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{{Acromegaly}}
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==Overview==
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]].


==Overview==
==Pathophysiology==
Acromegaly is a hormonal disorder that results from too much growth hormone in the body. Growth hormone is made by the pituitary gland in the brain, usually by a benign pituitary adenoma.
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>
 
===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]]).


Secretion of growth hormone by the pituitary gland 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 growth hormone production.
==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>


==Pathophysiology==
==Associated Conditions==
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 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]]


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).
== 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.


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>.
==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.
<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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