Acromegaly (from akros, Greek for “high” and megalos for “large”) is a condition that results from excessive levels of growth hormone (GH) in the blood and its consequences on the human body. In adults and in adolescent children who have gone through puberty, and whose bones have stopped growing, excess GH causes enlargement of the feet, hands, lips, nose, and jaws, referred to as acromegaly. Acromegaly can occur in children, and when it does, the excessive secretion of GH results in a condition that is closely related but distinct from acromegaly called “pituitary gigantism”, which results in a pathologically tall individual.
Acromegaly is a relatively uncommon disease; about five in every million people develop acromegaly each year. However, because the clinical diagnosis of acromegaly is often missed, these numbers are probably underestimated. In the United States, the condition is newly diagnosed in about 3-4 people per million per year, and about one person per 20,000 is estimated to have acromegaly. The most common age at time of diagnosis is 40-45 years and both males and females have equal chances of being affected by the disease.
Acromegaly is caused by prolonged overproduction of GH by the pituitary gland; GH is part of a cascade of hormones that regulate the physical growth of the body. This cascade begins in a part of the brain called the hypothalamus which produces hormones that regulate the function of the pituitary gland. One of these, growth hormone-releasing hormone (GHRH) stimulates the pituitary gland to produce GH. Another hypothalamic hormone, somatostatin, inhibits GH production and release.
Secretion of GH by the pituitary gland into the bloodstream causes the production of another hormone in the liver called insulin-like growth factor 1 (IGF-1) which is the factor that actually causes the physical changes that accompany acromegaly such as the overgrowth of bones, soft tissues and other features of acromegaly. The excess GH also causes changes in sugar and lipid metabolism which and can cause other systemic diseases such as diabetes. The levels of these three hormones, GH, GHRH and IGF-1, are tightly regulated via regulatory “feedback loops” that control the levels of secretion within the human body, their levels of secretion is also affected by daily activities including exercise, stress, food intake, and sleep.
In few patients, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs and adrenal glands that also lead to an excess of GH either because they directly produce GH or, more frequently, because they produce GHRH.
In more than 90 percent of acromegaly patients, the overproduction of GH is caused by a benign tumor of the pituitary gland called an adenoma. These tumors produce excess GH and as they expand, they compress the surrounding neural tissues such as the optic nerves causing the headaches and visual disturbances that are often symptoms of acromegaly. In addition, the tumor compresses the pituitary gland itself often altering the production of other pituitary hormones.
The classic symptoms of acromegaly include abnormal growth of the facial bones, hands and feet, as well as excessive sweating and heart disease. Gradual changes within the bones alter the patient’s face lowering the brow and causing prominent lower jaw protrusion. It can also cause excess perspiration and fatigue, widening of the spaces between the teeth, furrows in the forehead, and weakness in the hands. Due to the subtlety of the symptoms and the gradual nature of the disease progression, acromegaly may often be missed for long periods of time that may extend to years.
Later sequelae of the disease include arthritis and carpel tunnel syndrome (compression of the median nerve at the level of the wrist due to pressure from the hypertrophied bone and soft tissue), heart failure, diabetes, hypertension, and compression of the optic nerve(s) leading to loss of vision (mainly peripheral vision). If not treated, this disorder can result in serious illness and premature death.
In addition to a complete medical history and neurological examination, diagnostic procedures for acromegaly include: 1) serial photos of the patient taken periodically to observe any changes in his/her physical appearance, 2) X-rays to detect bone thickening and 3) blood tests to check the levels of different growth hormones, 3) magnetic resonance imaging (MRI) and computed tomography (CT) scans of the pituitary gland, and 4) Neuroopthalmological evaluation for potential visual deficits.
The level of GH is assessed in the blood after a patient has fasted overnight to determine if it is elevated. A single measurement of GH is not enough to diagnose acromegaly, because GH is secreted by the pituitary gland in spurts and its concentration in the blood can vary widely in the same individual at different times of the day. IGF-1 levels are also measured as it is more reliable and stable over the course of the day.
Imaging techniques, such as MRI and CT scans play an important role in locating the tumor that causes GH overproduction, identifying its size, characteristics, and detecting any possible invasion of the surrounding neurovascular structures. MRI is generally superior to CT in terms of the high definition of its image and its ability to detect small sized pituitary tumors. Dynamic MRI of the pituitary gland is also a new imaging tool, which has gained importance in the evaluation of pituitary adenomas due to its ability to delineate small microadenomas and differentiate them from the normal pituitary gland. If scans fail to detect a pituitary tumor, non-pituitary tumors in the chest, abdomen or pelvis should be considered as possible causes for the excess GH.
The goals of treatment are to reduce GH production to normal levels, to relieve the pressure on the surrounding pituitary gland and brain, to preserve other pituitary gland functions, and to reverse or ameliorate the symptoms of acromegaly. The ultimate target is to restore the pituitary gland to its normal function.
Treatment options include surgical removal of the tumor, radiation therapy and medical therapy. A single modality or a combination of modalities could be followed based on multiple factors such as the overall health and medical history of the patient, extent of the disease at time of diagnosis and the individual’s tolerance to specific medications.
Medical therapy, includes the control of GH oversecretion by the administration of different GH blocking drugs, two of which are the most common: 1) Bromocriptine (Parlodel) which is a dopamine agonist is usually the preferred primary drug of choice as it is taken orally and thus easy to administer 2) Octreotide (Sandostatin), a synthetic form of the brain hormone “somatostatin” that naturally inhibits GH secretion in the pituitary gland, is injected under the skin every eight hours for effective maintenance of low levels of GH. Other more recent medications include octreotide LAR (Sandostatin LAR) -a Long-acting somatostatin analogue which is injected under the skin every 4 weeks and pegvisomant (SOMAVERT) a GH-receptor antagonist that is injected under the skin every 24 hours. With all medications for acromegaly, long-term therapy is necessary because their withdrawal can lead to relapse with a rise in GH levels and tumor re-expansion. The use of medications alone to control excessive secretion of GH has numerous problems and is often impractical as it requires high doses of medications, side effects become intolerable and GH levels become uncontrolled.
Surgical treatment provides a direct and effective way to relieve the pressure on the pituitary gland and on the surrounding neurovascular structures such as the optic nerves. It represents a relatively rapid and unmediated way of lowering or normalizing the level of the GH as well as relieving the mass effect caused by the adenoma.
Radiation therapy (conventional or Gamma Knife) is a third option for treatment of pituitary adenomas and may be used in combination with surgery or medical treatment. Radiation therapy is not free from side effects; and therefore is usually reserved for patients that do not respond adequately to surgery or medication or if surgery could not be tolerated because of other serious health problems.
If left untreated acromegaly results in progressive physical and cosmetic deformities, and can result in serious illness such as diabetes mellitus and hypertension. It increases the patient’s risk for cardiovascular disease, colon polyps that may lead to colon cancer and premature death. Treatment has the potential to improve facial appearance and soft tissue swelling, normalize the levels of GH and IGF-1, and relieve the pressure on the pituitary gland and the surrounding neurovascular structures. Following successful treatment, regular follow up is required.
Gigantism (from gigas or gigantos, Greek for “giant”) is a condition characterized by excessive growth that results from excess growth hormone (GH) during childhood when the epiphyseal growth plates are still open. The term “gigantism” is applied to those whose heights are several standard deviations above the mean value for the same sex, age, ethnicity; and “pituitary gigantism” when a pituitary gland tumor is the source of excessive GH. Elevated levels of serum GH and insulin-like growth factor-1 (IGF-1), a hormone produced by the liver in response to GH, cause rapid excessive linear growth and, if unchecked, extremely tall stature.
Pituitary gigantism is an extremely rare condition. In the United States there are approximately 100 reported cases to date. The disease commences at any age prior to epiphyseal fusion and symptoms of the disease may be observed as early as the first six to nine months after birth. With a small quantity of available studies, due to the rarity of the disease, pituitary gigantism was reported to occur at a female-to-male ratio of 1:2, with no predilection for a certain race or ethnicity.
In more than ninety percent of individuals with GH excess, the underlying anomaly is a benign pituitary tumor comprised of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH-secreting and prolactin [PRL]-secreting cells) either in the form of a pituitary microadenoma or macroadenoma.
Although typically occurring as an isolated disorder, gigantism occasionally may present as a feature of other conditions such as multiple endocrine neoplasia (MEN) type I, McCune-Albright syndrome (MAS), neurofibromatosis, tuberous sclerosis, Klinefelter syndrome or Carney complex. There are about 50 even rarer genetic syndromes in which childhood growth is above average. These conditions are often associated with developmental delay or other more serious problems.
Pituiratry gigantism is also distinct from other causes of apparent excessive growth in childhood such as familial tall stature, exogenous obesity, precocious puberty, and a variety of other conditions associated with excessive amounts of testosterone or estrogen in childhood will result in rapid growth and weight gain by mid-childhood. The extent and frequency of gigantism seen in these conditions varies.
The primary effect of GH excess in childhood is excessive growth, but the “tallness” is accompanied by a body build that is characteristic for pituitary gigantism. All growth parameters are affected, although not necessarily symmetrically. Over time, GH excess is characterized by progressive cosmetic disfigurement and systemic organ manifestations. The typical body build involves heavy thick bones with large hands and feet and a heavy jaw.
The pattern of abnormal body growth in a child due to pituitary gigantism is recognizable to a physician. Medical history and neurological examination are important and focused on endocrinological problems or other possible causes of gigantism. A hormonal evaluation is essential, GH assays (age-adjusted reference range) are used to diagnose the disease and to define a biochemical cure. Serum IGF-1 concentration measurement is a sensitive screening test for both pituitary gigantism and acromegaly. Radiological evaluation (MRI/CT scan) is important for detecting and evaluating the size and location of a pituitary adenoma. Neuroopthalmological evaluation is important to obtain a “baseline” for vision or to assess any existing visual problems.
The goals of treatment are to control GH levels, to relieve the pituitary gland and the surrounding neurovascular structures from any mass effect exerted by the tumor, retain normal secretion of other pituitary hormones and prevent long-term recurrence of the disease.
Treatment options include medical, surgical and pituitary irradiation. Medical therapy, with growth hormone blocking medications alone, may cause hormonal levels to decrease to an extent but rarely to normalize and it is rarely effective with large macroadenomas that cause a mass effect. Radiotherapy, whenever possible, is avoided in childhood due to long term radiation effects including delayed hypopituitarism as a result of radionecrosis. However, if all other treatment modalities have failed to control GH hypersecretion, radiotherapy might represent a good option; radiation does not result in immediate shrinkage of the tumor but it helps prevent further growth of the tumor in many patients. Surgical intervention aiming at complete removal of tumor is the treatment of choice, it may be curative, and has been demonstrated to be as safe for children as it is for adults.
Because of the small number of patients that are affected with gigantism, the mortality and morbidity rates for this disease are unknown. In one series, the long-term recurrence rate for GH-secreting adenomas in children was found to be 13% after surgery, which indicates a favorable prognosis. All patients with a history of GH excess require periodic life-long evaluation.
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