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Acromegaly

NORD is very grateful to John D. Carmichael, MD, Associate Professor of Clinical Medicine, Keck School of Medicine of the University of Southern California, for assistance in the preparation of this report.

Synonyms of Acromegaly

  • No synonyms found.

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It occurs when the pituitary gland produces too much growth hormone (GH). The pituitary gland is a small gland located near the base of the skull that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many different bodily functions. In most cases, acromegaly is caused by the growth of a benign tumor (adenoma), affecting the pituitary gland. Symptoms of acromegaly include abnormal enlargement in bones of the hands, arms, feet, legs, and head. Enlargement of the bones in the jaws and in the front of the skull are typically the most apparent bony changes. Acromegaly may also cause thickening of the soft tissues of the body, including the heart, lips, and tongue. When the disease affects children prior to the end of puberty, excess growth hormone can lead to accelerated growth and tall stature, known as gigantism. If untreated, acromegaly can potentially cause serious illness and life-threatening complications.

Symptoms

The symptoms of acromegaly generally occur slowly and become more noticeable as affected individuals age. The specific symptoms that develop may vary greatly from one person to another. Acromegaly can potentially cause a wide variety of symptoms and physical findings.

Facial features gradually become coarse because of the overgrowth of soft tissues and cartilage. Facial bones gradually become prominent, the lower jaw protrudes (prognathism), and an underbite may cause a wide separation and misalignment between the teeth (malocclusion). Affected individuals may also have an abnormally large tongue and unusually thick, full lips. People with acromegaly eventually develop a deep and husky voice due to thickening of the vocal cords and enlargement of the sinuses.

Acromegaly also results in a gradual enlargement of the hands and feet. Affected individuals may notice that rings feel tighter or no longer fit at all, and that their shoe size and width has increased. Overgrowth (hypertrophy) of bone and enlargement of cartilage in the joints may result in inflammation and gradual degeneration of involved joints (osteoarthritis). Joint and muscle pain (arthralgia and myalgia) often develops, especially affecting the large joints such as the knees, shoulders, hands, wrists and hips.

In some people with acromegaly, the spine may abnormally curve from side to side and from front to back (kyphoscoliosis). Overgrowth of tissue may trap nerves, causing numbness and weakness of the hands (carpal tunnel syndrome). Abnormal darkening and thickening of patches of skin in certain areas of the body (acanthosis nigricans), an excessive amount of body hair (hirsutism), and small abnormal outgrowths of extra skin (skin tags) may also be present.

In some cases, acromegaly may cause abnormal enlargement of certain organs including the heart. Symptoms may include difficulty breathing upon exertion (dyspnea) and/or irregular heartbeats (arrhythmias). Heart involvement in acromegaly can ultimately lead to congestive heart failure, in which the heart cannot properly circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lung and various body tissues.

Additional symptoms of acromegaly may include abnormal enlargement of the liver (hepatomegaly), spleen (splenomegaly), and/or kidneys. The thyroid (goiter) and/or the adrenal glands may also become abnormally enlarged.

Approximately 25 percent of people with acromegaly have elevated blood pressure (hypertension). Abnormal enlargement of the pituitary gland, located at the base of the skull, may cause headaches, visual abnormalities, and/or hormonal deficiencies. In approximately 50 percent of people with acromegaly, excessive levels of growth hormone (GH) secreted by the pituitary gland may influence the production of insulin, a hormone produced by the pancreas that regulates blood sugar (glucose) levels by promoting the movement of glucose into cells in the body. Abnormalities in insulin action may result in elevated levels of blood sugar (glucose), and some individuals with acromegaly may develop insulin resistance or type 2 diabetes. Some people with acromegaly may have an increased metabolic rate, excessive sweating (hyperhidrosis), and/or increased production of oil (sebum) by the sebaceous glands in the skin, resulting in abnormally oily skin.

Individuals with acromegaly may develop breathing (respiratory) abnormalities including sleep apnea, a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include wakefulness during the night, excessive sleepiness during the day, loud snoring, and/or obesity. In obstructive apnea, the most common form of sleep apnea, labored breathing is interrupted by airway collapse or blockage from enlarged soft tissue. Partial awakening may then occur and the person may gasp for air. Sleep is resumed as breathing begins again. Untreated sleep apnea may be associated with high blood pressure, irregular heartbeats, swelling in the arms and/or legs, hallucinations, anxiety, and/or irritability.

Females with acromegaly may experience an abnormal flow of milk from the breasts (galactorrhea), and infrequent or delayed menstrual flow (oligomenorrhea). Males with acromegaly may experience impotence and a decrease in sexual drive (decreased libido). Individuals with acromegaly have an increased risk of developing polyps in the colon. Individuals with acromegaly may have a slightly greater risk of developing colon cancer than the general population.

Symptoms that may develop late during the course of acromegaly include muscle weakness and impaired function of peripheral nerves (i.e., nerves that lie outside the brain and spinal cord). Vision of some affected individuals may become impaired and possibly progress to blindness. If untreated, 25 percent of people with acromegaly experience symptoms associated with uncontrolled diabetes including an increase in the amount of sugar in their urine (glycosuria), abnormally excessive thirst (polydipsia), and/or an abnormally increased appetite (polyphagia).

Causes

Acromegaly is a rare disorder that is caused by excess levels of growth hormone (GH) in the body. In the majority of cases, excess levels of GH are causes by a benign (noncancerous) tumor in the pituitary gland (pituitary adenoma). Most adenomas usually form from a genetic mutation in one a single, pituitary cell called a somatotrope cell (the pituitary cell that normally secretes GH). This mutation causes uncontrolled growth and reproduction of these cells. The genetic mutation is not present at birth, is not inherited and happens later during life (acquired mutation). The exact reason this mutation occurs is unknown.

GH is a hormone that is involved in many different physiological processes in the body including helping to regulate the physical growth of the body. One of the functions of GH is to stimulate the production of another hormone, known as insulin-like growth factor-1 (IGF-1). Consequently, individuals with acromegaly also have elevated levels of IGF-1

Rarely acromegaly may be caused by the ineffective control of growth hormone-secreting cells by the hypothalamus (a gland in the brain that regulates hormone secretions). Growth hormone excess may sometimes be due to over-stimulation by production of too much growth hormone releasing hormone (GHRH) secreted by the hypothalamus or other tissues.

In rare cases, non-pituitary tumors in the pancreas, lungs or adrenal glands may cause acromegaly. These tumors may directly produce excess growth hormone or they may produce growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to release GH.

In some cases, acromegaly may occur as part of certain genetic syndromes including multiple endocrine neoplasia type 1, familial isolated pituitary adenoma, the Carney complex and McCune-Albright syndrome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)

Affected Populations

Acromegaly is a rare disorder that affects males and females in equal numbers. This disorder occurs in approximately 50 to 70 people per million. Researchers estimate that three people out of every million develop the disorder each year. However, because the symptoms of acromegaly may develop slowly, the disorder may often remain unrecognized and may therefore be underdiagnosed, making it difficult to determine the true frequency of acromegaly in the general population.

Acromegaly can occur at any age after puberty, but most often occurs during the fourth and fifth decades. When excessive secretion of growth hormone occurs before puberty, the disorder is known as gigantism, not acromegaly.

Related Disorders

Symptoms of the following disorders can be similar to those of acromegaly. Comparisons may be useful for a differential diagnosis:

Gigantism is an abnormal condition characterized by excessive height and size. This disorder typically occurs before puberty as a result of the over secretion of growth hormone by the pituitary gland. Gigantism is associated with enlarged soft tissues and late closure of the epiphyses (heads of the long bones), which results in excessive growth during childhood. Height may reach 7 or 8 feet. Low levels of gonadotropin (gonad stimulating) hormones may be secreted by the pituitary gland later in the course of this disorder and result in low levels of hormone secretions by the ovaries or testes. Sexual development may be normal or it may be affected by the low levels of circulating sex hormones. In some cases of gigantism, affected individuals may experience tingling and/or burning sensations in the arms and/or legs (peripheral neuropathy).

Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and degeneration of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from case to case. Marfan syndrome is inherited as an autosomal dominant trait. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to Marfan syndrome and related disorders. (For more information on this disorder, choose "Marfan" as your search term in the Rare Disease Database.)

Pachydermoperiostosis is a rare disorder characterized by clubbing of the fingers, thickening of the skin of the face (pachyderma), and excessive sweating (hyperhidrosis). It typically appears during childhood or adolescence, often around the time of puberty, and progresses slowly for about ten years. Specific symptoms include enlargement of the fingers and toes (clubbing), a condition in which there is a fibrous covering on the ends of the long bones (periostosis), coarse facial features, increased bulk of the skin on the scalp forming folds, depressions or furrows of the scalp (cutis verticis gyrata), and/or excessive sweating of the hands and feet. Pachydermoperiostosis is believed to be inherited as an autosomal dominant or recessive trait. (For more information on this disorder, choose "pachydermoperiostosis" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of acromegaly is sometimes difficult to make because the development of symptoms occurs slowly over several years. A diagnosis is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings, and specialized tests such as blood tests, a glucose tolerance test, magnetic resonance imaging (MRI) or computerized tomography (CT).

Physicians may test the blood for elevated levels of growth hormone or IGF-1 (insulin growth factor) associated with acromegaly. Measurement of growth hormone is often done in conjunction with a glucose tolerance test. During a glucose tolerance test, individuals ingest a specific amount of sugar that should lower GH levels in the blood. However in individuals with overproduction of growth hormone, this reduction does not occur.

Physicians may also order an MRI, preferably, or CT scan of the brain to reveal the presence and size of a pituitary tumor. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ's tissue structure.

Additional tests may be performed to assess the extent of acromegaly in an individual including echocardiography to evaluate whether the heart is involved, tests to determine whether sleep apnea is present and a colonoscopy to assess the health of the colon and establish a baseline for further testing. Patients with acromegaly may be at increased risk for bone fractures, and testing with X-rays or assessment of bone mineral density with a DXA (Dual X-ray absorptiometry) scan may be ordered.

Treatment
The treatment of acromegaly is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. The goals of treatment of acromegaly are to return growth hormone levels to normal, decrease the size of a pituitary adenoma (if present) thereby relieving pressure on the surrounding tissue, maintain normal pituitary function, and reverse or improve associated symptoms.

Acromegaly is usually treated by surgery, medications and radiation therapy. No single therapeutic option is effective for everyone. An individual's specific treatment plan will based on several factors including the size and location of the pituitary tumor; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular therapies should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

Acromegaly is usually treated by transsphenoidal surgery; a procedure in which all or part of a pituitary tumor is removed. Surgery often results in a rapid therapeutic response, immediately relieving pressure on surrounding brain structures and lowering growth hormone levels. When surgery is successful, soft tissue swelling may decrease in just a few days. Surgery is more effective in individuals with small tumors (microadenomas) than in those with large tumors (macroadenomas). Surgery may not successfully improve all symptoms (e.g., headaches may persist) and, in some cases, removal of the entire tumor may not be possible, resulting in growth hormone levels that remain too high.

Individuals treated by surgery should be periodically monitored by a physician because of the possible recurrence of the disorder. In some cases, surgery will improve the hormone levels, but not return them to normal, which necessitates further treatment often with medications.

Certain medications may be used to treat individuals with acromegaly. Medical therapy may be recommended in individuals in whom surgery in contraindicated, in whom surgery did not work or failed to return hormone levels to normal or to shrink large tumors before surgery.

Three different classes of medications are often used to treat individuals with acromegaly. These are somatostatin analogues including octreotide and lanreotide, growth hormone receptor antagonists such as pegvisomant and dopamine antagonists.

The Food and Drug Administration (FDA) has approved the drug octreotide acetate (Sandostatin® LAR) for its use in the treatment of acromegaly. Octreotide is an artificially produced (synthetic) compound similar to somatostatin (somatostatin analog), a natural hormone produced by the hypothalamus that serves to inhibit the secretion of growth hormone. (The hypothalamus is an area of the brain that plays a role in coordinating hormone function.) Safety and efficacy studies have been extensively published with decades of experience in treating patients with acromegaly. For more information, contact:

Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936
Phone: (888) 669-6682
Website: www.us.sandostatin.com
The FDA has also approved Somatuline® Depot (lanreotide) Injection for the treatment of acromegaly. The FDA approved Somatuline® Depot (lanreotide) Injection for the long-term treatment of individuals with acromegaly who have had inadequate response to or cannot be treated with surgery and/or radiation therapy. This treatment lowers the levels of GH and insulin-like growth factor-1. For more information, contact:

Ipsen
106 Allen Rd.
Basking Ridge, NJ 07920
Phone: (866) 837-2422
Fax: (908) 275-6301
Website: http://www.somatulinedepot.com/

The FDA has approved the orphan drug Somavert® (pegvisomant for injection) for the treatment of acromegaly in individuals who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. Somavert, which blocks the effects of excess growth hormone in acromegaly, is administered by subcutaneous injection. For more information, contact:

Pfizer, Inc.
235 East 42nd Street
NY, NY 10017
Website: www.somavert.com
The third class of medications sometimes used to treat individuals with acromegaly is dopamine agonists. However, these drugs, which include bromocriptine and cabergoline, are generally effective for fewer individuals than other medications. Physicians may prescribe these medications in conjunction with other medications used to treat acromegaly.

Surgery and medications may be supplemented by radiation treatment (proton beam, heavy particle, and supravoltage irradiation) or drug therapy. Radiation therapy is most often used in individuals in whom surgery has failed to sufficiently reduce tumor size or growth hormone levels. Conventional fractionated radiation therapy usually requires daily treatments over a four to six week period and may reduce growth hormones levels by 50 percent, but successful results may not occur until two to five years later. Because results are delayed, radiation therapy is rarely used to treat acromegaly without combining it with surgery or drug therapy.

After initial therapies, individuals with acromegaly will need to be routinely monitored by a physician to ensure that the pituitary is functioning normally and that the existing symptoms continue to improve.

In addition to conventional radiation therapy described above, some individuals may be treated by other forms radiotherapy. This forms of radiotherapy offers more precise targeting of high-beam radiation delivered at varying angles. This option limits the damage to surrounding tissue and can be delivered in a single session. A person is not eligible for this form of radiotherapy if the pituitary tumor is not at least 5mm away from the spot where the optic nerves from eyes cross at the base of the brain (optic chiasm). More research is necessary to determine the long-term safety and effective of this form of therapy for individuals with acromegaly.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contact for additional information about acromegaly:

John D. Carmichael, MD
Co-director, Pituitary Center of USC
Associate Professor of Clinical Medicine
Keck School of Medicine of USC
1333 San Pablo Street
BMT-B11
(323) 442-5720
John.Carmichael@med.usc.edu

Organizations related to Acromegaly

References

TEXTBOOKS
Murrary RD, Melmed S. Acromegaly. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:301.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1211-12.

Wilson JD, Foster DW. Textbook of Endocrinology. 8th ed. Philadelphia, PA: W. B. Saunders Co; 1992:268-290.

JOURNAL ARTICLES
Gadelha MR, Frohman LA. Pathogenesis of familial acromegaly. Front Horm Res. 2010;38:121-126.

Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009;119:3189-3202.

Castinetti F, Nagai M, Morange I, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab. 2009;94:3400-3407.

Higham CE, Thomas JD, Bidlingmaier M, Drake WM, Trainer PJ. Successful use of weekly pegvisomant administration in patients with acromegaly. Eur J Endocrinol. 2009;161:21-25.

Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab. 2009;94:1509-1517.

Trainer PJ, Drake WM, Katznelson L, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000;342:1171-7.

Utiger RD. Treatment of acromegaly. N Engl J Med. 2000;342:1210-11.

Stewart PM. Current therapy for acromegaly. Trends Endocrinol Metab. 2000;11:128-32.

Ezzat S, Strom C, Melmed S. Colon polyps in acromegaly. Ann Intern Med. 1991;114:754-5.

Melmed S. Acromegaly. N Engl J Med. 1990;322:966-77.

Melmed S. Medical progress: Acromegaly. N Engl J Med. 2006;355(24):2558-73.

INTERNET
National Institute of Diabetes and Digestive and Kidney Diseases. updated April 6, 2012. Available at: http://endocrine.niddk.nih.gov/pubs/acro/acro.aspx Accessed March 26, 2014.

Chanson P, Salenave S. Acromegaly. Orphanet encyclopedia, June 25, 2008. Available at: http://www.ojrd.com/content/pdf/1750-1172-3-17.pdf Accessed March 26, 2014.

Mayo Clinic for Medical Education and Research. Acromegaly. Feb. 05, 2013. Available at: http://www.mayoclinic.com/health/acromegaly/DS00478 Accessed March 26, 2014.

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Report last updated: 2014/04/02 00:00:00 GMT+0

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