Estriol placental

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. 

Fig. 5.3.7 Disorders that affect the placental/maternal synthesis of estriol and diagnostic analytes for serum and urine. ORD Oxidoreductase deficiency, STS steroid sulfatase deficiency...

Estriol (estra-1,3,5(10)-trien-3,16-a,17-8 -triol) is the major estrogen metabolite found in the urine. It is excreted in the form of its conjugate with glucuronic acid. The determination of this steroid as an index of placental function has become one of the most widely used endocrine determinations. As pregnancy progresses, the excretion increases and reaches very high levels near term. In abnormal fetoplacental function, the levels of estriol will fall in some cases. The fall is usually progressive, and, because of this, serial determinations of urinary estriol must be carried out. The drop in estriol can be taken as evidence of placental insufficiency, and close watch by the physician is indicated, as a continued drop may necessitate Cesarean section to save the life of the infant. 

The same assay procedure should be used for specimens from an individual. Some background in the use of urinary estriol as an index of placental function may be found in a number of reports on the use of this valuable clinical chemistry tool in obstetrics. More recently, Wolff et al. (5) reviewed the various pathologies and abnormalities of pregnancy versus values of estriol levels in urine. 

Estriol is the predominant hormone of late pregnancy. Maternal estriol is almost entirely (-90%) derived from fetal and placental sources. It is first detected during the 9th gestational week and gradually increases during the first and... 

The placenta produces several protein and steroid hormones (Figure 54-1). The major protein hormones are CG and placental lactogen (PL). The steroids include progesterone, estradiol, estriol, and estrone. The placenta secretes most of its products into the maternal circulation only small amounts reach the fetal circulation. Close proximity of the maternal blood vessels to the site of placental hormone production may explain some of this preferential accumulation of hormones in the maternal blood circulation. Generally, hormone production by the placenta increases in proportion to the increase in placental mass. Therefore concentrations of hormones derived from the placenta, such as PL, increase in maternal peripheral blood as the placenta increases in size CG, which peaks at the end of the first trimester, is an exception. 

Bradley LA, Canick JA, Palomaki GE, Haddow JE. Undetectable maternal serum unconjugated estriol levels in the second trimester risk of perinatal complications associated with placental sulfatase deficiency. Am J Obstet Gynecol 1997 176 531-5. 

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. 

Estrogens, placental (U) (as estriol) Depends on period of gestation mg/24 h 3.468 Depends on period of gestation Mmol/d XXX 1 Minol/d... 

L2. Levitz, M., Dancis, J., Goebelsmann, U., and Diczfalusy, E., The metabolism and disposition of estriol and estriol conjugates of the fetal-placental unit in the second trimester. Proc. 2nd Intern. Congr. Hormonal Steroids, Milan, 1966 pp. 646-652. Excerpta Med. Found., Amsterdam, 1966. 

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. 

Fig. 12.3 Steroidogenesis in the human corpus luteum, placenta, and feto-placental unit. The only P450 in the corpus luteum (a) is P450scc, which limits steroidogenesis primarily to Prog. The placenta (b) contains the same pathway to Prog as the corpus luteum, except using 3PHSD type 1 rather than type 2, and the placenta lacks StAR. In addition, the fetoplacental unit (c) produces estrone, estradiol, and estriol. The fetal adrenal above dashed line in box) is high in P450cl7 and...

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. 

Determination of Placental Estriol in Urine by Gas-Liquid Chromatography with Equilenin as Internal Standard... 

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.

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). 

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... 

Ryan (19r>9a, b) was the first to demonstrate the conversion of andro-stenelriol to estriol after human placental tissue incubation. These re.sulta were confirmed usiiig otlier ICa-hydroxy-Cu steroids in tlie. same tissue (Magendantii and Ryan, 1964a,b). 

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. 

It can be concluded that placental estriol could originate principally from three dilferent sources (1) from 16a-li3 drox3 -dc iydroepiandrostcrone. which is transformed into 16a-hydroxyandrostenedione, then into 16a-hydroxyestrone, and linally, by the reduction of tlie 17-keto function, is converted into e.striol (2) from androstenetriol which is first converted into 16a-hydroxytestosteroiic and then info estriol or (3) from 16-oxoandro-stenediol, which is converted into 18-oxotestosterone, then into 16-oxo-estradiol and finally into estriol. 

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. 

Figure 16 show s the principal transformations and conjugations of estriol in the fetal and placental compartments. 

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.

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. 

The transfers between the fetal, placental, and maternal compartments of these three estrogens arc very different. In the study of Manor el al. (1963) it w as established that the plasma concentration of estrone and estradiol in the umbilical vein is higher than that in the umbilical artery, indicating a transfer of the two estrogens from the placenta to the fetus on the other hand, the concentrations of cstriol in the umbilical artery and the umbilical vein are of the same order, indicating that most of the estriol is transferred to the maternal compartment. 

In conclusion, during pregnancy the forms of conjugation vary greatly for the three principal estrogens estrone, estradiol, and estriol. These differences are explained by the differences in the suifuryl- and glucuroriyl-transferases, by tlie differences in the hydrolytic activities for ester sulfates and gluciironides, particularly in the placental compartment, and by the differences in the renal clearance. 

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