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Background: Secondary adrenal insufficiency (SAI) may occur in patients after unilateral adrenalectomy for adrenal-dependent hypercortisolism (HC) or primary aldosteronism (PA). This study aimed to assess whether postoperative day (POD) 1 basal cortisol was predictive of an abnormal cosyntropin stimulation test (CST) result and the need for glucocorticoid replacement (GR)., Methods: A retrospective review of consecutive patients who underwent unilateral adrenalectomy for HC, PA, or both between September 2014 and September 2022 was performed. On POD1, CST was performed for all the patients with HC, and before 2021 for all the patients with PA. The patients with an abnormal CST result were deemed at risk of SAI and discharged with GR. Receiver operating characteristic (ROC) curves were generated to evaluate the sensitivity (SN) and specificity (SP) of basal cortisol thresholds to predict an abnormal CST result., Results: The patients underwent unilateral adrenalectomy for overt hypercortisolism (OH; n = 42), mild autonomous cortisol excess (MACE; n = 70), mixed PA/HC (n = 22), or PA (n = 73). On POD1, CST was performed for 152 patients (93% OH, 96% MACE,73% PA/HC, 41% PA), and 80 patients (53%) had SAI (67% OH, 55% MACE, 44% PA/HC, 33% PA). The SN and SP of a basal cortisol level of 10 µg/dL or lower to predict an abnormal CST were respectively 92% and 77% for OH, 94% and 73% for MACE, 100% and 85% for PA, and 100% and 67% for PA/HC. The optimal basal cortisol level for predicting an abnormal CST for patients with PA or PA/HC was 5 µg/dL or lower (SN/SP, 100%)., Conclusions: After unilateral adrenalectomy for HC, PA, or mixed PA/HC, POD1 CST improved identification of patients at risk for SAI compared with basal cortisol levels alone. The authors recommend that POD1 CST be performed to determine the risk for SAI and the need for postoperative GR after unilateral adrenalectomy for patients with HC., (© 2024. Society of Surgical Oncology.)

Introduction: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m ® (Mifepri st one) (CATALYST) trial., Methods and Analysis: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym ® ). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life., Ethics and Dissemination: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals., Trial Registration Number: NCT05772169., Competing Interests: Competing interests: RAF reports: advisory board with AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Renalytix, Corcept Therapeutics; research support from Boehringer Ingelheim, AstraZeneca; speaker's bureau with AstraZeneca. RJA reports: research support from Neurocrine Biosciences and Diurnal, Spruce Biosciences, Corcept Therapeutics, Sparrow Pharmaceuticals; consulting fees from Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Adrenas Therapeutics, PhaseBio Pharmaceuticals, Novo Nordisk, Recordati Rare Diseases, H Lundbeck A/S, OMass Therapeutics, Sparrow Pharmaceuticals. IB reports: consulting and/or advisory board with Corcept, HRA Pharma, Recordati, Sparrow, Neurocrine, Diurnal, Spruce; data safety monitoring board with Adrenas; funding for investigator initiated award from Recordati. LB reports: contracted fees paid to the Ochsner Clinic Foundation by Novo Nordisk for consulting work, and to Corcept Therapeutics for both speaking and consulting services. RSB reports: grant funding from Corcept pharmaceuticals; research funding from Novo, Lilly and Novartis; and speaker bureaus for Novo, Lilly, AstraZeneca, Amgen,and Bayer. JBB reports: contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support from Dexcom, Insulet, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion, Boehringer Ingelheim, CeQur, Cirius Therapeutics, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Medtronic, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns, Valo and Zealand Pharma; stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. JWF reports: consultant and investigator for Corcept, Recordati. VAF reports: research support (to Tulane): grants from Fractyl, Jaguar Gene Therapy, Corcept; honoraria for consulting and lectures from Asahi, Bayer, Abbott, Boehringer Ingelheim, Corcept; stock options in Mellitus Health, BRAVO4Health; stock in Amgen, Abbott; patents pending for 1) BRAVO risk engine for predicting diabetes complications, 2) PAX4 gene therapy for type 1 diabetes. JPF reports: research support from Akero, Altimmune, Boehringer Ingelheim, 89bio, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi, Shionogi, Corcept Therapeutics; advisory boards and consulting with Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, Sanofi, Sun Pharma; speaker’s bureau with Eli Lilly; employment and stock ownership in Biomea Fusion. OH reports: scientific advisory board participation with Corcept Therapeutics, Strongbridge Pharma, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Lantheus, Xeris. YH reports: research grant from Amgen, Applied Therapeutic, Corcept, Ionis, Lilly, Merck, Regor; advisory/consultant role with Amgen, Applied Therapeutic, AZ, Bayer, BI, Corcept, Esperion, Mankind Pharma, Merck, Merck-Pfizer, Novartis, Novo Nordisk, Sanofi; speaker’s bureau with Bayer, Esperion, Novo Nordisk. REP reports: consulting fees from Bayer AG, Corcept Therapeutics Incorporated, Dexcom, Hanmi Pharmaceutical Co., Merck, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma, Sun Pharmaceutical Industries; grants/research support from Hanmi Pharmaceutical Co., Janssen, Metavention, Novo Nordisk, Poxel SA, Sanofi. All funds are paid directly to REP’s employer, AdventHealth, a non-profit organisation that supports education and research. JR reports: advisory panels with Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma and Zealand; research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, Sanofi. ICT, AGM and DE report: employed by and own stock in Corcept Therapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism resulting from an ACTH-secreting tumor or from autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Nonneoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for more than 50 years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have nonneoplastic hypercortisolism: one from a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate stimulation test to aid in distinguishing neoplastic from nonneoplastic hypercortisolism., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Alcohol-induced hypercortisolism (AIH) is underrecognized and may masquerade as neoplastic hypercortisolism [Cushing syndrome (CS)] obscuring its diagnosis., Objective and Methods: In order to characterize AIH, we performed a chart review of eight patients (4 males and 4 females; 2014-2022) referred for evaluation and treatment of neoplastic hypercortisolism - six for inferior petrosal sinus sampling, one due to persistent CS after unilateral adrenalectomy, and one for pituitary surgery for Cushing disease (CD). Five underwent dDAVP stimulation testing., Results: All eight patients had clinical features of hypercortisolism and plasma ACTH levels within or above the reference interval confirming hypothalamic-pituitary mediation. All had abnormal low-dose dexamethasone suppression test and increased late-night salivary cortisol. Only one had increased urine cortisol excretion. In contrast to CD, the 5 patients tested had blunted or absent ACTH and cortisol responses to desmopressin. Two had adrenal nodules and one had abnormal pituitary imaging. Most patients underreported their alcohol consumption and one denied alcohol use. Elevated blood phosphatidyl ethanol (PEth) was required in one patient to confirm excessive alcohol use. All patients had elevations of liver function tests (LFTs) with AST>ALT., Conclusion: AIH is an under-appreciated, reversible cause of non-neoplastic hypercortisolism that is indistinguishable from neoplastic CS. Incidental pituitary and adrenal imaging abnormalities as well as under-reporting of alcohol consumption further confound the diagnosis. Measurement of PEth helps to confirm an alcohol use disorder. Elevations of LFTs (AST>ALT) and subnormal ACTH and cortisol responses to dDAVP help to distinguish AIH from neoplastic hypercortisolism., Competing Interests: TC is a consultant for Corcept Therapeutics and is a research investigator for Corcept Therapeutics and Recordati. BJ is a consultant for Clarus Therapeutics and research investigator for Amryt Pharma and Novartis Pharmaceuticals. HR is a consultant and receives research reagents from Corcept Therapeutics and is a consultant and does research for Cerium Pharmaceuticals. JF is a consultant for Corcept Therapeutics and Recordati. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Surani, Carroll, Javorsky, Raff and Findling.)

Introduction: While adrenal venous sampling (AVS) differentiates between the unilateral and bilateral disease in patients with primary aldosteronism (PA), it is unknown if AVS can determine laterality of pheochromocytoma in patients with bilateral adrenal masses. This study analyzes adrenal vein (AV) epinephrine and norepinephrine levels in nonpheochromocytoma patients to determine the "normal" range., Materials and Methods: We reviewed patients who underwent AVS for PA between 2009 and 2019 at a single institution; pheochromocytoma was excluded. Aldosterone, cortisol, epinephrine, and norepinephrine levels were obtained from the inferior vena cava (IVC), left adrenal vein (LAV), and right adrenal vein (RAV). Successful AV cannulation was defined by an AV/IVC cortisol ratio of ≥3:1 or an AV epinephrine level ≥364 pg/mL. Plasma measurements (pg/mL) are median values with interquartile ranges; normal ranges for epinephrine and norepinephrine are 10-200 pg/mL and 80-520 pg/mL, respectively., Results: AVS was performed in 172 patients in 405 AVs (173 LAV and 232 RAV). Median epinephrine levels were IVC = 19 (14 and 34), LAV = 3811 (1870 and 6915), and RAV = 2897 (1500 and 5288). Median norepinephrine levels were IVC = 325 (186 and 479), LAV = 1450 (896 and 2050), and RAV = 786 (436 and 1582). There was a difference between LAV and RAV epinephrine levels (P = 0.024) and between LAV and RAV norepinephrine (P = 0.002) levels., Conclusions: This extensive experience with AVS demonstrated a wide range of "normal" AV catecholamine levels in patients without pheochromocytoma, which suggests that the utility of AVS to determine disease laterality in patients with pheochromocytoma and bilateral adrenal nodules is likely to be limited., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Literature regarding endogenous Cushing syndrome (CS) largely focuses on the challenges of diagnosis, subtyping, and treatment. The enigmatic phenomenon of glucocorticoid withdrawal syndrome (GWS), due to rapid reduction in cortisol exposure following treatment of CS, is less commonly discussed but also difficult to manage. We highlight the clinical approach to navigating patients from GWS and adrenal insufficiency to full hypothalamic-pituitary-adrenal (HPA) axis recovery., Methods: We review the literature on the pathogenesis of GWS and its clinical presentation. We provide strategies for glucocorticoid dosing and tapering, HPA axis testing, as well as pharmacotherapy and ancillary treatments for GWS symptom management., Results: GWS can be difficult to differentiate from adrenal insufficiency and CS recurrence, which complicates glucocorticoid dosing and tapering regimens. Monitoring for HPA axis recovery requires both clinical and biochemical assessments. The most important intervention is reassurance to patients that GWS symptoms portend a favorable prognosis of sustained remission from CS, and GWS typically resolves as the HPA axis recovers. GWS also occurs during medical management of CS, and gradual dose titration based primarily on symptoms is essential to maintain adherence and to eventually achieve disease control. Myopathy and neurocognitive dysfunction can be chronic complications of CS that do not completely recover., Conclusions: Due to limited data, no guidelines have been developed for management of GWS. Nevertheless, this article provides overarching themes derived from published literature plus expert opinion and experience. Future studies are needed to better understand the pathophysiology of GWS to guide more targeted and optimal treatments., (© 2022. The Author(s).)

Objective: In patients with primary aldosteronism, adrenal venous sampling (AVS) is performed to determine the presence of unilateral or bilateral adrenal disease. During AVS, verification of catheter positioning within the left adrenal vein (AV) and the right AV by comparison of AV and inferior vena cava (IVC) cortisol levels can be variable. The objective of this study was to determine the utility of AV epinephrine levels in assessing successful AV cannulation., Methods: This was a single institution, retrospective review of patients who underwent AVS with cosyntropin stimulation for primary aldosteronism between 2009 and 2018. Successful cannulation of the AV was defined by an AV/IVC cortisol ratio selectivity index (SI) ≥3:1. Epinephrine thresholds to predict catheter placement in the AV were determined using logistic regression. The calculated epinephrine thresholds were compared with previously published thresholds., Results: AVS was performed on 101 consecutive patients and, based on the SI, successful cannulation of the left AV and right AV occurred in 98 (97%) and 91(90%) patients, respectively. The calculated optimal epinephrine threshold to predict AV cannulation was 364 pg/mL (sensitivity, 92.1%; specificity, 94.6%) and the calculated optimal AV/IVC epinephrine ratio threshold was 27.4, (sensitivity, 92.1%; specificity, 91.3%). Among the 14 patients with failed AV cannulation, 3 patients would have been considered to have successful AVS using AV epinephrine levels >364 pg/mL and AV/IVC epinephrine ratio >27.4 thresholds., Conclusion: Obtaining 2 right AV samples routinely as well as AV and IVC epinephrine levels during AVS could prevent unnecessary repeat AVS in patients with failed AV cannulation based on cortisol-based SI <3:1., (Published by Elsevier Inc.)

Context: An institutional study previously demonstrated that cosyntropin stimulation testing on postoperative day 1 (POD1-CST) identified patients at risk for adrenal insufficiency (AI) following unilateral adrenalectomy (UA) for adrenal-dependent hypercortisolism (HC) and primary aldosteronism (PA), allowing for selective glucocorticoid replacement (GR)., Objective: This study re-evaluates the need for GR following UA for patients with HC and PA in a larger cohort., Methods: A prospective database identified 108 patients who underwent UA for mild autonomous cortisol excess (MACE) (n = 47), overt hypercortisolism (OH) (n = 27), PA (n = 22), and concurrent PA/HC (n = 12) from September 2014 to October 2020; all underwent preoperative evaluation for HC. MACE was defined by the 1 mg dexamethasone suppression test (cortisol >1.8 μg/dL), with ≥5 defined as OH. GR was initiated for basal cortisol ≤5 or stimulated cortisol ≤14 (≤18 prior to April 2017) on POD1-CST., Results: Fifty-one (47%) patients had an abnormal POD1-CST; 54 (50%) were discharged on GR (27 MACE, 20 OH, 1 PA, 6 PA/HC). Median duration of GR was OH: 6.0 months, MACE: 2.1 months, PA: 1 month, PA/HC: 0.8 months. Overall, 26% (n = 7) of patients with OH and 43% (n = 20) of patients with MACE did not require GR. Two (2%) patients with OH had normal POD1-CST but developed AI several weeks postoperatively requiring GR. None experienced life-threatening AI., Conclusion: POD1-CST identifies patients with HC at risk for AI after UA, allowing for selective GR. One-quarter of patients with OH and nearly half of patients with MACE can forgo GR after UA. Patients with PA do not require evaluation for AI if concurrent HC has been excluded preoperatively., (© 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.)

Introduction: The coronavirus disease 2019 (COVID-19) is currently a major pandemic challenge, and cancer patients are at a heightened risk of severity and mortality from this infection. In recent years, immune checkpoint inhibitor (ICI) use to treat multiple cancers has increased in oncology, but equally has raised the question of whether ICI therapy and its side-effects is harmful or beneficial during this pandemic., Methods: A combination of published literature in PubMed between January 2010 and December 2020, recommended guidelines in non-cancer patients, and clinical experience was utilized to outline recommendations on glucocorticoid timing and dosing regimens in ICI-treated patients presenting with AI during this COVID-19 pandemic., Results: The potential immune interaction between ICIs and COVID-19 require major consideration because these agents act at the intersection between effective cancer immunotherapy and increasing patient susceptibility, severity and complications from the SARS-CoV-2 sepsis. Furthermore, ICI use can induce autoimmune adrenal insufficiency (AI) that further increases infection susceptibility. Thus, ICI-treated cancer patients with AI may be at greater risk of COVID-19 infection. Glucocorticoids are the cornerstone for replacement therapy, and for treatment and mitigation of adrenal crisis and relief of mass effects in ICI-related hypophysitis. High-dose glucocorticoids have also been used with cytotoxic chemotherapy as part of cancer treatment, and iatrogenic AI may arise after glucocorticoid discontinuation that increases the risk of adrenal crisis. Furthermore, in patients who develop the "long COVID-19" syndrome, when to discontinue glucocorticoid therapy becomes crucial to avoid unnecessary prolongation of therapy and the development of iatrogenic hypercortisolemia., Conclusion: During the COVID-19 pandemic, much of cancer care have been impacted and an important clinical question is how to optimally manage ICI-related AI during these unprecedented times. Herein, we suggest practical recommendations on the timing and dosing regimens of glucocorticoids in different clinical scenarios of ICI-treated cancer patients presenting with AI during this COVID-19 pandemic., Competing Interests: KCJY, MJM, AA, EF and JWF have no conflicts of interest to declare., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Context: The normal cortisol response 30 or 60 minutes after cosyntropin (ACTH [1-24] ) is considered to be ≥18 μg/dL (500 nmol/L). This threshold is based on older serum cortisol assays. Specific monoclonal antibody immunoassays or LC-MS/MS may have lower thresholds for a normal response., Objective: To calculate serum cortisol cutoff values for adrenocorticotropic hormone (ACTH) stimulation testing with newer specific cortisol assays., Methods: Retrospective analysis of ACTH stimulation tests performed in ambulatory and hospitalized patients suspected of adrenal insufficiency (AI). Serum samples were assayed for cortisol in parallel using Elecsys I and Elecsys II immunoassays, and when volume was available, by Access immunoassay and LC-MS/MS., Results: A total of 110 patients were evaluated. Using 18 μg/dL as the cortisol cutoff after ACTH stimulation, 14.5%, 29%, 22.4%, and 32% of patients had a biochemical diagnosis of AI using the Elecsys I, Elecsys II, Access, and LC-MS/MS assays, respectively. Deming regressions of serum cortisol were used to calculate new cortisol cutoffs based on the Elecsys I cutoff of 18 μg/dL. For 30-minute values, new cutoffs were 14.6 μg/dL for Elecsys II, 14.8 μg/dL for Access, and 14.5 μg/dL for LC-MS/MS. Baseline cortisol <2 μg/dL was predictive of subnormal stimulated cortisol values., Conclusion: To reduce false positive ACTH stimulation testing, we recommend a new serum cortisol cutoff of 14 to 15 μg/dL depending on the assay used (instead of the historical value of 18 μg/dL with older polyclonal antibody assays). Clinicians should be aware of the new cutoffs for the assays available to them when evaluating patients for AI., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: In December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease 2019 (COVID-19) that resulted in a global pandemic with substantial morbidity and mortality. Currently, there is no specific treatment or approved vaccine against COVID-19. The underlying associated comorbidity and diminished immune function of some pituitary patients (whether caused by the disease and its sequelae or treatment with excess glucocorticoids) increases their risk of contracting and developing complications from COVID-19 infection., Methods: A review of studies in PubMed and Google Scholar published between January 2020 to the time of writing (May 1, 2020) was conducted using the search terms 'pituitary,' 'coronavirus,' 'COVID-19', '2019-nCoV', 'diabetes mellitus', 'obesity', 'adrenal,' and 'endocrine.', Results: Older age and pre-existing obesity, hypertension, cardiovascular disease, and diabetes mellitus increase the risk of hospitalization and death in COVID-19 patients. Men tend to be more severely affected than women; fortunately, most men, particularly of younger age, survive the infection. In addition to general comorbidities that may apply to many pituitary patients, they are also susceptible due to the following pituitary disorder-specific features: hypercortisolemia and adrenal suppression with Cushing disease, adrenal insufficiency and diabetes insipidus with hypopituitarism, and sleep-apnea syndrome and chest wall deformity with acromegaly., Conclusion: This review aims to focus on the impact of COVID-19 in patients with pituitary disorders. As most countries are implementing mobility restrictions, we also discuss how this pandemic has affected patient attitudes and impacted our decision-making on management recommendations for these patients., Abbreviations: ACE = angiotensin-converting enzyme; AI = adrenal insufficiency; ARB = angiotensin receptor blocker; ARDS = acute respiratory disease syndrome; COVID-19 = coronavirus disease 2019; CPAP = continuous positive airway pressure; DI = diabetes insipidus; DM = diabetes mellitus; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Context: Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically., Objective Setting and Main Outcome Measures: Prospectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS., Design: Patients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis., Results: We identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for adrenocorticotropic hormone (ACTH)-independent CS (5 patients with at least 1 and 11 without any elevated salivary result). In patients with Cushing disease (CD), most nonelevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD., Conclusions: Since the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS., (© Endocrine Society 2020.)

The diagnosis of endogenous hypercortisolism (Cushing's syndrome) is extremely challenging. Chronic kidney disease (CKD) increases the activity of the hypothalamic-pituitary-adrenal axis making the diagnosis of Cushing's syndrome even more challenging. This is particularly so since urine free cortisol (UFC) testing is not useful in CKD. The case report by Stroud et al. in this issue of the European Journal of Endocrinology highlights this problem by finding normal UFC in a patient with pituitary ACTH-dependent Cushing's syndrome. Elevated late-night salivary cortisol (LNSC) testing was diagnostic and pituitary adenomectomy was curative. LNSC measurement is the diagnostic test of choice in patients with suspected Cushing's syndrome, particularly in the presence of CKD..

Objective: Demonstrate the safety and efficacy of a standardized intravenous etomidate infusion protocol in normalizing cortisol levels in patients with severe and life-threatening hypercortisolism., Methods: A retrospective case series of seven patients representing nine episodes of severe hypercortisolism at two large academic medical centers was conducted. Patients were included in this series if they received an etomidate infusion for the treatment of severe and life-threatening hypercortisolism. The etomidate infusion was administered via a newly developed protocol designed to safely reduce cortisol levels until more long-term medical or definitive surgical therapy could be instituted., Results: Seven patients representing nine episodes received etomidate treatment. In eight of nine episodes of therapy, rapid control of hypercortisolemia was achieved, generally defined as a serum cortisol level of 10 to 20 µg/dL. Patients with a median baseline cortisol of 105 µg/dL (range, 32 to 245 µg/dL) achieved a median nadir serum cortisol of 15.8 µg/dL (range, 6.9 to 27 µg/dL) after a median of 38 hours (range, 26 to 134 hours)., Conclusions: A standardized continuous intravenous etomidate infusion protocol is a safe and effective means of achieving a serum cortisol level of 10 to 20 µg/dL in patients with severe hypercortisolemia.

Introduction: In patients with primary aldosteronism (PA), adrenal venous sampling (AVS) is recommended to differentiate between unilateral (UNI) or bilateral (BIL) adrenal disease. A recent study suggested that lateralization could be predicted, based on the ratio of aldosterone/cortisol levels (A/C) between the left adrenal vein (LAV) and inferior vena cava (IVC), with a 100% positive predictive value (PPV). This study aimed to validate those findings utilizing a larger, multi-institutional cohort., Methods: A retrospective review was performed of patients with PA who underwent AVS from 2 tertiary-care institutions. Laterality was predicted by an A/C ratio of >3:1 between the dominant and non-dominant adrenal. AVS results were compared to LAV/IVC ratios utilizing the published criteria (Lt ≥ 5.5; Rt ≤ 0.5)., Results: Of 222 patients, 124 (57%) had UNI and 98 (43%) had BIL disease based on AVS. AVS and LAV/IVC findings were concordant for laterality in 141 (64%) patients (69 UNI, 72 BIL). Using only the LAV/IVC ratio, 54 (24%) patients with UNI disease on AVS who underwent successful surgery would have been assumed to have BAH unless AVS was repeated, and 24 (11%) patients with BIL disease on AVS may have been incorrectly offered surgery (PPV 70%). Based on median LAV/IVC ratios (left 5.26; right 0.31; BIL 2.84), no LAV/IVC ratio accurately predicted laterality., Discussion: This multi-institutional study of patients with both UNI and BIL PA failed to validate the previously reported PPV of LAV/IVC ratio for lateralization. Caution should be used in interpreting incomplete AVS data to differentiate between UNI versus BIL disease and strong consideration given to repeat AVS prior to adrenalectomy.

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.)

This report describes the presence of lower extremity insufficiency fractures in 10 women prior to the clinical and biochemical diagnosis of endogenous Cushing's syndrome (CS). Osteoporosis is a well-recognized complication of overt CS resulting in a high rate of vertebral and other fractures. After institutional review board (IRB) approval, we did a retrospective chart review of patients with lower extremity (LE) insufficiency fractures (IF) and CS. This chart review found 10 women in whom LE-IF preceded the diagnosis of endogenous CS. Low bone density was found in all but one patient. The CS was considered to be mild (or subclinical) in five patients. LE-IF should be considered part of the skeletal spectrum of CS. Physicians caring for patients with LE-IF should have a low threshold for the consideration of CS even in patients without overt physical evidence of cortisol excess.

Measuring salivary cortisol is a simple, convenient and accurate technique with potential value in monitoring patients with hypercortisolism. This analysis reports changes in late-night salivary cortisol (LNSC) during a 12-month, multicentre, Phase III study of patients with Cushing's disease who were randomized to pasireotide 600 or 900 μg sc bid. LNSC assessment was an exploratory objective based on a single, optional measurement at midnight ± 1 h on the same day as one of the 24-h urinary free cortisol (UFC) measurements. Of 162 enrolled patients, baseline LNSC was measured in 93. Sixty-seven patients had levels above the upper limit of normal (ULN); median baseline levels were 19.7 and 20.7 nmol/L in the groups subsequently randomized to 600 μg (n = 40) and 900 μg (n = 27), respectively. Median LNSC levels decreased from baseline to month 12; median changes in patients who had baseline LNSC > ULN in the 600 and 900 μg groups were -13.4 nmol/L (-52.6 %; n = 19) and -11.8 nmol/L (-56.1 %; n = 14), respectively. LNSC normalized at months 6 and 12 in 25/67 (37.3 %) and 13/67 (19.4 %) patients, respectively; 10/25 and 8/13 patients also had normalized UFC, and 7/25 and 4/13 had partial UFC control (UFC > ULN and ≥50 % decrease from baseline). There was a moderate correlation (r = 0.55) on the log scale between individual patient LNSC and UFC values when all time points were pooled. Pasireotide decreased LNSC levels during 12 months of treatment. Salivary cortisol may be a simple, convenient biomarker for assessing treatment response in patients with Cushing's disease., Competing Interests: J.W.F: Investigator and consultant for Novartis; investigator and consultant for Corcept; M.F.: Research grants to the Oregon Health & Science University from Cortendo, Ipsen, Novartis and Pfizer; occasional scientific consultant for Cortendo, Genentech and Novartis; J.N.P.: Investigator and consultant for Novartis and HRA Pharma; S.P.: Investigator and consultant for Novartis and Ipsen; R.P.: Principal investigator with grants from Novartis; research grants from Novartis, Viropharma, Pfizer and IBSA; lecture fees from Novartis and Pfizer; occasional consultant for Novartis, Ipsen, Italfarmaco, Pfizer, Ferring and Viropharma; A.K.: Employee of Novartis; A.M.P.: Employee of Novartis; B.M.K.B.: Principal investigator with grants to Massachusetts General Hospital from Novartis and Cortendo; occasional consultant to Novartis, Cortendo and HRA Pharma.

Objective: To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC)., Methods: The design was a single-center, retrospective chart review. Patients treated by the authors from 2008-2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST)., Results: We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements., Conclusion: LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker., Abbreviations: ACTH = adrenocorticotropic hormone CD = Cushing disease CS = Cushing syndrome CV = coefficient of variation DST = dexamethasone suppression test IPSS = inferior petrosal sinus sampling LNSC = late-night salivary cortisol QoL = quality of life TSS = transsphenoidal adenoma resection UFC = urinary free cortisol.

Background: Secondary adrenal insufficiency (AI) can occur after unilateral adrenalectomy for adrenal-dependent hypercortisolism. Postoperative glucocorticoid replacement (GR), although given routinely, may not be necessary. We sought to identify factors that, in combination with postoperative day 1 cosyntropin stimulation testing (POD1-CST), would predict the need for GR., Methods: We reviewed 31 consecutive patients who underwent unilateral adrenalectomy for hypercortisolism (study patients) or hyperaldosteronism (control patients). A standard POD1-CST protocol was used. Hydrocortisone was started for clinical evidence of AI, basal plasma cortisol ≤ 5 (μg/dL), or a stimulated plasma cortisol <18., Results: A normal POD1-CST was found in all nine control patients and 11 of 22 patients (50%) with Cushing's syndrome; the other 11 study patients (50%) received GR based on the POD1-CST. These patients were younger (51 vs 62 years; P = .017), had a higher body mass index (BMI; 31 vs 29 kg/m(2)), and smaller adrenal neoplasms (16.9 vs 33.0 g; P = .009) than non-GR study patients., Conclusion: After unilateral adrenalectomy for hypercortisolism, only 50% of patients received GR. No preoperative biochemical characteristics were associated with postoperative AI, although patients who received GR were younger, and tended to have a higher BMI and smaller adrenal nodules. Use of this novel protocol for postoperative dynamic adrenal function testing prevented unnecessary GR in 50% of patients and allowed for individualized patient care., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to demonstrate the importance of considering Cushing's syndrome (CS) as a potential etiology for weight gain and metabolic complications in patients undergoing bariatric surgery (BS)., Design and Methods: This is a retrospective chart review case series of patients (n = 16) with CS from five tertiary care centers in the USA who had BS., Results: Median age at BS surgery was 35.5 years (median 2.5 years between BS and CS surgery). CS was not identified in 12 patients prior to BS. Four patients had CS surgery prior to BS, without recognition of recurrent or persistent CS until after BS. Median body mass index (BMI) values before BS, nadir after BS, prior to surgery for CS, and after surgery for CS were 47, 31, 38, and 35 kg/m(2), respectively. Prior to BS, 55 % of patients had hypertension and 55 % had diabetes mellitus. Only 17 % had resolution of hypertension or diabetes mellitus after BS., Conclusion: CS may be under-recognized in patients undergoing BS. Testing for CS should be performed prior to BS in patients with features of CS and in post-operative BS patients with persistent hypertension, diabetes mellitus, or excessive weight regain. Studies should be conducted to determine the role of prospective testing for CS in subjects considering BS.

Objective: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome., Participants: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline., Evidence: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies., Consensus Process: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines., Conclusions: Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.

Context: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood., Objective: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients., Design and Setting: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study., Patients: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study., Interventions: Mifepristone (300-1200 mg) was administered once daily., Main Outcome Measures: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment., Results: A ≥2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 ± 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI., Conclusions: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable over time. Corticotroph tumor progression and regression may occur over time, but patients may have significant increases in ACTH levels without evidence of tumor growth.

Objective: Signs and symptoms of Cushing's disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushing's disease., Design: Phase III study with double-blind randomization of two pasireotide doses., Methods: Patients (n = 162) with persistent/recurrent or de novo Cushing's disease and urinary free cortisol (UFC) levels ≥1·5× upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 μg bid). At month 3, patients with UFC ≤2 × ULN and not exceeding the baseline value continued their randomized dose; all others received 300 μg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 μg bid. Changes in signs and symptoms of hypercortisolism over 12 months' treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control., Results: Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein (LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 72·8% of patients., Conclusions: In the largest Phase III study of medical therapy in Cushing's disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased., (© 2014 John Wiley & Sons Ltd.)

Objective: The use of ovine corticotropin releasing hormone (oCRH) maximizes the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome (CS). oCRH is marketed as ACTHrel and, understandably, may be confused with cosyntropin [ACTH (1-24)]. The inadvertent substitution of synthetic ACTH(1-24) for oCRH (ACTHrel) during IPSS may cause unexpected and misleading results. The aim of this report is to raise awareness of the potential confounding results created when synthetic ACTH(1-24) is mistakenly used during IPSS., Methods: We present 3 patients treated at 3 different centers with ACTH-dependent CS in whom ACTH(1-24) was mistakenly substituted for oCRH (ACTHrel) during IPSS., Results: In all patients, there was an abrupt and unexpected decrease in plasma ACTH in the inferior petrosal sinus (IPS) samples after presumptive stimulation with oCRH. Re-evaluation of the patients' pharmacy records confirmed that synthetic ACTH(1-24) had been used rather than oCRH during each procedure. Because "sandwich" immunometric assays for ACTH measure the entire pool of endogenous ACTH, the administration of synthetic ACTH(1-24) artifactually decreases the endogenous plasma ACTH(1-39) measurement by binding only to the N-terminal antibody raised against ACTH(1-17) and not to the C-terminal antibody raised against ACTH(34-39). This results in a lack of a detectable sandwich complex and explains the apparent reduction in ACTH concentration., Conclusion: An abrupt decrease in ACTH during IPSS suggests that synthetic ACTH(1-24) rather than oCRH (ACTHrel) has been administered. The labeling of oCRH as ACTHrel poses a potential patient safety problem about which endocrinologists, interventional radiologists, and pharmacists should be aware.

Objective: Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data., Design: Observational study (enrolment phase of Phase III study)., Methods: Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks., Results: Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism., Conclusions: There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity., (© 2013 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Purpose. Adrenocorticotropin- (ACTH-) secreting pituitary carcinomas are rare and require multimodality treatment. The aim of this study was to report the response to various therapies and discuss the potential development of secondary adrenal insufficiency with cytotoxic chemotherapy. Methods. This report describes a man with a large silent corticotroph adenoma progressing to endogenous hypercortisolism and metastatic ACTH-secreting pituitary carcinoma over a period of 14 years. Results. Seven years after initial presentation, progressive tumor enlargement associated with the development of hypercortisolism mandated multiple pituitary tumor debulking procedures and radiotherapy. Testing of the Ki-67 proliferation index was markedly high and he developed a hepatic metastasis. Combination therapy with cisplatin and etoposide resulted in a substantial reduction in tumor size, near-complete regression of his liver metastasis, and dramatic decrease in ACTH secretion. This unexpectedly resulted in symptomatic secondary adrenal insufficiency. Conclusions. This is the first reported case of secondary adrenal insufficiency after use of cytotoxic chemotherapy for metastatic ACTH-secreting pituitary carcinoma. High proliferative indices may be predictive of dramatic responses to chemotherapy. Given the potential for such responses, the development of secondary adrenal insufficiency may occur and patients should be monitored accordingly.

Patients with endogenous hypercortisolism, Cushing's syndrome, have significant morbidity and increased mortality when inadequately treated. When surgical therapy has been unsuccessful other treatment modalities are necessary. Previously available therapies have limited effectiveness or significant toxicity. Mifepristone, a glucocorticoid receptor antagonist, provides a novel approach to the treatment of hypercortisolism. It is rapidly absorbed, highly protein bound and has a long plasma half-life. Since it also serves as a progesterone receptor antagonist, mifepristone has been used in several other medical conditions. A recently published prospective trial of mifepristone therapy for Cushing's syndrome resulted in its recent approval by the U.S. Food and Drug Administration for use in Cushing's syndrome., (Copyright 2012 Prous Science, S.A.U. or its licensors. All rights reserved.)

Context: Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations., Objective: Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS., Design and Setting: We conducted a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers., Participants: Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT)., Intervention: Mifepristone was administered at doses of 300-1200 mg daily., Main Outcome Measures: We evaluated change in area under the curve for glucose on 2-h oral glucose test for C-DM and change in diastolic blood pressure from baseline to wk 24 for C-HT., Results: In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P < 0.0001). Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P < 0.001); fasting plasma glucose decreased from 149.0 ± 75.7 mg/dl (8.3 ± 4.1 mmol/liter) to 104.7 ± 37.5 mg/dl (5.8 ± 2.1 mmol/liter, P < 0.03). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). Mean weight change was -5.7 ± 7.4% (P < 0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P < 0.001) in women and -8.44 ± 5.9 cm (P < 0.001) in men. Overall, 87% (P < 0.0001) had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women., Conclusions: Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.

Background: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5., Methods: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12., Results: Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients., Conclusions: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).

Background: This is a retrospective study of 136 patients with Cushing disease treated with transsphenoidal microsurgery., Objective: To evaluate factors influencing immediate postoperative results and long-term outcomes., Methods: Data regarding clinical presentation, endocrine evaluation, imaging studies, surgical technique, immediate postoperative biochemical remission (IPBR), and long-term results were entered into a database and analyzed statistically. IPBR was based on biochemical evidence of adrenal cortical insufficiency and clinical evidence of such insufficiency., Results: IPBR for the entire series was 83.4%. In microadenomas, IPBR was 89.8% with a mean immediate postoperative plasma cortisol (IPPC) of 2.1 μg/dL (range, <0.5-5.3). Positive magnetic resonance imaging (MRI) was associated with 18 times greater odds of finding microadenoma at surgery (P < .001) and with 4.1 times greater odds of IPBR (P = .07). In patients with a negative MRI, a positive inferior petrosal sinus sampling (IPSS) test was associated with 93% of IPBR (P = .004). IPBR in macroadenomas was 30.7%. Of patients followed for 12 months or longer, 34.8% required glucocorticoid replacement for the duration of follow-up. The mean follow-up in microadenomas was 68.4 months with a 9.67% incidence of recurrences. The estimated actuarial incidence of recurrences increased with the passage of time and IPPC of greater than 2 μg/dL was associated with higher incidence of recurrences, although without statistical significance (P = .08)., Conclusion: In microadenomas, a positive MRI and positive IPSS test were associated with a higher incidence of IPBR. Recurrences increased with the passage of time, and an IPPC of greater than 2 μg/dL may be associated with higher incidence of recurrences.

Spontaneous Cushing's syndrome is well known but unusual clinical disorder. Many of the clinical features (central weight gain, glucose intolerance, hypertension, muscle weakness) are seen in other common conditions. Recognition of patients with multiple features, features unusual for their age (i.e. early onset osteoporosis or hypertension), patients with features more specific to Cushing's syndrome (i.e. easy bruising, facial plethora, and violaceous striae), and patients with incidental adrenal mass or polycystic ovary syndrome should prompt an evaluation for cortisol excess. Late-night salivary cortisol, 1 mg overnight dexamethasone suppression testing, or 24 h urine free cortisol determination have excellent diagnostic characteristics and should be obtain in patients with suspected Cushing' syndrome. If this initial testing is abnormal, further evaluation should be directed by an endocrinologist experienced in the diagnosis and differential diagnosis of Cushing' syndrome.

Purpose of Review: Cushing's syndrome is being recognized with greater frequency and in patients with milder disease. Many of these individuals have nonpituitary causes of their hypercortisolism. This review discusses the classification, presentation, diagnosis, and therapy of patients with Cushing's syndrome from nonpituitary causes., Recent Findings: Many previously unrecognized or poorly understood causes of Cushing's syndrome have been elucidated. It is now appreciated that essentially any form of exogenous glucocorticoid is capable of causing Cushing's syndrome. Additionally, new findings have led to a more complete understanding of bilateral nodular adrenal disease., Summary: The diagnosis of patients with less profound cortisol excess has increased the prevalence of Cushing's syndrome and made nonpituitary causes more common. As a result, clinicians must be cognizant of such patients and pursue the diagnosis when appropriate.

Objective: To report a meta-analysis of late-night salivary cortisol testing for the diagnosis of Cushing syndrome., Methods: MEDLINE and EMBASE computer databases were searched to identify relevant articles published between January 1950 and December 2007. The search strategy used the following medical subject headings and keywords: cortisol, Cushing or Cushing's, saliva, salivary, late-night, nocturnal, and nighttime. The results were limited to studies in humans older than 18 years. Titles and abstracts of all articles, as well as full text of relevant articles, were reviewed. Sensitivity, specificity, likelihood ratio positive, likelihood ratio negative, and diagnostic odds ratio were extracted by 2 authors. Discrepancies were resolved by mediation and discussion with a third author., Results: Seven articles contained sufficient information to be included in the analysis. A total of 947 patients (339 with Cushing syndrome) were identified. Pooled data from the 7 studies revealed a sensitivity of 92% (95% confidence interval [CI], 88%-94%), specificity of 96% (95% CI, 94%-97%), and diagnostic odds ratio of 311 (95% CI, 92-1059). Likelihood ratio positive was 21 (95% CI, 10-43), with a likelihood ratio negative of 0.08 (95% CI, 0.02-0.32). Inconsistencies for each of these results measured by the I2 statistic ranged from moderate to high., Conclusion: This analysis demonstrates that late night salivary cortisol has excellent diagnostic characteristics and as such, is a robust, convenient test for screening and diagnosis of Cushing syndrome.