Glucocorticoid Receptor Deficiency

A hereditary autosomal dominant disease characterized by increased plasma and urinary CORTISOL, resistance to adrenal suppression by DEXAMETHASONE, and the absence of clinical stigmata of CUSHING SYNDROME. Symptoms are variable but may include HYPOGLYCEMIA; HYPERTENSION, and metabolic ALKALOSIS; CHRONIC FATIGUE SYNDROME, and ANXIETY. In females, overproduction of adrenal ANDROGENS may cause INFERTILITY, ALOPECIA (male pattern bladness) HIRSUTISM, and menstrual irregularities. Caused by mutations in the NR3C1 gene. OMIM: 615962

Also Known As:

Body Composition, Beneficial; Cortisol Resistance from Glucocorticoid Receptor Defect; GCCR Deficiency; GCR Deficiency; Glucocorticoid Resistance; Pseudohermaphroditism, Female, With Hypokalemia, Due To Glucocorticoid Resistance

Networked: 587 relevant articles (10 outcomes, 41 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Asthma (Bronchial Asthma)
2.	Leukemia
3.	Inflammatory Bowel Diseases (Inflammatory Bowel Disease)
4.	Neoplasms (Cancer)
5.	Sepsis (Septicemia)

Experts

1.	Kino, Tomoshige: 22 articles (01/2018 - 04/2002)
2.	Chrousos, George P: 20 articles (01/2022 - 04/2002)
3.	Charmandari, Evangelia: 20 articles (01/2019 - 09/2002)
4.	Cidlowski, John A: 11 articles (10/2018 - 12/2002)
5.	Pariante, Carmine M: 8 articles (01/2020 - 07/2006)
6.	Pieters, Rob: 8 articles (06/2015 - 08/2005)
7.	den Boer, Monique L: 7 articles (06/2015 - 08/2005)
8.	Evans, William E: 6 articles (01/2020 - 12/2008)
9.	Sheridan, John F: 6 articles (01/2018 - 03/2002)
10.	Lock, Richard B: 5 articles (01/2022 - 03/2005)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Glucocorticoid Receptor Deficiency:

1.	GlucocorticoidsIBA 10/01/2020 - "These results indicate that UC patients with different glucocorticoids response types have different bacterial compositions and functions, which lays a foundation for further study of glucocorticoid resistance in UC patients." 12/10/2018 - "Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types." 12/01/2010 - "We present here two types of in vivo models for studying glucocorticoid resistance, that will be used to study the molecular mechanism of glucocorticoid signaling and resistance. " 11/01/2001 - "The goal of this study was to resolve this controversy by determining the molecular basis of glucocorticoid resistance not only in species of squirrel monkeys but also in other glucocorticoid-resistant New World primates. " 06/01/1996 - "In the present study, to address other mechanisms of glucocorticoid resistance, we examined the expression of hsp90 and hsp70 in addition to the number of glucocorticoid-binding sites and their affinity using glucocorticoid-sensitive and -resistant human leukemic cell lines. "
2.	Glucocorticoid Receptors (Glucocorticoid Receptor)IBA 01/01/2015 - "Influence of glucocorticoid receptor gene NR3C1 646 C>G polymorphism on glucocorticoid resistance in asthmatics: a preliminary study." 05/01/2012 - "Studies have revealed novel mechanisms, which are implicated in the glucocorticoid receptor (GR)-mediated action, providing a kind of glucocorticoid resistance. " 11/15/1992 - "We observe that this glucocorticoid resistance upon transformation cannot be explained by depletion of glucocorticoid receptors; previous studies have suggested that transformation causes an alteration in trafficking of such receptors. " 01/01/2023 - "Glucocorticoid resistance is commonly observed in depression, and has been linked to reduced expression and/or function of the glucocorticoid receptor (NR3C1 in human, hereafter referred to as GR). " 01/01/2022 - "LRH-1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistance."
3.	SteroidsIBA 10/01/2018 - "The therapeutic efficacy of these steroids is limited by side effects and glucocorticoid resistance. " 06/01/1996 - "Analysis of mutations within the receptor resulting in relative glucocorticoid resistance, both generalized inherited glucocorticoid resistance (GIGR) and directed mutagenesis, has identified two regions of clustered mutations in the proximity of previously identified affinity labeled residues directly affecting the steroid binding function. " 04/01/1996 - "Analysis of mutations within the receptor resulting in relative glucocorticoid resistance has identified two regions of clustered mutations in the proximity of previously identified affinity-labeled residues, the putative steroid-binding site. " 01/01/1984 - "We conclude that a lower GR level is associated with glucocorticoid resistance and furthermore that a decrease in the level of GR is a mechanism of acquiring steroid resistance." 12/16/2014 - "Prediction of individual sensitivity to steroids and identification of key players in development of glucocorticoid resistance are essential in individualized therapies. "
4.	Dexamethasone (Maxidex)FDA LinkGeneric 10/03/2021 - "The aim of the present study was to test the cytotoxic effects of EPA alone or EPA + Dexamethasone in dexamethasone-resistant MM cell (MM.1R) and investigate whether DHA can induce apoptosis and reverse acquired glucocorticoid resistance in dexamethasone-resistant MM cell (MM.1R). " 01/01/2016 - "The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. " 12/01/2003 - "Partial glucocorticoid resistance in obese children detected by very low dose dexamethasone suppression test." 03/01/2000 - "The sensitivity of corticotropes isolated from 2- and 13-month old male Sprague-Dawley rats to dexamethasone (DEX) in vitro was examined using a modification of the combined DEX/CRH challenge test that was originally designed for investigation of relative glucocorticoid resistance in vivo. " 05/01/1992 - "This difference between dogs and cats in [3H] dexamethasone binding receptors may contribute to the relative glucocorticoid resistance observed in cats."
5.	p38 Mitogen-Activated Protein KinasesIBA 03/01/2023 - "Taken together, icariin improved glucocorticoid resistance in a murine model of asthma with depression associated with enhancement of glucocorticoid receptor function and glucocorticoid receptor expression, and its effects on the glucocorticoid receptor function were related to decreased phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase." 09/25/2012 - "To establish a model of cigarette smoke exposure to asthmatic rats and glucocorticoid resistance induced by nicotine in alveolar epithelioid cells A549 and study the mechanism for the change of glucocorticoid sensitivity induced by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580. " 10/01/2007 - "The molecular mechanisms which have been uncovered to date which could account for glucocorticoid resistance are discussed, in particular the roles of AP-1 and p38 MAP kinase signaling, the role of the beta-isoform of the glucocorticoid receptor and the role of histone proteins and DNA folding. "
6.	Mineralocorticoid Receptors (Mineralocorticoid Receptor)IBA 11/15/2022 - "In contrast, it improved glucocorticoid resistance by reducing the mineralocorticoid receptor expression. " 06/01/2011 - "We provide an overview and diagnostic approach to apparent mineralocorticoid excess, glucocorticoid remediable aldosteronism, familial hyperaldosteronism type 2, Liddle's syndrome, Gordon's syndrome, activating mutations of the mineralocorticoid receptor, generalized glucocorticoid resistance and hypertensive forms of congenital adrenal hyperplasia." 10/22/2010 - "GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. " 01/01/2022 - "These can chiefly be classified as causing (i) excessive aldosterone synthesis (familial hyperaldosteronism), (ii) dysregulated adrenal steroid metabolism and action (apparent mineralocorticoid excess, congenital adrenal hyperplasia, activating mineralocorticoid receptor mutation, primary glucocorticoid resistance), and (iii) hyperactivity of sodium and chloride transporters in the distal tubule (Liddle syndrome and pseudohypoaldosteronism type 2). "
7.	Interleukin-2 (IL2)IBA 04/01/1987 - "These results suggest that significantly greater activity of IL-2 in the culture supernatants of steroid resistant subjects may represent a mechanism for glucocorticoid resistance in vitro and help explain the relationship between increased loss of grafts and steroid resistance in renal allograft recipients." 07/01/2004 - "The decrease of NF-kappaB p65 subunit and up-regulation of IL-2 are potential mechanism of glucocorticoid resistance in SRNS." 06/01/1999 - "Also, the mixture of IL-2 and IL-4 is not crucial for induction of glucocorticoid resistance of GM-CSF production." 06/01/1999 - "4. Thus, glucocorticoid resistance induced by IL-2 and IL-4 is not general at the cytokine production level. " 06/01/1999 - "1. The combination of interleukin-2 (IL-2) and IL-4 reduces the inhibitory effects of glucocorticoids on granulocyte-macrophage colony-stimulating factor (GM-CSF) production, in agreement with the hypothesis that this combination causes glucocorticoid resistance. "
8.	icariinIBA 03/01/2023 - "Icariin Improves Glucocorticoid Resistance in a Murine Model of Asthma with Depression Associated with Enhancement of GR Expression and Function." 07/01/2020 - "Effects of icariin on cell injury and glucocorticoid resistance in BEAS-2B cells exposed to cigarette smoke extract." 03/01/2023 - "Taken together, icariin improved glucocorticoid resistance in a murine model of asthma with depression associated with enhancement of glucocorticoid receptor function and glucocorticoid receptor expression, and its effects on the glucocorticoid receptor function were related to decreased phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase."
9.	CytokinesIBA 01/01/2019 - "The limited number of studies identified highlights the need for purpose-designed investigations that directly examine the relationship between glucocorticoid resistance and cytokine production in depression." 01/01/2019 - "Stratifying the four studies (147 patients and 118 controls) that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: d = 1.35; 95% CI 0.53-2.18). " 01/01/2019 - "We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). " 01/01/2019 - "Methods: We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. " 01/01/2022 - "Although the underlying mechanisms are unknown, both proinflammatory cytokines and chronic stress may contribute the most in the adrenals hyporesponsiveness and the target tissue glucocorticoid resistance that have been described, but not systematically studied. "
10.	Hydrocortisone (Cortisol)FDA LinkGeneric 01/01/2020 - "The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. " 01/01/2010 - "Glucocorticoid resistance is a rare genetic condition characterized by reduced sensitivity to cortisol signaling and subsequent hyperactivation of the hypothalamic-pituitary-adrenal axis. " 07/18/2008 - "Depression is often preceded by stressful life events and accompanied with elevated cortisol levels and glucocorticoid resistance. " 07/01/2006 - "On the contrary, this paper concludes that a lack of the 'positive' effects of cortisol on the brain, because of glucocorticoid resistance, is likely to be involved in the pathogenesis of depression." 07/01/2006 - "Squirrel monkeys have high cortisol compared to Old World primates to compensate for glucocorticoid resistance. "

Therapies and Procedures

1.	Therapeutics 01/01/2020 - "CRISPR-Cas9-Mediated Glucocorticoid Resistance in Virus-Specific T Cells for Adoptive T Cell Therapy Posttransplantation." 03/01/2018 - "New insights into the molecular mechanisms of glucocorticoid-resistance are needed in order to conceive more adequate GC-therapies." 07/25/2014 - "Altogether, our data indicate that loss of TBL1XR1 is a novel driver of glucocorticoid resistance in ALL and that epigenetic therapy may have future application in restoring drug sensitivity at relapse." 03/15/2019 - "Impaired GRα nuclear translocation and inhibited p-p65 expression might contribute to glucocorticoid resistance caused by MUC1 deficiency in TNF-α-induced necroptosis in 16HBE cells, and should be considered as a potential target for the development of novel therapeutics for asthma." 01/01/2019 - "Therapies directed at overcoming glucocorticoid resistance in visceral adipose tissue may improve remodeling and help prevent metabolic complications of visceral obesity."
2.	Drug Therapy (Chemotherapy) 11/01/2023 - "Since these drugs are the essential components of chemotherapy regimens for ALL and play an important role in stop of cell growth and induction of apoptosis, it is important to identify genes and the molecular mechanism that may affect glucocorticoid resistance. " 01/01/2014 - "Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia." 01/01/2010 - "Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. " 01/01/2016 - "Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. " 03/01/2015 - "Dexamethasone polymeric microparticles constitute an alternative to current dexamethasone administration systems in combined chemotherapy, whereas dexamethasone lipid microparticles represent a potential tool to revert glucocorticoid resistance."
3.	Hematopoietic Stem Cell Transplantation 12/01/2022 - "To investigate the efficacy and safety of VDZ (Vedolizumab) in the salvage treatment of glucocorticoid resistance to gastrointestinal graft-versus-host disease (GR-GI GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. "
4.	Salvage Therapy 12/01/2022 - "To investigate the efficacy and safety of VDZ (Vedolizumab) in the salvage treatment of glucocorticoid resistance to gastrointestinal graft-versus-host disease (GR-GI GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. "
5.	Organ Transplantation 12/01/2001 - "The receptor translocation into nuclei indicates that unknown post-receptor events might also be involved in glucocorticoid resistance that seriously impair successive glucocorticoid therapy after organ transplantation. "