Dr.Methaq A.M. Hussein
ACROMEGALY
Growth hormone (GH) stimulates the production of insulin-like growth factor 1 (IGF-
1), which is produced in the liver and many other tissues. IGF-1 is the main tissue
mediator of the actions of GH .
Acromegaly and gigantism are rare disorders caused by excessive secretion of GH,
or rarely ectopic production of GH or GH-releasing hormone (GHRH). Acromegaly
causes an overgrowth of all organ systems, bones, joints and soft tissues .
Gigantism occurs when an excess GH or IGF-1 occurs before the end of puberty and
epiphyseal closure, leading to increased linear growth .
Aetiology
Acromegaly is usually caused by a pituitary tumour (1:3 microadenoma to
macroadenoma .)
Rarely, ectopic GH from non-endocrine tumours - eg, lung cancer, cancer of the
pancreas or ovarian cancer - leads to acromegaly. In very rare cases, excess GHRH
arises from a hypothalamic tumour or from a neuroendocrine tumour of the lung or
pancreas .
There are several familial causes, including those associated with other endocrine
disorders (multiple endocrine neoplasia type 1, McCune-Albright syndrome and
Carney complex) or as an isolated disorder, called familial isolated pituitary adenoma
(FIPA) :]
.
Presentation
Often an insidious onset and symptoms may precede the diagnosis by several years .
Due to tumour :
Headaches (55%.)
Visual field defects: the most common defect is a bitemporal hemianopia .
Due to excess of GH :
Gradual change in appearance due to the effects on cartilage and soft tissues:
enlargement of hands and feet (increase in ring and shoe size), frontal bossing,
thickening of the nose, enlarged tongue (macroglossia), growth of the jaw
(prognathism) and coarsening of facial features .
Macroglossia may cause obstructive sleep apnoea leading to daytime tiredness .
Dental changes: separation and jaw malocclusion .
Excessive sweating (65%) and thick, oily skin, with development of skin tags. Women
may have mild hirsutism .
Articular overgrowth of synovial tissue and arthropathy leading to arthralgia and
osteoarthritis in 24%, back pain and kyphosis .
Visceral hypertrophy - eg, heart, thyroid (with a multinodular goitre), liver and
spleen .
Nerve compression symptoms may occur, especially carpal tunnel syndrome (20-
40%.)
Cardiac features include hypertension (40%), left ventricular hypertrophy,
cardiomyopathy and arrhythmias .
Type 2 diabetes mellitus (40-52%) and glucose intolerance (28-46%) due to insulin
resistance .
Colonic polyps.
Vertebral fractures, possibly due to low-quality bone despite high bone mass .
Due to associated hyperprolactinaemia - eg, galactorrhoea, amenorrhoea: in one
third of patients with a GH-producing adenoma, the adenoma is also prolactin-
secreting[ .]
Hypopituitarism: decreased secretion of anterior pituitary hormones and
compression of pituitary stalk
Investigations
IGF-1 is recommended as the initial screen for suspected acromegaly :
It has a correlation with GH levels, long half life of 15 hours and relatively stable
serum levels .
Highly sensitive, such that a normal level usually excludes acromegaly .
False positives may occur in pregnancy and late adolescence .
Hepatic disease and chronic kidney disease, malnutrition, hypothyroidism, severe
infection and poorly controlled diabetes may affect IGF-1 levels .
.
Oral glucose tolerance test is used to confirm a raised IGF-1 :
GH is normally inhibited by glucose. If the glucose load fails to suppress the GH level
below 1.0 mcg/L this confirms the diagnosis of acromegaly .
Random GH is not recommended; secretion is episodic and the half-life is short .
GHRH concentration can be obtained if clinically indicated .
Assessment of other pituitary hormones as clinically indicated: prolactin, adrenal,
thyroid and gonadal hormones .
MRI scan of pituitary and hypothalamus: more sensitive than CT scan .
Visual field tests are used :
If a tumour is found to abut the optic chiasm on imaging .
In pregnant women with a macroadenoma, when they may be performed serially.
CT scan may be indicated: for lung, pancreatic, adrenal or ovarian tumours that may
secrete ectopic GH or GHRH .
Total body scintigraphy with radio-labelled OctreoScan® (somatostatin) may be used
to aid localisation of the tumour but is rarely required .
Cardiac assessment: electrocardiogram, echocardiogram .
Screening for cancer
Patients with acromegaly have an increased risk of colon cancer and thyroid cancer.
The prevalence of breast and prostate cancer is not increased .
Because of the increased prevalence of colorectal adenomas and cancer, it is
recommended that patients with acromegaly should be offered regular colonoscopy
screening, starting at the age of 40 years, although screening at diagnosis has also
been suggested regardless of age (however, this is controversial). The frequency of
repeat colonoscopy should depend on the findings at the original screening and the
activity of the underlying acromegaly :
Management ]
The aim of management is to control the symptoms caused by the local effects of
the tumour and those due to the excess hormone production, and to normalise
hormone levels. No single treatment is completely effective in achieving these aims
and so a combination of treatments is required .
Trans-sphenoidal surgery is the treatment of choice in most cases :
Patients with residual disease are offered adjuvant drug treatment to reduce GH
levels.
Radiotherapy is used for refractory disease, as an adjuvant for large invasive
tumours and when surgery is contra-indicated. The mortality rate is higher in
patients treated with radiotherapy .]
Genetic counselling is important in young people presenting with acromegaly or
gigantism, regardless of family history, as many genetic causes have reduced
penetrance and first-degree relatives may not be affected
Drug treatment ]
Somatostatin analogues (somatostatin receptor ligands) are the first-choice medical
treatments :
Octreotide and lanreotide are analogues of the hypothalamic release-inhibiting
hormone, somatostatin .
Maximal benefit may be achieved after more than 10 years of treatment .
Side-effects are frequent and include abdominal discomfort and gallstones or
gallbladder sludge; ultrasound is advised if the patient develops symptoms
suggestive of gallbladder disease.
Dopamine agonists :
Bromocriptine, cabergoline and quinagolide are effective but are less effective than
somatostatin analogues .]
Cabergoline is the most effective dopamine agonist, is well tolerated and is safe to
use in pregnancy.
Chronic use of ergot-derived dopamine agonists is associated with a risk of fibrosis,
particularly cardiac fibrosis. Cardiac valvulopathy should be excluded by
echocardiography before treatment with cabergoline or bromocriptine.
Pegvisomant (PEG
:)
This is a genetically modified analogue of human GH and a highly selective GH
receptor antagonist which blocks the peripheral synthesis of IGF-1 .
It has been shown to normalise IGF-1 levels in 68-87% of patients: stringent upward
dose titration appears to be needed to achieve the best results .
In contrast to somatostatin analogues, PEG decreases fasting glucose and improves
glucose tolerance .
GH levels increase during treatment so cannot be used for monitoring. No decrease
in tumour size is seen and rarely the pituitary tumour may grow (2.2% of cases) -
serial MRI imaging is suggested .
Pregnancy
Medical therapy is withheld during pregnancy .
Short-acting octreotide may be used as needed when attempting to conceive .
Patients with macroadenomas should be monitored for headaches and visual
symptoms and undergo serial visual filed testing .
In reports of almost 80 women with prolactinomas, cabergoline has been shown to
be safe to the fetus .