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chapter 30
Endocrine Metabolism I: Introduction
why the intermediates such as DOC and the products
(corticosterone and cortisol) are different. Thus, whereas
in the mineralocorticoid pathway the initial substrate is
progesterone, in the glucocorticoid pathway it is 17a-
hydroxyprogesterone. The only difference between the
two substrates is the presence of a 17a-hydroxy group in
the latter. Note that this same difference is seen between
the two pathways at all three steps—substrate, intermedi-
ate, and product. The salient features here are:
1. The presence of 17a-hydroxy group confers maxi-
mal glucocorticoid activity to cortisol (Chapter 32); and
2. The zona fasciculata is the exclusive site of cortisol
formation.
The Sex Steroid Pathway Is Initiated by
17a-Hydroxylase/l7,20-Lyase (CYP17)
The valve that allows entry of 17-OH pregnenolone into
the “sex steroid” pathway is the 17,20-lyase compo-
nent of CYP17, the SER enzyme that catalyzes the 17a-
hydroxylation of steroids. As noted above, the lyase com-
ponent of the enzyme is active in certain tissues for reasons
that are not currently clear. Both A
4
and A
5
steroids are
known to feed into the sex steroid pathways although the
absence of 3/JHSD precludes the former. It should be em-
phasized that the formation of androgenic steroids is nec-
essary before estrogen formation is possible; therefore,
the initial reaction in the sex steroid pathway invariably
produces an androgenic steroid.
Synthesis of Androgens: 17,20-Lyase
In the adrenal cortex, the sites of sex steroid production
(fetal zone and zona reticularis) are lacking in 3/1HSD,
and pregnenolone is processed by both components of
CYP17 to become DHEA, as discussed above. Most of the
DHEA is sulfated at the 3-hydroxyl group and the prod-
uct, DHEAS, is secreted into the plasma. This occurs due
to the paucity or absence of any other steroid-modifying
enzymes in the tissue. In the Leydig cells of the testes and
the theca interna cells of the ovaries, both components of
CYP17 are active and will accept either pregnenolone and
progesterone as a substrate; radioactive tracer studies in-
dicate that the A
4
substrate (progesterone) is preferred.
Progesterone processing by the enzyme results in the for-
mation of androstenedione, which is secreted as such (by
the theca interna) or converted to the biologically active
androgen, testosterone (T) by a 17/1 -hydroxysteroid dehy-
drogenase (17/TSDH(-catalyzed reaction (by the Leydig).
Androstenedione and testosterone are 19-carbon steroids
are quantitatively the major androgens produced by the
gonads; however, the two biologically active androgens are
testosterone and dihydrotestosterone (DHT). Androstene-
dione is inactive because its 17-keto group is not recog-
nized by the androgen receptor. In the peripheral tissues,
androstenedione can be converted to T because of the pres-
ence of 17/JSDH and many androgen target tissues can
convert either androstenedione or T into DHT because of
the presence of 5a-reductase. CYP17 activity (both H a-
hydroxylase and 17,20-lyase activities) in the ovary and
testis is inhibited by estrogen.
Synthesis of Estrogens: Aromatase (CYP19)
Formation of estrogen is catalyzed by the enzyme aro-
matase (CYP19) which is present in the SER of a few tis-
sues (gonads, brain, placenta, and adipose). The enzyme is
expressed by a single gene (
cypl9
) on chromosome 15; it
catalyzes a multistep reaction in which a 19-carbon andro-
gen undergoes hydroxy lations at carbon 19 followed by the
removal of carbon 19 and the aromatization of ring A. The
overall aromatization reactions require an appropriate ring
A as substrate (either testosterone or androst-4-ene-3,17-
dione), 3 NADPH molecules, and 3 oxygen molecules.
The regulation of CYP19 activity differs among tissues;
FSH induces the enzyme in Sertoli and granulosa cells of
the gonads, whereas glucocorticoids induce the enzyme in
adipose tissue. The tissues that contain CYP19 are of two
varieties; one that produces estrogen
de novo
from choles-
terol (e.g., corpus luteum), and the other that lacks the
ability to produce its own 19-carbon substrate and relies
on a supply of androgens from other sources (e.g., Sertoli
cells of testis, granulosa cells of ovary, placenta, adipose
cells, hypothalamus, liver). CYP19 activity is inhibited by
the nonaromatizable androgen DHT and is stimulated by
the aromatizable androgen testosterone.
Steroidogenic enzymes are located mainly, but not
exclusively, in the three tissues that are authentically
steroidogenic (i.e., capable of converting cholesterol to
pregnenolone): the adrenal cortex, the gonads, and, in
pregnancy, the placenta. Steroidogenic enzymes are also
present in a few tissues that are not capable of
de novo
steroid synthesis from cholesterol but are able to take
up intermediates from plasma and convert them to active
hormones; for example, fat cells and the hypothalamus
contain CYP 19, which enables them to convert circulat-
ing androgens into estrogens. The kidney, one of the few
extra-adrenal sites with CYP21, converts progesterone to
the mineralocorticoid DOC.
A “steroid-modifying” enzyme catalyzes a reaction that
alters some structural feature of a steroid, resulting in the
formation of an active hormone or an inactive metabo-
lite. These enzymes are present in many tissues, although
