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Adrenal Gland: II Adrenocortical Hormones

Adrenal Gland: II Adrenocortical Hormones
Clinical background
Cushing’s syndrome is the name given to the clinical symptoms and physical signs induced by glucocorticoid excess (Fig. 17a; Table 17.1). It may be caused by excess adrenocorticotrophic hormone (ACTH) secretion by a pituitary tumour resulting in bilateral adrenocortical hyperplasia or by adrenal cortical tumours such as benign adenomas or malignant carcinomas (Fig. 17b). Patients with ACTH-dependent Cushing’s syndrome and adrenal carcinomas often demonstrate coexisting androgen hypersecretion, accounting for some of the clinical features of the syndrome. Adrenal Cushing’s syndrome can be diagnosed by finding elevated plasma cortisol concentrations with loss of the normal diurnal variation and failure to suppress following short and (usually) long dexamethasone suppression tests in the presence of undetectable plasma ACTH concentrations. Adrenal tumours are visualized by MRI or CT scanning and their treatment is surgical, followed by adrenolytic chemotherapy in those patients with malignant disease.

Adrenocortical hormones
The adrenal cortex synthesizes and secretes steroid hormones. The predominant hormones are:
1.     Cortisol: glucocorticoid action on carbohydrate metabolism and the response to stress. Excess  glucocorticoids have catabolic effects on protein metabolism.
2.     Aldosterone: regulates salt and water homeostasis.
3. Androgens: testosterone, androstenedione, 17 hydroxyprogesterone and dehydroepiandrosterone sulphate (DHEAS) all have effects on the maintenance of secondary sexual characteristics. Excess androgen production results in virilization in the female.

Biosynthesis of glucocorticoids Pregnenolone is formed from cholesterol (CH) by side-chain cleavage catalysed by the desmolase enzyme system. CH is
mainly transported in the blood in low density lipoprotein (LDL). The LDL consists of an inner hydrophobic core of CH esters and triglyceride, surrounded by a monolayer of polar phospholipid and apoproteins. One of the apoproteins, apolipo protein-E (APO-E), binds to receptors (LP receptors) on the plasma membrane of the adrenal cell, resulting in an ACTH- stimulated transport of CH into the cell. This sequence of actions is termed the LDL receptor pathway.
LDL has been linked with atherosclerotic disease, and the genetic disorder known as type III lipoproteinaemia, associated with premature atherosclerotic disease, possibly occurs because of the nature of the APO-E in these individuals. Their APO-E does not bind with normal affinity to the LP receptor.
After pregnenolone is released from the mitochondria, it is further metabolized in the smooth endoplasmic reticulum, where the double bond is switched from position 5 in the B ring to position 4 in the A ring, and the hydroxyl (OH) group at position 3 is oxidized to a keto group. Cortisol is formed through hydroxylation at the 11 position (Fig. 17c). Cortisol is the major glucocorticoid in humans, although further metabolism to another glucocorticoid, cortisone, occurs in the liver.

Synthesis of adrenal androgens
Adrenal androgens are biosynthesized from androstenedione, which is formed from 17-hydroxyprogesterone by the cleavage of the C17 side chain, and hydroxylation at C17.Androstenedione, an adrenal androgen, can be formed through isomerization at the C4–C5 positions, as described previously for glucocorti- coids, or after cleavage at C17.

Synthesis of adrenal estrogens
Estrogens are formed from testosterone and androstenedione by aromatization of the A ring. The term ‘aromatization’ refers to the formation of alternating double bonds in the six-membered ring. The conversion is achieved through the removal of the methyl group at C19, and further oxidation.
Neither the adrenal androgens nor the estrogens are normally produced in sufficient quantities to support reproductive function; the testis and ovary, respectively, are required for that purpose, but adrenal androgens and estrogens, and particularly the former, do become pathologically significant if produced in too high a concentration.

Mechanism of action of cortisol
Cortisol, like many other steroid hormones, passes freely into the cytoplasm where it combines with a receptor (Fig. 17d). The glucocorticoid receptor complex is translocated to the nucleus where it binds to specific response elements, resulting in RNA and protein synthesis, although transcription may sometimes be inhibited. There is evidence that some of the rapid actions of cortisol, for example on feedback in the brain and pituitary gland, are through cell membrane receptors for cortisol.