DHEA-S is the major precursor of estrogens in pregnancy (Baulieu, 1963; Siiteri, 1963). However, maternal adrenal glands do not produce suicient amounts of DHA-S to account for more than a fraction oftotal placental estrogen biosynthesis. he fetal adrenal glands are quantitatively the most important source of placental estrogen precursors in human pregnancy. hus, estrogen production duringpregnancy relects the unique interactions among fetal adrenal glands, fetal liver, placenta, and maternal adrenal glands.
More than 90 percent of estradiol and estriol formed in syncytiotrophoblast 'enters maternal plasma (Gurpide, 1966). And, 85 percent or more of placental progesterone enters maternal plasma, and little maternal progesterone crosses the placenta to the fetus (Gurpide, 1972).
his directional movement ofnewly formed steroid into the maternal circulation stems from basic characteristics of hemochorioendothelial placentation. In this system, steroids secreted from syncytiotrophoblast can enter maternal blood directly. Steroids that leave the syncytium do not enter fetal blood directly. hey must irst traverse the cytotrophoblast layer and then enter the stroma of the villous core and then fetal capillaries. From either ofthese spaces, steroids can reenter the syncytium. he net result of this hemochorial arrangement is that entry of steroids into the maternal circulation is substantially greater than that into fetal blood.
Morphologically, functionally, and physiologically, the fetal adrenal glands are remarkable. At term, the fetal adrenal glands weigh the same as those of the adult. More than 85 percent of the fetal gland is composed of a unique fetal zone, which has a great capacity for steroid biosynthesis. Daily steroid production of fetal adrenal glands near term is 100 to 200 mg/d. This compares with resting adult steroid secretion of 30 to 40 mg/d.
The fetal zone is lost in the irst year of life and is not present in the adult. In addition to ACTH, fetal adrenal gland growth is influenced by factors secreted by the placenta. This is exempliied by the continued growth of the fetal glands throughout gestation and by rapid involution immediately after birth and placental delivery.
Estradiol is the primary placental estrogen product at term. In addition, significant levels of estriol and estetrol are found in the maternal circulation, and levels also rise, particularly late in gestation (see Fig. 5-19). hese hydroxylated forms of estro gen derive from the placenta using substrates formed by the combined eforts of the fetal adrenal gland and fetal liver. For this, high levels of fetal hepatic 16a-hydroxylase act on adre nal-derived steroids. Ryan (1959b) and MacDonald and Siiteri (1965b) found that 16a-hydroxylated C19 steroids, particu larly 16a-hydroxydehydroepiandrosterone (16-0HDHEA), were converted to estriol by placental tissue. Thus, the dispro portionate increase in estriol formation during pregnancy is accounted for by placental synthesis of estriol principally from plasma-borne 16-0HDHEA-sulfate. Near term, the fetus is the source of 90 percent of placental estriol and estetrol precur sors in normal human pregnancy.
Maternal estriol and estetrol are produced almost solely by fetal steroid precursors. hus, in the past, levels of these steroids were used as an indicator of fetal well-being. However, the low sensitivity and speciicity of such tests have caused them to be discarded.