section 30.3
Steroid Hormones
705
substrate, pregnenolone enters the smooth endoplasmic
reticulum (SER) and is processed along whatever steroido-
genic pathway is active in the given tissue. Because no
single steroidogenic tissue normally expresses all of the
steroidogenic enzymes, the presence or absence of en-
zymes in a given tissue will determine what sort of steroid
hormone the tissue can produce from pregnenolone.
Pregnenolone serves as a substrate for either of two
enzymes;
the SER:3/3-hydroxysteroid dehydrogenase/
isomerase (3/SHSD) and
17a-hydroxylase/l7,20-lyase
(CYP17). In cells that contain both activities, preg-
nenolone is first processed by 3/3HSD, followed by
CYP17.
The A 4 Pathway: 3/3HSD
3/3HSD is a single, nonheme protein that catalyzes a
two-step conversion of a A
5
,3/J-hydroxyIated steroid to a
A
4
,3-ketosteroid in the SER of the adrenal cortex, ovary,
and testes. When pregnenolone is the substrate, the prod-
uct is progesterone, a biologically active steroid. In the
corpus luteum and the placenta, which are lacking in
progesterone-metabolizing enzymes, the nascent proges-
terone diffuses from the cells and enters the plasma. How-
ever, in other tissues progesterone serves as a substrate for
at least one other enzyme.
Directional Flow Valve: CYP17
The presence or absence of the enzyme, CYP17, is a major
determinant of the fate of pregnenolone (or progesterone).
The presence of the enzyme allows access to either the cor-
tisol or the androgenic (sex steroid) pathways but blocks
off the aldosterone synthetic pathway. The absence of the
enzyme allows for the formation of progesterone and al-
dosterone but precludes the formation of either cortisol or
androgens. (See following subsections on
corticosteroid
pathway
and
sex steroid pathway.)
CYP17 is a single protein that catalyzes the 17a-
hydroxylation of either pregnenolone or progesterone in
the SER. In some tissues, such as the gonads, this enzyme
catalyzes an additional reaction, involving lysis of the bond
between carbons 17 and 20 of the 17a-hydroxylated prod-
uct. This results in the formation of a 19-carbon androgenic
steroid: dehydroepiandrosterone (DHEA) is formed from
pregnenolone and A4-androstenedione (A
4
-A) is formed
from progesterone. Thus, the lyase reaction initiates the
sex steroid pathway. However, in other tissues that ex-
press the
CYP17
gene, such as the zona fasciculata of
the adrenal cortex, the enzyme does not catalyze the 17,
2 0
-lyase reaction to a significant extent, and the product is
a 17a-hydroxylated pregnenolone or progesterone, which
enters the cortisol synthetic pathway. In both tissues, the
enzyme is identical, with the same 17a-hydroxylation ac-
tivity; and it is not clear what confers the 17,20-lyase activ-
ity. In tissues that have CYP17 but are lacking in 3/3 HSD,
such as the fetal zone and the zona reticularis (Chapter 32),
the 17a-hydroxylation of pregnenolone favors the lyase
reaction and the formation of dehydroepiandrosterone
(DHEA), probably because no other options are available
in the A
5
pathway.
The Corticosteroid Pathway Is Initiated
by 21-Hydroxylase (CYP21)
The valve that allows entry of 17-OH progesterone into
the corticosteroid pathway is CYP21, a SER enzyme that
catalyzes the hydroxylation of carbon 21. In the absence
of CYP21, neither aldosterone nor cortisol can be pro-
duced. In the presence of this enzyme, two corticosteroid
pathways become available, each with a different sub-
strate requirement. Normally, the gene encoding CYP21
is expressed only in the adrenal cortex, primarily in the
outer two zones (glomerulosa and fasciculata). The kid-
ney and other tissues are also capable of
2 1
-hydroxylation
of steroids; however, these tissues contain an enzyme that
is not CYP21 and its activity is too low to interfere with
the normal endocrine function of the adrenals.
The
mineralocorticoidpathway
is catalyzed by two en-
zymes and utilizes progesterone as the initial substrate.
The first enzyme, CYP21, catalyzes the 21-hydroxylation
of progesterone, which converts it to the mineralocor-
ticoid, 11-deoxycorticosterone (DOC). This enzyme is
present in the outer two zones of the adrenal cortex.
The second enzyme is zone-specific in that each of the
two outer zones of the cortex expresses a different gene
for the enzyme. In the zona fasciculata, the
CYP11B1
gene expresses a mitochondrial enzyme that catalyzes
the 11/3-hydroxylation of DOC to form cortisol; in the
zona glomerulosa, another gene,
CYP11B2,
expresses a
mitochondrial enzyme (aldosterone synthase) that cat-
alyzes the three-step conversion of DOC to aldosterone
with the formation of the intermediates corticosterone and
18-hydroxycorticosterone. No other tissue in the body
normally expresses either of these two genes. Therefore,
production of DOC and corticosterone occurs only in the
two outer zones of the adrenal cortex, and aldosterone is
synthesized exclusively by the zona glomerulosa.
The
glucocorticoid pathway
is confined to the zona
fasciculata of the adrenal cortex and it is catalyzed by
the same CYP21 enzyme that is involved in the miner-
alocorticoid pathway in this zone along with CYP11B1.
The principal difference between the two pathways in the
zona fasciculata is the initial substrate, and this explains
