Acromegaly

Acromegaly is an endocrine disorder where there is a hormonal imbalance in the body. The condition is caused by too much growth hormone (GH).

Pathology

Growth hormone is normally produced by the pituitary gland. This is a small pea-sized gland that lies within the brain. In acromegaly, the pituitary produces excessive amounts of GH.

The excess production may be due to a benign, or noncancerous, tumor on the pituitary. These tumors are called adenomas.

Symptoms of acromegaly

Without treatment acromegaly can cause severe complications and even death. Acromegaly is treatable in most patients. It has a slow and gradual onset and often goes un-noticed in its initial phases.

Acromegaly and other disorders

Acromegaly may lead to other disorders including:

• type 2 diabetes
• high blood pressure
• cardiovascular disease
• colon polyps that may turn into colon cancers as they progress
• arthritis

Gigantism and acromegaly

If the disorder occurs in childhood, it leads to gigantism rather than acromegaly.  In children excess growth hormone leads to excess prolongation of the long bones (in the legs) and this leads to excessive height gain.

The long bones in response to the growth hormone especially grow at the growth plates—areas near either end of the bone.  Once the child attains puberty, the growth plates fuse and thus after attainment of puberty excess growth hormone does not lead to gigantism or excessive height gain.

Those with acromegaly usually have no growth of their limbs. However bones of the hands, feet, and face can still grow and these begin to grow. The hands appear like spades. The face bones grow to alter the shape of the face. The jaw becomes larger, with spaces appearing between the teeth, and the eyebrows become more prominent. The skin becomes rough and oily and there is excessive growth of the tongue as well.

Who is affected?

Acromegaly is most often diagnosed in middle-aged adults between ages 40 and 45. Symptoms of the condition may appear at any age. Around 3 to 4 million persons are affected annually.

Treatment

Treatment is targeted towards the pituitary tumor. The tumor may be treated using a combination of surgery to remove the tumour, radiotherapy to destroy any tumour cells and drugs to suppress the production of further growth hormone.

Acromegaly has a slow or gradual onset and the symptoms are also slow to appear. Obvious changes in appearance may not be detected immediately unless present photographs or appearance is compared with earlier photographs.

Some of the symptoms of acromegaly include:-

• Enlargement of the hands and feet. The hands appear like spades and feet continue to grow with currently used shoes becoming uncomfortable.
• Joint pains
• Due to excess growth of the hands, nerves of the wrist called the Median nerve may be compressed leading to a painful condition called Carpal tunnel syndrome. Even when carpal tunnel syndrome is not seen there may be a tingling sensation of hands and feet due to entrapment of small nerves.
• Thick, rough and oily skin. There is also excessive sweating, body odour and presence of skin tags. Skin tags are tiny bits of skin tissue hanging from the skin especially of the face and neck.
• Enlargement of lips and nose. There may be a protruding brow and enlarged tongue and jaw. Teeth become wide spaced as well. This alters appearance significantly. There is a protrusion of the lower jaw and this is called prognathism.
• There is deepening and coarsening of voice. This is because there is enlargement of sinuses and vocal cords. Due to enlargement of the tongue, structures within the neck and back of the throat there may be sleep apnea or obstruction of airways during sleep as well. This also leads to day time weakness, fatigue and tiredness due to lack of sleep.
• Due to altered growth of the facial bones there may be presence of headaches and impaired vision. Headaches may also indicate that the growth of the tumor of the pituitary gland is pressing on nearby tissues and nerves.
• There is presence of sexual dysfunction with loss of sex drive or libido and impotence among men and abnormal periods in women.
• Arthritis may be seen commonly.
• Organs of the body like heart, liver, prostate, kidneys and thyroid glands can increase in size.
• Heart disease including high blood pressure, heart failure, heart rhythm abnormalities and cardiomyopathies are seen commonly.
• Increased secretion of a hormone Prolactin from the pituitary may lead to galactorrhea (breast discharge) and amenorrhea (absence of periods) in women.

Growth hormone is produced and released by the pituitary gland. This is a pea-sized gland just below the brain. Normal release of growth hormone before attainment of puberty allows for normal growth of humans.

What stimulates growth hormone release?

Growth hormone release is stimulated by the hypothalamus of the brain. The hypothalamus makes hormones that regulate the pituitary. One of the hormones that regulates the growth hormone is the growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to produce GH.

What happens when growth hormone is released?

When growth hormone is released into the blood, it stimulates the liver to produce another hormone – insulin-like growth factor 1 (IGF-1). This IGF-1 causes growth of muscle, bones and cartilage throughout the body. In adults this process is required for growth and repair of body tissues.

Regulation of hormones

The hypothalamus makes another hormone called somatostatin. This inhibits GH production and release.  Normally the levels of each of the four hormones – GHRH, Somatostatin, Growth Hormone and IGF-1 are tightly regulated by each other and by other factors such as sleep, exercise, blood sugar levels, stress etc.

Pathology of acromegaly

Acromegaly is caused by prolonged over­production of GH by the pituitary gland. This leads to excessive rise of IGF-1 as well leading to bone overgrowth and organ enlargement. Rise in levels of IGF-1 changes glucose and fat metabolism leading to an increased risk of heart disease and diabetes.

Causes of acromegaly may be due to pituitary tumors or non-pituitary tumors.

Pituitary tumors

This is the cause of acromegaly in more than 95 percent of people with the condition. Acromegaly results from a benign or non cancerous tumor of the pituitary gland, called an adenoma. This tumor produces excess GH.

Pituitary tumors may be micro- or macro-adenomas determined by their size. Acromegaly is commonly caused by macro-adenomas. This means they are over 1cm in size.

These larger tumors may also press upon the nearby structures of the brain. If the tumor grows upwards, it presses on the optic chiasm. At this site the optic nerves that carry information about vision from the eyes to the brain from either eye cross each other. If the tumor presses on the optic chiasm, there may be vision problems and loss of vision.

Similarly if the tumor grows to its sides an area of the brain called the cavernous sinus may be encroached. This site contains several nerves that may be damaged.

Growth of the tumor also causes a derangement of other hormones produced by the pituitary gland. This can lead to problems like sexual dysfunction, loss of libido, abnormal menstruation and breast discharge in women. Thyroid hormone production may also be altered leading to underactive thyroids or hypothyroidism.

The adrenal gland functions of releasing hormone cortisol may also be affected if the pituitary gland functioning is altered. Decline in cortisol levels can cause weight loss, fatigue, low blood pressure etc. Excess secretion of other pituitary hormones like prolactin may be seen from the pituitary adenomas. Prolactin stimulates the breast to produce milk.

Most pituitary tumors develop on their own and are usually not linked to genes and are not inherited. The DNA of the pituitary cell may be altered to give rise to the tumor. This is called a mutation and is not present since birth. The mutation occurs in a gene that regulates the transmission of chemical signals and permanently switches on the signal that asks the cells to continue dividing uncontrolled.

Nonpituitary tumors

Acromegaly in very rare cases may also be caused by non-pituitary tumors. The other tumors include those of the lungs, pancreas, and other parts of the brain. These tumors also lead to excess GH, either because they produce GH themselves or because they produce GHRH that stimulates the pituitary to release GH.

If there is excess production of GHRH from these secondary tumors, the size of the pituitary may be increased leading to mistaken suspicion of a pituitary tumor.

Acromegaly has a slow course and symptoms often take months or even years to develop. If the condition is suspected, diagnostic tests are prescribed. The tests are outlined as follows.

Blood Tests

Blood tests are prescribed to detect the levels of growth hormone in the body. In persons with Acromegaly the levels of growth hormone is elevated.

For diagnosis, a single measurement of an elevated blood level of growth hormone is not enough. This is because normally this hormone is secreted by the pituitary in impulses or spurts and has several spikes and waves that may change the concentration in the blood from minute to minute. Thus those with Acromegaly may have normal levels of growth hormone at one point in time and someone who has normal pituitary function may have a level several times higher at the same point in time.

Thus to get an accurate idea about abnormal levels of growth hormone secretion the person is subjected to test conditions. Health care professionals often use the oral glucose tolerance test to diagnose Acromegaly.

In a normal person drinking 75 to 100 grams of glucose solution lowers blood levels of growth hormone to less than 1 nanogram per millilitre (ng/ml).  In those with Acromegaly and growth hormone overproduction this suppression does not occur. Thus the oral glucose tolerance test is a reliable method for confirming a diagnosis of Acromegaly.

Tests are also prescribed to measure blood levels of Insulin-like growth factor 1 (IGF-1). This level rises as the levels of growth hormone rises. Because IGF-I levels are much more stable than growth hormone throughout the day, screening for Acromegaly with IGF-1 levels is a more reliable method.

Elevated IGF-I levels almost always indicate Acromegaly. It must be remembered however that pregnancy causes a physiological rise in IGF-1 by two to three times and with age the IGF-1 levels decline. Levels may be low in persons with poorly controlled diabetes or liver or kidney disease.

IGF-binding protein-3 (IGFBP-3) is a protein that binds to circulating IGF in the body. When levels of IGF-1 are raised this protein levels also rises. This can be used in diagnosis of Acromegaly. Growth hormone-releasing hormone (GHRH) concentration can be estimated.

With involvement of the pituitary gland, other hormones may be affected. Assessment of these hormones including prolactin, adrenal, thyroid, and gonadal hormones may help detect abnormalities.

In addition, blood glucose, serum phosphate, and serum triglycerides may also be raised. Urine examination may reveal raised urinary calcium levels.

Imaging studies

After blood levels are found to be indicative of Acromegaly, imaging studies are prescribed. A magnetic resonance imaging (MRI) scan of the brain and pituitary gland especially is the first choice of investigation. This helps in detection of the location and size of the tumor.

MRI is the most sensitive imaging technique but as an alternative computerized tomography (CT) scans can be used.

In patients who have nonpituitary tumors elsewhere which are secreting growth hormone or Growth hormone releasing hormone (GHRH) a CT scan or a whole body MRI scan may be prescribed.

Total body scintigraphy with radio-labelled OctreoScan® (somatostatin) is prescribed in some patients for detection of these non-pituitary tumors.

Visual field tests

Visual field tests are conducted to see the extent of damage to the optic chiasma and the optic nerves.

Electrocardiogram and echocardiogram

Patients are screened for heart disease with Electrocardiogram and echocardiogram. Since there is a high risk of colon cancers and colonic polyps among Acromegaly patients, an assessment of the same is indicated.

Treatment of Acromegaly aims to reduce excess growth hormone, relieve the pressure that the tumour is exerting on the surrounding structures and thus improve symptoms of the disease. If not treated the condition may worsen and eventually lead to severe symptoms and death.

Treatment can be achieved in two manners – surgery or medications.

Surgical treatment

In most cases of acromegaly (85%) the cause of the condition is an adenoma in the pituitary gland. This is a non-cancerous and benign tumor but can press upon surrounding vital structures of the brain causing severe symptoms such as vision loss.

Surgery is undertaken to remove this tumor. Sometimes the tumour is too large to be removed completely. Removal of a pituitary adenoma is usually undertaken under general anaesthesia wherein the patient is made unconscious during surgery. The surgeon will make an incision though the nose or inside the upper lip to access the gland. The tumor is then removed and this may cause a dramatic relief of pressure on the surrounding structures and a lowering of growth hormone levels.

Trans-sphenoidal surgery is the treatment of choice in most cases. It has a remission rate or cure rate of 80-85% for microadenomas and 50-65% for macroadenomas. Patients may need drug treatment after surgery in order to reduce growth hormone levels.

In most cases surgery is the successful treatment if the tumor is not too big. After surgery there may be some soft tissue swelling and bruises that may disappear in a few days.

Although successful, pituitary surgery is a complex one and may lead to several complications like damage to the healthy parts of the pituitary gland, leakage of cerebrospinal fluid, bleeding and infection etc.

Radiation therapy for acromegaly

If the pituitary tumor is large and surgery is not possible, the tumor may be shrunk using radiation therapy. Radiation therapy has one disadvantage: reduction in growth hormone levels after radiation is very slow.

In addition, there is a risk of damage to the whole gland which may cause a gradual decline in the production of other hormones from the gland. This necessitates hormone replacement therapy for the rest of the patient’s life. Also, due to effects on the reproductive hormones from the pituitary, radiation may cause infertility.

Radiation may be given as conventional form where the tumour is targeted with external beams. The patient needs to attend the office of the radiologist to receive the radiation from a large X ray like machine in small doses over four to six weeks. Weekends are let off to allow normal tissues to heal. This type of radiation causes damage to the structures surrounding pituitary gland and brain tissues.

Radiation may also be given as stereotactic delivery. In this method high-dose beam of radiation can be precisely aimed at the tumour. The head is kept still by wearing a rigid head frame. The beam kills the tumors cells usually in a single session.

Pharmacotherapy or use of medications for treatment

Medications used in treatment of acromegaly include:-

• Bromocriptine or cabergoline suppress growth hormone production. These are however effective in a small number of patients. These are dopamine agonists.
• Octreotide or lanreotide control growth hormone release and also lead to shrinkage of the pituitary tumor in one third of the acromegaly patients. These are somatostatin analogues. Somatostain inhibits the release of growth hormone normally in the body. These are given as intramuscular injections once a month. These can be safely used over long term.
• Pegvisomant directly blocks the effects of growth hormone and can improve symptoms. It is a genetically modified analogue of human growth hormone and is a selective growth hormone receptor antagonist. It can lower the IGF-1 in 90 to 100% patients. This is given as once daily injections. Growth hormone levels increase during treatment and no decrease in tumour size is seen. Pegvisomant is licensed for the treatment of acromegaly in patients with inadequate response to surgery, radiotherapy or somatostatin analogues.

Acromegaly can cause several complications if left untreated. These complications, like the symptoms of the disease, are gradual in onset and may take months or years to develop.

Vigilance regarding these complications is part of management of acromegaly. Some of the complications include:-

• Heart disease – acromegaly increases the risk of ischemic heart disease leading to a worsening of risk of heart attacks and angina. Risk of heart failure also rises with enlargement of the heart and imbalance between demands of the body to the capacity of the heart to pump blood.
• Stroke risk is also raised in persons with acromegaly.
• The risk of diabetes mellitus rises to a great extent among those with acromegaly.
• Pregnant women with acromegaly have a heightened risk of developing gestational diabetes and pregnancy induced hypertension or high blood pressure. This may raise the risk of preterm birth or still birth.
• Those with acromegaly are at risk of arthritis and joint pains as well. This is called Acromegalic arthropathy and affects up to 70% of patients. Both the axial and peripheral skeleton may be affected. This involves the spine as well as the joints of the limbs. Due to compression of nerves of the hand, patient may develop Carpal tunnel syndrome.
• Due to overgrowth of structures of the back of the throat and tongue there may be development of Obstructive sleep apnoea and this leads to interrupted sleep.
• There is a high risk of development of colonic polyps. These polyps, if not detected early and removed, may go on to form adenocarcinoma of the colon or bowel cancer. Those with acromegaly thus require early and regular screening for bowel cancer.
• A pituitary tumor may cause increase in secretion of the hormone prolactin by the pituitary gland. There may be additional deficiencies of cortisol, thyroid hormone production and sex steroids due to the defects in pituitary hormone production.
• As the pituitary tumor grows, it may press upon the optic chiasm. This optic chiasm is a junction point where the optic nerves from both eyes converge. As the chiasm is pressed, there may be severe impairment of vision. The loss of vision typically affects the outer visual fields and is called bitemporal hemianopia.

• Severe headache may be seen as a complication of acromegaly.
• As a complication of surgery or radiation therapy, acromegaly patients may develop hypopituitarism. This leads to severe decline in hormones secreted by the pituitary. These may require replacement usually for life.
• There is a risk of developing kidney failure.