pituitary lecture3

Acromegaly

Dr Ahmed Abdalla Abass

consultant of internal medicine and
endocrinology
june 2021
Definition of acromegaly
Acromegaly is the clinical condition resulting from
prolonged excessive
GH and hence IGF-1 secretion in adults. GH
secretion is characterized by
blunting of pulsatile secretion and failure of GH to
become undetectable
during the 24h day, unlike normal controls
Epidemiology of acromegaly
.Rare. Equal sex distribution •
Prevalence 40–86 cases/million population. Annual •
incidence of new
.cases in the UK is 4/million population
Onset is insidious, and there is, therefore, often a •
considerable delay
between onset of clinical features and diagnosis.
Most cases are
diagnosed at 40–60 years. Typically, acromegaly
occurring in an older
patient is a milder disease, with lower GH levels and a
smaller tumour
Causes of acromegaly
CAUSES OF ACROMEGALY
Pituitary adenoma (>99% of cases). Macroadenomas 60– •
,80%
microadenomas 20–40%. Local invasion is common, but frank
.carcinomas are very rare
:GHRH secretion •
.Hypothalamic secretion •
Ectopic GHRH, e.g. carcinoid tumour (pancreas, lung) or •
other
.neuroendocrine tumours
Pituitary shows global enlargement. Somatroph hyperplasia •
seen on
.histology
Ectopic GH secretion. Very rare (e.g. pancreatic •
,islet cell tumour
.)lymphoreticulosis
There has been some progress on the molecular •
pathogenesis of the
GH-secreting pituitary adenomas—as mutations of
the Gsα are found
in up to 40% of tumours. This leads to an
abnormality of the G protein
that usually inhibits GTPase activity in the
somatotroph
Gene mutations have been shown in some young
patients with
acromegaly who also have large tumours (familial
isolated pituitary
adenoma) in whom a family history should be
sought
Associations of acromegaly
.MEN-1. Less common than prolactinomas •
Carney complex. AD, spotty cutaneous •
pigmentation, cardiac and other
myxomas, and endocrine overactivity,
particularly Cushing’s syndrome
due to nodular adrenal cortical hyperplasia and
GH-secreting pituitary
tumours in <10% of cases. Mainly due to
activating mutations of
protein kinase A
McCune–Albright syndrome Caused by somatic •
.mosaicism for the gsp mutation
:Familial isolated pituitary adenomas •
Existence of two or more cases of acromegaly or •
gigantism in a
family that does not exhibit MEN-1 or Carney
.complex
.Autosomal dominant •
Most have acromegaly, but acromegaly and •
prolactinoma families
.exist as rarely as do NFA families
cases have a mutation in the AIP gene 50%–30 •
(tumour
.)suppressor gene
.Early-onset disease (<30 years) •
.Poor response to somatostatin analogues •
Take a careful family history, especially in acromegalic •
patients with
a large pituitary tumour presenting below the age of 30
years, and
.consider screening for AIP
Clinical features of acromegaly
CLINICAL FEATURES OF ACROMEGALY
The clinical features arise from the effects of excess
GH/IGF-1, excess PRL
in some (as there is co-secretion of PRL in a minority (30%)
,of tumours or
.rarely, stalk compression), and the tumour mass
Symptoms
.i sweating—>80% of patients •
.Headaches—independent of tumour effect •
.Tiredness and lethargy •
.Joint pains •
.Change in ring or shoe size •
Signs
Facial appearance. Coarse features, oily skin, frontal bossing, •
enlarged
nose, deep nasolabial furrows, prognathism, and i interdental
.separation
.Deep voice—laryngeal thickening •
. Tongue enlargement—macroglossia •
Musculoskeletal changes. Enlargement of hands and feet, •
degenerative
.changes in joints lead to osteoarthritis. Generalized myopathy
Soft tissue swelling. May lead to entrapment neuropathies, such •
as
.carpal tunnel syndrome (40% of patients)
.Goitre and other organomegaly—liver, heart, kidney •
NB Fabry’s disease causes thickening of the lip
Complications
.Hypertension (40%) •
Insulin resistance and impaired glucose tolerance •
(40%)/diabetes
.mellitus (20%)
Obstructive sleep apnoea—due to soft tissue swelling in •
.nasopharyngeal region
increased risk of colonic polyps and colonic carcinoma— •
extent currently
.considered controversial
.Ischaemic heart disease and cerebrovascular disease •
Congestive cardiac failure and possible increased •
prevalence of regurgitant
valvular heart disease
Effects of tumour
.Visual field defects •
Hypopituitarism •
Investigations of acromegaly
Oral glucose tolerance test (OGTT)
In acromegaly, there is failure to suppress GH to •
<0.33 micrograms/L
in response to a 75g oral glucose load. In contrast,
the normal
.response is GH suppression to undetectable levels
False +ves. Chronic renal and liver failure, •
,malnutrition, diabetes mellitus
heroin addiction, adolescence (due to high
pubertal GH surges)
Random GH
Not useful in the diagnosis of acromegaly as,
although normal healthy subjects
have undetectable GH levels throughout the day,
there are pulses ofGH
which are impossible to differentiate from the
.levels seen in acromegaly
However,inuntreated patients a random
GH<0.33 micrograms/L practicallyexcludes the
.diagnosis
IGF-1
Useful in addition to the OGTT in differentiating
patients with acromegaly
from normals, as it is almost invariably elevated in
acromegaly, except in
severe intercurrent illness. It has a long half-life,
as it is bound to binding
proteins, and reflects the effect of GH on tissues.
However, abnormalities
.of GH secretion may remain while IGF-1 is normal
MRI
MRI usually demonstrates the
tumour (98%) and whether there
is extra-
sellar extension, either .1
suprasellar or into the
.cavernous sinus
Pituitary function testing
Serum PRL should be
measured, as some tumours co-
.secrete both GH and PRL
Serum calcium
Some patients are hypercalciuric due to i 1,25-
DHCC, as GH stimulates
renal 1α-hydroxylase. There may be an i
likelihood of renal stones due
to hypercalcaemia as well as hypercalciuria
(which occurs in 80%). Rarely,
hypercalcaemia may be due to associated MEN-1
.and hyperparathyroidism
GHRH
Occasionally, it is not possible to
demonstrate a pituitary tumour, or the
pituitary gland MRI reveals global
enlargement and histology reveals hyper-
plasia. A serum GHRH, in addition to
radiology of the chest and abdomen,
may then be indicated to identify the cause,
usually a GHRH-secreting
.carcinoid of lung or pancreas
Management of acromegaly
The management strategy depends on
the individual patient and also
on the tumour size. Lowering of GH is
essential in all situations
Transsphenoidal surgery
• This is usually the first line for treatment in most
centres.
• Reported cure rates vary: 40–91% for
microadenomas and 10–48% for
.macroadenomas, depending on surgical expertise
• A GHDC should be performed following surgery to
assess whether
‘safe’ levels of GH and IGF-1 have been attained. If the
mean GH is
<2.5 micrograms/L, then the patient can be followed up
with annual
IGF-1 and/or GH assessment. If safe levels of GH have
not been
achieved, then medical treatment and/or radiotherapy
.is indicated
 Surgical debulking of a large macroadenoma
should be undertaken,
even if cure is not expected, because this lowers
GH levels and
improves the cure rate with subsequent
.somatostatin analogues
Tumour recurrence following surgery
This is defined as tumour regrowth and increase in GH
levels, lead-
ing to active acromegaly following post-operative
normalization of GH
levels. Using the definition of post-operative cure as
mean GH <2.5
micrograms/L, the reported recurrence rate is low (6%
.at 5 years)
Radiotherapy
• This is usually reserved for patients following
unsuccessful
transsphenoidal surgery, only occasionally is it used
as primary therapy. The
largest fall in GH occurs during the first 2 years, but
GH continues to
fall after this. However, normalization of mean GH
may take several
years and, during this time, adjunctive medical
treatment (usually
.with somatostatin analogues) is required
With a starting mean GH
>25 micrograms/L, it takes, on average, 6 years
to achieve mean
GH <2.5 micrograms/L, compared with 4 years
with a starting mean
GH <25 micrograms/L.
After radiotherapy, somatostatin analogues should
be withdrawn on
an annual basis to perform a GHDC to assess
progress and identify
when mean GH <2.5 micrograms/L and, therefore,
radiotherapy has
been effective and somatostatin analogue
treatment is no longer
required.
Radiotherapy can induce GH deficiency which •
.may need GH therapy
definition of cure
• Controlled disease is, most recently, defined
as a random GH <1
micrograms/L or nadir GH <0.4 micrograms/L on
GTT + normal
.age-related IGF-1
• In treated patients, there is an
approximately 25% discordance of GH
and IGF-1. The management of this
situation is unclear, but if there are
symptoms, it should probably be
.treated
Drug treatment
Somatostatin analogues
(b also see Somatostatin analogues, p. 204.)
• Somatostatin analogues lead to suppression of
GH secretion in 20–60%
of patients with acromegaly. At least 40% of
patients are complete
responders, and somatostatin analogues will
lead to normalization of
.GH (<2.5 micrograms/L) and IGF-1
However, some patients are partial
responders, and although somatostatin
analogues will lead to lowering
of mean GH, they do not suppress to normal
despite dose escalation.
• Acute response to these drugs is assessed by
measuring GH at
hourly intervals for 6h, following the injection of
50–100 micrograms
.octreotide SC. This predicts long-term response
Depot preparations lanreotide Autogel® and
octreotide LAR® are
available. Octreotide LAR® 20mg IM is
administered every 4 weeks,
with dose alterations either down or up to 10–
30mg every 3 months.
Lanreotide Autogel® 90mg (deep SC) is
administered every 28 days,
with dose alteration either down to 60mg or up
to 120mg every
.months 3
Patients can be taught to self-administer
lanreotide.
• These drugs may be used as primary therapy
where the tumour does not
cause mass effects or in patients who have
received surgery and/or
radiotherapy who have elevated mean GH.
• Pasireotide stimulates somatostatin receptors 2
and 5, and treatment
may increase the response rate in patients with
acromegaly, but
glucose tolerance declines and patients may
.develop diabetes mellitus
Dopamine agonists

These drugs do lead to lowering of GH levels but, very rarely,

lead to
normalization of GH or IGF-1 (<30%). They may be helpful,
particularly
if there is coexistent secretion of PRL, and, in these cases,
there may be
significant tumour shrinkage. Cabergoline has recently been
shown to be
more effective than bromocriptine and may lead to IGF-1
normalization in
up to 30%. A lower pretreatment IGF-1 favours a good
.response
GH receptor antagonists (pegvisomant)
Indicated for somatostatin non-responders.
Liver function tests should
be monitored 6-weekly for 6 months. MRI of
the pituitary is indicated
6-monthly in case of pituitary enlargement
(5%). Therapy may be continued
with octreotide or lanreotide to decrease the
frequency of pegvisomant
injections (e.g. pegvisomant 10mg daily and
.lanreotide)
Normalization of lGF-1 in >90% of patients
is reported. More data on the effect on
tumour
size are required, as GH rises during
treatment. GH levels cannot, there-
fore, be used to guide treatment, and IGF-1
is used to monitor therapy.
Monitoring of liver biochemistry is
.necessary for safety