Figure 1.

A, Normal fetal adrenal steroidogenesis. Because the fetal adrenal has low levels of 3β-HSD, most steroidogenesis is directed toward DHEA (and thence to DHEA-sulfate), but small amounts of steroid enter the pathways toward aldosterone and cortisol. The adrenal 21-hydroxylase, P450c21, is essential in both pathways. The adrenal can make small amounts of testosterone via 17β-HSD. B, In the absence of the 21-hydroxylase activity of P450c21, three pathways lead to androgens. First, the pathway from cholesterol to DHEA remains intact. Although much DHEA is inactivated to DHEA-sulfate, the increased production of DHEA will lead to some DHEA being converted to testosterone and dihydrotestosterone (DHT). Second, although minimal amounts of 17-OHP are converted to androstenedione in the normal adrenal, the huge amounts of 17-OHP produced in CAH permit some 17-OHP to be converted to androstenedione and then to testosterone. Third, the proposed backdoor pathway depends on the 5α and 3α reduction of 17-OHP to 17OH-allopregnanolone. This steroid is readily converted to androstanediol, which can then be oxidized to DHT by the reversible 3α-HSD enzyme. Although first discovered in marsupials, mass spectrometric examinations of human urinary steroid metabolites indicate this pathway may also occur in the human adrenal (7,8).