Somatotroph cells in the normal pituitary are usually located in the lateral region of the pituitary, and at least in rodents this pool of somatotrophs expands significantly in puberty, possibly explaining the characteristic cavernous sinus invasion of these adenomas. Somatotroph adenomas can either be densely granulated with strong GH staining and diffuse distribution of cytokeratin or sparsely granulated with characteristic dot- like cytokeratin staining. The sparsely granulated somatotroph adenomas occur more often in young patients, have a greater tendency to tumour invasiveness and respond poorly to somatostatin analogue therapy. Expression of somatostatin receptors can be assessed by immunohistochemistry, with subtype 2 and 5 being the most prominent, and their correlation with response to first- and second- generation somatostatin analogues has been studied. Somatotroph hyperplasia can be seen in 25% of patients with X- linked acrogigantism, in 70% of patients with Carney complex, in patients with McCune– Albright syndrome, if the pituitary area is affected, with or without adenoma development and in patients with GHRH- secreting tumours. Silent somatotroph tumours (clinically non- functioning pituitary adenomas with GH staining on histology) have been observed in 7– 8% of somatotroph adenomas.

Molecular endocrinology of GH- Secreting Pituitary Adenomas

 The molecular pathogenesis of sporadic GH- secreting pituitary tumours is best considered by discussing changes which activate factors leading to increased tumour formation (e.g. oncogenes) or alterations which inactivate cell proliferation controlling genes (e.g. tumour sup pressor genes). The GHRH— GHRH receptor— stimulatory G- protein α- subunit—cAMP— protein kinase A— CREB—Pit-1 pathway is key for somatotroph cell function. Activating genetic alterations include the stimulatory guanine nucleotide- binding protein (G- protein) α- subunit gene (GNAS), the orphan G- protein associated 7 transmembrane receptor GPR101, cyclin D (CCDN1), fibroblast growth factor receptor 4 (FGFR4), and pituitary tumour transforming gene (PTTG).

The stimulatory G protein (Gs α) is involved in the activation of adenylate cyclase which mediates the regulatory actions of GHRH to stimulate GH synthesis and secretion. Missense mutations of GNAS at codons 201 and 227 (termed ‘gsp’ mutations) result in inhibition of the intrinsic GTPase activity of the α- subunit of the G protein, while its adenyl cyclase activating capacity is intact resulting in high intracellular levels of cyclic adenosine monophosphate (AMP). The downstream signalling pathway includes increased protein kinase A and cyclic AMP- response element binding protein (CREB) activity, increased binding, and activation of the POU1F1 promoter resulting in activate GH synthesis and release. This results in autonomous GH secretion (Figure 1). Somatic GNAS mutations have been demonstrated in 40% of human GH- secreting pituitary adenomas and are the most commonly described genetic defect. If the gsp mutation occurs in embryonic stage and is found in a mosaic form in various organs contributing to activation of various Gs- coupled receptors, the patient develops McCune– Albright syndrome (see next). Patients with GPR101 mutation develop infant onset somatotroph or somatomammotroph hyperplasia or tumours. The role of GPR101 is unclear in the somatotroph adenoma tumorigenesis. This cAMP- coupled receptor is normally expressed in the hypothalamus and could be upstream of GHRH. Embryonic overstimulation of GHRH and therefore GH/ PRL- secreting cells may lead to tumorigenesis, a phenomenon observed in animal models. Increased PTTG1 mRNA expression has been demonstrated in somatotroph adenomas and correlates with tumour size. FGFR4 and cyclin D overexpression have been described in pituitary tumours; however, this is not specific for somatotroph adenomas.

Fig1. The G- protein abnormality seen in the pituitary of 40% of Caucasian patients with acromegaly.

Tumour suppressor genes that may be involved in pituitary tumour pathogenesis include the retinoblastoma gene, cyclin- dependant kinase inhibitors, such as p27 (CDKN1B) and p16 (CDKN2A) as well as growth arrest and DNA damage- inducible protein (GADD45γ) and maternal imprinting gene 3 (MEG3). Some of these proteins are lost in pituitary tumours due to epigenetic mechanisms such as hypermethylation. p27 expression is reduced in all types of pituitary adenomas including somatotrophs. GADD45γ is a pro- apoptotic factor which is lost in GH- secreting adenomas. MEG3 is an imprinted gene encoding a non- coding RNA that suppresses tumour cell growth; it is lost in non- functioning pituitary adenomas but not in somatotroph tumours. Germline AIP mutations have been described in patients with sporadic or familial isolated pituitary adenomas and in vitro studies confirm that loss of function of this protein is in the pathogenesis of these adenomas. AIP may play a role in the somatostatin induced inhibitory pathway regulating the tumor suppressor gene ZAC1 or the inhibitory G protein Gi α2.

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مفاجأة.. تحسين القدرة على التحمل لا يعتمد العضلات فقط

المرتفعات والأكسجين.. دراسة "مبشرة" لمرضى السكري

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أسماك أعماق البحر تكشف نظاما بصريا يتجاوز "المألوف"

زوكربيرغ أمام القضاء في قضية إدمان المراهقين

"علي بابا" تكشف عن نموذج جديد للذكاء الاصطناعي

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مواضيع ذات صلة

Infections of the Urinary Tract : Pathogenesis

Infections of the Urinary Tract : Etiologic Agents

Infections of the Sinuses

clinical Features of Hyperprolactinaemia and Prolactinomas

Infections of the Ears : Diseases, Epidemiology, and Etiology of Disease

Encephalitis/Meningoencephalitis

Secondary Forms of Pure Red Cell Aplasia

Pathophysiology of Paroxysmal Nocturnal Hemoglobinuria

Clinical Manifestations of Paroxysmal Nocturnal Hemoglobinuria

Hypothyroidism: Etiology and Treatment

Introduction and History of Paroxysmal Nocturnal Hemoglobinuria

Diseases of The Central Nervous System