Steroid hormones circulating forms

Dietary vitamin A is stored in the liver and secreted into the bloodstream when needed. The circulating retinol is taken up by target cells and oxidized in part to retinoic acid, which induces the synthesis of proteins through the direct control of gene expression. This type of action—gene activation—establishes vitamin A (in the form of its metabolite, retinoic acid) as a hormone, similar to the steroid hormones and the thyroid hormone. 

Vitamin D3 is a precursor of the hormone 1,25-dihy-droxyvitamin D3. Vitamin D3 is essential for normal calcium and phosphorus metabolism. It is formed from 7-dehydrocholesterol by ultraviolet photolysis in the skin. Insufficient exposure to sunlight and absence of vitamin D3 in the diet leads to rickets, a condition characterized by weak, malformed bones. Vitamin D3 is inactive, but it is converted into an active compound by two hydroxylation reactions that occur in different organs. The first hydroxylation occurs in the liver, which produces 25-hydroxyvita-min D3, abbreviated 25(OH)D3 the second hydroxylation occurs in the kidney and gives rise to the active product 1,25-dihydroxy vitamin D3 24,25 (OH)2D3 (fig. 24.13). The hydroxylation at position 1 that occurs in the kidney is stimulated by parathyroid hormone (PTH), which is secreted from the parathyroid gland in response to low circulating levels of calcium. In the presence of adequate calcium, 25(OH)D3 is converted into an inactive metabolite, 24,25 (OH)2D3. The active derivative of vitamin D3 is considered a hormone because it is transported from the kidneys to target cells, where it binds to nuclear receptors that are analogous to those of typical steroid hormones. l,25(OH)2D3 stimulates calcium transport by intestinal cells and increases calcium uptake by osteoblasts (precursors of bone cells). 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

Cholesterol is an extremely important biological molecule that modulates the fluidity of animal cell membranes and is the precursor of steroid hormones (such as progesterone, testosterone, oestradiol and cortisol) and bile acids. Cholesterol is either derived from the diet or synthesised de novo. Regardless of the source, cholesterol is transported through the circulation in lipoprotein particles, as are cholesterol esters, the cellular storage form of cholesterol. The amount of cholesterol synthesised daily in the liver of a normal person is usually double that obtained from dietary sources. Other sites of cholesterol synthesis include the intestine, and the degree of production is highly responsive to cellular levels of cholesterol. Over 1.2 g of cholesterol is lost in the faeces daily in the form of free sterol or as bile acids. 

Human steroid hormones are synthesized primarily from cholesterol in the adrenal glands and gonads. In most cases, cholesterol is made available from the circulation in the form of low-density lipoprotein cholesterol (LDL). The uptake of... 

Fatty acids are also found esterified to the 3-hydroxyl group of cholesterol (cholesterol esters ChE). ChE, which are more hydrophobic than free cholesterol, are a transport and storage form of cholesterol. ChE are found in high concentrations in low-density lipoproteins. Intracellular lipid droplets containing ChE are found in steroidogenic tissues and are thought to be a reservoir of cholesterol for steroid-hormone synthesis. The fatty acid most commonly found in ChE is 18 1. It must be activated to its CoA derivative before transfer to cholesterol in a reaction catalyzed by acyl-CoA cholesterol acyltransferase. ChE are also formed within lipoproteins by the transfer of one fatty acyl chain from phosphatidyl choline to cholesterol, a reaction catalyzed by circulating lecithin cholesterol acyltransferase. 

Other steroids derived from cholesterol include certain vitamti (e.g. Vitamin D), several drugs and poisons, the bile acids of dige tion, and many hormones, in particular the sex hormones (si page 233). Derivatives of cholesterol itself circulate in the blooi stream and form part of the walls of arteries and veins, and di orders in the body s use of cholesterol are widely believed to t associated with arterial diseases, such as coronary thrombosis. 

Biosynthesis of testosterone. The primary precursor is acetyl-CoA, and biosynthesis proceeds via cholesterol (see Terpenes, Steroids). Testes and adrenal cortex also utilize cholesterol which they receive as cholesterol esters from plasma lipoproteins (see Lipoproteins). A second androgen, more potent than testosterone, is 5a-dihydrotestosterone this is formed from circulating testosterone at peripheral sites, and not by the Leydig cells of the testes. Ring A of 5a-testosterone cannot be aromatized, so this hormone cannot serve as an estrogen precursor. 

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