Glucocorticoids

Glucocorticoids (GCs) are a group of steroid hormones that affect carbohydrate, lipid, and protein metabolism. The biological functions of GCs are maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, inhibit corticotropin secretion, functioning of the central nervous system, and inhibiting the process of inflammation. They are powerful antiinflammatory agents.  They may be administered to treat chronic inflammatory conditions such as arthritis, asthma, inflamed joints, and allergic reactions. Some examples of CG drugs are prednisone, prednisilone, methylprednisilone, dexamethasone, and hydrocortisone. The biophysiological effects of GCs are discussed below.

Metabolism

GCs stimulate glucosneogenesis (glucose production from sources such as amino acids and lipids) in the liver. GCs enhance the expression of enzymes involved in gluconeogenesis. They serve as substrates for gluconeogenesis by mobilization of amino acids from extrahepatic tissues and help the inhibition of glucose uptake in muscle and adipose tissue. It stimulates fat breakdown by enhancing lipolysis in adipose tissue.

The secretion of GCs by the adrenal gland is regulated by the hypothalamic-pituitary-adrenal axis (HPA) axis via secretion of adrenocorticotropic hormone (ACTH). The main plasma cortisol is protein bound with 4 to 5 percent free fraction. The plasma cortisone is in the free unbound form. The equilibrium of cortisol and cortisone between the plasma and tissues are illustrated with the dotted bidirectional arrows. Tissue-specific GC metabolisms are also depicted. GCs are metabolized primarily in liver and the metabolites are excreted in the urine. Increased tissue concentrations of GCs in obesity are related to increased fat mass.

Obesity

GCs seem to be important in the development of obesity, as adrenalectomy or GC receptor antagonists attenuate weight gain and associated metabolic abnormalities. The role of GCs in obesity is unclear. The enhanced inactivation of cortisol by 5α-reductase and altered reactivation of cortisone to cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) was reported in obese men. The changes in GC metabolism may influence corticosteroid receptor activation and feedback regulation of the HPA. Increased secretion of GCs (e.g., in Cushing syndrome) is associated with obesity, and increased cortisol secretion is seen in subjects with idiopathic obesity, especially of central distribution.

Insulin resistance is viewed as an insufficiency in insulin action, with GCs being recognized to play a key role in its pathogenesis. In addition, clinical administration of GCs to treat acute and chronic inflammatory diseases has been associated with metabolic adverse effects such as hypertension, obesity, hyperlipidemia, and insulin resistance as seen in the metabolic syndrome. GC action is mediated by glucocorticoid receptors, a nuclear receptor that regulates physiological events through activation or repression of target genes involved in inflammation, gluconeogenesis and adipocyte differentiation.

Inflammation and Immune Function

GCs have potent antiinflammatory and immunosuppressive properties. GCs are widely used as drugs to [Page 332]treat inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.

Cardiometabolic Syndrome

GC metabolism is also abnormal in insulin-resistant states and may promote including insulin resistance, diabetes, and hypertension. Use of GCs may enhance the risk of heart failure. In a large population-based study, the use of GCs was associated with an increased risk for cardiovascular events (more than 2.5 times higher than nonusers), with a clear dose-response relationship.

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