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chapter32
Endocrine Metabolism III: Adrenal Glands
in excess production in ACTH and overstimulation of the
adrenal glands.
In utero,
female fetuses exposed to high
levels of androgen show masculinization (virilization) and
ambiguous genitalia. In contrast, male newborns with
2 1
-hydroxylase deficiency appear normal at birth.
In infants with classic congenital adrenal hyperplasia
as a result of
2 1
-hydroxylase deficiency, the mineralo-
corticoid deficiency causes a rapid evolving “salt wast-
ing” crisis due to renal loss of Na+ and accumulation
of K+. These changes result in hyponatremia, hyper-
kalemia, hyperreninemia, and hypovolemic shock. The
electrolyte disturbances are treated with fluid and Na+
replacement and administration of both mineralocorticoid
and glucocorticoid. The administration of glucocorticoid
also corrects hypoglycemia. Because this life-threatening
disorder is treatable, newborn screening programs con-
sisting of assaying 17a-hydroxyprogesterone from a fil-
ter paper-dried blood spot has been developed. In milder,
attenuated forms of
2 1
-hydroxylase deficiency, viriliza-
tion may be the sole clinical manifestation. In young
women, this condition may cause hirsutism and menstrual
irregularities.
The 21-hydroxylase gene (CYP21) is located in the
major histocompatibility complex (MHC)on chromosome
6
p. The functional gene of 21-hydroxylase is present in a
tandem arrangement with a pseudogene (CYP21P) and
genes for complement proteins C4A and C4B. The pseu-
dogene for
2 1
-hydroxylase is nonfunctional as it contains
several mutations. The importance of the pseudogene in
causing the
2 1
-hydroxylase deficiency is that it allows
transfer of mutations to the functional gene. The trans-
fer of mutations from pseudogene to functional gene can
occur due to unequal crossovers and gene conversions. A
variety of mutations in the pseudogene have been identi-
fied, which include premature 3' splice site, deletions, and
frameshift, nonsense, and missense mutations.
De novo
mutations of the functional gene (C YP21) that are not de-
rived from the psuedogene have also been identified.
Prenatal diagnosis and fetal therapy of affected female
fetuses may be desirable since corrective surgery of exter-
nal genitalia is not always optimal. Oral administration of
a synthetic glucocorticoid (dexamethasone, which crosses
the placenta) to the mother during pregnancy can limit the
virilization of a female fetus. Dexamethasone is used in-
stead of cortisol because cortisol does not readily cross the
placental barrier.
Deficiency of 17a-hydroxylase (CYP17), the enzyme
required for formation of cortisol and androgens, also
causes congenital adrenal hyperplasia. The genetic de-
fect also affects the gonads, which consequently can-
not synthesize androgens or estrogens. Thus, the ante-
rior pituitary increases its output of ACTH, LH, and FSH.
C h o lestero l
C Y P17
P re g n e n o lo n e - t -
|
:
*• 17 a -H y d ro x y p re g n e n o lo n e — »• D H EA — ► D H EA S
I
♦
P ro g e s te ro n e
1
17 a -H y d ro x y p ro g estero n e
D eo x y -
c o rtic o ste ro n e
1
I
I I -D eo x y co rtiso l
l
T
C o rtic o stero n e
C ortisol
i
A ld o stero n e
F I G U R E 3 2 - 5
Steroidogenic pathways in 17a-hydroxylase (CYP17) deficiency.
Synthesis of steroids within the boxed area is diminished as a result of
deficiency in the enzyme. Production of those steroids will increase
outside the boxed area.
Because 17o!-hydroxylase is absent from the zona fascic-
ulata, the flow of pregnenolone is directed at formation
of DOC, corticosterone, and 18-hydroxycorticosterone,
none of which is an effective suppressor of ACTH release
(Figure 32-5). Levels of DOC rise sufficiently to produce
sodium retention, hypokalemia, and hypervolemia, which
suppress renin release and aldosterone secretion. Thus,
low levels of cortisol and aldosterone are attended by a
mineralocorticoid excess and sex steroid deficiency. Ad-
ministration of a potent glucocorticoid (dexamethasone)
corrects the DOC excess by suppressing ACTH release;
this, in turn, restores blood volume, and the circulating
levels of renin and aldosterone return to normal. How-
ever, neither cortisol nor sex steroids will be normal-
ized because the enzyme that catalyzes their formation is
lacking.
Deficiency of 11/3-hydroxylase (CYP11B1) which is
required for formation of cortisol, produces the second
most common form of congenital adrenal hyperplasia.
This condition also is characterized by excessive ACTH
stimulation of the adrenal cortex and by elevated DOC
secretion, which lead to mineralocorticoid excess in the
face of low renin and aldosterone levels. Secretion of the
adrenal androgens is elevated (Figure 32-6). The height-
ened stimulation of the adrenal cortex by ACTH promotes
increased
formation
of pregnenolone
and
increased
flow of pregnenolone into androgen synthesis. Although
considerably less androgenic than testosterone, adrenal
androgens (DHEA and DHEAS) exert virilizing effects at
the concentrations that occur in CYP11B1 deficiency. In
addition, these steroids are converted to testosterone and
DHT by peripheral tissues. The effect of excessive adrenal
androgen production is best manifested in prepubertal
boys and in women since they do not normally exhibit
