acromegaly acromegaly acromegaly is a disorder that results in excess growth of certain parts of the human body. it is caused by excess growth hormone (gh) after the growth plates have closed. the initial symptom is typically enlargement of the hands and feet. there may also be an enlargement of the forehead, jaw, and nose. other symptoms may include joint pain, thicker skin, deepening of the voice, headaches, and problems with vision. complications of the disease may include type 2 diabetes, sleep apnea, and high blood pressure. acromegalylower jaw showing the classic spacing of teeth due to acromegaly.pronunciation/ˌækrəˈmɛɡəli, -roʊ-/ specialtyendocrinologysymptomsenlargement of the hands, feet, forehead, jaw, and nose, thicker skin, deepening of the voicecomplicationstype 2 diabetes, sleep apnea, high blood pressure, high cholesterol, heart problems, particularly enlargement of the heart (cardiomyopathy), osteoarthritis, spinal cord compression or fractures, increased risk of cancerous tumors, precancerous growths (polyps) on the lining of the colon.usual onsetmiddle agecausesexcess growth hormonediagnostic methodblood tests, medical imagingdifferential diagnosispachydermoperiostosistreatmentsurgery, medications, radiation therapymedicationsomatostatin analogue, gh receptor antagonistprognosisusually normal (with treatment), 10 year shorter life expectancy (no treatment)frequency3 per 50,000 people cause and diagnosis acromegaly is usually caused by the pituitary gland producing excess growth hormone. in more than 95% of cases the excess production is due to a benign tumor, known as a pituitary adenoma. the condition is not inherited. acromegaly is rarely due to a tumor in another part of the body. diagnosis is by measuring growth hormone after a person has consumed a glucose solution, or by measuring insulin-like growth factor i in the blood. after diagnosis, medical imaging of the pituitary is carried out to determine if an adenoma is present. if excess growth hormone is produced during childhood, the result is the condition gigantism rather than acromegaly, and it is characterized by excessive height. treatment treatment options include surgery to remove the tumor, medications, and radiation therapy. surgery is usually the preferred treatment; the smaller the tumor, the more likely surgery will be curative. if surgery is contraindicated or not curative, somatostatin analogues or gh receptor antagonists may be used. radiation therapy may be used if neither surgery nor medications are completely effective. without treatment, life expectancy is reduced by 10 years; with treatment, life expectancy is not reduced. epidemiology, history, and culture acromegaly affects about 3 per 50,000 people. it is most commonly diagnosed in middle age. males and females are affected with equal frequency. it was first described in the medical literature by nicolas saucerotte in 1772. the term is from the greek ἄκρον (akron) meaning "extremity", and μέγα (mega) meaning "large". signs and symptoms compared with the hand of an unaffected person (left), the hand of a person with acromegaly (right) is enlarged, with fingers that are widened, thickened and stubby, and with thicker soft tissuemandibular overgrowth leads to prognathism, maxillary widening, teeth spacing and malocclusionbrow ridge and forehead protrusion remaining after tumor removal and tissue swelling eliminated features that may result from a high level of gh or expanding tumor include: headaches – often severe and prolonged soft tissue swelling visibly resulting in enlargement of the hands, feet, nose, lips, and ears, and a general thickening of the skin soft tissue swelling of internal organs, notably the heart with the attendant weakening of its muscularity, and the kidneys, also the vocal cords resulting in a characteristic thick, deep voice and slowing of speech generalized expansion of the skull at the fontanelle pronounced brow protrusion, often with ocular distension (frontal bossing) pronounced lower jaw protrusion (prognathism) with attendant macroglossia (enlargement of the tongue) and teeth spacing hypertrichosis, hyperpigmentation and hyperhidrosis may occur in these people.: 499 skin tags carpal tunnel syndrome complications problems with bones and joints, including osteoarthritis, nerve compression syndrome due to bony overgrowth, and carpal tunnel syndrome hypertension diabetes mellitus cardiomyopathy, potentially leading to heart failure colorectal cancer sleep apnea thyroid nodules and thyroid cancer hypogonadism compression of the optic chiasm by the growth of pituitary adenoma leading to visual problems causes pituitary adenoma about 98% of cases of acromegaly are due to the overproduction of growth hormone by a benign tumor of the pituitary gland called an adenoma. these tumors produce excessive growth hormone and compress surrounding brain tissues as they grow larger. in some cases, they may compress the optic nerves. expansion of the tumor may cause headaches and visual disturbances. in addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men because of reduced testosterone production. a marked variation in rates of gh production and the aggressiveness of the tumor occurs. some adenomas grow slowly and symptoms of gh excess are often not noticed for many years. other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. in general, younger people tend to have more aggressive tumors. most pituitary tumors arise spontaneously and are not genetically inherited. many pituitary tumors arise from a genetic alteration in a single pituitary cell that leads to increased cell division and tumor formation. this genetic change, or mutation, is not present at birth but is acquired during life. the mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells; it permanently switches on the signal that tells the cell to divide and secrete growth hormones. the events within the cell that cause disordered pituitary cell growth and gh oversecretion currently are the subject of intensive research. pituitary adenomas and diffuse somatomammotroph hyperplasia may result from somatic mutations activating gnas, which may be acquired or associated with mccune-albright syndrome. other tumors in a few people, acromegaly is caused not by pituitary tumors, but by tumors of the pancreas, lungs, and adrenal glands. these tumors also lead to an excess of gh, either because they produce gh themselves or, more frequently, because they produce ghrh (growth hormone-releasing hormone), the hormone that stimulates the pituitary to make gh. in these people, the excess ghrh can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. when these nonpituitary tumors are surgically removed, gh levels fall and the symptoms of acromegaly improve. in people with ghrh-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from people with acromegaly so as to not overlook the possibility that a tumor elsewhere in the body is causing the disorder. diagnosis frequent serum gh measurements in normal subjects (left panel) demonstrate that gh can fluctuate between undetectable levels most of the time interspersed with peaks of up to 30 μg/l (90 miu/l); in acromegaly (right panel) gh hypersecretion is continuous with no undetectable levels. if acromegaly is suspected, medical laboratory investigations followed by medical imaging , if the lab tests are positive, confirms or rules out the presence of this condition. igf1 provides the most sensitive lab test for the diagnosis of acromegaly, and a gh suppression test following an oral glucose load, which is a very specific lab test, will confirm the diagnosis following a positive screening test for igf1. a single value of the gh is not useful in view of its pulsatility (levels in the blood vary greatly even in healthy individuals).magnetic resonance image of a pituitary macroadenoma that caused acromegaly with compression of the optic chiasm gh levels taken 2 hours after a 75- or 100-gram glucose tolerance test are helpful in the diagnosis: gh levels are suppressed below 1 μg/l in normal people, and levels higher than this cutoff are confirmatory of acromegaly. other pituitary hormones must be assessed to address the secretory effects of the tumor, as well as the mass effect of the tumor on the normal pituitary gland. they include thyroid stimulating hormone (tsh), gonadotropic hormones (fsh, lh), adrenocorticotropic hormone, and prolactin. an mri of the brain focusing on the sella turcica after gadolinium administration allows for clear delineation of the pituitary and the hypothalamus and the location of the tumor. a number of other overgrowth syndromes can result in similar problems. differential diagnosis pseudoacromegaly is a condition with the usual acromegaloid features, but without an increase in growth hormone and igf-1. it is frequently associated with insulin resistance. cases have been reported due to minoxidil at an unusually high dose. it can also be caused by a selective post receptor defect of insulin signalling, leading to the impairment of metabolic, but preservation of mitogenic, signalling. treatment site of action of the different therapeutic tools in acromegaly. surgery, radiotherapy, somatostatin analogues and dopamine agonists act at the level of the pituitary adenoma, while gh receptor antagonists act in the periphery by blocking the growth hormone receptor and thus impairing the effects of gh on the different tissues. the goals of treatment are to reduce gh production to normal levels thereby reversing or ameliorating the signs and symptoms of acromegaly, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, and to preserve normal pituitary function. currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary. somatostatin analogues the primary current medical treatment of acromegaly is to use somatostatin analogues – octreotide (sandostatin) or lanreotide (somatuline). these somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which stops gh production. the long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. most people with acromegaly respond to this medication. in many people with acromegaly, gh levels fall within one hour and headaches improve within minutes after the injection. octreotide and lanreotide are effective for long-term treatment. octreotide and lanreotide have also been used successfully to treat people with acromegaly caused by non-pituitary tumors. somatostatin analogues are also sometimes used to shrink large tumors before surgery. because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of people. in addition, approximately 25 percent of people with acromegaly develop gallstones, which are usually asymptomatic. in some cases, octreotide treatment can cause diabetes due to the fact that somatostatin and its analogues can inhibit the release of insulin. with an aggressive adenoma that is not able to be operated on, there may be a resistance to octreotide and in which case a second generation ssa, pasireotide, may be used for tumor control. however, insulin and glucose levels should be carefully monitored as pasireotide has been associated with hyperglycemia by reducing insulin secretion. dopamine agonists for those who are unresponsive to somatostatin analogues, or for whom they are otherwise contraindicated, it is possible to treat using one of the dopamine agonists, bromocriptine or cabergoline. as tablets rather than injections, they cost considerably less. these drugs can also be used as an adjunct to somatostatin analogue therapy. they are most effective in those whose pituitary tumours cosecrete prolactin. side effects of these dopamine agonists include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. these side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose. bromocriptine lowers gh and igf-1 levels and reduces tumor size in fewer than half of people with acromegaly. some people report improvement in their symptoms although their gh and igf-1 levels still are elevated. growth hormone receptor antagonists the latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. the only available member of this family is pegvisomant (somavert). by blocking the action of the endogenous growth hormone molecules, this compound is able to control the disease activity of acromegaly in virtually everyone with acromegaly. pegvisomant has to be administered subcutaneously by daily injections. combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant. surgery surgical removal of the pituitary tumor is usually effective in lowering growth hormone levels. two surgical procedures are available for use. the first is endonasal transsphenoidal surgery, which involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. the wall is reached by passing