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Acromegaly - A Big Problem for a Small Group

Christina Loguidice


The Guinness Book of World Records includes a category for tallest man. The current record holder is 32-year-old Sultan Kosen, who is 8’3” and lives in Turkey. Like Sultan Kosen, most of the handful of people medically documented as exceeding 8 feet in height achieved their great stature due to a pituitary adenoma—a benign tumor that arises from cells in the pituitary gland. Although an estimated 17% of people develop a pituitary adenoma in their lifetime, only a few each year get diagnosed with an active tumor that secretes excessive amounts of growth hormone (GH). Tumors located elsewhere in the body have also been found to release GH or to produce GH-releasing hormone, triggering release of GH from the pituitary and synthesis of insulin-like growth factor-1 (IGF-1).

In children, the elevated levels of GH lead to excessive linear growth and a condition called gigantism; in adults, prolonged hypersecretion of GH results in acromegaly, but because growth plates are fused in adults, only the bones in their hands, feet, and face become enlarged. Individuals with acromegaly also develop distinct facial features, such as a lantern jaw, bulging forehead, and thick lips and nose. Sultan Kosen has gigantism and acromegaly.

Gigantism and acromegaly are associated with a host of comorbid conditions, including excessive weight gain, diabetes, osteoarthritis, cardiovascular disease due to heart enlargement, headaches, vision impairment, excessive sweating, sleep apnea, fatigue, weakness, pain, and erectile dysfunction. Untreated acromegaly significantly increases the risk of fatal cardiovascular events.

Surgical Treatment

The Endocrine Society recently released clinical practice guidelines for diagnosing and treating acromegaly. Surgical excision of a pituitary adenoma using a transsphenoidal approach is recommended as primary treatment for most adults with acromegaly. Surgery typically causes a rapid decline in levels of GH and IGF-1 and reversal of some facial changes. The guidelines recommend performing an appropriate imaging study approximately 3 months after surgery to look for residual tumor tissue. After reviewing the literature on acromegaly, the Endocrine Society concluded that the remission rate after surgery is 85% for patients with microadenomas and 50% for patients with macroadenomas.

Medical Therapy

For patients who refuse surgery, who have nonresectable tumors, or who continue to have elevated GH levels after surgery, medical therapies are available to help control GH and IGF-1 levels. Neoadjuvant medical therapy may be appropriate for patients with certain comorbidities (see Endocrine Society Guidelines for specific recommendations).

Somatostatin analogs (somatostatin receptor ligands; SRLs) are the most common first-line medical therapies and include octreotide long-acting release (LAR) and lanreotide depot (Somatuline autogel), which are intramuscular agents administered monthly. Data show SRLs often improve common complaints of arthralgia, hyperhidrosis, and headache and may normalize IGF-1 levels in one-third of patients. In 60% of patients with tumors, SRLs reduce tumor volume by half. Response is dose-dependent, and gastrointestinal effects are common as patients adjust to the medication. In a small percentage of patients, SRLs compromise glucose control.

Pasireotide (Signifor) is an injectable SLR that was approved by the US Food and Drug Administration recently to treat patients with acromegaly.  It was also approved in 2012 to treat inoperable Cushing’s Disease. In November 2014, the European Commission approved pasireotide LAR for patients with acromegaly who cannot have surgery or did not enter remission after surgery and who have not achieved hormonal control with the older SRLs.  Pasireotide is more selective for a greater number of somatostatin receptor subtypes. In the phase 3 PAOLA trial, the drug reduced IGF-1 levels to normal in 35% of patients. Pasireotide may cause hyperglycemia in some individuals.

Other options for patients who do not respond to or cannot tolerate SRLs include pegvisomant, a GH-receptor agonist that is administered subcutaneously. Pegvisomant reduces IGF-1 levels but does not have antitumor effects. Dopamine agonists such as cabergoline were used to treat acromegaly before the introduction of SRLs and may be an option. Combining pegvisomant or a dopamine agonist with an SRL may be effective in some patients.

Radiotherapy

Radiation therapy is recommended as a last resort in patients for whom surgery is not possible and who do not respond to or are unable to use any of the recommended medications. The Endocrine Society recommends stereotactic radiotherapy over conventional radiation. Radiotherapy was associated with a 10% to 60% remission rate in patients followed for up to 15 years.

Emerging Therapies

Among the emerging treatments for acromegaly are  ATL1103, a second-generation GH receptor blocker.  In a randomized phase 2 trial of ATL1103, patients with acromegaly had a 26% reduction in IGF-I levels after 14 weeks of treatment, and a phase 3 trial is now being planned.

Rare Disease Quick Facts ­- Acromegaly


Image of man with acromegaly courtesy wikimedia commons
 
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