Acromegaly

Acromegaly is a rare condition characterized by an excess secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), most commonly due to a benign pituitary adenoma. In adults, whose epiphyseal plates are closed, acromegaly causes enlarged hands and feet, coarsened facial features, and pathological growth of internal organs. When excess GH and IGF-1 occurs in children, before epiphyseal plate closure, causes gigantism. The first step in diagnosis is to measure IGF-1 levels; if these are elevated, further testing includes an oral glucose tolerance test (OGTT) with measurement of GH levels. If glucose does not appropriately suppress GH, a biochemical diagnosis of acromegaly is confirmed. Subsequent diagnostics include imaging to determine the source of excess GH, starting with a pituitary MRI, and evaluation for complications of acromegaly (e.g., hypopituitarism, diabetes, and cardiovascular disease). Management should take place in a specialized multidisciplinary treatment center. First-line treatment is usually surgery. In patients with contraindications to surgery or with persistent disease after surgery, GH-inhibiting medication (somatostatin receptor ligands, dopamine agonists, and/or GH receptor antagonists) and radiotherapy may be used. Adequate treatment is vital to reduce the risk of complications, which may considerably increase mortality. Lifelong monitoring is required for recurrence and complications.

• Prevalence: 1–9/100,000 in the US ^[1]
• Age of onset: 3^rd decade of life (mean age at diagnosis usually 40–45 years) ^[1]
• Sex: ♀ = ♂ ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Benign GH-secreting pituitary adenoma (> 95% of cases) ^[2]
• Rare causes
  • Ectopic secretion of GH by neuroendocrine tumors (e.g., small cell lung carcinoma, pancreatic islet-cell tumor (as found in MEN1)
  • ↑ Secretion of GH-releasing hormone (GHRH) from a hypothalamic tumor or in paraneoplastic syndromes (e.g., small cell lung carcinoma, medullary thyroid cancer) ^[3]

• Physiology of GH and IGF-1
  • GH secretion induced by stress, sport, and hypoglycemia; inhibited especially by hyperglycemia or food intake
  • Hypothalamus secretes GHRH → ↑ secretion of GH ; → GH induces IGF-1 synthesis → ↑ serum IGF-1 via liver synthesis which leads to the following effects:
    • Binding to IGF-1 and insulin receptors → stimulation of cell growth and proliferation, inhibiting programmed cell death
      • Proliferative effects especially on bone, cartilage, skeletal muscle, skin, soft tissue, and organs
      • Impaired glucose tolerance caused by binding to insulin receptors
    • ↑ Secretion of somatostatin from the hypothalamus → ↓ serum GH and IGF-1 (negative feedback)
• Effects of a pituitary adenoma
  • Overproduction of GH → abnormally high serum IGF-1 levels → overstimulation of cell growth and proliferation → symptoms of acromegaly
  • Tumor mass compresses neighboring structures (e.g., optic chiasm) → symptoms of mass effect
  • Impaired secretion of other pituitary hormones; , especially gonadotropins → ↓ LH and FSH → ↓ estrogen and testosterone

Excess GH secretion before the conclusion of longitudinal growth (i.e., prior to epiphyseal plate closure) leads to pituitary gigantism with a possible height of ≥ 2 m. After epiphyseal plate closure, GH excess causes acromegaly, but no change in height!

• Tumor mass effects
  • Headache, vision loss (bitemporal hemianopsia), cranial nerve palsies
  • Decreased libido
  • ♀: Oligomenorrhea, secondary amenorrhea, galactorrhea, vaginal atrophy
  • ♂: Erectile dysfunction, ↓ testicular volume
• Skeletal effects
  • Slowly progressive coarsening of facial features
    • Enlargement of the nose
    • Frontal bossing
    • Protrusion (prognathism) and enlargement (macrognathia) of the jaw with widening of gaps between the teeth (diastema)
  • Widened hands, fingers, and feet
  • Painful arthropathy (ankles, knees, hips, spine)
• Soft tissue effects
  • Doughy skin texture, hyperhidrosis ^[4]
  • Deepening of the voice, macroglossia with fissures, obstructive sleep apnea (OSA)
• Features of complications of acromegaly: e.g., symptoms of heart failure, symptoms of diabetes mellitus

Consider acromegaly in patients who report having had to increase hat, shoe, glove, and ring sizes in the past!

Approach ^[2][5][6]

• Refer patients with suspected acromegaly to endocrinology for assessment.
• Initial screen: serum IGF-1 level; a normal result excludes acromegaly. ^[2]
• Elevated IGF-1 level: Perform an OGTT (baseline GH, then OGTT and measure GH within 2 hours). ; ^[2][5][7]
  • GH suppressed: acromegaly ruled out
  • GH not suppressed: confirmed acromegaly
• Patients with confirmed acromegaly
  • Evaluate for underlying etiology.
    • First-line: MRI of pituitary with and without contrast to assess for adenomas
    • If pituitary imaging is normal, evaluate for an extrapituitary cause.
  • Assess for complications of acromegaly.

To ensure consistency, use the same laboratory and assay for GH and IGF-1 measurements throughout a patient's care. ^[2]

Random GH measurements are not recommended for the diagnostic evaluation of acromegaly. ^[2]

Evaluation for complications of acromegaly ^[2][5][8]

• Blood pressure measurement
• Diagnostics for hypopituitarism
• Prolactin level
• Hyperglycemia testing
• Lipid panel
• ECG
• Echocardiogram
• Colonoscopy
• DEXA with vertebral morphometry
• Clinical evaluation for complications of acromegaly, with further studies as needed, e.g.:
  • Impaired peripheral vision or mass adjacent to optic chiasm: visual field testing
  • Palpable thyroid nodules: thyroid ultrasound
  • Clinical suspicion for OSA: diagnostics for OSA

• Marfan syndrome
• Pseudoacromegaly (e.g., medication-induced): insulin resistance, acromegaloid features, normal GH and IGF-1
• Prolactinoma: pituitary tumor; excess of prolactin, not GH
• Familial tall stature
• Sotos syndrome

The differential diagnoses listed here are not exhaustive.

General principles ^[6][7]

• Refer all patients to a specialized multidisciplinary treatment center for management.
• First-line treatment is usually surgery, as it may be curative. ^[2][5]
• In patients with inoperable tumors or persistent disease after surgery, medication and possibly radiotherapy are used to: ^[5][9]
  • Reduce tumor size
  • Limit the effects of GH and IGF-1
• Patients require lifelong follow-up to assess for recurrence and complications of acromegaly.

Surgery ^[6][7]

• First-line: transsphenoidal adenomectomy ^[2][5]
• Parasellar disease and inoperable tumors: surgical debulking

Repeat surgery may be necessary if there is residual intrasellar disease after initial surgery. ^[2][7]

Pharmacotherapy ^[2][6][7]

• Preoperative medical therapy or nonsurgical candidate: somatostatin receptor ligands (SRLs), e.g., octreotide, lanreotide ^[2]
• Postoperative medical therapy ^[2][10]
  • Significant persistent disease: SRLs or GH receptor antagonists (e.g., pegvisomant)
  • Mild persistent disease: dopamine agonists (e.g., cabergoline)
  • Pituitary hormone replacement: for confirmed hormone deficiency (e.g., adrenal, gonadal, thyroid)

SRLs and dopamine agonists can reduce both GH secretion and tumor size, while GH receptor antagonists only reduce GH secretion. ^[2]

Radiotherapy ^[2][5][7]

• Indications: third-line option if surgery and medical therapy are unsuccessful, poorly tolerated, or unavailable
• Stereotactic radiosurgery is preferred over conventional fractionated radiotherapy ^[5][6]

Follow-up ^[2][5][8]

• Obtain IGF-1 and random GH level 12 weeks after surgery, then annually, with goals of: ^[2]
  • Normal age-adjusted serum IGF-1 level
  • Suppressed GH level ^[2][7]
• Obtain diagnostics for hypopituitarism; : 6–12 weeks after surgery and then annually. ^[5][8]
• Perform an MRI pituitary:
  • At least 12 weeks after surgery ^[2]
  • Periodically in patients receiving pegvisomant ^[2]
• Perform ongoing monitoring for complications of acromegaly according to specialist guidance. ^[8]

Hypopituitarism may develop as a complication of acromegaly or as a result of its treatment (e.g., surgery, radiotherapy).

Complications may lead to increased mortality. ^[11]

• Cardiovascular complications
  • Hypertension (∼ 30% of cases) ^[11][12]
  • Left ventricular hypertrophy and cardiomyopathy
  • Arrhythmia
  • Valvular disease
• Impaired glucose tolerance and diabetes mellitus (up to 50% of cases)
• Colorectal polyps and cancer ^[13]
• Thyroid enlargement and cancer
• Carpal tunnel syndrome
• Cerebral aneurysm
• Hypopituitarism
• Obstructive sleep apnea
• Arthropathy
• Psychological impairment (↓ quality of life, anxiety, ↓ self-esteem)

Increased mortality in acromegaly is primarily due to cardiovascular and cerebrovascular events. ^[2][5]

We list the most important complications. The selection is not exhaustive.

Children ^[14][15]

Gigantism is a rare disorder characterized by abnormal linear growth during childhood due to GH excess while the epiphyseal growth plates are still open.

Etiology ^[14]

• Most common: GH secretion from a pituitary adenoma
  • Syndromes associated with ↑ incidence of pituitary tumors
    • Multiple endocrine neoplasia type 1
    • McCune-Albright syndrome
    • Carney complex
    • Neurofibromatosis type 1
  • Nonsyndromic genetic etiologies
• Less common: ↑ GHRH secretion (e.g., from hypothalamus or neural tumor)

Pathophysiology

• ↑ GH secretion from the anterior pituitary; (i.e., adenoma) → ↑ IGF-1 synthesis → ↑ cell growth and proliferation
• For more details, see “Pathophysiology of acromegaly.”

Clinical features

• Hallmark finding: tall stature with accelerated linear growth ^[15][16]
• Mild to moderate obesity ^[16][17]
• Possible progressive macrocephaly ^[16]
• Manifestations similar to clinical features of acromegaly
  • Tumor mass effects
  • Skeletal effects in adolescents (e.g., prognathism, frontal bossing) ^[15]

Soft tissue effects are less common in gigantism than in acromegaly. ^[16]

Diagnosis ^[5]

• Same as diagnostics for acromegaly
• Additional testing is obtained according to specialist guidance and may include: ^[5]
  • Prolactin level ^[2][5]
  • Bone age assessment
  • Visual field testing
  • Genetic testing
  • Diagnostic evaluation for associated conditions based on characteristic physical examination findings ^[15][16]

Management

• Management is similar to management of acromegaly; and involves a multidisciplinary team (e.g., neurosurgery, pediatric endocrinology).
• Additional considerations in children ^[14]
  • Repeat surgery and adjuvant therapy are frequently required. ^[2]
  • A primary goal of treatment is to avoid excessive height growth prior to puberty.
  • Risk of hypopituitarism may be higher than in adults.

Early normalization of hormones is recommended to reduce final height. ^[14]

Complications

See “Complications of acromegaly.”