Dehydroepiandrosterone sulfate direct

Fig. 6. 3a- H- C-dehydroepiandrosterone sulfate. Direct pathway to H- C-epiandrosterone sulfate, and indirect major pathway to C-epiandrosterone sulfate.

According to the classical view of metabolism the hormones are synthesized as free steroids in endocrine tissues and prepared for excretion in urine by peripheral metabolism and conjugation. This view had to be modified upon the isolation of dehydroepiandrosterone sulfate from adrenal tumor [307]. Thus dehydroepiandrosterone sulfate, a steroid conjugate, was shown to be secreted by the adrenal tissue. Isotopic methods also pointed in the same direction. Lieberman et al. [304], using... 

Metabolic studies carried out with isotopically labeled dehydroepi-androsterone sulfate [312] showed that this conjugated steroid may follow an indirect metabolic pathway initiated by the hydrolysis of the sulfate group. In the course of the metabolism the conjugated steroid thus becomes a free steroid first and the free steroid may undergo further metabolism. On the other hand, dehydroepiandrosterone sulfate may follow a direct metabolic pathway without a break of the ester group. 

The discovery of dehydroepiandrosterone sulfate secretion gave a new incentive to the whole study of conjugation, and it soon became evident that dehydroepiandrosterone sulfate could not only be biosynthesized from sulfo conjugated percursors along a direct biosynthetic pathway, but could also undergo further metabolism, with or without hydrolysis of the sulfate moiety (i.e., indirect or direct metabolism) and act as a privileged precursor of active steroids. 

Roberts et al. (1961) first described the conversion of dehydroepian-drosterone sulfate into androsterone and 5/3-androsterone glucuronides in vivo, thereby establishing that dehydroepiandrosterone sulfate can be split in vivo and that there is a dynamic equilibrium dehydroepiandrosterone sulfate dehydroepiandrosterone (Fig. 4). The conversion of dehydroepiandrosterone sulfate into androsterone and 5 -androsterone sulfates can only exist via an indirect pathway (Baulieu et al., 1965) (Fig. 5), but dehydroepiandrosterone sulfate can be transformed both directly and indirectly into epiandrosterone sulfate (Fig. 6). 

Indirect and direct metabolism of dehydroepiandrosterone sulfate are combined in estrogen formation during pregnancy, since dehydroepiandrosterone sulfate is hydroxylated into 16a-hydroxydehydroepiandrosterone... 

After the first demonstration of a direct metabolism of a steroid conjugate [androstenediol sulfate =i dehydroepiandrosterone sulfate (Baulieu et ah, 1963)], showing that a 17j8-hydroxysteroid oxidoreductase can have a sulfo conjugate as a substrate, other enzymic transformations of dehydroepiandrosterone sulfate were reported (Fig. 4). Dehydroepiandrosterone sulfate can undergo 16o -hydroxylation to 16a-hydroxy-dehydroepiandrosterone sulfate which can be further hydroxylated into androstenetriol sulfate its direct 17-hydroxylated metabolite, androstene-... 

Testosterone sulfate does not seem to be hydrolyzed in the organism, but its direct metabolites have not been identified, as only 3.5% of the radioactivity was found in urine after radioactive testosterone sulfate administration. Unlike dehydroepiandrosterone sulfate, testosterone sulfate is not transformed by indirect metabolism into estrogens during pregnancy (Dray, 1963). 

Most other in vitro or in vivo experiments, however, show little or no direct activity of steroid conjugates. Peillon and Racadot s study (1965) on the involution of LH-producing pituitary cells by dehydroepiandrosterone and dehydroepiandrosterone sulfate in the rat, and Holdens (Holden and Lozinski, 1950) results after sodium-testosterone sulfate administration to castrated rats show no efiFect of the conjugate. This was also the case in Josso s (1970) experiments on the influence of androstenediol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate on the maintenance of Wolffian canals of rat fetus in culture. 

Buiarelli et al. (2004) extended the above analytical approach to many more related steroids when they published a method for the direct analysis of 15 urinary anabolic steroids in a single run, namely T, epitestosterone, dehydroepiandrosterone (DHEA), androsterone, etiocholanolone, their sulfates and their glucuronides (Figure 2,2), They extracted 2 mL of human urine by solid-phase extraction with methanol elution and reconstituted the residue in aqueous methanol in the presence of deuterated internal standards (da-epitestosterone glucuronide, [16,16,17-"H3 testosterone sulfate and [16,16,17-2H3]testosterone), then monitored, for example, mJz. 289-97 and 109 for T and epitestosterone, miz 367-97 for their sulfates, and m/z 463-113 and 287 for their glucuronides. The method does not achieve quantitation, but it allows the estimation of ratios, which makes it possible to monitor the urinary steroid profile, which is useful for monitoring the abuse of anabolic steroids. 

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