PITUITARY

Acromegaly

Aetiology

Belayet Hossain

In 99% of cases, acromegaly is caused by a GH-secreting pituitary

adenoma. Acromegaly caused by ectopic secretion of GH-releasing
hormone is extremely rare.

William M Drake

Clinical features
The clinical features of acromegaly are listed in Figure 1. The
condition develops insidiously, such that the average time from
initial onset of symptoms to diagnosis is typically 510 years, and
often longer (Figure 2). In view of the nonspecific nature of many
of the common symptoms (e.g. fatigue, joint pain), it is recommended that acromegaly is considered by physicians, surgeons
and dental practitioners attending patients with the following
symptoms and/or signs:
increased sweating
carpal tunnel syndrome
dental malocclusion
multiple skin tags
sleep apnoea
recurrent colonic polyps
oligomenorrhoea/amenorrhoea
type 2 diabetes mellitus in the absence of a family history and/or
appropriate phenotype.
Clinical assessment of patients with suspected acromegaly should
focus particularly on the symptoms and syndromes listed in
Figure 1, but should also include detailed neuro-ophthalmic evaluation and should address the symptoms and signs that may suggest
any of the common complications of acromegaly (hypertension,
cardiac failure, large joint osteoarthritis, type 2 diabetes).

Acromegaly is a rare, chronic, debilitating condition in adults

associated with significantly increased morbidity and mortality. It
is almost invariably caused by a growth hormone (GH)-secreting
pituitary tumour. The same pathological process occurring before
epiphysial closure results in pituitary gigantism. Life expectancy
in untreated individuals is reduced by about 10 years.

Epidemiology
Acromegaly typically becomes apparent at age 4060 years. In
Europe, the incidence is 34/million/year and the prevalence
4060/million. Males and females are affected equally.

Belayet Hossain is Specialist Registrar in Diabetes and Endocrinology

in the North East Thames Region, London, UK. Conflicts of interest: none
declared.

Investigations and diagnosis

The major challenge in acromegaly is early diagnosis of a disease
that develops insidiously. GH secretion is pulsatile, with six to
ten pulses of release separated by long periods during which

William M Drake is Consultant Physician in the Department of

Endocrinology at St Bartholomews Hospital, London, UK. Conflicts of
interest: none declared.

Clinical features of acromegaly

Symptoms
Increased sweating
Change in shoe/ring size
Headache
Tiredness/lethargy
Joint pain
Symptoms of other anterior pituitary hormone deficiency
Signs
Characteristic facial appearance frontal bossing, enlarged nose, deep
nasolabial furrows, prognathism, increased interdental separation
Oily skin
Deep voice
Enlargement of hands, feet, tongue, lips
Signs resulting from compression of optic apparatus by pituitary tumour
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GH concentrations are virtually undetectable. This means that

measurement of a random GH level has little value in the diagnosis
of acromegaly. Although insulin-like growth factor I (IGF-I) mediates almost all of the actions of GH, the assays for this peptide are
less robust than those for GH, and circulating IGF-I levels I vary
considerably with factors such as nutrition, insulin resistance,
liver/renal disease and exogenous oestrogen administration. For
this reason, diagnostic tests for acromegaly include both serum
IGF-I concentration and the 75 g oral glucose tolerance test,
during which serum GH levels should decline to a nadir of less
than 1 mU/litre.

Investigations in acromegaly
Establish diagnosis
Serum IGF-I
Non-suppression of GH following 75 g oral glucose tolerance
test
Establish severity of disease
Mean of several serum GH samples
Serum IGF-I
Pituitary anatomy
MRI
Visual field perimetry

Further assessment: once the diagnosis is established, further

investigations (Figure 2) are directed at:
defining the severity of the disease (usually achieved by
calculating the average of several serum GH measurements
taken throughout the day, which complements IGF-I measurement)
assessing anterior pituitary function
documenting the pituitary and peripituitary anatomy, with a
view to possible surgery
assessing the presence or absence of complications.

Pituitary function
Serum thyroid-stimulating hormone plus free thyroxine
Serum cortisol at 9:00 a.m.
Serum gonadotrophins and sex hormones
Metabolic consequences of high GH
Fasting glucose oral glucose tolerance test
HbA1C

Management
Acromegaly is best managed in a centre with an experienced
endocrinologist, a pituitary surgeon and a radiotherapist. The
aims of treatment are:
control of the tumour and its mechanical effects
relief of symptoms
reducing serum GH/IGF-I to safe levels associated with
improved prognosis
preservation of normal pituitary function.

Identify coexistent disease

Serum calcium (multiple endocrine neoplasia type 1)
Identify any complications
ECG echocardiography
Chest radiography
Radiography of large joints
Sleep study (if sleep apnoea suspected)

Surgery: surgical adenomectomy remains the treatment of

choice in most patients, With an experienced surgeon, the
cure rate (defined by normal age-adjusted and sex-adjusted
IGF-I and post-glucose GH nadir of < 2 mU/litre) is about 90%
in patients with a microadenoma and 4050% in those with a
macroadenoma.

IGF-I, insulin-like growth factor I; GH, growth hormone

Drug treatment of acromegaly

Name, class

Mechanism of action

Cabergoline, dopamine
agonist
Octreotide, lanreotide,
somatostatin analogues
Pegvisomant, GH receptor
antagonist

Binds to D2 receptor on
somatotrophs
Bind to SMS receptors
2 and 5 on somatotrophs
No effect on GH secretion;
binds to GH receptors to
prevent functional activation
and IGF-I generation

Efficacy
(% normal IGF-I)
2040

Common side-effects

Parameter monitored
GH and IGF-I

60

Nausea, constipation (less

commonly, mood changes)
Nausea, diarrhoea, gallstones

97

Hepatitis (about 1%)

IGF-I only (serum GH

increases with pegvisomant
therapy)

GH and IGF-I

IGF-I, insulin-like growth factor I; GH, growth hormone

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Drug therapy: various medical therapies are available for patients

who are not cured by surgery or who are unwilling to have or unfit
for general anaesthesia (Figure 3). Dopamine agonists achieve
satisfactory biochemical control in only a few patients, but their
relative inexpense and oral administration mean that a therapeutic
trial is reasonable in most cases. Somatostatin analogues (e.g.
octreotide, lanreotide) are generally regarded as the gold-standard
medical therapy, though many patients (up to 40%) do not experience satisfactory control with this class of drug. For these patients,
the new therapy pegvisomant, which functions as a GH receptor
antagonist, is now available.
Radiotherapy: pituitary irradiation is a useful adjunctive treatment in some patients with acromegaly who are not cured by
surgery. Two techniques are used standard external beam
irradiation (typically given in 25 fractions over 5 weeks), and
highly focused stereotactic radiotherapy given as a single dose.
Both work relatively slowly and both cause hypopituitarism. The
number of patients receiving pituitary irradiation has declined as
more satisfactory medical therapies have become available, but
it remains an important treatment option, particularly in patients
with large, aggressive, invasive tumours.

FURTHER READING
AACE medical guidelines for clinical practice for the diagnosis and
treatment of acromegaly. Endocr Pract 2004; 10: 21325.
Trainer P J, Drake W M, Besser G M. Growth hormone receptor antagonist
therapy for acromegaly. Abstract S213 1999 AES San Diego.
Turner H E, Wass J A H. Modern approaches to treating acromegaly. QJM
2000; 93: 16.
Wass J A H. Acromegaly and gigantism. In: G M Besser, M O Thorner,
eds. Comprehensive clinical endocrinology. 3rd ed. St Louis: Mosby,
2002.

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