Acromegaly

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Acromegaly is a disease of excessive growth hormone secretion. The pituitary adenoma is the most common cause of acromegaly. Other causes of acromegaly include GHRH secreting tumors as hypothalamic tumors, small cell lung cancer, adrenal adenoma, and pheochromocytoma. Ectopic tumors as lymphoma and pancreatic islet cell tumor can cause acromegaly by secretion of GH. Pathogenesis of acromegaly depends on the hypersecretion of the growth hormone and insulin-like growth factor 1 (IGF-1). The IGF-1 causes the rapid increase in the hand and feet size, forehead protrusion, and jaw prominence. A genetic mutation in the alpha subunit of the guanine nucleotide stimulatory protein leads to increase synthesis of cAMP which increases the secretion of growth hormone. The prevalence of acromegaly is estimated to be 2.8 – 13.7 per 100.000 individuals worldwide. In the United States, the incidence of acromegaly is 0.11 per 100,000 individuals. Acromegaly affects men and women equally. Common risk factors in the development of acromegaly are the risk factors for pituitary adenoma development. These risk factors include a family history of pituitary adenoma, McCune Albright syndrome, lung cancers and adrenal tumors. If left untreated, 30% of patients with acromegaly may progress to develop cardiovascular manifestations, pulmonary dysfunction, and cerebral complications. Common complications of acromegaly include hypertension, arrhythmia, heart failure, sleep apnea, dyspnea, carpal tunnel syndrome, and spinal cord compression. Common symptoms of acromegaly include enlarged hands and feet, headache, increase sweating, sexual dysfunction, skin thickening, deepening of the voice and, an enlarged tongue. An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly. Endonasal transsphenoidal surgery is the mainstay of treatment for acromegaly due to pituitary adenoma. Patients with acromegaly are treated with somatostatin analogs like octreotide, dopamine agonists like bromocriptine, and GH receptor antagonist like pegvisomant. Radiation therapy is indicated in patients who do not respond to surgery or the medical therapy.

Acromegaly was first described by DR. Johannes Wier in 1567. Dr. Verga reported a case of acromegaly in 1864 and it was a case of a patient with a disproportionate big face. Through 1877 to 1900s, many physicians reported cases of acromegaly. In 1970, Dr. Besser used bromocriptine in the treatment of acromegaly and it showed a remarkable improvement in the patients. In 1988, FDA approved for the octreotide as a treatment to acromegaly.

There is no established system for the classification of acromegaly

Acromegaly pathogenesis depends mainly on the excessive secretion of the growth hormone from the pituitary gland. Pituitary somatotroph cell adenoma leads to hypersecretion of the growth hormone. Insulin-like growth factor 1 (IGF-1) inhibits the secretion of growth hormone in two ways. IGF-1 inhibits directly the somatotroph cells or stimulates secretion the somatostatin that inhibits the GH secretion. The IGF-1 is responsible for the acral features of the acromegaly. The IGF-1 causes the rapid increase in the hand and feet size, forehead protrusion, and jaw prominence. A genetic mutation in the alpha subunit of the guanine nucleotide stimulatory protein leads to increase synthesis of cAMP which increases the secretion of growth hormone. Acromegaly is associated with multiple endocrine neoplasia 1 (MEN-1), Carney complex, McCune-Albright syndrome, paraganglioma, and pheochromocytoma.

Common causes of acromegaly include pituitary adenoma and acidophil stem cell adenomas. Less common causes of acromegaly include GHRH secreting tumors as hypothalamic tumors, small cell lung cancer, adrenal adenoma, and pheochromocytoma. Other causes include GH secreting tumors as lymphoma and pancreatic islet cell tumor.

Acromegaly must be differentiated from other diseases that cause acral features like skin thickening and linear bone growth. These diseases such as Marfan syndrome, precocious puberty, prolactinoma, and pachydermoperiostosis.

The prevalence of acromegaly is estimated to be 2.8 – 13.7 per 100.000 individuals worldwide. In the United States, the incidence of acromegaly is 0.11 per 100,000 individuals. Acromegaly affects men and women equally.

Common risk factors in the development of acromegaly are the risk factors for pituitary adenoma development. These risk factors include a family history ofpituitary adenoma, MacCun Albright syndrome, lung cancers and adrenal tumors. Other risk factors include early menopause in females and young age females at the first childbirth.

According to the endocrine society, screening for acromegaly is recommended among patients with clinical features of acromegaly. These features include enlarged hands and feet, frontal protrusion, and skin thickening. The screening is performed by measurement of the IGF-1.

If left untreated, 30% of patients with acromegaly may progress to develop cardiovascular manifestations, pulmonary dysfunction, and cerebral complications. Common complications of acromegaly include hypertension, arrhythmia, heart failure, sleep apnea, dyspnea, carpal tunnel syndrome, and spinal cord compression. Prognosis of acromegaly is generally good with transsphenoidal surgery and the postoperative treatment.

Common symptoms of acromegaly include enlarged hands and feet, headache, increase sweating, sexual dysfunction, skin thickening, deepening of the voice and, an enlarged tongue. Less common symptoms of acromegaly include visual defects and irregular menses in the women. 

Patients with acromegaly usually appear tired. Physical examination of patients with acromegaly is usually remarkable for skin tags, acanthosis nigricans, and hyperhidrosis. Common findings in physical examination include frontal bossing, headache, macroglossia, and prognathism. Cardiovascular findings include ventricular hypertrophy, heart failure, and arrhythmias. Skeletal findings include joint effusion, osteopenia, kyphoscoliosis, muscle weakness, paraesthesia, and malocclusion of the mouth leading temporomandibular joint tenderness.  

An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly. 

On x-ray, acromegaly is characterized by widening of the joint spaces, soft tissue hypertrophy, and osteophyte formation. 

There are no CT findings associated with acromegaly.

Pituitary gland MRI may be helpful in the diagnosis of acromegaly as pituitary adenomas are the most common cause of acromegaly. Findings on MRI suggestive of acromegaly include enlarged pituitary gland and an adenoma that may extend to the suprasellar region. Spine MRI also may be helpful in the diagnosis as it shows hypertrophy of the spinal ligaments.

There are no ultrasound findings associated with acromegaly.

There are no other diagnostic studies associated with acromegaly.

There are no other imaging findings associated with acromegaly.

The mainstay of acromegaly treatment for is pharmacotherapy. Patients with acromegaly are treated with somatostatin analogs like octreotide, dopamine agonists like bromocriptine, and growth hormone receptor antagonist like pegvisomant. Radiation therapy is indicated in patients who do not respond to surgery or the medical therapy.

Surgery is the mainstay of treatment for acromegaly due to pituitary adenoma. The goal of the surgery will be the removal of the pituitary mass that causes acromegaly. The surgery to be performed is endonasal transsphenoidal surgery.

There are no established measures for the prevention of acromegaly.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Acromegaly was first described by DR. Johannes Wier in 1567. Dr. Verga reported a case of acromegaly in 1864 that was a case of a patient with a disproportionate big face. Through 1877 to 1900s, many physicians reported cases of acromegaly. In 1970, Dr. Besser used bromocriptine in the treatment of acromegaly and it showed a remarkable improvement in the patients condition. In 1988, FDA approved octreotide as a treatment to acromegaly.

• In 1567, Dr.  Johannes Wier was the first to describe a case of a giant female patient. Dr. Wier described the course of acromegaly in this patient in his article. He mentioned that she was of normal stature then she began to increase in height and size at age of fourteen. However, she had a normal good life. Dr. Wier was also the first who described link between the acromegaly and amenorrhea in this patient.^[1]
• In 1772, Dr. Nicolas Saucerotte reported a case which has a clinical presentation linked with acromegaly.^[2]
• In 1864, Dr. Andrea Verga reported a case of acromegaly. Dr. Verga reported a patient with disproportional big face.
• In 1877, Dr. Brigidi was the first who described pituitary adenoma. Dr. Brigidi reported a case of an actor who presented with chronic bone deformities. Dr. Bridgi then linked between the pituitary adenoma and the acromegaly.
• In 1884, Dr. Fritsche and Theodor Klebs also reported a case of acromegaly with pituitary adenoma.
• In 1886, Dr. Pierre Marie was the first who developed the name of acromegaly for the disease. Dr. Marie reported a patient presenting with hypertrophied extremities and he linked between this presentation and acromegaly.

• In the 1970s, bromocriptine, a dopamine agonist, was used by Dr. G. Michael Besser to treat acromegaly. Dr. Besser used bromocriptine on some patients and it showed a remarkable improvement in most of the patients. A reduction in the growth hormone was also observed.^[3]
• In 1973, Dr. Roger Guillemin and Paul Brazeau discovered somatostatin which is a polypeptide inhibitor of the growth hormone.^[4]
• In 1978, somatostatin analogs were developed by Dr. Wylie W. Vale. These somatostatin analogs provide the same inhibitory function and potency of somatostatin against acromegaly.^[5]
• In 1982, another somatostatin analog called octreotide was developed by Dr. Wilfried Bauer and his team. Octreotide had a greater potency in inhibiting the growth hormone and it can resist degradation by the enzymes.^[6]
• In 1988, FDA approved for the octreotide as a treatment to acromegaly.
• In 2001, growth hormone receptor antagonists drug, pegvisomant, was developed by Dr. John Kopchick. It has been successful in the treatment of acromegaly since 2001. Pegvisomant can be used with additional medications in the treatment of acromegaly.^[7][8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

There is no established system for the classification of acromegaly.

There is no established system for the classification of acromegaly.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Acromegaly pathogenesis depends mainly on the excessive secretion of the growth hormone from the pituitary gland. Pituitary somatotroph cell adenoma leads to hyper-secretion of the growth hormone. Insulin-like growth factor 1 (IGF-1) inhibits the secretion of growth hormone in two ways: IGF-1 inhibits directly the somatotroph cells or stimulates secretion the somatostatin that inhibits the GH secretion, IGF-1 is also responsible for the acral features of the acromegaly. The IGF-1 causes the rapid increase in the hand and feet size, forehead protrusion, and jaw prominence. A genetic mutation in the alpha subunit of the guanine nucleotide stimulatory protein leads to increase synthesis of cAMP which increases the secretion of growth hormone. Acromegaly is associated with multiple endocrine neoplasia 1 (MEN-1), Carney complex, McCune-Albright syndrome, paraganglioma, and Pheochromocytoma.

Acromegaly is believed to be caused by growth hormone (GH) secreting pituitary adenomas either microadenomas or macroadenomas. The pituitary adenoma leads to hypersecretion of the growth hormone from the somatotroph cells.^[1][2][3]

• Normally, the growth hormone is secreted and stored in the anterior pituitary gland particularly in the somatotroph cells.
• Growth hormone secretion is affected by several factors.
  • Growth hormone is stimulated by ghrelin and growth hormone releasing hormone.
  • Somatostatin inhibits the growth hormone secretion.
• Insulin-like growth factor 1 (IGF-1) inhibits the secretion of growth hormone in two ways.
  • IGF-1 inhibits directly the somatotroph cells or stimulates secretion the somatostatin that inhibits the GH secretion.
• Growth hormone is functioning through binding to its receptor which is a glycoprotein receptor.
• Binding of GH to its receptor stimulates proteins which start a process called signal transduction and transcription.

• In pituitary adenomas, a mutation in the alpha subunit of the guanine nucleotide stimulatory protein is responsible for the excess growth hormone secretion.
• The mutation in the alpha subunit will lead to increase synthesis of cAMP which is responsible for the growth of certain cells.
• Increase synthesis of cAMP will result in the increase secretion of the growth hormone.
• Signal transduction and transcription (STAT) induce production of IGF-1 from liver, bone and pituitary gland.
• The IGF-1 is responsible for the acral features of acromegaly. IGF-1 causes the rapid increase in the hand and feet size, forehead protrusion, and jaw prominence.
• The high level of IGF-1 is responsible for the following pathologic processes:
  • IGF-1 is responsible for the diabetes mellitus which is common in 20% of patients with acromegaly. IGF-1 interferes with insulin on its receptor which leads to insulin resistance and hyperglycemia.
  • IGF-1 causes hypertrophy of the body organs like the heart (cardiomegaly) and tongue (macroglossia).

• The development of acromegaly has been associated also with microduplications on chromosome Xq26.3 which is a location for G protein coupled receptor 101 gene (GPCR101).
• Microduplication of the chromosome Xq26.3 will be associated with mutations of the GPCR101 protein which leads to increase of the growth hormone secretion.^[4]

• Acromegaly may be associated with the following genetic diseases:^[5]
  • Familial isolated pituitary adenoma
  • Multiple Endocrine Neoplasia 1 (MEN-1)
  • Carney complex
  • McCune-Albright syndrome
  • Paraganglioma
  • Pheochromocytoma
  • Diabetes mellitus
  • Sleep apnea
  • Carpal tunnel syndrome
  • Hypertension
  • Osteoarthritis

Gross pathology of acromegaly shows pituitary gland adenoma in most of the cases. Findings include the following:

• Microprolactinomas (<10mm size) are usually found in the lateral wing of the pituitary gland. They are most often surrounded by well defined pseudocapsules composed of reticulin.
• Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause sellar expansion while others invade the base of the skull.
• About 50% of all prolactinoma grossly invade surrounding structures.

• Pituitary microadenomas are defined as adenomas less than 10 mm in size.
• Most frequently diagnosed as a result of investigating hormonal imbalance.
• They are confined to the sella and have no scope to produce mass effect related symptoms.

• 
  Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.^[6]
• 
  Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common causes of acromegaly include pituitary adenoma and acidophil stem cell adenomas. Less common causes of acromegaly include GHRH secreting tumors as hypothalamic tumors, small cell lung cancer, adrenal adenoma, and pheochromocytoma. Other causes include GH secreting tumors as lymphoma and pancreatic islet cell tumor.

Acromegaly may be caused by:

• Pituitary adenoma:^[1]
  • It is the most common cause of acromegaly.
  • A secretory pituitary adenoma is responsible for acromegaly by excess secretion of the growth hormone and the insulin like growth factor-1 (IGF-1).
• Other types of pituitary adenomas causing acromegaly:
  • Mixed growth hormone and prolactin cell adenomas
  • Acidophil stem cell adenomas
  • Mammosomatotroph cell adenomas
  • Pleurihormonal adenomas

Less common causes of acromegaly include:^[1]

• Hypothalamic tumors which secrete growth hormone releasing hormone (GHRH).
• Ectopic tumor secretion of GHRH. These tumors include the following:
  • Small cell lung cancer
  • Adrenal adenoma
  • Pheochromocytoma
  • Thyroid carcinoma
• Ectopic tumor secretion of GH. These tumors include the following:
  • Lymphoma
  • Pancreatic islet cell tumors

• Acromegaly is caused by a mutation in the guanine nucleotide stimulatory protein gene which is responsible for pituitary adenomas.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Acromegaly must be differentiated from other diseases that cause acral features like skin thickening and linear bone growth. These diseases such as Marfan syndrome, precocious puberty, prolactinoma, and pachydermoperiostosis.

• Acromegaly must be differentiated from other diseases that cause acral features like skin thickening and linear bone growth. These diseases such as Marfan syndrome, precocious puberty, prolactinoma, and pachydermoperiostosis.^[1][2][3][4]

Acromegaly should also be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females) including:

• Physiological:
  • Normal pregnancy^[5]
• Pathological:
  • Pituitary tumors (other than prolactinoma):^[6]
    • Somatotroph adenoma: Acromegaly
    • Corticotroph adenoma: Cushing’s syndrome
  • Suprasellar tumors (tumors present in the region of the pituitary stalk)
  • Hypothyroidism^[7]
  • Chronic renal failure^[8]
  • Liver disease^[9]
    • Cirrhosis (with or without encephalopathy)
    • Viral hepatitis (with encephalopathy)
  • Seizure disorder^[10][11]
• Medication-induced:
  • Antipsychotic medications:^[12]
    • Haloperidol
    • Risperidone
  • Antiemetic medications:
    • Metoclopramide^[13]
    • Domperidone^[14]
  • Antihypertensive medications:
    • Methyldopa^[15]
    • Verapamil^[16]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

The prevalence of acromegaly is estimated to be 2.8 – 13.7 per 100.000 individuals worldwide. In the United States, the incidence of acromegaly is 0.11 per 100,000 indvidual. Acromegaly affects men and women equally.

• The incidence of acromegaly is approximately 0.2 – 1.1 per 100,000 individuals worldwide.^[1][2][3]

• The prevalence of acromegaly is approximately 2.8 – 13.7 per 100,000 individuals worldwide.^[4][5]

• The incidence of acromegaly increases with age; the mean age at diagnosis of acromegaly is 40 years in males.
• The mean age at diagnosis of acromegaly is 45 years in females.

• There is no racial predilection to acromegaly.

• Acromegaly affects men and women equally.^[6]

• In the United States, acromegaly is very rare. The incidence of acromegaly in the United States is 0.11 per 100,000 individual.
• In Iceland, the incidence of acromegaly is 0.7 per 100,000 individual.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common risk factors in the development of acromegaly are the risk factors for pituitary adenoma development. These risk factors include a family history of pituitary adenoma, MacCun Albright syndrome, lung cancers and adrenal tumors. Other risk factors include early menopause in females and young age females at the first childbirth.

Common risk factors in the development of acromegaly are associated with the risk factors of pituitary adenoma development. The pituitary adenoma is the most common cause of acromegaly.

Common risk factors in the development of acromegaly include:

• Family history of pituitary adenoma
• MacCun Albright syndrome
• Lung cancers
• Adrenal tumors

Less common risk factors in the development of acromegaly include:^[1]

• Early menopausal females
• Surgical induced menopause
• Young age females at the first childbirth

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

There is insufficient evidence to recommend routine screening for acromegaly.

There is insufficient evidence to recommend routine screening for acromegaly.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

If left untreated, 30% of patients with acromegaly may progress to develop cardiovascular manifestations, pulmonary dysfunction, and cerebral complications. Common complications of acromegaly include hypertension, arrhythmia, heart failure, sleep apnea, dyspnea, carpal tunnel syndrome and spinal cord compression. Prognosis of acromegaly is generally good with transsphenoidal surgery and the postoperative treatment.

• If left untreated, 30% of patients with acromegaly may progress to develop cardiovascular manifestations, pulmonary dysfunction, and cerebral complications. These comorbidities will increase the mortality rate.^[1]

• Common complications of acromegaly include:
  • Cardivascualr complications:^[2]
    • Cardiovascular disease
    • Hypertension
    • Arrhythmias
    • Heart failure
    • Coronary arteriosclerosis
  • Respiratory complications:
    • Sleep apnea
    • Dyspnea and stridor
  • Neuromuscular complications:
    • Arthritis
    • Carpal tunnel syndrome
    • Spinal cord compression
    • Vision abnormalities
  • Abdominal complications:
    • Colonic polyps
    • Uterine fibroids in females

• Prognosis of acromegaly is generally good with transsphenoidal surgery and the postoperative treatment.
• Early diagnosis and treatment of acromegaly are associated with better prognosis.^[3]
• The acral features of the acromegaly in the face, hands, and feet usually return to normal after the surgery.

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