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

Abstract

Glucocorticoids (GC) affect virtually all organ systems, acting mainly via the glucocorticoid receptor (GR). The immune system is the best characterized tissue for assessing GC sensitivity. It is well established that the immune system GC sensitivity varies widely between normal subjects. However, it remains unclear whether measurements of the immune system GC-sensitivity reflect the GC-sensitivity in other GC target tissues of the same individual. Thus, in the present study we compared the GC sensitivity of the immune system, assessed by determining the dexamethasone inhibition of LPS-induced TNF-alpha production in peripheral leukocytes, with the feedback sensitivity of the HPA axis, assessed by a very low dose dexamethasone (0.25 mg) suppression test, in sixteen healthy volunteers. We observed a wide variation in the magnitude of the responses in the two GC targets. However, and in agreement with a number of previous reports, in a given subject the GC sensitivity of the immune system did not correlate with that of HPA axis inhibition, indicating a tissue specificity of GC sensitivity in the same individual. In summary, the bulk of current evidence suggests that GC sensitivity is tissue specific for a given individual. Additional studies are warranted to elucidate the exact mechanism(s) involved in the differential GC tissue responsiveness.

Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity

“…Others have shown that there is considerable interpersonal variability in glucocorticoid responses 23,25,26,29,30,46,51. Interestingly, serum cortisol did not correlate with genome-wide transcriptional analysis of GR and NFκB-regulated genes 38.…”

“…Glucocorticoid suppression of inflammatory- induced genes and/or proteins has been commonly used21,24,25,32–37,46 but this only assesses one mechanism through which glucocorticoids function. Surprisingly few studies have chosen to use GR upregulated genes 29.…”

“…Other assays that have been used include the dexamethasone suppression test,20–25 which measures the response of the adrenal glands to adrenocorticotropic hormone; inhibition of stimulated PBMC proliferation,20,27–30 which correlates with the response to glucocorticoid therapy in some diseases;12,13,48,49 quantification of the number and affinity of GR in the PBMCs;20,30,31 bioinformatics profiling;37,38 and cutaneous vasoconstrictor (skin blanching),21,39 which determines topical potency of glucocorticoids. Attempts to obtain concordance between many of these assays have failed.…”

“…Ebrecht et al found no concordance between the dexamethasone suppression of LPS-induced cytokines, skin blanching, and the dexamethasone suppression test in healthy volunteers, again suggesting target tissue specificity 21. Vasiliadi et al also found no concordance between the dexamethasone suppression test and dexamethasone inhibition of LPS-induced TNFα25 and Smit et al found no concordance between the dexamethasone suppression test and expression of GR up- and downregulated genes 26. Concordance between the cutaneous vasoconstrictor assay and glucocorticoid sensitivity in asthma has been varied 39,50…”

Unusual causes of Cushing's syndrome

“…Although there is a wide variation in glucocorticoid sensitivity amongst humans (45,46), clinically manifested Cushing's syndrome due to increased sensitivity of tissues to glucocorticoids is an extremely rare condition and its mechanism remains unclear. To date only 3 patients have been studied to this direction: two with spontaneous Cushing's syndrome and one with exogenous Cushing's syndrome.…”