section 30.3
Steroid Hormones
707
in most the result of steroid modification is inactivation;
for example, the liver contains a large number of steroid-
modifying enzymes, virtually all of which are involved in
steroid inactivation. The kidney is another tissue that con-
tains several steroid-modifying enzymes, most of which
serve to inactivate steroids. On the other hand, at least
three steroid-modifying enzymes are physiologically im-
portant, as demonstrated in the disorders resulting from a
deficiency in any one of them:
5a-Reductase,
an enzyme that is present in a few tis-
sues, serves to convert testosterone and other androgens to
DHT, a reduced form that is most active in those tissues.
There are two types of the enzyme (type 1 and type 2),
which are products of different genes. The two types of
5a-reductase do not differ in substrate specificity but dif-
fer in enzyme kinetics and tissue distribution. Tissues that
express the type
1
enzyme appear to be those contributing
to secondary sex characteristics (the hair follicles, seba-
ceous glands), while tissues that express the type
2
enzyme
are structures of the reproductive system (external genital
tissues of the fetus, prostate gland, and seminal vesicles).
A deficiency of 5a-reductase type 2 enzyme results in a
disorder of sexual differentiation in the male (Chapter 34).
The synthesis of 5a-reductase activity in prostate and skin
is regulated by androgens; activity in liver is regulated by
thyroid hormone.
17(3-Hydroxysteroid dehydrogenase (17/3HSD)
(also
called
17-ketosteroid
reductase;
17$-hydroxy steroid
ketoreductase) catalyzes the reversible conversion of un-
conjugated 17-ketosteroids to 17-hydroxysteroids and
supplies the physiologic mechanism for generating estra-
diol from estrone and testosterone from androstenedione,
conversions that lead to the formation of biologically ac-
tive hormones from inactive precursors. This enzyme is
present in the testes and ovaries and its activity is crit-
ical for the gonads’ ability to produce the biologically
active form of androgen (testosterone, DHT) and estrogen
(estradiol); a deficiency of this enzyme is known to cause
disturbances in sexual differentiation. The gene encod-
ing gonadal and placental 17/3HSD is on chromosome 17.
The same enzyme is also present in nonreproductive tis-
sues such as liver, lung, erythrocytes, and platelets, but the
gene encoding this enzyme is not subject to the same regu-
lation as its gonadal counterpart. Accordingly, in
pseudo-
hermaphroditism
due to hereditary 17/1HSD deficiency,
nongonadal 17$HSD activity is normal.
11 (3-Hydroxy steroid dehydrogenase (llfiH SD )
cat-
alyzes the conversion of
1 1
-hydroxysteroids into
1 1
-
ketosteroids, a physiologically important reaction that
converts the biologically active cortisol to cortisone, an
inactive metabolite. The presence of this enzyme in tis-
sues that respond to aldosterone is critical in the hormonal
regulation of blood volume (Chapter 32). It is not clear
whether the reverse reaction, one that converts corti-
sone to cortisol, is catalyzed by a separate enzyme,
11-oxidoreductase. From the clinical standpoint, this is
an important reaction because the effectiveness of corti-
sone treatment relies on it (Chapter 32). Evidence that
11-oxidoreductase and 11 $HSD are different enzymes
comes from the observation that patients with a deficiency
of 11-oxidoreductase activity may have normal 11$HSD
activity; however, there is evidence that the same enzyme
catalyzes both reactions but that different isoforms of the
enzyme exist. The activity of 11/3HSD (cortisone for-
mation) is inhibited by licorice and by carbenoxolone
while the activity of
1 1
-oxidoreductase is inhibited by
carbenoxolone.
A number of drugs have an inhibitory effect on one or
more steroidogenic/steroid modifying enzymes, and some
of these are used clinically to inhibit the production of
certain steroid hormones. Some of the important drugs
used for this purpose are broad spectrum while others are
hormone-specific; a few are listed below along with their
principle therapeutic use:
•
Aminoglutethimide—inhibits CYP11A and CYP19
(breast cancer,
Cushing’s syndrome)
•
Trilostane—inhibits 3$HSD (
Cushing’s syndrome)
•
Ketoconazole—inhibits CYP17 enzymes
(17o,-hydroxylase and C
1 7
,
2 0
-Iyase), particularly those
involved in testosterone synthesis. After
6
months of
treatment in hirsute women, serum testosterone
declines without a change in serum cortisol or
DHEAS.
•
Mitotane (o.p'-DDD)—inhibits adrenal CYP11A and
CYP11B1, but not CYP11B2 (neoplasms of adrenal
cortex)
•
Metyrapone—inhibits CYP11B1 (hypercorticism due
to adrenal neoplasms or ectopic ACTH production)
•
Finasteride—inhibits 5a-reductase type 2 (prostatic
hyperplasia)
•
Testolactone—inhibits CYP19 (breast cancer)
•
Fadrozole—inhibits CYP19 (breast cancer)
•
Spironolactone—primarily an aldosterone antagonist
but inhibits CYP17 in both ovary and testis. It is also
an inhibitor of androgen binding to the AR
(K+-sparing diuretic)
Steroid-Binding Serum Proteins
Steroid hormones are hydrophobic molecules that con-
vey information to diverse regions of the body by way
of the bloodstream. Because of their very limited solubil-
ity in water, however, steroid hormones would precipitate
