Table 5.

4 Dynamic tests of growth hormone (GH) status

Test

Results

75 g oral glucose tolerance test (OGTT)

Rapid suppression of GH secretion to a nadir of <0.3 ng/mL

(<0.8 mU/L) if normal
Remains high in acromegaly or gigantism

Insulin tolerance test (ITT) [serum glucose 2.2

mmol/L (40 mg/dL)]

Stimulation of GH secretion:
>6.7 ng/mL (>17 mU/L), normal
3-6.7 ng/mL (~8-17 mU/L), partial deficiency <3 ng/mL
(<8 mU/L), severe GH deficiency

Amino
acid
infusion
(commonly arginine)

Stimulation of GH secretion
(useful in patients where insulin-induced
hypoglycaemia is undesirable, e.g. in children)

Box 5.4 Growth hormone excess: a

constellation of signs and
symptoms caused by bony and soft
tissue overgrowth, and
metabolic disturbance
Gigantism: occurs prior to epiphyseal
closure and causes relatively proportionate
increased stature
Acromegaly: occurs after epiphyseal
closure and causes progressive, cosmetic
disfigurement because of disproportionate growth

diagnosis (Box 5.5 and Case history 5.1).

Making the diagnosis is important as
acromegaly increases mortality two- to threefold, mainly because of its cardiovascular
complications.
Inspection of the patient will usually reveal
many of the features of bony and soft tissue
overgrowth (Figure 5.8). However, examination
should
also include the cardiovascular system as blood
pressure might be increased and there might be
signs
of
congestive cardiac failure (e.g. ankle oedema,
basal
lung crepitations).
Investigation and diagnosis

presents prior to or after epiphyseal fusion.

Before
epiphyseal fusion, the excess GH promotes
increased
linear velocity, which remains relatively
proportionate and results in extremely tall final stature well
over 2 m. Gigantism is relatively easy to
recognize.
After epiphyseal fusion, linear growth is no
longer
possible, leading to disproportionate growth
and

Three approaches can diagnose GH excess:

serum
IGF-I measurement elevated above the ageand
the features of acromegaly (Figure 5.8). A
patient
with a GH-secreting adenoma that started
before
puberty and only presents after epiphyseal
fusion
will carry features of both phenotypes. In
isolation,
acromegaly is more difficult to diagnose. The
features are insidious, frequently causing a 10year
gap
between the retrospective onset of symptoms
and

sex-adjusted
normal
range;
repeatedly
detectable
GH in a series of serum measurements
illustrating
autonomous production rather than the normal
pulsatile secretion; and failure for GH to
suppress
[remaining >0.3 ng/mL (>0.8 mU/L) using
newer
immunoradiometric or chemiluscent assays
follow-

ing 75 g oral glucose (OGTT; Figure 5.7 and

Table
5.4)]. In all but exceptionally rare ectopic
GHRH secretion, the cause is a GH-secreting
pituitary adenoma. By MRI these tumours are
usually greater than 1 cm in diameter (i.e. a
macroadenoma) and may have extended and
eroded beyond the pituitary fossa at the time of
diagnosis (see earlier anatomical complications
of pituitary tumours).

abcdfreeer 5: The hypothalamus and pituitary gland / 79

(a)

Figure 5.8 Two patients with acromegaly.

(a) Patient 1. Note the large facial
features, frontal bossing, prognathia
causing under-bite (the lower teeth are
further forward than the upper teeth) and
dental separation, greasy skin quality,
and thickened spade-like hands. (b)
Patient 2. Note enlargement of the hands
and feet. The joints are abnormal and
(b)

there is thickening of soft tissues with

fluid retention, manifest here by ankle
oedema, although this might also be a
consequence of right-sided heart failure.

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bcdfree
Box 5.5 Symptoms and signs of
growth hormone excess

glucose loading of less than 0.3 ng/mL

(0.8 mU/L). This is sometimes very
difficult to achieve. There are several
options (Table 5.5).

Musculoskeletal (acromegaly unless

indicated)
Increased stature (gigantism)
Protruding mandible (prognathia), teeth
separation on lower jaw
Big tongue (macroglossia)
Enlarged forehead (frontal bossing)
Large hands and feet (carpal tunnel
syndrome, tight rings, increasing shoe
size)
Osteoarthritis from abnormal joint
loading
Cardiovascular
Dilated cardiomyopathy, cardiomegaly,
cardiac failure
Hypertension
Metabolic
Impaired glucose tolerance or potentially
secondary diabetes (see Chapter 11)
Skin
Irritating, thickened, greasy (increased
sebum production)
Excessive sweating
General
Headaches
Tiredness, often very disabling lowering
quality of life and ability to work
Local tumour effects
See earlier section on anatomy and
pituitary space-occupying lesions

Treatment

Restoring normal GH status returns ageadjusted mortality to normal. The goal

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is
a
normal
ageadjusted serum IGF-I and GH nadir on

If the tumour is accessible in its

entirety,
transsphenoidal surgery can be curative.
Serum
GH
falls promptly if successful; if it remains
elevated,
some neurosurgeons will re-operate
straight
away.
If surgery is not curative (the goal may
have
been
only to debulk an extensive tumour),
medical
therapy is possible. Normal somatotrophs
respond
to somatostatin via specific cell-surface
receptors
by
reducing GH secretion. Most GH-secreting
adenomas retain this feature to some extent so
that
they
can be treated by potent somatostatin
analogues
delivered by monthly intramuscular
injection.
If
these fail, dopamine agonists (see
treatment
of
prolactinomas later) can sometimes be
helpful,
especially if the tumour co-secretes
prolactin.
Pegvisomant antagonizes GH action at
the
GH
receptor. Although this is a beautiful
example
of
drug design (see Figure 3.7), it remains
prohibitively expensive for many patients in the
UK
and
other countries.
A common management pathway sees a
patient
treated with a somatostatin analogue
if
transsphenoidal surgery is not curative. If this
still
fails

to achieve normal GH status [e.g.

normal
serum
IGF-I, nadir GH <0.3 ng/mL (<0.8
mU/L)
on
OGTT], external beam radiotherapy can
be
administered. Hypopituitarism is common
after
radiotherapy, requiring attentive follow-up;
however,
once radiotherapy has been effective
(e.g.
IGF-I
in
the age- and sex-adjusted normal range),
somatostatin
analogue
therapy
can
be
withdrawn.
There is much debate over whether
GH
promotes bowel tumour formation and/or
growth.
Colonoscopy, at least once at diagnosis,
can
be
considered to look for colonic polyps with
malignant
potential. Long-term surveillance is
contentious,
but may have a role in patients who are
not
cured
by the above modalities, i.e. where there
is
ongoing
GH excess.
Growth hormone deficiency
Like GH excess, insufficient GH
presents
differently at different times of life. Prior to
final
height,
it comes to the attention of the
paediatric
endocrinologist as failure to grow (falling
off
height
centile charts; Figure 5.9). In adulthood,
it
presents
insidiously, often in conjunction with
other pitui-

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