Steroids that circulate in the free form (not bound to cortisol-binding protein [transcortin]) may cross the placentafrom mother to fetus, but ACTH does not. The placenta plays an important role in steroid biosynthesis in utero, acting as a metabolic mediator between mother and child.Because the fetal CRH-ACTH-adrenal axis is operationalin utero, deficiencies in cortisol synthesis lead to excessiveACTH secretion. If a virilizing adrenal enzyme defect ispresent, such as 21-hydroxylase deficiency, the fetal adrenalgland secretes excess androgens, virilizing the fetus. Normalvariation of serum cortisol and ACTH levels leads to values that are high early in the morning and lower at night. Thisnormal diurnal variation may take months to years to fullydevelop.
Figure 178-1 Diagram of the steroid biosynthetic pathways and the biosynthetic defects that result in congenital hyperplasia. The defect in patients with lipoid adrenal hyperplasia is not (except for one reported case) in the CYP11A1 (cholesterol side-chain cleavage) enzyme, but in StAR, the steroidogenic acute regulatory protein. This protein is involved in the transport of cholesterol from the outer mitochondrial membrane to the inner membrane, where the CYP11A1 enzyme is located. CYP11B1 (11β-hydroxylase) catalyzes 11β-hydroxylation of deoxycorticosterone and 11β-deoxycortisol primarily. CYP17 (17α-hydroxylase/17,20-lyase) catalyzes 17α-hydroxylation and splitting of the 17,20 bond, but for the latter it has preferential D5-17,20-lyase activity. CYP19 (aromatase) catalyzes the conversion of corticosterone to aldosterone. 3β-HSD I and 3β-HSD II, 3β-hydroxysteroid dehydrogenase/Δ4,5-isomerase types I and II; CYP21 (P450c21), 21-hydroxylase; 17β-HSD 3, 17β-hydroxysteroid dehydrogenase type 3. In the human, deletion of a homozygous null mutation of CYP11A (P450ccc) is probably lethal in utero, but a heterogeneous mutation caused congenital lipoid adrenal hyperplasia. (From Melmed S, Polonsky K, Kronenberg H, et al, editors: Williams Textbook of Endocrinology, ed 10, Philadelphia, 2003, Saunders, p 917.)
ADRENAL INSUFFICIENCY The dominant clinical features of congenital adrenal min eralocorticoid deficiency are hyponatremia and hyperkaDecision-Making Algorithms lemia, usually developing by 5 to 7 days after birth but not