Current Challenges and Future Directions in the Assessment of Glucocorticoid Status

Abstract

Glucocorticoid (GC) hormones are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels ie, markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or nonspecific. Current tools for assessing GC status are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intraindividual variation and do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11beta-hydroxysteroid dehydrogenase activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on the measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, micro RNA, gene expression, and epigenetic and other novel biomarkers such as growth differentiating factor 15 and osteocalcin, which could in the future aid in the objective classification of GC status.

Keywords: Addison's disease; adrenal; glucocorticoid; pituitary gland; steroids.

Graphical Abstract

Figure 1.

Factors affecting GC secretion, clinical factors affecting GC secretion, the clinical characteristics of an individual presenting with GC excess and GC depletion, and the investigations that a clinician can carry out to determine GC adequacy.

Figure 2.

GC signaling pathway. (A) GCs are bound and transported by plasma protein. CBG is the main GC-binding protein that binds to 80% to 90% of the GCs. (B) GCs freely diffuse through cell membranes due to their lipophilic nature. (C) Cortisol is metabolized to inactive cortisone by intracellular enzyme, 11β-HSD type 2, which is expressed in abundance in some tissues (eg, distal nephron) (126), whereas 11β-HSD type 1, which is highly expressed in the liver, adipose tissue, and skeletal muscles, catalyzes conversion of cortisone to cortisol (134) (D) GC receptors reside predominantly in the cytoplasm of cells as part of a large multiprotein complex consisting of hsp20, hsp70, p23 (147). (D) Inside the cell, GR first interacts with hsp70 and HOP (147). HOP recruits GR:hsp70 to hsp90 and co-chaperone (including FKBP51 and GDKP52) bind to hsp90 as HOP is released. p23 binds and stabilizes the GR:hsp90 heterocomplex (147). FKBP51 inhibits nuclear transactivation of GR while FKBP52 may promote translocation (147). (E) GC-activated GR regulates gene expression via direct interaction to 1-GRE or 2-nGRE, 3- indirect interaction by tethering to DNA-bound transcription factors, or 4- composite binding to DNA while interacting with neighboring DNA-bound transcription factors. (F) Depending on the cell type, GC can also signal in a nongenomic manner through activating adenylate cyclase/PKA or PLC/PKC or the PIP3/Akt pathway resulting in changes in calcium concentration. (G) GCs can also have direct interaction with cell membranes and trigger a cascade of activity of kinases; however, this mechanism is less well described, or GCs can exert its action via binding to membrane GR, and phosphorylation of Cav-1 and PKB/Akt in a Src-dependent manner can lead to downstream signaling pathways.