Acromegaly & Gigantism

Essentials of Diagnosis

• Pituitary neuroendocrine tumor

• Acromegaly: excessive growth of hands, feet, jaw, and internal organs

• Gigantism if growth hormone (GH) excess before closure of epiphyses; acromegaly if after closure

• Amenorrhea, hypertension, headaches, visual field loss, weakness

• Soft, doughy, sweaty handshake

• Elevated serum insulin-like growth factor 1 (IGF-1)

• Serum GH not suppressed following oral glucose

General Considerations

• GH exerts much of its effects by stimulating release of IGF-1

• Nearly always caused by pituitary adenoma, usually macroadenomas (> 1 cm); may be locally invasive but < 1% are malignant

• GH-secreting pituitary tumors usually cause hypogonadism by cosecretion of prolactin or direct pressure on pituitary

• Usually sporadic, rarely familial with < 3% being due to multiple endocrine neoplasia (MEN) types 1 or 4

• Rarely, acromegaly may be seen in McCune-Albright syndrome and Carney complex

• Occasionally caused by ectopic secretion of GH-releasing hormone or GH secreted by lymphoma, hypothalamic tumor, bronchial carcinoid, or pancreatic tumor

Symptoms and Signs

• Tall stature

• Head and neck

  • Facial features coarsen

  • Hat size increases, tooth spacing widens

  • Mandible becomes more prominent

  • Macroglossia and hypertrophy of pharyngeal and laryngeal tissue

    • Deep, coarse voice

    • May cause obstructive sleep apnea

  • Goiter may be noted

• Hands

  • Enlarged

  • Fingers widen and rings no longer fit

  • Carpal tunnel syndrome is common

• Feet grow, particularly as change in shoe width

• Hypertension (50%) and cardiomegaly

• Weight gain

• Arthralgias, degenerative arthritis, and spinal stenosis may occur

• Colon polyps common

• Skin

  • Hyperhidrosis

  • Thickening

  • Cystic acne

  • Skin tags

  • Acanthosis nigricans

• Symptoms of hypopituitarism

  • Hypogonadism: decreased libido, erectile dysfunction, irregular menses or amenorrhea common

  • Women who become pregnant have an increased risk of gestational diabetes mellitus and hypertension

  • Secondary hypothyroidism sometimes occurs, hypoadrenalism is unusual

  • Headaches and temporal hemianopia

Differential Diagnosis

• Familial tall stature, coarse features, or large hands and feet

• Physiologic growth spurt

• Pseudoacromegaly (acromegaly features, insulin resistance)

• Inactive ("burned-out") acromegaly (spontaneous remission due to pituitary adenoma infarction)

• Myxedema

• Isolated prognathism (jaw protrusion)

• Aromatase deficiency or estrogen receptor deficiency causing tall stature

• Other causes of increased GH level

  • Exercise or eating prior to test

  • Acute illness or agitation

  • Liver failure or kidney disease

  • Malnourishment

  • Diabetes mellitus

  • Drugs (estrogens, β-blockers, clonidine)

Laboratory Tests

• Assay for the following

  • Serum GH

  • IGF-1 (usually over five times normal in acromegalic patients)

  • PRL (cosecreted by many GH-secreting tumors)

  • Glucose (diabetes mellitus is common in acromegaly)

  • Liver enzymes and serum creatinine or urea nitrogen (liver failure or kidney disease can misleadingly elevate GH)

  • Serum calcium (to exclude hyperparathyroidism)

  • Serum inorganic phosphorus (frequently elevated)

  • Serum free T₄

  • TSH (secondary hypothyroidism is common in acromegaly; primary hypothyroidism may increase PRL)

• Acromegaly is excluded if any serum GH is < 1 mcg/L; however, many normal individuals can have a serum GH above this level

• Therefore, the glucose suppression test is usually performed:

  • Glucose syrup, 100 g orally

  • Serum GH is measured 60 min later

  • Acromegaly excluded if the serum GH is suppressed to < 0.4 mcg/L with an ultrasensitive GH assay

  • Serum IGF-1 and glucose-suppressed GH are usually complementary tests; however, disparities between the two occur in up to 30% of patients

Imaging Studies

• MRI shows pituitary tumor in over 90%

• MRI superior to CT, especially postoperatively

• Skull radiographs may show enlarged sella and thickened skull

• Radiographs may show tufting of terminal phalanges of fingers and toes

• Lateral view of foot shows increased thickness of heel pad

Medications

• Cabergoline (dopamine agonist)

  • Use if surgery does not produce clinical remission or normalization of GH

  • Dosage

    • Initially, 0.25 mg orally twice weekly

    • Then, gradually increased to a maximum dosage of 1 mg three times weekly

• Somatostatin analogs

  • Octreotide is given at a dose of 20–40 mg intragluteally every 4 weeks

  • Lanreotide acetate is given by subcutaneous intragluteal injection at a dosage of 60–120 mg every 4 weeks

  • Pasireotide

    • More effective at suppressing GH secretion in resistant patients

    • However, hyperglycemia is common and distribution is restricted in the United States

  • Therapy less effective in acromegalic patients with pretreatment serum GH levels exceeding 20 ng/mL

  • Side effects include injection site pain, loose acholic stools, abdominal discomfort, or cholelithiasis

• Raloxifene (selective estrogen receptor modulator [SERM])

  • May be useful for persistent acromegaly in men and in women who are postmenopausal or who have had breast cancer

  • 60 mg orally twice daily does not reduce serum GH levels but normalizes serum IGF-1 levels in 46% of patients

  • Serum testosterone levels increase in men

• Pegvisomant (GH receptor antagonist)

  • Starting dosage is 10 mg subcutaneously daily

  • Maintenance dosage can be increased by 5–10 mg every 4–6 weeks, based on serum IGF-I levels and liver transaminase levels

  • Maximum dosage is 40 mg subcutaneously daily

  • Hepatitis is a rare side effect

  • Other adverse effects include edema, flulike syndrome, nausea, and hypertension

  • Lipohypertrophy can occur at injection sites, so injection sites must be diligently rotated and inspected

Surgery

• Transsphenoidal pituitary surgery

  • Serum GH levels are controlled, defined as a serum GH nadir < 0.4 mcg/L (ultrasensitive assay) after an oral glucose load

  • Serum IGF1 levels return to the reference range but testing must be done at least 12 weeks after surgery

  • Infection, cerebrospinal fluid leak, or hypopituitarism develops in about 12% of patients

  • Hyponatremia can occur 4–13 days postoperatively in 21% of patients; serum sodium must be monitored closely

Therapeutic Procedures

• Stereotactic radiosurgery

  • Three types

    • Linear accelerator

    • Gamma knife radiosurgery

    • Proton beam

  • Causes anterior hypopituitarism in 35–60% of patients within 5 years, so patients must have regular monitoring of their pituitary function

Follow-Up

• Postoperative normal pituitary function usually preserved

• Postoperative GH levels > 5 ng/mL and rising IGF-1 levels usually indicate recurrent tumor

• Soft tissue swelling regresses but bone enlargement is permanent

• Hypertension frequently persists

• Carpal tunnel syndrome and diaphoresis often improve within a day of surgery

Complications

• Hypopituitarism

• Hypertension

• Diabetes mellitus

• Cardiomegaly, heart failure

• Colon polyps

• Carpal tunnel syndrome

• Arthritis of hips, knees, and spine

• Spinal cord compression may occur

• Visual field defects may be severe and progressive

• Tumor may be locally invasive, particularly into the cavernous sinus

• Acute loss of vision or cranial nerve palsy if tumor undergoes spontaneous hemorrhage and necrosis (pituitary apoplexy)

• Intubation may be difficult due to macroglossia and hypertrophy of pharyngeal and laryngeal tissue

Prognosis

• Acromegaly is usually chronic and progressive unless treated; spontaneous remissions are rare but have been reported following clinical or subclinical apoplexy (hemorrhage) within the tumor

• Persistent acromegaly usually causes premature cardiovascular disease and progressive acromegalic symptoms

• Those who are treated and have a random serum GH under 1.0 ng/mL or a glucose-suppressed serum GH under 0.4 ng/mL with a normal age-adjusted serum IGF-I level have reduced morbidity and mortality

• Transsphenoidal pituitary surgery

  • Achieves a remission in about 70% of patients monitored over 3 years

  • Successful in 80% if tumor < 2 cm and GH < 50 ng/mL

  • Extrasellar extension of the pituitary tumor, particularly cavernous sinus invasion, reduces the likelihood of surgical cure

• Conventional radiation therapy (alone) produces remission in 40% by 2 years and 75% by 5 years

• Gamma knife radiation reduces GH levels an average of 77%, with 20% in remission at 12 months

• Proton beam radiosurgery produces remission in 70% by 2 years and 80% by 5 years

• Radiation therapy usually produces some degree of hypopituitarism

• Conventional radiation therapy may cause some degree of organic brain syndrome and predisposes to small strokes