| Cortisol is the major glucocorticoid synthesized in man in the adrenal cortex and is under the direct control of pituitary ACTH
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| A simplified scheme of steroid biosynthesis is shown in Figure 37.7 (see also Fig. 16.7, p. 219). Cholesterol is the precursor for all steroid hormones. Cleavage of the cholesterol side chain liberates the C-21 corticosteroids; further side chain cleavage yields the C-19 androgens, and aromatization of the A ring results in the C-18 estrogens. The structures of the key steroid hormones are shown in Chapter 16. Several of the steroidogenic enzymes are members of the cytochrome P450 superfamily of oxidases.
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| The plasma concentration of cortisol shows a pronounced diurnal rhythm, being some 10 times higher at 08.00 h than at 24.00 h. This parallels the marked diurnal rhythm of secretion of ACTH. Approximately 95% of cortisol in plasma is bound to proteins, mainly CBG. As cortisol concentration rises, the percentage of free cortisol also rises, indicating that CBG binding is saturable. Cortisol has a half-life in plasma of about 100 minutes. It is metabolized in the liver and other organs by a combination of reduction, side chain cleavage, and conjugation to produce a wide range of inactive metabolites that are excreted in urine.
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| Figure 37.7 Summary of steroid hormone biosynthesis. 1, cholesterol 20,22-desmolase; 2,3β-hydroxysteroid dehydrogenaseΔα4,5-oxosteroid isomerase; 3, 21-hydroxylase; 4, 11-hydroxylase; 5, aldosterone synthase; 6, 17α-hydroxylase; 7, 17,20-lyase/desmolase; 8, 17β-hydroxysteroid dehydrogenase; 9, aromatase. These enzymes are part of the cytochrome P450-dependent superfamily of NADPH-dependent mono-oxygenases (see also Chapter 16). |
| Cortisol has a major influence on gluconeogenesis
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As the name glucocorticoid suggests, cortisol has a major influence on glucose homeostasis. It is a counter-regulatory hormone, like glucagon but slower acting, working through nuclear receptors to induce the biosynthesis of gluconeogenic enzymes. At the same time, cortisol has a diabetogenic effect, inhibiting glucose uptake and metabolism in peripheral tissues. Glycogen synthesis and deposition are increased, and lipolysis is stimulated. Protein and RNA synthesis are stimulated in the liver, but inhibited in peripheral tissues (muscle); proteolysis in muscle produces the amino acid substrates for hepatic gluconeogenesis. In this role, cortisol is working in tandem with several other hormones including insulin and GH.
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| Excess cortisol has a wide range of effects on the immune system, inhibiting the immune response and inflammation. Cortisone, a related glucocorticoid, is used as a topical anti-inflammatory agent. Cortisol also influences the heart, vasculature, blood pressure, water excretion, and electrolyte balance. It influences bone turnover through a variety of mechanisms, and osteoporosis is a recognized consequence of sustained cortisol excess.
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