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Acromegaly

Somatotroph adenoma, Growth hormone excess, Pituitary giant

Overview

Acromegaly is an extremely rare syndrome that results when the anterior pituitary gland produces excess growth hormone (GH) after epiphyseal plate closure at puberty. If GH is produced in excess prior to epiphyseal plate closure, the result is gigantism (or giantism). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs).

Acromegaly most commonly affects adults in middle age, and can result in severe disfigurement and fatal complications if unchecked. Because of its pathogenesis and slow progression, it is hard to diagnose in the early stages and is frequently missed for years until changes in external features, especially of the face, become noticeable.

Symptoms - Acromegaly

Features that result from high level of GH or expanding tumor include:

  • 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 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 patients.
  • Acrochordon (skin tags)
  • Carpal tunnel syndrome

Complications

  • Severe headache
  • Arthritis and carpal tunnel syndrome
  • Enlarged heart
  • Hypertension
  • Diabetes mellitus (excess of GH leads to insulin resistance)
  • Heart failure
  • Kidney failure
  • Colorectal cancer
  • Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia.)
  • Increased palmar sweating and sebum production over the face (seborrhea) are clinical indicators of active GH-producing pituitary tumors. These symptoms can also be used to monitor the activity of the tumor after surgery, although biochemical monitoring is confirmatory.

Causes - Acromegaly

Acromegaly is caused by the pituitary gland overproducing growth hormone (GH) over time. The pituitary, a small gland situated at the base of your brain behind the bridge of your nose, produces a number of hormones. GH plays an important role in managing your physical growth.

When GH is secreted into your bloodstream, it triggers your liver to produce a hormone called insulin-like growth factor-I (IGF-I). In turn, IGF-I stimulates the growth of bones and other tissues. If your pituitary gland makes too much GH, excessive amounts of IGF-I can result. Too much IGF-I can cause abnormal growth of your soft tissues and skeleton and other signs and symptoms characteristic of acromegaly and gigantism.

In adults, a tumor is the most common cause of too much GH production: 

  • Pituitary tumors. Most cases of acromegaly are caused by a noncancerous (benign) tumor (adenoma) of the pituitary gland. The tumor secretes excessive amounts of growth hormone, causing many of the signs and symptoms of acromegaly. Some of the symptoms of acromegaly, such as headaches and impaired vision, are due to the tumor mass pressing on nearby brain tissues.
  • Nonpituitary tumors. In a few people with acromegaly, tumors in other parts of the body, such as the lungs, pancreas or adrenal glands, cause the disorder. Sometimes, these tumors actually secrete GH. In other cases, the tumors produce a hormone called growth hormone-releasing hormone (GH-RH), which stimulates the pituitary gland to make more GH.

Prevention - Acromegaly

Acromegaly cannot be prevented. Early treatment may prevent complications of the disease from becoming worse. If untreated, acromegaly and its complications can lead to premature death.

Diagnosis - Acromegaly

To begin the diagnostic process, your doctor will take a medical history and conduct a physical exam. Then he or she may recommend the following steps:

  • GH and IGF-I measurement. After you've fasted overnight, your doctor will take a blood sample to measure your levels of GH and IGF-I. Elevated levels of these hormones suggest acromegaly.
  • Growth hormone suppression test. This is the definitive method for verifying acromegaly. In this test, your blood levels of GH are measured before and after you drink a preparation of sugar (glucose). Normally, glucose ingestion depresses levels of GH. If you have acromegaly, your GH level will tend to stay high.
  • Imaging. Your doctor may recommend that you undergo an imaging procedure, such as magnetic resonance imaging (MRI), to help pinpoint the location and size of a tumor of your pituitary gland. If radiologists, who usually perform the procedures, see no tumor of your pituitary gland, they may look for nonpituitary tumors that might be responsible for high levels of GH.

Prognosis - Acromegaly

Upon successful treatment, symptoms and complications generally improve substantially or disappear, including headaches, visual disturbances, excess sweating, and diabetes. Soft-tissue swellings generally decrease and acromegaly-associated facial features gradually return towards normal, although this may take some time. 

Life expectancy after the successful treatment of early acromegaly is equal to that of the normal population.

Treatment - Acromegaly

The goals of treatment are to reduce GH and IGF-1 production to normal levels, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary.

Medications

Somatostatin analogues

The primary current medical treatment of acromegaly is to use somatostatin analogues – octreotide (Sandostatin LAR), pasireotide (Signifor LAR), lanreotide (Somatuline). These somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which inhibits GH production.

The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most patients with acromegaly respond to this medication. In many patients, 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 patients 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 patients. In addition, approximately 25 percent of patients 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. On the other hand, scientists have found that in some acromegaly patients who already have diabetes, octreotide can reduce the need for insulin and improve blood sugar control.

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 (Parlodel) or Cabergoline. These have the advantage of being tablets rather than injections, and 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. However, bromocriptine lowers GH and IGF-1 levels and reduces tumor size in fewer than half of patients with acromegaly. Some patients report improvement in their symptoms although their GH and IGF-1 levels still are elevated.

Growth hormone recptor anatagonists

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 disease activity of acromegaly in virtually all patients. 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

Surgery is a rapid and effective treatment, of which there are two alternative methods. The first method, a procedure known as Endonasal Transphenoidal surgery, involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. The wall is reached by passing through the nostrils with microsurgical instruments. The second method is Transsphenoidal surgery during which an incision is made into the gum beneath the upper lip. Further incisions are made to cut through the septum to reach the nasal cavity, where the pituitary is located. Endonasal Transphenoidal surgery is a less invasive procedure with a shorter recovery time than the older method of Transphenoidal surgery, and the likelihood of removing the entire tumor is greater with reduced side-effects. Consequently, Endonasal Transphenoidal surgery is often used as a first option, with Transphenoidal and other treatments, such as medicinal therapy or stereotactic radiosurgery, being used to reduce the remaining adverse effects of the remaining tumor.

These procedures normally relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. Surgery is most successful in patients with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 patients worldwide immediately after surgery revealed that 60 percent had random GH levels below 5 ng/ml. Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.

Even when surgery is successful and hormone levels return to normal, patients must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These patients may then require additional treatment, usually with medications.

Radiation therapy

Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.

Choice of treatment

No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a patient must be monitored for a long time for increasing GH levels. If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The current first choice is generally octreotide or lanreotide. However, bromocriptine or cabergoline are much cheaper and easier to administer. With both types of medication, long-term therapy is necessary because their withdrawal can lead to rising GH levels and tumor re-expansion. Radiation therapy is generally used for patients whose tumors are not completely removed by surgery; for patients who are not good candidates for surgery because of other health problems; and for patients who do not respond adequately to surgery and medication.


Resources - Acromegaly

Refer to Research Publications.

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