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==Overview==
==Overview==
Acromegaly is caused by prolonged overproduction of GH by the pituitary gland.  GH is part of a cascade of hormones that, as the name implies, regulates the physical growth of the body.  This cascade begins in a part of the brain called the hypothalamus.  The hypothalamus makes hormones that regulate the pituitary. One of the hormones in the GH series, or "axis," is growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to produce GH.
Acromegaly pathogenesis depends mainly on the excessive secretion of the [[growth hormone]] from the [[pituitary gland]]. [[Pituitary adenoma|Pituitary somatotroph cell adenoma]] leads to hyper-secretion of the [[growth hormone]]. [[Insulin-like growth factor|Insulin-like growth factor 1 (IGF-1)]] inhibits the secretion of [[growth hormone]] in two ways: [[IGF-1]] inhibits directly the [[Somatotrophs|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 type 1|multiple endocrine neoplasia 1 (MEN-1)]], [[Carney complex|Carney complex,]] [[McCune-Albright syndrome]][[Paraganglioma|, paraganglioma,]] and [[Pheochromocytoma]].  
 
Secretion of GH by the pituitary into the bloodstream stimulates the liver to produce another hormone called insulin-like growth factor I (IGF-I).  IGF-I is what actually causes tissue growth in the body.  High levels of IGF-I, in turn, signal the pituitary to reduce GH production.
 
The hypothalamus makes another hormone called [[somatostatin]], which inhibits GH production and release.  Normally, GHRH, somatostatin, GH, and IGF-I levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake, and blood sugar levels. If the pituitary continues to make GH independent of the normal regulatory mechanisms, the level of IGF-I continues to rise, leading to bone overgrowth and organ enlargement.  High levels of IGF-I also cause changes in glucose (sugar) and lipid (fat) metabolism and can lead to diabetes, high blood pressure, and heart disease.


==Pathophysiology==
==Pathophysiology==
Growth hormone is synthesized and stored in somatotroph cells, which account for >50% of pituitary hormone secreting cells. Growth hormone production and secretion is regulated by hypothalamic GH-releasing hormone, ghrelin and somatostatin. IGF-1 inhibits growth hormone secretion by both direct effect on the somatrophs and indirectly through stimulation of somatostatin that inhibits growth hormone secretion. Growth hormone is secreted in sporadic pulses with minimal basal secretion determined by sex, age, neurotransmitters, exercise and stress.
Acromegaly is believed to be caused by [[GH|growth hormone (GH)]] secreting [[pituitary adenomas]] either [[Microadenoma of the pituitary gland|microadenomas]] or [[Macroadenoma of the pituitary gland|macroadenomas]]. The [[pituitary adenoma]] leads to hypersecretion of the [[growth hormone]] from the [[Somatotrophs|somatotroph cells]].<ref name="pmid26873451">{{cite journal| author=Dineen R, Stewart PM, Sherlock M| title=Acromegaly. | journal=QJM | year= 2016 | volume=  | issue=  | pages=  | pmid=26873451 | doi=10.1093/qjmed/hcw004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26873451  }} </ref><ref name="pmid2549426">{{cite journal| author=Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L| title=GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. | journal=Nature | year= 1989 | volume= 340 | issue= 6236 | pages= 692-6 | pmid=2549426 | doi=10.1038/340692a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2549426  }} </ref><ref name="pmid19884662">{{cite journal| author=Melmed S| title=Acromegaly pathogenesis and treatment. | journal=J Clin Invest | year= 2009 | volume= 119 | issue= 11 | pages= 3189-202 | pmid=19884662 | doi=10.1172/JCI39375 | pmc=2769196 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19884662  }}</ref>


Growth hormone action is achieved via its interaction with a single-chain transmembrane glycoprotein receptor (GHR). The growth hormone molecule interacts with a preformed dimer of identical GHR pairs, causing internalization of the receptor to initiate signaling. As a consequence, two Janus tyrosine kinase 2 molecules undergo autophosphorylation and in turn phosphorylate the GHR cytoplasmic domain. This activates intracellular proteins involved in signal transduction and transcription (STAT).
===Normal Physiology===
*Normally, the [[growth hormone]] is secreted and stored in the [[anterior pituitary gland]] particularly in the [[Somatotrophs|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 [[Somatotrophs|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]].
=== Pathogenesis ===
*In [[pituitary adenomas]], a [[mutation]] in the alpha subunit of the [[Guanine|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 gene encoding the GHR is ubiquitously expressed, particularly in liver, fat and muscle. Growth hormone activation of the intracellular molecule STAT5b induces transcription of IGF-1. Systemic IGF-1 is synthesized primarily in the liver but also in extraheptatic tissues including bone, muscle and kidney and in the pituitary gland itself. IGF-1 circulates in serum bound to IGF-1 binding protein (IGFBP-3), or IGFBP-5, and acid-labile subunit in a 150-kD complex. Less than 1% of total serum IGF-1 circulates as a free hormone. The IGF-1 cellular effects are mediated by the IGF-1 receptor (IGF-1R), a heterotetrameric protein structurally similar to the insulin receptor. IGF-1 acts to mediate tissue growth or locally synthesized IGF-1 acts in a paracrine manner to regulate local GH target tissue growth<ref name="pmid26873451">{{cite journal| author=Dineen R, Stewart PM, Sherlock M| title=Acromegaly. | journal=QJM | year= 2016 | volume= | issue= | pages= | pmid=26873451 | doi=10.1093/qjmed/hcw004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26873451 }} </ref>.
==Genetics==
*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.<ref name="pmid25470569">{{cite journal| author=Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO et al.| title=Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 25 | pages= 2363-74 | pmid=25470569 | doi=10.1056/NEJMoa1408028 | pmc=4291174 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25470569 }} </ref>


===Pathogenesis===
*The exact pathogenesis of [disease name] is not fully understood.
OR
*It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
*The progression to [disease name] usually involves the [molecular pathway].
*The pathophysiology of [disease/malignancy] depends on the histological subtype.
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*The development of [disease name] is the result of multiple genetic mutations.
==Associated Conditions==
==Associated Conditions==
*Acromegaly may be associated with the following genetic diseases:<ref name="pmid27657986">{{cite journal| author=Hannah-Shmouni F, Trivellin G, Stratakis CA| title=Genetics of gigantism and acromegaly. | journal=Growth Horm IGF Res | year= 2016 | volume= 30-31 | issue=  | pages= 37-41 | pmid=27657986 | doi=10.1016/j.ghir.2016.08.002 | pmc=5154831 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27657986  }} </ref>
**Familial isolated [[pituitary adenoma]]
**[[Multiple endocrine neoplasia type 1|Multiple Endocrine Neoplasia 1 (MEN-1)]]
**[[Carney complex]]
**[[McCune-Albright syndrome]]
**[[Paraganglioma]]
**[[Pheochromocytoma]]
**[[Diabetes mellitus]]
**[[Sleep apnea]]
**[[Carpal tunnel syndrome]]
**[[Hypertension]]
**[[Osteoarthritis]]


==Gross Pathology==
== Gross pathology ==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
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.


==Microscopic Pathology==
==Microscopic pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*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.
<gallery>
Pituitary adenoma (1) GH production.jpg|Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.<ref name=Wikipedia1> https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_%281%29_GH_production.jpg</ref>
Image:
Pituitary adenoma (2) GH production.jpg|Histopathological image of pituitary adenoma with GH production. Acidophilic cell type. Hematoxylin & esoin stain.<ref name=Wikipedia1> https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_%281%29_GH_production.jpg</ref>
</gallery>


==References==
==References==

Latest revision as of 12:14, 5 February 2018

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

Overview

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.

Pathophysiology

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]

Normal Physiology

Pathogenesis

Genetics

  • 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]

Associated Conditions

Gross pathology

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.

Microscopic pathology

  • 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]

  • 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]

References

  1. ↑ Dineen R, Stewart PM, Sherlock M (2016). "Acromegaly". QJM. doi:10.1093/qjmed/hcw004. PMID 26873451.
  2. ↑ Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L (1989). "GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours". Nature. 340 (6236): 692–6. doi:10.1038/340692a0. PMID 2549426.
  3. ↑ Melmed S (2009). "Acromegaly pathogenesis and treatment". J Clin Invest. 119 (11): 3189–202. doi:10.1172/JCI39375. PMC 2769196. PMID 19884662.
  4. ↑ Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO; et al. (2014). "Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation". N Engl J Med. 371 (25): 2363–74. doi:10.1056/NEJMoa1408028. PMC 4291174. PMID 25470569.
  5. ↑ Hannah-Shmouni F, Trivellin G, Stratakis CA (2016). "Genetics of gigantism and acromegaly". Growth Horm IGF Res. 30-31: 37–41. doi:10.1016/j.ghir.2016.08.002. PMC 5154831. PMID 27657986.
  6. ↑ 6.0 6.1 https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_%281%29_GH_production.jpg

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