Strategies for the Characterization of Disorders in Cortisol Sensitivity
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CONTEXT: The clinical presentation of abnormalities in glucocorticoid (GC) sensitivity is diverse, and therefore it is difficult to diagnose this condition. OBJECTIVE AND DESIGN: The objective of the study was to develop strategies for the characterization of GC sensitivity disorders. SETTING: The study was conducted in an outpatient clinic. PATIENTS: Nine patients with GC sensitivity disorders participated. INTERVENTIONS: Sequence analysis of the GC receptor (GR), determination of GR number per cell, GR ligand-binding affinity, and GR splice regulation were performed in freshly prepared peripheral blood mononuclear lymphocytes and Epstein-Barr virus-transformed lymphoblasts. Cellular GC sensitivity was determined ex vivo by measuring the effect of dexamethasone on GC-induced leucine-zipper and IL-2 mRNA levels and on cell proliferation. RESULTS: Differences in GR number per cell, GR affinity, GR splice variants, and effects on transactivation or transrepression of GC-sensitive genes were observed between patients and controls. Epstein-Barr virus transformation of lymphoblasts had no influence on GR affinity but increased the GR number 5-fold in healthy controls. In patients diagnosed as cortisol resistant, however, GR number after transformation was increased significantly less than 5-fold, whereas a higher GR number was observed in a patient suspected of cortisol hypersensitivity. CONCLUSION: This study illustrates several strategies to define abnormalities in GC sensitivity by describing nine patients with affected GC sensitivity, all with a unique clinical course and background.
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An ultra-low-dose dexamethasone suppression test showing suppressed morning serum cortisol levels is indicative of increased glucocorticoid sensitivity.
“An ultra-low-dose DST showing suppressed morning serum cortisol levels is also indicative of this rare condition, and functional testing of the glucocorticoid receptor or sequencing of the glucocorticoid receptor gene may be considered in specialized centers (31, 49, 50).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [49]
In rare increased glucocorticoid sensitivity, a clinical picture of Cushing syndrome is present, but laboratory tests show (borderline) low plasma and urinary cortisol values while responsiveness to ACTH (Cortrosyn) or metyrapone stimulation test and/or insulin-induced hypoglycemia is normal.
“In the rare condition of increased glucocorticoid sensitivity, a clinical picture of CS is present, but laboratory tests show (borderline) low plasma and urinary cortisol values while responsiveness to ACTH (Cortrosyn) or metyrapone stimulation test and/or insulin-induced hypoglycemia is normal (31, 49).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [49]
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References 34 · Cited by 43
- Authors
- Russcher, H., Smit, P., van Rossum, E. F. C., van den Akker, E. L. T., Brinkmann, A. O., de Heide, L. J. M., de Jong, F. H., Koper, J. W., & Lamberts, S. W. J.
- Affiliations
- Erasmus MC (NL)
- Corresponding author
- Koper, Jan W.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2006-02
- Volume
- 91
- Issue
- 2
- Pages
- 694-701
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2082853307
- Cited by
- 43
- References
- 34
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- glucocorticoid receptor, cortisol resistance, dexamethasone, IL-2 mRNA, transcriptional activation, transrepression, cell proliferation
- MeSH terms
- Adolescent, Adrenal Cortex Diseases, Adult, B-Lymphocytes, Cell Line, Transformed, Cell Transformation, Viral, DNA, Female, Glucocorticoids, Humans, Hydrocortisone, Male, Receptors, Glucocorticoid, Sequence Analysis, DNA, Gene Dosage, Polymorphism, Single Nucleotide
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