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      Recent Updates on the Diagnosis and Management of Cushing's Syndrome

      review-article
      Endocrinology and Metabolism
      Korean Endocrine Society
      Cushing syndrome, Hydrocortisone, Adrenocorticotropic hormone

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          Abstract

          Cushing's syndrome, a potentially lethal disorder characterized by endogenous hypercortisolism, may be difficult to recognize, especially when it is mild and the presenting features are common in the general population. However, there is a need to identify the condition at an early stage, as it tends to progress, accruing additional morbidity and increasing mortality rates. Once a clinical suspicion is raised, screening tests involve timed measurement of urine, serum or salivary cortisol at baseline or after administration of dexamethasone, 1 mg. Each test has caveats, so that the choice of tests must be individualized for each patient. Once the diagnosis is established, and the cause is determined, surgical resection of abnormal tumor/tissue is the optimal treatment. When this cannot be achieved, medical treatment (or bilateral adrenalectomy) must be used to normalize cortisol production. Recent updates in screening for and treating Cushing's syndrome are reviewed here.

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          Most cited references37

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          Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.

          The objective is to formulate clinical practice guidelines for treating Cushing's syndrome.
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            A 12-month phase 3 study of pasireotide in Cushing's disease.

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

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

                Author and article information

                Journal
                Endocrinol Metab (Seoul)
                Endocrinol Metab (Seoul)
                ENM
                Endocrinology and Metabolism
                Korean Endocrine Society
                2093-596X
                2093-5978
                June 2018
                21 June 2018
                : 33
                : 2
                : 139-146
                Affiliations
                Diabetes, Endocrine and Obesity Branch, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA.
                Author notes
                Corresponding author: Lynnette K. Nieman. Diabetes, Endocrine and Obesity Branch, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Building 10, CRC, 1 East, Rm 1-3140, 10 Center Dr, MSC 1109, Bethesda, MD 20892-1109, USA. Tel: +1-301-496-8935, Fax: +1-301-402-0884, NiemanL@ 123456nih.gov
                Author information
                https://orcid.org/0000-0003-0534-8025
                Article
                10.3803/EnM.2018.33.2.139
                6021313
                29947171
                ba8625c0-687a-4b17-89b8-df83bfa7a83d
                Copyright © 2018 Korean Endocrine Society

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 April 2018
                : 23 April 2018
                : 16 May 2018
                Funding
                Funded by: National Institutes of Health, CrossRef http://dx.doi.org/10.13039/100000002;
                Categories
                Review Article

                cushing syndrome,hydrocortisone,adrenocorticotropic hormone

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