Testosterone synthesis from cholesterol

Testosterone, the principal male sex steroid hormone, is synthesized in five steps from cholesterol, as shown below. In the last step, five isozymes catalyze the 17/3-hydroxysteroid dehydrogenase reactions that interconvert 4-androstenedione and testosterone. Defects in the synthesis or action of testosterone can impair the development of the male phenotype during embryogenesis and cause the disorders of human sexuality termed male pseudohermaphroditism. Specifically, mutations in isozyme 3 of the 17/3-hydroxysteroid dehydrogenase in the fetal testis impair the for-... 

A. In the Leydig cell the rate-limiting step in testosterone synthesis is the enzymatic cleavage of side chains from cholesterol to form pregnenolone. 

RUZICKA, LEOPOLD (1887-1976). A chemist who won the Nobel prize in 1939 with Adolf Friedrich Johann Butenandt. His work involved research in organic synthesis including polymethylenes and higher terpenes. He was the first chemist to synthesize musk, androsterone. and testosterone from cholesterol. His medical degree was awarded at the University of Basel, Switzerland, although he was born in Croatia and educated partially in Germany. 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

For the formation of testosterone (51), androsten-5-3-ol-17-one (50) obtained by oxidation from cholesterol was employed although it was also derivable from diosgenin by way of l6-dehydropregnenolone as described for the preparation of progesterone. The synthesis of the androgen followed the route shown and the acetate was isolated in an overall yield of nearly 40% in the Syntex procedure from the androstenone intermediate. 

A key intermediate for the synthesis of both testosterone and cortisol from cholesterol is... 

CYPs that catalyze steroid and bile acid synthesis have very specihc snbstrate preferences. For example, the CYP that prodnces estrogen from testosterone, CYP19 or aro-matase, can metabolize only testosterone, and does not metabolize xenobiotics. Specihc inhibitors for aromatase, snch as anastrozole, have been developed for use in the treatment of estrogen-dependent tnmors. The synthesis of bile acids from cholesterol occnrs in the liver where, snbseqnent to CYP-catalyzed oxidation, the bile acids are conjngated and transported throngh the bile duct and gallbladder into the small intestine. CYPs involved in bile acid prodnction have strict snbstrate reqnirements and do not participate in xenobiotic or drng metabolism. 

Testosterone is a male sex hormone, one of a class of compounds known as androgens. Included in this group are testosterone, dihydrotestosterone, and androstenedione. Androgens are synthesized from cholesterol and are considered steroid hormones, a category of hormones that includes female sex hormones such as estrogen. The isolation and synthesis of testosterone were reported in 1935. Chemists Adolf Butenandt and Leopold Ruzicka later received the Nobel Prize in chemistry (in 1939) for this work and related discoveries. 

In men, LH acts on testicular Leydig cells to stimulate de novo synthesis of testosterone from cholesterol. Testosterone is required for gametogenesis within the seminiferous tubules and for maintenance of libido and male secondary sexual characteristics (see Chapter 58). FSH acts on the... 

Figure 19.8 A brief summary of the pathways for formation and secretion of oestradiol and progesterone within the cells of the follicle. Cholesterol is taken up by thecal cells in a complex with low density lipoprotein. In the thecal cells, cholesterol is converted to testosterone which is released to be taken up by granulosa cells where it is converted into oestradiol. For synthesis of progesterone in the granulosa cells, cholesterol is synthesised de novo within the cells from acetyl-CoA. In the follicle the enzyme aromatase, which produces the aromab c ring in the female sex hormones, is restricted to the granulosa cells. The reacrions that are stimulated by LH and FSH increase synthesis and, therefore, secretion of testosterone and increased synthesis of oestrogens and progesterone.

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. 

This chapter examines the biosynthesis of three important components of biological membranes—phospholipids, sphingolipids, and cholesterol (Chapter 12). Triacylglycerols also are considered here because the pathway for their synthesis overlaps that of phospholipids. Cholesterol is of interest both as a membrane component and as a precursor of many signal molecules, including the steroid hormones progesterone, testosterone, estrogen, and cortisol. The biosynthesis of cholesterol exemplifies a fundamental mechanism for the assembly of extended carbon skeletons from five-carbon units. 

Figure 8-2. Synthesis of the steroid hormones. The rings of the precursor cholesterol are lettered. Dihydrotestosterone is produced from testosterone by reduction of the C - C double bond in ring A. DHEA = dehydroepiandrosterone.

We now turn our attention to the synthesis of the fundamental lipid cholesterol. This steroid modulates the fluidity of animal cell membranes (p. 343) and is the precursor of steroid hormones such as progesterone, testosterone, estradiol, and cortisol. All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process (Figure 26.6). 

F. 34.23. Synthesis of the steroid hormones. The rings of the precursor, cholesterol, are lettered. Dihydrotestosterone is produced from testosterone by reduction of the carbon-carbon double bond in ring A. Structural changes between the precursor and final hormone are noted in blue. DHEA = dehydroepiandrosterone. The dashed lines indicate alternative pathways to the major pathways indicated. The starred enzymes are those that may be defective in the condition congenital adrenal hyperplasia. 

The steroids are another group of compounds derived from mevalonic acid. They inciude i synthesis of the steroids is sex hormones such as testosterone and progesterone, and the cholesterol needed to build cell discussed in the online chapter membranes but also implicated in the damage to arteries caused by atherosclerosis. Natural products. ... 

Cholesterol is the starting material (the precursor molecule) for the synthesis of steroid sex hormones. One female sex hormone, progesterone, differs only slightly in structure from the male hormone, testosterone. In fact, relatively minor structural differences between many female and male sex hormones account for significandy different biological activities. 

Protecting groups, as described in the text, are essential parts of many organic syntheses. An example is the synthesis of the sex hormone testosterone (Section 4-7) from a cholesterol-derived starting material. Natural sources of steroid hormones are far too limited to meet the needs of medicine and research these molecules must be synthesized. In our case, the hydroxy function at C3 and carbonyl function at C17 of the starting mat al have to trade places to furnish the desired testosterone precursor. In other words, selective reduction of the carbonyl group at C17 and oxidation of the hydroxy group at C3 are required. In the scheme that was... 

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