Androstenediol sulfate

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-... 

The biologically inactive estrone sulfate (EIS) and dehydro-epiandrosterone-sulfate (DHEAS) are the most abundant circulating estrogenic precursors in the plasma of post-menopausal women [103]. Desulfation of inactive steroid-3-0-sulfates by estrone-sulfatase (STS) plays a key role in the regulation of levels of receptor-active estrogenic steroids (estradiol and androstenediol) in breast cancer cells (Fig. 9). There is strong evidence suggesting that estrone sulfatase (STS) and DHEA-sulfatase are the same enzyme [103]. 

K. Mitamura, Y. Nagaoka, K. Shimada, S. Honma, M. Namiki, E. Koh, A. Mizokami, Simultaneous determination of androstenediol 3-sulfate and DHEA sulfate in human serum using isotope diluted LC-ESI-MS, J. Chromatogr. B, 796 (2003) 121. 

Adrenal androgens also have a complex metabolic fate DHEA-S is formed in the adrenal cortex or by sulfokinases in the liver and kidney from DHEA and excreted by the kidney. DHEA and DHEA-S can be metabolized by 7a-and 16a-hydroxylases. 17p-Reduction of both compounds forms A -5-androstenediol and its sulfate. Androstenedione can be metabolized to androsterone after 3a- and 5a-reduction. 5P-Reduction results in the formation of etiocholanolone (see Eigure 51-7). These metabolites are conjugated to glucuronides and sulfates, which are then excreted in the urine. 

It will be noticed from Table 4 that the lowest arteriovenous concentration differences are shown for 21-OH-pregnenolone, 16 -OH-DHA, and androstenediol (mainly 17a). It is possible that their low uptake by the placenta is due to their being diconjugated (Table 15), and it is possible that though the placenta can readily hydrolyze 3 8-sulfates it may have difficulty hydrolyzing (P6), and therefore removing from circulation, steroids sulfated at other positions. 

Mitamura, K. Nagaoka, Y. Shimada, K. Honma, S. Namiki, M. Koh, E. Mizokami, A. Simultaneous determination of androstenediol 3-sulfate and dehydroepiandrosterone sulfate in human plasma using isotope diluted Uquid chromatography-electrospray ionization-mass spectrometry. J. Chromatogr. B, 2003, 796 (1), 121-130. 

Roberts et ah (1964) answered part of the question by injecting doubly labeled cholesterol sulfate into the splenic artery (supplying 90% of the blood to an adrenal carcinoma) of a female patient and isolating various steroid sulfates in the urine of the first 24 hours. Of the recovered radioactivity 0.46% was dehydroepiandrosterone sulfate, bearing the same H/ S ratio as the injected compound. Urinary androstenediol-3-monosulfate and 5-pregnene-3/3,17a,20a-triol-3-monosulfate as well as 16a-hydroxydehydroepiandrosterone-3-monosulfate also had the same ratio as the injected cholesterol sulfate, demonstrating that all these compounds have a common sulfated precursor, which could possibly be cholesterol sulfate. 

Reaction rates can be smaller for the conjugate than for the free homolog, as is the case for the oxidation of androstenediol glucuronide by the liver enzyme, when compared to testosterone (Milgrom and Baulieu, 1968) and for estradiol sulfate when compared to estradiol (Warren and Crist, 1967) with the placental enzyme. But, estriol sulfate is oxidized at a higher rate than estriol by a human red cell reductase (Jacobsohn and Hochberg, 1967) and testosterone sulfate is reduced faster than the free compound by a microsomal A -3-oxosteroid reductase preparation (Wu and Mason, 1965). 

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. 

Fetal brain tissues also possess very active sulfokinases for dehydro-epjandro.steronc, and after incubation of tritium dehydroepiandrosterone with minced brain tissue from a human fetus in the twelfth week of gestation, 6% of the radioactive material consisted of ester sulfates (principally dehydroejnandrostcrone and androstenetriol sulfates). Moreover, the free fraction was largely metabolized to androstenediol, androstenetriol, and 16-ketoandrostenediol (Kiiapstein et al., 1968). 

In the placental tissue, there is an extensive formation of androstenedione from dehydroepiandrosterone, which is obtained mostly by the hydrolysis of dehydroepiandrosterone sulfate, which is biosynthesized principally in the fetal compartment. On the other hand, as was indicated before (Section 111, B, 1, a), in the placental compartment very few if any Cw steroids arc formed from Cm steroids by side-chain cleavage (Warren and Cheatum, 1964 Jaffe et al., 1965). Also, since androstenedione is not a good substrate for 17d-rcductasc, it can be assumed that most of the placental t( Stosterone originates from fetal androstenediol (Uell Acqua et al., 1966, 1967a,b). It is interesting to note that thi.s latter steroid is a normal const.ituent of cord blood (Kberlein, 1965). 

Fig. 18. Schematic representation of the principal transformations of the Cu and Cl steroids and their conjugates in the fetal and placental compartments. Aj-P pregnenolone P progesterone ITd-IlO-Aj-P iTa-hydroxyprcgnenolone 17a-HO-P 17a-hydroxyprogesterone DTI A dehydroepiandrosterone AND androstenedione 17/J-.D1I-DHA androstenediol-lTp DIIA-S dehydroepiandrosterone sxilfate Ida-IIO-DHA 16a-hydroxydchydrocpiandrosterone 16 -1I0-D1IA-S 16a-hydroxydehydroepi-androstcrono sulfate androstenetriol-S androstenetriol sulfate E estriol Kj-S estriol sulfate T testosterone Ej estradiol Kj-S estradiol sulfate E[ estrone E -S estione sulfate.

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