The precursor for fetal adrenal steroidogenesis is cholesterol. he steroid biosynthesis rate in the fetal gland is so great that its steroidogenesis alone is equivalent to a fourth of the total daily LDL cholesterol turnover in adults. Fetal adrenal glands synthesize cholesterol from acetate. All enzymes involved in cholesterol biosynthesis are elevated compared with those of the adult adrenal gland (Rainey, 2001). Thus, the de novo cholesterol synthesis rate by fetal adrenal tissue is extremely high. Even so, it is insuicient to account for the steroids produced by fetal adrenal glands. Therefore, cholesterol must be assimilated from the fetal circulation and mainly from LDL (Carr, 1980, 1981 b, 1982; Simpson, 1979).
Most fetal plasma cholesterol arises by de novo synthesis in the fetal liver (Carr, 1984). The low LDL cholesterol level in fetal plasma is not the consequence of impaired fetal LDL synthesis, but instead results from the rapid use ofLDL by the fetal adrenal glands for steroidogenesis (Parker, 1980, 1983).
Several fetal disorders alter the availability of substrate for placental steroid synthesis and thus highlight the interdependence of fetal development and placental function.
Fetal demise is followed by a striking reduction in urinary estrogen levels. Similarly, after ligation of the umbilical cord with the fetus and placenta left in situ, placental estrogen production declines markedly (Cassmer, 1959). However, as previously discussed, placental progesterone production is maintained. In sum, an important source of precursors of pla cental estrogen-but not progesterone-biosynthesis is elimi nated with fetal death.
Anencephalic etuses have markedly atrophic adrenal glands.
his stems from absent hypothalamic-pituitary function, which precludes adrenal stimulation by ACTH. With absence of the adrenal cortex fetal zone, the placental formation of estrogen-especially estriol-is severely limited because of diminished availability of C19 steroid precursors. Indeed, uri nary estrogen levels in women pregnant with an anencephalic fetus are only about 10 percent of those found in normal preg nancy (Frandsen, 1961). With an anencephalic fetus, almost all estrogens produced arise from placental use of maternal plasma DHEA-S.
Fetal adrenal cortical hypoplasia occurs in perhaps 1 in 12,500 births (McCabe, 2001). Estrogen production in these pregnan cies is limited, which suggests the absence of C19 precursors.
Fetal-placental suatase diciency is associated with very low estrogen levels in otherwise normal pregnancies (France, 1969). Namely, sulfatase deficiency precludes the hydrolysis of C19 steroid sulfates, the first enzymatic step in the placental use of these circulating prehormones for estrogen biosynthesis. This deficiency is an X-linked disorder, and thus all afected fetuses are male. Its estimated frequency is 1 in 2000 to 5000 births and is associated with delayed labor onset. It also is associated with the development of ichthyosis in afected males later in life (Bradshaw, 1986).