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Guarnotta V, Giordano C, Reimondo G. Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity. J Endocrinol Invest 2025; 48:47-59. [PMID: 39352629 PMCID: PMC12031983 DOI: 10.1007/s40618-024-02455-7] [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: 09/18/2023] [Accepted: 08/20/2024] [Indexed: 11/10/2024]
Abstract
PURPOSE The current review aims to summarize and discuss the prevalence of confirmed hypercortisolism in patients with diabetes mellitus or obesity, analysing the screening tests used and their accuracy, in order to better identify whether patients with diabetes mellitus and obesity should be screened for Cushing's syndrome (CS) and how. METHODS A narrative review was performed including publications focusing on the current knowledge on prevalence of confirmed hypercortisolism in patients with type 2 diabetes mellitus (T2DM) or obesity and on screening tests used to detect CS. RESULTS The studies reviewed suggest that the prevalence of CS in patients with T2DM is variable, ranging from 0.6 to 9.3%. The most used screening test is the overnight cortisol after 1 mg of dexamethasone suppression test (DST), with a false positive rate ranging from 3.7 to 21%. The prevalence of CS among obese patients is generally about 1%, except for two studies which reported higher prevalence. For obese patients, 1 mg DST and late-night salivary cortisol are the most accurate screening tests for CS. CONCLUSIONS Clinical expertise remains the mainstay to identify which subjects should be screened for CS. The evaluation of the clinical stigmata of CS and the combination with clinical comorbidities typical of CS are the stronger predictors of CS. In addition, we could hypothesize that in patients with T2DM, overnight 1 mg DST is the more accurate screening test for CS. By contrast, in patients with obesity both LNSC and overnight 1 mg DST could be equally used for the screening of hypercortisolism.
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Affiliation(s)
- Valentina Guarnotta
- Section of Endocrinology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties "G. D'Alessandro" (PROMISE), University of Palermo, Piazza delle Cliniche 2, Palermo, 90127, Italy.
| | - Carla Giordano
- Section of Endocrinology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties "G. D'Alessandro" (PROMISE), University of Palermo, Piazza delle Cliniche 2, Palermo, 90127, Italy.
| | - Giuseppe Reimondo
- Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
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Ferreira NS, Costa VP, Miranda JF, Cintra LO, Barbosa LS, Barbosa da Silva MG, Abreu NA, Abe RY. Psychological Stress and Intraocular Pressure in Glaucoma: A Randomized Controlled Trial. Ophthalmol Glaucoma 2024; 7:518-530. [PMID: 39019157 DOI: 10.1016/j.ogla.2024.07.004] [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: 01/25/2024] [Revised: 06/09/2024] [Accepted: 07/08/2024] [Indexed: 07/19/2024]
Abstract
PURPOSE To evaluate the intraocular pressure (IOP) behavior after applying a standardized protocol to induce psychological stress in patients with primary open-angle glaucoma (POAG). DESIGN Randomized controlled trial. PARTICIPANTS A total of 39 patients with POAG were included: 18 in the stress group and 21 in the control group. METHODS Patients were randomized to undergo the Trier Social Stress Test (TSST) or to be included in the control group. All participants were submitted to a modified diurnal tension curve (DTC) 1-4 weeks before randomization, with 3 IOP measurements performed between 8:00 am and 2:00 pm. We evaluated the response to the TSST by measuring the levels of salivary cortisol, salivary amylase, IOP, mean arterial pressure, and heart rate before, immediately after, and 40 minutes after the TSST. The State Trait Anxiety Inventory (STAI) was applied to evaluate the levels of anxiety at the same time intervals. MAIN OUTCOME MEASURES Changes in IOP (mmHg), salivary cortisol and amylase, heart rate, mean arterial pressure, and STAI scores. RESULTS At baseline, there were no significant differences between the groups regarding age (P = 0.661), sex (P = 0.669), salivary cortisol (P = 0.104), and mean DTC IOP for the right (P = 0.439) and left (P = 0.576) eyes. We observed a significant mean IOP increase of 3.8 mmHg (right eye; P < 0.001) and 4.1 mmHg (left eye; P < 0.001) when we compared IOP measurements obtained during the DTC and immediately after TSST. Salivary cortisol (5.9 nmol/L; P = 0.004), salivary amylase (323 388 UL; P = 0.004), mean arterial pressure (10.1 mmHg; P < 0.001), and heart rate (12.9 bpm; P < 0.001) also increased significantly after the TSST. In addition, 61.1% (11 of 18) of the patients in the TSST group showed an IOP increase > 4 mmHg following the test. The STAI-state score significantly increased after the TSST compared to baseline (P < 0.001) and decreased from poststress to the recovery period (P < 0.001). CONCLUSIONS Patients with POAG present significant elevations of IOP, salivary cortisol and amylase, mean arterial pressure, heart rate, and STAI scores after psychological stress induced by the TSST. FINANCIAL DISCLOSURES Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
| | | | | | | | | | | | | | - Ricardo Yuji Abe
- Hospital Oftalmológico de Brasília, Brasília, Distrito Federal, Brazil; Department of Ophthalmology, University of Campinas, Campinas, Brazil.
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Flowers KC, Shipman KE. Pitfalls in the Diagnosis and Management of Hypercortisolism (Cushing Syndrome) in Humans; A Review of the Laboratory Medicine Perspective. Diagnostics (Basel) 2023; 13:diagnostics13081415. [PMID: 37189516 DOI: 10.3390/diagnostics13081415] [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: 02/21/2023] [Revised: 03/28/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Biochemical confirmation of a diagnosis of hypercortisolism (Cushing syndrome) is vital to direct further investigations, especially given the overlap with non-autonomous conditions, such as pseudo-Cushing, and the morbidity associated with missed diagnoses. A limited narrative review was performed focusing on the laboratory perspective of the pitfalls of making a biochemical diagnosis of hypercortisolism in those presenting with presumed Cushing syndrome. Although analytically less specific, immunoassays remain cheap, quick, and reliable in most situations. Understanding cortisol metabolism can help with patient preparation, specimen selection (e.g., consideration of urine or saliva for those with possible elevations of cortisol binding globulin concentration), and method selection (e.g., mass spectrometry if there is a high risk of abnormal metabolites). Although more specific methods may be less sensitive, this can be managed. The reduction in cost and increasing ease of use makes techniques such as urine steroid profiles and salivary cortisone of interest in future pathway development. In conclusion, the limitations of current assays, particularly if well understood, do not impede diagnosis in most cases. However, in complex or borderline cases, there are other techniques to consider to aid in the confirmation of hypercortisolism.
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Affiliation(s)
- Kade C Flowers
- Department of Clinical Chemistry, University Hospitals Sussex NHS Trust, Worthing BN11 2DH, UK
| | - Kate E Shipman
- Department of Clinical Chemistry, University Hospitals Sussex NHS Trust, Worthing BN11 2DH, UK
- Department of Medical Education, Brighton and Sussex Medical School, University of Sussex, Falmer Campus, Brighton BN1 9PX, UK
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Povaliaeva A, Bogdanov V, Pigarova E, Zhukov A, Dzeranova L, Belaya Z, Rozhinskaya L, Mel’nichenko G, Mokrysheva N. Assessment of Vitamin D Metabolism in Patients with Cushing's Disease in Response to 150,000 IU Cholecalciferol Treatment. Nutrients 2021; 13:nu13124329. [PMID: 34959880 PMCID: PMC8704048 DOI: 10.3390/nu13124329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 12/12/2022] Open
Abstract
In this study we aimed to assess vitamin D metabolism in patients with Cushing’s disease (CD) compared to healthy individuals in the setting of bolus cholecalciferol treatment. The study group included 30 adults with active CD and the control group included 30 apparently healthy adults with similar age, sex and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. All data were analyzed with non-parametric statistics. Patients with CD had similar to healthy controls 25(OH)D3 levels (p > 0.05) and higher 25(OH)D3/24,25(OH)2D3 ratios (p < 0.05) throughout the study. They also had lower baseline free 25(OH)D levels (p < 0.05) despite similar DBP levels (p > 0.05) and lower albumin levels (p < 0.05); 24-h urinary free cortisol showed significant correlation with baseline 25(OH)D3/24,25(OH)2D3 ratio (r = 0.36, p < 0.05). The increase in 25(OH)D3 after cholecalciferol intake was similar in obese and non-obese states and lacked correlation with BMI (p > 0.05) among patients with CD, as opposed to the control group. Overall, patients with CD have a consistently higher 25(OH)D3/24,25(OH)2D3 ratio, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. The observed difference in baseline free 25(OH)D levels is not entirely clear and requires further study.
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van Baal L, Wichert M, Zwanziger D, Dralle H, Weber F, Kreitschmann-Andermahr I, Führer D, Unger N. Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism. Horm Metab Res 2021; 53:662-671. [PMID: 34607366 DOI: 10.1055/a-1608-1720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Due to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing's disease and Cushing's disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.
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Affiliation(s)
- Lukas van Baal
- Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany
| | - Marc Wichert
- Department of Clinical Chemistry, University Duisburg-Essen, Essen, Germany
| | - Denise Zwanziger
- Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany
- Department of Clinical Chemistry, University Duisburg-Essen, Essen, Germany
| | - Henning Dralle
- Division of Endocrine Surgery, University Duisburg-Essen, Essen, Germany
| | - Frank Weber
- Division of Endocrine Surgery, University Duisburg-Essen, Essen, Germany
| | | | - Dagmar Führer
- Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany
| | - Nicole Unger
- Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany
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Belaya Z, Golounina O, Melnichenko G, Tarbaeva N, Pashkova E, Gorokhov M, Kalashnikov V, Dzeranova L, Fadeev V, Volchkov P, Dedov I. Clinical course and outcome of patients with ACTH-dependent Cushing's syndrome infected with novel coronavirus disease-19 (COVID-19): case presentations. Endocrine 2021; 72:12-19. [PMID: 33713312 PMCID: PMC7955209 DOI: 10.1007/s12020-021-02674-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/24/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To analyze the clinical presentations of patients with endogenous Cushing's syndrome (CS) affected by Coronavirus disease-19 (COVID-19). MATERIALS AND METHODS Patients who were referred to our clinic with active CS from 31st March to 15th May 2020 were screened for COVID-19 using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Late-night serum cortisol (64-327 nmol/L), late-night salivary cortisol (LNSC) (0.5-9.4 nmol/L), or 24-h urinary free cortisol (24 hUFC) (100-379 nmol/24 h) were measured by electrochemiluminescence immunoassay. RESULTS Among 22 patients with active CS we found three cases affected by COVID-19. Nonspecific inflammation markers were within the reference range or slightly elevated in these patients. A 71-year-old woman with newly diagnosed CS (late-night serum cortisol >1750 nmol/L, LNSC 908.6 nmol/L) developed dyspnea as an only symptom and died from bilateral polysegmantal hemorrhagic pneumonia 7 days later. A 38-year-old woman with a 5-year medical history of active Cushing's disease (CD) (late-night serum cortisol 581.3 nmol/L, 24 hUFC 959.7 nmol/24-h) suffered from dyspnea, cough, fever (39.3 °C) and chest pain. Oxygen therapy, antibiotics and symptomatic treatments lead to full recovery 24 days later. A 66-year-old woman with a 4-year medical history of mild CD (late-night serum cortisol 603.4 nmol/L, LNSC 10.03 nmol/L) tested positive for COVID-19 in routine screening and remained asymptomatic. CONCLUSIONS The outcome of COVID-19 in patients with CS depends on the severity of hypercortisolism. Thus, severe hypercortisolism is a warning sign that CS affected by COVID-19 could require emergency care despite a lack of clinical presentations and low inflammation biomarkers.
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Affiliation(s)
- Zhanna Belaya
- The National Medical Research Center for Endocrinology, Moscow, Russia.
| | - Olga Golounina
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | | | - Natalia Tarbaeva
- The National Medical Research Center for Endocrinology, Moscow, Russia
| | | | - Maxim Gorokhov
- The National Medical Research Center for Endocrinology, Moscow, Russia
| | | | - Larisa Dzeranova
- The National Medical Research Center for Endocrinology, Moscow, Russia
| | - Valentin Fadeev
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - Pavel Volchkov
- The National Medical Research Center for Endocrinology, Moscow, Russia
- Life Sciences Research Center, Moscow Institute of Physics and Technology, Dolgoprudniy, Russia
| | - Ivan Dedov
- The National Medical Research Center for Endocrinology, Moscow, Russia
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Abstract
Due to the variable clinical features and its rarity diagnosis of Cushing's disease (CD) is often delayed. Clearly, awareness for CD needs to be raised, accompanied by the availability of simple and accurate screening tests. Late-night salivary cortisol (LNSC), 1 mg dexamethasone suppression test (DST), and urinary free cortisol (UFC) have all been extensively studied, demonstrating high sensitivity and specificity for the diagnosis of Cushing's syndrome. However, each of those well-established tests has its own distinctive features, making it preferable in specific clinical conditions and patient groups. To choose the most appropriate test in individual patients, an expert endocrinologist should be consulted. This review will discuss the pitfalls for each of those tests.
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Ponzetto F, Settanni F, Parasiliti-Caprino M, Rumbolo F, Nonnato A, Ricciardo M, Amante E, Priolo G, Vitali S, Anfossi L, Arvat E, Ghigo E, Giordano R, Mengozzi G. Reference ranges of late-night salivary cortisol and cortisone measured by LC-MS/MS and accuracy for the diagnosis of Cushing's syndrome. J Endocrinol Invest 2020; 43:1797-1806. [PMID: 32772255 DOI: 10.1007/s40618-020-01388-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/02/2020] [Indexed: 01/09/2023]
Abstract
PURPOSE International guidelines recommend salivary cortisol for the diagnosis of Cushing's syndrome. Despite mass spectrometry-based assays are considered the analytical gold-standard, there is still the need to define reference intervals and diagnostic accuracy of such methodology. METHODS 100 healthy volunteers and 50 consecutive patients were enrolled to compare LC-MS/MS and electrochemiluminescence assay for the determination of late-night salivary cortisol and cortisone. Moreover, we aimed to determine reference intervals of salivary steroids in a population of healthy individuals and diagnostic accuracy in patients with suspected hypercortisolism and in a population including also healthy individuals. RESULTS Method comparison highlighted a positive bias (51.8%) of immunoassay over LC-MS/MS. Reference intervals of salivary cortisol (0.17-0.97 µg/L), cortisone (0.84-4.85 µg/L) and ratio (0.08-0.30) were obtained. The most accurate thresholds of salivary cortisol for the diagnosis of hypercortisolism were 1.15 µg/L in the population with suspected hypercortisolism (AUC 1) and 1.30 µg/L in the population including also healthy individuals (AUC 1). Cut-off values of salivary cortisone (7.23 µg/L; Se 92.9%, Sp 97.2%, AUC 0.960 and Se 92.9%, Sp 99.1%, AUC 0.985 in suspected hypercortisolism and in overall population, respectively) and cortisol-to-cortisone ratio (0.20; Se 85.7%, Sp 80.6%, AUC 0.820 and Se 85.7%, Sp 85.5%, AUC 0.855 in suspected hypercortisolism and in overall population, respectively) were accurate and similar in both populations. CONCLUSION LC-MS/MS is the most accurate analytical platform for measuring salivary steroids. Obtained reference intervals are coherent with previously published data and diagnostic accuracy for diagnosis of overt hypercortisolism proved highly satisfactory.
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Affiliation(s)
- F Ponzetto
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, City of Health and Science University Hospital, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - F Settanni
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, City of Health and Science University Hospital, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
| | - M Parasiliti-Caprino
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, City of Health and Science University Hospital, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
| | - F Rumbolo
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, City of Health and Science University Hospital, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
| | - A Nonnato
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
| | - M Ricciardo
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
| | - E Amante
- Department of Chemistry, University of Turin, Turin, Italy
| | - G Priolo
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
| | - S Vitali
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
| | - L Anfossi
- Department of Chemistry, University of Turin, Turin, Italy
| | - E Arvat
- Oncologic Endocrinology, Department of Medical Sciences, City of Health and Science University Hospital, University of Turin, Turin, Italy
| | - E Ghigo
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, City of Health and Science University Hospital, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - R Giordano
- Department of Biological and Clinical Sciences, University of Turin, Turin, Italy
| | - G Mengozzi
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, Turin, Italy
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Abe RY, Silva TC, Dantas I, Curado SX, Madeira MS, de Sousa LB, Costa VP. Can Psychologic Stress Elevate Intraocular Pressure in Healthy Individuals? Ophthalmol Glaucoma 2020; 3:426-433. [PMID: 32768362 DOI: 10.1016/j.ogla.2020.06.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 06/11/2023]
Abstract
PURPOSE To investigate if a stress event can influence intraocular pressure (IOP) in a group of healthy individuals. DESIGN Case-control study. PARTICIPANTS A total of 28 healthy subjects were included: 17 in the stress group and 11 in the control group. METHODS The Trier Social Stress Test (TSST) is a tool to evaluate cortisol response to psychologic stimulation based on the stress induced by public speaking. All participants underwent a modified diurnal tension curve (DTC) 1 week before the TSST, with 3 IOP measurements performed between 8:00 am and 2:00 pm. We evaluated the response to the TSST measuring the levels of salivary cortisol, IOP, and heart rate before, immediately after, and 40 minutes after TSST. The State Trait Anxiety Inventory (STAI) was applied to evaluate the levels of anxiety at the same time intervals. MAIN OUTCOME MEASURES Changes in IOP (mmHg), salivary cortisol, heart rate, and STAI scores. RESULTS At baseline, there were no significant differences between case and controls regarding age (52.2 ± 6.26 vs. 53.8 ± 8.4 years, P = 0.661), gender (52.94% male vs. 45.45% female, P = 0.669), and ethnicity. Salivary cortisol (6.8 nmol/l, P < 0.001) and heart rate (7.2 beats/min, P = 0.035) increased significantly after the TSST. We observed a mean IOP increase of 1.0 mmHg (right eye, P = 0.003) and 1.1 mmHg (left eye, P = 0.004) when comparing IOP measurements obtained during the DTC and immediately after TSST. In addition, 35% (6/17) of the subjects in the TSST group showed an IOP increase higher than 2 mmHg after the test compared with 18% (2/11) in the control group. The STAI state score significantly increased after the stress event compared with baseline (P = 0.026) and decreased from poststress to the recovery period (P = 0.006) in the TSST group. The control group did not show significant changes in IOP, heart rate, salivary cortisol levels, and STAI scores. CONCLUSIONS Significant elevations of IOP, salivary cortisol, STAI scores, and heart rate occurred after inducing psychologic stress with TSST in a group of healthy individuals.
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Affiliation(s)
- Ricardo Y Abe
- Hospital Oftalmológico de Brasília, Brasília, Distrito Federal, Brazil; Department of Ophthalmology - University of Campinas, Campinas, Brazil.
| | - Thairis C Silva
- Hospital Oftalmológico de Brasília, Brasília, Distrito Federal, Brazil
| | | | | | - Mariana S Madeira
- Hospital Oftalmológico de Brasília, Brasília, Distrito Federal, Brazil
| | | | - Vital P Costa
- Department of Ophthalmology - University of Campinas, Campinas, Brazil
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Ushiki K, Tsunekawa K, Shoho Y, Martha L, Ishigaki H, Matsumoto R, Yanagawa Y, Nakazawa A, Yoshida A, Nakajima K, Araki O, Kimura T, Murakami M. Assessment of exercise-induced stress by automated measurement of salivary cortisol concentrations within the circadian rhythm in Japanese female long-distance runners. SPORTS MEDICINE-OPEN 2020; 6:38. [PMID: 32804358 PMCID: PMC7431506 DOI: 10.1186/s40798-020-00269-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 08/04/2020] [Indexed: 11/30/2022]
Abstract
Background Overtraining syndrome, caused by prolonged excessive stress, results in reduced performance and cortisol responsiveness in athletes. It is necessary to collect saliva samples sequentially within circadian rhythm for assessing exercise stress by measuring cortisol concentrations, and automated cortisol measurements using electrochemiluminescence immunoassay (ECLIA) may be useful for measuring a large number of saliva samples. In this study, we evaluated the appropriate use of cortisol-based exercise stress assessment within the circadian rhythm, which may diagnose and prevent overtraining syndrome in athletes. Methods We collected saliva and sera from 54 healthy participants and analyzed the correlation between salivary cortisol concentrations measured by ECLIA and enzyme-linked immunosorbent assay (ELISA) or serum cortisol analysis. We also collected saliva continuously from 12 female long-distance runners on 2 consecutive days involving different intensities and types of exercise early in the morning and in the afternoon and measured salivary cortisol concentrations using ECLIA. Each exercise intensity of runners was measured by running velocities, Borg Scale score, and rate of change in the pulse rate by exercise. Results ECLIA-based salivary cortisol concentrations correlated positively with those detected by ELISA (ρ = 0.924, p < 0.001) and serum cortisol (ρ = 0.591, p = 0.001). In long-distance runners, circadian rhythm of salivary cortisol, including the peak after waking and the decrease promptly thereafter, were detected on both days by continuous saliva sampling. The rates of change in salivary cortisol concentrations were significantly lower after an early morning exercise than after an afternoon exercise on both days (day 1, p = 0.002, and day 2, p = 0.003). In the early morning exercise, the rate of change in salivary cortisol concentration was significantly higher on day 1 than on day 2 (p = 0.034), similar to a significant difference in running velocities (p = 0.001). Conclusions Our results suggest that automated ECLIA-based salivary cortisol measurements are able to detect the athletes’ circadian rhythm and compare the exercise stress intensities at the same times on different days, even in the early morning, possibly leading to the prevention of overtraining syndrome.
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Affiliation(s)
- Kazumi Ushiki
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan.,Clinical Laboratory Center, Gunma University Hospital, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Katsuhiko Tsunekawa
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan. .,Clinical Laboratory Center, Gunma University Hospital, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan.
| | - Yoshifumi Shoho
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan.,Faculty of Education, Ikuei University, 1-7-1 Tonya-machi Takasaki, Gunma, 370-0006, Japan
| | - Larasati Martha
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Hirotaka Ishigaki
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan.,Department of Medical Technology, Faculty of Health Science, Gunma Paz University, 1-7-1 Tonya-machi Takasaki, Gunma, 370-0006, Japan
| | - Ryutaro Matsumoto
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Yoshimaro Yanagawa
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan.,Faculty of Education, Ikuei University, 1-7-1 Tonya-machi Takasaki, Gunma, 370-0006, Japan
| | - Asuka Nakazawa
- Clinical Laboratory Center, Gunma University Hospital, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Akihiro Yoshida
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Kiyomi Nakajima
- Clinical Laboratory Center, Gunma University Hospital, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Osamu Araki
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Takao Kimura
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan.,Clinical Laboratory Center, Gunma University Hospital, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan
| | - Masami Murakami
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma, 371-8511, Japan.,Clinical Laboratory Center, Gunma University Hospital, 3-39-15 Showa-machi Maebashi, Gunma, 371-8511, Japan
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11
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Galm BP, Qiao N, Klibanski A, Biller BMK, Tritos NA. Accuracy of Laboratory Tests for the Diagnosis of Cushing Syndrome. J Clin Endocrinol Metab 2020; 105:5781205. [PMID: 32133504 DOI: 10.1210/clinem/dgaa105] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 02/27/2020] [Indexed: 12/11/2022]
Abstract
CONTEXT The diagnosis of Cushing syndrome (CS) can be challenging. It remains to be determined which diagnostic tests are the most accurate. OBJECTIVE To summarize the accuracy of diagnostic tests for CS using contemporary meta-analytic techniques (hierarchical models). DATA SOURCES PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systemic Reviews (inception until August 3, 2018). STUDY SELECTION Studies performed in adults that determined the accuracy of one or more diagnostic tests: overnight 1-mg dexamethasone suppression test (DST), 2-day low-dose DST (2d DST), 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), midnight serum cortisol (MSC), and the dexamethasone-suppressed CRH (dex-CRH) and desmopressin (dex-DDAVP) tests. DATA EXTRACTION Two authors independently extracted data and performed methodological assessments. DATA SYNTHESIS One hundred thirty-nine studies (14 140 participants) were included in the analysis. The respective sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio (95% confidence interval [CI]) estimates include the following: DST 98.6% (96.9%-99.4%), 90.6% (86.4%-93.6%), 10.5 (7.2-15.3), and 0.016 (0.007-0.035); 2d DST 95.3% (91.3%-97.5%), 92.8% (85.7%-96.5%), 13.2 (6.47-27.1), and 0.051 (0.027-0.095); UFC 94.0% (91.6%-95.7%), 93.0% (89.0%-95.5%), 13.3 (8.47-21.0), and 0.065 (0.046-0.092); LNSC 95.8% (93.%-97.2%), 93.4% (90.7%-95.4%), 14.6 (10.3-20.7), and 0.045 (0.030-0.066); MSC 96.1% (93.5%-97.6%), 93.2% (88.1%-96.3%), 14.2 (7.96-25.2), and 0.042 (0.026-0.069); and dex-CRH 98.6% (90.4%-99.8%), 85.9% (67.6%-94.7%), 7.0 (2.80-17.6), and 0.016 (0.002-0.118). A single study evaluated dex-DDAVP. Meta-regression and a novel network meta-analytic approach suggest that DST is the most sensitive while UFC is the least sensitive. CONCLUSIONS All of the included diagnostic tests for CS are highly sensitive and specific. It appears that the DST is the most sensitive while the UFC is less sensitive. The specificity of all first-line tests appears comparable.
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Affiliation(s)
- Brandon P Galm
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nidan Qiao
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Shanghai Pituitary Tumor Center, Shanghai Neurosurgical Research Institute, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, China
| | - Anne Klibanski
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Beverly M K Biller
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nicholas A Tritos
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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12
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Glyn TC, Ho MWJ, Lambert AP, Thomas JDJ, Douek IF, Andrews RC, King RJ. Patients with morbid obesity should not be routinely screened for Cushing's syndrome: Results of retrospective study of patients attending a specialist weight management service. Clin Obes 2020; 10:e12358. [PMID: 31994330 DOI: 10.1111/cob.12358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 11/30/2022]
Abstract
Cushing's syndrome (CS) is a rare condition which results in multi-system involvement and can lead to significant morbidity and mortality. Screening for CS in patients with obesity has been suggested to identify undiagnosed or occult cases. This study was performed to determine whether CS screening is indicated in a tier 3 weight management centre in the UK. A retrospective review of all patients referred to the weight management service between 2013 and 2016 inclusive was undertaken. A final cohort of 569 patients was obtained. Clinic letters and laboratory databases were used to obtain demographic information, patient characteristics and biochemical results. A total of 387 patients were screened using the 1 mg overnight dexamethasone suppression test (ODST) and 182 patients were screened with two 24-hour urinary free cortisol (UFC) collections. A total of 27 patients had an initial abnormal result, of which 16 underwent further testing and had normal results. Six were reviewed and did not demonstrate any clinical features of CS. Five did not attend their clinic appointments but there were neither concerning features within their referrals, nor subsequent diagnoses of CS made. No patients from this cohort were diagnosed with CS. This study does not support routine CS screening of patients affected by severe obesity referred to a specialist tier 3 weight management service. Clinical assessment should be undertaken first and further investigations performed only if deemed necessary.
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Affiliation(s)
- Tessa Carlin Glyn
- Taunton Weight Management Service, Musgrove Park Hospital, Taunton, UK
| | - May Wai-Jing Ho
- Taunton Weight Management Service, Musgrove Park Hospital, Taunton, UK
| | | | | | | | | | - Rhodri James King
- Taunton Weight Management Service, Musgrove Park Hospital, Taunton, UK
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13
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Belaya Z, Khandaeva P, Nonn L, Nikitin A, Solodovnikov A, Sitkin I, Grigoriev A, Pikunov M, Lapshina A, Rozhinskaya L, Melnichenko G, Dedov I. Circulating Plasma microRNA to Differentiate Cushing's Disease From Ectopic ACTH Syndrome. Front Endocrinol (Lausanne) 2020; 11:331. [PMID: 32582027 PMCID: PMC7291947 DOI: 10.3389/fendo.2020.00331] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 04/28/2020] [Indexed: 12/12/2022] Open
Abstract
Corticotropinomas and adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors exhibit differential levels of some microRNAs (miRs) compared to normal tissue. Because miRs can be released from tissues into circulation, they offer promise as novel disease biomarkers. Objective: To evaluate whether miRs are differentially detected in plasma samples of patients with ACTH-dependent Cushing's syndrome (CS). Design: Case-control study. Methods: Morning fasting plasma samples were collected from 41 consecutive patients with confirmed ACTH-dependent CS and 11 healthy subjects and stored at -80°C. Twenty-one miRs previously reported to be differentially expressed in ACTH-secreting tumors vs. healthy tissue samples were quantified in plasma by qPCR. Results: Among enrolled subjects, 28 were confirmed to have Cushing's disease (CD), 13 had ectopic ACTH secretion (EAS) and 11 were healthy controls. We found statistically significant differences in the circulating levels of miR-16-5p [45.04 (95% CI 28.77-61.31) in CD vs. 5.26 (2.65-7.87) in EAS, P < 0.001; q = 0.001], miR-145-5p [0.097 (0.027-0.167) in CD vs. undetectable levels in EAS, P = 0.008; q = 0.087] and differences in miR-7g-5p [1.842 (1.283-2.400) in CD vs. 0.847 (0.187-1.507) in EAS, P = 0.02; q = 0.14]. The area under the receiver-operator (ROC) curve was 0.879 (95% CI 0.770-0.987), p < 0.001, when using miR-16-5p to distinguish between CD and EAS. Circulating levels of miR-16-5p in the healthy control group differed from that of both the CD and EAS groups. Conclusions: Plasma miR levels differ in patients with CD and EAS. In particular, miR-16-5p, miR-145-5p and miR-7g-5p are promising biomarkers for further research to differentiate ACTH-dependent CS.
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Affiliation(s)
- Zhanna Belaya
- The National Medical Research Centre for Endocrinology, Moscow, Russia
- *Correspondence: Zhanna Belaya
| | - Patimat Khandaeva
- The National Medical Research Centre for Endocrinology, Moscow, Russia
| | - Larisa Nonn
- Department Pathology College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Alexey Nikitin
- Federal Research and Clinical Center FMBA of Russia, Moscow, Russia
| | | | - Ivan Sitkin
- The National Medical Research Centre for Endocrinology, Moscow, Russia
| | - Andrey Grigoriev
- The National Medical Research Centre for Endocrinology, Moscow, Russia
| | - Mikhail Pikunov
- National Medical Research Center of Surgery Named After A.V. Vishnevsky, Moscow, Russia
| | | | | | | | - Ivan Dedov
- The National Medical Research Centre for Endocrinology, Moscow, Russia
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14
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Melin EO, Hillman M, Landin-Olsson M. Midnight salivary cortisol secretion associated with high systolic blood pressure in type 1 diabetes. Endocr Connect 2019; 8:1520-1528. [PMID: 31671407 PMCID: PMC6893315 DOI: 10.1530/ec-19-0407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 10/31/2019] [Indexed: 12/03/2022]
Abstract
OBJECTIVE To explore associations between high midnight salivary cortisol (MSC) secretion and high blood pressure (BP) in type 1 diabetes (T1D). METHODS Cross-sectional study of 196 adult patients with T1D (54% men). Associations between high MSC (≥9.3 nmol/L) and high systolic BP (>130 mmHg), and high diastolic BP (>80 mmHg) were explored for all patients, users and non-users of antihypertensive drugs (AHD). Adjustments were performed for age, sex, diabetes-related variables, p-creatinine, smoking, physical inactivity, depression and medication. RESULTS The prevalence of high MSC differed between patients with high and low systolic BP in all 196 patients: 39 vs 13% (P = 0.001); in 60 users of AHD: 37 vs 12% (P = 0.039), and in 136 non-users of AHD: 43 vs 13% (P = 0.012). Significant associations with high systolic BP were for all patients: physical inactivity (adjusted odds ratio (AOR) 6.5), high MSC (AOR 3.9), abdominal obesity (AOR 3.7), AHD (AOR 2.9), age (per year) (AOR 1.07), and p-creatinine (per µmol/L) (AOR 1.03); for 60 users of AHD: high MSC (AOR 4.1) and age (per year) (AOR 1.11); for 136 non-users of AHD: abdominal obesity (AOR 27.4), physical inactivity (AOR 14.7), male sex (AOR 9.0), smoking (AOR 7.9), and age (per year) (AOR 1.08). High MSC was not associated with high DBP. CONCLUSIONS In adult patients with T1D, high systolic BP was associated with physical inactivity, high MSC secretion, abdominal obesity, p-creatinine, age, and AHD, the latter indicating treatment failure.
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Affiliation(s)
- Eva Olga Melin
- Diabetes Research Laboratory, Lund University, Lund, Sweden
- Department of Research and Development, Region Kronoberg, Växjö, Sweden
- Correspondence should be addressed to E O Melin:
| | - Magnus Hillman
- Diabetes Research Laboratory, Lund University, Lund, Sweden
| | - Mona Landin-Olsson
- Diabetes Research Laboratory, Lund University, Lund, Sweden
- Department of Endocrinology, Skane University Hospital, Lund, Sweden
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15
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Ceccato F, Marcelli G, Martino M, Concettoni C, Brugia M, Trementino L, Michetti G, Arnaldi G. The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study. J Endocrinol Invest 2019; 42:327-335. [PMID: 29987756 DOI: 10.1007/s40618-018-0921-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 06/26/2018] [Indexed: 11/25/2022]
Abstract
INTRODUCTION AND AIM A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.
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Affiliation(s)
- F Ceccato
- Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile, 105, 35128, Padua, PD, Italy.
| | - G Marcelli
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
| | - M Martino
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
| | - C Concettoni
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
| | - M Brugia
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
| | - L Trementino
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
| | - G Michetti
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
| | - G Arnaldi
- Division of Endocrinology, Department of Clinical and Molecular Sciences (DISCLIMO), Umberto I Hospital, Polytechnic University of Marche, Via Tronto 10B, 60020, Torrette, AN, Italy
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16
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Yilmaz N, Tazegul G, Bozoglan H, Sari R, Ozdem S, Altunbas HA, Balci MK. Diagnostic value of the late-night salivary cortisol in the diagnosis of clinical and subclinical Cushing's syndrome: results of a single-center 7-year experience. J Investig Med 2019; 67:28-33. [PMID: 30030305 DOI: 10.1136/jim-2018-000752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 06/05/2018] [Accepted: 06/13/2018] [Indexed: 11/04/2022]
Abstract
Late-night salivary cortisol (LNSaC) is an easy-to-use test reflecting the free cortisol level in the serum and does not require hospitalization. Controlled studies reported that LNSaC has a high sensitivity and specificity, but have not set a clearly defined cut-off value to be used in the diagnosis of Cushing's syndrome. In this study, we aimed to evaluate the diagnostic performance of LNSaC in patients with clinical Cushing's syndrome (CCS) and subclinical Cushing's syndrome (SCS). The data of 543 patients, whose LNSaC levels were assessed using electrochemiluminescence immunoassay method, were retrospectively evaluated. The study included a total of 324 patients: 58 patients with CCS, 53 patients with SCS, and 213 patients without Cushing's syndrome (NoCS). The cause of the Cushing's syndrome was hypophyseal in 26 patients (45%), adrenal in 24 patients (41%), and ectopic in 8 patients (14%) in the CCS group. Median LNSaC levels were 0.724 (0.107-33) µg/dL in CCS group, 0.398 (0.16-1.02) µg/dL in SCS group, and 0.18 (0.043-0.481) µg/dL in NoCS group (p=0.001). Accordingly, LNSaC had 89.6% sensitivity and 81.6% specificity at a cut-off value of 0.288 µg/dL in the diagnosis of CCS; and had 80.7% sensitivity and 85.1% specificity at a cut-off value of 0.273 µg/dL in the diagnosis of SCS. In the present study, a lower sensitivity and specificity than previously reported was found for LNSaC in the diagnosis of CCS. Moreover, the diagnostic performance of LNSaC in patients with SCS was close to its diagnostic performance in patients with CCS. Each center should determine its own cut-off value based on the method adopted for LNSaC measurement, and apply that cut-off value in the diagnosis of Cushing's syndrome.
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Affiliation(s)
- Nusret Yilmaz
- Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Gokhan Tazegul
- Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Humeyra Bozoglan
- Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Ramazan Sari
- Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Sebahat Ozdem
- Biochemistry, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Hasan Ali Altunbas
- Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Mustafa Kemal Balci
- Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Antalya, Turkey
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17
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Apilux A, Rengpipat S, Suwanjang W, Chailapakul O. Development of competitive lateral flow immunoassay coupled with silver enhancement for simple and sensitive salivary cortisol detection. EXCLI JOURNAL 2018; 17:1198-1209. [PMID: 30713483 PMCID: PMC6341426 DOI: 10.17179/excli2018-1824] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022]
Abstract
Cortisol is known as a stress biomarker. The measurement of cortisol levels is an early warning indicator for health conditions and diagnosis of stress-related diseases. Herein, a lateral flow immunoassay using a gold nanoparticle label with a silver enhancement system was developed for the simple, sensitive and rapid detection of cortisol. The developed assay was based on a competitive platform of which cortisol-BSA conjugate was immobilized at the test zone to compete with an analyte. The quantitative analysis was performed using gold nanoparticles (AuNPs) as signal labeling. Sequentially, the silver enhancement solution was applied in order to enhance the sensitivity of the assay with the results easily seen by the naked eye. Using this system, the limit of detection (LOD) was found to be 0.5 ng/mL with a 3.6 fold more sensitive detection than without the enhancement system (LOD = 1.8 ng/mL). The salivary cortisol analysis was in the range of 0.5-150 ng/mL (R2 = 0.9984), which is in the clinical acceptable range. For the semi-quantitative analysis, the intensity color of the results was analyzed using an image processing program. The proposed method was successfully applied to detect cortisol in saliva. In addition, the results from our method also complied with the ones of those obtained by using the commercial enzyme-linked immunosorbent assay (ELISA). This developed assay offers great promise for a non-invasive screening test of salivary cortisol.
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Affiliation(s)
- Amara Apilux
- Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, 999 Phutthamonthon 4 Road, Salaya, Nakhon Pathom 73170, Thailand
| | - Sirirat Rengpipat
- Department of Microbiology, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand
| | - Wilasinee Suwanjang
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, 999 Phutthamonthon 4 Road, Salaya, Nakhon Pathom 73170, Thailand
| | - Orawon Chailapakul
- Electrochemistry and Optical Spectroscopy Center of Excellence (EOSCE), Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand.,Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand
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18
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Aberle J, Schulze Zur Wiesch C, Flitsch J, Veigel J, Schön G, Jung R, Reining F, Lautenbach A, Rotermund R, Riedel N. Specificity of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay for Cushing's disease in an obese population. J Endocrinol Invest 2018; 41:1325-1331. [PMID: 29550934 DOI: 10.1007/s40618-018-0870-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 03/09/2018] [Indexed: 11/28/2022]
Abstract
PURPOSE Data about the specificity of late-night salivary cortisol (LNSC) in obese subjects are still conflicting. Therefore, with this study, we aimed to evaluate the specificity of LNSC measurement in an obese cohort with or without type 2 diabetes mellitus (T2DM) using an automated electrochemiluminescence immunoassay (ECLIA). METHODS A total number of 157 patients involving 40 healthy subjects (HS) with BMI < 25 kg/m2, 83 obese subjects (OS) with BMI ≥ 35 kg/m2, and 34 histopathologically proven Cushing's disease (CD) were included. All patients underwent LNSC testing. Salivary cortisol was measured at 11 p.m. for all groups using an ECLIA. Reference range was established using values of LNSCs of HS and ROC curves were used to determine diagnostic cutoffs. RESULTS In the HS group, mean LNSC was 4.7 nmol/l (SD ± 3.1), while the OS group had a mean value of 10.9 nmol/l (SD ± 7.5) and the CD group of 19.9 nmol/l (SD ± 15.4). All groups differed significantly (p < 0.001). The ROC analysis of CD against HS alone showed a sensitivity of 85.3% and a specificity of 87.5% with a cut-off value of 8.3 nmol/l. The ROC analysis between OS and CD showed a maximum sensitivity of 67.6% and specificity of 78.3% for a cut-off value of 12.3 nmol/l. Taken both (HS and OS) groups together against the CD group, ROC analysis showed a maximum sensitivity of 67.6% and specificity of 85.4% for a cut-off value of 12.3 nmol/l. No correlation was found between BMI, T2DM, and LNSC for all groups. CONCLUSIONS In our obese cohort, we found that LNSC assayed by ECLIA had a low specificity in the diagnosis of CD.
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Affiliation(s)
- J Aberle
- Department for Endocrinology and Diabetology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - C Schulze Zur Wiesch
- Department for Endocrinology and Diabetology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - J Flitsch
- Department for Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - J Veigel
- Department for Endocrinology and Diabetology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - G Schön
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - R Jung
- Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - F Reining
- Department for Endocrinology and Diabetology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - A Lautenbach
- Department for Endocrinology and Diabetology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - R Rotermund
- Department for Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - N Riedel
- Department for Endocrinology and Diabetology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
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19
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Gagnon N, Fréchette I, Mallet PL, Dubé J, Houde G, Fink GD. Establishment of reference intervals for the salivary cortisol circadian cycle, by electrochemiluminescence (ECLIA), in healthy adults. Clin Biochem 2018; 54:56-60. [DOI: 10.1016/j.clinbiochem.2018.02.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 02/16/2018] [Accepted: 02/17/2018] [Indexed: 10/18/2022]
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20
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Belaya ZE, Grebennikova TA, Melnichenko GA, Nikitin AG, Solodovnikov AG, Brovkina OI, Grigoriev AU, Rozhinskaya LY, Dedov II. Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans. Osteoporos Int 2018; 29:211-221. [PMID: 28980049 DOI: 10.1007/s00198-017-4241-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 09/21/2017] [Indexed: 12/13/2022]
Abstract
UNLABELLED Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts. INTRODUCTION The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing's disease (CD). METHODS Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture. RESULTS Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation. CONCLUSIONS An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.
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Affiliation(s)
- Z E Belaya
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036.
| | - T A Grebennikova
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - G A Melnichenko
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - A G Nikitin
- Federal Research and Clinical Center FMBA of Russia, Moscow, Russia
| | | | - O I Brovkina
- Federal Research and Clinical Center FMBA of Russia, Moscow, Russia
| | - A U Grigoriev
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - L Y Rozhinskaya
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - I I Dedov
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
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Brovkina OI, Belaya ZE, Grebennikova TA, Khodyrev DS, Grigoriev AJ, Khandaeva PM, Koshkin PA, Melnichenko GA, Nikitin AG. Expression of osteogenesis regulatory genes in the bone tissue of patients with acromegaly and endogenous hypercorticism. RUSS J GENET+ 2017. [DOI: 10.1134/s102279541707002x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Belaya ZE, Iljin AV, Melnichenko GA, Solodovnikov AG, Rozhinskaya LY, Dzeranova LK, Dedov II. Diagnostic performance of osteocalcin measurements in patients with endogenous Cushing's syndrome. BONEKEY REPORTS 2016; 5:815. [PMID: 27347399 DOI: 10.1038/bonekey.2016.42] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 04/17/2016] [Indexed: 11/09/2022]
Abstract
The aim of this study was to evaluate the diagnostic performance of osteocalcin (OC), as measured by automated electrochemiluminescence immunoassay (ECLIA), in identifying Cushing's syndrome (CS) in two separate populations: among obese and overweight subjects and among women of postmenopausal age with osteoporosis. Among the 106 referral patients with obesity, CS was confirmed in 42 cases. The patients of the referred population provided late-night salivary cortisol (LNSC), underwent low-dose dexamethasone suppression testing (DST) and were further evaluated until CS was pathologically confirmed. A threshold of OC-8.3 ng ml(-1) differentiated CS among obese and overweight subjects with a sensitivity of 73.8% (95% confidence interval (CI) 58.9-84.7) and a specificity of 96.9% (95% CI 89.3-99.1). The total area under the receiver operating characteristic curve (AUC) was 0.859 (95% CI 0.773-0.945), which was lower than LNSC or DST (P=0.01). In the retrospective portion of the study, the OC levels were evaluated in 67 subjects with newly diagnosed postmenopausal osteoporosis and in 23 patients (older than 45) with newly diagnosed CS and osteoporosis (presence of low traumatic fractures or T-score P-2.5). The diagnostic performance of OC for osteoporosis due to CS was within an AUC of 0.959 (95% CI 0.887-1.00). A threshold for OC of 8.3 ng ml-1 yielded a sensitivity of 95.4% (95% CI 78.2-99.2%) and a specificity of 98.5% (95% CI 92.0-99.7%). Thus, osteocalcin could be used in the diagnostic testing for endogenous hypercortisolism in patients referred to exclude CS and to identify CS among patients of postmenopausal age with osteoporosis.
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Affiliation(s)
- Zhanna E Belaya
- Department of Preventative and Family Medicine, Neuroendocrinology and Bone Disease, The National Research Centre for Endocrinology , Moscow, Russia
| | - Alexander V Iljin
- Department of Preventative and Family Medicine, Neuroendocrinology and Bone Disease, The National Research Centre for Endocrinology , Moscow, Russia
| | - Galina A Melnichenko
- Department of Preventative and Family Medicine, Neuroendocrinology and Bone Disease, The National Research Centre for Endocrinology , Moscow, Russia
| | - Alexander G Solodovnikov
- Department of Preventative and Family Medicine, Ural State Medical University , Ekaterinburg, Russia
| | - Liudmila Y Rozhinskaya
- Department of Preventative and Family Medicine, Neuroendocrinology and Bone Disease, The National Research Centre for Endocrinology , Moscow, Russia
| | - Larisa K Dzeranova
- Department of Preventative and Family Medicine, Neuroendocrinology and Bone Disease, The National Research Centre for Endocrinology , Moscow, Russia
| | - Ivan I Dedov
- Department of Preventative and Family Medicine, Neuroendocrinology and Bone Disease, The National Research Centre for Endocrinology , Moscow, Russia
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Machado MC, Fragoso MCBV, Moreira AC, Boguszewski CL, Vieira L, Naves LA, Vilar L, de Araújo LA, Czepielewski MA, Gadelha MR, Musolino NRC, Miranda PAC, Bronstein MD, Ribeiro-Oliveira A. Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing's disease in Brazil. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2016; 60:267-86. [PMID: 27355856 PMCID: PMC10522300 DOI: 10.1590/2359-3997000000174] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 03/10/2016] [Indexed: 11/22/2022]
Abstract
Although it is a rare condition, the accurate diagnosis and treatment of Cushing's disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing's syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing's syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing's disease, recommending follow-up of these patients at experienced referral centers. Arch Endocrinol Metab. 2016;60(3):267-86.
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Affiliation(s)
- Márcio Carlos Machado
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilUnidade de Neuroendocrinologia, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP); Departamento de Endocrinologia, A.C. Camargo Cancer Center, São Paulo, SP, Brasil;
| | - Maria Candida Barisson Vilares Fragoso
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilUnidade de Neuroendocrinologia, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP); Departamento de Endocrinologia, A.C. Camargo Cancer Center, São Paulo, SP, Brasil;
| | - Ayrton Custódio Moreira
- Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoSPBrasilDivisão de Endocrinologia e Metabologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brasil;
| | - César Luiz Boguszewski
- Serviço de Endocrinologia e MetabologiaHospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrasilServiço de Endocrinologia e Metabologia (SEMPR), Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil;
| | - Leonardo Vieira
- Serviço de EndocrinologiaHospital Universitário Clementino Fraga FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroRJBrasilServiço de Endocrinologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro (HUCFF/UFRJ), Rio de Janeiro, RJ, Brasil;
| | - Luciana A. Naves
- Serviço de EndocrinologiaHospital Universitário de BrasíliaUniversidade de BrasíliaBrasíliaDFBrasilServiço de Endocrinologia, Hospital Universitário de Brasília, Universidade de Brasília (UnB), Brasília, DF, Brasil;
| | - Lucio Vilar
- Serviço de EndocrinologiaHospital de ClínicasUniversidade Federal de PernambucoRecifePEBrasilServiço de Endocrinologia, Hospital de Clínicas, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brasil;
| | | | - Mauro A. Czepielewski
- Hospital de Clínicas de Porto AlegreFaculdade de MedicinaUniversidade Federal do Rio Grande do SulPorto AlegreRSBrasilServiço de Endocrinologia, Hospital de Clínicas de Porto Alegre (HCPA), Faculdade de Medicina da Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil;
| | - Monica R. Gadelha
- Serviço de EndocrinologiaHospital Universitário Clementino Fraga FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroRJBrasilServiço de Endocrinologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro (HUCFF/UFRJ), Rio de Janeiro, RJ, Brasil;
| | - Nina Rosa Castro Musolino
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilUnidade de Neuroendocrinologia, Divisão de Neurocirurgia Funcional, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP;Brasil
| | - Paulo Augusto C Miranda
- Serviço de EndocrinologiaSanta Casa de Belo HorizonteBelo HorizonteMGBrasilServiço de Endocrinologia, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil;
| | - Marcello Delano Bronstein
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilUnidade de Neuroendocrinologia, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP); Departamento de Endocrinologia, A.C. Camargo Cancer Center, São Paulo, SP, Brasil;
| | - Antônio Ribeiro-Oliveira
- Universidade Federal de Minas GeraisServiço de EndocrinologiaHospital de ClínicasBelo HorizonteMGBrasilServiço de Endocrinologia, Hospital de Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brasil
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24
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Saiegh L, Keren D, Rainis T, Sheikh-Ahmad M, Reut M, Nakhleh A, Wirsansky I, Chen-Konak L, Schiff E, Shechner C. Dexamethasone-suppressed corticotropin-releasing hormone stimulation test in morbid obese adults. Obes Res Clin Pract 2016; 10:275-82. [DOI: 10.1016/j.orcp.2015.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 07/11/2015] [Accepted: 07/13/2015] [Indexed: 12/25/2022]
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25
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Melin EO, Svensson R, Gustavsson SÅ, Winberg A, Denward-Olah E, Landin-Olsson M, Thulesius HO. Affect school and script analysis versus basic body awareness therapy in the treatment of psychological symptoms in patients with diabetes and high HbA1c concentrations: two study protocols for two randomized controlled trials. Trials 2016; 17:221. [PMID: 27121185 PMCID: PMC4848779 DOI: 10.1186/s13063-016-1347-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 04/18/2016] [Indexed: 11/25/2022] Open
Abstract
Background Depression is linked with alexithymia, anxiety, high HbA1c concentrations, disturbances of cortisol secretion, increased prevalence of diabetes complications and all-cause mortality. The psycho-educational method ‘affect school with script analysis’ and the mind-body therapy ‘basic body awareness treatment’ will be trialled in patients with diabetes, high HbA1c concentrations and psychological symptoms. The primary outcome measure is change in symptoms of depression. Secondary outcome measures are changes in HbA1c concentrations, midnight salivary cortisol concentration, symptoms of alexithymia, anxiety, self-image measures, use of antidepressants, incidence of diabetes complications and mortality. Methods Two studies will be performed. Study I is an open-labeled parallel-group study with a two-arm randomized controlled trial design. Patients are randomized to either affect school with script analysis or to basic body awareness treatment. According to power calculations, 64 persons are required in each intervention arm at the last follow-up session. Patients with type 1 or type 2 diabetes were recruited from one hospital diabetes outpatient clinic in 2009. The trial will be completed in 2016. Study II is a multicentre open-labeled parallel-group three-arm randomized controlled trial. Patients will be randomized to affect school with script analysis, to basic body awareness treatment, or to treatment as usual. Power calculations show that 70 persons are required in each arm at the last follow-up session. Patients with type 2 diabetes will be recruited from primary care. This study will start in 2016 and finish in 2023. For both studies, the inclusion criteria are: HbA1c concentration ≥62.5 mmol/mol; depression, alexithymia, anxiety or a negative self-image; age 18–59 years; and diabetes duration ≥1 year. The exclusion criteria are pregnancy, severe comorbidities, cognitive deficiencies or inadequate Swedish. Depression, anxiety, alexithymia and self-image are assessed using self-report instruments. HbA1c concentration, midnight salivary cortisol concentration, blood pressure, serum lipid concentrations and anthropometrics are measured. Data are collected from computerized medical records and the Swedish national diabetes and causes of death registers. Discussion Whether the “affect school with script analysis” will reduce psychological symptoms, increase emotional awareness and improve diabetes related factors will be tried, and compared to “basic body awareness treatment” and treatment as usual. Trial registration ClinicalTrials.gov: NCT01714986
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Affiliation(s)
- Eva O Melin
- Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden. .,Department of Research and Development, Region Kronoberg, Box 1223, SE-351 12, Växjö, Sweden. .,Primary Care, Region Kronoberg, Växjö, Sweden.
| | - Ralph Svensson
- Department of Psychology, Linnaeus University, Växjö, Sweden
| | | | | | | | - Mona Landin-Olsson
- Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden.,Department of Endocrinology, Lund University Hospital, Lund, Sweden
| | - Hans O Thulesius
- Department of Research and Development, Region Kronoberg, Box 1223, SE-351 12, Växjö, Sweden.,Primary Care, Region Kronoberg, Växjö, Sweden.,Department of Clinical Sciences, Family Medicine, Lund University, Malmoe, Sweden
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26
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Belaya ZE, Hans D, Rozhinskaya LY, Dragunova NV, Sasonova NI, Solodovnikov AG, Tsoriev TT, Dzeranova LK, Melnichenko GA, Dedov II. The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing's syndrome. Arch Osteoporos 2015; 10:44. [PMID: 26608406 DOI: 10.1007/s11657-015-0244-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/22/2015] [Indexed: 02/03/2023]
Abstract
UNLABELLED In a cohort study of 182 consecutive patients with active endogenous Cushing's syndrome, the only predictor of fracture occurrence after adjustment for age, gender bone mineral density (BMD) and trabecular bone score (TBS) was 24-h urinary free cortisol (24hUFC) levels with a threshold of 1472 nmol/24 h (odds ratio, 3.00 (95% confidence interval (CI), 1.52-5.92); p = 0.002). INTRODUCTION The aim was to estimate the risk factors for fracture in subjects with endogenous Cushing's syndrome (CS) and to evaluate the value of the TBS in these patients. METHODS All enrolled patients with CS (n = 182) were interviewed in relation to low-traumatic fractures and underwent lateral X-ray imaging from T4 to L5. BMD measurements were performed using a DXA Prodigy device (GEHC Lunar, Madison, Wisconsin, USA). The TBS was derived retrospectively from existing BMD scans, blinded to clinical outcome, using TBS iNsight software v2.1 (Medimaps, Merignac, France). Urinary free cortisol (24hUFC) was measured by immunochemiluminescence assay (reference range, 60-413 nmol/24 h). RESULTS Among enrolled patients with CS (149 females; 33 males; mean age, 37.8 years (95% confidence interval, 34.2-39.1); 24hUFC, 2370 nmol/24 h (2087-2632), fractures were confirmed in 81 (44.5%) patients, with 70 suffering from vertebral fractures, which were multiple in 53 cases; 24 patients reported non-vertebral fractures. The mean spine TBS was 1.207 (1.187-1.228), and TBS Z-score was -1.86 (-2.07 to -1.65); area under the curve (AUC) was used to predict fracture (mean spine TBS) = 0.548 (95% CI, 0.454-0.641)). In the final regression model, the only predictor of fracture occurrence was 24hUFC levels (p = 0.001), with an increase of 1.041 (95% CI, 1.019-1.063), calculated for every 100 nmol/24-h cortisol elevation (AUC (24hUFC) = 0.705 (95% CI, 0.629-0.782)). CONCLUSIONS Young patients with CS have a low TBS. However, the only predictor of low traumatic fracture is the severity of the disease itself, indicated by high 24hUFC levels.
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Affiliation(s)
- Zhanna E Belaya
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia.
| | - Didier Hans
- Center of Bone Diseases, Lausanne University Hospital, Lausanne, Switzerland
| | - Liudmila Y Rozhinskaya
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Natalia V Dragunova
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Natalia I Sasonova
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | | | - Timur T Tsoriev
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Larisa K Dzeranova
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Galina A Melnichenko
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Ivan I Dedov
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
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Hayes LD, Sculthorpe N, Herbert P, Baker JS, Hullin DA, Kilduff LP, Reed D, Spagna R, Grace FM. Salivary testosterone measurement does not identify biochemical hypogonadism in aging men: a ROC analysis. Endocrine 2015; 50:256-9. [PMID: 25542187 DOI: 10.1007/s12020-014-0516-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/17/2014] [Indexed: 10/24/2022]
Affiliation(s)
- Lawrence D Hayes
- School of Human Sciences, London Metropolitan University, Holloway Road, London, N7 8DB, UK,
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D’Aurizio F, Tozzoli R, Dorizzi RM, Brescia V, Esposito E, Fortunato A, Giovanella L, Guzzaloni G. La diagnostica di laboratorio delle malattie del surrene. Raccomandazioni pratiche per la sindrome di Cushing. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s13631-015-0088-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Melnichenko GA, Dedov II, Belaya ZE, Rozhinskaya LY, Vagapova GR, Volkova NI, Grigor’ev AY, Grineva EN, Marova EI, Mkrtumayn AM, Trunin YY, Cherebillo VY. Cushing’s disease: the clinical features, diagnostics, differential diagnostics, and methods of treatment. ACTA ACUST UNITED AC 2015. [DOI: 10.14341/probl201561255-77] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The present guidelines on diagnostics, differential diagnostics, and methods of treatment of Cushing’s disease have been developed by a group of Russian specialists.
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Gungunes A, Sahin M, Demirci T, Ucan B, Cakir E, Arslan MS, Unsal IO, Karbek B, Calıskan M, Ozbek M, Cakal E, Delibasi T. Cushing's syndrome in type 2 diabetes patients with poor glycemic control. Endocrine 2014; 47:895-900. [PMID: 24740545 DOI: 10.1007/s12020-014-0260-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 03/28/2014] [Indexed: 10/25/2022]
Abstract
Cushing's syndrome may be more frequent in some specific patient groups such as type 2 diabetes and obesity. The aim of this study was to investigate the prevalence of Cushing's syndrome in outpatients with type 2 diabetes with poor glycemic control despite at least 3-months insulin therapy. Outpatients with type 2 diabetes whose glycemic control is poor (Hb Alc value >7 %) despite receiving at least 3-months long insulin treatment (insulin alone or insulin with oral antidiabetics) were included. Patients with classic features of Cushing's syndrome were excluded. Overnight 1 mg dexamethasone suppression test (DST) was performed as a screening test. A total of 277 patients with type 2 diabetes whose glycemic control is poor (Hb Alc value >7 %) despite insulin therapy were included. Two of the 277 patients with type 2 diabetes were diagnosed with Cushing's syndrome (0.72 %). Hypertension was statistically more frequent in the patients with cortisol levels ≥1.8 μg/dL than the patients with cortisol levels <1.8 μg/dL after overnight 1 mg DST (p = 0.041). Statistically significant correlation was determined between cortisol levels after 1 mg DST and age, daily insulin dose (r = 0.266 and p < 0.001, r = 0.163 and p = 0.008, respectively). According to our findings, the prevalence of Cushing's syndrome among patients with type 2 diabetes with poor glycemic control despite insulin therapy is much higher than in the general population. The patients with type 2 diabetes with poor glycemic control despite at least three months of insulin therapy should be additionally tested for Cushing's syndrome if they have high dose insülin requirements.
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Affiliation(s)
- Askin Gungunes
- Department of Endocrinology and Metabolic Diseases, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey,
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Melin EO, Thunander M, Landin-Olsson M, Hillman M, Thulesius HO. Depression, smoking, physical inactivity and season independently associated with midnight salivary cortisol in type 1 diabetes. BMC Endocr Disord 2014; 14:75. [PMID: 25224993 PMCID: PMC4236572 DOI: 10.1186/1472-6823-14-75] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 09/05/2014] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Disturbances of the circadian rhythm of cortisol secretion are associated with depression, coronary calcification, and higher all-cause and cardiovascular mortality.The primary aim of this study was to test the associations between midnight salivary cortisol (MSC), depression and HbA1c, and control for behavioural, environmental and intra individual factors with possible impact on cortisol secretion, like smoking, physical inactivity, season, medication, diabetes duration, severe hypoglycemia episodes, age and gender in patients with type 1 diabetes. Secondary aims were to present MSC levels for a reference group of non-depressed type 1 diabetes patients with a healthy life style (physically active and non-smoking), and to explore seasonal variations. METHODS A cross-sectional population based study of 196 patients (54% men and 46% women) aged 18-59 years that participated in a randomized controlled trial targeting depression in type 1 diabetes. Depression was assessed by the Hospital Anxiety and Depression Scale-depression subscale. MSC, HbA1c, serum-lipids, blood pressure, waist circumference and data from medical records and the Swedish National Diabetes Registry were collected. RESULTS Thirty four patients (17%) had MSC ≥9.3 nmol/L, which was associated with smoking (AOR 5.5), spring season (AOR 4.3), physical inactivity (AOR 3.9), self-reported depression (AOR 3.1), and older age (per year) (AOR 1.08). HbA1c >70 mmol/mol (>8.6%) (AOR 4.2) and MSC ≥9.3 nmol/L (AOR 4.4) were independently linked to self-reported depression. Season was strongly associated with MSC levels and no other variables studied showed seasonal variations. In a reference group of 137 non-depressed patients with a healthy life style (physically active, non-smoking) the median MSC level was 4.6 nmol/L (range 1.9-23.0). CONCLUSIONS In this study of patients with type 1 diabetes high MSC was linked to smoking, physical inactivity, depression, season and older age. Thus a high cortisol value identified three major targets for treatment in type 1 diabetes.
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Affiliation(s)
- Eva O Melin
- Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden
- Primary Care, Kronoberg County Council, Växjö, Sweden
- Department of Research and Development, Kronoberg County Council, Växjö, Sweden
- Box 1223, 351 12 Växjö, Sweden
| | - Maria Thunander
- Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden
- Department of Research and Development, Kronoberg County Council, Växjö, Sweden
- Department of Internal Medicine, Central Hospital, Kronoberg County Council, Växjö, Sweden
| | - Mona Landin-Olsson
- Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden
- Department of Internal Medicine, Lund University Hospital, Lund, Sweden
| | - Magnus Hillman
- Department of Clinical Sciences, Endocrinology and Diabetes, Lund University, Lund, Sweden
| | - Hans O Thulesius
- Primary Care, Kronoberg County Council, Växjö, Sweden
- Department of Research and Development, Kronoberg County Council, Växjö, Sweden
- Department of Clinical Sciences, Family Medicine, Lund University, Malmö, Sweden
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Tirabassi G, Boscaro M, Arnaldi G. Harmful effects of functional hypercortisolism: a working hypothesis. Endocrine 2014; 46:370-86. [PMID: 24282037 DOI: 10.1007/s12020-013-0112-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 10/31/2013] [Indexed: 01/15/2023]
Abstract
Functional hypercortisolism (FH) is caused by conditions able to chronically activate hypothalamic-pituitary-adrenal axis and usually occurs in cases of major depression, anorexia nervosa, bulimia nervosa, alcoholism, diabetes mellitus, simple obesity, polycystic ovary syndrome, obstructive sleep apnea syndrome, panic disorder, generalized anxiety disorder, shift work, and end-stage renal disease. Most of these states belong to pseudo-Cushing disease, a condition which is difficult to distinguish from Cushing's syndrome and characterized not only by biochemical findings but also by objective ones that can be attributed to hypercortisolism (e.g., striae rubrae, central obesity, skin atrophy, easy bruising, etc.). This hormonal imbalance, although reversible and generally mild, could mediate some systemic complications, mainly but not only of a metabolic/cardiovascular nature, which are present in these states and are largely the same as those present in Cushing's syndrome. In this review we aim to discuss the evidence suggesting the emerging negative role for FH.
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Affiliation(s)
- Giacomo Tirabassi
- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, Polytechnic University of Marche, Ancona, Italy
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Tarantino G, Finelli C. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease. World J Gastroenterol 2013; 19:6735-6743. [PMID: 24187449 PMCID: PMC3812473 DOI: 10.3748/wjg.v19.i40.6735] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 09/10/2013] [Accepted: 09/16/2013] [Indexed: 02/06/2023] Open
Abstract
Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing's syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing's syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing's syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing's syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.
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Kaushik A, Vasudev A, Arya SK, Pasha SK, Bhansali S. Recent advances in cortisol sensing technologies for point-of-care application. Biosens Bioelectron 2013; 53:499-512. [PMID: 24212052 DOI: 10.1016/j.bios.2013.09.060] [Citation(s) in RCA: 176] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/14/2013] [Accepted: 09/17/2013] [Indexed: 10/26/2022]
Abstract
Everyday lifestyle related issues are the main cause of psychological stress, which contributes to health disparities experienced by individuals. Prolonged exposure to stress leads to the activation of signaling pathways from the brain that leads to release of cortisol from the adrenal cortex. Various biomarkers have been affected by psychological stress, but cortisol "a steroid hormone" is known as a potential biomarker for its estimation. Cortisol can also be used as a target analyte marker to determine the effect of exposure such as organophosphates on central nervous system, which alters the endocrine system, leading to imbalance in cortisol secretion. Cortisol secretion of individuals depends on day-night cycle and field environment hence its detection at point-of-care (POC) is deemed essential to provide personalized healthcare. Chromatographic techniques have been traditionally used to detect cortisol. The issues relating to assay formation, system complexity, and multistep extraction/purification limits its application in the field. In order to overcome these issues and to make portable and effective miniaturized platform, various immunoassays sensing strategies are being explored. However, electrochemical immunosensing of cortisol is considered as a recent advancement towards POC application. Highly sensitive, label-free and selective cortisol immunosensor based on microelectrodes are being integrated with the microfluidic system for automated diurnal cortisol monitoring useful for personalized healthcare. Although the reported sensing devices for cortisol detection may have a great scope to improve portability, electronic designing, performance of the integrated sensor, data safety and lifetime for point-of-care applications, This review is an attempt to describe the various cortisol sensing platforms and their potential to be integrated into a wearable system for online and continuous monitoring of cortisol rhythm at POC as a function of one's environment.
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Affiliation(s)
- Ajeet Kaushik
- Bio-MEMS and Microsystems Laboratory, Department of Electrical and Computer Engineering, Florida International University, Miami, FL 33174, United States.
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Raff H. Update on late-night salivary cortisol for the diagnosis of Cushing's syndrome: methodological considerations. Endocrine 2013; 44:346-9. [PMID: 23839587 DOI: 10.1007/s12020-013-0013-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 07/02/2013] [Indexed: 12/21/2022]
Abstract
Late-night salivary cortisol (LNSC) is now considered the best approach to screen patients suspected of having endogenous hypercortisolism (Cushing's syndrome). As the use of LNSC increases, new preanalytic and analytic issues have arisen. The routine immunoassay for salivary cortisol seems to have better diagnostic performance than liquid chromatograph/tandem mass spectrometry, although measurement of normal salivary cortisone concentrations with the latter technique is very useful in identifying samples contaminated with topical hydrocortisone. LNSC is very useful in screening for Cushing's syndrome in women with increased corticosteroid-binding globulin resulting from estrogen therapy or pregnancy. Two LNSCs from each patient is recommended for routine screening, although one adequate saliva sample seems to perform well. The overnight dexamethasone suppression test remains superior to LNSC in the evaluation of potential subclinical hypercortisolism in patients with adrenal incidentalomas. Periodic assessment of LNSC is extremely useful in monitoring patients for recurrence of Cushing's disease after pituitary surgery. With the large increase in the number LNSCs being ordered around the world, it is likely that more preanalytic and analytic issues will arise, which laboratorians and clinical chemists will need to resolve.
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Affiliation(s)
- Hershel Raff
- Endocrine Research Laboratory, Department of Endocrinology, Aurora St. Luke's Medical Center, Aurora Research Foundation, 2801 W KK River Pky Suite 245, Milwaukee, WI, 53215, USA,
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Belaya ZE, Rozhinskaya LY, Melnichenko GA, Solodovnikov AG, Dragunova NV, Iljin AV, Dzeranova LK, Dedov II. Serum extracellular secreted antagonists of the canonical Wnt/β-catenin signaling pathway in patients with Cushing's syndrome. Osteoporos Int 2013; 24:2191-9. [PMID: 23358608 DOI: 10.1007/s00198-013-2268-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 01/07/2013] [Indexed: 10/27/2022]
Abstract
UNLABELLED Patients with endogenous hypercortisolism have higher sclerostin, but do not differ in Dickkopf 1 (Dkk1) or secreted frizzled-related protein 1 (SFRP1) levels as compared to healthy control. INTRODUCTION Endogenous Cushing's syndrome (CS), usually affecting young and otherwise healthy patients, is a good model to validate the effects of supraphysiological levels of glucocorticoids in humans. This study evaluates circulating levels of extracellular antagonists of the Wnt/β-catenin signaling pathway (sclerostin, Dkk1, SFRP1) in patients with CS versus healthy individuals. METHODS Forty patients with clinically and biochemically evident CS and 40 sex-, age-, and body mass index-matched healthy subjects provided fasting serum samples for sclerostin, SFRP1 and Dkk1, along with bone turnover markers. RESULTS Patients with CS had higher sclerostin levels (34.5 (30.3-37.1) pmol/L) versus healthy individuals (29.9 (24.3-36.8) pmol/L) (p = 0.032). Differences in sclerostin were due to the lack of lower sclerostin values rather than an increase in protein levels above the upper limits of the healthy control. The odds of sclerostin levels being higher than 30 pmol/L were greater in patients with CS as compared with the odds in healthy subjects (odds ratio = 3.81 95 % confidence interval 1.45-10.02) (p = 0.01). It coexisted with suppressed bone formation and unchanged bone resorption markers. Dkk1, SFRP1 did not differ from the control group. CONCLUSIONS Of all the tested proteins (sclerostin, Dkk1, SFRP1), only sclerostin showed a significant difference when contrasting CS with healthy subjects. Hypercortisolism might prevent the down-regulation of sclerostin. Targeting sclerostin seems to be a promising therapeutic approach to treating osteoporosis in patients with CS.
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Affiliation(s)
- Z E Belaya
- The National Research Center for Endocrinology, ul. Dmitria Uljanova, 11, Moscow 117036, Russia.
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Iacovazzo D, Bianchi A, Lugli F, Milardi D, Giampietro A, Lucci-Cordisco E, Doglietto F, Lauriola L, De Marinis L. Double pituitary adenomas. Endocrine 2013; 43:452-7. [PMID: 23325364 DOI: 10.1007/s12020-013-9876-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 01/07/2013] [Indexed: 10/27/2022]
Abstract
Double pituitary adenomas represent up to 2.6 % of pituitary adenomas in large surgical series and up to 3.3 % of patients with Cushing's disease have been found to have double or multiple pituitary adenomas. We report the case of a 60-year-old male patient whose medical history began in 2002 with erectile dysfunction; hyperprolactinemia was found and MRI showed a 6-mm area of delayed enhancement in the lateral portion of the right pituitary lobe. Treatment with cabergoline was started with normalization of prolactin levels; the following MRI, performed in 2005 and 2008, showed shrinkage of the pituitary lesion. In 2005, the patient began to manifest weight gain, hypertension, and facial plethora, but no further evaluations were done. In January 2010, the patient came to our attention and underwent multiple tests that suggested Cushing's disease. A new MRI was negative. Bilateral inferior petrosal sinus sampling showed significant pituitary-to-peripheral ratio and, in May 2010, the patient underwent exploratory pituitary surgery with evidence of a 1-2-mm white-coloured midline area compatible with pituitary adenoma that was surgically removed. Post-operatively, the patient's clinical conditions improved with onset of secondary hypoadrenalism. The histologic examination confirmed a pituitary adenoma (immunostaining was found to be positive for ACTH and negative for prolactin). We report the case of an ACTH-producing microadenoma metachronous to a prolactin secreting microadenoma although not confirmed histologically, shrunk by medical treatment. A review of data in the literature regarding double or multiple pituitary adenomas has also been done.
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Affiliation(s)
- D Iacovazzo
- Department of Endocrinology, Catholic University, Policlinico A. Gemelli, Largo A. Gemelli, 8, 00168, Rome, Italy.
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Doi SAR, Clark J, Russell AW. Concordance of the late night salivary cortisol in patients with Cushing's syndrome and elevated urine-free cortisol. Endocrine 2013; 43:327-33. [PMID: 23238876 DOI: 10.1007/s12020-012-9855-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 12/03/2012] [Indexed: 11/29/2022]
Abstract
The concordance of the late night salivary cortisol (LNSC) results with the 24-h urine-free cortisol (UFC) results in the biochemical screening for Cushing's syndrome is unknown. We investigated this in a population of Cushing's syndrome subjects. We used meta-analytic methods to pool proportions of LNSC-positive subjects from diagnostic evaluations of Cushing's syndrome subjects where both tests were performed and the UFC was elevated (any level). Cushing's syndrome was confirmed in all subjects by two out of three conventional tests. LNSC was collected between 22:00 to 24:00 h and measured around the same time period as the UFC. Minimum cutoffs of ≥4 and ≥10 nmol/L were used to determine concordance with the UFC and studies were limited to those that used radioimmunoassays or electrochemiluminiscence immunoassays for LNSC. The concordance of LNSC ≥4 nmol/L was 97 % (95 % CI 95-99 %) and studies were homogeneous. With LNSC ≥10 nmol/L, there was heterogeneity and two groups were discernible with a pooled concordance of 69 % (95 % CI 60-77 %) and 95 % (95 % CI 92-97 %). Within these sub-groups, studies were homogeneous and there was no difference between them in collection methods, assays used, geographic location, year of publication, or the quality of the underlying studies. The LNSC at a very specific cutoff detects at best 95 % of cases and at worst 69 % of cases of Cushing's syndrome that are UFC positive. The two tests become equivalent at the more sensitive cutoff (>4 nmol/L). We conclude that, given its many benefits and the currently documented equivalence to the UFC, the LNSC should replace the conventional 24-h UFC as the frontline test when screening for Cushing's syndrome.
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Affiliation(s)
- Suhail A R Doi
- School of Population Health, University of Queensland, Brisbane, QLD, Australia.
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Caprirolo G, Ghanayem NS, Murkowski K, Nugent ML, Simpson PM, Raff H. Circadian rhythm of salivary cortisol in infants with congenital heart disease. Endocrine 2013; 43:214-8. [PMID: 22976914 PMCID: PMC4545231 DOI: 10.1007/s12020-012-9791-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 09/03/2012] [Indexed: 10/27/2022]
Abstract
Children with congenital heart disease (CHD) have associated extracardiac co-morbidities at the time of surgery and during ongoing growth and development. Perioperative events include disrupted glucose homeostasis, capillary leak, and fluid retention. The hypothalamic-pituitary-adrenal (HPA) axis has an important role in homeostasis in that the secretion of cortisol contributes to the response to stress, glucose regulation, blood volume control, and immune regulation. We investigated the diurnal rhythm of the HPA axis in infants with CHD by measuring salivary cortisol in the morning (0600-0900 h-circadian peak) and evening (2100-2400 h-circadian nadir). Twenty-nine infants aged 12 weeks to 1 year were included: 16 with acyanotic disease (SpO₂ ≥ 90 %) and 13 with cyanotic disease (SpO2 < 90 %). Morning salivary cortisol was similar between the two groups [acyanotic 7.0 nmol/L (1.8-23.1); cyanotic 9.7 nmol/L (0.9-15.6); p = 0.68]. Evening salivary cortisol was similar between the two groups [acyanotic 0.9 nmol/L (0.2-8.5); cyanotic 1.4 nmol/L (0.5-14.9); p = 0.32]. Both cyanotic and acyanotic groups demonstrated an intact diurnal rhythm. In conclusion, chronic hypoxia secondary to cyanotic CHD does not affect the circadian rhythm of the HPA axis. By 12 weeks of age, infants with hypoxia secondary to cyanotic CHD have a normal cortisol diurnal rhythm.
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Affiliation(s)
- Giovanna Caprirolo
- Division of Pediatric Critical Care, Medical College of Wisconsin, 9000 W. Wisconsin Avenue, Milwaukee, WI 53226, USA.
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Mizoguchi Y, Sakami A, Imamura Y, Tsuruta T, Egami M, Yamada S. The effect of oral presentation on salivary 3-methoxy-4-hydroxy-phenylglycol (MHPG) and cortisol concentrations in training doctors: a preliminary study. Endocrine 2012; 42:752-3. [PMID: 22531863 DOI: 10.1007/s12020-012-9673-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Belaya ZE, Melnichenko GA. Practical evaluation of late-night salivary cortisol: a real-life approach. Endocrine 2012; 42:222-3; author reply 224-5. [PMID: 22644839 DOI: 10.1007/s12020-012-9709-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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