Defective Expression of Prohormone Convertase 1/3 in Silent Corticotroph Adenoma

Tateno, Toshitake; Izumiyama, Hajime; Doi, Masaru; Akashi, Takumi; Ohno, Kikuo; Hirata, Yukio

doi:10.1507/endocrj.k07-059

Cited by 41 publications

(31 citation statements)

References 19 publications

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“…Immunohistochemical and RT-PCR studies have already demonstrated a decrease in PC1/3 expression in SCAs than in corticotroph adenomas (26,27) or non-functioning pituitary adenomas (7,26,27). However, in these rare studies, few SCAs were analyzed, the hormonal data at presentation were sparse, and no distinction was made between micro-or macro-ACTH tumours.…”

Section: Discussionmentioning

confidence: 99%

Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease

Raverot¹,

Wierinckx²,

Jouanneau³

et al. 2010

European Journal of Endocrinology

104

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Objective: Silent corticotroph adenomas (SCAs) are rare pituitary tumours immunoreactive for ACTH, but without clinical evidence of Cushing's disease. We characterized SCAs based on clinical, hormonal and molecular data, and compared the characteristics of these tumours with those of macro (MCA)-and micro (mCA)-ACTH adenomas with Cushing's disease. Methods: Fifty ACTH adenomas (14 SCAs, 15 MCAs and 21 mCAs) with complete corresponding clinical, radiological and biochemical data were selected. Histological corticotroph differentiation; immunostaining for ACTH, b-endorphin and b-LPH; and mRNA expression levels of TPIT, POMC, GRa, prohormone convertase 1/3 (PC1/3) and galectin-3 were compared in 21 representative tumours. Results: Despite the absence of clinical hypercortisolism in patients with SCA, elevated plasma ACTH levels that were similar to those associated with mCA were observed. The cortisol/ACTH ratio was similar between SCA and MCA groups and lower than that found with mCA (P!0.05). This dissociation could be explained by lower expression of PC1/3 in SCA and MCA than in mCA (P!0.05). After an i.v. dexamethasone suppression test, ACTH levels were significantly higher in patients with MCA than in those with mCA (P!0.05). Cytological and immunocytochemical analyses as well as mRNA expression levels of TPIT, POMC and GRa confirmed corticotroph differentiation in both mCAs and MCAs and in half of the SCAs, with a strong correlation between TPIT and POMC mRNA expression levels in SCAs (R 2 Z0.72; P!0.01) and in MCAs (R 2 Z0.65; P!0.05). Conclusions: Despite the absence of hypercortisolism, SCAs exhibit histological, biochemical and molecular corticotroph differentiation. SCA and MCA show hormonal and molecular similarities differentiating them from mCA.

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Section: Discussionmentioning

confidence: 99%

Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease

Raverot¹,

Wierinckx²,

Jouanneau³

et al. 2010

European Journal of Endocrinology

104

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“…SCAs potentially derive from POMC producing cells in the vestigial pars intermedia of the human pituitary [17], and the clinical silence may be due to dysregulated POMC processing [37]. Prohormone convertase (PC) 1/3 transcripts, which cleave POMC to ACTH, indeed are downregulated in SCAs [51], with CD having 30-fold higher levels than SCAs, and 10-fold higher levels observed in type I compared to type II SCAs which further suggest a defect in conversion of POMC to ACTH in SCAs [20].…”

Section: Pathogenesismentioning

confidence: 99%

Silent corticotroph adenomas

2018

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Purpose-Silent corticotroph adenomas (SCAs) comprise 20% of all corticotroph adenomas and 3-19% of nonfunctioning adenomas (NFAs). As they do not manifest clinical or biochemical hypercortisolism, they are diagnosed after pathologic examination of resected tumor tissue demonstrates positive ACTH expression. While preoperative features are similar to those of NFAs, SCAs may have more cavernous sinus invasion. Further, patients with SCAs tend to have more frequent and earlier recurrences than those with NFAs, often necessitating multiple surgeries and other modalities of treatment. This article reviews the incidence, pathogenesis, and clinical behavior of SCAs.Methods-A systematic literature review was performed using PubMed for information regarding silent corticotroph adenomas.Results-Up to date findings regarding epidemiology, pathogenesis, pathology, clinical presentation, postoperative course, and management of patients with SCAs are presented.Conclusions-This review highlights the necessity of rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.

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“…Interestingly, a family with FIPA harbouring subtype 2 silent corticotroph adenoma has recently been described [6]. The silent corticotroph adenoma subgroup members (subtypes 1 and 2) seem to have a more aggressive clinical course and higher recurrence rate than null cell adenomas and oncocytomas [13,14,15]. Corticotroph carcinoma presenting as a silent corticotroph adenoma has also been described [16].…”

Section: Silent Pituitary Adenomasmentioning

confidence: 99%

“…Several studies suggest that this last mechanism, related to reduced prohormone convertase, could play a role [14, 26], but it has not been uniformly found. Other genes were also differentially expressed in silent corticotropinomas compared with corticotroph adenomas, such as NeuroD1 , CRHR , V1bR and 11 β -HSD2 [27].…”

Section: Why Are Silent Corticotroph Adenomas Silent?mentioning

confidence: 99%

Recent Clinical and Pathophysiological Advances in Non-Functioning Pituitary Adenomas

Korbonits

Carlsen²

2009

Horm Res Paediatr

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Pituitary adenomas are being recognized and diagnosed with increasing frequency. One of the most common forms of pituitary lesion is the clinically non-functioning pituitary adenoma (NFPA), which is often diagnosed incidentally. The vast majority of pituitary adenomas are sporadic, but familial adenomas can occur in the multiple pituitary adenoma type 1 syndrome, in Carney complex or in familial isolated pituitary adenoma. Distinguishing NFPA from prolactinomas can occasionally cause a differential diagnostic problem due to the ‘stalk effect’. NFPA often show hormone synthesis on tissue immunostaining without causing clinical symptoms. Most often these are silent gonadotroph adenomas, with silent corticotroph or somatotroph adenomas occurring less frequently. It is unclear why these silent adenomas do not release hormones at a clinically recognizable level, although it is probable that there is a continuum between fully functional and completely silent adenomas. Another intriguing feature of NFPAs is the lack of clinical response to somatostatin analogues, despite the presence of somatostatin receptors and an often good response in the in vitro setting. Temozolomide has been successfully used for the treatment of a few aggressive pituitary adenomas, and the response to this drug could be influenced by the expression of the DNA repair enzyme O-6-methylguanine DNA methyltransferase. The early diagnosis, prediction of long-term outcome and treatment of NFPAs remain a challenge for endocrinologists.

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Defective Expression of Prohormone Convertase 1/3 in Silent Corticotroph Adenoma

Cited by 41 publications

References 19 publications

Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease

Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease

Silent corticotroph adenomas

Recent Clinical and Pathophysiological Advances in Non-Functioning Pituitary Adenomas

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