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Araujo-Castro M, Iriarte-Durán MB, Parra-Ramírez P, Donato S. Management of adrenal incidentalomas: who, why and how? Curr Opin Endocrinol Diabetes Obes 2025:01266029-990000000-00130. [PMID: 40366015 DOI: 10.1097/med.0000000000000917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
PURPOSE OF REVIEW To summarize the epidemiology and clinical implications of adrenal incidentalomas, as well as the recommended hormonal and radiological evaluation, treatment and follow-up that should be carried out in patients with adrenal incidentalomas. RECENT FINDINGS The prevalence of adrenal incidentalomas has increased in the last decades due to advanced and more sensitive imaging modalities, their increased utilization, and the aging population. The evaluation of patients with adrenal incidentalomas should be focused on addressing two questions: Is the tumor functional, and is the tumor malignant? In relation to functionality, although most adrenal incidentalomas are clinically nonfunctioning, a significant proportion of patients have mild autonomous cortisol secretion and a lower proportion over functional adrenal syndromes. The differentiation between malignant and benign lesions is usually based on the radiological appearance of the lesion in CT and/or MRI. Adrenalectomy is considered the first-line treatment for malignant and functioning tumors. Radiological follow-up is not necessary for lesions classified as benign, but for indeterminate lesions, CT/MRI should be repeated in 6-12 months. SUMMARY Adrenal incidentalomas are a common clinical problem, and their assessment should be focused on ruling out hormonal hypersecretion and malignancy. In general, adrenalectomy is considered the treatment of choice for malignant and functioning adrenal tumors.
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Affiliation(s)
- Marta Araujo-Castro
- Endocrinology & Nutrition Department, Hospital Universitario Ramón y Cajal
- Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain
| | - María Bernarda Iriarte-Durán
- Endocrinology Unit of the Internal Medicine Department, Hospital Universitario Fundación Valle del Lili, Cali, Colombia
| | - Paola Parra-Ramírez
- Endocrinology & Nutrition Department, Hospital Universitario La Paz, Madrid, Spain
| | - Sara Donato
- Endocrinology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
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Iriarte-Durán MB, Donato S, Herrera A, Vega A, Jiménez Casinello JM, Marazuela M, Araujo-Castro M. The impact of mild autonomous cortisol secretion and proposed interventions. Expert Rev Endocrinol Metab 2025:1-16. [PMID: 40152752 DOI: 10.1080/17446651.2025.2480704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025]
Abstract
INTRODUCTION Mild autonomous cortisol secretion (MACS) is the most common hormonal alteration in patients with adrenal incidentalomas (AIs). Given its prevalence and associated adverse outcomes, reviewing its impact and interventions is essential. AREAS COVERED In this article, we provide a comprehensive review on the diagnosis of MACS, the cardiometabolic burden associated with MACS and on its surgical and medical treatment. The diagnosis of MACS requires three criteria: hormonal evidence of hypercortisolism, the absence of typical Cushing's syndrome signs, and the presence of an AI. The most recommended test for MACS diagnosis is the 1 mg dexamethasone suppression test. There is plenty of evidence of the detrimental effect of MACS, including an increased risk of diabetes, hypertension, dyslipidemia and all-cause mortality. Surgery should be considered for patients with significant comorbidities and has been shown to significantly improve anthropometric variables, hyperglycemia and blood pressure. Medical therapy to lower cortisol offers an effective alternative, particularly for patients with bilateral AI, when surgery is contraindicated, or the patient declines surgery. EXPERT OPINION Based on our expert opinion, steroid profiling has the potential to become the gold standard for MACS diagnosis, and further studies should identify which patients benefit most from specific treatment to guiding evidence-based recommendations.
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Affiliation(s)
- María Bernarda Iriarte-Durán
- Endocrinology Unit of the Internal Medicine Department, Hospital Universitario Fundación Valle del Lili, Cali, Colombia
| | - Sara Donato
- Endocrinology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Aura Herrera
- Department of Endocrinology and Nutrition, University Hospital Reina Sofia, Cordoba, Spain
| | - Arturo Vega
- Endocrinology & Nutrition Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | - Mónica Marazuela
- Endocrinology & Nutrition Department, Hospital Universitario La Princesa, Madrid, Spain
| | - Marta Araujo-Castro
- Endocrinology & Nutrition Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
- Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain
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Dos Santos Marques AC, Brito B, Gorett Brito Fontes J, Reis Alves Carneiro G, Dickson Rebelo JF, Barbosa Moraes A, Vieira Neto L, Costa Padilha M. Cortisol quantification in human plasma and urine by liquid chromatography coupled to mass spectrometry: Validation, analysis and application in a reference population and patients with adrenal incidentalomas. Clin Chim Acta 2025; 566:120055. [PMID: 39557229 DOI: 10.1016/j.cca.2024.120055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/16/2024] [Accepted: 11/15/2024] [Indexed: 11/20/2024]
Abstract
Cortisol is a glucocorticoid hormone, which is involved in cardiovascular, metabolic, inflammatory and behavioral processes in the human body. Immunoassays, used for routine analysis of analytes, usually lead to erroneous quantification due to the low specificity of these methods. In this study, we developed LC-MS/MS methods with surrogating matrices for evaluating cortisol in both urine and plasma samples and validated them according to Brazilian Health Regulatory Agency guidelines. Urine samples were prepared with an enzymatic hydrolysis stage, followed by a solid-phase extraction (C18 cartridges) using dichloromethane:methanol 9:1 as elution solvent. Plasma samples were prepared by protein precipitation with acetonitrile, using 50 μL of sample. HPLC was performed using a C8 column under 300 mL min-1 flow gradient conditions with water and methanol, both containing 5 mM ammonium formate and 0.1 % formic acid. Mass spectrometer with electrospray ionization in positive mode and selected reaction monitoring as detection technique were employed. Calibration curves were linear over a concentration range of 1-200 ng mL-1 for urine (r2 = 0.9950) and 0.5-300 ng mL-1 for plasma (r2 = 0.9970). The methods were selective, showed suitable precision, accuracy, and sensibility (limit of quantification = 0.85 ng mL-1 for urine and 0.15 ng mL-1 for plasma). Validated methods were successful applied to 22 real samples and a cohort of patients [n = 63 urines and n = 79 plasmas (from the Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil)].
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Affiliation(s)
- Andressa Cristina Dos Santos Marques
- Federal University of Rio de Janeiro - UFRJ, Brazilian Doping Control Laboratory - LBCD, LADETEC, Av. Horácio Macedo, 1281 - Polo de Química - Bloco C - Cidade Universitária - Ιlha do Fundão, Rio de Janeiro, Brazil.
| | - Bruna Brito
- Federal University of Rio de Janeiro - UFRJ, Brazilian Doping Control Laboratory - LBCD, LADETEC, Av. Horácio Macedo, 1281 - Polo de Química - Bloco C - Cidade Universitária - Ιlha do Fundão, Rio de Janeiro, Brazil
| | - Jéssica Gorett Brito Fontes
- Federal University of Rio de Janeiro - UFRJ, Brazilian Doping Control Laboratory - LBCD, LADETEC, Av. Horácio Macedo, 1281 - Polo de Química - Bloco C - Cidade Universitária - Ιlha do Fundão, Rio de Janeiro, Brazil
| | - Gabriel Reis Alves Carneiro
- Federal University of Rio de Janeiro - UFRJ, Brazilian Doping Control Laboratory - LBCD, LADETEC, Av. Horácio Macedo, 1281 - Polo de Química - Bloco C - Cidade Universitária - Ιlha do Fundão, Rio de Janeiro, Brazil
| | - João Felipe Dickson Rebelo
- Department of Internal Medicine and Endocrine Unit, Universidade Federal do Rio de Janeiro, School of Medicine, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, RJ, Brazil
| | - Aline Barbosa Moraes
- Department of Clinical Medicine and Endocrine Unit, Universidade Federal Fluminense, School of Medicine, Hospital Universitário Antônio Pedro, Niterói, RJ, Brazil
| | - Leonardo Vieira Neto
- Department of Internal Medicine and Endocrine Unit, Universidade Federal do Rio de Janeiro, School of Medicine, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, RJ, Brazil
| | - Monica Costa Padilha
- Federal University of Rio de Janeiro - UFRJ, Brazilian Doping Control Laboratory - LBCD, LADETEC, Av. Horácio Macedo, 1281 - Polo de Química - Bloco C - Cidade Universitária - Ιlha do Fundão, Rio de Janeiro, Brazil
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Favero V, Parazzoli C, Bernasconi DP, Chiodini I. Cardiometabolic comorbidities and cardiovascular events in "non-functioning" adrenal incidentalomas: a systematic review and meta-analysis. J Endocrinol Invest 2024; 47:2929-2942. [PMID: 39347906 PMCID: PMC11549128 DOI: 10.1007/s40618-024-02440-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/03/2024] [Indexed: 10/01/2024]
Abstract
OBJECTIVE Recent studies investigated the prevalence of arterial hypertension (AH), diabetes mellitus (DM) and/or prediabetes, dyslipidemia (DL), metabolic syndrome (MS) and cardiovascular events (CVE) in patients with non-functioning adrenal incidentalomas (NFAI). We aimed to investigate the available literature to determine the prevalence of AH, DM, DM and/or prediabetes (Composite DM, C-DM), DL, MS and CVE in patients with NFAI as compared to patients without adrenal incidentalomas (AI). DESIGN Systematic review and meta-analysis. METHODS A meta-analysis was performed using studies that evaluated the prevalence of AH, DM, C-DM, DL, MS and CVE in patients with NFAI versus matched subjects without AI. A random-effects model (DerSimonian and Laird) was used to calculate the pooled odds ratio (OR) and 95% Confidence Interval (95%CI) for each outcome. RESULTS Among the 36 available studies, 19 studies provided the necessary data (4716 subjects, mean age 57.6 ± 4.6). The association between AH, DM, C-DM, DL, MS and CVE was reported in 18 (4546 subjects), 7 (1743 subjects), 5 (4315 subjects), 11 (3820 subjects), 8 (1170 subjects) and 5 (2972 subjects), respectively. The presence of NFAI was associated with AH (OR 1.87, 95%CI 1.39-2.51), C-DM (OR 2.04, 95%CI 1.70-2.45) and MS (OR 2.89, 95%CI 1.93-4.32), but not with DM, DL and CVE. CONCLUSIONS Patients with NFAI have higher prevalence of AH, C-DM and MS than control subjects without NFAI.
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Affiliation(s)
- Vittoria Favero
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, 20100, Italy
- Unit of Endocrinology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, Milan, 20162, Italy
| | - Chiara Parazzoli
- Unit of Endocrinology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, Milan, 20162, Italy
| | - Davide Paolo Bernasconi
- Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Unit of Clinical Research and Innovation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Iacopo Chiodini
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, 20100, Italy.
- Unit of Endocrinology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, Milan, 20162, Italy.
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Rahimi L, Kittithaworn A, Gregg Garcia R, Saini J, Dogra P, Atkinson EJ, Achenbach SJ, Kattah A, Bancos I. Kidney Function in Patients With Adrenal Adenomas: A Single-Center Retrospective Cohort Study. J Clin Endocrinol Metab 2024; 109:e1750-e1758. [PMID: 38157409 PMCID: PMC11318994 DOI: 10.1210/clinem/dgad765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 11/27/2023] [Accepted: 12/28/2023] [Indexed: 01/03/2024]
Abstract
CONTEXT Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD); however, factors associated with CKD are unknown. OBJECTIVE We aimed to identify the factors associated with CKD and assess the effect of adrenalectomy on kidney function in patients with NFA or MACS. METHODS A single-center cohort study of patients with NFA and MACS, 1999 to 2020, was conducted. MACS was diagnosed based on post dexamethasone suppression test (DST) cortisol greater than or equal to 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and postadrenalectomy delta eGFR. RESULTS Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 mL/min/1.73 m2; P < .001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, postadrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow-up. Factors associated with increased eGFR were younger age, lower preadrenalectomy eGFR, and longer follow-up period. CONCLUSION DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Patients with both MACS and NFA demonstrate an increase in eGFR post adrenalectomy, especially younger patients with lower eGFR pre adrenalectomy.
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Affiliation(s)
- Leili Rahimi
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Annop Kittithaworn
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Raul Gregg Garcia
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Jasmine Saini
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Prerna Dogra
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Elizabeth J Atkinson
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Sara J Achenbach
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Andrea Kattah
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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Barlas T, Gultekin II, Altintop SE, Cindil E, Yalcin MM, Cerit ET, Sozen TS, Poyraz A, Altinova AE, Toruner FB, Karakoc MA, Akturk M. Beyond symptomatology: A comparative analysis of unilateral and bilateral macronodular mild autonomous cortisol secretion. Clin Endocrinol (Oxf) 2024; 101:99-107. [PMID: 38935859 DOI: 10.1111/cen.15109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/29/2024]
Abstract
OBJECTIVE To investigate the clinical, laboratory findings and signal intensity index (SII) on magnetic resonance imaging (MRI) of patients with bilateral and unilateral macronodular mild autonomous cortisol secretion (MACS). PATIENTS AND MEASUREMENTS Clinical and laboratory findings of 81 patients with MACS were examined from retrospective records. SII of adenomas and internodular areas were evaluated by MRI. The unilateral group included patients with an adrenal macronodule (≥1 cm) in a single adrenal gland, while the bilateral group included patients with at least one macronodule in both adrenal glands. RESULTS In total, 46 patients were in the unilateral (57%), while 35 (43%) patients were in the bilateral groups. The dehydroepiandrosterone sulphate (DHEA-S) level was lower in the unilateral than in the bilateral group (p < .001). The presence of type 2 diabetes mellitus (T2DM), glycosylated haemoglobin (HbA1c) and low-density lipoprotein (LDL) concentrations were higher in the bilateral group (p < .05). However, no significant difference was detected in terms of adrenocorticotropic hormone (ACTH) and overnight 1 mg dexamethasone suppression test (DST) between the two groups (p > .05). There was no difference in SII between adenomas within the same patient, as well as between the unilateral and bilateral groups (p > .05). Logistic regression analysis based on the differentiation between unilateral and bilateral macronodular MACS demonstrated that DHEA-S, HbA1c and LDL concentrations were associated factors. CONCLUSION DHEA-S levels may not be as suppressed in patients with bilateral macronodular MACS as compared to those with unilateral adenoma. T2DM and hypercholesterolaemia have a higher frequency in bilateral patients. However, ACTH, overnight 1 mg DST and SII may not provide additional information for differentiation of bilaterality and unilaterality.
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Affiliation(s)
- Tugba Barlas
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Isil Imge Gultekin
- Department of Radiology, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Sabri Engin Altintop
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Emetullah Cindil
- Department of Radiology, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Mehmet Muhittin Yalcin
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Ethem Turgay Cerit
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Tevfik Sinan Sozen
- Department of Urology, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Aylar Poyraz
- Department of Pathology, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Alev Eroglu Altinova
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Fusun Balos Toruner
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Mehmet Ayhan Karakoc
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
| | - Mujde Akturk
- Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey
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Trandafir AI, Ghemigian A, Ciobica ML, Nistor C, Gurzun MM, Nistor TVI, Petrova E, Carsote M. Diabetes Mellitus in Non-Functioning Adrenal Incidentalomas: Analysis of the Mild Autonomous Cortisol Secretion (MACS) Impact on Glucose Profile. Biomedicines 2024; 12:1606. [PMID: 39062179 PMCID: PMC11274780 DOI: 10.3390/biomedicines12071606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/12/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing's syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to highlight the most recent data concerning the glucose profile, particularly, type 2 diabetes mellitus (T2DM) in NFAIs with/without mild autonomous cortisol secretion (MACS). This was a comprehensive review of the literature; the search was conducted according to various combinations of key terms. We included English-published, original studies across a 5-year window of publication time (from January 2020 until 1 April 2024) on PubMed. We excluded case reports, reviews, studies on T1DM or secondary diabetes, and experimental data. We identified 37 studies of various designs (14 retrospective studies as well 13 cross-sectional, 4 cohorts, 3 prospective, and 2 case-control studies) that analysed 17,391 individuals, with a female-to-male ratio of 1.47 (aged between 14 and 96 years). T2DM prevalence in MACS (affecting 10 to 30% of NFAIs) ranged from 12% to 44%. The highest T2DM prevalence in NFAI was 45.2% in one study. MACS versus (non-MACS) NFAIs (n = 16) showed an increased risk of T2DM and even of prediabetes or higher fasting plasma glucose or HbA1c (no unanimous results). T2DM prevalence was analysed in NFAI (N = 1243, female-to-male ratio of 1.11, mean age of 60.42) versus (non-tumour) controls (N = 1548, female-to-male ratio of 0.91, average age of 60.22) amid four studies, and two of them were confirmatory with respect to a higher rate in NFAIs. Four studies included a sub-group of CS compared to NFAI/MACS, and two of them did not confirm an increased rate of glucose profile anomalies in CS versus NFAIs/ACS. The longest period of follow-up with concern to the glycaemic profile was 10.5 years, and one cohort showed a significant increase in the T2DM rate at 17.9% compared to the baseline value of 0.03%. Additionally, inconsistent data from six studies enrolling 1039 individuals that underwent adrenalectomy (N = 674) and conservative management (N = 365) pinpointed the impact of the surgery in NFAIs. The regulation of the glucose metabolism after adrenalectomy versus baseline versus conservative management (n = 3) was improved. To our knowledge, this comprehensive review included one of the largest recent analyses in the field of glucose profile amid the confirmation of MACS/NFAI. In light of the rising incidence of NFAI/AIs due to easier access to imagery scans and endocrine evaluation across the spectrum of modern medicine, it is critical to assess if these patients have an increased frequency of cardio-metabolic disorders that worsen their overall comorbidity and mortality profile, including via the confirmation of T2DM.
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Affiliation(s)
- Alexandra-Ioana Trandafir
- PhD Doctoral School of “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Clinical Endocrinology V, “C.I. Parhon” National Institute of Endocrinology, 011863 Bucharest, Romania; (A.G.); (E.P.); (M.C.)
| | - Adina Ghemigian
- Department of Clinical Endocrinology V, “C.I. Parhon” National Institute of Endocrinology, 011863 Bucharest, Romania; (A.G.); (E.P.); (M.C.)
- Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mihai-Lucian Ciobica
- Department of Internal Medicine and Gastroenterology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine I and Rheumatology, “Dr. Carol Davila” Central Military University Emergency Hospital, 010825 Bucharest, Romania
| | - Claudiu Nistor
- Department 4-Cardio-Thoracic Pathology, Thoracic Surgery II Discipline, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Thoracic Surgery Department, “Dr. Carol Davila” Central Military University Emergency Hospital, 010242 Bucharest, Romania
| | - Maria-Magdalena Gurzun
- Cardiology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Laboratory of Non-Invasive Cardiovascular Exploration, “Dr. Carol Davila” Central Military University Emergency Hospital, 010242 Bucharest, Romania
| | - Tiberiu Vasile Ioan Nistor
- Medical Biochemistry Discipline, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania;
| | - Eugenia Petrova
- Department of Clinical Endocrinology V, “C.I. Parhon” National Institute of Endocrinology, 011863 Bucharest, Romania; (A.G.); (E.P.); (M.C.)
- Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mara Carsote
- Department of Clinical Endocrinology V, “C.I. Parhon” National Institute of Endocrinology, 011863 Bucharest, Romania; (A.G.); (E.P.); (M.C.)
- Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Beninato T, Duh QY, Long KL, Kiernan CM, Miller BS, Patel S, Randle RW, Wachtel H, Zanocco KA, Zern NK, Drake FT. Challenges and controversies in adrenal surgery: A practical approach. Curr Probl Surg 2023; 60:101374. [PMID: 37770163 DOI: 10.1016/j.cpsurg.2023.101374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Affiliation(s)
- Toni Beninato
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
| | - Quan-Yang Duh
- Veterans Affairs Medical Center, San Francisco, San Francisco, CA
| | | | - Colleen M Kiernan
- Vanderbilt University Medical Center, Veterans Affairs Medical Center, Tennessee Valley Health System, Nashville, TN
| | - Barbra S Miller
- Division of Surgical Oncology, The Ohio State University, Columbus, OH
| | - Snehal Patel
- Emory University School of Medicine, Atlanta, GA
| | | | | | - Kyle A Zanocco
- David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA
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Favero V, Aresta C, Parazzoli C, Cairoli E, Eller-Vainicher C, Palmieri S, Salcuni AS, Arosio M, Persani L, Scillitani A, Morelli V, Chiodini I. The degree of cortisol secretion is associated with diabetes mellitus and hypertension in patients with nonfunctioning adrenal tumors. Cardiovasc Diabetol 2023; 22:102. [PMID: 37131218 PMCID: PMC10155432 DOI: 10.1186/s12933-023-01836-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 04/16/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile. PATIENTS AND METHODS In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST < 1.8 µg/dL [50 nmol/L]) F-1mgDST and adrenocorticotroph hormone (ACTH) levels and data on HT, DM, OB, DL and CVEs prevalence were retrospectively collected. RESULTS HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p < 0.001 for all comparisons) but not with ACTH. The cut-off for identifying patients with either HT or DM or HT plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST < 1.2 µg/dL (n = 289), patients with F-1mgDST 1.2-1.79 µg/dL (33-49.4 nmol/L) (n = 326) had lower ACTH levels (17.7 ± 11.9 vs 15.3 ± 10.1 pg/mL, respectively, p = 0.008), older age (57.5 ± 12.3 vs 62.5 ± 10.9 years, respectively, p < 0.001), and higher prevalence of HT (38.1% vs 52.5% respectively p < 0.001), DM (13.1% vs 23.3%, respectively, p = 0.001), HT plus DM (8.3% vs 16.9%, respectively, p < 0.002) and CVE (3.2% vs 7.3%, respectively, p = 0.028). F-1mgDST 1.2-1.79 µg/dL was associated with either HT (odd ratio, OR, 1.55, 95% confidence interval, 95% CI 1.08-2.23, p = 0.018) or DM (OR 1.60, 95% CI 1.01-2.57, p = 0.045) after adjusting for age, gender, OB, DL, and DM (for HT) or HT (for DM), and with the presence of HT plus DM (OR 1.96, 95% CI 1.12-3.41, p = 0.018) after adjusting for age, gender, OB and DL. CONCLUSIONS In NFAT patients, F-1mgDST 1.2-1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results.
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Affiliation(s)
- Vittoria Favero
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Carmen Aresta
- Endocrinology Department & Lab of Endocrine and Metabolic Research, IRCCS - Istituto Auxologico Italiano, Milan, Italy
| | - Chiara Parazzoli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Elisa Cairoli
- Endocrinology Department & Lab of Endocrine and Metabolic Research, IRCCS - Istituto Auxologico Italiano, Milan, Italy
| | | | - Serena Palmieri
- Unit of Endocrinology, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonio Stefano Salcuni
- Unit of Endocrinology and Metabolism, University-Hospital S. Maria Della Misericordia, Udine, Italy
| | - Maura Arosio
- Unit of Endocrinology, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Luca Persani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
- Endocrinology Department & Lab of Endocrine and Metabolic Research, IRCCS - Istituto Auxologico Italiano, Milan, Italy
| | - Alfredo Scillitani
- Ospedale "Casa Sollievo della Sofferenza" IRCCS, San Giovanni Rotondo, FG, Italy
| | - Valentina Morelli
- Endocrinology Department & Lab of Endocrine and Metabolic Research, IRCCS - Istituto Auxologico Italiano, Milan, Italy.
| | - Iacopo Chiodini
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
- Unit of Endocrinology, Ospedale Niguarda Cà Granda, Milan, Italy
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10
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Akirov A, Dery L, Fleseriu M, Rudman Y, Shimon I, Manisterski Y, Aviran-Barak N, Nadler V, Alboim S, Shochat T, Tsvetov G, Hirsch D. Cushing's syndrome in women: age-related differences in etiology and clinical picture. Pituitary 2023; 26:144-151. [PMID: 36515786 DOI: 10.1007/s11102-022-01292-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/20/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To evaluate the clinical presentation, biochemical profile, and etiology of Cushing's syndrome (CS) in women stratified by age. METHODS Retrospective study of patients with CS, treated at Rabin Medical Center from 2000 to 2020, or Maccabi Healthcare Services in Israel from 2005 to 2017. Disease etiology, presentation and biochemical profile were compared according to age at diagnosis: ≤ 45, 46-64, or ≥ 65 years. Study was approved by the Ethics Review Boards of both facilities with waiver of consent. RESULTS The cohort included 142 women (mean age, 46.0 ± 15.1 years):81 (57.0%) with Cushing's disease (CD), and 61 (43.0%) with adrenal CS. Pituitary etiology was more common among women < 45 (70.6%), compared with patients ≥ 65 years (31.6%) (P < 0.05). Among CS patients, hypercortisolism was diagnosed in the context of screening after an adrenal incidentaloma detection in 15.0% of patients < 45 and 53.8% of ≥ 65 years (P < 0.001). Weight gain was evident in 57.4% of women < 45 (56.3% CD, 60.0% CS), and 15.8% of women ≥ 65 years (50% CD, 0% CS) (P = 0.011). Mean UFC levels were highest for women < 45 (3.8 × ULN) and lowest for ≥ 65 years (2.3 × ULN) (P < 0.001). CONCLUSION We have shown for the first time that women with CS ≥ 65 years of age more commonly have adrenal etiology. The initial presentation of CS also differs between age groups, where women < 45 years are likely to present with weight gain, while those ≥ 65 years are frequently diagnosed incidentally, when screening for hypercortisolism in the presence of an adrenal incidentaloma.
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Affiliation(s)
- Amit Akirov
- Institute of Endocrinology, Rabin Medical Center Beilinson Hospital, 49100, Petach Tikva, Israel.
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Laura Dery
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Maria Fleseriu
- Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Yaron Rudman
- Institute of Endocrinology, Rabin Medical Center Beilinson Hospital, 49100, Petach Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ilan Shimon
- Institute of Endocrinology, Rabin Medical Center Beilinson Hospital, 49100, Petach Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | | | - Varda Nadler
- Maccabi Health Care Services-Central Laboratory, Rehovot, Israel
| | - Sandra Alboim
- Maccabi Health Care Services-Central Laboratory, Rehovot, Israel
| | - Tzipora Shochat
- Statistical Consulting Unit, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
| | - Gloria Tsvetov
- Institute of Endocrinology, Rabin Medical Center Beilinson Hospital, 49100, Petach Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Maccabi Health Care Services, Tel Aviv, Israel
| | - Dania Hirsch
- Institute of Endocrinology, Rabin Medical Center Beilinson Hospital, 49100, Petach Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Maccabi Health Care Services, Tel Aviv, Israel
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11
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Kalara N, Manzano A. Mifepristone-Induced Hypothyroidism. J Investig Med High Impact Case Rep 2023; 11:23247096231191874. [PMID: 37565673 PMCID: PMC10422905 DOI: 10.1177/23247096231191874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/05/2023] [Accepted: 07/14/2023] [Indexed: 08/12/2023] Open
Abstract
Medications are known to affect the thyroid physiology and are a known cause of hypothyroidism. There is an ever-growing list of medications that affect the thyroid by 1 or more mechanisms. Mifepristone is presently used for the treatment of mild autonomous cortisol secretion (MACS). Hypothyroidism is not a known side effect of this medication. We present a 71-year-old woman with newly diagnosed impaired fasting glucose, dyslipidemia, and osteopenia presenting with a 3-year history of unintentional 15-pound weight gain (despite exercise and a good diet) and increased anxiety. Her physical examination was pertinent for mild lower extremity edema, easy bruising, and skin thinning. Workup revealed adrenocorticotropic hormone (ACTH)-independent MACS from bilateral micronodular hyperplasia of the adrenals. Since she was not a surgical candidate, medical management with mifepristone was chosen. While on mifepristone, she complained of excessive fatigue, a workup done revealed new-onset hypothyroidism. Given her symptoms and bloodwork, she was started on levothyroxine. After stopping mifepristone, she was biochemically and clinically euthyroid and was eventually off levothyroxine. The mechanism by which mifepristone induces hypothyroidism is unknown. Except for a multicenter case series suggesting that mifepristone increases thyroid hormone requirements in patients with central hypothyroidism, to the best of our knowledge, the literature on euthyroid patients developing hypothyroidism secondary to mifepristone is scarce. In conclusion, while the hypothyroidism seems reversible our case highlights the importance of getting baseline thyroid function tests (TFTs) and repeating them while on the medication. Treatment of hypothyroidism is based on symptoms and bloodwork.
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Affiliation(s)
- Niketa Kalara
- Mount Sinai Medical Center, Miami Beach, Florida, USA
| | - Alex Manzano
- Mount Sinai Medical Center, Miami Beach, Florida, USA
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12
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Mittal M, Jethwani P, Naik D, Garg MK. Non-medicalization of medical science: Rationalization for future. World J Methodol 2022; 12:402-413. [PMID: 36186743 PMCID: PMC9516546 DOI: 10.5662/wjm.v12.i5.402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/13/2022] [Accepted: 07/22/2022] [Indexed: 02/08/2023] Open
Abstract
As we delve into the intricacies of human disease, millions of people continue to be diagnosed as having what are labelled as pre-conditions or sub-clinical entities and may receive treatments designed to prevent further progression to clinical disease, but with debatable impact and consequences. Endocrinology is no different, with almost every organ system and associated diseases having subclinical entities. Although the expansion of these “grey” pre-conditions and their treatments come with a better understanding of pathophysiologic processes, they also entail financial costs and drug adverse-effects, and lack true prevention, thus refuting the very foundation of Medicine laid by Hippocrates “Primum non nocere” (Latin), i.e., do no harm. Subclinical hypothyroidism, prediabetes, osteopenia, and minimal autonomous cortisol excess are some of the endocrine pre-clinical conditions which do not require active pharmacological management in the vast majority. In fact, progression to clinical disease is seen in only a small minority with reversal to normality in most. Giving drugs also does not lead to true prevention by changing the course of future disease. The goal of the medical fraternity thus as a whole should be to bring this large chunk of humanity out of the hospitals towards leading a healthy lifestyle and away from the label of a medical disease condition.
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Affiliation(s)
- Madhukar Mittal
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur 342005, India
| | - Parth Jethwani
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur 342005, India
| | - Dukhabandhu Naik
- Department of Endocrinology and Metabolism, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - MK Garg
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur 342005, India
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13
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Delivanis DA, Vassiliadi DA, Tsagarakis S. Current approach of primary bilateral adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2022; 29:243-252. [PMID: 35621176 DOI: 10.1097/med.0000000000000725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To discuss the most recent findings on the pathophysiology, the genetic and molecular causes of primary bilateral adrenal hyperplasia (PBAH). The diagnostic approach of patients with PBAH will also be presented in detail with an emphasis on the emerging diagnostic tools and finally, the treatment of PBAH will be discussed with an emphasis on the newest surgical and medical treatment approaches. RECENT FINDINGS PBAH is a highly heterogeneous condition mostly detected incidentally on abdominal imaging. Based on the size of the nodules, PBAH is subdivided into primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia. A substantial proportion of patients with PBMAH harbor a germline mutation of the armadillo repeat containing 5 tumor suppression gene and therefore genetic testing is strongly recommended. Measurements of plasma or urinary multisteroid profiles show promising results in that PBMAH has a distinctive plasma steroid fingerprint that can help in diagnosis and subtyping of PBMAH. Finally, although surgery is the mainstay of treatment of patients with PBAH, medical therapy is increasingly emerging as an alternative option. SUMMARY PBAH is a poorly studied and therefore a challenging disease to diagnose and treat. Hopefully with these newest diagnostic and therapeutic tools, a more comprehensive approach will be adopted.
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Affiliation(s)
- Danae A Delivanis
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Dimitra A Vassiliadi
- Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece
| | - Stylianos Tsagarakis
- Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece
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14
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Olmos R, Mertens N, Vaidya A, Uslar T, Fernandez P, Guarda FJ, Zúñiga Á, San Francisco I, Huete A, Baudrand R. Discriminative Capacity of CT Volumetry to Identify Autonomous Cortisol Secretion in Incidental Adrenal Adenomas. J Clin Endocrinol Metab 2022; 107:e1946-e1953. [PMID: 35020922 PMCID: PMC9272424 DOI: 10.1210/clinem/dgac005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Indexed: 01/12/2023]
Abstract
CONTEXT Incidentally discovered adrenal adenomas are common. Assessment for possible autonomous cortisol excess (ACS) is warranted for all adrenal adenomas, given the association with increased cardiometabolic disease. OBJECTIVE To evaluate the discriminatory capacity of 3-dimensional volumetry on computed tomography (CT) to identify ACS. METHODS Two radiologists, blinded to hormonal levels, prospectively analyzed CT images of 149 adult patients with unilateral, incidentally discovered, adrenal adenomas. Diameter and volumetry of the adenoma, volumetry of the contralateral adrenal gland, and the adenoma volume-to-contralateral gland volume (AV/CV) ratio were measured. ACS was defined as cortisol ≥ 1.8 mcg/dL after 1-mg dexamethasone suppression test (DST) and a morning ACTH ≤ 15. pg/mL. RESULTS We observed that ACS was diagnosed in 35 (23.4%) patients. Cortisol post-DST was positively correlated with adenoma diameter and volume, and inversely correlated with contralateral adrenal gland volume. Cortisol post-DST was positively correlated with the AV/CV ratio (r = 0.46, P < 0.001) and ACTH was inversely correlated (r = -0.28, P < 0.001). The AV/CV ratio displayed the highest odds ratio (1.40; 95% CI, 1.18-1.65) and area under curve (0.91; 95% CI, 0.86-0.96) for predicting ACS. An AV/CV ratio ≥ 1 (48% of the cohort) had a sensitivity of 97% and a specificity of 70% to identify ACS. CONCLUSION CT volumetry of adrenal adenomas and contralateral adrenal glands has a high discriminatory capacity to identify ACS. The combination of this simple and low-cost radiological phenotyping can supplement biochemical testing to substantially improve the identification of ACS.
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Affiliation(s)
- Roberto Olmos
- Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
- Program for Adrenal Disorders, CETREN UC, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
| | - Nicolás Mertens
- Department of Radiology, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
| | - Anand Vaidya
- Center for Adrenal Disorders, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Thomas Uslar
- Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
- Program for Adrenal Disorders, CETREN UC, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
| | - Paula Fernandez
- Program for Adrenal Disorders, CETREN UC, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
| | - Francisco J Guarda
- Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
| | - Álvaro Zúñiga
- Department of Urology, Pontificia Universidad Catolica de Chile, Santiago 8330077, Chile
| | - Ignacio San Francisco
- Department of Urology, Pontificia Universidad Catolica de Chile, Santiago 8330077, Chile
| | - Alvaro Huete
- Department of Radiology, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
| | - René Baudrand
- Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
- Program for Adrenal Disorders, CETREN UC, Pontificia Universidad Catolica de Chile, Santiago, 8330077, Chile
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15
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Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside. Int J Mol Sci 2022; 23:ijms23020673. [PMID: 35054858 PMCID: PMC8775422 DOI: 10.3390/ijms23020673] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 02/07/2023] Open
Abstract
Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).
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16
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[Autonomous cortisol secretion : Laboratory artifact or disease?]. Internist (Berl) 2021; 63:18-24. [PMID: 34709420 DOI: 10.1007/s00108-021-01188-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Autonomous cortisol secretion was mentioned for the first time in 2016 in the European Guideline on the management of adrenal incidentalomas. OBJECTIVES Review of the state of knowledge on diagnosis, epidemiology, co-morbidities, mortality and treatment of autonomous cortisol secretion in comparison to non-hormone producing adenomas. Recommendation for clinical practice based on the current European guideline. MATERIALS UND METHODS Analysis of relevant clinical studies, discussion of basic literature and expert opinions. RESULTS AND CONCLUSIONS Autonomous cortisol secretion is a term used to describe abnormal cortisol secretion diagnosed by a pathological 1‑mg dexamethasone suppression test in patients with adrenal incidentaloma, but without clinical manifestation of overt Cushing's syndrome. It is associated with increased mortality and morbidity, especially hypertension, diabetes mellitus type II, dyslipidemia and obesity. Adrenalectomy, as the only specific therapy option, should be considered in an interdisciplinary tumour board.
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17
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Favero V, Cremaschi A, Falchetti A, Gaudio A, Gennari L, Scillitani A, Vescini F, Morelli V, Aresta C, Chiodini I. Management and Medical Therapy of Mild Hypercortisolism. Int J Mol Sci 2021; 22:ijms222111521. [PMID: 34768949 PMCID: PMC8584167 DOI: 10.3390/ijms222111521] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/30/2022] Open
Abstract
Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-βhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.
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Affiliation(s)
- Vittoria Favero
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy; (V.F.); (A.C.); (I.C.)
| | - Arianna Cremaschi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy; (V.F.); (A.C.); (I.C.)
| | - Alberto Falchetti
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20149 Milan, Italy;
| | - Agostino Gaudio
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy;
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy;
| | - Alfredo Scillitani
- Unit of Endocrinology and Diabetology “Casa Sollievo della Sofferenza” Hospital, IRCCS, 71013 San Giovanni Rotondo (FG), Italy;
| | - Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. M. Misericordia of Udine, 33100 Udine, Italy;
| | - Valentina Morelli
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Carmen Aresta
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20149 Milan, Italy;
- Correspondence: ; Tel.: +39-02-61911-2738
| | - Iacopo Chiodini
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy; (V.F.); (A.C.); (I.C.)
- Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20149 Milan, Italy;
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18
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Delivanis DA, Andrade Hurtado MD, Cortes T, Athimulam S, Khanna A, Atkinson E, McKenzie T, Takahashi N, Moynagh MR, Bancos I. Abnormal body composition in patients with adrenal adenomas. Eur J Endocrinol 2021; 185:653-662. [PMID: 34406976 PMCID: PMC8511231 DOI: 10.1530/eje-21-0458] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 08/18/2021] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease. DESIGN Cross-sectional study, 2014-2018. METHODS Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level. RESULTS Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18-89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9-6.5), 2.0 (1.3-3.2), and 1.8 (1.2-2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0-0.09), 0.31 (0.18-0.49), and 0.3 (1.2-2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 (P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm2 (P = 0.03). CONCLUSION Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.
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Affiliation(s)
- Danae A Delivanis
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Maria D. Andrade Hurtado
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic Health System, La Crosse, WI, USA
| | - Tiffany Cortes
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Shobana Athimulam
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
- Division of Endocrinology, Diabetes, Bone and Mineral Disorders, Henry Ford Health System, Detroit, MI, USA
| | - Aakanksha Khanna
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth Atkinson
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA
| | - Travis McKenzie
- Division of Endocrine and Metabolic Surgery, Mayo Clinic, Rochester, MN
| | | | | | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
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Giovanelli L, Aresta C, Favero V, Bonomi M, Cangiano B, Eller-Vainicher C, Grassi G, Morelli V, Pugliese F, Falchetti A, Gennari L, Scillitani A, Persani L, Chiodini I. Hidden hypercortisolism: a too frequently neglected clinical condition. J Endocrinol Invest 2021; 44:1581-1596. [PMID: 33394454 DOI: 10.1007/s40618-020-01484-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/07/2020] [Indexed: 01/06/2023]
Abstract
PURPOSE Classic Cushing's syndrome (CS) is a severe disease characterized by central obesity, hypertension, easy bruising, striae rubrae, buffalo hump, proximal myopathy and hypertricosis. However, several CS cases have also been reported with unusual or camouflaged manifestations. In recent years, several authors investigated the prevalence of "hidden hypercortisolism" (HidHyCo) among subjects affected with bone fragility, hypertension and type 2 diabetes mellitus (DM2). The prevalence of the HidHyCo is estimated to be much higher than that of classic CS. However, similarly to classic CS, HidHyCo is known to increase the risk of fractures, cardiovascular disease and mortality. METHODS We reviewed all published cases of unusual presentations of hypercortisolism and studies specifically assessing the HidHyCo prevalence in diabetic, osteoporotic and hypertensive patients. RESULTS We found 49 HidHyCo cases, in whom bone fragility, hypertension and diabetes were the presenting manifestations of an otherwise silent hypercortisolism. Amongst these cases, 34.7%, 32.7%, 6.1% and 19.0%, respectively, had bone fragility, hypertension, DM2 or hypertension plus DM2 as the sole clinical manifestations of HidHyCo. Overall, 25% of HidHyCo cases were of pituitary origin, and bone fragility was the very prevalent first manifestation among them. In population studies, it is possible to estimate that 1-4% of patients with apparent primary osteoporosis has a HidHyCo and the prevalence of this condition among diabetics ranges between 3.4 and 10%. CONCLUSION These data indicate that patients with resistant or suddenly worsening hypertension or DM2 or unexplainable bone fragility should be screened for HidHyCo using the most recently approved sensitive cut-offs.
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Affiliation(s)
- L Giovanelli
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - C Aresta
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - V Favero
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - M Bonomi
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - B Cangiano
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - C Eller-Vainicher
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - G Grassi
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - V Morelli
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - F Pugliese
- Unit of Endocrinology and Diabetology "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, FG, Italy
| | - A Falchetti
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
| | - L Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - A Scillitani
- Unit of Endocrinology and Diabetology "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, FG, Italy
| | - L Persani
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - I Chiodini
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, IRCCS, Via Magnasco 2, 20149, Milan, Italy.
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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20
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Wu N, Katz DA, An G. A Target-Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults. J Clin Pharmacol 2021; 61:1442-1453. [PMID: 34110620 PMCID: PMC8596879 DOI: 10.1002/jcph.1925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 06/08/2021] [Indexed: 11/17/2022]
Abstract
SPI‐62 is a selective and potent small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1). SPI‐62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose‐dependent volume of distribution, nonlinear PK following the first dose, and dose‐proportional PK at steady state, as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI‐62 is the saturable binding of SPI‐62 to its pharmacological target HSD‐1, a phenomenon known as target‐mediated drug disposition (TMDD). Because of the nonlinear and complex PK of SPI‐62, the relationship among SPI‐62 dose, exposure, and response is no longer intuitive and consequently dose selection can be challenging. To facilitate dose selection and clinical trial design, in the current study population PK analysis was performed to characterize SPI‐62 dose‐exposure relationship in humans quantitatively. SPI‐62 PK was best characterized by a 2‐compartment TMDD model with 3 transit absorption compartments. The model was successfully established to explain the substantial and unusual nonlinear PK of SPI‐62 in humans, and it provided adequate fitting for both single‐ and multiple‐dose data. Our modeling work has provided a strong foundation for dose selection in future SPI‐62 clinical trials.
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Affiliation(s)
- Nan Wu
- Division of Pharmaceutics and Translational TherapeuticsCollege of PharmacyUniversity of IowaIowa CityIowaUSA
| | | | - Guohua An
- Division of Pharmaceutics and Translational TherapeuticsCollege of PharmacyUniversity of IowaIowa CityIowaUSA
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21
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Ivović M, Marina LV, Šojat AS, Tančić-Gajić M, Arizanović Z, Kendereški A, Vujović S. Approach to the Patient with Subclinical Cushing's Syndrome. Curr Pharm Des 2021; 26:5584-5590. [PMID: 32787757 DOI: 10.2174/1381612826666200813134328] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 07/08/2020] [Indexed: 01/07/2023]
Abstract
A growing number of patients with adrenal incidentalomas and subclinical Cushing's syndrome (SCS) led to an increasing number of different guidelines, and diagnostic and treatment recommendations. Excess cortisol secretion in patients with SCS is associated with several comorbidities, such as hypertension, dyslipidemia, type 2 diabetes mellitus, and obesity, which in the long-term increase mortality of these patients. Subtle cortisol secretion affects bone health, quality of life and causes depression, but due to the unapparent clinical features, patients with SCS are often at risk between over and under treatment. This narrative review aimed to summarize the latest recommendations on the approach to the patient with subclinical Cushing's syndrome.
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Affiliation(s)
- Miomira Ivović
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Ljiljana V Marina
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Antoan S Šojat
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Milina Tančić-Gajić
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Zorana Arizanović
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Aleksandra Kendereški
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
| | - Svetlana Vujović
- Department for Obesity, Metabolic and Reproductive Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia
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22
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Li D, Kaur RJ, Zhang CD, Ebbehoj A, Singh S, Atkinson EJ, Achenbach SJ, Rocca W, Khosla S, Bancos I. Risk of bone fractures after the diagnosis of adrenal adenomas: a population-based cohort study. Eur J Endocrinol 2021; 184:597-606. [PMID: 33606665 PMCID: PMC7974392 DOI: 10.1530/eje-20-1396] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 02/19/2021] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. DESIGN Population-based cohort study, Olmsted County, Minnesota, USA, 1995-2017. METHODS Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. RESULTS Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20-96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0-21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07-1.52) for developing a new fracture during follow up when compared to referent subjects. CONCLUSIONS Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.
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Affiliation(s)
- Dingfeng Li
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Ravinder Jeet Kaur
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Catherine D. Zhang
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Andreas Ebbehoj
- Department of Clinical Medicine, Department of Endocrinology and Diabetes, Aarhus University, Aarhus, Denmark
| | - Sumitabh Singh
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Elizabeth J. Atkinson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Sara J. Achenbach
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Walter Rocca
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
- Women’s Health Research Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Sundeep Khosla
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
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Athimulam S, Grebe S, Bancos I. Steroid profiling in the diagnosis of mild and overt Cushing's syndrome. Best Pract Res Clin Endocrinol Metab 2021; 35:101488. [PMID: 33589355 PMCID: PMC8164982 DOI: 10.1016/j.beem.2021.101488] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In this review, we provide a comprehensive overview of the utility of steroid profiling for diagnosis of management of overt Cushing syndrome and mild autonomous cortisol secretion. A diagnosis of Cushing syndrome is made through a multistep process that includes confirmation of endogenous hypercortisolism, followed by determination of its cause. Steroid metabolomic testing applied to serum or urine steroids and their metabolites can provide additional and novel insights into alterations of steroid biosynthesis and metabolism and its causes. In particular, increased availability and advances in mass spectrometry-based steroid analysis, coupled with machine learning-based algorithms, have facilitated the development of tailored diagnostic and subtyping approaches for autonomous cortisol secretion and might be useful for detecting low grade autonomous glucocorticoid secretion and in predicting and monitoring of disease severity and associated comorbidities.
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Affiliation(s)
- Shobana Athimulam
- Department of Medicine, Division of Endocrinology, Diabetes, Bone and Mineral Disorders, Henry Ford Health System, Detroit, MI, USA.
| | - Stefan Grebe
- Department of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Mayo Clinic, Rochester, MN, USA; Department of Medicine, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.
| | - Irina Bancos
- Department of Medicine, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.
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Yozamp N, Vaidya A. Assessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses. Best Pract Res Clin Endocrinol Metab 2021; 35:101491. [PMID: 33593680 DOI: 10.1016/j.beem.2021.101491] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Incidentally discovered adrenal masses are common and mostly benign and non-functioning adenomas. However, evolving evidence suggests that a notable proportion of these adrenal adenomas may demonstrate mild autonomous cortisol secretion (MACS), which has been associated with an increased risk for hypertension, hyperglycemia, obesity, dyslipidemia, vertebral fractures, adverse cardiovascular events, and mortality. Therefore, it is advised that all patients with an incidentally discovered adrenal mass be tested for MACS. When there is convincing evidence for MACS, surgical adrenalectomy has been associated with an improvement in certain metabolic parameters and a reduction in vertebral fractures; however, conclusive evidence demonstrating decreased cardiovascular outcomes or mortality are not yet available. Future studies with adequate randomization and follow-up to assess adverse clinical endpoints are needed to determine the optimal management and follow-up of patients with MACS.
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Affiliation(s)
- Nicholas Yozamp
- Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anand Vaidya
- Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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25
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Kannankeril J, Carroll T, Findling JW, Javorsky B, Gunsolus IL, Phillips J, Raff H. Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome. J Endocr Soc 2020; 4:bvaa107. [PMID: 32935666 PMCID: PMC7480956 DOI: 10.1210/jendso/bvaa107] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/20/2020] [Indexed: 01/15/2023] Open
Abstract
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.
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Affiliation(s)
- Joshua Kannankeril
- Division of Endocrinology and Molecular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ty Carroll
- Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - James W Findling
- Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Bradley Javorsky
- Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ian L Gunsolus
- Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jonathan Phillips
- Endocrine Research Laboratory, Aurora St. Luke’s Medical Center, Advocate Aurora Research Institute, Milwaukee, Wisconsin
| | - Hershel Raff
- Division of Endocrinology and Molecular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
- Endocrine Research Laboratory, Aurora St. Luke’s Medical Center, Advocate Aurora Research Institute, Milwaukee, Wisconsin
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Singh S, Atkinson EJ, Achenbach SJ, LeBrasseur N, Bancos I. Frailty in Patients With Mild Autonomous Cortisol Secretion is Higher Than in Patients with Nonfunctioning Adrenal Tumors. J Clin Endocrinol Metab 2020; 105:5867964. [PMID: 32628749 PMCID: PMC7382051 DOI: 10.1210/clinem/dgaa410] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT Mild autonomous cortisol secretion (MACS) affects up to 50% of patients with adrenal adenomas. Frailty is a syndrome characterized by the loss of physiological reserves and an increase in vulnerability, and it serves as a marker of declining health. OBJECTIVE To compare frailty in patients with MACS versus patients with nonfunctioning adrenal tumors (NFAT). DESIGN Retrospective study, 2003-2018. SETTING Referral center. PATIENTS Patients >20 years of age with adrenal adenoma and MACS (1 mg overnight dexamethasone suppression (DST) of 1.9-5 µg/dL) and NFAT (DST <1.9 µg/dL). MAIN OUTCOME MEASURE Frailty index (range 0-1), calculated using a 47-variable deficit model. RESULTS Patients with MACS (n = 168) demonstrated a higher age-, sex-, and body mass index-adjusted prevalence of hypertension (71% vs 60%), cardiac arrhythmias (50% vs 40%), and chronic kidney disease (25% vs 17%), but a lower prevalence of asthma (5% vs 14%) than patients with NFAT (n = 275). Patients with MACS reported more symptoms of weakness (21% vs 11%), falls (7% vs 2%), and sleep difficulty (26% vs 15%) as compared with NFAT. Age-, sex- and BMI-adjusted frailty index was higher in patients with MACS vs patients with NFAT (0.17 vs 0.15; P = 0.009). Using a frailty index cutoff of 0.25, 24% of patients with MACS were frail, versus 18% of patients with NFAT (P = 0.028). CONCLUSION Patients with MACS exhibit a greater burden of comorbid conditions, adverse symptoms, and frailty than patients with NFAT. Future prospective studies are needed to further characterize frailty, examine its responsiveness to adrenalectomy, and assess its influence on health outcomes in patients with MACS.
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Affiliation(s)
- Sumitabh Singh
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Elizabeth J Atkinson
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Sara J Achenbach
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Nathan LeBrasseur
- Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
- Correspondence and Reprint Requests: Irina Bancos, MD, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905. E-mail:
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Foster T, Bancos I, McKenzie T, Dy B, Thompson G, Lyden M. Early assessment of postoperative adrenal function is necessary after adrenalectomy for mild autonomous cortisol secretion. Surgery 2020; 169:150-154. [PMID: 32693952 DOI: 10.1016/j.surg.2020.05.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/26/2020] [Accepted: 05/27/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND The diagnostic threshold for mild autonomous cortisol secretion using low dose, overnight, dexamethasone suppression testing is recognized widely as a serum cortisol ≥1.8 mcg/dL. The degree to which these patients require postoperative glucocorticoid replacement is unknown. METHODS We reviewed adult patients with corticotropin (ACTH)-independent hypercortisolism who underwent unilateral laparoscopic adrenalectomy for benign disease with a dexamethasone suppression testing ≥1.8 mcg/dL at our institution from 1996 to 2018. Patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL were compared with those with a dexamethasone suppression testing >5 mcg/dL. RESULTS We compared 68 patients with a preoperative dexamethasone suppression testing of 1.8 to 5 mcg/dL to 53 patients with a preoperative dexamethasone suppression testing >5 mcg/dL. Preoperative serum ACTH (mean 10.0 vs 9.2 pg/mL), adenoma size (mean 3.4 vs 3.5 cm), and side of adrenalectomy (37 and 47% right) were similar between groups (P > .05 each). Patients with a dexamethasone suppression testing 1.8 to 5 mcg/dL were older (mean values 58 ± 11 vs 52 ± 16 years ; P = .01), less likely to be female (63 vs 81%; P = .03), had greater body mass indexes (33.1 ± 8.4 vs 29.1 ± 5.6; P = .01), and had lesser 24 hour preoperative urine cortisol excretions (32.6 ± 26.7 vs 76.1 ± 129.4 mcg; P = .03). Postoperative serum cortisol levels were compared in 22 patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL to 14 patients with a dexamethasone suppression testing >5 mcg/dL. Those with dexamethasone suppression testing 1.8 to 5 mcg/dL had greater postoperative serum cortisol levels (8.0 ± 5.7 vs 5.0 ± 2.6 mcg/dL; P = .03), were less likely to be discharged on glucocorticoid replacement (59% vs 89%; P = .003), and had a decreased duration of treatment (4.4 ± 3.8 vs 10.7 ± 18.0 months; P = .04). CONCLUSION Assessment of early postoperative adrenal function with mild autonomous cortisol secretion is necessary to minimize unnecessary glucocorticoid replacement.
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Affiliation(s)
| | - Irina Bancos
- Department of Surgery, Mayo Clinic, Rochester, MN
| | | | - Benzon Dy
- Department of Surgery, Mayo Clinic, Rochester, MN
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