Estriol formation

The estriol route is the most significant, judging from the fact that estriol is the major urinary estrogen in humans. As its name suggests, estriol contains three hydroxyl groups, two of which are identical to those of estradiol (3, 11 ), but the third is unique to estriol, a 16a-hydroxyl group that is attached to either estrone or estradiol. Estriol formation is increased in obesity and hypothyroidism, and is decreased in hyperthyroidism. Catecholestrogen formation is catalyzed by a 2-hydroxylase that is present in the liver, nerve cells, and other tissues, and both estrone and estradiol... 

The increased levels of estradiol stimulate the biosynthesis of the steroid hormone binding protein. The reduction of estriol formation in liver cirrhosis is likely to result in part from cholestasis which interrupts the enterohepatic circulation and in more severe cases from poor uptake of estrogens by the hepatic cells, thus preventing the conversion of estrogen to estriol. 

Antioxidant activity of estrogens was compared on the basis of their activity to inhibit formation of ABTS,+. Estriol, estrone, 17/3-estradiol, and 17a-ethinyl-estradiol showed more than twofold higher activity than diethylstilbestrol, 2-hydro-xyestradiol, and 4-hydroxyestradiol. Antioxidant activity of mestranol was negligible. On a molar basis, estrone was 2.43 times more effective than Trolox (R24). 

Other workers [358] carried out the acylation of estrogens in acetone and reported the following conditions as optimal for the preparation of tris-HFB-estriol 0.1—0.3 jul of acetone per 1 jug of the substrate and 0.05 ml of HFB anhydride at room temperature for 10 min. The use of a larger amount of another solvent (benzene, methylene chloride, dimethyl sulphoxide, diethyl ether, dioxane) was said to result in the formation of a number of by-products. Poole and Morgan [359], however, stated that the HFB derivatives of some steroids are not thermally stable and that only the decomposition product is detected, e.g., cholesta-3,5-diene is produced from cholesterol. This leads to a considerably lower ECD response, so that the detection limit, which under favourable circumstances can be as low as 0.005 ng, is usually not achieved. As steroids that form unstable HFB derivatives they reported cholesterol, lumisterol, ergosterol, estradiol, pregnanetriol and others. 

Placental synthesis of estrogens. The placenta lacks the key enzyme necessary for formation of estrogens from cholesterol (CYP 17) and relies on androgenic precursors from the maternal and fetal compartments. The major androgen used comes from the fetal zone of the fetal adrenal this is DHEAS, which is also taken up and metabolized by fetal liver into Iba-hydroxy-DHEAS. The placenta converts DHEAS into estrone (E ) and estradiol (E2) and proces.ses 16a-hydroxy-DHEAS into estriol (Ej). Estrogens enter the maternal circulation and appear in maternal urine as conjugated estrogens. 

The thermodynamic parameters for estriol, estradiol, ethinyloestradiol, and estrone with and y-CyD measured by Sadlej-Sosnowska [49] in methanol-water and acetonitrile-water mixtures indicate that the values of enthalpy changes due to complex formation with and y-CyD are more negative in methanol than in... 

Estrogen, conjugates, see also under Estriol glucuronide and Estrone sulfate, IX, 216-218 formation, IX, 217-218, 233 Estrogens, see also under names of individual compounds action on egg, VIII, 191, 203, 204 activation in tissues, IX, 224 activity,... 

The formation of 2-methoxyestrogens from the estrogens requires also 2-hydroxylation of the phenolic steroids. It has recently been shown by Fishman et al. (1960a) that this reaction does in fact occur in human tissues. Following the injection of estradiol-l7 9-i5-C into a 22-year-old man, 2-hydroxyestrone was isolated from the urine. The extent of 2-hydroxylation appears to be considerable about 12% of the administered radioactivity was recovered from the urine as radioactive 2-hydroxyestrone. An extensive study on 2-hydroxylation of estriol by rat liver in vitro was carried out by King (1961 a,b). It was found that the 2-hydroxylase activity is limited to the microsomal fraction and requires either NADHj or NADPHz, and possibly a folic acid derivative ATP appears to stimulate the 2-hydroxylase. 

Macrae HF, Dale DG, Common RH. Formation in vivo of 16-epiestriol and 16-ketoestradiol-17 beta from estriol by the laving hen and occurrence of equol in hen s urine and feces. Can. J. Biochem. Physiol. 38, 523-532, 1960. 

Engel, L. L., B. Baggett, and M. Halla The formation of i C-labelled estriol from 16- C-estradiol-17j5 by human fetal liver slices. Biochim. biophys. Acta (Amst.) 30, 435 (1958). 

It is interesting to note that in spite of a very large concentration of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the umbilical artery, no 16af-hydroxylation takes plaa in placental tissue (Jackanicz and Diczfalusy, 1968) consequently, the formation of placental estriol re.sults mainly from fetal precursors. 

Placental estriol is biosynthesified from fetal lOa-hydroxydehydroepi-androslerone which reaches the placenta oi the form of ester sulfate (see Section III, 2, a), Androstcnetriol also reaches the placenta from the fetus in the form of ester sulfate and contributes to the formation of e.striol. 

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