What Is Acromegaly?

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Acromegaly

Acromegaly is a rare hormonal condition that results from an excess amount of growth hormone (GH) in the body. The extra amount of GH causes excess growth in the bones and soft tissues of the body. Children with the condition can grow to abnormal heights. They may also have an exaggerated bone structure. Acromegaly mostly affects the arms, legs, and face.

Acromegaly is a hormonal disorder that develops when your pituitary gland produces too much growth hormone during adulthood. When this happens, your bones increase in size, including those of your hands, feet and face. Acromegaly usually affects middle-aged adults.

Gigantism refers to abnormally high linear growth (see the image below) due to excessive action of insulinlike growth factor I (IGF-I) while the epiphyseal growth plates are open during childhood. Acromegaly is the same disorder of IGF-I excess but occurs after the growth plate cartilage fuses in adulthood.

In acromegaly, a severe disease that is often diagnosed late, morbidity and mortality rates are high, particularly as a result of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.

Researchers have identified a gene on the X chromosome, GPR101, which was overexpressed 1000-fold more than normal in a genetic study of 43 patients affected by sporadic or inherited gigantism that manifested during childhood or adolescence. This duplication was not evident in patients who began abnormal growth at age 9 or 10, but only in those who started to grow excessively before the age of 3. In a separate analysis of 248 patients with sporadic acromegaly, a mutation in the GPR101 gene was found in about 4% of cases.

In children who are still growing, too much growth hormone can cause a condition called gigantism. These children have exaggerated bone growth and an abnormal increase in height.

Because acromegaly is uncommon and physical changes occur gradually, the condition often isn’t recognized immediately: sometimes not for years. If not treated promptly, acromegaly can lead to serious illness and even become life-threatening. However, available treatments for acromegaly can reduce your risk of complications and significantly improve your symptoms, including the enlargement of your features.

A retrospective review of 208 cases of gigantism internationally established a genetic etiology in 46% of the cases; 29% had aryl hydrocarbon receptor interacting protein (AIP) gene mutations or deletions; and 10% had X-linked acro-gigantism (X-LAG) due to chromosome Xq26.3 microduplications on the GPR101 gene. The remaining 7% of genetic causes of gigantism were due to McCune-Albright syndrome (MAS), Carney complex, and MEN1. Male predominance was seen among AIP-mutated gigantism, whereas X-LAG had a strong female predilection.

When GH-producing tumors occur in childhood, the disease that results is called gigantism rather than acromegaly. A child’s height is determined by the length of the so-called long bones in the legs. In response to GH, these bones grow in length at the growth plates—areas near either end of the bone. Growth plates fuse after puberty, so the excessive GH production in adults does not result in increased height. However, prolonged exposure to excess GH before the growth plates fuse causes increased growth of the long bones and thus increased height. Pediatricians may become concerned about this possibility if a child’s growth rate suddenly and markedly increases beyond what would be predicted by previous growth and how tall the child’s parents are.

As the tumor grows it may cause headaches or impair peripheral vision as it presses on nearby nerves that run from the eyes to the brain. The tumor may damage the rest of the pituitary gland and cause underproduction of other hormones. The pituitary regulates many body processes and damage to it in this way commonly results in problems with impotence, infertility, or irregular periods.

Signs and Symptoms

One of the most common signs of acromegaly is enlarged hands and feet. People with this disorder often notice that they can no longer put on rings that used to fit and that their shoe size has progressively increased.

Acromegaly may also cause you to experience gradual changes in the shape of your face, such as a protruding lower jaw and brow, an enlarged nose, thickened lips, and wider spacing between your teeth.

 

What Is Acromegaly?

What Is Acromegaly?

Because acromegaly tends to progress slowly, early signs may not be readily apparent for several years. Sometimes, people notice the condition only by comparing old photographs.

The presentation of patients with gigantism is usually dramatic, unlike the insidious onset of acromegaly in adults. Manifestations include the following:

Acromegaly may produce the following signs and symptoms, which can vary from one person to another:

Acromegaly

Signs and symptoms of acromegaly include the following:

  • Enlarged hands and feet
  • Coarsened, enlarged facial features
  • Coarse, oily, thickened skin
  • Excessive sweating and body odor
  • Small outgrowths of skin tissue (skin tags)
  • Fatigue and muscle weakness
  • A deepened, husky voice due to enlarged vocal cords and sinuses
  • Severe snoring due to obstruction of the upper airway
  • Impaired vision
  • Headaches
  • Enlarged tongue
  • Pain and limited joint mobility
  • Menstrual cycle irregularities in women
  • Erectile dysfunction in men
  • Enlarged liver, heart, kidneys, spleen and other organs
  • Increased chest size (barrel chest)
  • Doughy-feeling skin over the face and extremities
  • Thick and hard nails
  • Deepening of creases on the forehead and nasolabial folds
  • Noticeably large pores
  • Thick and edematous eyelids
  • Enlargement of the lower lip and nose (the nose takes on a triangular configuration)
  • Wide spacing of the teeth and prognathism
  • Cutis verticis gyrata (ie, furrows resembling gyri of the scalp) [6]
  • Small sessile and pedunculated fibromas (ie, skin tags)
  • Hypertrichosis
  • Oily skin (acne is not common)
  • Hyperpigmentation (40% of patients)
  • Acanthosis nigricans (a small percentage of patients)
  • Excessive eccrine and apocrine sweating
  • Breast tissue becoming atrophic; galactorrhea
  • High blood pressure
  • Mitral valvular regurgitation
  • Mild hirsutism (in women)

Gigantism

  • Tall stature
  • Mild to moderate obesity (common)
  • Macrocephaly (may precede linear growth)
  • Headaches
  • Visual changes
  • Hypopituitarism
  • Soft tissue hypertrophy
  • Exaggerated growth of the hands and feet, with thick fingers and toes
  • Coarse facial features
  • Frontal bossing
  • Prognathism
  • Hyperhidrosis
  • Osteoarthritis (a late feature of IGF-I excess)
  • Peripheral neuropathies (eg, carpel tunnel syndrome)
  • Cardiovascular disease
  • Benign tumors
  • Endocrinopathies

Causes

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.

GH is part of a cascade of hormones that, as the name implies, regulates the physical growth of the body. This cascade begins in a part of the brain called the hypothalamus. The hypothalamus makes hormones that regulate the pituitary. One of the hormones in the GH series, or “axis,” is growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to produce GH.Secretion of GH by the pituitary into the bloodstream stimulates the liver to produce another hormone called insulin-like growth factor I (IGF-I). IGF-I is what actually causes tissue growth in the body. High levels of IGF-I, in turn, signal the pituitary to reduce GH production.

The hypothalamus makes another hormone called somatostatin, which inhibits GH production and release. Normally, GHRH, somatostatin, GH, and IGF-I levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake, and blood sugar levels. If the pituitary continues to make GH independent of the normal regulatory mechanisms, the level of IGF-I continues to rise, leading to bone overgrowth and organ enlargement. High levels of IGF-I also cause changes in glucose (sugar) and lipid (fat) metabolism and can lead to diabetes, high blood pressure, and heart disease.

In rare cases, a tumor elsewhere in the body, such as the lungs, adrenal glands, or pancreas, can lead to an overproduction of GH, resulting in symptoms of acromegaly.

This growth hormone may either be produced by the tumors themselves or because the pituitary gland is responding to a stimulus to produce GH. For example, some hypothalamic tumors may secrete growth hormone releasing hormone (GHRH), which tells the body to produce GH.

Sometimes, acromegaly is due to increased growth hormone production from outside the pituitary gland, such as from neuroendocrine tumors like small cell lung cancer or carcinoid tumors.

GH is part of a group of hormones that regulate the growth and development of the body. People with acromegaly have too much GH. It accelerates bone growth and organ enlargement. Because of this growth stimulation, the bones and organs of people with acromegaly are much larger than other people’s bones and organs.

GH is made in the brain’s pituitary gland. According to the National Institutes of Health (NIH), more than 95 percent of people with acromegaly have a benign tumor affecting their pituitary. This tumor is called an adenoma. Adenomas are common. They affect about 17 percent of people. In most people, these tumors don’t cause excess GH, but when they do can result in acromegaly.

Treatment

Surgery

Acromegaly is traditionally treated with transsphenoidal pituitary surgery and adenoma removal. However, cure may be difficult to achieve in patients with particularly large or invasive tumors. In such instances, medical therapy and/or radiation therapy may be necessary to control GH levels. In general, the higher the pre-operative GH level, the lower the chance for cure. Long-term cure of acromegaly after transsphenoidal surgery is seen in approximately 80-85% or patients with microadenomas (tumors less than 1 cm in size) and in approximately 50-60% of patients with macroadenomas (tumors greater than 1cm)

Medical Therapy

For patients with persistent GH elevation after surgery (or those who decline to have surgery), Octreotide (Sandostatin) or stereotactic radiosurgery or both are generally indicated. Octreotide (given three times a day by injection or by one monthly injection) achieves long-acting suppression of GH in about 70% of patients. It causes some degree of tumor shrinkage in 30-50% of patients, and often improves symptoms of soft tissue swelling, headache, joint pains and sleep apnea. The preoperative use of Octreotide may facilitate tumor removal and lessen the risks of general anesthesia. Side effects may include loose stools, malabsorption, cholelithiasis (gall stones), local pain at the injection site. Bromocriptine (Parlodel) and Cabergoline (Dostinex) are “dopamine agonist” pills which lower GH secretion in about 15% of acromegalic patients. The major side effect is gastrointestinal upset. Growth hormone lowering and tumor shrinkage are seen in only 10 – 15% of patients with acromegaly.

Pegvisomant (Somavert) is approved for the treatment of acromegaly. This drug is generally self-administered as a daily injection and blocks the actions of GH. Although it is very effective in lowering IGF-1 levels, it does not shrink the pituitary tumor. In rare cases, elevations of liver tests have been reported.

Somatuline Depot (lanreotide) is indicated for the long-term treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation, and for patients who cannot tolerate surgery or radiation. Somatuline Depot is the latest advancement in acromegaly treatment and is the first somatostatin analogue available in a prefilled syringe that achieves effective and long-acting suppression of GH and IGF-1 levels in patients. Somatuline® Depot uses a shorter needle to deliver the injection deep subcutaneously, instead of into the muscle.

Common side effects of Somatuline Depot include diarrhea, cholelithiasis, abdominal pain, nausea, injection site reactions, flatulence, arthralgia, and loose stools. In clinical trials, Somatuline was well tolerated with only 1.9 % of patients discontinuing therapy due to treatment-related adverse events.

Acromegaly requires expert care. Too much GH and IGF-1 in the blood lower both your quality of life and how long you might live. The main goal of treatment is to lower GH and IGF-1 levels to normal. Treatment may be surgery, pituitary irradiation (radiation therapy on the pituitary gland), medication, or a combination of these options.

If the cause of acromegaly is a pituitary tumor, surgery to remove the tumor is the first treatment. Complete removal of some tumors is difficult and other types of therapy are often needed to reach normal GH and IGF-1 levels. If your GH level isn’t normal after surgery, or if you aren’t a candidate for surgery, then pituitary irradiation and medication are also options.

Irradiation can take a long time to bring GH levels down to normal. It may even take 10 to 20 years to be fully effective. Once the goal is reached, however, the effects of irradiation are permanent.

Drugs are also available to treat acromegaly, but they are not a cure. If surgery or radiation does not lower your GH levels, you’ll probably have to take medication for the rest of your life. (Rarely, when medications are stopped, control of the disease continues.) The most effective medications for acromegaly are somatostatin analogs and a GH receptor antagonist. Another type of medication (dopamine agonists) works for some but not most patients. Some patients may benefit from a combination of these medicines.

Radio-Therapy

For patients whose acromegaly is not controlled with surgery, both conventional (external beam) and stereotactic radiosurgery are relatively effective. However, the lowering of GH and IGF-1 levels takes significantly longer with external beam radiotherapy (average 7 years) compared to stereotactic radiotherapy (average 18 months). Also, external beam radiation reliably causes loss of normal pituitary function over 5 to 10 years. Neurologic complications such as visual loss, weakness, and memory impairment have rarely been reported with both external beam and stereotactic radiotherapy.

How is acromegaly diagnosed?

Due to the subtlety of the symptoms, acromegaly is often not diagnosed until years later. In addition to a complete medical history and medical examination, diagnostic procedures for acromegaly may include:

  • serial photos taken over the years (to observe physical changes in the patient)
  • x-rays (to detect bone thickening)
  • blood tests (to check the growth hormone level)

Who develops acromegaly?

Acromegaly is rare. About two to four people in a million develop acromegaly each year in the UK. It mainly develops in adults who are middle-aged (average age 40 years). Men and women are equally affected.

Rarely, it affects children. If it develops in a child (it usually occurs between the ages of 15 to 17 years), it causes the condition called gigantism. This is because growth hormone promotes growth of bones in the body and a child’s bones can still grow.

Acromegaly and cancer screening

As mentioned earlier, people with acromegaly have an increased chance of developing small benign growths (polyps) in the bowel and bowel cancer. Therefore, if you are diagnosed with acromegaly and are aged 40 years or more, you will normally be offered a routine colonoscopy every three to five years (You may only be offered one every ten years if your hormone levels are always normal.) A colonoscopy is a test where an operator – a doctor or nurse – looks into your large bowel (colon) with a flexible telescope. It can diagnose bowel problems such as polyps and bowel cancer. The aim is to detect those people who develop cancer as early as possible (before symptoms develop) when the chance of a complete cure is high.

However, you should always tell your doctor if you develop any new symptoms from your bowel, such as persistent diarrhoea, passing mucus, passing blood, or tummy (abdominal) pain.

People with acromegaly also have an increased chance of developing thyroid cancer. The thyroid is a small gland in the front of your neck. Your doctor will want to examine your thyroid gland every so often and may arrange for you to have an ultrasound scan of your neck if you have developed any lumps in your thyroid.

Acromgealy is not linked to any other cancers, such as breast cancer or prostate cancer.

Complications of acromegaly

Without medical treatment, acromegaly can cause a range of complications including:

  • that the person regularly stops breathing or chokes while asleep (sleep apnoea)
  • arthritis
  • carpal tunnel syndrome
  • diabetes
  • high blood pressure (hypertension)
  • heart disease
  • premature death.

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