Patient information: Acromegaly

ACROMEGALY OVERVIEW

Acromegaly is 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 benign tumor (adenoma) of the somatotroph cells, which produce growth hormone. These cells are 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 and even death 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 (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)".)

• 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 and disrupted sleep) (see "Patient information: Sleep apnea in adults".
• Hands and feet — The hands and feet enlarge, often requiring patients to wear 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.
• Tumors — Patients with acromegaly have an increased risk of noncancerous (benign) tumors, especially if growth hormone levels are not controlled. Benign tumors of the uterus (fibroids) are more common in acromegaly. (See "Patient information: Fibroids".) Polyps of the colon are more common, and can become cancerous if not surgically removed. (See "Patient information: Colon polyps".)

• 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 be a direct result of excessive growth hormone production, which causes insulin resistance. Diabetes is more common in people with acromegaly, and people with previously diagnosed diabetes may require higher doses of medication.

Life expectancy may be reduced by approximately 10 years, especially when growth hormone levels are uncontrolled and diabetes and heart disease are present. Patients with controlled hormone levels generally have a normal life expectancy.

Features due to the size of the somatotroph adenoma — If the somatotroph 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 of the eyes (optic chiasm), causing visual impairment, especially peripheral (side) vision.

ACROMEGALY DIAGNOSIS

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

The blood level of IGF-1 can be determined in a single blood sample drawn at any time of day. Growth hormone must be measured by taking several samples of blood, drawn before and after drinking a glucose (sugar) solution.

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

ACROMEGALY TREATMENT

Patients with acromegaly are treated to avoid the risk of complications, even if there are no obvious symptoms. The goal of therapy is to lower the level of growth hormone and IFG-1 in the blood. If therapy is successful, the soft tissue changes will regress 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 somatotroph adenoma can be completely removed. This is most likely in people whose adenoma does not extend outside the normal boundaries of the pituitary. 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). The incision is extended through the sphenoid sinus, allowing the surgeon to visualize and remove the adenoma. An endoscope (a thin, lighted tube with a camera) may be used to ensure that the adenoma has been removed completely. Alternately, the entire procedure may be performed using the endoscope.

People who may need surgery should discuss their situation with a neurosurgeon who performs transsphenoidal surgery frequently. Patients should specifically ask about the number of transsphenoidal surgeries done per year; studies suggest that surgeons who perform at least 50 per year have better outcomes.

Efficacy — Surgery is usually effective in reducing growth hormone levels, although levels do not always return 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 eighty percent of people with small adenomas (less than 1 cm [0.5 inch]). On the other hand, only about 30 percent of people who have larger adenomas that extend beyond the pituitary will have normal hormone levels after surgery.

If the adenoma is completely excised, the blood GH 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 an experienced neurosurgeon. The chance of serious complications, such as worsening of vision, hormonal imbalance, meningitis, nasal leakage, or very rarely, death, is less than 5 percent. The chance of damage to the pituitary gland is about 7 percent; damage can lead to underactivity of the thyroid gland, adrenal glands, and the ovaries in women and testicles in men.

Medications — There are three classes of medications used to treat acromegaly:

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

Somatostatin analogs — Somatostatin analogs inhibit secretion of growth hormones from the growth hormone-secreting cells of the pituitary.

Octreotide (Sandostatin®) is made in short-acting and long-acting forms. The short-acting form is given three times a day by injection, and the long-acting form is given every four weeks by injection.

Lanreotide (Somatuline® Depot) is available in a long-acting form that is injected every four weeks.

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 concentration after transsphenoidal surgery.

• Efficacy — 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 less than half of patients. Somatostatin analogs may also reduce adenoma size.
• Side effects — Somatostatin analogs are usually well-tolerated, but there are some side effects. Common side effects include
• Abdominal cramps, abdominal discomfort, bloating, and loose stools during the first week or two of treatment, especially with the short-acting preparations. These symptoms generally resolve as treatment continues.
• 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".)

Growth hormone receptor antagonist — Growth hormone receptor antagonists block the effects of growth hormone by binding to the hormone receptor, decreasing IGF-1 production and thereby decreasing growth effects. Pegvisomant (Somavert®) is given daily by injection.

• Side effects — Reversible liver function abnormalities occur occasionally, so liver enzymes should be measured periodically. Adenoma size may continue to increase during GH receptor antagonist use, and MRI is recommended once per year to monitor adenoma size.

Dopamine agonists — Dopamine agonists may inhibit growth hormone secretion and therefore decrease IGF-1 levels, although they are not usually as effective as other classes of medications. They can be taken orally and may be more convenient than other forms of treatment.

• Efficacy — Some studies report that cabergoline (Dostinex®) 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. Cabergoline is of great benefit in those who respond since it can be taken orally and has few side effects. Bromocriptine (Parlodel®) is another dopamine agonist, although is less effective and not recommended.
• Side effects — The most common side effects of dopamine agents 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

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 somatotroph adenomas. Radiation can be delivered in one of several ways:

• A linear accelerator
• A cobalt source (gamma radiation)
• A cyclotron (proton beam)

Radiation can be given as a single large dose or in multiple smaller doses. Whatever the source and number of doses, the radiation is directed stereotactically (three-dimensionally) to the adenoma by a computerized program.

Efficacy — 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. It is very rare but permanent.

Before radiation therapy was delivered stereotactically, blood vessel disease (hardening of the arteries) sometimes developed several years after radiation therapy. The risk of blood vessel disease with current radiation therapy delivery methods is not known.

Within 10 years after treatment, about 50 percent of patients treated with pituitary radiation 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 impairment develops. MRI is generally considered to be safe for a mother and her fetus during pregnancy.

ACROMEGALY MONITORING

Patients with acromegaly need to be monitored over their lifetime to minimize the risk of treatment and disease side effects and complications. In particular, the following areas are of concern:

Changes in features — Patients with acromegaly should note whether treatment improves their symptoms, such as headache. The patient and healthcare provider 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 healthcare providers should be vigilant about treating sleep apnea if it is present. (See "Patient information: Sleep apnea in adults".)

Because of the increased risk of colon polyps, colonoscopy should be performed every three to four years after age 50 or sooner if there are multiple skin tags. (See "Patient information: Colon cancer screening".)

Growth hormone and IGF-1 levels — The blood level of IGF-1 should be measured to monitor response to treatment.

Other pituitary hormone levels — People who undergo surgery or radiation may produce inadequate amounts of other pituitary hormones. 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).

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. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Hirsutism (excess hair growth)
Patient information: Sleep apnea in adults
Patient information: Fibroids
Patient information: Colon polyps
Patient information: Gallstones
Patient information: Colon cancer screening

Professional Level Information:
Clinical manifestations of acromegaly
Diagnosis of acromegaly
Pituitary gigantism
Rheumatic and bone disorders associated with acromegaly
Treatment of acromegaly

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

• 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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