Acromegaly

Acromegaly

Basics

Excess secretion of growth hormone results in the clinical syndrome known as acromegaly. This is an endocrine condition that develops insidiously over decades.

Epidemiology

Patients with the condition usually present between the ages of 40 and 45. However, diagnosis is usually delayed 7–10 years after the onset of symptoms (1). Children and adolescents who have excess growth hormone before the epiphyseal growth plates are fused can develop pituitary gigantism.

Incidence

3 cases per 1 million persons per year (1)

Prevalence

60 per million (1)

Risk Factors

The most common cause is a growth hormone-secreting adenoma of the anterior pituitary or somatotroph. More than 90% of acromegaly patients have such a lesion.

Genetics

• The genetics of this disorder are still under investigation. However, it appears that most somatotroph adenomas overexpress pituitary tumor transforming gene, which plays a role in tumor invasiveness. In addition, 40% of these tumors have an activating mutation of the alpha subunit of the guanine nucleotide stimulatory protein gene.
• Rare causes of acromegaly include ectopic secretion of growth hormone-releasing hormone by nonendocrine tumors (small-cell lung cancers, carcinoid tumors), an excess secretion of this hormone by hypothalamic tumors, and ectopic GH secretion by nonendocrine tumors.

General Prevention

There are currently no preventative strategies for this condition.

Etiology

Excess secretion of GH stimulates the liver to secrete insulinlike growth factor-I (IGF-1), which causes most of the condition's clinical features.

Commonly Associated Conditions

• Rarely, the disease is associated with familial syndromes, including Carney syndrome, McCune-Albright syndrome, familial acromegaly, and multiendocrine neoplasia type I (1).
• Associated with increased risk of colon polyps and cancer of the colon, esophagus, stomach
• Associated with increased risk of melanoma (2)

Diagnosis

• Associated with cardiovascular abnormalities, including cardiomyopathy characterized by diastolic dysfunction and arrhythmias, hypertension, and left ventricular hypertrophy
• Sleep apnea (1/3 of cases are central and 2/3 are obstructive) occurs in 50% (2)
• Associated with hyperinsulinism, insulin resistance, diabetes
• Bone density may be increased.

History

• Often, onset is recognized by looking at old photographs.
• Enlarged, swollen hands and feet:
  • Enlarging shoe and glove size and need to enlarge rings are typical signs.
• Coarse facial features:
  • Enlarged jaw (macrognathia), nose, and frontal bones
  • Teeth spread apart
  • Enlarged tongue (macroglossia)
• Deepened voice
• Hand numbness
• Fatigue, weakness
• Headache, vision changes may be the result of local tumor effects

Physical Exam

• Neurologic:
  • Bitemporal hemianopsia in 10% of patients
  • Headaches in 60% of patients
  • Hand paresthesias:
    • Carpal tunnel syndrome presents in 20% of patients.
• Musculoskeletal:
  • Hypertrophic arthropathy of spine, hips, knees, ankles
  • Prognathism
  • Gigantism
  • Jaw malocclusion
• Skin:
  • Skin thickening
• Endocrine:
  • Menstrual dysfunction in females, galactorrhea, hyperprolactinemia may occur if the somatotroph macroadenoma decreases secretion of other pituitary hormones
  • Goiter
• Visceromegaly: Enlarged prostate in men, kidneys, liver, heart, thyroid may occur

Diagnostic Tests & Interpretation

Lab

• Hyperphosphatemia seen in 70%.
• Hypercalciuria, increased 25-hydroxyvitamin D₃

Initial lab tests

• Initial testing (1):
  • Serum IGF-1 will be elevated.
  • Serum GH will be elevated and changes little throughout the day, unlike in normal subjects, whose concentrations range from 2–10 ng/mL and change with food or exercise.
• Follow-up testing:
  • An oral glucose tolerance test with 75 g of glucose will not suppress serum GH concentrations.
  • In normal subjects, this glucose load would cause a GH fall to 1 ng/mL or less within 2 hours, but the postglucose values are greater than 2 ng/m in acromegaly.

Imaging

Pituitary magnetic resonance imaging (MRI) is the next step in confirmation of the disease:

• Such a study will detect tumors as small as 2 mm in diameter.
• Study does not differentiate between functioning and nonfunctioning tumors

Follow-Up & Special Considerations

If the initial MRI is normal, chest and abdominal computed tomography should be performed to look for extrapituitary causes of acromegaly and GHRH should be measured.

Treatment

Goals of treatment:

• Lower the serum IGF-1 to within the reference range for the patient's age and gender
• Lower serum GH <1 ng/mL as measured after glucose load

Medication

• Pharmacologic treatment is only utilized if surgery alone has not reduced the serum IGF-1 and GH to normal:
  • Primary therapy is with long-acting somatostatin analogs (2)[B].
  • If somatostatin analogs are ineffective, a dopamine agonist may be used (2)[C].
  • If both or a combination is ineffective, pegvisomant may be tried (2)[B].
• Patients with continued increase in adenoma size despite medications may be candidates for radiotherapy or repeat surgery (2)[B].

First Line

Somatostain analogs (3):

• Mechanism of action: Inhibit GH secretion
• Forms:
  • Octreotide: Initial dose: 100 mcg SC q.8h. If the serum IGF-1 concentration does not decrease to normal within 1–2 months, the dose can be increased up to maximum of 400 mcg SC q.8h. Long-acting form: 10 mg IM once monthly up to 40 mg IM once monthly
  • Lanreotide: Initial dose: 30 mg IM q.20–14 days or 60–120 mg SC q.4 weeks

Second Line

• Dopamine agonists (cabergoline):
  • Mechanism of action: Inhibit GH secretion
  • Less efficacious than somatostatin analogs
  • Dose: 1–4 mg p.o. every week
  • Side effects: Nausea
• GH receptor antagonist (pegvisomant):
  • Used if acromegaly has not responded to other treatments
  • Dose: 10 mg SC every day up to a maximum of 40 mg/day
  • Side effects: Elevated serum aminotransferases

Additional Treatment

Radiotherapy:

• Used if acromegaly is uncontrolled by surgery or medical therapy
• Conventional, proton beam, and stereotactic radiotherapy have been used.
• Complication: Hypopituitarism (50%) (1)

General Measures

A multidisciplinary team approach experienced in managing pituitary tumors is essential.

Surgery/Other Procedures

• Selective transphenoidal surgical resection by neurosurgeon is the treatment of choice for patients with somatotroph adenomas that are resectable (4).
• If serum IGF-1 is normalized after surgery (within 7–10 days after resection), no further therapy is recommended (2)[B].

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

• At baseline (4):
  • Echocardiogram
  • Colonoscopy
• Every 3–4 months:
  • Evaluation by clinical exam to include cardiovascular exam and measurement of blood pressure to look for hypertension
  • Labs:
    • Measurement of serum GH after glucose load
    • Measurement of serum IGF-1
• Annually:
  • MRI of brain
• Patients with complications (cardiomyopathy, sleep apnea, colon polyps) should be followed appropriately according to guidelines for these conditions.

Patient Education

Patients can learn more about acromegaly from the 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 (4).
• Death is due primarily to cancer (15%) and respiratory (25%) and cardiovascular (60%) diseases (2).

Complications

• Diabetes mellitus
• Sleep apnea
• Cardiac:
  • Cardiovascular disease
  • Arrhythmia
  • Cardiomyopathy
• Colon cancer