Acromegaly pathophysiology

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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

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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

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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

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* 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.

### Pathogenesis

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* 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).

## Genetics

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* 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

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* 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

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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

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* 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]

## References

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1. ↑ Dineen R, Stewart PM, Sherlock M (2016). "Acromegaly". QJM. doi:10.1093/qjmed/hcw004. PMID 26873451.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
6. ↑ 6.0 6.1 https://en.wikipedia.org/wiki/Pituitary_adenoma#/media/File:Pituitary_adenoma_(1)_GH_production.jpg

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