Acromegaly is a disorder caused by an excessive production of growth hormone from the anterior pituitary gland, resulting in excessive growth of body tissues and other metabolic dysfunctions. Adult patients with acromegaly have the characteristic facial features of a large lower jaw, prominent forehead, and large hands and feet. This takes place after the growth plates are fused, distinguishing acromegaly from gigantism which occurs before fusion of growth plates.
Pituitary Tumor: In more than 95% of cases, the excessive growth hormone is caused by a pituitary tumor, usually a benign microadenoma of the pituitary gland.
Non-Pituitary Tumor: Tumors of the adrenals, lungs, and pancreas are implicated in a few cases. These tumors secrete growth hormone or growth hormone releasing Hormone (GH-RH).
Elevated levels of growth hormone stimulate the liver to produce Insulin-like growth factor-1 (IGF-1). Elevated levels of Insulin-like growth factor-1 stimulate the excessive growth of body tissues.
Acromegaly has a worldwide prevalence of about 4,600 per million population, with about 116.9 new cases per million per year. Mean age at diagnosis 40 for men and 45 for women.
In about 95% of cases, acromegaly is associated to a pituitary microadenoma, while the remaining 5% are from non-pituitary ectopic sources of growth hormone or GH-RH. The common effect of the abnormal rise in growth hormone is the production of Insulin-like growth factor-1 (IGF-1) from the liver. The effect of IGF-1 on body tissues results in the multisystemic manifestation of acromegaly. IGF-1 also known as Somatomedin C is encoded by the IGF-1 gene on chromosome 12q23.2.
The pathologic effect of IGF-1 after fusion of the growth plates result in the acral growth spurts manifested as large hands and feet and a prominent jaw and forehead. It is clearly different from the linear size increase that occurs in gigantism in which the effect of elevated IGF-1 occurs before closure of the growth plate.
Acromegaly leads to elevated IGF-1 that affects the following pathways of metabolism:
Competes with insulin for insulin receptor, resulting in relative insulin resistance which may be responsible for the co-existing diabetes mellitus in 10% to 20% of patients with acromegaly.
Results in general somatic hypertrophy seen as enlarged body organs, for example, macroglossia, acromegalic heart, large kidneys, and bulky skeletal muscles.
Somatic growth by binding insulin-like growth factor-1 Receptor (IGF-1R) which is relatively ubiquitous. IGF-1R is a receptor tyrosine kinase which brings about phosphorylation and activation of several intracellular signaling pathways, one of which is the AKT pathway activation that results in somatic cell growth and proliferation.
IGF-1 is an insulin-like protein produced majorly in the liver. It is a single chain of 70 amino acids and three disulfide bridges with a molecular weight of approximately eight kilodaltons. IGF-1 level peaks around puberty, with low levels at extreme ages.
Synthetic IGF-1 analog is used in the treatment of growth disorders, for example, dwarfism.
IGF-1 almost always exists in the bound form. It is bound by the IGF-binding proteins (IGF-BPs), and the most abundant of them is IGFBP-3.
Nutrition also plays some role, as high protein intake tends to increase growth hormone and IGF-1 levels.
History and Physical
Acromegaly is usually a slow progressing disorder, with onset usually in the third or fourth decade of life. The presenting complaints include the following:
joint pain due to hypertrophic arthropathy
wrist pain and numbness from carpal tunnel syndrome
snoring and sleep disorders, like sleep apnea, due to macroglossia
headaches and visual disturbances (bitemporal hemianopia) and pressure effects of pituitary adenoma on adjoining structures in the brain, for example, compression of the optic chiasma
erectile dysfunction or low sex drive
abnormal menses in women
sweaty palms and soles (hyperhidrosis)
Signs upon physical examination include the following:
observe for raised JVP (in acromegalic cardiomyopathy)
skin is thick and rough
abnormal or excess hair distribution, e.g., hirsutism(in women), hypertrichosis
acanthosis nigricans especially in the axilla
dry atrophied skin
problems of acromegalic cardiomyopathy
elevated blood pressure
cardiac murmur (a pansystolic murmur may indicate mitral valve regurgitation)
bibasal crepitation may indicate a congestive heart failure in a patient with acromegalic cardiomyopathy
acral enlargement: large hands (with stubby fingers) and feet
GH suppression test:
administer 100 g glucose to the patient orally
one hour later measure serum growth hormone levels
result: normal GH levels which are less than five ng/ml excludes acromegaly, while elevated levels of greater than ten ng/ml is suggestive of acromegaly
a direct dose-response relationship with growth hormone levels
levels measured for age and sex
useful for diagnosis and treatment monitoring
pregnancy can cause elevated IGF-1 levels
Growth Hormone Releasing Hormone (GHRH) Levels
elevated levels usually > 300ng/mL is suggestive of extra-pituitary sources
Elevated prolactin levels due to pituitary stalk compression by an adenoma or by a co-prolactin producing pituitary adenoma.
MRI is more sensitive in visualizing the Sella turcica and adjacent structures, but a CT scan can be done if this is not available
Skull x-ray: thickened calvaria, enlarged sella, long and thick mandibles, exaggerated ridges, dilated sinuses
Chest x-ray: barrel rib cage with long ribs
Hand x-ray: cortical thickening, ungal tufting, wide distal phalangeal bases, osteophytes and soft tissue hypertrophy
Treatment / Management
Endonasal Transphenoidal Surgery: A minimally invasive surgery using an endoscope through a small incision in the nose or at the upper lip to remove the pituitary adenoma will promptly relief the pressure symptoms as well as lower elevated growth hormone (GH) levels. Recovery time is shorter compared to traditional transsphenoidal surgery.
Transnasal Transsphenoidal Microscopic Surgery: This is a traditional pituitary surgery that utilizes direct visualization of the tumor using a microscope. Recent retrospective studies showed gross total resection with a resolution of IGF-1 endonasal approach which is comparable to transnasal transsphenoidal microscopic surgery.
Medical Therapy: Either as an adjunct to surgery or when surgery is not desirable.
Somatostatin analogs (octreotide, Lanreotide): These act on the somatostatin receptor to bring about inhibition of growth hormone secretion. It is usually administered as once-monthly intramuscular injections. It also can be used to shrink large pituitary adenomas before surgery.
Dopamine receptor agonists (cabergoline, bromocriptine): These act on D2 receptors and are not as effective as the Somatostatin analogs. They are often used as adjuncts. Cabergoline is more potent than bromocriptine in lowering GH levels.
GH- Receptor antagonist (Pegvisomant): This novel drug blocks growth hormone at the receptors, lowering IGF-1 levels while GH levels remain unaffected.
Conventional radiotherapy: Often administered as an adjunct to surgery to either prevent relapse or when surgery is not able to bring about the acceptable lowering of GH levels. It is associated with the risk of irradiating adjacent brain tissues.
Stereotactic radiosurgery: This is precision radiotherapy, directing high dose radiation to the tumor, and minimizing risk to nearby healthy brain tissues.
Pearls and Other Issues
Minoxidil use has been associated with a condition characterized by facial features of acromegaly, but with normal growth hormone and IGF-1 blood levels. This condition is known as pseudoacromegaly.
Enhancing Healthcare Team Outcomes
Acromegaly is not a common disorder in North America, but when it presents, it is associated with a very high morbidity and mortality rates. Because the presentation of acromegaly is systemic, a multidisciplinary approach is necessary. In particular a cardiologist, oncologist, neurologist, and a pulmonologist should be involved as the disorder is associated with malignancies, adverse cardiac, CNS and pulmonary events. The mortality rates of patients with acromegaly are 3 times the general population, with most dying from respiratory and cardiac complications. These patients also develop several types of tumors including prostatic hypertrophy, uterine myomas, and skin tags. The overall outcome depends on whether the cause of acromegaly can be treated. even after surgical removal of a pituitary tumor, some patients may need treatment as a result of residual disease. The quality of life in these patients is poor.