The biosynthesis of steroid hormones begins with cholesterol as the substrate. The initial event, removal of the side chain from position C-20, is a rate-limiting step and is under the control of ACTH. Additional intermediate enzymatic steps are also under ACTH control so overall synthesis of glucocorticoids is regulated by ACTH.
Cortisol is the major glucocorticoid synthesized and is bound by two plasma proteins, albumin (6%) and cortisol-binding protein (90%). The remainder is free in equilibrium with the bound fraction. Unbound steroid molecules cross the plasma membrane of target cells, and are bound by specific cytosolic steroid receptors and transported to the cell nucleus to regulate the synthesis of new messenger RNA and thus the cell protein product. Different target cells have different steroid receptors with variable functions and affinities. Metabolized glucocorticoids are excreted in the urine primarily as 17-hydroxycorticosteroids. Some glucocorticoids undergo cleavage of side chains in the liver, resulting in 17-ketosteroids, which are also eliminated in the urine. A small fraction of free cortisol is also excreted in the urine.
Cortisol has a number of effects on intermediary metabolism, most of which are considered catabolic and oppose the effects of insulin. Glucocorticoids promote proteolysis to provide necessary substrate for gluconeogenesis. Cortisol-induced protein breakdown releases branched-chain and other amino acids, as well as lactate, from muscle. Cortisol induces gluconeogenic enzymes in the liver. Cortisol further promotes hyperglycemia by reducing the utilization of glucose in peripheral tissues; insulin binding by insulin-sensitive tissues and glucose uptake into fat cells are both decreased. An additional catabolic effect of cortisol is the enhancement of lipolysis. Serum-free fatty acids and triglycerides increase under the influence of cortisol. The characteristic truncal obesity of Cushing syndrome (hypercortisolism) may be explained by the fact that truncal adipocytes may be more influenced by insulin (lipogenesis), whereas extremity adipocytes may be more sensitive to cortisol (lipolysis).
Cortisol also has a number of effects on other tissues relevant to the surgeon. Cortisol has both inotropic and chronotropic effects on the myocardium, as well as the ability to increase peripheral vascular resistance. These effects, along with the increase in sodium reabsorption in the distal renal tubule, account for the hypertension frequently seen with cortisol excess. In the gastrointestinal tract, glucocorticoids decrease mucosal cell replication and prostaglandin synthesis. These effects may play a role in the development of the peptic ulcers seen with steroid administration and may also explain the more frequent incidence of acute pancreatitis in steroid-treated patients. Cortisol also has an effect on bone, leading to osteopenia as a result of decreased bone formation. This is believed to be due to decreased osteoblast development, which leads to a deficiency of protein in the extracellular matrix.
Every surgeon is aware of the ability of cortisol to decrease inflammation, blunt the immune response, and impair wound healing. Cortisol excess appears to act principally by decreasing lymphocyte response to specific antigenic stimulation. This explains the efficacy of glucocorticoids in the prevention of rejection in organ transplantation. This blunted response is responsible, at least in part, for the clinical observation that steroid-treated patients are vulnerable to a variety of opportunistic and conventional infectious organisms. Leukocytosis occurs in circulating blood as a result of cortisol administration, but both chemotaxis and phagocytosis are impaired and granulocyte-dependent bacterial killing is less efficient. Wounds have decreased tensile strength in the presence of excess cortisol because both lymphocytes and granulocytes are essential early components of the wound-healing process. In addition, both epithelialization and scar contraction are impaired by cortisol.
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