Acromegaly and Gigantism

Acromegaly and gigantism are caused by an excessive production of growth hormone (GH) by the pituitary gland. Tall stature is a clinical sign observed in some patients with gigantism. Increased GH and insulin-like growth factor-1 (IGF-1) are responsible for inducing hypersomatotropism. Acromegaly is usually produced by pituitary tumors secreting GH or, less commonly, by extrapituitary disorders. Gigantism typically results in children from excess GH before growth-plate closure; acromegaly typically results from excess GH after growth-plate closure. Diagnosis involves neuroimaging of the pituitary and laboratory tests to evaluate the hypothalamic-pituitary axis. Treatment depends on the operative status of the tumor (if present), or a nonoperative treatment strategy may be utilized.

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Epidemiology and Etiology

Epidemiology

  • The median age of diagnosis is 40 years old with a lag time of 10 years from onset to diagnosis.
  • Life expectancy is shortened by approximately 10 years.
  • Children treated early can have a normal life expectancy.

Etiology

  • Benign pituitary adenoma in > 95% of cases
  • Growth hormone (GH)- and growth hormone-releasing hormone (GHRH)-secreting tumors of the pancreas, lungs, and adrenal glands (rare)

Pathophysiology

Pathophysiology

  • Acromegaly and gigantism result from excessive GH.
  • GH, also known as somatotropin, is secreted by the anterior pituitary.
  • GH mediates growth and metabolic functions.
  • GH interacts with insulin to control fat, glucose, and protein metabolism during fasting and feeding states.
  • Main effects: 
    • Lipolysis in adipose tissue 
    • Promotes gluconeogenesis (in the liver) and stimulates insulin-like growth factor-1 (IGF-1) secretion, resulting in increased glucose levels
    • Muscle increases amino acid uptake and protein synthesis.
    • Bones promote linear growth by the proliferation of epiphyseal cartilage in children (gigantism).

Regulation

Regulation is a step-wise process:

  1. The hypothalamus secretes GHRH and somatostatin (growth hormone-inhibiting hormone).
  2. Adenohypophysis secretes GH.
  3. The liver produces IGF-1.
  4. Proliferative effects on bone, cartilage, skeletal muscle, skin, soft tissue, organs, and glucose tolerance:
    • Stimulation: hypoglycemia, stress, physical strain, deep sleep, puberty
    • Inhibition: glucose, somatostatin, somatomedin (from the liver)
Schematic diagram of the direct and indirect effects of the growth hormone

Schematic diagram of the direct and indirect effects of growth hormone (GH)

Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical Presentation

Clinical findings

  • In children, growth plates have not yet fused, leading to gigantism:
    • Characterized by the symmetrical enlargement of body tissues, which leads to an overgrowth of long bones
    • Patients are commonly over 6’6” tall.
  • In adults, growth plates have fused, leading to acromegaly with an overgrowth of characteristic areas:
    • Nose
    • Supraorbital bulges
    • Jaw
    • Hands
    • Cranium
  • Visceromegaly:
    • Goiter
    • Cardiomyopathy
    • Colon polyps
  • Deep voice
  • Thickening of the dermis (pachydermia)
  • Hypoesthesia or paresthesia
  • Macroglossia
  • Separation of the teeth and broadened interdental grooves
  • Prognathism
  • Headache
  • Fatigue
  • Perspiration
  • Bone pain
  • Vision loss

Complications

  • Disturbances in the visual field
  • Cranial nerve palsies
  • Disturbances of the menstrual cycle
  • Galactorrhea
  • Erectile dysfunction
  • Decreased libido
  • Osteoarthritis 
  • Carpal tunnel syndrome
  • Sleep apnea
  • Diabetes mellitus 
  • Hypertension
  • Cardiomyopathy and heart failure
  • Secondary hypogonadism
  • Increased incidence of colorectal cancer

Diagnosis

Clinical presentation is typically the most important aspect of diagnosis.

  • Labs: GH low point greater than 0.4 µg/L or 1 µg/L (depending on GH standards) during the oral glucose tolerance test, and elevated, age-adjusted IGF-1 level
  • Imaging: 
    • MRI: 
      • Can show a pituitary mass
      • If a pituitary adenoma is absent, search the chest and abdomen for other tumors.
    • CT scan:
      • Abdomen and pelvis: Evaluate for pancreatic, adrenal, and ovarian tumors secreting GH/GHRH.
      • Chest: Evaluate for bronchogenic carcinoma secreting GH/GHRH.

Management

  • Surgical option: transsphenoidal adenomectomy via endonasal access (pituitary adenomas)
  • Nonsurgical options:
    • Nonpharmacological:
      • Stereotactic radiosurgery
      • Proton therapy
      • Conventional radiation therapy
    • Pharmacological:
      • Dopamine-D2-agonists (bromocriptine) inhibit GH production by the pituitary adenoma.
      • GH-receptor-antagonists (pegvisomant) normalize the elevated IGF-1 level.
      • Somatostatin-analogs (octreotide) decrease the size of the adenoma and normalize the GH level.

Differential Diagnosis

  • McCune-Albright syndrome: a rare, hypersecretory syndrome consisting of polyostotic fibrous dysplasia, cutaneous pigmentation, precocious puberty, hyperthyroidism, hypercortisolism, hyperprolactinemia, and acromegaly due to somatotroph hyperplasia. Patients are differentiated by additional constellations of signs and symptoms.
  • Multiple endocrine neoplasia: GH-cell pituitary adenoma is a component of the autosomal-dominant, multiple endocrine neoplasia (MEN) type 1 syndrome, which also includes parathyroid and pancreatic tumors. In addition to the finding of excess GH, the patient demonstrates other endocrine anomalies. 
  • Acromegaloidism: soft tissue and skin changes usually associated with acromegaly, a normal baseline, dynamic GH/IGF-1, and no demonstrable pituitary or extrapituitary tumor. Acromegaloidism is rare.
  • Pachydermoperiostosis: Patients present with enlargement of the fingers and toes, swelling or pain of the large joints, coarsening of facial features, and grooves/depressions in the scalp. Pachydermoperiostosis is caused by mutations in HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase, the key enzyme of prostaglandin degradation. The grooves/depressions of the scalp help to differentiate pachydermoperiostosis from acromegaly. 

References

  1. Melmed, S. (2020). Treatment of acromegaly. In Snyder, P.J. (Ed.), UpToDate. Retrieved June 2, 2021, from https://www.uptodate.com/contents/treatment-of-acromegaly
  2. Melmed, S. et al. (2018). Primary Immune Deficiency Diseases. In Jameson J., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Chapter 373). McGraw-Hill.

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