Progesterone, formation from cholesterol

FIGURE 25.43 The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to /3-estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone. 

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. 

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.

Activation of the LH receptor results in an increase of intracellular cyclic adenosine monophosphate (cAMP) levels via activation of a G protein and adenylate cyclase. In the presence of elevated concentrations of cAMP, cholesterol esterase activation occurs. This enzyme catalyzes the cleavage of cholesterol esters to free cholesterol, v/hich is then converted in mitochondria to pregnenolone as described previously. The formation of progesterone from pregnenolone is catalyzed by 5-ene-3p-hydroxysteroid dehydrogenase and 3-oxosteroid-4,5-isomerase (steps c and d in Fig. 46.3). 

In the isolation of steroids from natural sources one must, of course, consider their stability prior to enzyme inactivation, which usually occurs at the commencement of the isolation procedure, when the tissue is extracted with organic solvents. Kahnt and Neher (1965) could observe in bovine adrenal homogenates only trace amounts of 20a-hydroxycholesterol and (22R)-20,22-dihydroxy-cholesterol, as well as pregnenolone or progesterone (< figlgm). As stated earlier the absence of certain derivatives may be due to either their lack of formation or their rapid disappearance from the system. Until recently, primarily because of the lack of appropriate substrates of high specific activity, quantitative studies on the elucidation of the mechanism of the desmolase reaction could not be performed. The study of Ichii et al. (1967a) appears to entail the assumption of a steady state, for which no proof seems to have been provided. Also,... 

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