section 32.1
Adrenal Cortex
759
F I G U R E 3 2 - 6
Steroidgenic pathways in 11/i-hydroxylase CYPB1 and CYPB2
deficiency. A CYP1 IB 1
defect causes a deficiency of cortisol and the
disorder
co n g en tia l a d ren a l h yp erp la sia
(CAH). A CYP11B2 defect
causes an aldosterone deficiency. Synthesis of steroids within the
boxed areas is decreased and steroids outside the boxed area increased,
respectively, for each enzyme deficiency.
secondary sex characteristics that typify the adult male.
Administration
of dexamethasone
suppresses
ACTH
release, restores electrolyte balance, and reduces the pro-
duction of adrenal androgen toward normal. Deficiency of
11/1-hydroxylase
CYP11B2
(aldosterone
synthase),
which is required for the conversion of corticosterone,
to aldosterone, causes aldosterone deficiency without
causing congenital adrenal hyperplasia (Figure 32-6).
Deficiencies of other enzymes are rare. Deficiency
of CYP11A (cholesterol desmolase) prevents all steroid
biosynthesis,
is
incompatible
with
extrauterine
life,
and is the rarest adrenal cortex enzyme deficiency.
З/1-Hydroxysteroid dehydrogenase deficiency impairs
the
synthesis
of glucocorticoids,
mineralocorticoids,
and adrenal androgens and estrogens. Deficiency of
18-hydroxylase or 18-hydroxy dehydrogenase decreases
aldosterone
production.
17-Hydroxy steroid
dehydro-
genase or 17,20-desmolase (or 17,20-lyase) deficiency
causes androgen deficiency without affecting cortisol
biosynthesis.
Steroid sulftase
(STS)
deficiency
due to an X-linked in-
born error of metabolism causes a skin disorder (
ichthyao-
sis
) in affected males. In heterozygous females, STS
deficiency leads to decreased estrogen synthesis during
the later stages of pregnancy due to inability to convert
DHEAS to DHEA, which is then metabolized to estrogen
in the maternal-fetal-placental unit. The diminished estro-
gen synthesis results in prolonged labor. STS deficiency
also causes increased levels of cholesterol sulfate in the
blood and skin. In the keratocytes, cholesterol sulfate in-
hibits cholesterol synthesis, which may be responsible for
skin abnormalities.
Excess
Inappropriately large amounts of aldosterone
or cortisol result from a disturbance at the level of the
adrenals (primary) or of the regulation of adrenal function
(secondary).
Primary hyperaldosteronism (Conn’s syndrome
)
usu-
ally results from an adrenocortical adenoma that produces
aldosterone but is unresponsive to regulation by potas-
sium or by the renin-angiotensin system. Aldosterone ex-
cess leads to excessive sodium retention and potassium
wastage, hypokalemia, and hypervolemia. Muscle weak-
ness or paralysis and hypertension are common symptoms.
Because of hypernatremia and hypervolemia, renin lev-
els are depressed. However, if the condition is chronic,
blood volume increases to a point at which the glomeru-
lar filtration rate is increased, causing an aldosterone-
insensitive urinary loss of sodium and water. This “escape”
phenomenon, presumably not hormonally regulated, ac-
counts for the rarity of severe hypertension in this syn-
drome. Conn’s syndrome can be controlled by treatment
with spironolactone, an aldosterone antagonist.
Secondary
hyperaldosteronism
is
usually
distin-
guished from the primary disorder because plasma renin
levels are elevated. This disorder may be due to a de-
fect in the juxtaglomerular apparatus (autonomous renin
secretion) or to a dysfunction of a peripheral organ that
affects vascular dynamics. Primary hyperaldosteronism
leads to hypertension, whereas the secondary form may
not. In the case of autonomous renin secretion, an ele-
vated renin level leads to elevated angiotensin II and aldos-
terone levels, which in turn leads to an increase in plasma
sodium concentration and to hypervolemia. Increased lev-
els of angiotensin II, in the presence of elevated plasma
sodium, promote vasoconstriction, which, in the face of
hypervolemia, can lead to hypertension. Because the jux-
taglomerular apparatus functions autonomously, it is not
responsive to negative feedback by sodium, angiotensin
II, blood pressure, or blood volume changes. An example
of a peripheral organ disease affecting the vascular system
is the combination of congestive heart failure, cirrhosis of
the liver, and nephrosis, without any defect in the renin-
angiotensin-aldosterone axis. The cardiac and hepatic fail-
ures decrease venous return to the heart, which, together
with the low plasma albumin level (due to liver damage),
results in hypovolemia. This lowers the mean renal arterial
blood pressure, thereby stimulating the release of renin and
aldosterone. Aldosterone increases sodium retention and
blood volume. However, because plasma albumin levels
are low, the hypervolemia does not increase blood pressure
but instead causes the shunting of fluid into the interstitial
spaces. The result is a condition of normotensive edema.
Glucocorticoid-remediable aldosteronism
(
GRA
) is
due to mutations involving the 11/i-hydroxylase gene
