Acromegaly is a rare chronic endocrine disorder caused by hypersecretion of growth hormone (GH).

Epidemiology

• Incidence – 3-5/1,000,000
• Age – mean onset is 40 years
• Sex – M:F, equal

Etiology

• Most cases are secondary to pituitary adenomas
• Rare causes – growth hormone secretion from tumors (carcinoid or small cell lung cancer)
• Genetic diseases associated with acromegaly – MEN1, McCune-Albright syndrome, Carney complex

Pathophysiology

• GH is synthesized and has pulsatile secretion from the somatotroph cells of the anterior lobe of the pituitary gland
• GH secretion is regulated by the hypothalamus
  • Stimulation by GH releasing hormone (GHRH)
  • Inhibition by somatostatin
• Circulating GH stimulates synthesis and secretion of insulin-like growth factor 1 (IGF-1) from the liver
• IGF-1 inhibits GH secretion at the pituitary and hypothalamus level creating a negative feedback loop
• Pituitary tumors mimic stimulation of adenylyl cyclase by GHRH receptor activation causing autonomous GH secretion
  • Symptoms are related to both excess GH and IGF-1 secretion and to the expanding pituitary mass

Clinical Presentation

• Indolent course
• Pituitary mass expansion symptoms
  • Headaches
  • Visual field defects
  • Cranial nerve palsies
• GH excess symptoms
  • Musculoskeletal
    • Hypertrophic arthropathy – both axial and peripheral skeleton
    • Carpal tunnel syndrome
    • Coarse facial features, macrognathia
    • Spade-shaped hands
    • Enlarged feet
    • Growth of mandible – prognathism
    • If epiphyses are open – linear bone growth causes gigantism
  • Cardiovascular
    • Hypertension – about 30% of patients
    • Cardiomyopathy
    • Arrhythmias
  • Endocrine
    • May cause deficiency of other pituitary hormones from mass effect
  • Dermatologic
    • Acanthosis nigricans
  • Metabolic
    • Diabetes mellitus
    • Dyslipidemia
  • Neoplastic
    • Development of premalignant colon polyps increases risk of colon cancer
• Carney complex – rare syndrome associated with acromegaly
  • Pigmented skin, myxoma, cardiac myxoma, thyroid nodules or carcinoma, primary pigmented nodular adrenocortical disease

Treatment

• Three goals of treatment
  • Control hypersecretion of GH
  • Decrease morbidity/mortality related to hypersecretion
  • Reduce mass effects of tumor
• Surgical removal of tumor – usually initial therapy
• Radiotherapy
• Medical therapy
  • Dopamine agonists
  • Somatostatin analogues
  • GH receptor antagonists

Indications for Testing

• Chronic headaches or musculoskeletal growth in an adult

Laboratory Testing

• Fasting or random GH and IGF-1 levels
  • GH secretion is pulsatile and may or may not be elevated
  • IGF-1 usually elevated
  • GH <0.25 ng/mL and normal IGF-1 excludes acromegaly
  • Consensus criteria – nadir GH >1 ng/mL with high IGF-1 levels is diagnostic
• If either test does not meet the criteria above, perform oral glucose tolerance test (OGTT) and measure GH
  • Administer 75g glucose and perform GH measurements over 120 minutes
    • Failure to suppress GH is diagnostic
    • GH <0.25 ng/mL excludes acromegaly
  • Usefulness limited in high catabolic states, patients on estrogen replacement, tall adolescents

Histology

• Immunohistochemistry staining for growth hormone; may also need to stain for other anterior pituitary hormones

Imaging Studies

• MRI is preferred modality to evaluate adenoma
  • Can detect tumors as small as 2 mm

Differential Diagnosis   

• Headache, visual field cuts – other pituitary tumors
• Glucose intolerance – Cushing syndrome, diabetes mellitus type 2
• Malignancy with ectopic GH secretion

• Monitor GH and IGF-1 levels for effectiveness of therapy
  • Active disease
    • Random GH >1 ng/mL and nadir GH after OGTT ≥0.4 ng/mL
    • IGF-1 elevated
    • Also consider periodic MRI for active disease
  • Controlled disease
    • GH <1 ng/mL or nadir GH after OGTT <0.4 ng/mL
    • IGF-1 normal

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Bonadonna S, Doga M, Gola M, Mazziotti G, Giustina A. Diagnosis and treatment of acromegaly and its complications: consensus guidelines. J Endocrinol Invest. 2005; 28 (11 Suppl International) :43-47.PubMed
• Chanson P, Bertherat J, Beckers A, Bihan H, Brue T, Caron P, Chabre O, Cogne M, Cortet-Rudelli C, Delemer B, Dufour H, Gaillard R, Gueydan M, Morange I, Souberbielle JC, Tabarin A. French consensus on the management of acromegaly. Ann Endocrinol (Paris). 2009; 70 (2) :92-106.PubMed
• Duncan E, Wass JA. Investigation protocol: acromegaly and its investigation. Clin Endocrinol (Oxf). 1999; 50 (3) :285-293.PubMed
• Giustina A, Barkan A, Chanson P, Grossman A, Hoffman A, Ghigo E, Casanueva F, Colao A, Lamberts S, Sheppard M, Melmed S. Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults. J Endocrinol Invest. 2008; 31 (9) :820-838.PubMed
• Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, Trainer P, Ghigo E, Ho K, Melmed S. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010; 95 (7) :3141-3148.PubMed
• Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, Clemmons D, Chanson P, Laws E, Schlechte J, Vance ML, Ho K, Giustina A. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab. 2009; 94 (5) :1509-1517.PubMed

General

• Ayuk J, Sheppard MC. Growth hormone and its disorders. Postgrad Med J. 2006; 82 (963) :24-30.PubMed
• Bidlingmaier M, Strasburger CJ. Growth hormone assays: current methodologies and their limitations. Pituitary. 2007; 10 (2) :115-119.PubMed
• Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J. Pituitary tumours: acromegaly. Best Pract Res Clin Endocrinol Metab. 2009; 23 (5) :555-574.PubMed
• Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis. 2008; 3 :17-.PubMed
• Cordero RA, Barkan AL. Current diagnosis of acromegaly. Rev Endocr Metab Disord. 2008; 9 (1) :13-19.PubMed
• Ferone D, Resmini E, Bocca L, Giusti M, Barreca A, Minuto F. Current diagnostic guidelines for biochemical diagnosis of acromegaly. Minerva Endocrinol. 2004; 29 (4) :207-223.PubMed
• Katznelson L. Diagnosis and treatment of acromegaly. Growth Horm IGF Res. 2005; 15 Suppl A :S31-S35.PubMed
• Tzanela M. Dynamic tests and basal values for defining active acromegaly. Neuroendocrinology. 2006; 83 (3-4) :200-204.PubMed

Adrenal Hyperfunction
Cardiovascular Disease (Traditional Risk Markers)
Colorectal Cancer
Diabetes Mellitus
Multiple Endocrine Neoplasias
Thyroid Disease