulness of MET-PET in determining whether equivocal MRI findings were recurrent tumors or postsurgical cavities and deciding further treatment options. All patients had undergone at least one TSS, and most had undergone multiple TSSs and had pathologically confirmed corticotroph tumors with hypercortisolemia., Results: Overall, 15 patients with recurrent CD (10 females and 5 males) were included, all of whom had undergone MET-PET. All patients had been subjected to multiple treatments, including TSSs or radiosurgeries. Their MRI scans demonstrated less-enhanced lesions that were not confirmed as recurrences even with cutting-edge MRI because they could not be distinguished from postsurgical changes with confidence. MET uptake was positive in 8 patients (9 examinations) and negative in 7. Following MET-PET, repeat TSS was performed in 5 patients. Corticotroph tumors were identified in all 5 patients, even though one of them had negative MET uptake. The MET uptake precisely identified a tumor location on the opposite side of the MRI-suspected lesion in 2 patients. Meanwhile, patients with negative uptake and mild hypercortisolism were only observed. Nonsurgical options were also used in other patients: temozolomide (TMZ) was administered in 2 patients owing to a prior history of multiple TSSs and radiosurgery and the drug-resistant nature of the disease. TMZ was highly effective in these patients; their Cushing's symptoms ameliorated, and their adrenocorticotropic hormone and cortisol levels continued to decline. Interestingly, MET uptake disappeared following TMZ treatment., Conclusions: MET-PET is extremely useful for confirming equivocal lesions on MRI in patients with recurrent CD and for deciding further treatment options. The authors propose a novel protocol based on MET-PET results for treating patients with relapsing CD in whom the recurrent tumors cannot be confirmed with MRI.

Background: Cushing disease represents a challenge for neurosurgeons, with high recurrence rates reported. Characteristics associated with remission are incompletely understood; thus, an intraoperative predictor for outcome would be valuable for assessing resection of adrenocorticotropic hormone (ACTH) secreting tissue., Objective: To evaluate whether intraoperative ACTH measurement could predict outcome after surgery for Cushing disease., Methods: Retrospective cohort study of 55 consecutive encounters with Cushing disease who had peripheral plasma ACTH levels measured intraoperatively before, during, and after tumor resection. The primary outcome measure was remission, defined by either 2 negative 24-hour urine free cortisol or 2 negative midnight salivary cortisol measurements. A logistic regression machine learning model was generated using recursive feature elimination., Results: Fifty-five operative encounters, comprising 49 unique patients, had a mean follow-up of 2.73 years (±2.11 years) and a median follow-up of 2.07 years. Remission was achieved in 69.1% (n = 38) of all operations and in 78.0% (n = 32) of those without cavernous sinus invasion. The final ACTH level measured intraoperatively correctly predicted outcome (area under the curve = 0.766; P value = .002). The odds ratio of remission in patients with the lowest quartile vs highest quartile final intraoperative ACTH was 23.4 ( P value = .002). Logistic regression machine learning model resulted in incorporating postoperative day 1 morning cortisol, final intraoperative ACTH that predicted outcome with an average area under the curve of 0.80 ( P = .0027)., Conclusion: Intraoperative ACTH may predict outcome after surgery in Cushing disease; furthermore, investigation is warranted., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Objective: Recurrent Cushing disease (CD) is characterized by the reappearance of clinical and hormonal aspects of hypercortisolism that occur more than 6 months after an initial post-treatment remission., Methods: We performed a systematic review and meta-analysis to synthesize the evidence about remission and complication rates after transsphenoidal surgery (TSS) radiotherapy (RT) and medical therapy (MT) in recurrent CD patients. A quantitative systematic review was performed. Article selection was performed by searching MEDLINE (using PubMed), and Cochrane electronic bibliographic databases through 2020., Results: We noted 61 articles described therapeutic management of recurrent CD patients with representative outcome. A total of 723 patients received different therapeutic modality for their recurrent CD. The remission rates were 0.65 (95% confidence interval [CI] 0.60-0.70), 0.57 (95% CI 0.51-0.63), and 0.75 (95% CI 0.60-0.86) in the TSS, RT, and MT subgroups, respectively. The total remission rate after therapeutic approaches on recurrent CD patients was 0.64 (95% CI 0.60-0.68). A test for subgroup differences revealed there was a statistically significant difference between different subgroups (P = 0.01). The post hoc test showed that in comparison with RT, TSS (P = 0.0344) and MT (P = 0.0149) had a higher rate of remission. However, there was no statistically significant difference between separate therapeutic modalities in terms of complications including diabetes insipidus (P = 1.0) and hypopituitarism (P = 0.28)., Conclusions: Compared MT and TSS, RT has a statistically lower rate of remission. Although there is robust superiority of surgery over RT, interpretation of MT data must considered with caution due to the small number of included cases and wide CI range., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Pituitary neuroendocrine corticotroph tumors commonly cause Cushing's disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors., Methods: Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry., Results: Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8 -mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors., Conclusions: Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kober, Rusetska, Mossakowska, Maksymowicz, Pękul, Zieliński, Styk, Kunicki, Działach, Witek and Bujko.)

Background: Cushing disease (CD) arises due to a pituitary corticotroph adenoma, which is the most common cause of Cushing syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) is a safe method for differentiating CD from ectopic adrenocorticotropic hormone (ACTH)-dependent CS. Enhanced high-resolution magnetic resonance imaging (MRI) can localize tiny pituitary lesions. The aim of this study was to compare the preoperative diagnostic accuracy of BIPSS versus MRI for CD in CS patients. We performed a retrospective study of patients who underwent BIPSS and MRI between 2017 and 2021. Low- and high-dose dexamethasone suppression tests were performed. Blood samples were collected simultaneously from the right and left catheter and femoral vein before and after desmopressin stimulation. MRI images were obtained, and endoscopic endonasal transsphenoidal surgery (EETS) was performed in confirmed CD patients. Dominant sides of ACTH secretion during BIPSS and MRI were compared with surgical findings., Results: Twenty-nine patients underwent BIPSS and MRI. CD was diagnosed in 28 patients, 27 of whom received EETS. Localizations of microadenomas by MRI and BIPSS agreed with the EETS findings in 96% and 93% of the cases, respectively. BIPSS and EETS were successfully performed on all patients., Conclusion: BIPSS was the most accurate method (gold standard) for establishing a preoperative diagnosis of pituitary-dependent CD and was more sensitive than MRI in diagnosing microadenoma. High-resolution MRI with enhancement had an advantage over BIPSS in microadenoma lateralization diagnostics. The combined use of MRI and BIPSS could improve the preoperative diagnosis accuracy in ACTH-dependent CS patients., (© 2023. The Author(s).)

Cushing's disease (CD) is associated with an increased risk of venous thromboembolic events. The purpose of this review is to discuss preventive strategies for post-operative thrombosis in CD patients and their impact on patient outcomes. A systematic review under PRISMA guidelines was conducted within PubMed, Embase, Web of Science, and Cochrane databases through July 2022. Of the 3207 papers retrieved, seven articles were included in this systematic review. Four hundred forty-eight patients were presented in the reviewed studies and the overall reported mortality was 2.67% (12/448). Three studies utilized prophylaxis methods including graduated compression stockings (GCS) and early ambulation (EA) while the remaining four studies only used anticoagulation medicine. Only 20 patients received pre-operative prophylactic treatment, while 366 patients received post-operative prophylaxis which was delivered either immediately after surgery or at different time intervals within 2 days following the surgery. Thrombotic events mainly occurred within two to 3 months after surgery. Overall, a higher frequency of thromboembolic events and mortality was observed in the control groups in comparison to groups receiving prophylaxis. A combination of anticoagulation, EA, and GCS might reduce thrombotic events and mortality in CD patients after treatment. Although the early commencement of a prophylactic anticoagulation regimen on the same day of surgery and continuing up to 3 months seems beneficial, the application of a prophylactic regimen should be utilized with caution since the number of included studies was insufficient to draw a strong conclusion, as well as neither prospective study nor randomized controlled trials existed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To investigate the association of bone mineral density (BMD) Z-scores with early-postoperative remission rate and clinical parameters in patients with Cushing's disease (CD)., Methods: We retrospectively evaluated the records of patients diagnosed with CD. After the exclusion of 230 patients, 87 CD patients were finally enrolled. BMD was determined by dual-energy x-ray absorptiometry (DXA) at the lumbar spine 1-4 (L1-4) and left femur. Early-postoperative remission was defined as a morning cortisol concentration on the first day after surgery of less than 5 μg/dL. The diagnosis of BMD "below the expected range for age" was defined as a Z-score≤-2.00 standard deviations., Results: DXA results were not significantly associated with early postoperative remission. They also did not significantly differ between eugonadal and menopausal groups. Preoperative morning cortisol significantly negatively but weakly correlated with Z-score of the total femur, while preoperative adrenocorticotropic hormone/cortisol ratio positively but weakly correlated with DXA results of L1-4., Conclusion: The severity of bone loss was not significantly related to the failure of transsphenoidal surgery for Cushing's disease.

Purpose: Pregnancy is associated with the activation of the hypothalamus-pituitary-adrenal axis, which can cause a misdiagnosis of Cushing's syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence rate in Cushing's disease (CD) patients., Methods: This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14-45), PS remission, a follow-up of ≥6 months (median of 122 months, 6-402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing's syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA)., Results: Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses., Conclusions: There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Microscopic and endoscopic transsphenoidal surgeries represent the standard treatment for Cushing's disease (CD). At our institution a new exoscopic approach was implemented. After proof of the general use for transsphenoidal pituitary surgery, the aim of this study was to compare the exoscopic 4K3D video microscope with the microscopic transsphenoidal surgery for patients with CD. We conducted a retrospective analysis on 388 patients with CD treated in our medical center via microscopic transsphenoidal surgery (MTS) between January 2008 and July 2019 or via exoscopic transsphenoidal surgery (ExTS) between May 2019 and May 2021. Parameters investigated included histology, pre- and postoperative MRI with tumor size, pre- and postoperative ACTH and cortisol levels, duration of surgery, perioperative and postoperative complications as well as clinical outcome. Patients who underwent ExTS in CD experienced a lower incidence of SIADH/diabetes insipidus (p = 0.0164), a higher rate of remission (p = 0.0422), and a shorter duration of surgery (p < 0.0001), compared to MTS. However, there was no significant difference regarding new postoperative pituitary insufficiency and intraoperative CSF space opening. We found that ExTS had multiple benefits compared to MTS for tumor resection in case of CD. These results are in line with our previous publication on the general applicability of an exoscope in pituitary surgery. To our knowledge, this is the first clinical study proving the superiority of ExTS in CD. These results are promising, nevertheless further studies comparing exoscopic with the endoscopic approach are necessary to finally evaluate the utility of the new technique., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pituitary-dependent hypercortisolism (PDH) is one of the most common endocrine disorders in veterinary medicine. However, there are few reports on pituitary tumor apoplexy (PTA) in dogs and no reports on its surgical intervention in veterinary medicine. Accordingly, the appropriate treatment is unknown. Herein, a case of PDH and PTA in a dog treated surgically is described., Case Presentation: A mongrel female dog (spayed; age, 8 years and 8 months; weight, 6.1 kg) with persistently elevated alkaline phosphatase underwent adrenocorticotropic hormone (ACTH) stimulation testing (post-stimulation cortisol: 20.5 μg/dL), abdominal ultrasonography (adrenal gland thickness: left, 5.7 mm; right, 8.1 mm), and brain magnetic resonance imaging (MRI) (pituitary-to-brain ratio [PBR], 0.61) at the referral hospital, resulting in a diagnosis of PDH (day 0). On day 9, the dog visited XXXX for the preparation of pituitary surgery to treat PDH. However, on days 10-15, the dog developed a loss of energy and appetite, bloody diarrhea, vomiting, and a decreased level of consciousness. However, on day 16, the dog's condition recovered. A preoperative MRI scan performed on day 52 (the day of surgery) showed apoplexy in the dorsal pituitary region (PBR, 0.68). Based on the PTA findings, the risks of surgery were described to the owner, and approval was obtained. At the time of trans-sphenoidal surgery, a partial pituitary resection was performed with preservation of the PTA area due to adhesions between the PTA area of the right side of the pituitary and surrounding tissues. The resected pituitary tissue was diagnosed as an ACTH-producing adenoma, with necrotic and hemorrhagic findings. As of day 290, endogenous ACTH and cortisol levels did not exceed the reference range., Conclusions: The acute signs that occurred on days 10-15 were most likely caused by PTA. Therefore, when signs similar to those detected in acute hypoadrenocorticism are observed in dogs with PDH, it is necessary to include PTA as a differential diagnosis. Trans-sphenoidal surgery may be effective in PDH-affected dogs that develop PTA, but careful attention should be paid to tissue adhesions secondary to hemorrhage that may occur after PTA., (© 2022. The Author(s).)