To recap

As preparation for understanding the role of the adrenal gland, review the synthesis of steroid

hormones and hormones derived from tyrosine described in Chapter 2

To understand the effects of hormones from the adrenal gland, begin by reviewing hormone

action, especially that of steroid hormones, described in Chapter 3

Cross-reference
The adrenal cortex is regulated by the anterior pituitary corticotroph such that the bodys

cortisol status reflects whether the corticotroph is physiologically normal, underactive or

overactive (see Chapter 5)
Endocrine neoplasia syndromes can involve the adrenal gland resulting in cortisol excess

(ectopic hormone-secreting tumours) or phaeochromocytoma and paraganglioma (see

Chapter 10)

The adrenal cortex

Embryology and anatomy
Understanding the development of the
adrenal gland can be necessary to appreciate
adrenal
pathology (Box 6.1).
The adrenal cortex forms from epithelial
cells
that line the abdominal (coelomic) cavity of
the
developing embryo during the fifth week of
development (Figure 6.1). These cells generate
concentric functional layers called the outer
definitive
and
the inner fetal zones of the adrenal cortex.
This
pattern is distinctive to higher primates and
only
begins its reorganization after birth into the
more
characteristic layers of the adult adrenal
cortex
(Figure 6.2 and Box 6.2). The development of
the
adrenal medulla is described later.
The adrenal gland lies immediately
superior
to
the kidney (hence the anatomical name,
suprarenal
gland). This anatomy can be important
clinically
in
hypersecretion or tumours. For instance,
when
sampling the veins that drain centripetally
through
the
adrenal gland to measure hormone secretion,
access

on the left is via the renal vein and

technically
more
challenging. The adrenal and kidney
capsules
are
closely assimilated. Removal of the kidney
(nephrectomy) almost always includes ipsilateral
adrenalec-

tomy. In contrast, either adrenal can be

removed,
increasingly by laparoscopic approaches,
without
disturbing the adjacent kidney. However,
embryological variations can present challenges to
the
endocrine surgeon. Additional or unusual
blood
vessels can supply and/or drain the organ, or
embryological rests of adrenocortical cells can lie
outside
the gland.
Biochemistry by zones
Although what determines and maintains the
distinct adrenocortical zones remains unclear,
knowl-

edge of the different regions is important

because they define, and are defined by, very
different
biochemical
activity
(Box
6.2).
This
compartmentalized function is all the more remarkable in
light of the
prevailing
theory
of
adrenocortical
ageing, whereby steroid
secretion changes as cells migrate from the
outer glomerulosa to the innermost reticularis where they undergo apoptosis.
The principles of steroidogenesis were
introduced in Chapter 2. To recap, the steroid
product
depends on the complement of enzymes that
catalyze
the
sequential
modification
of
cholesterol
(Figure 6.3 and Box 6.3). Many of these
enzymes
are members of the cytochrome P450
superfamily.
Although
the
nomenclature
for
the
corresponding

Chapter 6: The adrenal gland / 101

Neural crest cells

Spinal cord
Posterior
root
ganglia
Sympathetic
ganglia

Aorta
Sympathetic
ganglia

Developing
adrenal
Mesonephros

Coelomic
epithelium
Mesentery

Abdominal
cavity

Gut

Figure 6.1 Development of the adrenal gland. The cortex is derived in part from the epithelium lining the
abdominal cavity. Neural crest cells migrate from the back of the embryo; some give rise to dorsal root and
sympathetic ganglia, while others invade the adrenal cortex to form the medulla. The rim of coelomic
epithelium shown in black also gives rise to steroidogenic cells of the gonad.

Box 6.1 Clinical consequences

of embryology
The adrenal cortex and medulla develop
separately - clinical disorders almost
always affect either the cortex or medulla,
but not both
Forming the organ requires cell migration
- adrenal disorders can occasionally cause
trouble in unexpected places from
embryological rests of cells
The cells forming the adrenal cortex also
form the steroidogenic cell lineages in the
gonad - disorders of steroid production
can affect both organs simultaneously

genes has been unified, several

names
remain
in
common
usage
(Table
6.1).
Awareness
of
these
names is important as several of the
genes
are
subject
to mutation in congenital adrenal
hyperplasia
(CAH), one of the more common
paediatric
endocrine emergencies.

Function and regulation of the

hormones
Aldosterone and cortisol serve as
ligands
for
nuclear
hormone
receptors,
which
then
function
as
transcription factors that influence target
gene
expression (review Chapter 3). It seems
that
both
hormones also have more rapid
non-genomic
actions, although these are less well
understood.
The
mechanism
of
action
for
dehydroepiandrosterone (DHEA) remains unclear, other
than
serving
as an extra-gonadal precursor for sex
hormone
biosynthesis.
Cortisol
Cortisol is the major glucocorticoid in
humans.
Like all steroid hormones, it is not
stored
but
synthesized according to acute changes in

demand.
Its
release into the circulation influences
cells
in
virtually every organ of the body. In the
blood,
cortisol
is largely bound (>90%) to cortisolbinding
globu-

lin (CBG) and is assayed as total

serum
cortisol.
Anything that alters the amount of
CBG
(e.g.
oral
contraceptive use or critical illness)
alters total

102 / Chapter 6: The adrenal gland

Figure 6.2 Section through

the adrenal cortex. (a) The
blood vessels run from outer
capsule to medullary venule.
(b) A zona fasciculata cell with
large lipid droplets, extensive
smooth endoplasmic
reticulum and mitochondria.

(a)
Capsule

(b)
Smooth endoplasmic reticulum

Zona
glomerulosa

Capillary

Zona
fasciculata
Lipid droplets Mitochondria

Zona
reticularis

Medulla
Venule

Box 6.2 Zones of the adult

adrenal cortex and their steroid
hormone secretion
Zona glomerulosa, nests of closely packed
small cells creating the thinnest, outermost
layer; secretes aldosterone
Zona fasciculata, larger cells in columns
making up three-quarters of the cortex;
secretes cortisol and some sex steroid
precursors
Zona reticularis, net-like arrangements of
innermost cells, formed at 6-8 years to
herald a poorly understood change called
adrenarche; secretes sex steroid
precursors and some cortisol

cortisol measurement; an important

clinical
issue.
Like thyroid hormones, it is only the
free
component that enters target cells. The free
component
also passes into urine - urinary free
cortisol
(UFC)
where its collection and assay over
24 h has been

used as a test of glucocorticoid excess

(UFC is 1% of cortisol production
by the adrenal glands). Measuring
salivary cortisol similarly avoids
issues with fluctuating serum CBG.
Regulation of cortisol biosynthesis and
secretion - the hypothalamic-pituitaryadrenal axis
The
major
regulation
of
the
adrenal
cortex
comes from the anterior pituitary, via
the
production
and
circulation
of
adrenocorticotrophic
hor
mone (ACTH), a cleavage product of
the
proopiomelanocortin (POMC) gene (review
Chapter
5).
In turn, ACTH is regulated by
corticotrophinreleasing hormone (CRH) from the
hypothalamus
(Figure 6.4). By binding to cell-surface
receptors
and
activating
cAMP
second
messenger
pathways,
ACTH increases flux through the
pathway
from
cholesterol to cortisol, particularly

at
the
ratelimiting step catalyzed by CYP11A1.
This
happens
acutely such that a rise in ACTH
increases
cortisol

levels within 5 min. Cortisol provides

feedback
to
the
anterior
pituitary
and
hypothalamus to