Box 6.

5 Cortisol, like glucagon,

epinephrine and growth hormone,
can be thought of as antagonistic
to insulin (also see Figure 11.11)
Cortisol tends to increase blood glucose levels by:
Promoting gluconeogenesis
Raising hepatic glucose output
Inhibiting glucose uptake by muscle and
fat
Other effects
Lipolysis from adipose tissue
Protein catabolism to release amino acids

catabolic effects reduce protein synthesis,

resulting
in atrophy. Similar catabolic effects in bone shift
the
balance of activity from osteoblast (the
boneforming cell type) to osteoclast (the boneresorbing
cell type), predisposing to osteoporosis (see
Chapter
9). Taken together, there is a net flow of amino
acids towards the liver.
Salt and water homeostasis and blood
pressure

Glucocorticoids can potentially increase

sodium
resorption and potassium loss at the distal
tubule
through effects, not on the glucocorticoid
receptor
(GR),
but
thought
to
be
via
the
mineralocorticoid
receptor (MR). More proximally, cortisol
increases
glomerular filtration rate (GFR) and inhibits
vasopressin to increase free water clearance.
Cortisol
raises blood pressure by several mechanisms,
including increased sensitivity of the vasculature
to
catecholamines.
Growth and development

Cortisol

is

an

important

hormone

during

growth
and development of the fetus. It stimulates
the
differentiation of cell types to their mature
phenotype.
This is particularly evident in the lung,
where
it
stimulates the production of surfactant,
which
reduces alveolar surface tension. This is one
of
the
final steps in preparing the fluid-filled fetal
airways

for post-natal life. Too much glucocorticoid

inhibits growth, in keeping with its largely
catabolic effects on the musculoskeletal system.
Cushing syndrome presents to the paediatric
endocrinologist
as
cessation of linear growth.

Post-partum, cortisol is required for the

initiation of lactation by PRL. Its loss leads to a
gradual
reduction in milk secretion.

tion of asthma. Raised circulating neutrophil

count
does not necessarily mean infection; it may
simply
reflect glucocorticoid treatment. In tissues,
for
instance, the acutely inflamed joints of a
patient
with rheumatoid arthritis, glucocorticoids
rapidly
suppress inflammation by inhibiting cytokine
production and antagonizing macrophage action.

Central nervous system and psyche

Aldosterone

Lactation

The role of glucocorticoids in the brain is highly

complex, matched by their potential to cause a
range of emotional symptoms from euphoria to
depression.
Anti-inflammatory effects

Glucocorticoid
actions
on
inflammation
and
autoimmunity are among its most important,
reflected by the use of potent synthetic steroids
to
treat a range of disorders. With glucocorticoid
treatment,
circulating
T
lymphocytes
and
eosinophils
fall; however, neutrophils rise. This is a catch to
remember
exacerba-

for

the

patient

with

an

acute

The synthesis of aldosterone in the zona

glomerulosa is demarcated by the absence of CYP17A1
and
the presence of CYP11B2. The hormone
circulates
in 1000-fold lower concentration and with a
shorter half-life (20-30 min) than cortisol. In
part,
this results from a diminished affinity for
serum
carrier proteins. It acts via binding the MR to
influence gene expression in the nucleus of target
cells
(review Chapter 3). The MR is not specific for
aldosterone, binding cortisol with equal
affinity.
However,
specificity
is
preserved
by
HSD11B2,

Chapter 6: The adrenal gland / 107

Box 6.6 Aldosterone is the bodys

major mineralocorticoid
Promotes sodium resorption from the urine
and potassium excretion
Increases blood pressure
Aldosterone biosynthesis is regulated
primarily by:
Renin-angiotensin system (forming a
negative feedback loop)
Serum potassium concentration

which inactivates cortisol to cortisone, at

the
major
sites of mineralocorticoid action, the
distal
tubule
and collecting ducts of the kidney (Table
3.2).
Here,
aldosterone acts on the Na+/K+-ATPase
transporter
to
increase
sodium
resorption
in
exchange
for
potassium excretion (Box 6.6). The net
effect
is
to
increase osmotic potential within the
circulation,
causing expansion of circulating volume.
The
direct
effect of aldosterone to increase blood
pressure
comes from vasoconstriction.
Regulation of aldosterone secretion
The enzyme, renin, is synthesized
predominantly
in
the kidney, in specialized cells of the
juxtaglomerular
apparatus. These cells surround the
afferent
arteriole
before it enters the glomerulus (Figures
6.6
and
6.7)
and form a sensing mechanism for
intravascular
volume whereby decreased volume
stimulates
renin
biosynthesis. Renin acts upon its
substrate,
circulat-

ing angiotensinogen, to generate the

decapeptide,
angiotensin I, which is subsequently
converted
into
angiotensin
II (AII).
This
latter
octapeptide
binds
to the type 2 angiotensin II receptor
in
the
zona
glomerulosa
cells
to
stimulate
aldosterone
pro
duction. In addition, AII is a very
potent
pressor
agent,
causing
arteriolar
vasoconstriction.
Reninangiotensin axes exist to some extent
within
individual organs, providing an element of
paracrine
adrenocortical
regulation
of
aldosterone
biosynthesis and secretion. High potassium also
stimulates
aldosterone biosynthesis (Figure 6.6).
ACTH
plays
a minor role in regulating aldosterone
synthesis,
although too much or too little ACTH
does not

impact
on
circulating
aldosterone
levels.
More importantly, the cellular
mass
of
the
zona
glomerulosa
influences
longer
term
mineralocorticoid
production. Thus, westernized high salt
diets, which expand the intravascular
volume and raise blood pressure,
suppress the renin-angiotensin system,
leading to a shrivelled zona glomerulosa.
Sex steroid precursors
DHEA and its downstream derivative,
androstenedione, possess only weak androgenic
activity;
however, their conversion in other tissues
can
give
rise in adults to both potent androgen
(e.g.
testosterone)
and
oestrogen
(e.g.
oestradiol)
(review
Figure 2.6). Therefore, these 19-carbon
steroids
are
best termed sex steroid precursors
(rather
than
adrenal androgens). Like cortisol,
biosynthesis
is
primarily regulated by ACTH but
emanates
predominantly from the reticularis zone. The
relative
activity of CYP17A1 and HSD3B2 on
17hydroxypregnenolone
determines
the
production
of
DHEA (and androstenedione) versus
cortisol.
The function of the sex steroid

precursors
is
debated. During the first trimester of
pregnancy,
the
fetal adrenal gland actually secretes
some
potent
androgen (including testosterone) even
in
females.
During
the
second
and
third
trimesters,
huge
amounts of DHEA and its sulphated
derivative,
DHEAS, are generated. However, these
steroids
are not essential and their roles remain
poorly
understood. Post-natally, little sex steroid
precursor
is produced until adrenarche at 7-8
years
when
the
zona
reticularis
becomes
functionally
mature.
Further metabolism of the precursors to
active
sex
steroids stimulates linear growth in
middle
childhood, sometimes accompanied by some
pubic
and
axillary hair growth. This physiology is
important
as it needs to be distinguished from
precocious
puberty, the hallmarks of which include
breast
development in females and testicular
enlargement
in males (see Table 7.5).
Clinical disorders
The major clinical disorders affecting
the adrenal cortex arise from either too
much
or
too
little
cortisol and aldosterone.

108 / Chapter 6: The adrenal gland

Extracellular fluid
volume
+
Juxtaglomerular
cells

Renin
+
Angiotensinogen

Angiotensin I

Extracellular
fluid volume

Angiotensin II
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
+
Adrenal cortex

Aldosterone

Sodium
(and water)
resorption

Potassium
ACTH
Figure 6.6 The renin-angiotensin-aldosterone axis. A fall
in extracellular fluid (ECF) volume produces
increased activity in renal nerves, reduced sodium flux in
the macula densa and a fall in transmural pressure.
These activate the juxtaglomerular apparatus to
increase renin production, which catalyzes the
beginning of the cascade that ends with angiotensin

Hypoadrenalism
Primary hypoadrenalism arises from
direct
destruction of the adrenal cortex, whereas
secondary
disease
arises from loss of the anterior
pituitary
corticotroph. In all circumstances there is
shortage
of
cortisol and in primary disease additional
deficiency
of
aldosterone.
Primary hypoadrenalism - Addison disease
Worldwide, the commonest cause of
adrenocortical
deficiency results from infection (either
AIDS
or
tuberculosis). In the western world,

autoimmune
destruction of the cortex, first described
by
Thomas
Addison in 1855, is prevalent. The
disorder
carries
his eponymous title with the adjective
Addisonian
referring to the clinical crisis from
acute,
severe
cortisol (and aldosterone) deficiency.
Other causes

Symptoms and signs relate to:

II-stimulated aldosterone secretion. This leads to
increased sodium resorption with expanding ECF
volume providing negative feedback on further renin
production. High potassium, and to a lesser extent
adrenocorticotrophic hormone (ACTH), also
increase aldosterone production.

of underactivity are more unusual,

although
developmental abnormalities should not be
discounted in the paediatric setting
(Case history 6.1).
Symptoms and signs

Diminished vascular volume and tone

Renal sodium loss
Bowel water and electrolyte loss
Removal of negative feedback (causing
pigmentation, see Chapter 5)
Loss of cortisol action on hepatic and
peripheral metabolism (Box 6.7).
The consequent classical laboratory
findings
are
hyponatraemia (the vast majority) and
hyperkalaemia (in most cases). Raised urea (a sign
of con-