Molecular mechanisms of glucocorticoid resistance

Abstract

Background As a powerful anti‐inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined. Methods The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included ‘glucocorticoid resistance/insensitive’, ‘steroid resistance/insensitive’, ‘NR3C1’, and ‘glucocorticoid receptor’. Results Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported. Conclusion The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated.

Glucocorticoid‐induced adrenal suppression: physiological basis and strategies for glucocorticoid weaning

“…22 There is a wide variability in glucocorticoid activity of a given oral dose in different individuals due to differences in absorption, metabolism, glucocorticoid receptor expression, and downstream gene activation. 12,23,24 High intra-individual variability in glucocorticoid Perspectives sensitivity is apparent in estimates of daily cortisol production rates at 9.9 mg per day (standard deviation, 2.7 mg per day) and a threefold variation in 24-hour urine-free cortisol in healthy individuals. 25 Several tests have been used to assess cortisol secretion and the extent of glucocorticoid suppression from exogenous glucocorticoids.…”

“…The highest risk is seen in patients taking oral glucocorticoids (48.7%) and intra‐articular forms (52%), with lower rates for inhaled (7.8%), topical (4.7%) and nasal (4.2%) glucocorticoids 22 . There is a wide variability in glucocorticoid activity of a given oral dose in different individuals due to differences in absorption, metabolism, glucocorticoid receptor expression, and downstream gene activation 12,23,24 . High intra‐individual variability in glucocorticoid sensitivity is apparent in estimates of daily cortisol production rates at 9.9 mg per day (standard deviation, 2.7 mg per day) and a threefold variation in 24‐hour urine‐free cortisol in healthy individuals 25 …”

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

“…Most affected individuals present with hypertension, hypokalemia, and suppressed renin concentrations in childhood. The initial tests include the measurement of cortisol, androstenedione, testosterone, DHEAS, 11-deoxycortisol, and DOC concentrations ( 5 , 12 ).…”

“…Differential diagnoses of PGCR include Cushing’s disease, pseudo-Cushing (depression and generalized anxiety disorder), conditions with increased cortisol-binding globulin (CBG) (pregnancy and estrogen treatment), hyperaldosteronism, essential hypertension, hyperandrogenism [polycystic ovary syndrome (PCOS), idiopathic hirsutism, and CAH] ( 12 ). Bone mineral density measurement is useful to differentiate PGCR from Cushing’s syndrome, and it is maintained in patients with GCR and increased in women due to androgen excess ( 15 ).…”

A teenage girl with altered mental status and paraparesis

“…There are a few reasons why TNF blockade may work better than dexamethasone. First, patients may exhibit dexamethasone resistance due to decreased expression of glucocorticoid receptors from its long-term use [41] . M. tuberculosis also triggers IL-6, which inhibits responses to glucocorticoids [42] .…”