Estriol sulfate, fetal

Fig. is. XransformAtioQs and conjugations of estriol in the fetal and placental ix)inpartments. l.oa-HO-Ej l.oa-lsj-droxyes(riol Ej-S estriol sulfate Ej-16a-Glu estriol lS(z-gluciironide Ks-3S, I6 -Giu estrio)-3n.suifatc, iSa-glueuronide. 

Estriol circulates in the fetal compartment principally in conjugated form. Touch.stone and Greene (1960) observed the conjugation of estriol in cord blood and Levitz el ol. (19(37) established that aulfurylation was the principal means of conjugation in fetal life. Trocn et cA. (1961) isolated estriol-3-sulfate from the cord blood and Menini and Diczfalusy (1961) isolated tbe same conjugate in human meconium. Consequent, estriol sulfate is the main transformation product of estriol in the fetal compartment and this 3-sulfate is the most important form in which this estrogen circulates in the fetal compartment. 

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.

Significant ejuantities of estriol, estriol sulfate, and estriol glucuronidc are localized in the amniotic fluid (TToen et aL, 1961), and since this compartment exhibits a high sulfatase activity, it can be concluded that fetal membranes and the amniotic cavity are actively involved in the interchange of steroid conjugates between fetus and mother. 

The presence of an important quantity of estriol circulating in maternal blood as 3-suIfate, 16a-gIucuronide permits the suggestion that this conjugate represents an intermediary step between fetal estriol sulfate and maternal urinary estriol glucuronide. This hypothesis is supported by the presence of estriol-3-sulfatc,16 t-gIucuronide in pregnancy urine (Straw et al., 1955). 

Estriol is also produced by another pathway in the syncytiotrophoblast cells of the placenta DHEAS from fetal adrenal is converted to 16a-hydroxydehydroepiandrosterone sulfate in the fetal liver, followed by removal of the sulfated chain to produce 16a-hydroxy-dehydroepiandrosterone, which is then aromatized to estriol. Estriol is the predominant estrogen produced during pregnancy, and almost all of tiie estriol and estradiol produced by the placental syncytiotrophoblast enters the maternal circulation. By the 7th week of gestation, the placenta produces the majority of the estrogen in the maternal circulation. 

It will be seen from Table 3 that lower levels of estrone and estradiol, but higher levels of estriol, are found in cord blood compared with maternal blood. Estrone and estradiol can be formed from DHA-sulfate reaching the placenta from the fetus (B25) or the mother (B4, B25, S18, W2). These steroids are then secreted by the placenta into the maternal and fetal compartments. Estrone and estradiol reaching the fetus by the umbilical vein can be 16a-hydroxylated to form estriol, but most of the estriol is probably formed by placental aromatization of the large amounts of 16a-OH-DHA sulfate synthesized by the fetus (D6). Estriol is rapidly catabolized by infants (see Section 4.1.3), but if this is so for the fetus, the similar concentration in arterial and venous cord blood is difficult to explain, though a small amount of the estriol in the arterial blood may have been formed by the fetus from estrone and estradiol supplied by the placenta. 

CYB5A, yielding dehydroepiandrosterone (DHEA), which enters the circulation as DHEA sulfate (DHEAS), a substrate for P450 3A7 in the fetal liver below dashed line in box). In the plaeenta, steroid sulfatase removes the sulfate from 16a-hydroxyDHEAS, and 3PHSD1 oxidizes and isomerizes 16a-hydroxyDHEA, to yield 16a-hydroxyandrostenedione. Placental P450aro and 17PHSD1 catalyze the final transformations to 16a-hydroxyestrone and estriol, respectively. 

Fig. 7. Biosynthesis of placental estrogens. Sequence of some chemical reactions. Dehydroepiandrosterone sulfate (DS) to androstene triol-sulfate and estrone (Ei) to estriol (Em) take place only in fetal or maternal liver.

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. 

Using simultaneous intravenous injection of estradiol- H and dehydroepi-androstcronc- C-sulfate to the mother during pregnancy, it w as established that after 20 weeks of gestation more than 70% of estriol originates in the fetal and placental compartments (Siitcri and MacDonald, 1966). These results confirm the data of Bradshaw and Jessop (19.53), w ho observed a rapid decrease of urinary estrogens and particularly of estriol after removal... 

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. 

Part of the estriol and epiestrbl produced by the placenta is transferred to the fetal compartment and conjugated priricipalh to sulfuric acid, then returned to the placenta as ester sulfate. 

As indicated previously (Section 111, F, 1 and 2), the two quantitatively most important steroids circulating in the fetal compartment are dehydro-epiandrosterone sulfate and 16a-hydroxydehydroepiandrosteronc sulfate. The concentration of these two steroids is higher in the umbilical artery than in the umbilical vein, indicating their production in the fetal compartment and their secretion to the placenta, in placental tissue, the major part of these steroid conjugatiis is hydrolyzed and aromatized and the respective estrogens (estrone, 17d-est.radiol, and estriol) are largely transferred to the mother while a small part returns to the fetus. 

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