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Cushing's syndrome is characterized by chronic glucocorticoid oversecretion and diverse clinical manifestations. Distinguishing between adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent forms is crucial for determining treatment options. Plasma ACTH levels aid in the differential diagnosis, with undetectable or low levels suggesting ACTH-independent hypercortisolemia. ACTH is derived from pro-opiomelanocortin, and its processing involves prohormone convertase 1/3. High-molecular-weight ACTH is generally found in ACTH-producing pituitary tumors and ectopic ACTH syndrome. The mechanism of negative feedback and the process of high-molecular-weight ACTH alternation during ACTH-independent Cushing's syndrome remain unclear. A 40-year-old woman with hypertension and multiple fractures developed symptoms suggestive of Cushing's syndrome. Computed tomography revealed a left adrenocortical tumor along with atrophy of the right adrenal gland. ACTH levels were undetectable at the previous clinic, indicating ACTH-independent Cushing's syndrome. However, subsequent measurements at our hospital revealed non-suppressed ACTH (18.1 pg/mL), prompting further investigation. Gel exclusion chromatography confirmed the presence of high-molecular-weight ACTH. Metyrapone treatment decreased the cortisol levels. In this situation, in which ACTH levels should be elevated, a decrease in high-molecular-weight ACTH levels was observed. Histological findings revealed cortisol-producing adenoma without ACTH expression. This case highlights the importance of assay differences in evaluating ACTH concentrations and introduces a novel finding of circulating high-molecular-weight ACTH. The observed decline in high-molecular-weight ACTH levels suggests a potential time lag in the negative feedback within the hypothalamic-pituitary-adrenal axis exhibited by glucocorticoids. This temporal aspect of the regulation of ACTH-related molecules warrants further exploration to enhance our understanding of the hypothalamic-pituitary-adrenal axis feedback mechanism., (© 2024 British Society for Neuroendocrinology.)

Trilostane is the current treatment of choice for managing pituitary-dependent hypercortisolism (PDH) in dogs. While prescribing higher initial doses may elevate the risk of iatrogenic hypocortisolism, opting for more conservative approach could result in delayed disease control, since most individuals end up requiring dosage increases. The adrenocorticotrophin stimulation test (ACTHst), a widely recognized hormonal test for assessing adrenal function, is an essential tool for monitoring the pharmacological treatment of canine hypercortisolism (CH) that can also be used for diagnostic purposes. The aim of this study was to investigate the relationship between post-ACTH cortisol (cpACTH) at PDH diagnosis and the required trilostane dose for sign control and endogenous cortisol regulation in dogs, considering a hypothesis that higher serum cpACTH concentration would necessitate a higher trilostane dosage for disease management. Data for 43 dogs with PDH had their diagnostic cpACTH recorded and correlated to the trilostane dosage necessary to control clinical signs and achieve satisfactory cortisol levels (ideally 2-7 μg/dL). The odds ratio (p=0.042) suggests that dogs with cpACTH ≥ 27 μg/dL at diagnosis are 96% more likely to need a higher trilostane dosage for achieving satisfactory control of PDH. Thus, cpACTH was found to be associated with the final trilostane dose for controlling PDH in dogs., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cushing's syndrome, a clinical condition characterized by hypercortisolemia, exhibits distinct clinical signs and is associated with cyclic cortisol secretion in some patients. The clinical presentation of cyclic Cushing's syndrome can be ambiguous and its diagnosis is often challenging. We experienced a 72-year-old woman with cyclic ACTH-dependent Cushing's syndrome caused by a pulmonary carcinoid tumor. Diagnosis was challenging because of the extended trough periods, and the responsible lesion was initially unidentified. A subsequent follow-up computed tomography revealed a pulmonary lesion, and ectopic ACTH secretion from this lesion was confirmed by pulmonary artery sampling. Despite the short peak secretion period of ACTH (approximately one week), immunostaining of the surgically removed tumor confirmed ACTH positivity. Interestingly, stored plasma chromogranin A levels were elevated during both peak and trough periods. The experience in evaluating this patient prompted us to investigate the potential use of plasma chromogranin A as a diagnostic marker of ACTH-dependent Cushing's syndrome. A retrospective study was conducted to determine the efficacy of plasma chromogranin A in three patients with ectopic ACTH syndrome (EAS), including the present case, and six patients with Cushing's disease (CD) who visited our hospital between 2018 and 2021. Notably, plasma chromogranin A levels were higher in patients with EAS than in those with CD. Additionally, a chromogranin A level in the present case during the trough phase was lower than that in the peak phase, and was similar to those in CD patients. The measurement of plasma chromogranin A levels could aid in differentiating EAS from CD.

Purpose: Adrenal venous sampling (AVS) is recommended for subtyping primary aldosteronism (PA). However, in cases of PA, concurrent subclinical Cushing's syndrome (SCS) has the potential to confound AVS results. Pentixafor, a CXC chemokine receptor type 4-specific ligand, has been reported as a promising marker to evaluate functional nature of adrenal adenomas. This study aims to investigate the clinical value of Gallium-68 Pentixafor Positron Emission Tomography-Computed Tomography ( 68 Ga-Pentixafor PET/CT) in the localization diagnosis of patients with PA plus SCS., Methods: Two patients with a confirmed diagnosis of PA plus SCS underwent AVS and 68 Ga-Pentixafor PET/CT., Results: AVS results revealed no lateralization for both patients while 68 Ga-Pentixafor PET/CT showed a unilateral adrenal nodule with increased uptake of 68 Ga-Pentixafor. Unilateral adrenalectomy was performed based on the results of 68 Ga-Pentixafor PET/CT. Subsequently, complete biochemical remission of autonomous aldosterone and cortisol secretion were achieved in both cases., Conclusions: 68 Ga-Pentixafor PET/CT shows promising potential for the localization of aldosterone and cortisol co-secreting adrenal adenoma in patients with PA plus SCS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To evaluate the function of serum dehydroepiandrosterone sulfate (DHEAS) in adult adrenal space-occupying lesions. Methods: In this cross-sectional study, 395 patients with adrenal space-occupying lesions who had their DHEAS levels measured were collected from the First Medical Center of Chinese PLA General Hospital from January 2010 to June 2021. They were divided into the adrenal Cushing syndrome (ACS) group ( n =100) and non-ACS group ( n =295). The former was divided into the cortisol-producing adrenal adenoma (CPA) group ( n =67) and primary bilateral macronodular adrenal hyperplasia (PBMAH) group ( n =33). Clinical data of each group were collected and compared among groups by independent samples t -test, chi-square test, and Mann-Whitney U test. Serum DHEAS ratio corrected for age and sex was further constructed to identify the receiver operating characteristic curve and the optimal tangent point value for different adrenal occupation. Results: Patients in the ACS group were younger (44.9±13.7 vs. 49.9±12.5, P =0.001); had a larger proportion of women (79/100 vs.139/295, P =0.001); and had higher cortisol levels [8∶00Am, 497.31 (343.52, 606.50) vs. 353.11 (267.50, 487.91) nmol/L, P <0.001] than those in the non-ACS group. The serum DHEAS level and ratio in the ACS group were significantly lower than those in the non-ACS group [0.50 (0.40, 1.21) vs. 2.68 (1.56, 4.32) μmol/L, 1.00 (0.43, 1.68) vs. 3.17 (2.21, 4.54), both P <0.001]. When the serum DHEAS ratio cut-off point was 1.29, the sensitivity and specificity for differential diagnosis of ACS and non-ACS were 72.0% and 91.5% respectively. The ratio of DHEAS in the CPA group was lower [0.58 (0.27, 1.05) vs. 1.14 (1.04, 2.40), P< 0.001] than that in the PBMAH group. When the serum DHEAS ratio cut-off point was 0.99, the sensitivity and specificity for differential diagnosis of CPA and PBMAH were 64.2% and 81.2% respectively. Conclusion: Corrected age-sex DHEAS ratio can assist in the functional assessment of adrenal space-occupying lesions.

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., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Secondary hypogonadism (SH) is common in men with Cushing's syndrome (CS), but its impact on comorbidities is largely unknown and longitudinal data are scarce. If SH also affects men with mild autonomous cortisol secretion (MACS) is unknown., Methods: We included 30 treatment-naïve adult men with CS and 17 men with MACS diagnosed since 2012. Hypogonadism was diagnosed based on total testosterone (TT) concentrations < 10.4 nmol/L and age-specific cut-offs. Outcomes were compared to age- and BMI-matched controls. In 20 men in remission of CS, a longitudinal analysis was conducted at 6, 12, and 24 months., Results: Men with CS had significantly lower concentrations of TT, bioavailable T, and free T compared to controls (P < .0001) with lowest concentrations in ectopic CS. Likewise, TT was lower in men with MACS compared to controls. At baseline, 93% of men with CS and 59% of men with MACS had SH. Testosterone correlated negatively with late night salivary cortisol and serum cortisol pre- and post-1 mg dexamethasone suppression test. Following successful surgery, TT increased significantly (P = .001), normalising within 6 months. Despite normalisation, several RBC parameters remained lower in men with CS even 2 years after successful surgery., Conclusions: Secondary hypogonadism is common in men with CS and MACS but usually reversible after successful surgery. The persisting changes observed in RBC parameters need to be further investigated in larger cohorts and longer follow-up durations., Competing Interests: Conflict of interest: F.B. serves as the incoming Editor-in-Chief of EJE. All other authors have no competing interests., (© 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.)

Purpose: Surgical therapy represents the first-line treatment for endogenous Cushing's syndrome (CS). While postoperative glucocorticoid replacement is mandatory after surgical remission, the role of perioperative glucocorticoid therapy is unclear., Methods: We recruited patients with central or adrenal CS in whom curative surgery was planned and patients who underwent pituitary surgery for other reasons than CS as a control group. Patients did not receive any perioperative glucocorticoids until the morning of the first postoperative day. We performed blood samplings in the morning of surgery, immediately after surgery, in the evening of the day of surgery, and in the morning of the first and third postoperative day before any morning glucocorticoid intake. We continued clinical and biochemical monitoring during the following outpatient care., Results: We recruited 12 patients with CS (seven with central CS, five with adrenal CS) and six patients without CS. In patients with CS, serum cortisol concentrations <5.0 µg/dL (<138 nmol/L) were detected in the morning of the first and third postoperative day in four (33%) and six (50%) patients, respectively. Morning serum cortisol concentrations on the third postoperative day were significantly lower when compared to preoperative measurements (8.5 ± 7.6 µg/dL vs. 19.9 ± 8.9 µg/dL [235 ± 210 nmol/L vs. 549 ± 246 nmol/L], p = 0.023). No patient developed clinical or biochemical signs associated with hypocortisolism. During follow-up, we first observed serum cortisol concentrations >5.0 µg/dL (>138 nmol/L) after 129 ± 97 days and glucocorticoids were discontinued after 402 ± 243 days. Patients without CS did not require glucocorticoid replacement at any time., Conclusion: Perioperative glucocorticoid replacement may be unnecessary in patients with central or adrenal CS undergoing curative surgery as first-line treatment., (© 2024. The Author(s).)

Purpose: The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status., Methods: This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter., Results: The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85 years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70 g/dL vs. 13.12 g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20 g/dL and 40.08% in patients with CD and aCS vs. 13.20 g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001)., Conclusion: Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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

Introduction: Patients with Cushing's syndrome (CS) in remission show sustained fatigue, myopathy, and an increased prevalence of sarcopenia. The mechanisms that determine these persistent muscle problems are not well known. We aimed to identify circulating microRNAs (miRNAs) with differential expression that could be potential biomarkers for the diagnosis and/or prognosis in CS., Patients and Methods: Thirty-six women in sustained remission for 13 ± 7 years (mean ± SD) from CS, with a median age (IQ range) of 51 (45.2-60) years and mean ± SD BMI of 27 ± 4 Kg/m 2 , and 36 matched healthy controls were investigated. In 7 patients sarcopenia was present according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Small RNA libraries were generated and indexed using a modified Illumina TruSeq small RNA-sequencing protocol. MiRNAs were identified in plasma using bioinformatic analysis, and validation was carried out using RT-qPCR. For the validation, Taqman probes were performed on QuantStudio 5 equipment (Applied Biosystems)., Results: In a first discovery group using RNA-sequencing, plasma samples of 18 CS patients and 18 healthy subjects were investigated; circulating miR-28-5p, miR-495-3p and miR-654-5p were upregulated in CS patients as compared with controls (p<0.05). In a validation study of the 3 upregulated miRNAs in 36 patients and 26 controls, no differences were observed by RT-qPCR; however, the expression of circulating miR-28-5p was upregulated in CS patients with sarcopenia as compared with those without (AUC for fold-change in the ROC analysis, 0.798; p=0.0156). The optimized cut-off value for miR-28-5p to identify CS patients with sarcopenia was 3.80, which yielded a sensitivity of 86% and a specificity of 69%., Conclusion: MiR-28-5p, a muscle-specific microRNA involved in myotube proliferation and differentiation in vivo , may serve as an independent non-invasive biomarker for identifying CS patients at high-risk of sarcopenia despite biochemical remission., Competing Interests: JSI-C was employed by company EpiDisease S.L. JLG-G is a founding partner of EpiDisease SL, a Spin-off from the Center for Biomedical Network Research of Spain. The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission., (Copyright © 2024 Seco-Cervera, Ibáñez-Cabellos, Pallardo, García-Giménez, Aulinas, Martel-Duguech, Webb and Valassi.)

Introduction: The management of Mild Autonomous Cortisol Secretion (MACS) remains a topic of debate among clinicians, with differing opinions on the effectiveness of surgical intervention compared to conservative treatment methods. This meta-analysis provides a comprehensive assessment of available literature to determine the most effective approach for treating this condition., Methods: On December 1, 2023, an exhaustive literature search of English databases Embase, PubMed, the Cochrane Library, Scopus, Web of Science, as well as the Chinese databases China HowNet, Wanfang Database, SinoMed Database, and Weipu Database using the keywords "Mild Autonomous Cortisol Secretion", "Subclinical Cushing's Syndrome", "Subclinical Hypercortisolism", "Mild Cortisol Autonomous Secretion", "Adrenal Incidentaloma", "Surgical Treatment" and "Adrenalectomy". The data were statistically analyzed using STATA version 15.0., Results: In this comprehensive analysis involving 629 patients with MACS, the therapeutic efficacy of adrenalectomy was evident. The meta-analysis results indicate that compared to conservative treatment, surgical intervention more effectively improves obesity indicators in patients: waist circumference (SMD=-0.62, 95% CI: -1.06 to -0.18), BMI (SMD=-0.41, 95% CI: -0.62 to -0.20), enhances glycemic control: fasting blood glucose (SMD=-0.47, 95% CI: -0.68 to -0.26), glycated hemoglobin (SMD=-0.66, 95% CI: -0.95 to -0.38), improves lipid metabolism: triglycerides (SMD=-0.45, 95% CI: -0.73 to -0.16), lowers blood pressure: systolic blood pressure (SMD=-1.04, 95% CI: -1.25 to -0.83), diastolic blood pressure (SMD=-0.89, 95% CI: -1.12 to -0.65), and ameliorates hormonal metabolic disorder: 24h urinary free cortisol (SMD=-1.10, 95% CI: -1.33 to -0.87), ACTH (SMD=2.30, 95% CI: 1.63 to 2.97). All these differences are statistically significant., Conclusion: This meta-analysis shows that, compared to conservative treatment, surgical treatment is more effective in improving obesity indicators, glycemic control, lipid metabolism, reducing blood pressure, and ameliorating hormonal metabolic disorders in patients with MACS. These statistically significant results highlight the importance of considering surgical intervention in the management of patients with MACS., Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023492527., 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 Ren, Nan and Zhang.)

Objective: Cushing's syndrome is characterized by high morbidity and mortality with high interindividual variability. Easily measurable biomarkers, in addition to the hormone assays currently used for diagnosis, could reflect the individual biological impact of glucocorticoids. The aim of this study is to identify such biomarkers through the analysis of whole blood transcriptome., Design: Whole blood transcriptome was evaluated in 57 samples from patients with overt Cushing's syndrome, mild Cushing's syndrome, eucortisolism, and adrenal insufficiency. Samples were randomly split into a training cohort to set up a Cushing's transcriptomic signature and a validation cohort to assess this signature., Methods: Total RNA was obtained from whole blood samples and sequenced on a NovaSeq 6000 System (Illumina). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore the transcriptome profile. Ridge regression was used to build a Cushing's transcriptome predictor., Results: The transcriptomic profile discriminated samples with overt Cushing's syndrome. Genes mostly associated with overt Cushing's syndrome were enriched in pathways related to immunity, particularly neutrophil activation. A prediction model of 1500 genes built on the training cohort demonstrated its discriminating value in the validation cohort (accuracy .82) and remained significant in a multivariate model including the neutrophil proportion (P = .002). Expression of FKBP5, a single gene both overexpressed in Cushing's syndrome and implied in the glucocorticoid receptor signaling, could also predict Cushing's syndrome (accuracy .76)., Conclusions: Whole blood transcriptome reflects the circulating levels of glucocorticoids. FKBP5 expression could be a nonhormonal marker of Cushing's syndrome., Competing Interests: Conflict of interest: G.A. is on the editorial board of EJE. G.A. was not involved in the review or editorial process for this paper, on which he is listed as an author., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Changes in neutrophil-to-lymphocite ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been identified in dogs with hypercortisolism (HC), but, no studies have investigated the changes in these inflammatory biomarkers as cost-effective and available parameters for the diagnosis and management of HC. This study was performed to evaluate whether NLR and PLR could be used as biomarkers for the diagnosis and treatment response in dogs with HC. This retrospective study included 67 dogs with HC, 58 dogs with non-adrenal illness (NAI), and 39 healthy dogs. NLR and PLR were compared among the three groups. Cut-off values of NLR and PLR for HC screening and percent change in biomarkers for assessing treatment response were evaluated. In addition, the NLR and PLR were compared before and after trilostane treatment. NLR and PLR were significantly higher in the HC group than in the NAI and healthy groups. The NLR cut-off value of 4.227 had a sensitivity of 67.16% and specificity of 65.52%, and the PLR cut-off value of 285.0 had a sensitivity of 56.72% and specificity of 70.69% for differentiating between dogs with HC and those with NAI, respectively. Furthermore, a significant decline in NLR was observed after treatment in the well-controlled HC group. The cutoff value of percent change in NLR to identify well-controlled HC was -7.570%; sensitivity and specificity were 100% and 63.64%, respectively. Therefore, NLR and PLR might be used cautiously as supportive biomarkers for HC diagnosis, and NLR could be a potential monitoring tool in assessing the treatment response of HC in dogs., Competing Interests: Declaration of competing interest 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 Elsevier Inc. All rights reserved.)

Selective venous sampling (SVS), an invasive radiographic procedure that depends on contrast media, holds a unique role in diagnosing and guiding the treatment of certain types of secondary hypertension, particularly in patients who may be candidates for curative surgery. The adrenal venous sampling (AVS), in particular, is established as the gold standard for localizing and subtyping primary aldosteronism (PA). Throughout decades of clinical practice, AVS could be applied not only to PA but also to other endocrine diseases, such as adrenal Cushing syndrome (ACS) and Pheochromocytomas (PCCs). Notably, the application of AVS in ACS and PCCs remains less recognized compared to PA, with the low success rate of catheterization, the controversy of results interpretation, and the absence of a standardized protocol. Additionally, the AVS procedure necessitates enhancements to boost its success rate, with several helpful but imperfect methods emerging, yet continued exploration remains essential. We also observed renal venous sampling (RVS), an operation akin to AVS in principle, serves as an effective means of diagnosing renin-dependent hypertension, aiding in the identification of precise sources of renin excess and helping the selection of surgical candidates with renin angiotensin aldosterone system (RAAS) abnormal activation. Nonetheless, further basic and clinical research is needed. Selective venous sampling (SVS) can be used in identifying cases of secondary hypertension that are curable by surgical intervention. Adrenal venous sampling (AVS) and aldosterone measurement for classificatory diagnosis of primary aldosteronism (PA) are established worldwide. While its primary application is for PA, AVS also holds the potential for diagnosing other endocrine disorders, including adrenal Cushing's syndrome (ACS) and pheochromocytomas (PCCs) through the measurements of cortisol and catecholamine respectively. In addition, renal venous sampling and renin measurement can help to diagnose renovascular hypertension and reninoma., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Purpose: Thyroid disorders have been reported in hypercortisolism patients. Endogenous Cushing's syndrome (CS) potentially complicates its metabolic sequelae. We investigated thyroid function in CS patients to determine this relationship., Methods: In this cross-sectional study, we screened CS patients from 2016 to 2019 at our hospital. Patient demographic, medical history, and laboratory data were collected. Additionally, we performed a meta-analysis to demonstrate the prevalence of thyroid dysfunction in patients with CS., Results: Among 129 CS patients, 48.6% had triiodothyronine (TT3), 27.9% had thyroxine (TT4), 24.6% had free T3 (FT3), 27.7% had free T4 (FT4), and 6.2% had thyroid-stimulating hormone (TSH) levels below the reference values. Those with clinical CS showed more pronounced thyroid suppression than did those with subclinical CS. Cortisol levels were markedly greater in patients with pituitary hypothyroidism (P < 0.001). Serum cortisol levels throughout the day and post low-dose dexamethasone-suppression test (LDDST) results correlated with thyroid hormone levels, particularly in ACTH-independent CS. Correlations varied by thyroid status; FT3 and TSH were linked to cortisol in euthyroid individuals but not in those with low T3 or central hypothyroidism. TSH levels notably halved from the lowest to highest cortisol tertile post-LDDST. Finally, meta-analysis showed 22.7% (95% CI 12.6%-32.9%) central hypothyroidism in 528 CS patients of nine studies., Conclusion: Thyroid hormone levels are significantly correlated with cortisol levels and are impaired in patients with CS. However, the physiological adaptation and pathological conditions need further study., (© 2024. The Author(s).)

The aim of this study was to determine whether ascorbic acid (AA) supplementation can lower plasma levels of Cortisol and dehydroepiandrosterone-sulphate (DHEA-S) in patients diagnosed with functional hypercortisolemia due to unspecified chronic stress. Study includes data from 69 female with elevations in the cortisol and DHEA-S levels. Duration of follow-up was 2 months. Patients were divided into 3 groups. Group I included patients 23 with elevated cortisol, Group II-patients 24 with elevated levels of both hormones, Group III- patients 22 with normal cortisol and increased DHEA-S. Each group was randomly divided into two subgroups. The first subgroup was prescribed 1000 mg daily oral dose of AA. The diet of the second subgroup were left unaltered. All patients have their hormones levels re-examined 2 months later. After 2 months of AA supplementation the mean levels of elevated plasma cortisol and DHEA-S decreased. In Group I the level of cortisol fell from 780 ± 57-446 ± 26 nmol/L, p = 0.000065 in Group II from 657 ± 47-515 ± 29 nmol/L, p = 0.005. The elevated levels of DHEA-S have also declined in patients from AA-treated subgroups (from 13.9 ± 1.6-9.9 ± 1.2, p = 0.0007 in Group II, and from 12.8 ± 1.0-7.8 ± 1.4, p = 0.003 in Group III). In untreated subgroups changes in hormone levels were insignificant. The study shows that female patients with functional hypercortisolemia or elevated levels of DHEA-S can be treated with AA to bring level of these hormones closer to a normal range., (© 2023 John Wiley & Sons Ltd.)

Importance: Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders., Observations: Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate., Conclusions and Relevance: The incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy.

This case report shares the management experience of a patient with pregnancy combined with adrenal adenoma causing ACTH-independent Cushing's syndrome (CS), accompanied by obstetric antiphospholipid syndrome (OAPS) and severe pre-eclampsia. The case was a 26-year-old that presented with typical clinical symptoms and signs of CS. The patient had a history of 4 spontaneous abortions in the last 4 years. The 24-hour urinary free cortisol was significantly increased, an abnormal cortisol circadian rhythm was demonstrated by a high late-night salivary cortisol, blood ACTH was suppressed (< 1ng/dL), anticardiolipin antibody was positive, and imaging examination showed an adrenal tumor. The patient underwent laparoscopic adrenal tumor resection under general anesthesia at 23 weeks of gestation. The tumor was pathologically confirmed to be an adrenocortical adenoma. The patient underwent a cesarean section at 39 weeks of gestation to give birth to a healthy baby girl with an Apgar score of 10. Pregnancy complicated by CS is clinically rare, easily masked by normal physiological changes of pregnancy, and is difficult to diagnose. The determination of 24-hour urinary free cortisol, the circadian rhythm of serum cortisol, ultrasound, and MRI can be helpful in the diagnosis of CS during pregnancy. Surgery is the first choice for the treatment of CS during pregnancy. As a subtype of antiphospholipid syndrome, patients with OAPS are prone to thrombotic events and recurrent miscarriages if not treated accordingly. To our knowledge no cases of CS with OAPS and severe pre-eclampsia have been reported. We summarize the experience of the treatment of this patient and review the literature to improve clinicians' awareness of this disease., 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 Xu, Liu, Xu, Che, Zhang, Li, Huang, Yu, Zha, Peng, Huang and Tang.)

Introduction: Nearly half of the adult population in the United States has been diagnosed with hypertension. Adrenal hormonal hypersecretion is a leading cause of secondary hypertension. Adrenal vein sampling (AVS) may assist in differentiating between unilateral and bilateral adrenal hormonal hypersecretion to identify patients who are candidates for adrenalectomy. We reviewed the use of AVS at our institution along with associated outcomes after adrenalectomy. Materials and Methods: A retrospective chart review was conducted of patients with a diagnosis of primary hyperaldosteronism (PA) or adrenocorticotropic hormone-independent Cushing syndrome (AICS) and who underwent adrenalectomy between January 1, 2010, and December 1, 2021. Patient data of baseline characteristics, preoperative workup, including AVS, and postoperative outcomes were collected and analyzed. Results: Seventy-one patients were identified in the study period (48 PA and 23 AICS). Computed tomography scan identified unilateral adrenal nodules in 52 patients (29 left; and 23 right), bilateral nodules in 13 patients, and no nodules in 6 patients. AVS was performed in 45 patients with PA (93%) and 5 patients with AICS (21%). After surgery, the number of PA patients with hypokalemia or requiring potassium supplementation significantly decreased after adrenalectomy (before surgery: 33 [68.7%]; and after surgery: 5 [10.4%], P  < .01). The number of medications required for hypertension in AICS patients also significantly decreased. No major adverse events were noted. Conclusions : Our long-term experience demonstrates the ongoing use of AVS during workup of patients with primary hyperaldosteronism and for select patients with adrenocorticotropic hormone-independent Cushing syndrome. However, a low level of discordance between imaging and AVS findings in PA patients suggests that there may be a subset of patients in whom preoperative AVS is not necessary.

Objective: Inflammatory biomarkers, such as absolute neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), platelet (PLT)-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), are associated with the progression and development of several disorders. Although patients with Cushing syndrome (CS) have immunosuppression with altered leucocyte counts, the profile of the inflammatory biomarkers in these patients has not been extensively studied., Design: We compared a panel of inflammatory biomarkers in patients with active endogenous CS (n of complete blood count (CBC) reports = 319) and eucortisolemic subjects of similar age, gender and BMI (n of CBC reports = 93). Patients were divided into two age groups (6-12 years at the time of CBC and >12 years at the time of CBC) based on age differences in normal reference ranges., Results: Patients with CS had higher NLR vs controls (6-12 years: 2.47 (1.86, 3.32) vs 1.35 (1.11, 2.27), P < 0.0001; >12 years: 3.00 (2.23-4.17) vs 1.80 (1.23-2.31), P < 0.0001). Similarly, absolute neutrophil and lymphocyte counts, MLR and PLR differed between patients with CS and controls. The inflammatory biomarkers correlated with indices of cortisol secretion, such as midnight serum cortisol, 24-h urinary free cortisol and morning cortisol. On receiver operating characteristic analysis, NLR showed high area under the curve (AUC) (6-12 years: cutoff of 1.72 had AUC: 0.77, >12 years: cutoff of 2.35 had AUC: 0.81)., Conclusions: We conclude that multiple inflammatory biomarkers differed between patients with CS and controls suggesting substantial effects of hypercortisolemia on the immune system.

Context: Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding., Objective: We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup., Design and Setting: Cross-sectional study conducted in a tertiary medical center., Participants: Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP)., Measurements: Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay)., Main Outcome Measures: Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol., Results: Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02)., Conclusions: Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We reviewed clinical research investigating the applications of adrenal vein sampling (AVS). AVS could be applied not only to primary aldosteronism (PA) but also to other endocrine diseases, such as adrenocorticotropic hormone (ACTH) independent Cushing syndrome (AICS) and hyperandrogenemia (HA). However, the AVS protocol requires improvements to increase its success rate. Using the computed tomography image fusion, coaxial guidewire technique, and fast intraprocedural cortisol testing (CCF) technique could improve the success rate of catheterization in AVS for PA. ACTH loading could be considered in medical centers with a low selectivity of AVS for PA but is not essential in those with mature AVS technology. The continuous infusion method should be recommended for ACTH stimulation in AVS for PA to reduce adverse events. AVS has not been routinely recommended before management decisions in AICS, but several studies verified that AVS was useful in finding out the source of excess cortisol, especially for distinguishing unilateral from bilateral disease. However, it is necessary to reassess the results of AVS in AICS with the use of reference hormones to fully normalize cortisol levels. In addition, it is essential to determine the optimal model that combines AVS results and mass size to guide the selection of surgical plans, including identifying the dominant gland and presenting the option of staged adrenalectomy, to minimize the impact of bilateral resection. For HA, AVS combined with ovarian intravenous sampling to locate excess androgens could be considered when imaging results are equivocal., 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 © 2022 Zhong, Zhang, He, Yu, Liu, Li, Song and Xu.)

Context: Somatic gene mutations have been identified in only about half of cortisol-producing adenomas (CPAs). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1., Objective: This work aims to expand our understanding of the prevalence of somatic mutations in CPAs from patients with overt Cushing syndrome (OCS) and "subclinical" mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue., Methods: We analyzed FFPE adrenal tissue from 77 patients (n = 12 men, 65 women) with either OCS (n = 32) or MACE (n = 45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPAs (32 OCS CPAs and 46 MACE CPAs). Genomic DNA was isolated from the FFPE CPAs and subjected to targeted amplicon sequencing for identification of somatic mutations., Results: Somatic mutations were identified in 71.8% (56/78) of the CPAs. While PRKACA was the most frequently mutated gene in OCS CPAs (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE CPAs. Most GNAS mutations were observed in MACE CPAs (5/7, 71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored 2 adjacent tumors within the same adrenal gland - one patient had 2 CPAs, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase)., Conclusion: A comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPAs. OCS CPAs demonstrated a distinct mutation profile compared to MACE CPAs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Cushing's syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing's syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing's syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers., Design: We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing's syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation., Methods: Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850 000 CpG sites). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features., Results: Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing's syndrome correction. In Cushing's syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts., Conclusions: Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assessment of glucocorticoid action beyond hormone assays.

Background: Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity., Objective: We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells., Methods: Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells., Results: Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well., Conclusions: We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it., (Published by Elsevier Inc.)

Objective: Patients with Cushing's syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission., Design and Methods: Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group., Results: Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7)., Conclusions: Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients., (© 2021. The Author(s).)

Background: MicroRNAs (miRNA) identified as critical molecular regulators for bone development, function, and modeling/remodeling process and could be predictable for osteoporotic fractures in postmenopausal elderly women., Aim: The potential diagnostic role of circulating miRNAs, miR-148a and miR-122-5p, in the pathogenesis of osteoporosis and its association with bone markers, hypercortisolism, and vitamin D deficiency were explored in postmenopausal elderly women with osteoporosis., Methods: A total of 120 elderly women aged 50-80 years old were recruited in this study, of which only 100 eligible women with amenorrhea of at least 12 consecutive months or surgical menopause participated in this study. Based upon bone mineral density (BMD) measurements, the participants were classified according into two groups: normal ( n = 45; T score of ≥-1.0) and osteoporosis ( n = 55; T score: ≤-2.5). Circulating miRNAs, miR-148a and miR-122-5p, were estimated by real-time RT-PCR analysis. In addition, bone markers, hypercortisolism, and vitamin D deficiency were colorimetrically and ELISA immune assay estimated. The potential role of miR-148a, miR-122-5p, cortisol, and vitamin D in the diagnosis of osteoporosis was predicted using the analysis of the respective area under the receiver operating characteristic curve (AUC-ROC)., Results: The expressed level of miR-148a significantly increased and miR-122-5p significantly decreased in the serum of osteoporotic patients compared to healthy controls. In addition, a significant increase in the levels of cortisol, s-BAP, and CTx and significant decrease in the levels of T-BMD, the levels of OC, and s-Ca were also identified. All parameters significantly correlated with fracture risk parameters; BMD, and T score lumbar spine (L2-L4). Thus, the data showed AUC cut off values (miR-148a; 0.876, miR-122-5p; 0.761) were best evaluated for clinical diagnosis of patients with osteoporosis and that AUC cut off values of 0.748 for cortisol and 0.635 for vitamin D were the best cut off values, respectively, reported for the prediction of osteoporosis clinical diagnosis., Conclusion: In this study, expressed miRNAs miR-148a and miR-122-5p and changes in the levels of both cortisol and vitamin D status are significantly associated with bone loss or osteoporosis. Thus, circulation miRNAs alone or in combination with cortisol and vitamin D status might be considered predictable biomarkers in the diagnosis or the pathogenesis of osteoporosis in elderly postmenopausal women; however, more studies are recommended., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Hadeel A. Al-Rawaf et al.)

Context: Traditionally, low-dose dexamethasone suppression test (LDDST) was used to confirm the diagnosis of Cushing's syndrome (CS), and high-dose dexamethasone suppression test (HDDST) was used to differentiate Cushing's disease (CD) and ectopic adrenocorticotropin (ACTH) syndrome (EAS), but some studies suggested that HDDST might be replaced by LDDST. For the differential diagnosis of CS, dexamethasone suppression test was usually combined with other tests such as bilateral petrosal sinus sampling (BIPSS) and pituitary magnetic resonance imaging, but the optimal pathway to incorporate these tests is still controversial., Objectives: To develop an optimized pathway for the differential diagnosis of CD and EAS based on LDDST., Design and Setting: Single-center retrospective study (2011-2019)., Patients: Two hundred sixty-nine CD and 29 EAS patients with pathological diagnosis who underwent consecutive low- and high-dose DST., Results: For the differential diagnosis of CD and EAS, the area under curve (AUC) of LDDST using urine free cortisol (0.881) was higher than that using serum cortisol (0.685) (p < 0.001) in head-to-head comparison among a subgroup of 108 CD and 10 EAS. The AUC of LDDST (0.883) was higher than that of HDDST (0.834) among all the included patients. With the cutoff of <26%, the sensitivity and specificity of LDDST were 39.4% and 100%. We designed a new pathway in which BIPSS was only reserved for those patients with unsuppressed LDDST and adenoma <6mm, yielding an overall sensitivity of 97.7% and specificity of 86.7%., Conclusion: LDDST had similar value to HDDST in differentiating CD and EAS using the specific cutoff point. The pathway that combined LDDST and BIPSS could differentiate CD and EAS accurately., 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 © 2021 Chen, Chen, Lu, Zhu, Zhang, Tong, Pan, Wang and Lu.)

Endogenous Cushing syndrome (CS) is an endocrine disorder marked by excess cortisol production rendering patients susceptible to visceral obesity, dyslipidemia, hypertension, osteoporosis and diabetes mellitus. Adrenal CS is characterized by autonomous production of cortisol from cortisol-producing adenomas (CPA) via adrenocorticotropic hormone-independent mechanisms. A limited number of studies have quantified the steroid profiles in sera from patients with CS. To understand the intratumoral steroid biosynthesis, we quantified 19 steroids by mass spectrometry in optimal cutting temperature compound (OCT)-embedded 24 CPA tissue from patients with overt CS (OCS, n = 10) and mild autonomous cortisol excess (MACE, n = 14). Where available, normal CPA-adjacent adrenal tissue (AdjN) was also collected and used for comparison (n = 8). Immunohistochemistry (IHC) for CYP17A1 and HSD3B2, two steroidogenic enzymes required for cortisol synthesis, was performed on OCT sections to confirm the presence of tumor tissue and guided subsequent steroid extraction from the tumor. LC-MS/MS was used to quantify steroids extracted from CPA and AdjN. Our data indicated that CPA demonstrated increased concentrations of cortisol, cortisone, 11-deoxycortisol, corticosterone, progesterone, 17OH-progesterone and 16OH-progesterone as compared to AdjN (p < 0.05). Compared to OCS, MACE patient CPA tissue displayed higher concentrations of corticosterone, 18OH-corticosterone, 21-deoxycortisol, progesterone, and 17OH-progesterone (p < 0.05). These findings also demonstrate that OCT-embedded tissue can be used to define intra-tissue steroid profiles, which will have application for steroid-producing and steroid-responsive tumors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Classic Cushing's syndrome (CS) is a severe disease characterized by central obesity, hypertension, easy bruising, striae rubrae, buffalo hump, proximal myopathy and hypertricosis. However, several CS cases have also been reported with unusual or camouflaged manifestations. In recent years, several authors investigated the prevalence of "hidden hypercortisolism" (HidHyCo) among subjects affected with bone fragility, hypertension and type 2 diabetes mellitus (DM2). The prevalence of the HidHyCo is estimated to be much higher than that of classic CS. However, similarly to classic CS, HidHyCo is known to increase the risk of fractures, cardiovascular disease and mortality., Methods: We reviewed all published cases of unusual presentations of hypercortisolism and studies specifically assessing the HidHyCo prevalence in diabetic, osteoporotic and hypertensive patients., Results: We found 49 HidHyCo cases, in whom bone fragility, hypertension and diabetes were the presenting manifestations of an otherwise silent hypercortisolism. Amongst these cases, 34.7%, 32.7%, 6.1% and 19.0%, respectively, had bone fragility, hypertension, DM2 or hypertension plus DM2 as the sole clinical manifestations of HidHyCo. Overall, 25% of HidHyCo cases were of pituitary origin, and bone fragility was the very prevalent first manifestation among them. In population studies, it is possible to estimate that 1-4% of patients with apparent primary osteoporosis has a HidHyCo and the prevalence of this condition among diabetics ranges between 3.4 and 10%., Conclusion: These data indicate that patients with resistant or suddenly worsening hypertension or DM2 or unexplainable bone fragility should be screened for HidHyCo using the most recently approved sensitive cut-offs., (© 2021. Springer Nature Switzerland AG part of Springer Nature.)

Bilateral inferior petrosal sinus sampling (BIPSS) is the current gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome (CS). However, BIPSS is an invasive procedure, and its availability is limited. We retrospectively analysed the 24-hour urinary free cortisol (UFC) level during the high-dose dexamethasone suppression test (HDDST) and plasma ACTH/cortisol levels after the desmopressin stimulation test (DDAVP test) in subjects with confirmed Cushing's disease (CD) (n = 92) and ectopic ACTH-dependent CS (EAS) (n = 16), and evaluated the positive predictive value (PPV) of the two combined-tests in the aetiological diagnosis of ACTH-dependent CS. The percent changes in UFC levels after the HDDST and in ACTH/cortisol levels after DDAVP administration relative to the corresponding basal levels and the area under the receiver operating characteristic (ROC) curve (AUC) were analysed. UFC suppression below 62.7% suggested a pituitary origin with a sensitivity (SE) of 80% (95% CI: 70-88) and a specificity (SP) of 80% (95% CI: 52-96). A threshold increase in the ACTH level after DDAVP stimulation of 44.6% identified CD with an SE of 91% (95% CI: 83-97) and an SP of 75% (95% CI: 48-93). The combination of both tests yielded an SE of 95.5% and PPV of 98.4% for CD, and significantly improved the efficiency of the differential diagnosis between CD and EAS. These dual non-invasive endocrine tests may substantially reduce the need for BIPSS in the etiological investigation of ACTH-dependent CS.

Context: Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally., Objective: To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design., Methods: Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants)., Results: One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38)., Conclusion: Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

To evaluate the diagnostic value of serum levels of adrenal steroids for diagnosing and subtyping Cushing's syndrome. Patients diagnosed with endogenous Cushing's syndrome (34 and 19 patients with adrenal and pituitary Cushing's syndrome, respectively) and healthy controls (n = 34) were consecutively enrolled at Seoul National University from 2016 to 2020. Morning serum samples were collected before and 3 months after treatment. Serum steroids were profiled using liquid chromatography-mass spectrometry. The diagnostic value of each and the combination of steroids were assessed using the area under the curve of receiver operating characteristic (AUROC) and decision tree analysis. Tetrahydrocortisone and 6β-hydroxycortisol showed the highest AUROC (0.893 and 0.890, respectively) for the diagnosis of endogenous Cushing's syndrome. The decision tree composed of tetrahydrocortisone and 6β-hydroxycortisol correctly classified 79/87 (90.8 %) subjects. For subtyping into adrenal or pituitary Cushing's syndrome, dehydroepiandrosterone sulfate (DHEA-S) showed the highest AUROC (0.988), which was similar to that of plasma ACTH (0.994, P = 0.458). The decision tree composed of only DHEA-S correctly classified 51/53 (96.2 %) of the Cushing's syndrome subtype. DHEA-S showed a significant linear correlation with the plasma ACTH level, but not with the 24 -h urine free cortisol or dexamethasone suppression test results. All steroids, except allo-tetrahydrocortisol and tetrahydrocortisone, decreased significantly at 3 months post-treatment with similar patterns in both adrenal and pituitary Cushing's syndrome. Serum steroid profiling using a single morning serum sample provides valuable information for diagnosing and subtyping Cushing's syndrome., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis., (© 2021 Wiley Periodicals LLC.)

Glucocorticoid excess often causes a variety of cardiovascular complications, including hypertension, atherosclerosis, and cardiac hypertrophy. To abrogate its cardiac side effects, it is necessary to fully disclose the pathophysiological role of glucocorticoid in cardiac remodelling. Previous clinical and experimental studies have found that omentin-1, one of the adipokines, has beneficial effects in cardiovascular diseases, and is closely associated with metabolic disorders. However, there is no evidence to address the potential role of omentin-1 in glucocorticoid excess-induced cardiac injuries. To uncover the links, the present study utilized rat model with glucocorticoid-induced cardiac injuries and clinical patients with abnormal cardiac function. Chronic administration of glucocorticoid excess reduced rat serum omentin-1 concentration, which closely correlated with cardiac functional parameters. Intravenous administration of adeno-associated virus encoding omentin-1 upregulated the circulating omentin-1 level and attenuated glucocorticoid excess-induced cardiac hypertrophy and functional disorders. Overexpression of omentin-1 also improved cardiac mitochondrial function, including the reduction of lipid deposits, induction of mitochondrial biogenesis, and enhanced mitochondrial activities. Mechanistically, omentin-1 phosphorylated and activated the GSK3β pathway in the heart. From a study of 28 patients with Cushing's syndrome and 23 healthy subjects, the plasma level of glucocorticoid was negatively correlated with omentin-1, and was positively associated with cardiac ejection fraction and fractional shortening. Collectively, the present study provided a novel role of omentin-1 in glucocorticoid excess-induced cardiac injuries and found that the omentin-1/GSK3β pathway was a potential therapeutic target in combating the side effects of glucocorticoid.

Bilateral adrenalectomy (BLA) is a treatment option for patients with Cushing's Disease (CD) if transsphenoidal pituitary surgery fails or is not a therapeutic option. For most patients, BLA eliminates endogenous glucocorticoid and mineralocorticoid production, but for a small number of patients, endogenous secretion of adrenal hormones from adrenal tissue continues or recurs, leading to signs and symptoms of hypercortisolism. If adrenal tissue is confined to the adrenal bed, it is considered adrenal remnant tissue , while if it is outside the adrenal bed, it is considered adrenal rest tissue . We retrospectively evaluated morning serum cortisol, nighttime serum cortisol, nighttime salivary cortisol, and 24-h urine free cortisol on at least three occasions in 10 patients suspected of having endogenous cortisol production. Imaging of adrenal remnant tissue was also reviewed. Ten of 51 patients who underwent BLA during this time period had adrenal remnant/rest tissue marked by detectable endogenous glucocorticoid production; 9 of the 10 patients had signs and symptoms of hypercortisolism. Localization and treatment proved difficult. We conclude that the incidence of adrenal remnant/rest tissue in those undergoing BLA following unsuccessful pituitary surgery was 12% although there may have been a selection bias affecting this prevalence. The first indication of remnant tissue occurrence is a reduction in glucocorticoid replacement with symptoms of hypercortisolism. If this occurs, endogenous cortisol production should be tested for by cortisol measurements using a highly specific cortisol assay while the patient is taking dexamethasone or no glucocorticoid replacement. Endocrinologists need to monitor the development of both adrenal remnant tissue and Nelson's syndrome following BLA., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Context: Cushing's syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging., Objective: Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes., Methods: We included three groups of patients from the German Cushing's registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing's Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls., Results: NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression., Outcome: In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself., 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 © 2021 Vetrivel, Zhang, Engel, Altieri, Braun, Osswald, Bidlingmaier, Fassnacht, Beuschlein, Reincke, Chen, Sbiera and Riester.)

Objective: Assessing excess adrenal hormones is important in patients with adrenal mass. Current screening tests for excess cortisol hormones are complex, so it cannot be done sometimes due to the limited medical resources. The aim of the study was to evaluate whether the neutrophil-lymphocyte ratio (NLR) can be used as an initial screening biomarker for Cushing's syndrome (CS) in patients with an adrenal mass., Methods: This retrospective study included a total of 185 patients with CS and 185 patients with nonfunctional adrenal adenoma (matched 1 : 1 by sex, body mass index, and discharge date). The NLR was compared between the two groups. The association between NLR and serum and urinary cortisol concentrations was analyzed, and an NLR cut-off value for CS screening was calculated., Results: NLR (3.38 (2.33, 5.45) vs. 2.13 (1.74, 3.00), P < 0.001) was significantly higher in the CS group than in the nonfunctional adenoma group. In CS patients, the NLR was positively associated with serum cortisol concentrations at 8 am, with 24-hour urine free cortisol and with serum cortisol after a 1 mg dexamethasone suppression test ( P < 0.001 each). An NLR cut-off of 2.2 had a sensitivity of 80.0% and a specificity of 54.05%. The weighted Youden index for the NLR was similar to that of the 24-hour urine free cortisol and late-night serum cortisol tests, which are recommended initial tests for CS diagnosis., Conclusion: The NLR may be useful for initial screening for CS among patients with an adrenal mass as an easy and convenient marker., Competing Interests: The authors declare no conflicts of interest regarding publication of this paper., (Copyright © 2021 Wei Wang et al.)

Background: Endogenous Cushing's syndrome (CS) results in increased cardiovascular (CV) morbidity and mortality. So far, most studies focussed on distinct disease entities rather than the integrity of the CV system. We here describe the design of the Cardiovascular Status in Endogenous Cortisol Excess Study (CV-CORT-EX), a study aiming to comprehensively investigate the health status of patients with endogenous CS (with a particular focus on CV phenotypes, biochemical aspects, quality of life, and psychosocial status)., Method: A prospective non-interventional cohort study performed at a German tertiary referral centre. At the time of enrolment, patients will be categorised as: (1) newly diagnosed overt CS, (2) recurrent overt CS, (3) CS in remission, (4) presence of mild autonomous cortisol excess (MACE). The target cohorts will be n = 40 (groups 1 + 2), n = 80 (group 3), and n = 20 (group 4). Patients with overt CS at the time of enrolment will be followed for 12 months after remission (with re-evaluations after 6 and 12 months). At each visit, patients will undergo transthoracic echocardiography, cardiac magnetic resonance imaging, 24-h electrocardiogram, 24-h blood pressure measurement, and indirect evaluation of endothelial function. Furthermore, a standardised clinical investigation, an extensive biochemical workup, and a detailed assessment of quality of life and psychosocial status will be applied. Study results (e.g. cardiac morphology and function according to transthoracic echocardiography and cardiac magnetic resonance imaging; e.g. prevalence of CV risk factors) from patients with CS will be compared with matched controls without CS derived from two German population-based studies., Discussion: CV-CORT-EX is designed to provide a comprehensive overview of the health status of patients with endogenous CS, mainly focussing on CV aspects, and the holistic changes following remission., Trail Registration: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) NCT03880513, registration date: 19 March 2019 (retrospectively registered). Protocol Date: 28 March 2014, Version 2.

Background: The diagnostic threshold for mild autonomous cortisol secretion using low dose, overnight, dexamethasone suppression testing is recognized widely as a serum cortisol ≥1.8 mcg/dL. The degree to which these patients require postoperative glucocorticoid replacement is unknown., Methods: We reviewed adult patients with corticotropin (ACTH)-independent hypercortisolism who underwent unilateral laparoscopic adrenalectomy for benign disease with a dexamethasone suppression testing ≥1.8 mcg/dL at our institution from 1996 to 2018. Patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL were compared with those with a dexamethasone suppression testing >5 mcg/dL., Results: We compared 68 patients with a preoperative dexamethasone suppression testing of 1.8 to 5 mcg/dL to 53 patients with a preoperative dexamethasone suppression testing >5 mcg/dL. Preoperative serum ACTH (mean 10.0 vs 9.2 pg/mL), adenoma size (mean 3.4 vs 3.5 cm), and side of adrenalectomy (37 and 47% right) were similar between groups (P > .05 each). Patients with a dexamethasone suppression testing 1.8 to 5 mcg/dL were older (mean values 58 ± 11 vs 52 ± 16 years ; P = .01), less likely to be female (63 vs 81%; P = .03), had greater body mass indexes (33.1 ± 8.4 vs 29.1 ± 5.6; P = .01), and had lesser 24 hour preoperative urine cortisol excretions (32.6 ± 26.7 vs 76.1 ± 129.4 mcg; P = .03). Postoperative serum cortisol levels were compared in 22 patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL to 14 patients with a dexamethasone suppression testing >5 mcg/dL. Those with dexamethasone suppression testing 1.8 to 5 mcg/dL had greater postoperative serum cortisol levels (8.0 ± 5.7 vs 5.0 ± 2.6 mcg/dL; P = .03), were less likely to be discharged on glucocorticoid replacement (59% vs 89%; P = .003), and had a decreased duration of treatment (4.4 ± 3.8 vs 10.7 ± 18.0 months; P = .04)., Conclusion: Assessment of early postoperative adrenal function with mild autonomous cortisol secretion is necessary to minimize unnecessary glucocorticoid replacement., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this review, we provide a comprehensive overview of the utility of steroid profiling for diagnosis of management of overt Cushing syndrome and mild autonomous cortisol secretion. A diagnosis of Cushing syndrome is made through a multistep process that includes confirmation of endogenous hypercortisolism, followed by determination of its cause. Steroid metabolomic testing applied to serum or urine steroids and their metabolites can provide additional and novel insights into alterations of steroid biosynthesis and metabolism and its causes. In particular, increased availability and advances in mass spectrometry-based steroid analysis, coupled with machine learning-based algorithms, have facilitated the development of tailored diagnostic and subtyping approaches for autonomous cortisol secretion and might be useful for detecting low grade autonomous glucocorticoid secretion and in predicting and monitoring of disease severity and associated comorbidities., Competing Interests: Declaration of competing interest IB reports consulting with Corcept, Strongbridge, HRA Pharma, and Sparrow Pharmaceutics outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Ectopic Cushing Syndrome (EAS) is a rare condition responsible for about 5-20% of all Cushing syndrome cases. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The aim of this study is to present a 20-year experience in the diagnosis and clinical course of patients with EAS in a single Clinical Centre in Southern Poland as well as a comparison of clinical course and outcomes depending on the source of ectopic ACTH production-especially neuroendocrine tumors with other neoplasms., Methods: Twenty-four patients were involved in the clinical study with EAS diagnosed at the Department of Endocrinology between years 2000 and 2018. The diagnosis of EAS was based on the clinical presentation, hypercortisolemia with high ACTH levels, high dose dexamethasone suppression test and/or corticotropin-releasing hormone tests. To find the source of ACTH various imaging studies were performed., Results: Half of the patients were diagnosed with neuroendocrine tumors, whereby muscle weakness was the leading symptom. Typical cushingoid appearance was seen in merely a few patients, and weight loss was more common than weight gain. Patients with neuroendocrine tumors had significantly higher midnight cortisol levels than the rest of the group. Among patients with infections, we observed a significantly higher concentrations of cortisol 2400 levels in gastroenteropancreatic neuroendocrine tumors. Chromogranin A correlated significantly with potassium in patients with neuroendocrine tumors and there was a significant correlation between ACTH level and severity of hypokalemia., Conclusion: EAS is not common, but if it occurs it increases the mortality of patients; therefore, it should be taken into consideration in the case of coexistence of severe hypokalemia with hypertension and muscle weakness, especially when weight loss occurs. Because the diagnosis of gastroenteropancreatic neuroendocrine tumor worsens the prognosis-special attention should be paid to these patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Previous studies have shown inconsistent results about the usefulness of bilateral inferior petrosal sinus sampling (BIPSS) in differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. This meta-analysis evaluated the diagnostic value of BIPSS via the published literature., Methods: This study searched PubMed, Embase, Web of Science, Cochrane library, and Wanfang database for published data on the use of BIPSS in Cushing syndrome differential diagnosis as of October 2019. Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and receiver operating characteristic (ROC) curves were calculated based on the relevant data., Results: This meta-analysis included a total of 23 studies with 1642 patients. The calculated sensitivity, specificity, PLR, and NLR were 0.94 (95% confidence interval, CI: 0.91-0.96), 0.89 (95% CI: 0.79-0.95), 8.8 (95% CI: 4.3-17.9), and 0.07 (95% CI: 0.04-0.11), respectively. The pooled DOR and area under the ROC curve were 129 (95% CI: 48-345) and 0.97 (95% CI: 0.95-0.98), respectively., Conclusion: This meta-analysis indicated that BIPSS had high diagnostic value for detecting ACTH in patients with ACTH-dependent Cushing syndrome, and BIPSS should be used as an effective method to identify ACTH-secretion sources.