Biomarkers

Target: Cortisol

Cortisol is the main glucocorticoid secreted by the adrenal cortex and it is involved in the stress response. Its synthetic counterpart hydrocortisone is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Synthetic cortisol known as hydrocortisone is synthesized from pregnenolone and is used as an immunosuppressive drug given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an Addisonian crisis. Cortisol inhibits production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha, and tumor-necrosis-factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulates IL-4, IL-10, and IL-13 by Th2 cells. In addition to its immunosuppressive effects, cortisol increases glomerular filtration rate, and renal plasma flow from the kidneys thus increasing phosphate excretion, as well as increasing sodium and water retention and potassium excretion. Cortisol works with adrenaline to create memories of short-term emotional events. This is the proposed mechanism for the formation and storage of “flash bulb” memories. Cortisol increases blood pressure, blood sugar levels, may cause infertility in women, and suppresses the immune system. The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning, in response to stress and low blood-glucose concentrations. In adults (>18 years old) undergoing a period of stress, cortisol is found to be significantly increased in the saliva at a concentration of 8.69 μM (PMID: 15257879) compared to normal adults at a concentration of 2.35 μM (PMID: 15257879). It is found in lower levels in the evening, several hours after the onset of sleep. Cortisol is found to be associated with ACTH deficiency and glucocorticoid deficiency, which are inborn errors of metabolism. Blood cortisol levels in children between 2-17 year old are found to be significantly decreased in those with ACTH deficiency at a concentration of 0.22 μM (p = 0.022) compared to normal individuals with a concentration of 0.46 μM (PMID : 23705938). In adult individuals with glucocorticoid deficiency, blood cortisol levels are found to be significantly elevated where disease individuals have cortisol concentrations of 0.84 (0.68 - 0.99) μM compared to normal individuals with a cortisol concentration of 0.14 (0 - 0.28) μM (PMID : 2165347). Cortisol binds to the cytosolic glucocorticoid receptor. After binding the receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA-bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition of arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically, glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes and prevents phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products of inflammation, prostaglandins and leukotrienes, are inhibited by the action of glucocorticoids. Glucocorticoids also stimulate the escape of lipocortin-1 into the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes. Additionally, the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding.