Search

Context: The clinical presentation of Cushing syndrome (CS) overlaps with common conditions. Recommended screening tests are serum cortisol after 1-mg overnight dexamethasone suppression test (DST), urinary free cortisol (UFC), and late-night salivary cortisol (LNSC)., Objective: We analyzed the diagnostic accuracy of screening tests in 615 patients without CS (263 suspected CS, 319 adrenal and 33 pituitary incidentaloma) and 40 with CS., Methods: Principal component analysis, K-means clustering, and neural network were used to compute an integrated analysis among tests, comorbidities, and signs/symptoms of hypercortisolism., Results: The diagnostic accuracy of screening tests for CS was high; DST and UFC were slightly superior to LNSC. The threshold of DST should be adapted to the population considered, especially in adrenal incidentaloma (AI) with mild autonomous cortisol secretion: The cutoff to differentiate CS should be increased to 196 nmol/L. Diabetes, hypertension, and obesity were more common in patients without CS: The direction of their vectors was not aligned and their correlation with screening tests was poor. Clustering allowed us to differentiate those patients without CS into cluster 1 (aged osteoporotic patients with impaired screening tests), cluster 2 (hypertensive and metabolic phenotype), and cluster 3 (young individuals with a low likelihood of overt CS). A neural network model that combined screening tests and clinical presentation was able to predict the CS diagnosis in the validation cohort with 99% precision and 86% accuracy., Conclusion: Despite the high diagnostic accuracy of screening tests to detect CS, cortisol-related comorbidities or AI should be considered when interpreting a positive test., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. 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. See the journal About page for additional terms.)

Objective: To evaluate liver fat content in patients with non-functional adrenal incidentalomas (NFAI), mild autonomous cortisol secretion (MACS), and Cushing's syndrome (CS), and assess its relationship with cortisol levels., Methods: This cross-sectional study used retrospective data from 103 NFAI patients, 100 MACS (serum cortisol after a 1-mg dexamethasone test >50 nmol/L), and 59 with CS. Abdominal CT scans measured hepatic and splenic CT values to calculate the liver-to-spleen (L/S) ratio. Metabolic indicators including fasting plasma glucose (FPG), LDL-c, HDL-c, HbA1c, etc were measured. Mediation analysis was used to explore the indirect effects of metabolic traits on the cortisol-liver fat relationship., Results: Patients included 103 NFAI, 100 MACS, and 59 CS. MACS patients had higher NAFLD prevalence (57%) than NFAI (26.2%, p < 0.001) but lower than CS (66.1%, p < 0.001). MACS and CS were associated with NAFLD (OR 3.83 and OR 5.73, p < 0.01), adjusted for age, body mass index (BMI), and covariates. Midnight serum cortisol correlated with L/S ratio (p < 0.001). HbA1c and Triglyceride-glucose index (TyG) mediated 24.5% and 49.5% of the cortisol and L/S ratio association, respectively. FPG, HbA1c, HDL-c, and TyG mediated the association between MACS or CS and the L/S ratio. Homeostasis model assessment of insulin resistance (HOMA-IR), fructosamine, and triglycerides mediated for MACS, while alkaline phosphatase did so for CS. Total cholesterol, LDL-c, ALT, AST, γ-GT, insulin, and uric acid did not mediate the association., Conclusion: MACS and CS are linked to significant metabolic disturbances, including increased liver fat and impaired glucose and lipid metabolism, contributing to fatty liver., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests. Ethics approval: This study was conducted in accordance with the principles of the Declaration of Helsinki. Written, informed consent was obtained from all of the participants, and the study was approved by the ethics committee of Zhongshan Hospital, Fudan University, China., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metyrapone is commonly used in the initial management of Cushing's syndrome to reduce hypercortisolemia, but its optimal dosage and timing can vary significantly between patients. Currently, there are limited guidelines on adjustment methods for its administration to individual needs. This study aimed to evaluate responsiveness of each patient to metyrapone and identify the patient characteristics associated with the indices of cortisol responsiveness following a low-dose metyrapone. This single-center retrospective observational study included 15 treatment-naïve patients, 7 of whom had Cushing's disease and 8 had adrenal Cushing's syndrome. Serum cortisol levels were measured hourly from the time of administration of 250 mg of metyrapone up to four hours afterward. Parameters analyzed included the nadir of serum cortisol levels (F nadir ), the difference between basal and nadir serum cortisol levels ( Δ F), the time to nadir, and the characteristics of the patients. As a result, cortisol suppression curves showed significant variability among patients, particularly in the time to nadir. While the median time to nadir was 2 hours, 20% of patients required 4 hours or more, and these responses were not associated with patient characteristics. F nadir was positively correlated with early-morning serum cortisol levels, serum cortisol levels after low-dose dexamethasone suppression test (LDDST), and urinary free cortisol (UFC) levels, whereas Δ F was positively correlated with late-night serum cortisol levels, serum cortisol levels after LDDST, and UFC levels. In conclusion, the duration of response to metyrapone appeared unpredictable in patients with Cushing's syndrome and did not correlate with patient characteristics at baseline. Tracking the effect of metyrapone following a single low-dose administration may explain this variability and provide insights for optimizing individual dosing regimens. Further studies are required to validate these findings and guide more personalized treatment adjustments., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tsujimoto, Yamamoto, Bando, Yamamoto, Ohmachi, Motomura, Oi-Yo, Sasaki, Suzuki, Urai, Takahashi, Iguchi, Ogawa and Fukuoka.)

Objective: Cushing's syndrome (CS) results in increased cardiovascular (CV) morbidity and mortality. Subtype-specific differences and possible reversibility after biochemical cure are not well investigated., Design: Prospective cohort study evaluating the CV status in different forms of endogenous cortisol excess., Methods: Patients with overt CS (n = 40, 47 ± 13 years, 75% women; 18 pituitary, 13 adrenal, and 9 ectopic), biochemically cured CS (n = 56, 53 ± 12 years, 79% women; 30 pituitary, 21 adrenal, and 5 ectopic), and adrenal incidentalomas with mild autonomous cortisol secretion (MACS) (n = 18, 62 ± 11 years, 56% women) underwent comprehensive biochemical, metabolic, and CV assessment. Results were compared with a representative sample of the general population of Würzburg (n = 4965, 55 ± 12 years, 52% women)., Results: Overt CS was associated with left ventricular (LV) remodeling along with hypertrophy and impaired longitudinal systolic/diastolic function at echocardiography. In 20 CS patients followed for a median of 8 (quartiles: 6, 11) months after biochemical remission, hypertension, and hyperglycemia were better controlled, while cardiac alterations only partially improved. Patients with previous CS (median time of biochemical remission: 95 [36, 201] months) had worse diastolic function than the general population (LV relaxation velocity e' 0.08 [0.07, 0.10] ms-1 vs 0.10 [0.08, 0.12] ms-1, P < .001). In MACS, cardiac remodeling was even more pronounced than in individuals with metabolic syndrome., Conclusions: In patients with overt CS, cured CS, and MACS, we found a sizable and significant deviation from the general population mean regarding cardiac structure and function. Even mild cortisol excess is associated with glucocorticoid-induced cardiac alterations, which appear to persist despite long-term biochemical remission., Competing Interests: Conflict of interest: C.M. reports a research cooperation between the University of Würzburg and Tomtec Imaging Systems (funded by a research grant from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany), honoraria from Alexion, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, EBR Systems, Janssen, Novo Nordisk, Pfizer, SOBI, and Tomtec, and her role as principal investigator in clinical trials sponsored by Alnylam, AstraZeneca, Bayer, and Novo Nordisk. G.G. reports a research cooperation between the University of Würzburg and Tomtec Imaging Systems (funded by a research grant from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany). M.K. received advisory fees and speaker honoraria from Advanz Pharma, Bayer, Eisai, HRA Pharma, Lilly, Recordati Rare Diseases, Roche, and Sanofi, reimbursement of travel costs from Lilly, and research support as principal investigator of a clinical trial from Corcept Therapeutics, Ipsen, and Lilly. S.F. received consultancy and lecture fees as well as reimbursement of travel costs from Abbot, Abiomed, Amarin, Amgen, AstraZeneca, Bayer, Berlin-Chemie, Biotronik, Boehringer, Bristol-Myers Squibb, Daiichi Sankyo, Edwards, Lilly, Novartis, Novo Nordisk, Pfizer, sanofi-aventis, Siemens, Vifor, and Zoll. S.H. reports no personal honoraria but consultancy fees from Takeda paid to the institution. All other authors declare no competing interests. P.U.H. reports research grants from the Bavarian State, the European Union, the Federal Joint Committee (G-BA) within the Innovationsfonds, the German Cancer Aid, the German Heart Foundation, the German Ministry of Research and Education, the German Parkinson Society, the German Research Foundation, the University Göttingen (within FIND-AF randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer Ingelheim), the University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer Ingelheim, and Daiichi Sankyo), and the University Hospital Würzburg, all outside the submitted work. S.S. has received consultancy and lecture fees as well as reimbursement of travel costs from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Servier. T.D. received advisory fees and speaker honoraria from HRA Pharma and Novartis, reimbursement of travel costs from Novo Nordisk and Recordati Rare Diseases and research support as principal investigator of a clinical trial from Corcept Therapeutics., (© 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.)

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.)

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).)

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.)

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.

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: 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).)

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.)

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.

Purpose: Ectopic Cushing's syndrome (ECS) caused by an ACTH secreting neuroendocrine neoplasm (NEN) is a rare and challenging condition. We aimed to detect predictive and prognostic parameters for ECS patients identified from a retrospective, comprehensive cohort of NENs treated at a tertiary referral center., Methods: Medical records of 886 patients with NENs were reviewed. We identified 51 patients with ECS (33 females/18 men); mean age 52 ± 15 years (SD). Clinical parameters including symptoms, biochemical markers, and survival were extracted and further analyzed., Results: The primary tumor was located in the thorax (n = 28) or pancreas (n = 15) or was of unknown primary origin (n = 8). In 30 patients, tumor and ECS were diagnosed simultaneously. In 12 patients, the NEN diagnosis preceded ECS development, with a median time of 43.5 months (range: 9-96), and 10 of these showed radiological tumor progression at ECS diagnosis. Twenty-one patients had multiple hormone secretion, which correlated with shorter overall survival (OS), p = 0.012 (HR 2.4 (95% CI 1.2-4.9)), as did high morning cortisol, p = 0.037 (HR 2.3 (1.0-5.2)), higher tumor grade, p = 0.044 (HR 2.3 (1.0-5.1)), and diabetes, p = 0.050 (HR 2.4 (1.0-6.0))., Conclusions: Multiple hormone secretion, high morning cortisol, higher tumor grade, and diabetes were correlated with shorter OS. Development of ECS in patients with a non-functioning NEN may indicate tumor progression. Multiple hormone secretion should be considered as a bad prognostic sign in ECS patients and should lead to intensified clinical management.

Background and Aim: Dexamethasone Suppression Test (DST), recommended for Cushing's Syndrome (CS) diagnosis, explores the pituitary feedback to glucocorticoids. Its diagnostic accuracy could be affected by dexamethasone bioavailability, and therefore, we have developed and validated a dexamethasone threshold after 1-mg DST., Materials and Methods: We studied 200 subjects: 125 patients were considered retrospectively and 75 were enrolled prospectively as the validation cohort. Serum dexamethasone, Late Night Salivary Cortisol (LNSC), and Urinary Free Cortisol (UFC) were measured with LC-MS/MS. Normal LNSC and UFC levels were used to exclude CS. The lower 2.5th percentile of dexamethasone distribution in non-CS patients with cortisol ≤ 50 nmol/L after 1-mg DST was used as threshold., Results: 16 patients were CS and 184 non-CS (108 adrenal incidentaloma and 76 excluded CS); 4.5 nmol/L resulted the calculated threshold. Cortisol after 1-mg DST confirmed high sensitivity (100% at 50 nmol/L cut-off) and moderate-low specificity (63%, increased to 91% at 138 nmol/L) to diagnose CS in the whole cohort of patients. We could reduce the number of false-positive results (from 10 to 6 and from 7 to 4 in AI and excluded CS) considering adequate dexamethasone levels. Dexamethasone levels were not affected by hypercortisolism, age, gender, smoke, weight, and creatinine. 6% of non-CS patients did not achieve adequate dexamethasone levels (40% of tests with serum cortisol > 138 nmol/L after 1-mg DST)., Conclusions: We developed and validated the routine dexamethasone measurement during 1-mg DST: it is independent from patient's clinical presentation, and it should be used to increase the specificity of serum cortisol levels.

A 50-year-old man was referred to our department for overt Cushing's syndrome (CS). His plasma cortisol concentrations were 314 μg/L, and his urinary cortisol concentrations were 431 μg/day. The plasma adrenocorticotropic hormone (ACTH) concentration was below the detectable limit. Computed tomography revealed atrophy of both adrenal glands and the presence of a left pararenal tumor. 131I-6β-iodomethyl-norcholesterol scintigraphy showed an intense uptake by the left pararenal tumor. These findings suggested that the left pararenal tumor was ectopic cortisol-producing adrenocortical adenoma. This case serves as a reminder that 131I-6β-iodomethyl-norcholesterol scintigraphy is an effective method for diagnosing ACTH-independent CS in which no adrenal tumor has been found.

Hypokalemia is a common feature in patients with Cushing's syndrome (CS). Whether the occurrence of hypokalemia is associated with cortisol and adrenocorticotropic hormone (ACTH) levels is still unclear. Approximately 80% of cases of endogenous CS are due to Cushing's disease (CD). The purpose of this study was to determine the association of hypokalemia with cortisol and ACTH levels in patients with CD. The retrospective study included 195 patients with CD referred to our medical center from January 2011 to December 2017. The results show that 25.64% (50/195) of the patients had hypokalemia. The 24-h urinary free cortisol (UFC) and plasma cortisol levels were significantly higher in patients with hypokalemia than those with normokalemia (P < 0.05). Plasma ACTH levels were similar between the patients with hypokalemia and normokalemia (P > 0.05). Cortisol levels were negatively correlated with plasma potassium levels (08:00: r = -0.344 (P < 0.01), 00:00: r = -0.435 (P < 0.01); 24-h UFC: r = -0.281 (P < 0.05)). There was no significant correlation between the plasma ACTH and potassium (08:00: r = -0.093 (P > 0.05), 00:00: r = -0.184 (P > 0.050)). Our current data suggest that cortisol level, instead of ACTH level, is correlated with plasma potassium level. A high cortisol level may be the principal cause of hypokalemia., (© 2019 New York Academy of Sciences.)

Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.

Purpose: To study the usefulness of adrenal venous sampling (AVS) in distinguishing unilateral from bilateral cortisol production in patients with ACTH-independent hypercortisolism and bilateral adrenal lesions, or morphologically normal adrenal glands., Methods: A retrospective analysis of ten consecutive patients with ACTH-independent hypercortisolism who underwent AVS at our institution between 2009 and 2017. Unilateral dominant cortisol production was defined as a side-to-side cortisol/aldosterone lateralization ratio >2., Results: Four of ten patients had overt Cushing's syndrome. Of these, two had bilateral adrenal lesions on computed tomography and two had normal adrenal glands. One of the two patients with bilateral adrenal lesions had, based on the AVS, a unilateral dominant cortisol production. Following unilateral adrenalectomy the patient developed adrenal insufficiency. The other three patients were considered to have bilateral cortisol production and underwent bilateral adrenalectomy. Six patients had a mild autonomous cortisol secretion and bilateral adrenal lesions. Based on AVS, one patient was considered to have unilateral dominant cortisol production, underwent unilateral adrenalectomy and developed transient adrenal insufficiency postoperatively., Conclusions: AVS may contribute to appropriate treatment in patients with ACTH-independent hypercortisolism and bilateral adrenal lesions. In our series, AVS was helpful in the decision-making of two out of ten patients, avoiding chronic treatment with steroidogenesis inhibitors, or inappropriate bilateral adrenalectomy.

Background and Objective: In this study, a presentation is made for the automatic control of the hypothalamus-pituitary-adrenal axis which plays an important role in the immune stress responses and the circadian rhythms of mammalian organisms., Methods: Control approaches are implemented on a novel second order nonlinear system which accepts adrenocorticotropin hormone as an input and models the variation of plasma concentrations of adrenocorticotropin and cortisol respectively. The control methods are based on back-stepping and input-output feedback linearization techniques. The controllers adjust the adrenocorticotropin injection to maintain the daily rhythm of the cortisol concentration. In accordance with the periodicity of biological clock mechanism, we provide a sinusoidally varying cortisol reference to the controllers., Results: Numerical simulations are performed (on MATLAB) to demonstrate the closed loop performance of the controllers. Major concerns in the selection of the control gains are chattering and negative concentration in responses. The simulation results showed that one can successfully find gain levels which do not lead to those issues. However, the gains lie in different ranges for back-stepping and feedback linearization based controllers., Conclusion: The results showed that, both back-stepping and feedback linearization based controllers fulfilled their duty of synchronization of the cortisol concentration to a reference daily periodic rhythm. In addition to that, the risk of negative valued adrenocorticotropin injection can be eliminated by properly choosing the controller gains., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Context: Cushing's syndrome is caused by increased exposure to cortisol. Discrimination of different causes of endogenous hypercortisolism can make a diagnostic dilemma., Patients and Methods: In serum samples from patients with Cushing's syndrome (47 with Cushing's disease, 6 with ectopic ACTH-dependent Cushing's syndrome, 16 with adrenal adenoma, 7 bilateral adrenal hyperplasia (BMAH) with overt Cushing's syndrome, 42 controls from the general population) using novel method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) we measured 94 serum steroids to search for steroid fingerprint of each subtype., Results: Patients with Cushing's disease and ectopic ACTH producing tumors showed elevated levels of androgens and their metabolites when compared with healthy controls. Mineralocorticoid precursors were also elevated in ectopic ACTH syndrome. The levels of androgens were decreased in adrenal adenomas and BMAH. ROC analysis showed 100% sensitivity and 93.6% specificity for 11β-hydroxyepiandrosterone sulfate for discrimination of Cushing's disease from ectopic ACTH secretion. We didn't find any significant (p < 0.05) difference in steroids that would discriminate BMAH from unilateral adenomas causing Cushing's syndrome., Conclusion: Various causes of Cushing's syndrome show particular steroid fingerprints that can be used to discriminate and may help to achieve appropriate clinical diagnosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Analyses using the largest Korean cohort of adrenal incidentaloma (AI) revealed that subtle cortisol excess in premenopausal women and reduced dehydroepiandrosterone-sulfate (DHEA-S) in postmenopausal women and men are associated with bone mineral density (BMD) reduction in Asian patients with subclinical hypercortisolism (SH)., Introduction: Few studies evaluated bone metabolism in Asians with SH. We investigated associations of cortisol and DHEA-S, an adrenal androgen, with BMD in Asians with AI, with or without SH., Methods: We used cross-sectional data of a prospective multicenter study from Korea. We measured BMD, bone turnover markers, cortisol levels after 1-mg dexamethasone suppression test (1-mg DST), DHEA-S, and baseline cortisol to DHEA-S ratio (cort/DHEA-S) in 109 AI patients with SH (18 premenopausal, 38 postmenopausal women, and 53 men) and 686 with non-functional AI (NFAI; 59 premenopausal, 199 postmenopausal women, and 428 men)., Results: Pre- and postmenopausal women, but not men, with SH had lower BMDs at lumbar spine (LS) than those with NFAI (P = 0.008~0.016). Premenopausal women with SH also had lower BMDs at the hip than those with NFAI (P = 0.009~0.012). After adjusting for confounders, cortisol levels after 1-mg DST demonstrated inverse associations with BMDs at all skeletal sites only in premenopausal women (β = - 0.042~- 0.033, P = 0.019~0.040). DHEA-S had positive associations with LS BMD in postmenopausal women (β = 0.096, P = 0.001) and men (β = 0.029, P = 0.038). The cort/DHEA-S had inverse associations with LS BMD in postmenopausal women (β = - 0.081, P = 0.004) and men (β = - 0.029, P = 0.011). These inverse associations of cort/DHEA-S remained significant after adjusting for cortisol levels after 1-mg DST (β = - 0.079~- 0.026, P = 0.006~0.029). In postmenopausal women, the odds ratios of lower BMD by DHEA-S and cort/DHEA-S was 0.26 (95% CI, 0.08-0.82) and 3.40 (95% CI, 1.12-10.33), respectively., Conclusion: Subtle cortisol excess in premenopausal women and reduced DHEA-S in postmenopausal women and men may contribute to BMD reduction in Asians with SH.

Adrenal incidentalomas (AI) are one of the most frequent reasons for consultation in Endocrinology, as they are present in 3-10% of the general population. Up to 20% of them may have autonomous cortisol secretion (ACS), a term that refers to AI carriers with biochemical evidence of excess cortisol, but without the "specific" clinical signs of Cushing's syndrome. As ACS is associated with an increased risk of diabetes, obesity, high blood pressure (HBP), osteoporosis, cardiovascular events, and global mortality; its correct identification is of great importance. There are different laboratory assays to detect ACS, but all of them have some limitations. The dexamethasone suppression test is the most accepted for screening. However, there is no consensus on the cutoff point that should be used. Low levels of ACTH and DHEA-S and high urinary free cortisol are also associated with ACS, but in isolation they are of little value to establish the diagnosis. Considering its clinical implications and the lack of consensus in the diagnosis and in which is the most appropriate management of these patients, this review offers a quick reference guide of ACS, presenting an exhaustive review of the topic: its definition, epidemiology, diagnosis, clinical implications, treatment, and follow-up.

Adrenal Cushing's syndrome (CS) is caused by cortisol-producing adrenal adenoma and is frequently accompanied by glucose metabolism disorders, which are characterized by increased insulin resistance and insufficient β-cell compensation. However, considering the rarity of CS, few studies have assessed whether the glucose metabolism disorders could be ameliorated by surgical treatment. In this case series, we evaluated glucose metabolism before and after surgery in 11 patients (10 women and 1 man) who underwent unilateral adrenalectomy for overt adrenal CS between 2005 and 2016. Patients with pre-diagnosed diabetes mellitus (DM) were excluded. Pre- and post-operative 75-g oral glucose tolerance tests were performed. Cortisol secretion decreased significantly after surgery (median 24-h urinary free cortisol: 582.0 μg/day [interquartile range: 321.0-743.0 μg/day] to 31.3 μg/day [23.6-40.6 μg/day], p = 0.001). The results of the OGTT generally improved after surgery (normal glucose tolerance/impaired glucose tolerance/DM: 2/8/1 to 8/3/0), with significant decreases in the immunoreactive insulin and glucose levels. We also found a decrease in the median homeostatic model assessment of insulin resistance (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and increases in the median Matsuda index (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001), median insulinogenic index (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.08), and median disposition index (609.1 [237.8-1,095.2] to 1,286.0 [1,034.6-1,857.6], p = 0.002). These findings indicate that adrenalectomy for adrenal CS without overt DM may help ameliorate glucose metabolism disorders, and improve both insulin resistance and insulin secretion.

Previous studies have linked systemic glucocorticoid use with intestinal perforation. However, the association between intestinal perforation and endogenous hypercortisolism has not been well described, with only 14 previously published case reports. In this study, we investigated if intestinal perforation occurred more frequently in patients with ectopic ACTH syndrome and in those with a greater than 10-fold elevation of 24-hour urinary free cortisol level. Of 110 patients with ACTH-dependent Cushing's syndrome followed in two clinics in Canada, six cases with intestinal perforation were identified over 15 years. Age of patients ranged from 52 to 72, five females and one male, four with Cushing's disease and two with ectopic ACTH production, one from a pancreatic neuroendocrine tumor and one from medullary carcinoma of the thyroid. Five had diverticular perforation and one had intestinal perforation from a stercoral ulcer. All cases had their lower intestinal perforation when the cortisol production was high, and one patient had diverticular perforation 15 months prior to the diagnosis of Cushing's disease. As in previously reported cases, most had hypokalemia and abdominal pain with minimal or no peritoneal symptoms and this occurred during the active phase of Cushing's syndrome. Whereas all previously reported cases occurred in patients with 24-hour urinary free cortisol levels greater than 10-fold the upper limit of normal when measured and 11 of 14 patients had ectopic ACTH production, only one of our patients had this degree of hypercortisolism and four of our six patients had Cushing's disease. Similar to exogenous steroid use, patients with endogenous hypercortisolism also have a higher risk of intestinal, in particular diverticular, perforation and should be monitored closely for its occurrence with a low threshold for investigation and surgical intervention. Elective colonoscopy probably should be deferred until Cushing's syndrome is under control.

Objective: During follow-up in cancer patients, adrenal lesions are frequently found by computer tomography imaging. In these patients, the frequency of subclinical Cushing's syndrome (SCS) has not been fully explored. The aim of the present study was to investigate the presence of SCS in cancer patients with adrenal lesions in comparison to patients with true adrenal incidentalomas., Design: We studied 95 patients with adrenal lesions: 57 patients (group A, 20 males and 37 females) had a history of extra-adrenal malignancy and adrenal lesions were discovered during staging of the primary cancer, and 38 patients (group B, 6 males and 32 females) had adrenal incidentalomas. The two groups had similar BMI. All patients had unenhanced HU < 10 in computed tomography to ensure low risk of adrenal metastatic disease. Patients' morning plasma cortisol levels and ACTH were measured. An overnight 1 mg dexamethasone suppression test (ODST) was performed in all participants; in case of abnormal results, 24-h urine cortisol and the low-dose dexamethasone suppression test were additionally conducted. The cutoffs of morning cortisol values used for ODST were 1.8 and 5 μg/dl., Results: When the cutoff of 1.8 μg/dl for suppressed morning cortisol was used, 42.1% of group A and 39.5% of group B had abnormal results (p = 0.95). By using the threshold of 5 μg/dl after ODST, 5.3% of group A and 13.2% of group B did not have suppressed cortisol levels with the 1 mg ODST (p = 0.18). The main factors found to influence suppressed cortisol levels after ODST in both groups were BMI and size of the adrenal lesion., Conclusions: Patients with extra-adrenal malignancies and adrenal lesions had similar rates of subclinical hypercortisolemia compared to patients with true adrenal incidentalomas.

Background: Management of patients with bilateral adrenal masses and ACTH-independent Cushing's syndrome (AICS) is challenging, as bilateral adrenalectomy can lead to steroid dependence and lifelong risk of adrenal crisis. Adrenal venous sampling (AVS) has been previously reported to facilitate lateralization for guiding adrenalectomy. The aim of the current study was to investigate the utility of AVS using protocol from study by Young et al. in the management of patients with bilateral adrenal masses and AICS., Methods and Design: A retrospective review of all patients with bilateral adrenal masses and AICS who underwent AVS from 2008 to 2016 was performed. AVS for cortisol and epinephrine was performed with dexamethasone suppression. The adrenal vein to peripheral vein cortisol ratios and side-to-side cortisol lateralization ratios were calculated., Results: AVS was successful in 8 of 9 patients. All 8 patients had AVS results indicating bilateral cortisol hypersecretion. Six patients underwent adrenalectomy: 3 had unilateral adrenalectomy of the larger size mass, 2 had bilateral adrenalectomy (both sides >4 cm.) and 1 had stepwise bilateral adrenalectomy. Final pathology revealed macronodular adrenal hyperplasia in all 6 patients that underwent surgery., Conclusion: AVS was useful in excluding a unilateral adenoma as the source of AICS in this study of patients with bilateral adrenal masses and AICS. However, adrenal mass size influenced surgical decision making more than AVS results. More data are needed before AVS can be advocated as essential for management of patients with bilateral adrenal masses and AICS.

Background: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS)., Case Presentation: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated., Conclusions: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome.

Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking., Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS., Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy., Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%)., Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Despite ethnic differences in cortisol sensitivity, only one study in Caucasians has assessed trabecular bone score (TBS) in patients with subclinical hypercortisolism (SH). We showed that both subtle cortisol excess and reduced adrenal androgen may contribute to impaired bone quality in Asian women with SH., Introduction: One study in Caucasians has assessed trabecular bone score (TBS), an index of bone microstructure, in adrenal incidentaloma (AI) patients with subclinical hypercortisolism (SH). There are ethnic differences in cortisol sensitivities between Caucasian and Asian populations. We investigated the associations of cortisol and the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) with TBS in AI patients with SH, adrenal Cushing's syndrome (CS), and nonfunctional AI (NFAI)., Methods: We measured TBS, cortisol levels after the overnight 1 mg dexamethasone suppression test (1 mg DST), and cortisol/DHEA-S in 61 patients with SH (30 men; 31 women), 19 with adrenal CS (4 men; 15 women), and 355 with NFAI (213 men; 142 women)., Results: After adjusting for confounders, the serum cortisol level after 1 mg DST was inversely correlated with TBS in men (β = -0.133, P = 0.045) and women (β = - 0.140, P = 0.048). Higher cortisol/DHEA-S ratio was associated with lower TBS in women (β = - 0.252, P < 0.001), but not men. This inverse association of cortisol/DHEA-S ratio in women remained statistically significant after adjusting for the serum cortisol level after 1 mg DST (β = - 0.221, P = 0.008). Compared with women with NFAI, women with SH had 2.2% lower TBS (P = 0.040). Deteriorated bone microstructure (TBS < 1.230) was associated with the serum cortisol level after 1 mg DST (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.04-4.53) and cortisol/DHEA-S ratio (OR, 2.05; 95% CI, 1.03-4.08)., Conclusions: Subtle cortisol excess in both genders and reduced DHEA-S, especially in women, may contribute to impaired bone quality in Asian patients with SH.

Circadian variations impact thyrotropin (TSH) secretion; in Cushing's syndrome (CS) patients, the nocturnal serum TSH surge is abolished. The aim of this prospective study is to examine whether serum TSH surge may be a useful diagnostic method for CS. This prospective study recruited 136 inpatients for differential diagnosis of CS or subclinical CS (SCS), and 21 inpatients with depression at Osaka University Hospital. Serum TSH surge was assessed by the midnight-to-morning serum TSH ratio (2300-2400 h to 0800-0900 h). The diagnostic accuracy (sensitivity and specificity) between TSH ratio and ordinary screening tests [low-dose dexamethasone suppression test (LDDST), late-night serum cortisol and urine free cortisol (UFC)] were compared. Twenty-two patients were diagnosed as CS (12 overt CS and 10 SCS) and the remaining 120 patients were excluded for CS. The diagnostic accuracy of TSH ratio (cutoff value 1.0) yielded sensitivity 90.9% [95% confidence interval (CI) 70.8-98.9], specificity 95.0% (95% CI 89.4-98.1), and a high positive and low negative likelihood ratio [18.2 (95% CI 8.2-40.1) and 0.096 (95% CI 0.026-0.359), respectively]. The specificity of TSH ratio was significantly higher than LDDST and midnight serum cortisol test. The sensitivity of TSH ratio was significantly higher than UFC. TSH ratio showed more than 1.0 in all patients with depression and CYP3A4 inducer users. TSH ratio is a novel supportive diagnostic method with higher specificity than the current diagnostic methods for CS.

Objectives: To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome., Methods: The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis., Results: All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume <0.745 cm 3 , contralateral adrenal width <6.15 mm and serum cortisol after a 1-mg dexamethasone suppression test >2.65 μg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post-surgical steroid replacement., Conclusions: Contralateral adrenal width seems to represent a significant predictive factor for the duration of post-surgical steroid replacement in subclinical Cushing syndrome patients. Pre-surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy., (© 2018 The Japanese Urological Association.)

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 μg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 μg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.

Studies in our laboratory have shown that modest chronic increases in maternal cortisol concentrations over the last 0.20 of gestation impair maternal glucose metabolism and increase the incidence of perinatal stillbirth. Previous studies had found that an increase in maternal cortisol concentrations from 115 to 130 days of gestation in sheep increased both proliferation in fetal cardiomyocytes and apoptosis in the fetal cardiac Purkinje fibers. We hypothesized that the adverse effects of excess cortisol may result in defects in cardiac conduction during labor and delivery. In the present study, we infused cortisol (1 mg·kg -1 ·day -1 ) into late gestation pregnant ewes and continuously monitored fetal aortic pressure and ECG through labor and delivery. We found that, although the fetuses of cortisol infused ewes had normal late gestation patterns of arterial pressure and heart rate, there was a significant decrease in fetal aortic pressure and heart rate on the day of birth, specifically in the final hour before delivery. Significant changes in the fetal ECG were also apparent on the day of birth, including prolongation of the P wave and P-R interval. We speculate that chronic exposure to glucocorticoids alters cardiac metabolism or ion homeostasis, contributing to cardiac dysfunction, precipitated by active labor and delivery.

Objective: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS)., Methods: Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission., Results: We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 μg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively., Conclusion: UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS., Abbreviations: ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin-releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno-assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol.

Introduction: The cortisol/ACTH ratio was supposed to be helpful in the screening of subclinical hypercortisolism (SHC) in the published literatures. This study assessed the cortisol/ACTH ratio in patients with adrenal incidentaloma (AI) confirmed to have SHC and investigated its role for screening SCS in patients with AI., Methods: This descriptive retrospective study included 183 patients with AIs [45 with SHC and 138 with non-functional adenoma (NFA)]. Cortisol and ACTH levels were measured at 8:00, 16:00, and 0:00, and the cortisol/ACTH ratio was calculated. ROC curve was used to evaluate efficacy of the cortisol/ACTH ratio, explore the best cut-off value and its corresponding sensitivity and specificity., Results: The cortisol/ACTH ratios at all time points were significantly higher in the SHC group than the NFA group (P<0.05) and were significantly correlated with serum cortisol levels after the 1-mg dexamethasone suppression test (DST). Area Under the Curve (AUC) of the cortisol/ACTH ratio at 0:00 and midnight serum cortisol levels were 0.893 (0.843-0.943) and 0.831 (0.765-0.806), respectively. A cortisol/ACTH ratio at 0:00 cut-off of 32.18 nM/pM showed a sensitivity of 100% and specificity of 39.1%. The optimal cut-off was 68.83 nM/pM (sensitivity 86.7%, specificity 75.4%)., Conclusions: Patients with SHC have a higher cortisol/ACTH ratio than those with NFAs. The cortisol/ACTH ratio is significantly correlated with serum cortisol after the 1-mg DST. The diagnostic performance of the cortisol/ACTH ratio at 0:00 is superior to midnight serum cortisol. Therefore, the cortisol/ACTH ratio at 0:00 may be a reliable parameter for SHC screening in patient with AI., Competing Interests: The authors have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The purpose of this study is to measure intraocular pressure (IOP) and evaluate the correlation between IOP and midnight plasma cortisol (MPC) level in patients with Cushing's disease (CD) and other endogenous Cushing's syndrome (ECS)., Methods: This is a cross-sectional study from a single center including newly diagnosed patients with CD or ECS. All patients underwent detailed ophthalmological evaluation. IOP was measured by Goldmann applanation tonometry in the morning and evening on two consecutive days. MPC value was obtained for each patient. The data were compared using paired and unpaired t-test, Mann-Whitney U-test, and Spearman's rank correlation coefficient., Results: Among 32 patients, 22 were CD (68.75%) and 10 patients were other ECS (31.25%). A total of 25 patients (78.12%) in our study group had normal IOP (<22 mmHg), and seven patients (21.88%) had increased IOP (≥22 mmHg). The percentage of patients with normal IOP was found to be significantly higher compared to percentage of patients with high IOP (P = 0.001) using one-sample Chi-square test. Mean MPC value was 468.6 ± 388.3 nmol/L in patients having IOP ≥22 mmHg and 658.5 ± 584 nmol/L in those with IOP <22 mmHg from both CD and ECS groups, but the difference was not statistically significant. No correlation was found between IOP and MPC (Spearman's rank correlation rho = -0.16 [P = 0.38])., Conclusion: In CD and ECS patients, IOP elevation is an uncommon feature, and high IOP in either group does not correlate with MPC level.

Objective: Endogenous hypercortisolism is a chronic condition associated with severe metabolic disturbances and cardiovascular sequela. The aim of this study was to characterize metabolic alterations in patients with different degrees of hypercortisolism by mass-spectrometry-based targeted plasma metabolomic profiling and correlate the metabolomic profile with clinical and hormonal data., Design: Cross-sectional study., Methods: Subjects ( n  = 149) were classified according to clinical and hormonal characteristics: Cushing's syndrome ( n  = 46), adrenocortical adenomas with autonomous cortisol secretion ( n  = 31) or without hypercortisolism ( n  = 27). Subjects with suspicion of hypercortisolism, but normal hormonal/imaging testing, served as controls ( n  = 42). Clinical and hormonal data were retrieved for all patients and targeted metabolomic profiling was performed., Results: Patients with hypercortisolism showed lower levels of short-/medium-chain acylcarnitines and branched-chain and aromatic amino acids, but higher polyamines levels, in comparison to controls. These alterations were confirmed after excluding diabetic patients. Regression models showed significant correlation between cortisol after dexamethasone suppression test (DST) and 31 metabolites, independently of confounding/contributing factors. Among those, histidine and spermidine were also significantly associated with catabolic signs and symptoms of hypercortisolism. According to an discriminant analysis, the panel of metabolites was able to correctly classify subjects into the main diagnostic categories and to distinguish between subjects with/without altered post-DST cortisol and with/without diabetes in >80% of the cases., Conclusions: Metabolomic profiling revealed alterations of intermediate metabolism independently associated with the severity of hypercortisolism, consistent with disturbed protein synthesis/catabolism and incomplete β-oxidation, providing evidence for the occurrence of metabolic inflexibility in hypercortisolism., (© 2017 European Society of Endocrinology.)

Numerous epidemiologic studies have identified an independent association between Alzheimer's disease (AD) and diabetes mellitus (DM), which remains unexplained. This review contends that the association is mediated by mild hypercortisolemia that is manifested in AD by early stages, as empirical evidence indicates that hypercortisolemia is diabetogenic even at subclinical levels. Subclinical Cushing's syndrome is discussed as the paradigm. It is proposed that hypercortisolemia increases the risk of pre-diabetes and DM during early AD and the preceding decades. That hypercortisolemia is exhibited during the AD prodromal stage has yet to be determined, but may be inferred from concurrent metabolic parameters as documented in the literature. Studies refuting association between AD and DM also are evaluated, and the relationship between AD and DM is deduced to be more complex than directly causal, with DM of longstanding duration having a protective role. Association between DM and AD may require reappraisal by APOE ε4 carrier status, in view of newly identified roles of APOE ε4 in pre-diabetes. That association of APOE ε4 with DM in AD may have been underestimated in epidemiologic studies also is highlighted. At the core of arguments and mechanisms presented in this review is the circadian rhythm of cortisol secretion, which is the main determinant of glycemic control in humans. Alterations to that rhythm and to the hypothalamic-pituitary-adrenal axis occurring in AD are examined. Consequently the cause of hypercortisolemia in AD, and therefore of association between AD and DM, is proposed to be adrenal hyper-responsiveness to adrenocorticotropic hormone., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cortisol is a steroid hormone produced in response to stress. It is essential for maintaining health and wellbeing and leads to significant morbidity when deficient or present in excess. It is lipophilic and is transported bound to cortisol-binding globulin (CBG) and albumin; a small fraction (∼10%) of total serum cortisol is unbound and biologically active. Serum cortisol assays measure total cortisol and their results can be misleading in patients with altered serum protein concentrations. Automated immunoassays are used to measure cortisol but lack specificity and show significant inter-assay differences. Liquid chromatography - tandem mass spectrometry (LC-MS/MS) offers improved specificity and sensitivity; however, cortisol cut-offs used in the short Synacthen and Dexamethasone suppression tests are yet to be validated for these assays. Urine free cortisol is used to screen for Cushing's syndrome. Unbound cortisol is excreted unchanged in the urine and 24-h urine free cortisol correlates well with mean serum-free cortisol in conditions of cortisol excess. Urine free cortisol is measured predominantly by immunoassay or LC-MS/MS. Salivary cortisol also reflects changes in unbound serum cortisol and offers a reliable alternative to measuring free cortisol in serum. LC-MS/MS is the method of choice for measuring salivary cortisol; however, its use is limited by the lack of a single, validated reference range and poorly standardized assays. This review examines the methods available for measuring cortisol in serum, urine and saliva, explores cortisol in disease and considers the difficulties of measuring cortisol in acutely unwell patients and in neonates.

Endogenous hypercortisolism (Cushing's syndrome) usually implies the presence of a pathologic condition caused by either an ACTH-secreting neoplasm or autonomous cortisol secretion from a benign or malignant adrenal neoplasm. However, sustained or intermittent hypercortisolism may also accompany many medical disorders that stimulate physiologic/non-neoplastic activation of the HPA axis (formerly known as pseudo-Cushing's syndrome); these two entities may share indistinguishable clinical and biochemical features. A thorough history and physical examination is often the best (and sometimes only) way to exclude pathologic/neoplastic hypercortisolism. The presence of alcoholism, renal failure, poorly controlled diabetes and severe neuropsychiatric disorders should always raise suspicion that the presence of hypercortisolism may be related to physiologic/non-neoplastic Cushing's syndrome. As late-night salivary cortisol and low-dose dexamethasone suppression have good sensitivity and negative predictive value, normal studies exclude Cushing's syndrome of any form. However, these tests have imperfect specificity and additional testing over time with clinical follow-up is often needed. When there is persistent diagnostic uncertainty, secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may provide evidence for the presence or absence of an ACTH-secreting tumor. This review will define and characterize the numerous causes of physiologic/non-neoplastic hypercortisolism and provide a rational clinical and biochemical approach to distinguish it from pathologic/neoplastic hypercortisolism (true Cushing's syndrome)., (© 2017 European Society of Endocrinology.)

Context: Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations., Objective: To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI., Setting and Patients: In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L)., Results: 29 patients (16%) were diagnosed with SH. Adrenocorticotropin was <10 pg/mL (<2.2 pmol/L) in all patients with SH. We calculated age- and sex-specific DHEAS ratios (derived by dividing the DHEAS by the lower limit of the respective reference range) for all patients. Receiver operating characteristic curve analyses demonstrated that a ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%)., Conclusion: A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs., (Copyright © 2017 by the Endocrine Society)

Cushing syndrome (CS) is characterized by increased morbidity and mortality compared to the general population. However, there are patients who have more clinical aggressive forms than others. Aim of the study is to evaluate whether the degree of hypercortisolism, defined by the number of times urinary free cortisol (UFC) levels exceed the upper limit of the normal range (ULN), is related to the worsening of phenotypic features, as well as metabolic and cardiovascular parameters, in a cohort of CS patients. A cross-sectional study was conducted on 192 patients with active CS, consecutively presenting at the outpatients' clinic of the University Hospitals of Ancona, Naples, and Palermo. Patients were grouped into mild (UFC not exceeding twice the ULN), moderate (2-5 times the ULN), and severe (more than 5 times the ULN) hypercortisolism. Thirty-seven patients (19.3 %) had mild, 115 (59.8 %) moderate, and 40 (20.9 %) severe hypercortisolism. A significant trend of increase among the three groups was demonstrated for 8-, 16-, and 24-h serum cortisol levels (p < 0.001) and serum cortisol after low dose of dexamethasone suppression test (p = 0.001). No significant trend of increase was found regarding phenotype and comorbidities. The degree of hypercortisolism by itself does not appear to be a sufficient parameter to express the severity of CS. Therefore, estimating the severity of CS according to biochemical parameters remains a challenge, while the clinical phenotype and the associated comorbidities might be more useful to assessing the severity of the CS.