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Unlike somatotroph tumors, the data on correlates of tumor granulation patterns in functional TPIT lineage pituitary neuroendocrine tumors (corticotroph tumors) have been less uniformly documented in most clinical series. This study evaluated characteristics of 41 well-characterized functional corticotroph tumors consisting of 28 densely granulated corticotroph tumors (DGCTs) and 13 sparsely granulated corticotroph tumors (SGCTs) with respect to preoperative clinical and radiological findings, tumor proliferative activity (including mitotic count and Ki-67 labeling index), and postoperative early biochemical remission rates. The median (interquartile range (IQR)) tumor size was significantly larger in the SGCT group [16.00 (16.00) mm in SGCT vs 8.5 (9.75) mm in DGCT, p = 0.049]. T2-weighted signal intensity and T2 intensity (quantitative) did not yield statistical significance based on tumor granulation; however, the T2 intensity-to-white matter ratio was significantly higher in SGCTs (p = 0.049). The median (IQR) Ki-67 labeling index was 2.00% (IQR 1.00%) in the DGCT group and 4.00% (IQR 7.00%) in the SGCT group (p = 0.043). The mitotic count per 2 mm2 was higher in the SGCT group (p = 0.001). In the multivariate analysis, the sparse granulation pattern (SGCT) remained an independent predictor of a lower probability of early biochemical remission irrespective of the tumor size and proliferative activity (p = 0.012). The current study further supports the impact of tumor granulation pattern as a biologic variable and warrants the detailed histological subtyping of functional corticotroph tumors as indicated in the WHO classification of pituitary neuroendocrine tumors. More importantly, the assessment of the quantitative T2 intensity-to-white matter ratio may serve as a preoperative radiological harbinger of SGCTs. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery. [ABSTRACT FROM AUTHOR]

Osilodrostat is an 11β-hydroxylase inhibitor used in the treatment of adult patients with Cushing disease. Prolonged adrenal insufficiency (AI) after osilodrostat use is a rare but significant adverse effect. We present the case of a 41-year-old woman treated with osilodrostat for persistent hypercortisolism following pituitary surgery and Gamma Knife radiosurgery. After 11 months of osilodrostat therapy, she reported AI symptoms, and biochemical testing revealed low serum cortisol following cosyntropin stimulation as well as high plasma adrenocorticotropic hormone (ACTH). The patient was started on physiologic replacement dose of hydrocortisone, which was discontinued 23 months after last osilodrostat exposure when laboratory testing revealed recovery of endogenous cortisol production. The mechanism responsible for the prolonged AI noted with osilodrostat use is unclear and unexpected, given the short half-life of the drug. Although prolonged AI after osilodrostat use is not well understood, providers should be aware of this potential adverse effect and have a low threshold to test for AI in patients reporting AI-related symptoms. [ABSTRACT FROM AUTHOR]

Context Spatial transcriptomic (ST) analysis of tumors provides a novel approach to studying gene expression along with the localization of tumor cells in their environment to uncover spatial interactions. Design We present ST analysis of corticotroph pituitary neuroendocrine tumors (PitNETs) from formalin-fixed, paraffin-embedded tissues. ST data were compared to immunohistochemistry results. Gene expression profiles were reviewed for cluster annotations, and differentially expressed genes were used for pathway analysis. Results Seven tumors were used for ST analysis. In situ annotation of tumor tissue was inferred from the gene expression profiles and was in concordance with the annotation made by a pathologist. Furthermore, relative gene expression in the tumor corresponded to common protein staining used in the evaluation of PitNETs, such as reticulin and Ki-67 index. Finally, we identified intratumor heterogeneity; clusters within the same tumor may present with different transcriptomic profiles, unveiling potential intratumor cell variability. Conclusion Together, our results provide the first attempt to clarify the spatial cell profile in PitNETs. [ABSTRACT FROM AUTHOR]

Context During bilateral inferior petrosal sinus sampling (BIPSS), the side-to-side adrenocorticotropic hormone (ACTH) ratio, referred to as sampling lateralization , was used to predict pituitary adenoma localization. Objective To investigate the potential different diagnostic accuracy of BIPSS for differentiating Cushing disease (CD) and ectopic ACTH secretory syndrome (EAS) patients with low lateralization (inferior petrosal sinus [IPS]:IPS ≤ 1.4) and high lateralization (IPS:IPS > 1.4). Methods This single-center retrospective study (2011-2021) included (all patients had BIPSS results and confirmed pathologic diagnoses) 220 consecutive CD patients (validation set), 30 EAS patients, and 40 of the CD patients who had digital subtraction angiography (DSA) videos (discovery set). Results In the discovery set, the low-lateralization CD group (n = 11) had a higher median plasma ACTH concentration (62.2, IQR 44.7-181.0 ng/L) than the high-lateralization CD group (n = 29) (33.0, IQR 18.5-59.5, P =.013). Lower IPS to peripheral ratios were observed in the low-lateralization group during BIPSS, both before and after stimulation (P =.013 and P =.028). The sensitivity of BIPSS before stimulation in differentiating CD from EAS was lower in the low-lateralization group than the high-lateralization group (54.6% vs 93.1%, P =.003), as validated in the validation set. DSA videos revealed higher vascular area difference visible in the 2 sides of the pituitary in low lateralization (median 1.2 × 105 pixels, IQR 0.5-1.8) than the high-lateralization group (0.4 × 105 pixels, IQR 0.1-0.7, P =.008). The vascular area ratio of the 2 sides was also significantly higher in low (1.55, IQR 1.31-2.20) than high lateralization (1.19, IQR 1.07-1.35, P =.010). Conclusion Our study suggested that low lateralization in CD patients may reduce the diagnostic sensitivity of BIPSS, which might be potentially associated with peripituitary vascular anatomy. [ABSTRACT FROM AUTHOR]

Glucocorticoid withdrawal syndrome is a challenging clinical phenomenon that can complicate the postsurgical recovery of Cushing syndrome. It is characterized by physical tolerance and dependence to supraphysiologic glucocorticoid exposure during active Cushing syndrome followed by the abrupt decline in cortisol levels after surgical treatment. The symptoms of glucocorticoid withdrawal often overlap with those of postoperative adrenal insufficiency and can be difficult for patients to cope with and for clinicians to treat. This mini review will discuss the clinical characteristics, pathophysiology, and management of glucocorticoid withdrawal syndrome while highlighting recent data in the field. [ABSTRACT FROM AUTHOR]

Objective: Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure. Methods: Two cases of DPA patients with Cushing's disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission. Results: Among 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing's syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/ 118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (<1cm) were the most frequent in terms of tumor size (62/92, 67.39%). The detection rate for double lesions on 3.0T MRI was 50.00% (14/28), which significantly higher than 1.5T MRI (P = 0.034). Univariate analysis revealed that female, Cushing's syndrome and only single lesion detected by surgical exploration were associated with significantly worse prognosis (P<0.05). Multivariate analysis identified double lesion detected by surgical exploration (OR = 0.08, P = 0.003) and contiguous type tumor (OR = 0.06, P = 0.017) as independent protective factors for DPA patients. Conclusions: The double lesion detected by surgical exploration is independently associated with a better prognosis for DPA patients. Comprehensive intraoperative exploration are crucial measures to avoid missing causative lesions. [ABSTRACT FROM AUTHOR]

Context Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. Objective We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. Methods Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naïve (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. Results The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P <.01). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells. Conclusion We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu. [ABSTRACT FROM AUTHOR]

We evaluated the accuracy of the 10 mg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering DACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Dcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of DACTH > 35% and Dcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering DACTH, Dcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different. [ABSTRACT FROM AUTHOR]

Context Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling (IPSS), is expensive and not widely available. Objective Evaluate the performance of the corticotropin-releasing hormone stimulation test (CRH-ST) and the 8 mg high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease (CD) from ectopic ACTH syndrome (EAS). Methods Retrospective review in a tertiary referral center. A total of 323 patients with CD or EAS (n = 78) confirmed by pathology or biochemical cure (n = 15) in 96% underwent CRH-ST and HDDST performed between 1986 and 2019. We calculated test sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value, and diagnostic accuracy (DA) for the diagnosis of CD, and determined optimal response criteria for each test, alone and in combination. Results The CRH-ST performed better than the HDDST (DA 91%, 95% CI 87-94% vs 75%, 95% CI 69-79%). Optimal response criteria were a ≥40% increase of ACTH and/or cortisol during the CRH test and a ≥69% suppression of cortisol during the HDDST. A ≥40% cortisol increase during the CRH test was the most specific measure, PPV 99%. Seventy-four percent of subjects had concordant positive CRH test and HDDST results, yielding Se 93%, Sp 98%, DA 95%, and PPV 99%, with a pretest likelihood of 85%. A proposed algorithm diagnosed 64% of patients with CD with near perfect accuracy (99%), obviating the need for IPSS. Conclusion CRH is a valuable tool to correctly diagnose the etiology of ACTH-dependent CS. Its current worldwide unavailability impedes optimal management of these patients. [ABSTRACT FROM AUTHOR]

Morphometric vertebral fractures (VFs) and osteopathy are prevalent and clinically significant complications of Cushing disease (CD). However whether they represent an early occurrence in the natural progression of the disease is an ongoing debate. This study aimed to assess the prevalence and determinants of VFs in patients newly diagnosed with CD. This cross-sectional case–control study recruited 75 newly diagnosed CD patients and compared them with a control group of individuals without pituitary disorders or secondary forms of osteoporosis. Demographic, clinical and biochemical data were collected. The VFs were assessed using preoperative lateral chest radiography. We found a significantly higher prevalence of VFs in the CD group than in the control group (58.7% vs. 14.5%; P < 0.001). Among the CD patients with VFs, 27 (61.4%) showed moderate/severe VFs. The CD patients with VFs had significantly higher preoperative 8 am serum cortisol (8ASC) levels than those without VFs (P < 0.001). The preoperative 4 pm adrenocorticotropic hormone (ACTH) levels (P = 0.031), preoperative 0 am ACTH levels (P = 0.021) and systolic blood pressure were slightly higher in CD patients with VFs than in those without VFs (P = 0.028). A binary multiple logistic analysis showed that 8ASC was an independent predictor of VF risk (P = 0.003). The optimal cut-off value of the preoperative serum 8ASC level for predicting VFs was 22.18 ng/mL. This is the first study reporting a high prevalence of radiologic VFs in recently diagnosed CD patients. VFs may represent an early manifestation of CD and may be related to cortisol levels. Therefore, VF assessment should be included in the workup during CD diagnosis. [ABSTRACT FROM AUTHOR]

Context: In Cushing disease, the association between the rate of serum Cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized. Objective: To analyze postoperative serum cortisol and recurrence rates in Cushing disease. Methods: Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables. Results: A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P< .0001). Conclusion: Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery. [ABSTRACT FROM AUTHOR]

While magnetic resonance imaging (MRI) is the current standard imaging method for diagnosing and localizing corticotropinomas in Cushing disease, it can fail to detect adenomas in up to 40% of cases. Recently, positron emission tomography (PET) has shown promise as a diagnostic tool to detect pituitary adenomas in Cushing disease. We perform a scoping review to characterize the uses of PET in diagnosing Cushing disease, with a focus on describing the types of PET investigated and defining PET-positive disease. A scoping review was conducted following the PRISMA-ScR guidelines. Thirty-one studies fulfilled our inclusion criteria, consisting of 10 prospective studies, 8 retrospective studies, 11 case reports, and 2 illustrative cases with a total of 262 patients identified. The most commonly utilized PET modalities in prospective/retrospective studies were FDG PET (n = 5), MET PET (n = 5), 68 Ga-DOTATATE PET (n = 2), 13N-ammonia PET (n = 2), and 68 Ga-DOTA-CRH PET (n = 2). MRI positivity ranged from 13 to 100%, while PET positivity ranged from 36 to 100%. In MRI-negative disease, PET positivity ranged from 0 to 100%. Five studies reported the sensitivity and specificity of PET, which ranged from 36 to 100% and 50 to 100%, respectively. PET shows promise in detecting corticotropinomas in Cushing disease, including MRI-negative disease. MET PET has been highly investigated and has demonstrated excellent sensitivity and specificity. However, preliminary studies with FET PET and 68 Ga-DOTA-CRH PET show promise for achieving high sensitivity and specificity and warrant further investigation. [ABSTRACT FROM AUTHOR]

A 41-year-old woman presented with a headache, diplopia, weight gain, moon face, and central obesity. Her plasma adrenocorticotropin (ACTH) level was 25.5 pmol/L (116 pg/mL) (normal range, 1.6-13.9 pmol/L [7.2-63.3 pg/mL]), serum cortisol level was 397.3 nmol/L (14.4 µg/dL) (normal range, 195.1-540.7 nmol/L [7.1-19.6 µg/dL]), and urinary free cortisol was 413.9 nmol/day (150.3 µg/day) (normal range, <221.5 mmol/day [<80.3 µg/day]). ACTH-dependent hypercortisolism was present, with cortisol suppression using a high-dose dexamethasone suppression test. Cushing disease was diagnosed and a contrast-enhanced magnetic resonance imaging scan demonstrated a 36-mm pituitary tumor with right cavernous sinus invasion. Before surgery, 20 mg pasireotide long-acting-release was initiated, and her symptoms rapidly improved. After 1 month, obvious tumor shrinkage was observed, ACTH and cortisol levels decreased, and diplopia resolved; therefore, we continued medical therapy. After 11 months, her ACTH and cortisol levels normalized, and most of the tumor had disappeared. The clinical course in this case suggests that pasireotide may be useful for preoperative treatment and primary medical therapy, at least in some patients with Cushing disease caused by a large tumor predicted to have difficulty achieving remission by surgery. [ABSTRACT FROM AUTHOR]

The occurrence of a second neoplasm possibly constitutes an adverse and uncommon complication after radiotherapy. The incidence of a second pituitary tumor in patients irradiated for adrenocorticotropic hormone secreting pituitary adenoma is rare. We report a case of a 40-year-old female with Cushing disease who underwent surgical management followed by radiotherapy. After 5 years of initial treatment, an increase in tumor size was evident at the same location, with a significant interval growth of the parasellar component of the lesion. Histology revealed an undifferentiated highly malignant sarcoma. In the span of next 2 years, the patient was followed with 2 repeat decompression surgeries and radiotherapy because of significant recurrent compressive symptoms by locally invasive malignant tumor. Despite the best efforts, the patient remained unresponsive to multiple treatment strategies (eg, surgical resections and radiotherapy) and succumbed to death. [ABSTRACT FROM AUTHOR]

Crooke cell adenoma (CCA) is a rare and aggressive subtype of a corticotroph adenoma, which requires lifetime surveillance. There have been 106 cases of CCAs reported in the English literature. We describe 2 cases of CCA, a 48-year-old man and an 84-year-old woman who both presented with binocular diplopia and temple pain. Neither case had clinical Cushing syndrome. Laboratory values for the 48-year-old man revealed, adrenocorticotropin (ACTH) 103 pg/mL (22 pmol/L) (RR: 7-63 pg/mL) and evening cortisol 14 µg/dL (386 nmol/L) (RR: 2.7-10.5 µg/dL). Computed tomography imaging demonstrated a mass adjacent to the right cavernous sinus extending into the sphenoid sinus. He underwent tumor resection with adjuvant radiation and has had a stable residual tumor for 4 years. Preoperative laboratory values for the 84-year-old woman revealed, ACTH 69 pg/mL (15 pmol/L) (RR: 7-63 pg/mL) and evening cortisol 16.2 µg/dL (447 nmol/L) (RR: 2.7-10.5 µg/dL). Brain magnetic resonance imaging revealed, a mass compressing the optic chiasm. She underwent resection and has had a stable residual tumor for 2 years. Surgical pathology in both cases revealed cytoplasmic hyaline deposits of more than 50% of the tumor cells, consistent with CCA. The CCA although rare, should be considered when evaluating cases with subclinical Cushing disease and visual symptoms. [ABSTRACT FROM AUTHOR]

Background: Cushing disease (CD) is a very rare form of hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Clinical manifestations of CD can include central fat accumulation, arterial hypertension, glucose intolerance, skin atrophy with striae, and hypogonadism. Children are frequently diagnosed due to a growth stunt and excessive weight gain while classic cushingoid signs might be initially absent. Other children-specific presentations of CD are early or delayed puberty and hyperandrogenism in girls. Summary: We present the main outcomes of clinical trials of osilodrostat (Isturisa®, Recordati) for CD, and its initial development as an aldosterone synthase inhibitor. Osilodrostat is indicated only when the surgical therapy of the pituitary adenoma is not an option or has not been curative; additionally, other steroidogenesis inhibitors were briefly summarized. Clinical trials of osilodrostat in children are lacking and we describe its potential role in the pediatric population. Key Messages: Osilodrostat is the first adrenal steroidogenesis inhibitor to be European Medicines Agency- and United States Food and Drug Administration-approved (both in 2020) for the treatment of adults with Cushing syndrome/disease. Phase II and III clinical trials have shown its efficacy in normalizing 24-h urinary-free cortisol and a good safety profile. Osilodrostat's pharmacological properties and safety are currently being evaluated in a small Phase II trial (NCT03708900) – the first trial in the pediatric population (<18 years) with an estimated completion date in the year 2023. [ABSTRACT FROM AUTHOR]

Background: Cushing disease (CD) may lead to accelerated cardiovascular remodeling and increased mortality. There are suspected differences in the mechanism of cardiovascular dysfunction between males and females with CD. The purpose of this study was to assess the effect of patient sex on the hemodynamic profile assessed via impedance cardiography and echocardiography in patients newly diagnosed with CD. Material and methods: The 54 patients newly diagnosed with CD (mean age 41 years; 77.8% of females) who were included in this prospective clinical study underwent impedance cardiography to assess specific parameters (including systemic vascular resistance index [SVRI], total arterial compliance index [TACI], Heather index [HI], stroke index [SI], cardiac index [CI], velocity index [VI], and acceleration index [ACI]) and transthoracic echocardiography to assess heart chamber diameters and left ventricular systolic and diastolic function. Results: Males with CD exhibited higher afterload, with higher SVRI (3,169.3 ± 731.8 vs. 2,339.3 ± 640.8 dyn*s*cm-5*m² in males and females, respectively; p=0.002), lower TACI (0.80 ± 0.30 vs. 1.09 ± 0.30 mL/mmHg*m²; p=0.008), and lower hemodynamic parameters of left ventricular function, with lower HI (9.46 ± 2.86 vs. 14.1 ± 5.06 Ohm/s²; p=0.0007), lower VI (35.1 ± 11.9 vs. 44.9 ± 13.1 1*1000-1*s-1; p=0.009), lower SI (36.5 ± 11.7 vs. 43.6 ± 9.57mL/m²; p=0.04), lower CI (2.36 ± 0.46 vs. 3.17 ± 0.76 mL*m-2*min-1; p=0.0009), and lower ACI (50.4 ± 19.8 vs. 73.6 ± 25.0 1/100/s²; p=0.006). There were no significant differences between the sexes in left ventricular systolic or diastolic function assessed by echocardiography. Conclusion: In comparison with females with CD, males with CD have a less favorable hemodynamic profile, with higher afterload and worse left ventricular function. Sex differences in cardiovascular system function should be taken into consideration in designing personalized diagnostic and therapeutic management of patients with CD. [ABSTRACT FROM AUTHOR]

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

The article discusses the challenges in diagnosing and treating Cushing disease (CD), a condition characterized by excessive cortisol production. While surgery is the preferred treatment, some patients experience relapse and require alternative options. Currently available medications have limitations and side effects. The article highlights several novel targeted therapies for CD, including tyrosine kinase inhibitors and ACTH-neutralizing monoclonal antibodies, but notes that these are not yet available for clinical use. The article also discusses a recent study that screened over 2400 compounds and identified an antibiotic called thiostrepton (TS) as a potential treatment option. However, further research is needed to determine its effectiveness in controlling hormonal hypersecretion in human patients. [Extracted from the article]

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism resulting from an ACTH-secreting tumor or from autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Nonneoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for more than 50 years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have nonneoplastic hypercortisolism: one from a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate stimulation test to aid in distinguishing neoplastic from nonneoplastic hypercortisolism. [ABSTRACT FROM AUTHOR]

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Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function. [ABSTRACT FROM AUTHOR]

Cushing disease (CD) is the main cause of endogenous Cushing syndrome (CS) and is produced by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma. Its relevance in pediatrics is due to the retardation of both growth and developmental processes because of hypercortisolism. In childhood, the main features of CS are facial changes, rapid or exaggerated weight gain, hirsutism, virilization, and acne. Endogenous hypercortisolism should be established after exogenous CS has been ruled out based on 24-hour urinary free cortisol, midnight serum or salivary cortisol, and dexamethasone suppression test; after that, ACTH dependence should be established. The diagnosis should be confirmed by pathology. The goal of treatment is to normalize cortisol level and reverse the signs and symptoms. Treatment options include surgery, medication, radiotherapy, or combined therapy. CD represents a challenge for physicians owing to its multiple associated conditions involving growth and pubertal development; thus, it is important to achieve an early diagnosis and treatment in order to control hypercortisolism and improve the prognosis. Its rarity in pediatric patients has led physicians to have limited experience in its management. The objective of this narrative review is to summarize the current knowledge about the pathophysiology, diagnosis, and treatment of CD in the pediatric population. [ABSTRACT FROM AUTHOR]

Successful treatment of endogenous Cushing disease (CD) is often followed by a period of adrenal insufficiency (AI). We performed an exploratory study on genetic factors potentially involved in the hypothalamic-pituitary-adrenal (HPA) axis recovery in patients with CD after remission. We identified 90 patients who achieved remission after surgery and had a minimum of 3 months follow-up. Variants in a selected panel of genes that were rare in the general population and predicted as damaging in silico were retrieved from whole exome sequencing analysis. We did not identify any variant with significant correlation with recovery time after adjusting for multiple comparisons. On gene-specific analysis the BAG1 gene showed a correlation with shorter duration of postsurgical AI, but both patients with BAG1 variants later experienced a recurrence. After excluding patients with recurrence, no statistical association was recorded. To conclude, we did not identify a strong genetic modifier of HPA recovery in this exploratory study. [ABSTRACT FROM AUTHOR]

Context: Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. Objective: The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. Methods: This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. Results: Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. Conclusion: The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed. [ABSTRACT FROM AUTHOR]

Abstarct: Purpose: The diagnostic value of adding a Corticotropin-Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. Methods: We identified 65 patients with Cushing disease (CD) and 42 patients in whom a diagnosis of Cushing disease could not be confirmed (NCD) after a minimum follow-up of 14 months who underwent the Dex-CRH test. Results: The female sex ratio, median (range) age, and BMI were similar between the two groups. The follow-up for patients with CD and NCD was 74 (4–233) and 52 (14–146) months, respectively. Among 65 patients with CD, 5 (7.7%) had a cortisol level ≤1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of three patients, the LDDST was marginally normal (cortisol was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cutoff value of >1.4 µg/dL during the Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded (n = 74), the sensitivity did not change, but the specificity and accuracy of the Dex-CRH test increased to 97 and 99%, respectively. Conclusion: The Dex-CRH Test provided additional case detection in 5/65 (7.7%) patients with CD. It resulted in one false-positive case compared to LDDST. Measurement of dexamethasone improved diagnostic accuracy of the test. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate and compare the clinical, biochemical and radiological profile and outcomes of patients with ectopic ACTH syndrome (EAS) and Cushing disease (CD) treated over a period of 10 years (2013–2022). Methods: In this ambispective observational study, we collected data for 146 patients with ACTH-dependent CS (EAS, n = 23; CD, n = 94; occult ACTH source, n = 29). Relevant details were filled in a predesigned proforma and outcomes were ascertained at the most recent visit. Results: EAS was more common in males (65.2 vs. 27.6%, p < 0.001). Patients with EAS had a shorter duration of symptoms [12 (6–12) vs. 31.5 (15–48) months, p < 0.001] and were more likely to have hypokalemia (82.6 vs. 21.0%, p = 0.001), pedal edema (65.2 vs. 34.2%, p = 0.015), weight loss (34.8 vs. 4.0%, p < 0.001) and systemic infection (30.4 vs. 6.5%, p = 0.006). They also had significantly higher 8 a.m. serum cortisol, midnight serum and salivary cortisol and 8 a.m. plasma ACTH levels. Bronchial carcinoid (n = 10, 43.5%) was the most common etiology of EAS. Bilateral adrenalectomy was performed in 11 (47.8%) patients with EAS. Eight patients (34.8%) with EAS died at the last follow-up, of whom 7 (87.5%) had metastatic disease. In CD group, overall remission rate was 69.4% (56.1%, early and 13.3%, delayed) and 26.3% of patients with an initial remission had recurrence. Conclusions: Bronchial carcinoid was the most common cause of EAS in our cohort. Bilateral adrenalectomy was performed in approximately every 1 in 2 patients with EAS and approximately every 1 in 3 patients expired till the last follow-up. [ABSTRACT FROM AUTHOR]

Context: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. Objective: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). Methods: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; =50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or = 50% reduction in UFC from baseline to study end. Results: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4±140.3 µg/24 hours at baseline to 131.3± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved = 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P=0.01) in patients who achieved = 48% UFC reduction. Three patients developed grade = 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liverrelated serious adverse events that resolved within 4 weeks of seliciclib discontinuation. Conclusion: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination. [ABSTRACT FROM AUTHOR]

Background: The complex nature and heterogeneity involving pituitary surgery results have increased interest in machine learning (ML) applications for prediction of outcomes over the last decade. This study aims to systematically review the characteristics of ML models involving pituitary surgery outcome prediction and assess their reporting quality. Methods: We searched the PubMed, Scopus, and Web of Knowledge databases for publications on the use of ML to predict pituitary surgery outcomes. We used the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) to assess report quality. Our search strategy was based on the terms "artificial intelligence", "machine learning", and "pituitary". Results: 20 studies were included in this review. The principal models reported in each article were post-surgical endocrine outcomes (n = 10), tumor management (n = 3), and intra- and postoperative complications (n = 7). Overall, the included studies adhered to a median of 65% (IQR = 60–72%) of TRIPOD criteria, ranging from 43% to 83%. The median reported AUC was 0.84 (IQR = 0.80–0.91). The most popular algorithms were support vector machine (n = 5) and random forest (n = 5). Only two studies reported external validation and adherence to any reporting guideline. Calibration methods were not reported in 15 studies. No model achieved the phase of actual clinical applicability. Conclusion: Applications of ML in the prediction of pituitary outcomes are still nascent, as evidenced by the lack of any model validated for clinical practice. Although studies have demonstrated promising results, greater transparency in model development and reporting is needed to enable their use in clinical practice. Further adherence to reporting guidelines can help increase AI's real-world utility and improve clinical practice. [ABSTRACT FROM AUTHOR]

The article discusses the challenges in diagnosing Cushing syndrome (CS), a complex disease that can be caused by adrenocorticotrophic hormone (ACTH)-dependent or -independent factors. The gold standard for differentiating between these causes is bilateral inferior petrosal sinus sampling (BIPSS), an invasive but safe procedure. However, BIPSS is not widely available, leading researchers to explore alternative noninvasive tests such as the high-dose dexamethasone suppression test (HDDST) and corticotrophin-releasing hormone (CRH) stimulation test. The study by Elenius and colleagues proposes an algorithm using these tests to aid in the differential diagnosis of ACTH-dependent CS, potentially reducing the need for BIPSS. However, more research is needed to validate these noninvasive strategies. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

In Cushing's disease (CD) patients, the aim of the present study is to confirm sensitivity of several ACTH and cortisol concentration values in different time points, during corticotropin-releasing hormone (CRH) stimulation test and during CRH stimulation following dexamethasone suppression (DEX-CRH) test. We retrospectively analyzed cortisol and ACTH concentration increment during CRH and DEX-CRH tests in 23 patients with confirmed CD. Cortisol and ACTH concentrations were determined immediately before, 15 min and 30 min after CRH stimulation. We evaluated the sensitivity of different cutoff values including those reported in previous studies, in the diagnosis of CD. During DEX–CRH test, 15 min serum cortisol concentration of 1.4 μg/dl (38 nmol/L) had a sensitivity of 90.9%, and serum cortisol concentration ≥1.27 μg/dl (35 nmol/L) had a sensitivity of 100%. For plasma ACTH, sensitivity of 100% was obtained using ACTH ≥3.5pmol/L (16 pg/ml) at 30 min. During CRH test, 35% increase from baseline in ACTH concentration had a sensitivity of 72.7%. Twenty percent increase in cortisol 30 minutes after stimulation yielded a sensitivity of 85.7%. The best sensitivity of ACTH and cortisol increment was obtained 15 min after stimulation, using 19% and 9% increase, respectively (sensitivity of 100% and 92.8%, respectively). During CRH and DEX-CRH tests, the study findings agree with the good sensitivity of ACTH and cortisol cutoff values suggested in previous studies; yet, other cutoff values may give a higher diagnostic sensitivity. [ABSTRACT FROM AUTHOR]

Purpose: Cushing Syndrome (CS) is a rare endocrine disorder associated with physical and mental symptoms that can drastically affect quality of life (QoL). This study characterizes QoL in patients with CS, describes their treatment experiences, and identifies patient subsets associated with decreased QoL or shared impressions of treatment. Methods: A 136-question survey addressing QoL factors and treatment experiences was completed by adult patients with CS from the Cushing Support and Research Foundation. Patient demographics, tumor characteristics, and treatment information were collected. Bivariate analyses were conducted to determine if patients' symptoms or treatment experiences were significantly associated with demographics or other variables. Results: A total of 178 patients, predominantly female (94%) with mean age 53 years, completed the survey. Anxiety and/or depression (n = 163, 94%), loss of physical strength (n = 164, 93%), loneliness (n = 156, 90%), fatigue from treatment (n = 142, 89%), memory loss (n = 153, 88%), insomnia (n = 144, 83%), and pain (n = 141, 83%) were symptoms most commonly experienced by respondents. Patients experiencing delay of diagnosis >10 years were more likely to have suicidal thoughts (p = 0.002). Younger patients were more likely to express concerns about hair loss (p = 0.007), loneliness (p = 0.025), pain (p = 0.004), or the impact of CS on their marriage (p = 0.039) or children (p = 0.024). Conclusion: This survey demonstrates CS impacts patients across many dimensions, emphasizing the need for holistic support. We identified patient subsets in which QoL may be improved with additional patient resources or provider attention. [ABSTRACT FROM AUTHOR]

This case report describes a practical approach for diagnosing and treating a 17-month-old Syrian hamster with hyperadrenocorticism based on: history, systemic signs, dermatological lesions, and therapeutic trial. The patient was monitored for 16 weeks while he was treated with trilostane and achieved hair regrowth and the resolution of systemic and demeanour signs. [ABSTRACT FROM AUTHOR]

Cushing disease (CD) is caused by a pituitary tumor which oversecretes adrenocorticotropic hormone (ACTH). It is a serious endocrine disease associated with increased mortality and impaired quality of life. The management of CD remains challenging. Although transsphenoidal surgery is the treatment of choice in most cases, in approximately half of CD patients, second or third-line treatment options are needed. Currently, new medical therapies are available which target adrenal steroidogenesis, pituitary somatostatin and dopamine receptors, and glucocorticoid receptors. Selection of which medication to use should be individualized and is determined by many factors including severity of the disease, possible side effects, patients preferences and local availability. The aim of this article is to describe currently available medical therapy to help clinicians individualize the treatment options in the context of recently updated Pituitary Society recommendations. [ABSTRACT FROM AUTHOR]

Copyright of Nouveau Praticien Vétérinaire Canine & Féline is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The desmopressin test was first described 30 years ago. Based on the differential secretagogue properties of desmopressin on adrenocorticotropin (ACTH) release between normal and corticotroph tumor cells, this test was intended to facilitate the diagnosis of Cushing syndrome (CS). The distinct expression of the various arginine vasopressin receptors between normal pituitary, corticotroph tumors, or neuroendocrine tumors cells secreting ACTH ectopically suggested that this test could facilitate the etiological diagnosis of ACTH-dependent CS. In this review, we analyze the merits and pitfalls of desmopressin use in the diagnostic procedures of CS. Desmopressin response is not able to completely differentiate the various etiologies of CS; its wider availability has allowed its use for inferior petrosal sinus sampling confirmation of a pituitary source of ACTH excess. In addition, desmopressin can be useful to demonstrate adequate corticotroph tumor resection when its stimulatory effect is lost following pituitary surgery of patients with Cushing disease. Desmopressin response can also be a marker of the risk of longer-term postoperative recurrence. However, this review also highlights the lack of consensual criteria of normal or abnormal response to desmopressin in its various uses and requirement for further research on its usefulness. [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) is a diagnosis used to describe multiple causes of serum hypercortisolism. Cushing's disease (CD), the most common endogenous subtype of CS, is characterized by hypercortisolism due to a pituitary tumor secreting adrenocorticotropic hormone (ACTH). A variety of tests are used to diagnose and differentiate between CD and CS. Hypercortisolism has been found to cause many metabolic abnormalities including hypertension, hyperlipidemia, impaired glucose tolerance, and central adiposity. Literature shows that many of the symptoms of hypercortisolism can improve with a low carb (LC) diet, which consists of consuming <30 g of total carbohydrates per day. Here, we describe the case of a patient with CD who presented with obesity, hypertension, striae and bruising, who initially improved some of his symptoms by implementing a LC diet. Ultimately, as his symptoms persisted, a diagnosis of CD was made. It is imperative that practitioners realize that diseases typically associated with poor lifestyle choices, like obesity and hypertension, can often have alternative causes. The goal of this case report is to provide insight on the efficacy of nutrition, specifically a LC diet, on reducing metabolic derangements associated with CD. Additionally, we will discuss the importance of maintaining a high index of suspicion for CD, especially in those with resistant hypertension, obesity and pre-diabetes/diabetes. [ABSTRACT FROM AUTHOR]

First-line treatment for Cushing´s disease is transsphenoidal surgery. But in cases of persistent or recurrent disease after surgery, contraindications to surgery, severe hypercortisolism control before surgery, or for patients waiting for radiotherapy effects, medical therapy may be indicated. Pituitary-directed agents include cabergoline and pasireotide. Both drugs present similar potential for biochemical control and pasireotide has additionally been proved to reduce tumor volume. Moreover, pasireotide was evaluated in high quality studies. In respect to safety, both drugs are well tolerated and safe, but special attention should be given for cardiac valve disease and psychiatric disorder for cabergoline, and hyperglycemia for pasireotide. [ABSTRACT FROM AUTHOR]

Context: Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease. Objective: This work investigated whether defined patient populations should be screened outside the at-risk populations defined in current guidelines. Methods: As part of the prospective German Cushing registry, we studied 377 patients with suspected CS. The chief complaint for CS referral was documented. Using urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test as well as long-term clinical observation, CS was confirmed in 93 patients and ruled out for the remaining 284. Results: Patients were referred for 18 key symptoms, of which 5 were more common in patients with CS than in those in whom CS was ruled out: osteoporosis (8% vs 2%; P = .02), adrenal incidentaloma (17% vs 8%, P = 0.01), metabolic syndrome (11% vs 4%; P = .02), myopathy (10% vs 2%; P < .001), and presence of multiple symptoms (16% vs 1%; P < .001). Obesity was more common in patients in whom CS was ruled out (30% vs 4%, P < .001), but recent weight gain was prominent in those with CS. A total of 68 of 93 patients with CS (73%) had typical chief complaints, as did 106 of 284 of patients with ruled-out CS status (37%) according to the Endocrine Society practice guideline 2008. Conclusion: The 2008 Endocrine Society Practice guideline for screening and diagnosis of CS defined at-risk populations that should undergo testing. These recommendations are still valid in 2022. [ABSTRACT FROM AUTHOR]

Context: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks' open-label osilodrostat). Results: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusion: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable. [ABSTRACT FROM AUTHOR]

Context: Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. Objectives: This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. Methods: A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. Results: Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). Conclusion: This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas. [ABSTRACT FROM AUTHOR]

Context Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion. Objective Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD). Design Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission. Results Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4], P  = 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3], P  = 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4), P  = 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status. Conclusions A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively. [ABSTRACT FROM AUTHOR]

Purpose: Literature regarding endogenous Cushing syndrome (CS) largely focuses on the challenges of diagnosis, subtyping, and treatment. The enigmatic phenomenon of glucocorticoid withdrawal syndrome (GWS), due to rapid reduction in cortisol exposure following treatment of CS, is less commonly discussed but also difficult to manage. We highlight the clinical approach to navigating patients from GWS and adrenal insufficiency to full hypothalamic-pituitary-adrenal (HPA) axis recovery. Methods: We review the literature on the pathogenesis of GWS and its clinical presentation. We provide strategies for glucocorticoid dosing and tapering, HPA axis testing, as well as pharmacotherapy and ancillary treatments for GWS symptom management. Results: GWS can be difficult to differentiate from adrenal insufficiency and CS recurrence, which complicates glucocorticoid dosing and tapering regimens. Monitoring for HPA axis recovery requires both clinical and biochemical assessments. The most important intervention is reassurance to patients that GWS symptoms portend a favorable prognosis of sustained remission from CS, and GWS typically resolves as the HPA axis recovers. GWS also occurs during medical management of CS, and gradual dose titration based primarily on symptoms is essential to maintain adherence and to eventually achieve disease control. Myopathy and neurocognitive dysfunction can be chronic complications of CS that do not completely recover. Conclusions: Due to limited data, no guidelines have been developed for management of GWS. Nevertheless, this article provides overarching themes derived from published literature plus expert opinion and experience. Future studies are needed to better understand the pathophysiology of GWS to guide more targeted and optimal treatments. [ABSTRACT FROM AUTHOR]

We report a case of a patient who presented for ACTH‐dependent Cushing after a confirmed hypercortisolism and an inadequate normal ACTH. A transsphenoidal surgery of a pituitary picoadenoma has been done. After surgery, the patient showed the persistence of hypercortisolism. CT scan revealed adrenal adenomas removed surgically and improved the patient. The concomitant coexistence of ACTH‐dependent and independent Cushing syndrome remains extremely rare. The difficulty is to determine whether the adrenal dependency existed at the time of the diagnosis or if it developed postoperatively. [ABSTRACT FROM AUTHOR]

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors. [ABSTRACT FROM AUTHOR]

Context: Spinal Epidural Lipomatosis (SEL) is a rare and frequently unrecognized complication of Cushing syndrome (CS). Only nine previous cases of SEL have been described in CS. Here, we present a case of severe SEL and review the literature. Case report: A 29-year-old man who had severe CS secondary to an ACTH-secreting pituitary macroadenoma. He presented with progressive lower limb weakness over a 2-year period leading to complete paraplegia in the last 4 months. In addition, he had classic symptoms and signs of severe CS. His evaluation confirmed the diagnosis of CS with a 4-fold increase in his daily free urinary cortisol (1190 mg/day), a positive 1-mg dexamethasone suppression test (AM cortisol 729 nmol/l) and an elevated ACTH of 196 ng/dl (10–65). Magnetic resonance imaging (MRI) revealed a 20-mm pituitary adenoma and extensive fat accumulation in the spinal canal extending from C7 to S5 with significant spinal cord compression from T2-T10. The patient underwent an urgent spinal cord decompression surgery. He showed an immediate improvement and was able to walk with crutches 3 weeks later and independently 3 months later. About 13 days after the spinal surgery, he underwent a trans-sphenoidal surgery resulting in eucortisolemia. Conclusion: SEL is a rare and serious complication of CS. It should be considered in any patient with CS, especially when there is neurological symptoms or disproportionate weakness of the lower limbs. Its management should be individualized but prompt surgical decompression should be considered even in patients with relatively long history of paraparesis. [ABSTRACT FROM AUTHOR]

Purpose: In Cushing disease, early post-operative serum cortisol fluctuations have not been adequately characterized, and their association with initial remission and recurrence is unclear. Methods: A retrospective cohort study of patients with Cushing disease was conducted at two institutions. A "riser" was defined a priori as a paradoxical increase in serum cortisol with an immediate incremental increase in serum cortisol over three consecutive cortisol draws separated by roughly 6-h (definition 1). Post hoc analyses used a definition of two consecutive increases (definition 2). Risers were compared to non-risers for initial remission and time-to-recurrence. Results: A total of 505 patients with Cushing disease were screened, and 469 had adequate data for group assignment. Analysis of post-operative cortisol showed a subgroup of "risers" with a frequency of 3.6% for definition 1 and 42.6% for definition 2. In these patients, cortisol levels were significantly higher until approximately 36 h post-operatively, and cortisol had a significantly longer mean serum half-life. In the post hoc analysis, definition 2 risers had a lower remission rate compared to non-risers (162/196, 82.7%, versus 243/264, 92.0%) with an odds ratio of 0.41 (0.23–0.73; p = 0.003). For both definitions, recurrence was similar between groups. Conclusions: We found that almost half of Cushing disease patients experienced a temporary increase in serum cortisol level during the early post-operative period. Serum cortisol half-life was longer, and the remission rates were lower, however, recurrence rates were similar to non-risers. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of hypercortisolism on the developing brain we performed clinical, cognitive, and psychological evaluation of children with Cushing disease (CD) at diagnosis and 1 year after remission. Study Design: Prospective study of 41 children with CD. Children completed diverse sets of cognitive measures before and 1 year after remission. Neuropsychological evaluation included the Wechsler Intelligence Scale, California Verbal Learning Test, Trail Making Test, the combined subset scores of Wide Range Achievement Test and Woodcock‐Johnson Psychoeducational Battery Test of Achievement, and the Behavioral Assessment System for Children. Results: Comprehensive cognitive evaluations at baseline and 1 year following cure revealed significant decline mostly in nonverbal skills. Decrements occurred in most of the various indices that measure all aspects of cognitive function and younger age and early pubertal stage largely contributed to most of this decline. Results indicated that age at baseline was associated with positive regression weights for changes in scores for verbal, performance, and full intelligence quotient (IQ) scores and for subtests arithmetic, picture completion, coding, block design, scores; indicating that older age at baseline was associated with less of a deterioration in cognitive scores from pre‐ to posttreatment. Conclusion: Our findings suggest that chronic glucocorticoid excess and accompanying secondary hormonal imbalances followed by eucortisolemia have detrimental effects on cognitive function in the developing brain; younger age and pubertal stage are risk factors for increased vulnerability, while older adolescents have cognitive vulnerabilities like that of adult patients affected with CD. [ABSTRACT FROM AUTHOR]