Acromegaly: Tumor causes rare giant growth

A benign tumor in the pituitary gland ensures that too many growth hormones (German: somatotropin – STH – or English: human growth hormone – HGH or GH) are formed. GH not only regulates the child’s growth, but also has an important function in the fat, blood sugar and protein metabolism in healthy adults. Its secretion from the pituitary gland is normally subject to a feedback loop that ensures that neither too much nor too little hormone gets into the blood. Here are two major hormones from the basal hypothalamus – the brain part, which is directly above the pituitary gland – regulate the secretion of growth hormone:

• Somatoliberin (English: growth hormone-releasing hormone or GHRH), which has an activating effect on the production of the growth hormone
• Somatostatin (English: growth hormone-inhibiting hormone or GHIH), which has an inhibitory effect on the production of growth hormone

However, in acromegaly, the benign pituitary adenoma (an adenoma is a tumor consisting of glandular tissue) autonomously forms excess growth hormone. If such a benign pituitary tumor develops in the child or in adolescents before the completion of bone growth, the picture of gigantism (giant growth) develops.

Another role for acromegaly is the insulin-like growth factor IGF-1 (insulin-like-growth-factor-1). IGF-1 is produced in the liver under the influence of the growth hormone GH and gets into the blood from there. IGF-1 mediates much of the effects of GH, for example, in bone tissue and muscle. Most symptoms of acromegaly are caused by an increased concentration of IGF-1.

Is acromegaly inheritable?

Multi-generational familial acromegaly is extremely rare, more common is familial multiple endocrine neoplasia (MEN) type 1, a disorder in which, in addition to pituitary tumors, parathyroid and pancreatic tumors also occur.

Virtually all the pancreatic changes in the pituitary gland are benign tumors. This means that the tumor does not expose any secondary tumors in other parts of the body, ie it is locally limited and usually also grows slowly. However, this fact does not change the fact that treatment is essential, as otherwise a severe deterioration in quality of life and a reduction in life expectancy must be expected.

When hands, feet and genitals get bigger and bigger: symptoms of acromegaly

The change in the external appearance – such as the growth of the hands and feet as well as the genitals, the coarsening of the facial features, very pronounced zygomatic arches and malocclusions – is certainly the most conspicuous sign of acromegaly. At first unnoticed often remains that the excess of growth hormone affects the entire organism, which can lead to serious symptoms over time.

The most common symptoms at a glance:

• Enlargement of the hands; usually noticeable when finger rings become too tight
• Also the feet are getting bigger and bigger, which sufferers often discover that shoes are no longer fit.
• Enlargement of the genitals
• coarsened facial features
• Malocclusions
• Speech disorders due to enlargement of the tongue
• Joint problems and limited mobility
• Numbness and tingling in the hands
• irregular menstrual bleeding
• a headache
• Diabetes mellitus (diabetes)
• heart disease
• Vision problems, limitations of the visual field
• Snoring ; Breathing disorders during sleep ( sleep apnea )
• Loss of sexual desire and impotence
• increased blood pressure
• excessive sweating

These symptoms rarely occur at the same time. However, many of these severely affect health and quality of life and, at worst, shorten life expectancy.

The symptoms of acromegaly initially remain inconspicuous. As the disease progresses slowly and is also very rare, an average of nine years elapse from the onset of the first symptoms to diagnosis. During this time, those affected fight with diffuse and for them inexplicable symptoms that can significantly limit everyday life and even lead to occupational disability.

Problems with the bit and unpleasant body odor

So many complain about rapid fatigability, decreased exercise capacity, lack of concentration and general malaise. The face typically shows a prominent chin, an enlarged nose and pronounced lips and cheekbones. However, these changes are usually imperceptible and often only occur to people with acromegaly, because their shoes are too small, and finger rings and hats are no longer suitable.

Since the jaw also continues to grow, an increasing malposition of the dentition with corresponding orthodontic problems becomes noticeable. Those affected can have difficulty feeding, as biting through the displaced rows of teeth becomes more difficult. Even a denture that no longer fits properly, is sometimes an indication of acromegaly. This explains why the dentist is often visited first to clarify the corresponding abnormalities. For many, the changes in the outer body shell are also very unpleasant: the skin becomes thicker and darker, and the body hair becomes denser. The sweat and sebaceous glands of the skin increase in size and produce more sweat. Therefore, it often comes to disturbing body odor.

Breathing, heart and circulation are affected

As the tongue, larynx and parts of the nose grow along with the lips and jaws, breathing becomes more difficult over time. Very often, sleep apnea syndrome occurs, in which sufferers – almost always snoring – suffer from nocturnal respiratory arrest, lasting more than ten seconds. These breathing pauses can occur up to 300 times in one night and thus disturb the nocturnal recovery. Increased daytime fatigue and high blood pressure are often the result. The cardiovascular system is also burdened by an enlarged heart, which can be found in almost three quarters of all patients. Cardiac arrhythmias and heart failureas a result, are a serious threat to those affected. The sooner an acromegaly is treated, the sooner the changes in the heart can be stopped.

The skeletal system also suffers

The afflicted also plague a number of painful symptoms. After all, acromegaly also leaves its mark on the joints, which swell and become stiff as a result of the loss of cartilage. For many, this is even the first sign of the disease, as the painful joints often limit the quality of life of patients even more than the other changes. With the joint complaints the so-called carpal tunnel syndrome is closely linked. This swells the median nerve, which pulls through the carpal tunnel from the arm to the hand. The result can be burning pain, emotional distress and even muscle atrophy if no treatment is given. About half of those affected also suffer from back pain.

Hormone balance gets out of balance

Last but not least, people with acromegaly suffer from altered metabolism and impaired hormone regulation. It can be an elevated blood sugar levelto diabetes (diabetes mellitus) occur because the growth hormone is an antagonist of the blood sugar-lowering insulin and thus increase the blood sugar level. The pressure of the tumor on the healthy parts of the pituitary gland also disturbs the hormonal control circuits and can lead to loss of libido, menstrual disorders and hypofunction of the adrenals or thyroid gland. The local pressure effect of the tumor is expressed by headaches or – if it is already particularly large – an impairment of the optic nerve with tunnel vision, possibly even threatens the loss of vision. After successful treatment of acromegaly usually also many of the sequelae soon after, if they are not yet advanced.

Diagnosis: Acromegaly is often recognized late

The sooner the treatment starts and the smaller the tumor, the higher the chance of curing acromegaly. In most cases, the first suspected diagnosis is made by a general practitioner when patients come to him with one of the acromegaly-typical symptoms and no other cause can be found. Dentists, orthodontists or surgeons are also at the forefront of the diagnosis of this rare disease.

In order to clarify whether a disorder of the pituitary function is responsible for the symptoms and there is an acromegaly, then a specialist in hormone diseases, an endocrinologist, is used. This will first check the medical history ( anamnesis ) and ask about the first appearance and the development of the complaints. Subsequently, he will initiate a general physical examination and various general laboratory tests of blood and urine .

Blood values ​​as proof of acromegaly

Special laboratory tests provide definite assurance of a possible acromegaly disease. Among other things, the endocrinologist determines the concentration of the growth hormone GH in the blood. However, since the growth hormone in the body is not distributed evenly, but is ejected jerky, individual measurements have little relevance. If acromegaly is suspected, the so-called glucose load test (also OGTT : oral glucose tolerance test) is carried out, which allows a reliable statement about the GH levels.

In the glucose load test, the patient drinks a certain amount of glucose solution. Subsequently, the concentration of GH and glucose in the blood is measured at certain intervals. Only in healthy people does glucose lead to a reduction in growth hormone levels. With existing acromegaly this reduction is missing. This proves the autonomous growth hormone secretion and thus the acromegaly.

As the growth hormone stimulates the growth of the growth factor IGF-1 in the liver, the concentration of IGF-1 in the blood is also determined to ensure the diagnosis. The measurement of IGF-1 levels is important not only for diagnosis but also for the follow-up of acromegaly.

MRI makes the tumor visible

Should laboratory tests confirm the suspicion of acromegaly, imaging techniques such as magnetic resonance imaging ( MRI ) will be used to further validate the diagnosis. The pituitary gland and surrounding tissue are displayed and recorded in layers, so that even minimal deviations become visible. Unlike computed tomography ( CT ), MRI is more accurate. The patient is not exposed to radiation during MRI. The examination is painless, but some patients find the long lay time of about an hour unpleasant.

Treatment of acromegaly: surgery, medication or radiation?

Although acromegaly is based on a benign tumor that does not expose to secondary tumors and therefore only grows locally, therapy is essential because of possible sequelae. The vast majority of patients with acromegaly can be treated successfully today. The aim of the measures is to normalize the excessive secretion of the growth hormone GH or of the growth factor IGF-1. There are three options for this:

• Surgery,
• Medicines or
• Irradiation.

Surgery offers good chances of recovery

Surgery remains the most important treatment for acromegaly today. More than three-quarters of all patients with tumors smaller than one centimeter in diameter (microadenoma) are completely healed of their acromegaly after surgery, provided the procedure is performed by an experienced surgeon.

Due to the position of the pituitary behind the root of the nose, a surgical technique was developed on the way through the nose almost 90 years ago (transsphenoidal surgery). Since about 1974, the further development of the surgical microscope and a special instrumentation led to this method being able to prevail. It takes place under general anesthesia and is painless.

With transsphenoidal surgery, it is now possible to remove pituitary tumors very gently and to maintain the healthy tissue of the pituitary gland as far as possible. Only in a few cases do complications occur after removal of the pituitary tumor. Possible after the surgery slight headache and a swollen nasal mucosa. Air travel is not recommended one month after the procedure.

Larger tumors, so-called macroadenomas, whose diameter is more than one centimeter, can only rarely be completely removed. Growth hormone levels do not normalize at incomplete removal. In this case of acromegaly is also a drug therapy, possibly also a radiotherapy , necessary.

Drugs block growth hormones

In acromegaly, drug therapy is either used prior to surgery to stem growth hormone production, or when a larger tumor can not be completely removed and remains “active.” In addition, drugs are an alternative when surgery is not possible or promising for a variety of reasons.

For drug therapy of acromegaly three substance classes are available. Treatment may be performed with either somatostatin analogs or dopamine agonists, as well as failure of the foregoing with GH receptor antagonists. Overall, somatostatin analogues were found to be significantly more effective than acromegaly dopamine agonists. All therapies have in common that the treatment usually has to be permanent. The discontinuation of the medication occurs only with intolerance reactions or when the desired effect and disease control is not or no longer achieved.

Somatostatin analogues 

Somatostatin analogues are considered the drug of choice in the treatment of acromegaly today. In Germany, two different somatostatin analogues are available: octreotide and lanreotide.

Drug therapy with a somatostatin analog leads to an effective symptom treatment of acromegaly. Headaches improve within a few hours and tissue swelling becomes visible after two to four days. A reduction in growth hormone levels is achieved in 80 to 95 percent of patients with acromegaly, and a reduction below the important threshold of 2.5 micrograms / liter is achieved in about two-thirds of patients with octreotide. Furthermore, therapy with somatostatin analogs may lead to a reduction of the pituitary tumor.

The predominant side effects of somatostatin analogues in the treatment of acromegaly patients are transient gastrointestinal complaints. In some cases the formation of gallstones has been reported during long-term treatment. Therefore, ultrasound examination of the gallbladder should be performed regularly every three to six months. When semolina occurs in the gallbladder, dissolving with bile acids is usually successful.

Dopamine agonists 

A reduction in growth hormone secretion by a tablet-based dopamine agonist is achieved in about 30 to 50 percent of patients – however, complete control of disease can only be achieved in 10 to 20 percent of patients with acromegaly. Therefore, dopamine agonists are no longer used so often in acromegaly today. In order to regulate excess GH production, high doses are usually required, so that various quality of life-affecting side effects such as nausea , drop in blood pressure, fatigue and poor concentration often occur.

GH-receptor antagonists

A growth hormone receptor antagonist (also GH receptor antagonist) such as the active ingredient pegvisomant has a high binding affinity to the growth hormone receptor. The GH receptor antagonist blocks the binding site and thus competes with the physiological growth hormone. Normally, the binding of the hormone to the receptor triggers signals that are transmitted to the cell interior, where among other things to the formation of IGF-1, which is responsible for the symptoms of acromegaly lead. If an antagonist occupies the binding site at the GH receptor, no signal transmission takes place and IGF-1 is not formed. Thus, GH receptor antagonists can mitigate the signs of acromegaly. The GH receptor antagonist is approved in Germany for the treatment of acromegaly in patients,

Radiotherapy 

It is also called radiotherapy and is used in acromegaly only when a patient may not be operated on because of other diseases or if the tumor is too large and could not be completely removed. The X-rays are directed to the diseased tissue in such a high dose that the cells can no longer divide and multiply. Gradually they all die. Accordingly, the tumor slowly shrinks. The effect occurs only over the course of years. A complete cure of acromegaly is usually not achieved, so patients need to take additional medication. 

As a result of radiotherapy may weaken the normal pituitary gland function and rarely an optic nerve damage occur in the long term there is an increased risk of strokes. As a rule, radiotherapy is the third-choice drug if there is no symptom-free operation and medication. However, in many cases it is a useful alternative, for example, if surgery can not be performed, the tumor could not be completely removed by surgery, or the patient does not respond to medication.

Course: How does acromegaly affect life expectancy? 

The life expectancy for acromegaly is statistically shorter than for the healthy metabolism, but the difference is not very large overall. Crucial is whether the growth hormone and IGF-1 are normalized by surgery or drug therapy. If successful, life expectancy is normal. However, if growth hormone and IGF-1 are elevated and, in addition, high blood pressure, diabetes or cardiac insufficiency occur, life expectancy can be shortened, in some cases considerably. 

In many acromegaly patients, the cardiovascular system is affected during the course of the disease. With timely therapy, this process can be reversed, especially in younger patients. The excess of growth and other hormones also upsets the metabolism of acromegaly patients. Those affected are prone to diabetes, high blood lipid levels and high blood pressure – all of which are risk factors for arteriosclerosis, which in the worst case can lead to a heart attack or stroke .