ACROMEGALY - also known as pituitary gigantism is caused by a pituitary neoplasm made up of growth hormone releasing cells called somatotrophs which lead to excessive production of growth hormone (GH) by the pituitary gland. About 95% of all Acromegaly cases are caused by this benign pituitary adenoma. It is most prevalent in the adult age group between 30 years and 50 years. If the onset of the disease is before the time a child stops growing the condition is specifically referred to as Gigantism.
In very rare cases hypothalamic tumors may lead to overproduction of growth hormone releasing hormone (GHRH) which also triggers unregulated production of GH by the pituitary hence Acromegaly ensues. Other rare causes are ectopic GHRH from nonendocrine tumors and ectopic secretion of GH by nonendocrine tumors. The symptoms of Acromegaly develop insidiously over a long period of time before they become prominent. Because of this patients live with Acromegaly for years before diagnosis.
Typical Signs and symptoms
There are many other symptoms which were not included in the list above. The symptoms manifest differently in different people and patients may show a few of the symptoms above.
Diagnosis
Acromegaly is diagnosed by conducting what they call oral glucose tolerance test (OGTT). The Physician gets the patient to fast over night and blood samples are taken the next morning to measure blood glucose levels. The patient is given 75g of glucose by mouth a few minutes before blood samples are taken. The ingestion of sugar glucose normally suppresses blood GH levels to less than 2ng/ml in healthy people. In patients with excessive GH production, the blood GH levels remain higher than 2ng/ml. Suppression test as OGTT is alternatively called is the most reliable method of confirming a diagnosis of Acromegaly.
The physician can also measure IGF-1 levels in patients with suspected Acromegaly. Elevated GH levels increase IGF-1 blood levels. However IGF-1 levels are a more reliable measure as they are much more stable over the course of the day than GH levels which vary from one minute to another because the pituitary releases GH into the blood in spurts.
After OGTT results have indicated positive for Acromegaly, the next step is to locate the position of the tumor through imaging techniques. An X-ray of the pituitary fossa may be taken which normally shows an enlarged pituitary fossa in cases of pituitary tumors Computed Tomography scanning (CT) or Magnetic Resonance Imaging (MRI) may be used to get a much better visualization of the tumor without surgery. If the scans indicate absence of pituitary tumor the physician the looks for non-pituitary tumors in the chest, abdomen or pelvis as possible cause for excess GH.
Treatment options
The available treatment options for Acromegaly include surgery, medical therapy and radiation therapy. Patients may receive one of these treatments or a combination of two or more treatments depending on the severity of the case. People with macroadenomas usually need a combination of these treatments .
Surgery
The Role of Surgery
The goals of surgery, as with all Acromegaly therapies, include normalizing GH and IGF-1, eliminating mass effect from the tumor, and alleviating associated morbidities Additional goals of surgery include preserving normal pituitary function, preventing recurrence of the tumor, and obtaining tissue for analysis. Advantages of surgery include rapid lowering of GH and the possibility of cure. Limitations include lower success rates with larger invasive tumors and/or less experienced surgeons. The guidelines recommend that surgery be considered as the first therapeutic option in all patients with Acromegaly. Patients with mass effects will require surgery on an urgent basis. For patients not eligible or unwilling to undergo surgery, medical therapy can be selected.
Effectiveness
Several factors need to be considered in the surgical management of Acromegaly:
Surgical resection of the adenoma when not contraindicated is the initial treatment for Acromegaly. Contraindications include:
Patients who are poor surgical or anesthesia risks because of age or poor general health.
Patients who delay surgery because they want to maintain pituitary function, e.g., women who want to become pregnant.
Patients who refuse surgery.
Cure rates reach 90% in patients with small, well-defined microadenomas (size < 10 mm), and surgery provides rapid symptomatic relief .Cure rates for patients with macroadenomas (size >10 mm), which comprise the majority of GH tumors, are only 48% .Relapse may occur with macroadenomas, particularly those with extrasellar growth, after an initial improvement or apparent cure because of incomplete removal of tumor tissue .
Surgery is the first option recommended for most people with Acromegaly, as it is often a rapid and effective treatment. The surgeon reaches the pituitary via an incision through the nose or inside the upper lip and, with special tools, removes the tumor tissue in a procedure called Transsphenoidal surgery. This procedure promptly relieves the pressure on the surrounding brain regions and leads to a rapid lowering of GH levels. If the surgery is successful, facial appearance and soft tissue swelling improve within a few days.
Surgery is most successful in patients with blood GH levels below 45 ng/ml before the operation and with pituitary tumors no larger than 10 millimeters (mm) in diameter. Success depends in large part on the skill and experience of the surgeon, as well as the location of the tumor. Even with the most experienced neurosurgeon, the chance of a cure is small if the tumor has extended into critical brain structures or into the cavernous sinus where surgery could be risky.
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-I levels. The overall rate of remission control of the disease after surgery ranges from 55 to 80 percent.
A possible complication of surgery is damage to the surrounding normal pituitary tissue, which requires lifelong use of pituitary hormone replacement. The part of the pituitary that stores antidiuretic hormone a hormone important in water balance—may be temporarily or, rarely, permanently damaged and the patient may require medical therapy. Other potential problems include cerebrospinal fluid leaks and, rarely, meningitis. Cerebrospinal fluid bathes the brain and can leak from the nose if the incision area doesn’t heal well. Meningitis is a bacterial or viral infection of the meninges, the outer covering of the brain.
Even when surgery is successful and hormone levels return to normal, people with Acromegaly must be carefully monitored for years for possible recurrence of the disease. More commonly, hormone levels improve, but do not return to normal. Additional treatment, usually medications, may be required.Transsphenoidal Surgery In this invasive procedure, a neurosurgeon enters through the nose and approaches the pituitary through the sphenoid bone at the base of the skull. Occasionally, large pituitary tumors may require transcranial surgery, in which the surgeon cuts into the skull (above the eye and ear) and retracts a portion of the brain to reach the tumor.
Medical Therapy:
For patients with persistent GH elevation after surgery (or those who decline to have surgery), Octreotide 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.
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.
In very rare cases hypothalamic tumors may lead to overproduction of growth hormone releasing hormone (GHRH) which also triggers unregulated production of GH by the pituitary hence Acromegaly ensues. Other rare causes are ectopic GHRH from nonendocrine tumors and ectopic secretion of GH by nonendocrine tumors. The symptoms of Acromegaly develop insidiously over a long period of time before they become prominent. Because of this patients live with Acromegaly for years before diagnosis.
Typical Signs and symptoms
- Field visual disturbances (double peripheral vision)
- Migraines
- Frontal bossing of the suprasellar orbital ridge
- Prognathism
- Macroglosia
- Carpal tunnel syndrome (tingling of the hands)
- Hyperhydrosis
- Lethargy
- Anxiety or depression
- Impotence in men
- Amenorrhea in women.
- Sleep apnoea
- Thickening of the soft tissues
- Enlarged hands, feet and skull. ( Increase in ring size, shoe size and hat size).
- Joint pains ( Arthralgia/arthritis)
- Oily skin and excessive skin pigmentation
- Skin tags.
- Abnormal distribution of body hair.
There are many other symptoms which were not included in the list above. The symptoms manifest differently in different people and patients may show a few of the symptoms above.
Diagnosis
Acromegaly is diagnosed by conducting what they call oral glucose tolerance test (OGTT). The Physician gets the patient to fast over night and blood samples are taken the next morning to measure blood glucose levels. The patient is given 75g of glucose by mouth a few minutes before blood samples are taken. The ingestion of sugar glucose normally suppresses blood GH levels to less than 2ng/ml in healthy people. In patients with excessive GH production, the blood GH levels remain higher than 2ng/ml. Suppression test as OGTT is alternatively called is the most reliable method of confirming a diagnosis of Acromegaly.
The physician can also measure IGF-1 levels in patients with suspected Acromegaly. Elevated GH levels increase IGF-1 blood levels. However IGF-1 levels are a more reliable measure as they are much more stable over the course of the day than GH levels which vary from one minute to another because the pituitary releases GH into the blood in spurts.
After OGTT results have indicated positive for Acromegaly, the next step is to locate the position of the tumor through imaging techniques. An X-ray of the pituitary fossa may be taken which normally shows an enlarged pituitary fossa in cases of pituitary tumors Computed Tomography scanning (CT) or Magnetic Resonance Imaging (MRI) may be used to get a much better visualization of the tumor without surgery. If the scans indicate absence of pituitary tumor the physician the looks for non-pituitary tumors in the chest, abdomen or pelvis as possible cause for excess GH.
Treatment options
The available treatment options for Acromegaly include surgery, medical therapy and radiation therapy. Patients may receive one of these treatments or a combination of two or more treatments depending on the severity of the case. People with macroadenomas usually need a combination of these treatments .
Surgery
The Role of Surgery
The goals of surgery, as with all Acromegaly therapies, include normalizing GH and IGF-1, eliminating mass effect from the tumor, and alleviating associated morbidities Additional goals of surgery include preserving normal pituitary function, preventing recurrence of the tumor, and obtaining tissue for analysis. Advantages of surgery include rapid lowering of GH and the possibility of cure. Limitations include lower success rates with larger invasive tumors and/or less experienced surgeons. The guidelines recommend that surgery be considered as the first therapeutic option in all patients with Acromegaly. Patients with mass effects will require surgery on an urgent basis. For patients not eligible or unwilling to undergo surgery, medical therapy can be selected.
Effectiveness
Several factors need to be considered in the surgical management of Acromegaly:
Surgical resection of the adenoma when not contraindicated is the initial treatment for Acromegaly. Contraindications include:
Patients who are poor surgical or anesthesia risks because of age or poor general health.
Patients who delay surgery because they want to maintain pituitary function, e.g., women who want to become pregnant.
Patients who refuse surgery.
Cure rates reach 90% in patients with small, well-defined microadenomas (size < 10 mm), and surgery provides rapid symptomatic relief .Cure rates for patients with macroadenomas (size >10 mm), which comprise the majority of GH tumors, are only 48% .Relapse may occur with macroadenomas, particularly those with extrasellar growth, after an initial improvement or apparent cure because of incomplete removal of tumor tissue .
Surgery is the first option recommended for most people with Acromegaly, as it is often a rapid and effective treatment. The surgeon reaches the pituitary via an incision through the nose or inside the upper lip and, with special tools, removes the tumor tissue in a procedure called Transsphenoidal surgery. This procedure promptly relieves the pressure on the surrounding brain regions and leads to a rapid lowering of GH levels. If the surgery is successful, facial appearance and soft tissue swelling improve within a few days.
Surgery is most successful in patients with blood GH levels below 45 ng/ml before the operation and with pituitary tumors no larger than 10 millimeters (mm) in diameter. Success depends in large part on the skill and experience of the surgeon, as well as the location of the tumor. Even with the most experienced neurosurgeon, the chance of a cure is small if the tumor has extended into critical brain structures or into the cavernous sinus where surgery could be risky.
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-I levels. The overall rate of remission control of the disease after surgery ranges from 55 to 80 percent.
A possible complication of surgery is damage to the surrounding normal pituitary tissue, which requires lifelong use of pituitary hormone replacement. The part of the pituitary that stores antidiuretic hormone a hormone important in water balance—may be temporarily or, rarely, permanently damaged and the patient may require medical therapy. Other potential problems include cerebrospinal fluid leaks and, rarely, meningitis. Cerebrospinal fluid bathes the brain and can leak from the nose if the incision area doesn’t heal well. Meningitis is a bacterial or viral infection of the meninges, the outer covering of the brain.
Even when surgery is successful and hormone levels return to normal, people with Acromegaly must be carefully monitored for years for possible recurrence of the disease. More commonly, hormone levels improve, but do not return to normal. Additional treatment, usually medications, may be required.Transsphenoidal Surgery In this invasive procedure, a neurosurgeon enters through the nose and approaches the pituitary through the sphenoid bone at the base of the skull. Occasionally, large pituitary tumors may require transcranial surgery, in which the surgeon cuts into the skull (above the eye and ear) and retracts a portion of the brain to reach the tumor.
Medical Therapy:
For patients with persistent GH elevation after surgery (or those who decline to have surgery), Octreotide 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.
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.
