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chapter 32
Endocrine Metabolism III: Adrenal Glands
(
CYP11B1
)
and
the
aldosterone
synthase
gene
(CYP11B2),
which are located in close proximity on
chromosome
8 8
and are 95% homologous in nucleotide
sequence. It is hypothesized that during meiosis, when
the chromosomes duplicate, an unequal crossing over
between the chromosomes occurs, resulting in a hybrid
gene containing the regulatory sequence of the
CYP11B1
gene and the coding sequence of the
CYP11B2
gene. Since
the 5' portion of this hybrid gene contains the promoter
region of the
CYP11B1
gene, it is under ACTH regulation.
The 3' region of the hybrid contains the coding region
of the aldosterone synthase and therefore expresses an
enzyme with aldosterone synthase activity. This enzyme
converts corticosterone to aldosterone, but also converts
cortisol to 18-hydroxycortisol and 18-oxocortisol. The
important feature is that aldosterone synthesis is now
under direct ACTH control, and this ultimately shuts
down aldosterone production in the glomerulosa.
Primary hypercortisolism (Cushing’s syndrome)
is
usually due to an autonomous adrenocortical tumor and
is characterized by low levels of circulating ACTH. Virtu-
ally all of the effects that have been described for gluco-
corticoid excess occur in this syndrome. Skeletal muscle,
skin, bone, and lymphoid tissue exhibit protein loss, which
can lead to muscle weakness, fragility of the skin, os-
teoporosis, and diminished immunocompetence, respec-
tively. Chronic excess of cortisol encourages lipolysis in
adipose tissues and favors fat deposition in the face and
trunk regions, resulting in the characteristic “moon face”
and central obesity. Because cortisol is an insulin antago-
nist, some glucose intolerance may develop. Removal of
the adrenal tumor corrects this syndrome, but it also creates
adrenocortical insufficiency for which exogenous gluco-
corticoid treatment is required. In the case of a unilateral
tumor, the other adrenal atrophies in Cushing’s syndrome
because ACTH secretion is chronically suppressed. Re-
covery of ACTH and cortisol secretion following removal
of the tumor may take several months.
Overproduction of cortisol by hyperplastic adrenal cor-
tices can result from oversecretion of ACTH (
secondary
hypercortisolism)
due to a defect at the level of the pi-
tuitary or median eminence or to ectopic production of
ACTH. The former condition is known as
Cushing’s dis-
ease
and the latter as
ectopic ACTH syndrome.
In both
conditions, the adrenal cortex functions normally and se-
cretes cortisol in proportion to the level of ACTH.
Cushing’s disease, which is more prevalent than ectopic
ACTH syndrome, can be distinguished from the latter by
its glucocorticoid suppressibility. Large doses of dexam-
ethasone administered for three consecutive days suppress
ACTH secretion. In ectopic ACTH syndrome, malignant
transformation in some tissues (notably the lung) induces
in that tissue the synthesis and release of ACTH. Because
the transformed tissue is unresponsive to cortisol, ACTH
and cortisol levels continue to rise and cannot be depressed
by dexamethasone.
32.2 Adrenal Medulla
The adrenal medulla is a modified sympathetic ganglion
that lacks postsynaptic axonal projections; as such, it can
be regarded as the endocrine component of the sympa-
thetic division of the autonomic nervous system. Like
its sympathetic ganglia counterparts, the adrenal medulla
receives numerous preganglionic cholinergic fibers from
the spinal cord that transmit autonomic efferent signals
from the brain stem and higher centers. Unlike its sympa-
thetic ganglia counterparts, which release norepinephrine
into synaptic junctions at target cells, the adrenal medulla
releases mainly epinephrine, into the systemic circula-
tion. Cells of the adrenal medulla are often referred to as
“chromaffin cells” because they contain “chromaffin gran-
ules,” electron-dense membrane-bound secretory vesicles
with an affinity for chromic ions (hence the name “chro-
maffin”). Chromaffin granules contain catecholamines
(~20%), various proteins (~35%), ATP (15%), lipids
(~
2 0
%), calcium ions, ascorbic acid, and other sub-
stances; they are the adrenal medullary counterparts of
secretory vesicles in ganglion cells.
Regulation of Release
The catecholamine content of mature chromaffin gran-
ules has been estimated to consist of 80% epinephrine
(E), 16% norepinephrine (NE) and 4% dopamine (DA),
although the percentage of E depends on the rate of cor-
tisol production (discussed later). Upon cholinergic stim-
ulation and depolarization of the adrenal medullary cells,
the intracellular Ca2+ ion concentration increases, promot-
ing fusion of chromaffin granules with the plasma mem-
brane. This leads to exocytosis of all soluble granule con-
stituents, including the catecholamines, ATP, dopamine
/
1
-hydroxylase, calcium ions, and chromogranins.
Adrenal medullary cells have plasma membrane re-
ceptors for acetylcholine (ACh) of the neuronal nico-
tinic subtype (Nn). These receptors are cation chan-
nels that span the plasma membrane and are activated
by ACh to rapidly increase Na+ and K+ permeabilities
(Na+ influx rate ~ 5 x 10
7
ions/s), causing the cells to
depolarize and release their catecholamines by exocytosis.
The cholinergic stimulation of exocytosis is accompanied
by an activation of tyrosine hydroxylase activity within the
adrenal medullary cell, and this promotes biosynthesis of
