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Adrenal Cortex and Glucocorticoid Synthesis

The mineralocortico(stero)ids aldosterone, corticosterone and 11-desoxycorticosterone (^ pp. 182ff. and 294) are synthesized in the glomerular zone of the adrenal cortex (^ A1), whereas the glucocortico(stero)ids cortisol (hydrocortisone) and cortisone (^ p. 294, small quantities) are synthesized in the fascicular zone (^ A2). Androgens are synthesized in the reticular zone of the adrenal cortex (^ A3). One of the androgens is dehydroepian-drosterone (DHEA), which is used (partly in its sulfated form, DHEA-S) to synthesize various sex hormones in other tissues (^ p. 304).

Cortisol transport. Most of the plasma cortisol is bound to transcortin, or cortisol-binding globulin (CBG), a specific transport protein with a high-affinity binding site for cortisol. Cortisol is released in response to confor-mational changes of CBG due to inflammation etc.

CRH and ACTH regulate cortisol synthesis and secretion (^ A4, A5; see also p. 270). ACTH ensures also structural preservation of the adrenal cortex and supplies cortisol precursors, e.g., by forming cholesterol from its esters, by de novo synthesis of cholesterol and by converting it to progesterone and 17a-hy-droxyprogesterone (^ pp. 256 and 294). ACTH secretion is stimulated by CRH and epineph-rine and inhibited (negative feedback control) by cortisol with or without the aid of CRH (^ A; see also p. 273 A).

A circadian rhythm of CRH secretion and thus of ACTH and Cortisol secretion can be observed. The peak secretion is in the morning B, mean values). Continuous hormone conc. sampling at short intervals have shown that ACTH and cortisol are secreted in 2-3-hour episodes (^ B).

Receptor proteins (^ p. 278) for glucocorticoids can be found in virtually every cell. Glucocorticoids are vital hormones that exert numerous effects, the most important of which are listed below.

Carbohydrate and amino acid (AA) metabolism (see also pp. 283 A and 285 C): Cortisol uses AA derived from protein degradation to increase the plasma glucose concentration (gluconeogenesis), which can lead to the so-

called steroid diabetes in extreme cases. Thus, cortisol has a catabolic effect (degrades proteins) that results in the increased excretion of urea.

Cardiovascular function: Glucocorticoids increase myocardial contractility and vasoconstriction due to enhancement of cate-cholamine effects (^ pp. 194 and 214). These are described as permissive effects of cortisol. Cortisol increases the synthesis of epinephrine in the adrenal medulla (^ A6) and of angioten-sinogen in the liver (^ p. 184).

Especially when administered at high doses, glucocorticoids induce anti-inflammatory and anti-allergic effects because they stabilize lymphokine synthesis and histamine release (^ p. 100). On the other hand, inter-leukin-1, interleukin-2 and TNF-a (e.g., in severe infection) leads to increased secretion of CRH and high cortisol conc. (see below).

Renal function: Glucocorticoids delay the excretion of water and help to maintain a normal glomerular filtration rate. They can react also with aldosterone receptors but are converted to cortisone by Hfi-hy-droxysteroid oxidoreductase in aldosterone target cells. Normal cortisol conc. are therefore ineffective at the aldosterone receptor. High conc., however, have the same effect as aldosterone (^ p. 182).

Gastric function: Glucocorticoids weaken the protective mechanisms of the gastric mucosa. Thus, high-dose glucocorticoids or stress (see below) increase the risk of gastric ulcers (^ p. 242).

Cerebral function: High glucocorticoid conc. change hypothalamic (^ A) and electrical brain activity (EEG) and lead to psychic abnormalities.

Stress: Physical or mental stress increases cortisol secretion as a result of increased CRH secretion and increased sympathetic tone (^ A). Many of the aforementioned effects of cortisol therefore play a role in the body's response to stress (activation of energy metabolism, increase in cardiac performance, etc.). In severe physical (e.g., sepsis) or mental stress (e.g., depression), the cortisol plasma conc. remains at a very high level (up to 10 times the normal value) throughout the day.

Stress

Hypothalamus CRH N-

Negative feedback

Stress

Hypothalamus CRH N-

Negative feedback

Feedback Stress

P B. Circadian rhythm of ACTH and cortisol secretion c to T3

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