Acromegaly

Acromegaly is a condition in which benign pituitary adenomas lead to an excess secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). In adults, whose epiphyseal plates are closed, the disease causes enlarged hands and feet, coarsened facial features, and pathological growth of internal organs. If the condition occurs in children, before epiphyseal plate closure, it is known as gigantism, which is discussed in a separate article. The first step in diagnosing acromegaly is to measure IGF-1 levels. Further testing includes an oral glucose tolerance test (OGTT) with assessment of GH levels, and evaluation of pituitary tumors via cranial MRI. Management consists of transsphenoidal adenomectomy for operable tumors, or GH-inhibiting medication and radiotherapy if surgery is contraindicated or unsuccessful. Adequate treatment is vital to reduce the risk of complications, such as cardiovascular disease and cerebral aneurysms, as these may considerably increase mortality.

• 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 growth hormone-secreting pituitary adenoma (> 95% of cases) ^[2]
• Very rare: neuroendocrine or hypothalamic tumors, paraneoplastic syndromes
  • Ectopic secretion of growth hormone by neuroendocrine tumors (e.g., small cell lung carcinoma, pancreatic islet-cell tumor (as found in MEN1)
  • ↑ Secretion of growth hormone-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
  • ♀: Oligomenorrhea, secondary amenorrhea, galactorrhea, vaginal atrophy
  • ♂: Erectile dysfunction, decreased libido, ↓ testicular volume
• Soft tissue effects
  • Doughy skin texture, hyperhidrosis ^[4]
  • Deepening of the voice, macroglossia with fissures, obstructive sleep apnea
• Skeletal effects
  • Coarsening of facial features slowly progressing with age; : enlarged nose, forehead, and jaw (macrognathia) with diastema
  • Widened hands, fingers, and feet
  • Painful arthropathy (ankles, knees, hips, spine)

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

• Hormone analysis ^[5][6]
  • Serum IGF-1 concentration: the best single test
    • Elevated IGF-1 level: acromegaly suspected; conduct oral glucose tolerance test (OGTT).
    • Normal IGF-1 level: acromegaly ruled out
  • OGTT with baseline GH and measure GH after 2 hours: the most specific test
    • If GH suppressed: acromegaly ruled out
    • If GH not suppressed: confirmed acromegaly; conduct pituitary MRI to determine the source of excess GH
• Pituitary MRI ^[5][6]
  • Imaging modality of choice
  • Usually shows a visible mass: confirmed GH-secreting pituitary adenoma
  • If normal: screen for an extrapituitary cause (e.g., CT scan of the chest and abdomen, measure GHRH)

• Gigantism: excess GH secretion in children, before epiphyseal plate closure
• 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
• McCune-Albright syndrome

The differential diagnoses listed here are not exhaustive.

Transsphenoidal adenomectomy is the method of choice for treating acromegaly. In patients with inoperable tumors or unsuccessful surgery, medication and radiotherapy are indicated to reduce tumor size and limit the effects of GH and IGF-1. ^[5][6]

• Surgery
  • Transsphenoidal adenomectomy (preferred method)
  • Surgical debulking (in patients with parasellar disease and inoperable tumors)
• Medication
  • Somatostatin analogs (e.g., octreotide, lanreotide)
  • Dopamine agonists (e.g., cabergoline): reduce tumor size and GH secretion
  • GH receptor antagonists (e.g., pegvisomant)
• Radiotherapy ^[7]
  • Conventional fractionated radiotherapy
  • Stereotactic radiosurgery (e.g., Gamma Knife, CyberKnife, proton beam)
• Follow-up ^[5]
  • Assessing IGF-1 and random GH level 12 weeks after the surgery and then annually
  • Annual hormonal testing for hypopituitarism
  • Performing MRI at least 12 weeks after the surgery
  • Serial imaging with MRI in patients receiving pegvisomant

Danger of hypopituitarism following surgery or radiotherapy!

Complications lead to increased mortality. ^[8]

• Cardiovascular complications: the main cause of death
  • Hypertension (∼ 30% of cases) ^[8][9]
  • Left ventricular hypertrophy and cardiomyopathy
  • Arrhythmia
  • Valvular disease
• Impaired glucose tolerance and diabetes mellitus (up to 50% of cases)
• Colorectal polyps and cancer ^[10]
• Thyroid enlargement and cancer
• Carpal tunnel syndrome
• Cerebral aneurysm
• Hypopituitarism
• Psychological impairment (↓ quality of life, anxiety, ↓ self-esteem)

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