Gigantism and Acromegaly
Growth hormone (GH) stimulates somatic growth and regulates metabolism. Growth hormone–releasing hormone (GHRH) is the major stimulator and somatostatin is the major inhibitor of the synthesis and release of GH. GH controls synthesis of insulin-like growth factor 1 (IGF-1, also called somatomedin-C), which largely controls growth. Although IGF-1 is produced by many tissues, the liver is the major source. The metabolic effects of GH are biphasic. GH initially exerts insulin-like effects, increasing glucose uptake in muscle and fat, stimulating amino acid uptake and protein synthesis in liver and muscle, and inhibiting lipolysis in adipose tissue. Several hours later, more profound anti– insulin-like metabolic effects occur. They include inhibition of glucose uptake and use, causing blood glucose and lipolysis to increase, which increases plasma free fatty acids.
Many growth hormone (GH)–secreting adenomas contain a mutant form of the Gs protein, which is a stimulatory regulator of adenylate cyclase. Cells with the mutant form of Gs protein secrete GH even in the absence of growth hormone–releasing hormone (GHRH). A few cases of ectopic GHRH-producing tumors, especially of the pancreas and lung, also have been described.
This rare condition occurs if GH hypersecretion begins in childhood, before closure of the epiphyses. Skeletal growth velocity and ultimate stature are increased, but little bony deformity occurs. However, soft-tissue swelling occurs, and the peripheral nerves are enlarged. Delayed puberty or hypogonadotropic hypogonadism is also frequently present, resulting in a eunuchoid habitus.
In acromegaly, GH hypersecretion usually starts between the 20s and 40s. When GH hypersecretion begins after epiphyseal closure, the earliest clinical manifestations are coarsening of the facial features and soft-tissue swelling of the hands and feet. Appearance changes, and larger rings, gloves, and shoes are needed. Photographs of the patient are important in delineating the course of the disease.
In adults with acromegaly, coarse body hair increases and the skin thickens and frequently darkens. The size and function of sebaceous and sweat glands increase, such that patients frequently complain of excessive perspiration and offensive body odor. Overgrowth of the mandible leads to protrusion of the jaw (prognathism) and malocclusion of teeth. Cartilaginous proliferation of the larynx leads to a deep, husky voice. The tongue is frequently enlarged and furrowed. In long-standing acromegaly, costal cartilage growth leads to a barrel chest. Articular cartilaginous proliferation occurs early in response to GH excess, with the articular cartilage possibly undergoing necrosis and erosion. Joint symptoms are common, and crippling degenerative arthritis may occur.
Peripheral neuropathies occur commonly because of compression of nerves by adjacent fibrous tissue and endoneural fibrous proliferation. Headaches are common because of the pituitary tumor. Bitemporal hemianopia may develop if suprasellar extension compresses the optic chiasm. The heart, liver, kidneys, spleen, thyroid gland, parathyroid glands, and pancreas are larger than normal. Cardiac disease (eg, coronary artery disease, cardiomegaly, sometimes cardiomyopathy) occurs in perhaps one third of patients, with a doubling in the risk of death from cardiac disease. Hypertension occurs in up to one third of patients. The risk of cancer, particularly of the gastrointestinal tract, increases 2-fold to 3-fold. GH increases tubular reabsorption of phosphate and leads to mild hyperphosphatemia. Impaired glucose tolerance occurs in nearly half the patients with acromegaly and in gigantism, but clinically significant diabetes mellitus occurs in only about 10% of patients.
Galactorrhea occurs in some women with acromegaly, usually in association with hyperprolactinemia. However, galactorrhea may occur with GH excess alone, because GH itself stimulates lactation. Decreased gonadotropin secretion often occurs with GH-secreting tumors. About one third of men with acromegaly develop erectile dysfunction, and nearly all women develop menstrual irregularities or amenorrhea.
Diagnosis can be made from the characteristic clinical findings. CT, MRI, or skull x-rays disclose cortical thickening, enlargement of the frontal sinuses, and enlargement and erosion of the sella turcica. X-rays of the hands show tufting of the terminal phalanges and soft-tissue thickening.
Serum IGF-1 should be measured in patients with suspected acromegaly; IGF-1 levels are typically substantially elevated (3-fold to 10-fold), and because IGF-1 levels do not fluctuate like GH levels do, they are the simplest way to assess GH hypersecretion. IGF-1 levels also can be used to monitor response to therapy.
Plasma GH levels measured by radioimmunoassay are typically elevated. Blood should be taken before the patient eats breakfast (basal state); in normal people, basal GH levels are < 5 ng/mL (< 5 mcg/L). Transient elevations of GH are normal and must be distinguished from pathologic hypersecretion. The degree of GH suppression after a glucose load remains the standard and thus should be measured in patients with elevated plasma GH; however, the results are assay-dependent, and the cutoff for normal suppression is controversial. Secretion in normal people is suppressed to < 2 ng/mL ([<2 mcg/L] a cutoff of < 1 ng/mL [< 1 mcg/L] is often used) within 90 minutes of oral administration of 75 g of glucose. Most patients with acromegaly have substantially higher values. Basal plasma GH levels are also important in monitoring response to therapy.
CT or MRI of the head should be done to look for a tumor. If a tumor is not visible, excessive secretion of pituitary GH may be due to a non-central nervous system tumor producing excessive amounts of ectopic GHRH. Demonstration of elevated levels of plasma GHRH can confirm the diagnosis. Lungs and pancreas may be first evaluated in searching for the sites of ectopic production.
Screening for complications, including diabetes, heart disease, and gastrointestinal cancer, should be done at the time of diagnosis. Fasting plasma glucose levels, glycosylated Hb (HbA1C), or an oral glucose tolerance test can be done to test for diabetes. Electrocardiography and, preferably, echocardiography are done to detect heart disease. Colonoscopy is done to detect colon cancer. Follow-up screening depends on the results of the initial testing and the patient's response to treatment.
Ablative therapy with surgery or radiation is generally indicated. Transsphenoidal resection is preferred, but choices vary at different institutions. Stereotactic supervoltage radiation, delivering about 5000 cGy to the pituitary, is used, but GH levels may not fall to normal for several years. Treatment with accelerated protons (heavy particle radiation) permits delivery of larger doses of radiation (equivalent to 10,000 cGy) to the pituitary; such therapy poses higher risk of cranial nerve and hypothalamic damage and is available only in a few centers.
Development of hypopituitarism several years after irradiation is common. Because radiation damage is cumulative, proton beam therapy should not be used after conventional gamma-irradiation. A combined approach with both surgery and radiation therapy is indicated for patients with progressive extrasellar involvement by a pituitary tumor and for patients whose entire tumor cannot be resected, which is often the case.
Surgical removal of the tumor is likely to have been curative if GH levels measured after a glucose load and IGF-1 levels reach normal values. If one or both values are abnormal, further therapy is usually needed. If GH excess is poorly controlled, hypertension, heart failure, and a doubling in the death rate occur. If GH levels are < 5 ng/mL (< 5 mcg/L), however, mortality does not increase.
In general, drug therapy is indicated if surgery and radiation therapy are contraindicated, if they have not been curative, or if radiation therapy is being given time to work. In such instances, a somatostatin analog, octreotide, is given at 0.05 to 0.15 mg subcutaneously every 8 to 12 hours; it suppresses GH secretion effectively. Longer-acting somatostatin analogs, such as mannitol-modified release octreotide (octreotide LAR) given 10 to 30 mg IM every 4 to 6 weeks and lanreotide given 30 mg IM every 10 to 14 days, are more convenient. Bromocriptine mesylate (1.25 to 5 mg orally twice a day) may effectively lower GH levels in a small percentage of patients but is less effective than somatostatin analogs.
Pegvisomant, a GH receptor blocker, has been shown to reduce the effects of GH and lower IGF-1 levels in people with acromegaly, without apparent increase in pituitary tumor size. This drug may find a place in treating patients who are partially or totally unresponsive to somatostatin analogs.
Gigantism and acromegaly are usually caused by a pituitary adenoma that secretes excessive amounts of growth hormone (GH); rarely, they are caused by non-pituitary tumors that secrete growth hormone–releasing hormone (GHRH).
Gigantism occurs if GH hypersecretion begins in childhood, before closure of the epiphyses.
Acromegaly involves GH hypersecretion beginning in adulthood; a variety of bony and soft tissue abnormalities develop.
Diagnose by measuring insulin-like growth factor 1 and GH levels; do central nervous system imaging to detect a pituitary tumor.
Remove pituitary tumors surgically or using radiation therapy.
If tumors cannot be removed, give octreotide or lanreotide to suppress GH secretion.
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