Chapter 7).

A pituitary adenoma secreting

functional LH or FSH is incredibly rare.
Commonly, however, non-functioning pituitary
adenomas may stain by immunohistochemistry
for the -subunit, perhaps giving an indication
of the developmental lineage, but little else.
Deficiency of the gonadotrophins
During childhood, it is normal for the
gonadotrophins to be low and relatively unresponsive
to
GnRH;
however,
continued
gonadotroph
inactivity
will delay puberty (see Chapter 7). This can
be
tested by GnRH stimulation when serum LH
and
FSH are measured 30 and 60 min later. A
normal
response is a two- to three-fold increase
from
basal serum levels. After puberty, loss of
gonadotrophins causes secondary hypogonadism.
In
women, this is very common at some stage of
the
reproductive years as cyclical gonadotrophin
secretion is very vulnerable to stress, such as
major
exercise (e.g. marathon running), excessive
dieting
or, most commonly, emotional anxiety of
relatively
minor proportions. A rise in prolactin levels is
also
sufficient
to
suppress
LH
and
FSH
production
(see earlier). Several syndromes from
mutations
in any one of a number of genes also result in
loss
of
gonadotrophins
because
of
absent
GnRH.
Kallman syndrome is a combination of
absent
GnRH-secreting
neurones
and
lack
of
smell
(anosmia).
Clinically, it is important to realize that, in
the

face of significant hypogonadal symptoms

and
signs, and low levels of sex hormones,
gonadotrophins within the normal range are
inappropriately low. In women, where significant
fluctuation
of gonadotrophins accompanies the normal
menstrual cycle, this can be more difficult to
identify.
It
tends to manifest as amenorrhoea with low or
undetectable serum oestrogen. In both sexes the
disorder
is
described
as
hypogonadotrophic
hypogonadism
(Box 5.8; see Chapter 7).

Hypopituitarism
Syndromes of pituitary hormone excess tend
to
be
restricted to one particular hormone. In
contrast,
deficiency commonly affects several of the
anterior

Box
5.8
hypogonadism

Hypogonadotrophic

Low or

+
symptoms, signs and biochemistry
= hypogonadotrophic hypogonadism

consequences demands consideration. History taking

and
examination need to include all the features of

normal gonadotrophins hypogonadal

pituitary hormones and, potentially, those of the

posterior pituitary (see next section). This is
termed
hypopituitarism and when all hormones are
inadequate,
panhypopituitarism.
In
adult
endocrinology,
hypopituitarism
is
most
commonly
encountered
as a result of compression from non-functioning
pituitary adenomas or their treatment by surgery
or
radiotherapy.
In
paediatric
practice,
congenital
absence or malformation of the pituitary gland,
or
inactivating mutations affecting the synthesis of
a
particular hormone are more relevant.
Clinical issues relating to the lack of
individual
anterior pituitary hormones are covered in
preceding sections. The clinical approach to
hypopituitarism where multiple hormones may be missing is
brought together here and in Box 5.9.
Each
hormone that is potentially missing and its

hormone deficiency described in each of the

preceding
sections,
e.g.
hypogonadism,
hypothyroidism
and hypoadrenalism. For instance, diagnosing
deficiency of LH and FSH, but missing
concomitant
ACTH deficiency might lead to a patients
death
from hypoadrenalism (see Chapter 6 and
Case
history 5.4).
Mutations in several genes cause pituitary
hypoplasia (Box 5.9). Those responsible for early
formation of the pituitary gland tend to cause broader
loss
of anterior pituitary cell types and can include
malformation of other nearby structures (e.g.
absent
corpus
callosum
and
optic
nerve
underdevelopment
in septo-optic dysplasia due to HESX1
mutations).
In contrast to the other lineages, isolated TSH
deficiency
is
rarely
a
problem.
Because
corticotrophs
are
set aside relatively early during anterior
pituitary
differentiation, ACTH tends to be spared in
cases
of congenital hypopituitarism. However,
isolated

Chapter 5: The hypothalamus and pituitary gland / 91

Box 5.9 Hypopituitarism

Clinical suspicion requires investigation of all
the hormone axes
Pituitary destruction
Adenoma or other tumours
(craniopharyngioma, meningioma,
metastasis)
Previous surgery
Radiotherapy
Infarction
Congenital pituitary disorders
Pituitary hypoplasia or aplasia
.g. mutations in POU1F1, PROP1,

HESX1,
E
LHX2

utations in TPIT tend to affect only the

corticotroph
M
lineage
Others

Impaired secretion of hypothalamic

hormones (e.g. loss of GnRH neurones in
Kallman syndrome; see Chapter 7)
Disconnection of the hypothalamicpituitary axis (e.g. stalk tumour, trauma or infection)

ACTH
deficiency
is
caused
by
inactivating
mutations in TPIT.
In adults, the hypothalamic-pituitary
axes
are
particularly vulnerable to irradiation.
Loss
of
pituitary hormones, especially GH, can
become
almost
inevitable after cranial radiotherapy, but
may
take
up to 10 years to manifest. In contrast,
gonadotrophin
secretion
is
particularly
vulnerable
to
trauma such as surgery. Infarction of
the
pituitary
is rare, although one well-described
condition,
Sheehan syndrome, reflects hypotension
following
major post-partum haemorrhage. The
sudden
vas-

cular insufficiency to a hypertrophied

gland
(i.e.
following pregnancy) leads to sudden
death
of
pituitary tissue. Major headache and the
symptoms
and
signs of sudden hormone loss (e.g.
failure
of
lactation, hypoadrenalism) are clues.
Having defined which hormone axes
are
underactive, replacement of the appropriate
hormones
needs
consideration.
In
hypopituitarism, it is man-

value at 30 min of 305 nmol/L (10.9 g/dL).

datory to replace missing cortisol using

hydrocortisone (see Chapter 6) and thyroid
hormone
using
thyroxine (see Chapter 8). Depending on
age
and
sex, gonadal hormones (in men and premenopausal
women; see Chapter 7) and GH (during
childhood,
adolescence and in some adults; see
earlier)
may
also
be appropriate.

Case history 5.4

A patient has been diagnosed with
acromegaly and referred to an
endocrinologist. Visual field assessment
reveals bitemporal hemianopia. MRI
demonstrates a large pituitary mass
extending to and compressing the optic
chiasm. Serum PRL was 1200 mU/L
(57 ng/mL), TSH was undetectable, fT4
was 5.3 pmol/L (0.4 ng/dL) and an ACTH
stimulation test gave a serum cortisol

What do these biochemistry results

indicate?
What urgent treatments are needed and
in what order?
Answers, see p. 97

Hormones of the posterior

pituitary
The two hormones synthesized in the
hypothalamus and released from the posterior
pituitary are oxytocin and vasopressin
(see Table 5.1). Although structurally
similar, being composed of nine amino
acids, they have markedly different
physiological roles (review Figure 1.3).
Vasopressin
Clinically, vasopressin is also known as
antidiuretic hormone (ADH) and has
also been called arginine vasopressin.
The biology of vasopressin is summarized in Box 5.10.

92 / Chapter 5: The hypothalamus and pituitary gland

Box 5.10 Summary of vasopressin

biology
Physiology
Circulates largely unbound rapidly
metabolized in the liver and filtered by the
kidney t1/215 min
Function
Regulates water excretion by the kidney
- its main action at normal circulating
vasopressin levels:

cts on the distal convoluted tubule

increased permeability to water water

resorption increased urine
concentration
Potent vasoconstrictor
Cellular mechanism of action
Distinct cell-surface G-protein-coupled
receptor (V) sub-types and second
messengers:

V1

(two further sub-types)

phosphatidylinositol (PI) metabolism and

raised intracellular Ca2+ vascular
smooth muscle contraction
cAMP renal water excretion

V(receptor
2
antagonized by vaptan class
of drugs)

Effects and mechanism of action

In the
kidney,
the
presence
of
vasopressin and the high osmolality of
the renal interstitium lead to water
movement out of the final section of the
distal convoluted tubule along the
osmotic gradient. The effect can be truly
remarkable. For example, a child
weighing 30 kg needs to excrete a
solute load of 800 mOsm in 24 h: at its
most dilute (50 mOsm/ kg), this load
requires 16 L of urine; under maximal
vasopressin stimulation, it can be
achieved with little over 700 mL (1100
mOsm/kg).
Vasopressin
is
a
potent
vasoconstrictor
and
has
been utilized either directly or in
synthetic
analogue

form to achieve haemostasis, e.g. in

severe
gastrointestinal
bleeding
or
post-partum
haemorrhage.
It
also acts on vascular tone at normal
physiological
levels.
During
fetal
development,
vasopressin serves

Box 5.11 Regulation of

vasopressin
Serum osmolality (SOSM)
High (e.g. dehydration) increased
vasopressin release increased water
retention decreased SOSM
Low (e.g. water intoxication) decreased
vasopressin release decreased water
retention increased SOSM
Volume
Fall in blood volume8% (e.g.
haemorrhage) increased vasopressin
release vasoconstriction O2
and CO2 tension
Decreased arterial O 2 partial pressure
(PaO2) increased vasopressin release
Increased arterial CO2 partial pressure
(PaCO2) increased vasopressin release

as an additional stimulus
release from corticotrophs.

for ACTH

Regulation of production
The main physiological regulator of
vasopressin
release is serum osmolality detected by
osmoreceptors in the hypothalamus (see earlier for
functions

of
the
hypothalamus).
Circulating
volume
is
detected by baroreceptors in the
carotid
sinus
and
aortic arch, and by plasma volume
receptors
in
the
left atrium.
In addition to the factors listed in
Box
5.11,
angiotensin II, epinephrine, cortisol and
the
female
sex
steroids,
oestrogen
and
progesterone,
can
also
modulate vasopressin release. The latter
may
explain
the fluid retention that can occur in the
latter
part
of the menstrual cycle. As with other
hypothalamic
hormones, the CNS plays an important
part
in
the
regulation of vasopressin. Pain and
trauma
associated
with surgery cause a marked increase in
the
circulating vasopressin concentration, as do
nausea
and
vomiting.
The
activity
of
the
neurohypophyseal
system
is
also
influenced
by
environmental
temperature; a rise in temperature stimulates
vasopressin
release prior to any change in plasma
osmolality.