Sensitivity of mononuclear leucocytes to glucocorticoids in elderly hip-fracture patients resistant to suppression of plasma cortisol by dexamethasone

Abstract

Objective: Elderly women with proximal femur fracture show a prolonged increase in plasma cortisol, which could have undesirable catabolic effects. Suppression of cortisol by dexamethasone is impaired, suggesting resistance to glucocorticoid effects at feedback inhibitory sites. We therefore wished to find out whether peripheral glucocorticoid sensitivity is normal. Design: Peripheral blood mononuclear leucocytes were used as a model tissue. Blood samples were taken from elderly women about 2 weeks after hip fracture and from elderly control women. Each patient was then given 1 mg dexamethasone at 2300 h followed by further sampling at 0800 and 1600 h the next day. Methods: Glucocorticoid-receptor binding parameters were measured by incubating whole cells with 3 H]thymidine than the control cells in the absence of dexamethasone. The percentage inhibition by a saturating concentration of dexamethasone was unchanged but the concentration giving half-maximal inhibition was decreased (sensitivity was increased) at the higher of the two concanavalin A concentrations used. Conclusions: These experiments in mononuclear leucocytes give no evidence of peripheral resistance to glucocorticoids in hip-fracture patients with impaired suppression of cortisol by dexamethasone. European Journal of Endocrinology 138 659-666

A comparison of in vitro bioassays to determine cellular glucocorticoid sensitivity

“…It has been reported recently that the E max of isolated PBMC in mitogenbased assays ranges from 0% to almost 100% (11,16). Like others (14,17,27,28), we could not detect such a wide variation with any of the mitogen-based assays we have performed, as the E max ranged from 51.8% to 96.6%. Although we have performed the assays exactly as described in the literature, slight differences in experimental procedures and the number of control subjects tested may have caused this discrepancy.…”

“…Numerous protocols have been described, differing in, for example, the use of diluted wholeblood or isolated PBMC, the type and concentration of mitogen, and the incubation time (11 -15). Such differences, however, may affect the results obtained with these bioassays (16,17). Moreover, the GC sensitivity of stimulated PBMC may very well be affected by the stimulation itself, as transcription and translation patterns are profoundly altered by mitogens (18 -20).…”

Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment

“…Thus, the subset of upregulated genes will show a relative enrichment of promoter TFBMs for the activated TF (for example, CREB) relative to that observed in a control set of genes (for example, the basal prevalence across all genes in a genome, or TFBM prevalence in a parallel derived set of downregulated genes, which better controls for the fact that about half of the genome is not expressible in any given cell type because of intrinsic variations in the transcriptional basis for cell development and differentiation). In the present study, we conducted such promoter TFBM enrichment analyses to test a series of a priori theories regarding the transcription control pathways that may be activated in the context of MDD, including the CREB/ATF family, 18 , 22 the GR, 25 , 26 , 27 , 28 , 29 , 30 , 50 , 51 , 52 EGR family TFs, 31 , 32 , 33 , 34 the nuclear factor kappa-B cell (NF-κB)/Rel family of TFs that mediate signaling by many pro-inflammatory cytokines, 36 , 37 , 39 , 40 interferon regulatory factor (IRF) family TFs that mediate signaling by Type I interferons 37 , 41 , 42 , 43 , 53 and the nuclear factor erythroid-derived 2-like 2 (NRF2) TF that mediates transcriptional responses to oxidative stress. 40 , 44 , 45 , 46 …”

Glucocortidoid sensitivity assessed in peripheral blood cells do not correlate with the feedback sensitivity of the hypothalamo-pituitary adrenal AXIS

“…For example, GC sensitivity in various tissues demonstrates a seasonal and even a diurnal variation 3,11 . Also, various types of stressors affect GC sensitivity in several target tissues [24][25][26][27] . The role of an altered GR sequence in the observed GC sensitivity is also of high current research interest 3, 28,29 .…”