Epidemiology

Acromegaly most commonly presents between the ages of 40 and 45 years, but the diagnosis is typically delayed for 7 to 10 years after the onset of symptoms.

Incidence
3 cases per million persons per year

Prevalence
60 to 480 cases per million persons

Etiology and Pathophysiology

• >90% of patients with acromegaly have a benign GH-secreting, or somatotroph, adenoma of the anterior pituitary.
• Excess secretion of GH stimulates the liver to secrete insulin-like growth factor 1 (IGF-1), which causes most of the condition’s clinical features.
• The remaining 10% have ectopic GH secretion, most commonly from pancreatic islet cell tumors or lymphomas, or hypersecretion of growth hormone–releasing hormone (GHRH), most commonly from hypothalamic gangliocytomas or peripheral neuroendocrine tumors such as carcinoid, islet cell tumors, small cell lung cancer, adrenal adenomata, medullary thyroid cancer, or pheochromocytoma (1).

• A majority may have a loss of expression of growth arrest and DNA-damage-inducible (GADD) 45 gamma peptide.
• 40% may have an activating mutation of the α-subunit of the guanine nucleotide stimulatory protein gene.
• In those undergoing genetic analysis, 4.4% found to have an overexpression mutation in GP101, an X-linked G protein–coupled receptor.
• Familial syndromes that include acromegaly as a feature, such as Carney syndrome, McCune-Albright syndrome, familial acromegaly, and multiple endocrine neoplasia type 1 (MEN1) are rare.

General Prevention

There are currently no preventive strategies for this condition.

Commonly Associated Conditions

• Cardiovascular
  • Hypertension
  • Cardiomyopathy
  • Arrhythmias
• GI
  • Colon polyps/cancer
• Neurologic
  • Sleep apnea, both central and obstructive
  • Narcolepsy
  • Carpal tunnel syndrome
• Endocrine
  • Insulin resistance/impaired glucose tolerance/impaired fasting glucose/diabetes mellitus
  • Hypertriglyceridemia
  • Infertility
  • Visceromegaly
  • Thyroid disease/cancer

History

• Musculoskeletal
  • Enlarging shoe and ring size
  • Arthralgias/myalgias
• Neurologic
  • Headache
  • Vision changes, particularly temporal hemianopsia
  • Hand numbness/carpal tunnel syndrome
  • Fatigue, weakness
  • Sleep disturbance
• Dermatologic
  • Increased sweating
  • Oily skin
• Endocrine
  • Deepened voice
  • Decreased libido
  • Female: amenorrhea or other menstrual dysfunction, hot flashes, vaginal atrophy
  • Male: erectile dysfunction
  • Galactorrhea

Physical Exam

• Presentation may be subtle and is often aided by review of old photographs. Look for facial coarsening:
  • Enlarging jaw (macrognathia), nose, and frontal bones
  • Teeth spreading and change in bite/jaw malocclusion
  • Enlarging tongue (macroglossia)
• Neurologic
  • Bitemporal hemianopsia
  • Other cranial nerve defects
• Musculoskeletal
  • Hypertrophic arthropathy of spine, hips, knees, ankles
  • Prognathism
  • Vertebral fractures
  • Gigantism (if pediatric or adolescent)
• Dermatologic
  • Skin thickening, skin tags
• Visceromegaly: enlargement of the prostate (in men), kidneys, liver, spleen, heart, salivary glands, thyroid (goiter), and tongue

Diagnostic Tests & Interpretation

• Initial testing
  • Serum IGF-1 (best single test for diagnosis; adjust for age). Levels 2 times the upper limit are more suggestive of acromegaly (2)[B].
  • Falsely low IGF-1 may be seen in hypothyroidism, malnutrition, poorly controlled DM1, liver/renal failure, and oral estrogens; perform oral glucose tolerance test (OGTT).
• Concurrent laboratory findings
  • Hyperprolactinemia; either through mass effect of the GH-secreting tumor or through prolactin/GH cosecretion
  • Hyperphosphatemia
  • Hypercalciuria
  • Increased 25-hydroxyvitamin D
  • Decreased sex hormone–binding globulin and thyroxine-binding globulin
• Follow-up testing
  • A 75-g OGTT: In normal subjects, GH should drop to ≤1 ng/mL within 2 hours, but postglucose GH levels may remain >2 ng/mL in patients with acromegaly.
• MRI of the sella (with and without contrast)
  • Will detect tumors as small as 2 mm in diameter
  • Does not differentiate between functioning and nonfunctioning tumors

Follow-Up Tests & Special Considerations
If the sellar MRI is normal, perform a CT scan of the chest and abdomen to evaluate for extrapituitary source of acromegaly. Plasma GHRH should also be measured using a diagnostic threshold of 250 to 300 ng/L (1)[B].

General Measures

A multidisciplinary team experienced in managing pituitary tumors is essential for treatment.

Medication

Pharmacologic treatment is generally used if inadequate response to surgery or poor surgical candidate:

• Primary medical therapy is with long-acting somatostatin analogs (octreotide, lanreotide).
• Dopamine agonist (cabergoline) may be used in combination with somatostatin analog.
• If above is ineffective, pegvisomant may be tried.

Somatostatin analogs (4)[A]

• Mechanism of action: Inhibit GH secretion.
• Forms
  • Octreotide: short-acting form: Initial dose is 50 μg SC q8h. If the serum IGF-1 concentration does not normalize within 1 to 2 months, titrate upward to a maximum dose of 500 μg SC q8h. Long-acting form: Initial dose is 10 mg IM q4wk, titrated up to 40 mg IM q4wk.
  • Lanreotide: Initial dose is 60 to 90 mg SC q4wk, titrated to a normal IGF-1 level; if IGF-1 is normal on 60 or 90 mg SC q4wk, may attempt 120 mg q6wk or q8wk

• Dopamine agonist (cabergoline) (5)[A]
  • Less efficacious than somatostatin analogs and is typically used in combination with somatostatin analogs
  • Dose: 0.25 mg PO once weekly, titrated to a maximum dose of 1 mg PO twice weekly
  • Side effect: nausea
• GH-receptor antagonist (pegvisomant)
  • Use if acromegaly has not responded to other treatments.
  • Dose: initial loading dose of 40 mg SC and then 10 mg SC daily, titrated to a maximum maintenance dose of 30 mg/day
  • Side effects: elevated serum aminotransferases
• Estrogen or selective estrogen receptor modulators (SERMS) (raloxifene and tamoxifen) (6)[B]
  • Likely effective only in females
  • Estrogens more potent in IGF-1 reduction than are SERMS

Pregnancy Considerations

• GH and IGF-1 increase risk for gestational diabetes and gestational hypertension.
• Pregnant women with acromegaly would benefit from endocrinology and MFM referrals.
• Test visual fields at end of the 1st trimester and then every 6 weeks.
• Consider MRI without contrast if new symptoms develop or visual field testing suggests chiasmal lesion.
• If planned pregnancy, consider discontinuing long-acting somatostatin.

Additional Therapies

Radiotherapy

• Used if acromegaly is uncontrolled by surgery or medical therapy
• Conventional, proton beam, and stereotactic radiotherapy have been used.
• Complication: hypopituitarism (50%)

Surgery/Other Procedures

• Transsphenoidal surgical resection by an experienced neurosurgeon is the treatment of choice for patients with pituitary tumors that are resectable.
• If serum IGF-1 is normalized after surgery (within 7 to 10 days after resection), no further therapy is recommended.

Follow-up Recommendations

Monitoring for medical and surgical treatment:

• At baseline
  • Echocardiogram
  • Colonoscopy
• Every 3 to 4 months
  • Cardiovascular exam and BP measurement
  • Measurement of serum IGF-1
• Annually
  • MRI of pituitary sella
• Patients with complications (cardiomyopathy, sleep apnea, colon polyps) should be followed appropriately according to guidelines for these conditions.
• Specifically after surgical resection: random IGF-1, GH level, and pituitary MRI performed 12 weeks

Patient Education

Pituitary Patient Resource Guide, published by the Pituitary Network Association (www.acromegaly.org)

Prognosis

• Patients with GH levels <2.5 after treatment have a mortality similar to the general population (5).
• Death is primarily caused by cancer (15%), respiratory diseases (25%), and cardiovascular diseases (60%).
• If untreated, there is an associated 30% decrease in lifespan related to the above complications.

Complications

See section on “Commonly Associated Conditions.”

See Also

Algorithm: Tall Stature

ICD-10

• E22.0 Acromegaly and pituitary gigantism

ICD-9

• 253.0 Acromegaly and gigantism

SNOMED

• 230581008 Neuropathy in acromegaly (disorder)
• 240089002 Myopathy in acromegaly (disorder)
• 267386008 Gigantism and acromegaly
• 74107003 Acromegaly (disorder)
• 80849007 Gigantism (disorder)