5
11-Deoxycorticosterone
P450c11AS
Aldosterone
11-Deoxycortisol
P450c11β
Cortisol
11OH-Androstenedione
(11OHA4)
11βHSD2
11-Ketoandrostenedione
17βHSD5
11-Ketotestosterone (11KT)
17OH-Allopregnanolone
P450c17
Androsterone
17βHSD5
Androstanediol
(a) Normal fetal adrenal steroidogenesis. Because the
fetal adrenal has low levels of 3β-hydroxysteroid
dehydrogenase, most steroidogenesis is directed
toward dehydroepiandrosterone (DHEA) and thence
to DHEA sulfate, but small amounts of steroids
enter the pathways toward aldosterone and cortisol.
e adrenal 21-hydroxylase P450c21 is essential in
both pathways. e adrenal can synthesize small
amounts of testosterone via 17βHSD5 (AKR1C3).
Included to the lower right is the 11-oxyandrogen
pathway, in which androstenedione is converted
in the adrenal to 11β-hydroxyandrostenedione
(11OHA4) and then in the adrenal and/or peripheral
tissues to 11-ketoandrostenedione and ultimately
11-ketotestosterone (11KT). e production of
11OHA4 and 11KT is an important pathway in
postnatal life and may also occur in the fetal adrenal.
(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 17OHP are converted to
androstenedione in the normal adrenal, the massive
amounts of 17OHP produced in CAH permit some
17OHP to be converted to androstenedione and
then to testosterone. ird, the alternative pathway
depends on the 5α and 3α reduction of 17OHP
to 17OH-allopregnanolone. is steroid is readily
converted to androstanediol, which can then be
oxidized to DHT by an oxidative 3α-hydroxysteroid
dehydrogenase (3αHSD) enzyme. e role of
the alternative pathway in CAH is evidenced by
increased levels of metabolites of its unique steroidal
intermediates in the urine of infants, children, and
adults with CAH [Kamrath et al. J Clin Endocrinol
Metab. 2012;97(3):E367–E375].
