Changes in the face due to an excess of growth hormone: acromegaly-man-same-healthy-
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The essence in brief.
Acromegaly is a condition caused by a benign tumor in the pituitary gland that produces excessive growth hormones. This leads to various physical changes and symptoms such as enlargement of facial features, hands, and feet, as well as organ enlargement. The tumor can also affect vision and hormonal balance. Symptoms develop slowly over time, and patients may experience headaches, numbness, tingling, and excessive sweating. Treatment is necessary to alleviate symptoms and prevent complications.
The tumors of the pituitary gland are almost all benign, meaning they do not form metastases and grow very slowly. If they produce hormones, treatment of these benign tumors is necessary as these hormones cause symptoms. If they do not produce hormones, they can be observed initially as long as they do not cause symptoms. However, if they grow, they can press on the optic chiasm (the crossing point of the optic nerves) and lead to visual field defects or interfere with the secretion of other hormones from the pituitary gland. In this case, they also need to be treated.
Acromegaly is a benign pituitary tumor that produces an excess of growth hormones (somatotropic hormone STH). The tumor can press on the optic chiasm, causing visual disturbances. This results in the loss of the outer upper quadrants of the visual field. The growth hormone stimulates the production of growth factors, such as insulin-like growth factor 1 (IGF-1), in the liver. These factors mediate many effects of the growth hormone, including skeletal growth. Long bone growth can only occur during childhood and adolescence when the growth plates have not yet ossified. In adulthood, longitudinal growth no longer takes place. However, the overproduction of growth hormones from a tumor has negative effects on the body. It leads to enlargement of the eye ridges and protrusion of the forehead. The nose, lips, and tongue also increase in size. Additionally, the lower jaw grows, and gaps between the teeth form. The growth hormone also affects the thyroid gland, leading to its enlargement, often with nodules, known as nodular goiter. It also affects internal organs, resulting in enlargement of the heart, liver, adrenal glands, thickening of the intestinal wall, and the formation of polyps in the colon. It stimulates growth in the hands and feet, causing an increase in shoe size. This leads to joint discomfort and limited mobility. Indirectly, the tumor can influence other functions of the pituitary gland and result in decreased production of luteinizing hormone (LH), for example. LH is the hormone that stimulates the production of the male sex hormone (testosterone) in men. If LH secretion is reduced due to the tumor in the pituitary gland, testosterone levels will decrease, and the man will become impotent. Conversely, it will cause ovarian dysfunction in women, resulting in irregular menstrual bleeding, among other symptoms. Other symptoms and complaints in patients often include headaches, numbness and tingling in the hands, and excessive sweating. These symptoms and changes do not occur suddenly but develop slowly and often go unnoticed, causing patients to suffer from their symptoms for years before a diagnosis is made and appropriate treatment can be initiated.
Due to the aforementioned symptoms, the general practitioner may suspect “acromegaly” and refer the patient to an endocrinologist, a specialist in hormonal disorders. Menstrual irregularities or erectile dysfunction are often reasons for referral. In most cases, an experienced endocrinologist can recognize the condition by the appearance of the patient. After carefully questioning the symptoms and conducting a thorough physical examination, the endocrinologist will likely be quite certain that it is acromegaly. To further confirm the suspected diagnosis, laboratory tests will be performed to measure growth hormone levels and insulin-like growth factor 1 (IGF-1). Growth hormone does not directly affect organs but acts indirectly by increasing the production of IGF-1. IGF-1 is a hormone primarily produced in the liver, stimulated by growth hormone, and responsible for most of its effects. If the diagnosis is still not definitive, a glucose tolerance test, also known as an oral glucose tolerance test, will be conducted. Patients drink a solution of glucose, and blood levels of growth hormone are measured at specific intervals. The rise in blood glucose levels normally suppresses the secretion of growth hormone from the pituitary gland, leading to a decrease in its levels in the blood. In patients with acromegaly, this suppression does not occur, and growth hormone levels remain elevated. After these investigations, the diagnosis of “acromegaly” is typically confirmed. The following tests are necessary to plan the next steps.
The essence in brief.
Before treatment, additional investigations are conducted to assess the impact of the pituitary tumor on hormone secretion and determine the size and location of the tumor using MRI. Other tests include a visual field examination, ultrasound of the thyroid gland, cardiac evaluation, abdominal ultrasound, and colonoscopy to assess the effects of acromegaly on various organs. These investigations help guide the treatment plan and assess potential complications associated with the condition.
Before initiating treatment, it is necessary to determine the extent to which the tumor has affected other hormone secretions from the pituitary gland. For this purpose, a comprehensive evaluation of pituitary gland function is conducted. The size of the tumor is determined using magnetic resonance imaging (MRI) of the pituitary gland. This imaging technique provides layered images of the pituitary gland and the surrounding tissues at intervals of a few millimeters. The size of the pituitary tumor can be measured based on the images obtained. It is considered a macroadenoma if the diameter is over 1.0 cm, and a microadenoma if it is <1.0 cm. Although 1.0 cm may not be considered particularly large by our standards, the pituitary tissue has very little space within its bony sella turcica boundary, making a 1.0 cm adenoma large for the pituitary gland. The location of the tumor can also indicate whether it poses a risk to the crossing of the optic nerves. A visual field examination is performed by an ophthalmologist to determine if there are any visual field defects. Additionally, further investigations are usually ordered to assess the effects of acromegaly. An ultrasound of the thyroid gland is performed to measure its size and identify the presence of nodules. The cardiologist will assess whether there is thickening of the heart muscle, which increases the risk of cardiac arrhythmias. This is particularly important since untreated patients with acromegaly often die from cardiac arrhythmias. The thickening of the heart muscle can lead to atrial fibrillation-associated thromboembolism, where blood clots form in the heart and can then be released into the bloodstream, potentially causing blockages in cerebral arteries and resulting in a stroke. To assess the impact of growth hormone on internal organs, an abdominal ultrasound is conducted to measure the size of the liver, spleen, and other internal organs. As growth hormone can promote the formation of polyps in the colon, a colonoscopy should also be performed.
The primary treatment method for acromegaly is the removal of the pituitary tumor through surgery. For tumors <1.0 cm, the success rate in specialized neurosurgical centers is around 95%, while for macroadenomas, it is approximately 45%. Initially, the idea of undergoing skull/brain surgery may sound frightening to patients. They may be afraid of potential permanent damage and believe that brain surgery is a complex and arduous procedure with a long recovery period. However, this is not the case with pituitary surgery. The operation is performed painlessly for the patient, and they can already get up and move around the day after the surgery. Typically, patients are discharged 3-4 days after the operation. Therefore, the surgery is generally not highly burdensome for the patient.
How is the operation performed?
The essence in brief.
Pituitary surgery is typically performed through a procedure known as transsphenoidal surgery, which involves accessing the pituitary gland through the nose. After pituitary surgery, hormonal replacement therapy may be required to replace deficiencies in hormones such as testosterone and cortisol. Lifelong replacement therapy is necessary in cases of permanent pituitary axis failure. Additionally, postoperative follow-up examinations are conducted to ensure complete tumor removal and normal levels of growth hormone and IGF-1. Imaging techniques such as MRI are used to detect any recurrence of pituitary adenoma.
Today, pituitary surgery is typically performed through a procedure known as transsphenoidal surgery, which involves accessing the pituitary gland through the nose. This transsphenoidal approach can be used in over 95% of cases.
Before the operation, endocrinological evaluations are conducted to assess the functioning of other hormone secretions from the pituitary gland. Additionally, a visual field examination is performed to assess any visual impairments. Other routine preoperative tests, such as an electrocardiogram (EKG) and chest X-ray, are also conducted, as is the case with any surgery requiring anesthesia. For most patients, the operation is primarily a psychological burden, often due to the waiting period leading up to the surgical date. Having a clear understanding of the operation and how it is performed can help alleviate fears.
During transsphenoidal surgery, the nasal passage and parts of the nasal sinuses are used as the pathway to reach the sphenoid sinus located beneath the middle skull base. Typically, an incision is made below the upper lip to access the nasal cavity. Within the facial skull, there is a system of cavities, and beneath the pituitary gland lies the sphenoid sinus. The sphenoid sinus is accessed through the nasal cavity, providing entry to the sella turcica where the pituitary gland is located. For this operation, a specially designed microsurgical suction/irrigation system consisting of mirrors and an operating microscope is used. With this instrument, the surgeon can work slowly and precisely while visualizing the pituitary gland. The optic system allows for differentiation between tumor tissue and healthy pituitary tissue. The tumor tissue is then suctioned out using the irrigating suction device. This highly advanced instrument allows the surgery to be performed with great precision and minimal damage to healthy tissue. In most cases, the tumor tissue can be completely removed without harming surrounding healthy tissue. Once the tumor tissue has been completely suctioned out and the surgical area has been thoroughly irrigated, it is sealed with a transplant graft obtained from the patient’s thigh. The incision below the upper lip is closed using absorbable materials, and the nose is packed to prevent deformation of the nasal septum. Typically, the nasal packing can be removed one day after the procedure. There are no visible signs of the head surgery externally following the procedure. Occasionally, patients may experience mild headaches or swelling of the nasal mucosa after the operation, but these symptoms generally subside within a few days. During the first four weeks after the operation, it is advised to avoid air travel and travel to high altitudes to prevent significant pressure fluctuations in the nasal sinuses. Diving should also be avoided. The procedure is performed in such a gentle manner that, in most cases, patients can be discharged 3-4 days after the surgery. This indicates that the procedure is not highly burdensome for the patient, even though the surgical technique is complex and should only be performed by neurosurgeons with significant experience in pituitary surgery.
After the operation, a complete assessment of pituitary function must be conducted to determine if any damage has occurred and whether any hormones are deficient. If hormonal deficiencies are identified, hormone replacement therapy must be initiated. However, it is important to note that the pituitary hormones themselves cannot be replaced; instead, the hormones produced by the glands controlled by the pituitary gland must be replaced. For example, if thyroid-stimulating hormone (TSH) is no longer secreted, thyroid hormone replacement therapy is required. Similarly, if luteinizing hormone (LH) is no longer adequately secreted due to the surgery, testosterone replacement therapy is required. If adrenocorticotropic hormone (ACTH) is no longer adequately produced by the pituitary gland, cortisol replacement therapy is necessary as cortisol is produced by the adrenal glands. Such replacement therapy is lifelong and essential in cases of permanent failure of the pituitary axis. Furthermore, it is important to assess the functioning of the water-electrolyte balance and ensure that the posterior pituitary lobe is not damaged. Above all, it is crucial to verify if the tumor has been completely removed and if growth hormone and IGF-1 levels are within normal range. In such cases, no further treatment for acromegaly is necessary. However, occasional follow-up examinations are still conducted. Imaging techniques such as MRI are used to check for the presence of recurrence, which refers to the development of a new pituitary adenoma.
As an alternative to surgery, radiation therapy can be used to treat pituitary tumors. This option is considered when the patient is not suitable for surgery, refuses surgery, or if the tumor could not be completely removed during surgery due to its size. Radiation therapy is computer-controlled, administered over multiple sessions, and can be highly precise. In addition to conventional radiotherapy, treatment can also be performed using techniques such as the “Gamma Knife” or linear accelerators (LINAC), which have increased accuracy and effectiveness. However, it is possible that healthy pituitary tissue may be damaged by radiation therapy. This can result in pituitary insufficiency with the loss of various hormones, as described above. The effects of radiation therapy are not immediate; it may take months or even years to achieve complete effectiveness. During this time, the patient may require medication to manage symptoms.
The essence in brief.
In cases where complete tumor removal is not possible, medication is used to treat acromegaly. The available treatment options include dopamine agonists, somatostatin analogs, and growth hormone receptor blockers. Dopamine agonists can reduce growth hormone secretion but may require high doses and have significant side effects. Somatostatin analogs, administered through injections, effectively lower growth hormone levels and improve symptoms. They are generally well-tolerated, although some gastrointestinal side effects may occur. Growth hormone receptor blockers prevent growth hormone from binding to its receptors, leading to a decrease in IGF-1 levels. These medications offer alternative approaches to surgery and can effectively manage acromegaly symptoms.
In some cases, the tumor may be too large to be completely removed through surgery. In such situations, treatment with medication is necessary to prevent further damage from growth hormone. Currently, three different classes of substances are available for the treatment of acromegaly.
Dopamine agonists
For a portion of patients (30-50%), a reduction in growth hormone secretion from the pituitary tumor can be achieved with dopamine agonists. This is the cheapest and simplest therapy as dopamine agonists are available in tablet form. However, high doses of dopamine agonists are often required to control growth hormone production. These medications have a high rate of side effects, making it difficult to achieve sufficient suppression of growth hormone. Unfortunately, only about 20% of patients experience an adequate response to this treatment. Therefore, the preferred treatment for acromegaly today is usually with a somatostatin analog.
Somatostatin analogs
The hormone somatostatin is an antagonist of growth hormone and inhibits its release. However, somatostatin itself has a very short duration of action and cannot be taken orally as it is digested in the stomach. To address this, somatostatin analogs have been developed. These analogs have a longer duration of action and can be administered subcutaneously (under the skin) or intramuscularly. Octreotide or lanreotide are somatostatin analogs that can significantly lower growth hormone levels. Patients experience an improvement in symptoms within a few hours. Octreotide is available in various forms. It can be self-administered by subcutaneous injection into the abdomen, similar to insulin treatment. There are also depot preparations that are injected into the muscle and released slowly, requiring injections only every 4 weeks. Somatostatin analogs are generally well-tolerated. Side effects may include gastrointestinal symptoms, especially oily stools in the initial period as pancreatic function may be slightly inhibited. However, these side effects usually resolve in most cases. An increased occurrence of gallstones can be a potential complication, necessitating occasional ultrasound examinations. In some cases, supplemental therapy with bile acids may be required. The dosage of somatostatin analogs is adjusted to normalize IGF-1 levels as much as possible.
Growth hormone receptor blockers
In addition to somatostatin analogs, growth hormone receptor blockers can also be used. Growth hormone does not exert its effects directly; it must first bind to a receptor on the cell surface, triggering its actions. The receptor blocker pegvisomant prevents growth hormone from binding to this receptor, thus blocking the effects of growth hormone and lowering IGF-1 levels.
Acromegaly: An Endocrine Society Clinical Practice Guideline,
Laurence Katznelson, Edward R. Laws, Shlomo Melmed, Mark E. Molitch, Mohammad Hassan Murad, Andrea Utz, John A. H. Wass, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 11, 1 November 2014, Pages 3933–3951, https://doi.org/10.1210/jc.2014-2700