ACROMEGALY OVERVIEW

Acromegaly is characterized by the overgrowth of bodily tissues that causes broadening and enlargement of facial features and an increase in the size of the hands and feet. It is caused by prolonged, excessive secretion of growth hormone (GH). The most common cause of acromegaly is a tumor (adenoma) of the cells that produce growth hormone. These tumors are not cancerous; they are always benign. These cells are situated within the anterior pituitary gland, located in the middle of the head just below the brain (figure 1).

Acromegaly is uncommon; only three to four cases are diagnosed per million people each year. It develops very gradually and may not be recognized until it has been present for many years.

Acromegaly can lead to serious illness if not treated; however, most patients can be treated successfully.

ACROMEGALY SIGNS AND SYMPTOMS

Excessive production of growth hormone stimulates overproduction of another hormone, called insulin-like growth factor-1 (IGF-1). IGF-1 stimulates the growth of skin, connective tissue, cartilage, bone, organs, and other tissues in the body; an exception is the bones of the arms and legs, which do not continue to grow after middle to late puberty. Other symptoms of acromegaly are caused by the pituitary adenoma, which can compress nearby structures.

Features due to excessive growth hormone — Excessive growth of soft tissue, cartilage, and bone in the face, hands, and feet are the most prominent symptoms of acromegaly.

• Face and head — Facial features (nose, lips, ears, and forehead) become broader and larger and swollen (picture 1), the tongue enlarges, the space between the teeth increases, and the lower jaw grows, resulting in an under bite and extended lower jaw. Headache may be present. Facial hair growth increases, which may be especially bothersome to women. (See "Patient information: Hirsutism (excess hair growth in women) (Beyond the Basics)".)
• Throat — Excessive soft tissue growth of the throat and voice box can lead to a hoarse voice or sleep apnea (a condition in which a person stops breathing temporarily during sleep, causing lowered levels of oxygen, disrupted sleep, and daytime sleepiness). (See "Patient information: Sleep apnea in adults (Beyond the Basics)".)
• Hands and feet — The hands and feet enlarge, often requiring larger sized rings, gloves, and shoes (picture 2). Overgrowth of tissues in the wrist can compress nerves to the hands, leading to tingling or pain in the fingers (called carpal tunnel syndrome).
• Skin — The skin may thicken and skin tags may appear. Excessive sweating, even while resting, is common.
• Bones — Overgrowth of the ends of bones can damage neighboring cartilage and lead to arthritis, especially of the knees.
• Heart — The incidence of heart disease is increased, likely due to enlargement of the heart muscle, which impairs functioning of the muscle (called cardiomyopathy). High blood pressure is more common in acromegaly. Some people have problems with their heart valves. Heart failure may occur if acromegaly is uncontrolled.
• Diabetes — Higher blood glucose levels may result from excessive growth hormone production. Diabetes is more common in people with acromegaly, and people with previously diagnosed diabetes may require higher doses of medication.
• Tumors — Patients with acromegaly have an increased risk of noncancerous (benign) tumors, especially if growth hormone levels are not controlled. Polyps of the colon are more common and can become cancerous if not surgically removed. (See "Patient information: Colon polyps (Beyond the Basics)".) Benign tumors of the uterus (fibroids) are more common in acromegaly. (See "Patient information: Uterine fibroids (Beyond the Basics)".)

Life expectancy may be reduced by approximately 10 years, especially when growth hormone levels are uncontrolled and diabetes and heart disease are present. Patients who are successfully treated for acromegaly and whose growth hormone levels fall to normal generally have a normal life expectancy.

Features due to the size of the pituitary adenoma — If the pituitary adenoma becomes large (eg, 2 cm [1 inch] or greater), the increased pressure on surrounding structures can cause symptoms.

If the adenoma grows upward, it may stretch the nerves to the eyes (optic chiasm), causing vision problems, especially with peripheral (side) vision.

ACROMEGALY DIAGNOSIS

If acromegaly is suspected based upon a person's appearance, the diagnosis must be confirmed by measurement of blood levels of IGF-1 and/or growth hormone.

The blood level of IGF-1 can be determined in a single blood sample drawn at any time of day. Growth hormone levels fluctuate normally, so measurement of a single sample of blood for growth hormone is not helpful in making the diagnosis of acromegaly, but measurement of growth hormone several times before and after drinking a glucose (sugar) solution is helpful.

Once excessive growth hormone secretion has been confirmed, magnetic resonance imaging (MRI) is done to determine if an adenoma can be seen in the pituitary.

ACROMEGALY TREATMENT

Patients with acromegaly are treated to avoid the risk of the consequences described above, even if there are no obvious symptoms. The goal of therapy is to lower the level of growth hormone and IGF-1 in the blood to normal. If treatment is successful, the soft tissue changes will go away over a period of several months and the risk of early death returns to normal. Sometimes, initial treatment is not entirely successful and additional treatment is needed.

There are three main forms of treatment: surgery, medications, and radiation therapy.

Surgery — Surgery offers the chance of a cure if the pituitary tumor can be completely removed, which is most likely in people whose adenoma is small and does not extend outside the normal boundaries of the pituitary. For this reason, surgery is the first choice in this situation. Surgery is also the first choice of treatment when the adenoma is very large and impairing or threatening vision.

During surgery, a small incision is made in the nose (figure 2), through which the surgeon is able to visualize and remove adenoma tissue. Neurosurgeons often use a device called an endoscope to see the area around the pituitary better. People considering surgery should ask to be referred to a neurosurgeon who performs transsphenoidal surgery frequently. You should specifically ask about the number of transsphenoidal procedures the surgeon performs per year; studies suggest that surgeons who perform at least 50 per year have better surgical outcomes.

How well does surgery work? — Surgery is usually effective in reducing growth hormone levels, although not always to normal. The chance that the growth hormone levels will be normal after surgery is directly related to the size of the adenoma before surgery. The levels of growth hormone and IGF-1 will return to normal in about 80 percent of people with small adenomas (less than 1 cm [0.5 inch]). On the other hand, less than 40 percent of people who have larger adenomas that extend beyond the pituitary will have normal hormone levels after surgery.

If the adenoma is completely removed, the blood growth hormone level falls to normal within hours after surgery and the blood IGF-1 level returns to normal within weeks to months.

Complications — Serious complications are uncommon when the procedure is performed by a neurosurgeon highly experienced in pituitary surgery. The chance of serious complications, such as worsening of vision, meningitis, or nasal leakage of spinal fluid is less than 5 percent. The chance of damage to the pituitary gland is about 7 percent; this damage can lead to underactivity of the thyroid gland, adrenal glands, and the ovaries in women and testicles in men.

Medications — Three classes of medications are used to treat acromegaly. They work by lowering blood levels of growth hormone or blocking the effects of growth hormone:

• Somatostatin analogs (octreotide or lanreotide)
• Growth hormone receptor antagonist (pegvisomant)
• Dopamine agonists, especially cabergoline

Somatostatin analogs — Somatostatin analogs block the release of growth hormone from tumor cells in the pituitary.

Octreotide (brand name: Sandostatin LAR®) is a long-acting form given every four weeks by injection.

Lanreotide (brand name: Somatuline® Depot) is available in a long-acting form given every four to six weeks by injection.

These medications can be used as an initial treatment, especially when an adenoma is too large to remove completely with surgery. They can also be used as secondary treatment for people who have remaining adenoma tissue and an elevated blood growth hormone or IGF-1 concentration after transsphenoidal surgery.

• Results — Somatostatin analogs reduce blood concentrations of growth hormone and IGF-1 to some degree in most patients with acromegaly, although levels return to normal in only about half of patients. Somatostatin analogs may also stabilize or even reduce adenoma size.
• Side effects — Somatostatin analogs are usually well-tolerated, but there are possible side effects.

• Common side effects include abdominal cramps, abdominal discomfort, bloating, and loose stools during the first month of treatment. These symptoms often occur after the first dose, less often after the second, and uncommonly thereafter.
• Gallstones develop in about 20 percent of patients within the first six months of treatment. These do not usually require the person to discontinue treatment, except in the small percentage of people who experience inflammation of the gallbladder (cholecystitis). (See "Patient information: Gallstones (Beyond the Basics)".)

Growth hormone receptor antagonist — The one growth hormone receptor antagonist available (pegvisomant; brand name: Somavert®) blocks the effects of growth hormone by binding to its receptor, decreasing IGF-1 production and thereby decreasing growth. It is given daily by injection.

• Results — More than 70 percent of subjects who are treated with pegvisomant have a lowering of IGF-1 to normal.
• Side effects — Reversible liver function abnormalities occur occasionally, so liver tests should be measured periodically. As adenoma size may continue to increase during GH receptor antagonist use in some patients, MRI is recommended once per year to monitor adenoma size.

Dopamine agonists — Dopamine agonists may decrease growth hormone secretion and, therefore, may decrease IGF-1 levels to normal, although not as often as the medications described above. Because they can be taken orally, they are more convenient than other forms of treatment.

• Results — Some studies report that cabergoline reduces the level of growth hormone and IGF-1 to normal in one-third of patients, although most endocrinologists have not found cabergoline to be this successful. Bromocriptine (brand name: Parlodel®) is another dopamine agonist, although it is even less effective and not recommended.
• Side effects — The most common side effects of dopamine agents, especially at the higher doses used for acromegaly, are:

• Nausea, less likely with cabergoline than bromocriptine
• Lightheadedness after standing due to a fall in blood pressure
• Mental fogginess or mood disturbances
• Fatigue
• Sinus congestion
• Bad dreams
• Constipation, which is uncommon but can be severe

Side effects, especially nausea, can be minimized by taking the medication with meals or at bedtime and beginning with the lowest dose and increasing gradually.

Radiation therapy — Radiation therapy has been used for many years for treatment of pituitary adenomas, including those that make growth hormone. Radiation can be delivered in one of several ways:

• A linear accelerator, which delivers x-radiation in multiple small doses over the course of a month or in one or a few large doses.
• A cobalt source, which delivers gamma radiation only as a single large dose. This radiation is referred to as “gamma knife.”
• A cyclotron (proton beam), which delivers protons in multiple small doses or a single large dose.

A single large dose of radiation is used only if the adenoma tissue to be radiated is far enough away from the optic chiasm (nerves to the eyes) that the radiation will not cause damage. Multiple small fractions can be used even if the adenoma is close to the optic chiasm.

Results — Radiation therapy is usually effective in stopping or even reversing adenoma growth and in decreasing growth hormone and IGF-1 production. However, the decline in growth hormone secretion (and clinical improvement) is very slow. Even 10 to 15 years after radiation, only a small percentage of patients achieve a normal blood growth hormone level.

Side effects — Side effects that occur during or shortly after treatment include fatigue, nausea, loss of scalp hair, and loss of taste and smell. These problems usually resolve within weeks to months after treatment. Damage (called optic neuritis) to the nerve that controls vision can result in blindness, usually in one eye; blindness generally develops between 6 and 24 months after radiation therapy. This occurs very rarely, but is permanent.

Before radiation therapy was delivered stereotactically, blood vessel disease (hardening of the brain arteries) sometimes developed several years after radiation therapy. The risk of cerebral blood vessel disease with or without stroke has been reported to be increased with current radiation therapy delivery methods.

Within 10 years after radiation treatment, about 50 percent of patients develop a deficiency of one or more pituitary hormones, including the hormones that control the thyroid gland, adrenal glands, and ovaries or testicles.

PREGNANCY AND ACROMEGALY

Little is known about the interaction between acromegaly and pregnancy, although it appears that women are usually able to carry their pregnancy to full term. Reasonable guidelines for women with acromegaly include the following:

• Consult an endocrinologist prior to trying to become pregnant. Women should understand which medications will need to be discontinued and what effect acromegaly may have on their individual situation.
• When pregnancy is confirmed, a woman should speak with her endocrinologist as soon as possible.
• Visual fields should be monitored during pregnancy in women with adenomas larger than 1 cm (0.5 inch). MRI is recommended if new visual problems develop. MRI is generally thought to be safe for a mother and her fetus during pregnancy if it is performed without the use of gadolinium (dye).

MONITORING ACROMEGALY

Patients with acromegaly need to be monitored over their lifetime to ensure that treatment is optimal and to minimize the risk of disease complications and treatment side effects. The following should especially be monitored:

Changes in features — Patients with acromegaly should note whether treatment improves their symptoms, such as headache or excess perspiration. The patient and his/her doctor should note whether treatment improves the signs of acromegaly, including enlargement of the face, hands, and feet.

Until the blood levels of growth hormone and IGF-1 return to normal, patients and their doctors should be vigilant about treating sleep apnea if it is present. (See "Patient information: Sleep apnea in adults (Beyond the Basics)".)

Because of the increased risk of colon polyps, colonoscopy should be performed every three to four years after age 50 or sooner. (See "Patient information: Colon and rectal cancer screening (Beyond the Basics)".)

Growth hormone and IGF-1 levels — The blood level of IGF-1 should be measured to monitor response to treatment. The goal is to keep the IGF-1 level in the middle of the normal range for the person’s age and gender.

Other pituitary hormone levels — People who have acromegaly may produce inadequate amounts of other pituitary hormones because of compression from the adenoma on the normal pituitary or due to surgery or radiation therapy. Levels of hormones produced by the thyroid gland, adrenal glands, and ovaries or testes should be monitored and replaced as needed.

Size of the adenoma — If the adenoma was initially larger than 1 cm (0.5 inch), it is important to determine if treatment has decreased its size. This is generally done by magnetic resonance imaging (MRI) of the pituitary area.

If the initial treatment has not been entirely successful, additional treatments should be considered carefully. Patients with well-controlled disease generally have a lower risk of complications, other underlying medical conditions, and early death.

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Acromegaly (The Basics)
Patient information: Pituitary adenoma (The Basics)
Patient information: Growth hormone treatment (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Hirsutism (excess hair growth in women) (Beyond the Basics)
Patient information: Sleep apnea in adults (Beyond the Basics)
Patient information: Uterine fibroids (Beyond the Basics)
Patient information: Colon polyps (Beyond the Basics)
Patient information: Gallstones (Beyond the Basics)
Patient information: Colon and rectal cancer screening (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Causes and clinical manifestations of acromegaly
Diagnosis of acromegaly
Pituitary gigantism
Rheumatic and bone disorders associated with acromegaly
Treatment of acromegaly

The following organizations also provide reliable health information:

• National Library of Medicine
  
  (www.nlm.nih.gov/medlineplus/healthtopics.html)
• The National Institute of Diabetes and Digestive and Kidney Disorders
  
  (www.niddk.nih.gov/)
• The Hormone Foundation
  
  (www.hormone.org/public/pituitary.cfm, available in English and Spanish)

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