Acromegaly
Definition
Acromegaly is a rare condition caused by abnormally high amounts of human growth hormone (HGH). An organ in the brain known as the pituitary gland, normally secretes this growth hormone. Normal amounts of HGH are needed for normal growth and physical maturity in children. However, in acromegaly, there is an increased amount of HGH released, generally by a tumor that forms in the pituitary. Untreated, acromegaly can lead to numerous disabling conditions, as well as a significantly decreased life span.
Description
Acromegaly was first described in scientific detail by the French physician, Pierre Marie. In 1886, Dr. Marie, along with his assistant, Souza-Leite, described in detail 48 patients with acromegaly. These patients all exhibited a rapid growth in their height; significantly enlarged hands and feet; change in appearance of their faces; frequent headaches; and a high incidence of visual problems. Dr. Marie believed all of these problems were due to a defect in the patients' pituitary gland, a small glandular structure located in the middle of the brain.
While Dr. Marie was the first to formally state that a problem in the pituitary gland was responsible for the condition of acromegaly, the link between pituitary defects and acromegaly remained controversial for many years. It was not until 1909, when Dr. Harvey Cushing introduced the concepts of hyperpituitarism in reference to acromegaly, that the association became generally accepted. Dr. Cushing believed acromegaly was due to the pituitary gland, a small structure located deep in the brain and known to be somehow involved in growth, over-secreting some type of substance that caused patients to become "giants." Dr. Cushing also put forth the idea that the over-activity of the pituitary gland was caused by a tumor in the gland, an idea that was proven by autopsies done on patients with acromegaly. At the time, however, it still was not clear how a tumor in the pituitary gland could cause such changes in people afflicted with the tumor.
In the decades after World War II, the structure and function of the pituitary gland was further studied. Dr. Herbert Evans at the University of California at Berkley was the first to isolate many secretions, also known as hormones, which were found to be made in and secreted from the pituitary gland. One of these hormones was found to be human growth hormone, or HGH. It was also discovered that certain tumors can form in the pituitary gland and secrete high levels of HGH, resulting in abnormal growth and, as time progresses, acromegaly.
Acromegaly is a rare condition, with only about 1,000 cases per year in the United States among a total population of 250 million. Its striking consequence of excessive height has caused it to remain a fascinating disease among both scientists, doctors, and the public. Besides causing great height and unusual facial features, it is now known that acromegaly also causes serious conditions that can be life threatening, such as heart disease, respiratory disease, arthritis, neuromuscular problems, and diabetes. With early detection and treatment, the consequences of acromegaly can be minimized and patients afflicted with the condition can lead mainly healthy, productive lives.
Genetic profile
The genetics behind the majority of cases of acromegaly is still poorly understood. The most common cause of acromegaly is a benign (non-cancerous) tumor in the pituitary gland that secretes HGH. It is known that the benign tumor arises from cells in the pituitary gland, possibly due to a defect in the pituitary gland itself. The gene responsible for this tumor formation is unknown.
Even though the genetics of tumor formation in the pituitary gland leading to most cases of acromegaly is not yet known, there are other conditions that lead to acromegaly in which the genetic causes of the conditions are known. In a very rare condition called familial acromegaly, there is a gene on chromosome 11 believed to cause the formation and growth of an HGH-secreting tumor in the pituitary gland. Familial acromegaly is transmitted in an autosomal dominant pattern—which means that it has an equal chance of affecting both boys and girls in a single family. This condition can also cause tumors in other areas of the body besides the pituitary, including the parathyroid gland, which controls the amount of calcium in the bloodstream, and the pancreas, which regulates insulin needed for the body to process sugars.
Another uncommon condition causing HGH-secreting tumors in the pituitary gland is called multiple endocrine neoplasia-1, or MEN-1. This is an autosomal dominant condition characterized by a combination of pituitary, parathyroid, and pancreatic tumors. The gene for this condition has also been found on chromosome 11 and is known as the MEN-1 gene. About half the patients with this abnormal gene will eventually develop acromegaly.
Carney syndrome is a rare autosomal dominant disorder that can cause HGH-secreting pituitary tumors and acromegaly in about 20% of patients who have the syndrome. Carney syndrome is associated with a defective gene on chromosome 2. Besides acromegaly, people with Carney syndrome also frequently have abnormal skin pigmentation, heart tumors, and tumors of the testicles and adrenal glands.
McCune-Albright syndrome is a very rare disorder that can cause acromegaly through HGH-secreting tumors in the pituitary. Other conditions associated with this syndrome are polycystic fibrous dysplasia (affecting bone growth, especially in the pelvis and long bones of the arms and legs), abnormal skin pigmentation, early puberty, and thyroid problems. The gene for the syndrome, named GNAS1, is located on chromosome 20.
Demographics
Acromegaly is a very rare condition. It is estimated to occur in about 30-60 individuals per million people. Both males and females seem to be affected equally. There also does not seem to be any difference in secondary complications of acromegaly between males and females. The condition has been recorded at all ages of life, from early childhood into old age. The frequency of chronic complications increases with age in both men and women.
Most cases of acromegaly are detected on an initial visit to a family physician, although some early or mild cases may be missed, causing a delay in the diagnosis. Some patients with acromegaly are initially diagnosed in specialty clinics, such as cardiology clinics and diabetic clinics when they present with secondary problems caused by the condition.
There is very little data on the differences of the occurrence of acromegaly among various ethic and racial lines. The few studies that have been done show no real difference among racial or ethnic groups, with acromegaly showing up equally in Caucasians, African-Americans, and Asian-Americans.
Signs and symptoms
The signs and symptoms of acromegaly can range from striking to almost unseen. The most visible signs of the condition are greatly increased height and coarse facial features. People with acromegaly who have not received treatment early in the course of their condition have grown to be well over seven feet tall. Almost always with this spurt in height there is coarsening of facial features due to abnormal growth of the facial bones. Another very noticeable feature is enlargement of both the hands and feet, which, like the abnormal facial features, is the product of hormones and results in increased bone growth.
Other less visible, yet common, signs of acromegaly are increased sweating, constant and at times debilitating
headaches, visual disturbances, and increase in hair growth. Loss of sexual desire is often seen in both men and women. Amenorrhea, the cessation of menses (stop-ping of menstruation), is often a secondary condition associated with acromegaly in women.
There are further secondary complications of acromegaly that are not visible but can be life threatening. People with acromegaly are at greater risk for developing high blood pressure, cardiac disease, high cholesterol levels, arthritis and other degenerative diseases of the joints and spine, and diabetes. Acromegly also increases the risk of other tumors, some of them cancerous, in other areas of the body, especially the breast, colon, and to a lesser degree, prostate.
With adequate treatment, especially early in the course of the condition, many of the secondary symptoms of acromegaly can be halted or even reversed. Less life-threatening complications, such as headaches, visual problems and increased sweating can be almost eliminated after adequate and timely treatment. More serious conditions such as heart disease, high blood pressure, and diabetes can be brought under control with treatment, although many times not totally eliminated.
Diagnosis
For most forms of acromegaly, there are no genetic tests yet available to diagnosis the condition in newborns or before birth. Diagnosis is made by recognizing the clinical signs and symptoms previously described. In certain very rare conditions such as multiple endocrine neoplasia-1 and Carney syndrome, the genetics of the conditions are known and can theoretically be tested for. However, the conditions are so seldom encountered that unless a family member has the condition, genetic testing
is usually not done until clinical signs and symptoms are apparent.
Treatment and management
The treatment and management of acromegaly has evolved over the past one hundred years from crude surgery to genetically engineered medications. Today, through precise surgery and medications, a large percentage of patients with acromegaly can have their symptoms brought under control, and in some cases totally cured.
The goal of all therapies, be it surgery or medications, is a reduction in the level of HGH to levels seen in people without acromegaly. This goal can be achieved either through the removal or destruction of the tumor secreting the hormone, inhibition of HGH from the tumor, or blocking the effects of increased HGH on organs and other body systems outside the pituitary.
Surgical removal of the pituitary tumor is still the first treatment of choice for acromegaly. The rate at which a cure is achieved is determined by several factors, including the size of the tumor, whether or not it has spread outside the pituitary, and the level of HGH before the surgery. In patients with small tumors confined to the pituitary and exhibiting only moderately high HGH levels, the cure rate can be as high as 80–90%. In patients with larger tumors, especially those extending out of the pituitary, cure rates with surgery can be reduced to 40–60%.
Radiation therapy is often a second line choice of treatment for acromegaly, especially in patients who have not achieved a cure with surgery. The treatment of acromegaly with radiation was used early on in the history of the condition, with the first report being written in 1909. Careful application of radiation can significantly reduce the size of pituitary tumors, subsequently decreasing high HGH levels. However, this decrease is often very slow, and it can take over ten years for the HGH levels to drop to normal. Treatment with radiation can also have significant side effects, including damage to the pituitary gland itself, visual loss, and brain damage. Some studies have also suggested that treatment with radiation can lead to tumor formation in other areas of the brain.
The use of medications in the treatment of acromegaly has gained importance over the past few decades in the treatment of the condition. Medications available today include Bromocriptine, octreotide and lanreotide, and a genetically engineered HGH receptor antagonist known as Pegvisomant. All of these medications are generally used in combination with surgery or radiation, although there is debate whether or not the medications could or should be used as first-line agents.
Bromocriptine is known as a dopamine agonist, and was one of the first pharmaceutical agents to be used to lower HGH levels in acromegaly. However, bromocriptine is not effective in a majority of cases, and the medications octreotide and lanreotide have supplemented its use. These medications are also known as somatostatin analogues. They decrease both the size of HGH-secreting pituitary tumors and the secretion of HGH itself. In multiple studies, they have been shown to normalize HGH levels in about 50% of cases and show significant tumor shrinkage in 45% of cases. The drawbacks to using both octreotide and lanreotide include multiple weekly dosing over a 12-month period, as well as acute side effects such as nausea, stomach pain, and diarrhea. Also, long term use of these medications results in an increased risk of developing gallstones.
Pegvisomant is a unique, recently developed genetically engineered HGH receptor antagonist. This medication does not decrease the amount of HGH secreted from pituitary tumors; rather, it desensitizes other organs of the body to the effects of the increased HGH circulating in the body. In medical trials, Pegvisomant was well tolerated and resulted in significant symptomatic improvement. It is hoped that with a combination of surgery to decrease the tumor size and the use of a HGH antagonist like Pegvisomant, both the acute and chronic debilitating symptoms of acromegaly can be greatly diminished, if not totally eliminated.
Prognosis
The prognosis for patients with acromegaly who receive prompt treatment is good, although there are still complications. Patients who do not receive treatment, or those who receive it late in the course of the condition, have frequent and debilitating secondary complications as well as a greater chance for early death.
There are only a few reliable studies examining the overall health benefits of treatment versus no treatment for patients with acromegaly. One study showed that those receiving treatment before the age of 40 years had a much better chance of not developing serious complications then those who were treated after 40 years of age. Those receiving earlier treatment had less chance of developing heart disease, high blood pressure, and diabetes, as well as other secondary complications of the condition.
Even with treatment, mortality rates for people with acromegaly are increased when compared to the rest of the population. The principal causes of early death are cardiac disease, strokes, cancer, and respiratory failure. The level of HGH after treatment appears to offer the best statistics for predicting early mortality, with higher levels of post-treatment HGH corresponding to a greater, earlier mortality risk.
