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Background Cushing’s syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in patients with CS are currently lacking. We aimed to map the current clinical practice for thromboprophylaxis management in patients with CS across reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), which are endorsed specifically for the diagnosis and treatment of CS. Using the EU survey tool, a primary screening survey, and subsequently a secondary, more in-depth survey were developed. Results The majority of the RCs provided thromboprophylaxis to patients with CS (n = 23/25), although only one center had a standardized thromboprophylaxis protocol (n = 1/23). RCs most frequently started thromboprophylaxis from CS diagnosis onwards (n = 11/23), and the majority stopped thromboprophylaxis based on individual patient characteristics, rather than standardized treatment duration (n = 15/23). Factors influencing the initiation of thromboprophylaxis were ‘medical history of VTE’ (n = 15/23) and ‘severity of hypercortisolism’ (n = 15/23). Low-Molecular-Weight-Heparin was selected as the first-choice anticoagulant drug for thromboprophylaxis by all RCs (n = 23/23). Postoperatively, the majority of RCs reported ‘severe immobilization’ as an indication to start thromboprophylaxis in patients with CS (n = 15/25). Most RCs (n = 19/25) did not provide standardized testing for variables of hemostasis in the postoperative care of CS. Furthermore, the majority of the RCs provided preoperative medical treatment to patients with CS (n = 23/25). About half of these RCs (n = 12/23) took a previous VTE into account when starting preoperative medical treatment, and about two-thirds (n = 15/23) included ‘reduction of VTE risk’ as a goal of treatment. Conclusions There is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with CS, even in Endo-ERN RCs. Randomized controlled trials are needed to establish the optimal prophylactic anticoagulant regimen, carefully balancing the increased risk of (perioperative) bleeding, and the presence of additional risk factors for thrombosis.

BackgroundAlthough surgery is considered the first-line treatment for patients with endogenous Cushing’s syndrome (CS), medical therapy is often required to control severe hypercortisolism. Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, however, their therapeutic effectiveness has not yet been directly compared. This study aimed to evaluate metyrapone and osilodrostat in the short-term therapy of CS.MethodsRetrospective analysis of patients with endogenous CS treated with metyrapone or osilodrostat as monotherapy for at least 4 weeks. Main outcome measures were serum cortisol and 24h urinary free cortisol (UFC) at baseline (T0) and after 2 (T1), 4 (T2), and 12 weeks (T3) of therapy.Results16 patients with endogenous CS were identified (pituitary n=7, adrenal n=4, ectopic CS n=5). Each 8 patients were treated with metyrapone and osilodrostat. Despite heterogeneity, both groups showed comparable mean UFC levels at T0 (metyrapone: 758 µg/24h vs osilodrostat: 817 µg/24h; p=0.93). From T0 to T1, the decrease of UFC was less pronounced under metyrapone than osilodrostat (-21.3% vs -68.4%; median daily drug dose: 1000 mg vs 4 mg). This tendency persisted at T2 (-37.3% vs -50.1%; median drug dose: 1250 mg vs 6 mg) while at T3 a decrease in UFC from T0 was more pronounced in the metyrapone group (-71.5% vs -51.5%; median dose 1250 mg vs 7 mg). Under osilodrostat, a QTc-interval prolongation was identified at T3 (mean 432 ms vs 455 ms). From T0 to T2, the number of antihypertensive drugs remained comparable under metyrapone and decreased under osilodrostat (n= -0.3 vs n= -1.0).ConclusionAlthough both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster.

Context Cushing syndrome (CS) is associated with different hematological abnormalities. Nevertheless, conflicting data about erythropoiesis in CS have been reported. Furthermore, it is unclear whether CS sex and subtype-specific alterations in red blood cells (RBC) parameters are present. Objective To investigate sex and subtype-specific changes in RBC in patients with CS at initial diagnosis and after remission. Design Retrospective, monocentric study including 210 patients with CS (women, n = 162) matched 1:1 for sex and age to patients with pituitary microadenomas or adrenal incidentalomas (both hormonally inactive). RBC parameters were evaluated at initial diagnosis and after remission. Results Women with CS had higher hematocrit (median 42.2 vs 39.7%), hemoglobin (14.1 vs 13.4 g/dl) and mean corpuscular volume (MCV) (91.2 vs 87.9 fl) compared to the controls (all p < 0.0001). Women with Cushing disease (CD) showed higher hematocrit, RBC and hemoglobin levels than those with ectopic Cushing (ECS) (all p < 0.005). Men with CS had lower hematocrit (42.9 vs 44.7%), RBC count (4.8 vs 5.1n*106/µl) and hemoglobin (14.2 vs 15.4 g/dl), but higher MCV (90.8 vs 87.5 fl) than controls (all p < 0.05). In men with CS, no subtype-specific differences were identified. Three months after remission hemoglobin decreased in both sexes. Conclusion CS is characterized by sexual and subtype-specific differences in RBC parameters. Compared to controls, women with CS showed higher hematocrit/hemoglobin levels, whereas men had lower hematocrit/hemoglobin, which further decreased directly after remission. Therefore, anemia should be considered as complication of CS in men. In women, differences in RBC parameters may help to differentiate CD from ECS.

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

Objective: Endogenous hypercortisolism predisposes to impaired immune function and infections. To date, however, it is unknown whether there is a subtype-specific pattern in white blood cell (WBC) and WBC differential (WBCD) count. Methods: Retrospective monocentric cohort study in patients with overt endogenous Cushing’s syndrome (CS) or adrenal incidentalomas and autonomous cortisol secretion (ACS), with WBC/WBCD analysis at initial diagnosis and after biochemical remission. Cut-offs were obtained by receiver operating characteristics analysis. Results: 253 patients were analyzed (Cushing´s disease (CD); n=88; ectopic CS (ECS), n=31; cortisol-producing adrenal adenomas (CPA), n=40; ACS, n=45; adrenocortical carcinomas (ACC), n=49). Total leukocytes and neutrophils correlated positively with serum cortisol after 1-mg dexamethasone (r=0.314 and r=0.428), while a negative correlation was observed for lymphocytes and eosinophils (r= -0.374 and r= -0.380) (each p<0.0001). Similar observations were made for 24h-urinary free cortisol. CD and ECS differed in numbers of neutrophils and lymphocytes (p<0.0001) and were well differentiated at a cut-off of 6.1 for the neutrophil/lymphocyte ratio (NLR; sensitivity 90.0%, specificity 89.4%, AUC 0.918). For adrenocorticotropic hormone (ACTH)-independent CS, the best diagnostic outcome was obtained for the discrimination of CPA and ACC at a cut-off of 187.9 for the platelet/lymphocyte ratio (sensitivity 59.6%, specificity 80.6%, AUC 0.713). For ECS, CPA, and CD, neutrophils decreased (delta -47.0%, -29.7%, and -26.2%) and lymphocytes increased (+123.2%, +78.1%, and +17.7%) already 3 months after remission. Conclusion. Most immune cells correlate with the degree of hypercortisolism and differ among CS subtypes. WBCD changes are already identified three months after remission from endogenous hypercortisolism.

Objective Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing’s syndrome (ECS). However, published data e.g. on the diagnostic value of additional prolactin analysis is controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study. Design and methods Retrospective study in 5 European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing’s syndrome at the time of BIPSS with human corticotropin-releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristics analyses (reference: CD). Results 156 patients with BIPSS were identified. Of these, 120 patients (92 (77%) females; 106 (88%) CD, 14 (12%) ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% (95%CI 73.2-88.6), specificity 85.7% (95%CI 56.2-97.5), AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% (95%CI 83.6-95.7), specificity 92.9%(95%CI 64.1-99.6), AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% (95%CI 77.7-99.9), specificity 100% (95%CI 56.1-100), AUC 0.99). Conclusion Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing's syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.

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