Increased gluconeogenesis
Increased glycogenesis
Increased redistribution of body fat
Involution of lymphatic tissue
Reduction in inflammatory response
Increased gastric acid
Decreased adrenocorticotrophin release
Sodium retention
Redistribution of body fluids
Diabetes mellitus
Thinning of soft connective tissue
Central obesity/peripheral muscle atrophy
Susceptibility to infection
Poor healing
Gastric tissue ulceration
Chronic supression of adrenocorticotrophic hormone.
Hypertension
Osteoporosis
Immunosupression surfaced as an adverse side effect of glucocorticoids shortly after their introduction for use in treatment of inflammation. This is believed to be due to the sharing of fundamental cellular-molecular mechanisms between immunity and inflammatory processes. Both responses involve the control of cytokines and other mediators. (DeGroot 1647) Studies suggest that endogenous glucocorticoids control inflammatory and autoimmune responses.
In a quarterly publication published by Harvard University, Duncan Smith-Rohrberg explains that while sympathetic stress causes an HPA-mediated changes in levels of interleukins and tumor necrosis factors, the HPA activation also stimulates change to systemic levels of corticosteroids. IL-1 is a chemical messenger responsible for stimulation of lymphocyte differentiation. It is part of a fever-production pathway. �IL-1 was found to lose its pyrogenic effects when � the Vagus was severed. This indicated that, in addition to crossing the blood-brain barrier, IL-1 would act locally on parasympathetic ganglia in the gut to stimulate the vagus, which would then stimulate the brain to promote fever.� (Smith-Rohrberg 5) Interleukin 6 (IL-6) is responsible for immunological changes, as well.
Studies with mice have revealed that when placed under conditions of external stress (i.e.: placed in an open field type setting), levels of IL-6 increase during the short term. IL-6 �induces differentiation of B cells into plasma cells; enhances proliferation and activity of T cells; stimulates (the) liver to secrete mannose-binding protein, which triggers complement binding to bacteria with mannose sugar in their capsules.� (Huether 819) Interestingly, however, the same stress that mediates the increase in IL-6 also triggers increased activity of the HPA axis, resulting in increased levels of plasma corticosteroids, which ultimately decreases levels of IL-6. (Smith-Rohrberg 5) This is one example of how the same glucocorticoid that keeps the immune system from trending out of homeostatic balance can, under conditions of chronic exposure, inhibit the levels of interleukins from being high enough to complete their beneficial tasks. �These interactions help ensure that the body�s stress response system does not overreact in its respons to a stressor�(the) constant adjustment and readjustment of hormone levels around a target concentration has been called the �allostatic load�.� (Adinoff 68)
Glucose and Insulin
Steroid hormones, including glucocorticoids, exert their influence on target cells by modification of gene activity. (Marieb 633) In the condition of steroid diabetes, as found in moderate to severe cases of Cushing�s syndrome, patients experience persistent hyperglycemia. (Marieb 633-4) During an HPA axis shift, blood glucose is raised and effects of insulin are countered by means of four distinct actions. (Degroot 1646) These actions include increased gluconeogenesis by the liver with concurrent gluconeogenic substrate release from peripheral tissues; permissive enhancement of gluconeogenesis and glycogenolysis by glucagon and epinephrine; inhibition of peripheral glucose use; and promotion of liver-mediated glycogen synthesis for acute response to glycogenolytic action by glucagon and epinephrine. (DeGroot 1646).
Gluconeogenesis involves a complex series of steps and appears to be stimulated by glucocorticoids, mainly through the increased activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, enzymes which catalyze oxaloacetate to phosphoenolypyruvate and g-6-p to glucose, respectively. Insulin, glucagon, and catecholemines also play a part in the gluconeogenesis cascade. (DeGroot 1646) Glucagon causes the breakdown of glycogen into glucose, the synthesis of glucose from lactic acid and amino acids, and a direct release of glucose stored in hepatocytes. (Marieb 636) To illustrate the relative potency of glucagon, one molecule of the hormone can cause the release of 100 million molecules of glucose into the blood. (Marieb 636)
The PEPCK gene has a complex glucocorticoid response unit, two glucocorticoid receptor binding sites and two accessory factor-binding sites, all of which are required for glucocorticoid regulation. Within the GRU are insulin-responsive and retinoic acid responsive sequences. Substrates needed for gluconeogenesis are increased by glucocorticoids through release of amino acids from muscle and other peripheral tissues. (Degroot 1646)
As demonstrated in normal organisms and isolated cells, glucocorticoid inhibits peripheral use of glucose, which accounts for significant insulin antagonism and early rise in blood glucose levels seen after glucocorticoid therapy. (DeGroot 1646) It is believed that extracellular presence of glucocorticoid causes a migration of glut4 (glucose translocation protein), which is responsible for glucose uptake, from the cell membrane to intracellular sites. (Marieb 640, DeGroot 1646) A similar phenomenon is seen in patients with primary diabetes mellitus, in which Marieb believes the cause to be the release of Tumor Necrosis Factor-alpha by adipose cells of the obese patient which depresses synthesis of glut4. (641) Thus, in primary Cushing�s patients, the theory is that the protein is translocated from the membrane to the cytoplasm, disabling the facilitated movement of glucose into the cell; and in primary DM patients, the cause of the disability is decreased presence of glut4 secondary to TNF-alpha�s interruption of the protein�s synthesis.