Glucocorticoid Receptor Mutations and Hypersensitivity to Endogenous and Exogenous Glucocorticoids
Open accessAbstract
Background: The glucocorticoid receptor (GR) consists of two alternatively spliced isoforms: GRα, which activates gene transcription, and GRβ, a dominant-negative receptor. Theoretically, inactivating variants of GRβ could result in glucocorticoid hypersensitivity. Design: A 46-year-old woman presented for evaluation of adrenal insufficiency prompted by low plasma cortisol levels and multiple unexplained symptoms but without clinical evidence of glucocorticoid insufficiency. To explain these findings, extensive clinical, genetic, and molecular studies were performed. Methods: Standard clinical methods assessed the patient's hypothalamic-pituitary-adrenal axis. Validated molecular techniques were used for receptor sequencing, stable transfections, stimulation of candidate genes, cDNA arrays, Ingenuity Pathway Analysis, volcano analysis, and isolation and analysis of the patient's mononuclear cells. Results: Clinical studies excluded primary or secondary adrenal insufficiency, established consistently low basal cortisol levels, and demonstrated hypersensitivity to ultra-low-dose dexamethasone. Receptor sequencing identified two variants of GR9β (A3669G and G3134T) as well as the known Bcl1 polymorphism. Reductionist studies using stable osteosarcoma cell lines transfected with the GRβ variants demonstrated glucocorticoid hypersensitivity of transcribed genes on cDNA array analysis. The patient's monocytes responded to hydrocortisone with exaggerated stimulation of the candidate genes GILZ and FKBP5. Conclusion: Two variants of the dominant-negative GRβ, in conjunction with a common Bcl1 intron variant, resulted in hypersensitivity to endogenous and exogenous glucocorticoids and, as a reflection of severity, low circulating cortisol levels without clinical evidence of glucocorticoid insufficiency. This prismatic case exemplifies the unique effects of variants of a dominant-negative receptor.
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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 [31]
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 [31]
Suspected unreported exogenous glucocorticoid administration can be detected with urinary or blood mass spectrometry assays designed to detect exogenous glucocorticoids.
“Suspected unreported exogenous glucocorticoid administration can be detected with urinary or blood mass spectrometry assays designed to detect exogenous glucocorticoids (31).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [31]
Cites
Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans
Bamberger, C. M., Bamberger, A. M., de Castro, M., & Chrousos, G. P. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117943 · Cited by 642 · see citing works
van Rossum, E. F. C. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.333 · Cited by 381 · see citing works
Clinical Features Associated with Glucocorticoid Receptor Polymorphisms: An Overview
Manenschijn, L., van den Akker, E. L. T., Lamberts, S. W. J., & van Rossum, E. F. C. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05013.x · Cited by 249 · see citing works
Charmandari, E., Kino, T., Ichijo, T., & Chrousos, G. P. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0040 · Cited by 201 · see citing works
Clinical aspects of glucocorticoid sensitivity
Lamberts, S. W. J., Huizenga, A. T. M., de Lange, P., de Jong, F. H., & Koper, J. W. (1996) · Steroids · doi:10.1016/0039-128x(96)00005-0 · Cited by 99 · see citing works
Westberry, J. M., Sadosky, P. W., Hubler, T. R., Gross, K. L., & Scammell, J. G. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.03.004 · Cited by 91 · see citing works
Jewell, C. M., & Cidlowski, J. A. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0642 · Cited by 60 · see citing works
Self-citationGross, K. L., Oakley, R. H., Scoltock, A. B., Jewell, C. M., & Cidlowski, J. A. (2011) · Molecular Endocrinology · doi:10.1210/me.2010-0051 · Cited by 56 · see citing works
Self-citationNicolaides, N. C., & Charmandari, E. (2017) · Hormones · doi:10.14310/horm.2002.1728 · Cited by 52 · see citing works
Moreira, R. P. P., Gomes, L. G., Mendonca, B. B., & Bachega, T. A. S. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044893 · Cited by 38 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Approach to the Patient: Diagnosis of Cushing Syndrome
Savas, M., Mehta, S., Agrawal, N., van Rossum, E. F. C., & Feelders, R. A. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac492 · Cited by 91 · see citing works
“Suspected unreported exogenous glucocorticoid administration can be detected with urinary or blood mass spectrometry assays designed to detect exogenous glucocorticoids (31).”
BackgroundChronic Stress and Headaches: The Role of the HPA Axis and Autonomic Nervous System
Sič, A., Bogicevic, M., Brezić, N., Nemr, C., & Knežević, N. N. (2025) · Biomedicines · doi:10.3390/biomedicines13020463 · Cited by 89 · see citing works
“This dysregulation of cortisol could increase susceptibility to stress-related conditions, including chronic headaches [68,69].”
Sevilla, L. M., Jiménez‐Panizo, A., Alegre‐Martí, A., Estébanez‐Perpiñá, E., Caelles, C., & Pérez, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221810049 · Cited by 72 · see citing works
“As functional characterization of the mutants has been thoroughly revised [5,12,23,67], it will not be discussed in detail in this chapter.”
BackgroundVariation in glucocorticoid sensitivity and the relation with obesity
Lengton, R., Iyer, A. M., van der Valk, E. S., Hoogeveen, E. K., Meijer, O. C., van der Voorn, B., & van Rossum, E. F. C. (2021) · Obesity Reviews · doi:10.1111/obr.13401 · Cited by 44 · see citing works
“The isoforms GR-P and GR-A miss large regions of the LBD and do not bind GCs.34 Little is known about GR-A, but GR-P was reported to increase the activity of GRα.”
BackgroundInfluentialRecognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome
Findling, J. W., & Raff, H. (2023) · Journal of the Endocrine Society · doi:10.1210/jendso/bvad087 · Cited by 30 · see citing works
“Finally, although extremely rare, there are reports of glucocorticoid receptor hypersensitivity in patients with low serum cortisol in whom the features of hypercortisolism appear when the patients receive exogenous glucocorticoids [87].”
BackgroundSelf-citationGeneralized and tissue specific glucocorticoid resistance
Martins, C. S., & de Castro, M. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111277 · Cited by 30 · see citing works
Jia, Y., Wang, Y., Wang, Z., Zhang, Z., Zhang, J., Zhang, J., Sun, K., Hua, Y., Chai, G., & Hu, F. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1370619 · Cited by 19 · see citing works
Kageyama, K., Iwasaki, Y., Watanuki, Y., Niioka, K., & Daimon, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115724 · Cited by 19 · see citing works
Paragliola, R. M., Costella, A., Corsello, A., Urbani, A., & Concolino, P. (2020) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-020-00480-9 · Cited by 15 · see citing works
Steroid-resistant nephrotic syndrome: pharmacogenetics and epigenetic points and views
Hejazian, S. M., Vahed, S. Z., Sani, H. M., Nariman-Saleh-Fam, Z., Bastami, M., Khatibi, S. M. H., Ardalan, M., & Samadi, N. (2019) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2020.1702877 · Cited by 9 · see citing works
“promoter polymorphism can lead to hypersensitivity to GCs [27].”
BackgroundDassonvalle, J., Díaz‐Castro, F., Donoso-Barraza, C., Sepúlveda, C., la Fuente, F. P.-D., Pino, P., Espinosa, A., Chiong, M., Llanos, M. N., & Troncoso, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207582 · Cited by 10 · see citing works
Foussier, L., Vitellius, G., Bouligand, J., Amazit, L., Bouvattier, C., Young, J., Trabado, S., & Lombès, M. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00028 · Cited by 7 · see citing works
“, the polymorphisms N363S, localized in the NTD (rs6195), and BclI (rs41423247), localized in the first intron of the NR3C1 gene] [8], the unique gain-offunction D401H mutation of the NTD [13] and a double mutant of the 30-UTR of exon 9b, coupled with a polymorphism (A3669G/G3134T and BclI) alleviating the dominant ne…”
BackgroundCardiometabolic Health in Adolescents and Young Adults with Congenital Adrenal Hyperplasia
Navardauskaitė, R., Semeniene, K., Šukys, M., Pridotkaite, A., Vanckavičienė, A., Žilaitienė, B., & Verkauskienė, R. (2022) · Medicina · doi:10.3390/medicina58040500 · Cited by 9 · see citing works
“CAH patients with the Bcl1 variant of the GC receptor gene—which increases the receptor’s activity—could have higher BMI, waist circumference, and systolic blood pressure [37], while GRα works oppositely and decreases GR activity, and could be related to a lower risk of development cardiometabolic complications, regar…”
BackgroundSong, T., Chang, H., Du, L., Yin, L., Shi, F., & Zhang, X. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04376-8 · Cited by 8 · see citing works
Chen, X., & He, H. (2025) · Hormone and Metabolic Research · doi:10.1055/a-2619-5035 · Cited by 6 · see citing works
“Two variants of GRβ (A3669G and G3134T), as well as the known Bcl1 polymor - phism, were found in a subject with GC hypersensitivity [17].”
Disparities in urban vegetation degradation and heat exposure during drought periods in U.S. cities
Yu, Y., Dong, C., Liu, Z., Lin, K., Chen, X., Huang, Z., AghaKouchak, A., & MacDonald, G. M. S. D. (2025) · npj Urban Sustainability · doi:10.1038/s42949-025-00319-4 · Cited by 2 · see citing works
“It is noteworthy that an increasing number of Americans have been relocating to the Sunbelt states since the 1950s 71 , drawn by the warmer climate in the southern regions than the north.”
Zhao, X., Xu, Z., Su, H., Zheng, R., Zhan, M., Huang, Y., & Su, Z. (2022) · BMC Pediatrics · doi:10.1186/s12887-022-03722-3 · Cited by 3 · see citing works
Genetic polymorphism and the link to stress-induced metabolic dysfunction
Mofolorunso, A. M., Awobajo, F. O., & Okwute, P. G. (2023) · Babcock University Medical Journal · doi:10.38029/babcockuniv.med.j..v6i2.311 · Cited by 1 · see citing works
“There were reports that factors such as genetic polymorphism determine the sensitivity of these receptors to corticosteroids (13, 14).”
BackgroundDexamethasone, cortisol and glucocorticoid receptor mutations.
Funder, J. (2019) · Journal of Hypertension · doi:10.1097/hjh.0000000000002066 · Cited by 1
“Classically, and in GRS, the mutation(s) blunt, or on occasion, abolish GR activation: very recently, a mutation in GRb, which differs from GRa in having a truncated C-terminus, was shown to underlie a ‘supersensitive’ GR, presumably in the absence of its normal inhibitory activity [6].”
BackgroundThe Adrenal Cortex and Its Disorders
Miller, W. L., Flück, C. E., Breault, D. T., & Feldman, B. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-62520-3.00014-2 · Cited by 14 · see citing works
Gao, Y., Mu, D., Ma, Y.-C., Li, Y., Li, M., Hu, Y.-Y., Qiu, L., Yu, S., & Cheng, X.-Q. (2025) · Endocrine Practice · doi:10.1016/j.eprac.2025.12.017
Brutvan, T., Kotasová, M., Krausová, A., Křížová, J., Psenicka, O., Ševčík, J., Ševčík, M., Vitkova, H., & Ježková, J. (2025) · Endocrine Connections · doi:10.1530/ec-25-0281
“…several factors, including variable gastrointestinal absorption of dexamethasone, impaired hepatic or renal function, individual variations in DXM metabolism, glucocorticoid receptor polymorphisms, drugs interfering with cytochrome P450 (CYP3A4) activity, or patient noncompliance (5, 6, 7, 8, 9).”
A patient with glucocorticoid hypersensitivity syndrome
Wu, C.-H., Ma, A., Sun, Q., & Zhao, X.-L. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000001977
“Bcl1 single-nucleotide polymorphism (homozygous) in theGR gene (NR3C1, rs41423247) was detected, which is an intronic mutation and is reported to be associated with hypersensitivity.([2]) But the frequency of hetero/homozygote variants of Bcl1 is estimated to be 35% to 46%, respectively, in the European population,([3…”
Background(2018) · Reactions weekly · doi:10.1007/s40278-018-54081-5
- Authors
- Santen, R. J., Jewell, C. M., Yue, W., Heitjan, D. F., Raff, H., Katen, K. S., & Cidlowski, J. A.
- Affiliations
- University of Virginia Health System (US)
- National Institute of Environmental Health Sciences (US)
- Southern Methodist University (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Santen, Richard J
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-07-17
- Volume
- 103
- Issue
- 10
- Pages
- 3630-3639
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC6179182
- OpenAlex
- W2884533276
- Cited by
- 25
- References
- 0
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 1
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- 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, glucocorticoid receptor beta, dominant negative receptor, glucocorticoid hypersensitivity, adrenal insufficiency, low cortisol, dexamethasone, GILZ, FKBP5, monocytes, glucocorticoid receptor alpha
- MeSH terms
- Female, Glucocorticoids, Humans, Hydrocortisone, Hypersensitivity, Middle Aged, Mutation, Prognosis, Receptors, Glucocorticoid, Biomarkers, Incidence
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