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Article ; Online: Systematic Investigation of Expression of G2/M Transition Genes Reveals CDC25 Alteration in Nonfunctioning Pituitary Adenomas.

Butz, Henriett / Németh, Kinga / Czenke, Dóra / Likó, István / Czirják, Sándor / Zivkovic, Vladimir / Baghy, Kornélia / Korbonits, Márta / Kovalszky, Ilona / Igaz, Péter / Rácz, Károly / Patócs, Attila

Pathology oncology research : POR

2017 Volume 23, Issue 3, Page(s) 633–641

Abstract: ... demonstrating alteration of G2/M transition in nonfunctioning pituitary adenomas (NFPAs) suggest that G2/M ... of members of the G2/M transition in NFPAs and to investigate potential microRNA (miRNA) involvement. Totally ... of the G2/M transition was profiled on 34 NFPA and 10 NP samples on TaqMan Low Density Array. Expression ...

Abstract	Dysregulation of G1/S checkpoint of cell cycle has been reported in pituitary adenomas. In addition, our previous finding showing that deregulation of Wee1 kinase by microRNAs together with other studies demonstrating alteration of G2/M transition in nonfunctioning pituitary adenomas (NFPAs) suggest that G2/M transition may also be important in pituitary tumorigenesis. To systematically study the expression of members of the G2/M transition in NFPAs and to investigate potential microRNA (miRNA) involvement. Totally, 80 NFPA and 14 normal pituitary (NP) tissues were examined. Expression of 46 genes encoding members of the G2/M transition was profiled on 34 NFPA and 10 NP samples on TaqMan Low Density Array. Expression of CDC25A and two miRNAs targeting CDC25A were validated by individual quantitative real time PCR using TaqMan assays. Protein expression of CDC25A, CDC25C, CDK1 and phospho-CDK1 (Tyr-15) was investigated on tissue microarray and immunohistochemistry. Several genes' expression alteration were observed in NFPA compared to normal tissues by transcription profiling. On protein level CDC25A and both the total and the phospho-CDK1 were overexpressed in adenoma tissues. CDC25A correlated with nuclear localized CDK1 (nCDK1) and with tumor size and nCDK1 with Ki-67 index. Comparing primary vs. recurrent adenomas we found that Ki-67 proliferation index was higher and phospho-CDK1 (inactive form) was downregulated in recurrent tumors compared to primary adenomas. Investigating the potential causes behind CDC25A overexpression we could not find copy number variation at the coding region nor expression alteration of CDC25A regulating transcription factors however CDC25A targeting miRNAs were downregulated in NFPA and negatively correlated with CDC25A expression. Our results suggest that among alterations of G2/M transition of the cell cycle, overexpression of the CDK1 and CDC25A may have a role in the pathogenesis of the NFPA and that CDC25A is potentially regulated by miRNAs.
Language	English
Publishing date	2017-07
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1375979-6
ISSN	1532-2807 ; 1219-4956
ISSN (online)	1532-2807
ISSN	1219-4956
DOI	10.1007/s12253-016-0163-5
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Zs.A 4936: Show issues

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Article ; Online: Metabolic complications of glucocorticoids. Prevention by metformin.

Korbonits, Márta

Annales d'endocrinologie

2023 Volume 84, Issue 3, Page(s) 352

MeSH term(s)	Humans ; Glucocorticoids/adverse effects ; Metformin/therapeutic use ; Hypoglycemic Agents/therapeutic use ; Metabolic Syndrome
Chemical Substances	Glucocorticoids ; Metformin (9100L32L2N) ; Hypoglycemic Agents
Language	English
Publishing date	2023-03-24
Publishing country	France
Document type	Journal Article
ZDB-ID	299-9
ISSN	2213-3941 ; 0003-4266
ISSN (online)	2213-3941
ISSN	0003-4266
DOI	10.1016/j.ando.2023.03.018
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Article ; Online: Tumour microenvironment and pituitary tumour behaviour.

Marques, P / Korbonits, M

Journal of endocrinological investigation

2023 Volume 46, Issue 6, Page(s) 1047–1063

Abstract: The pituitary tumour microenvironment encompasses a spectrum of non-tumoural cells, such as immune, stromal or endothelial cells, as well as enzymes and signalling peptides like cytokines, chemokines and growth factors, which surround the tumour cells ... ...

Abstract	The pituitary tumour microenvironment encompasses a spectrum of non-tumoural cells, such as immune, stromal or endothelial cells, as well as enzymes and signalling peptides like cytokines, chemokines and growth factors, which surround the tumour cells and may influence pituitary tumour behaviour and tumourigenic mechanisms. Recently, there has been intensive research activity in this field describing various pituitary tumour-infiltrating immune and stromal cell subpopulations, and immune- and microenvironment-related pathways. Key changes in oncological therapeutic avenues resulted in the recognition of pituitary as a target of adverse events for patients treated with immune checkpoint regulators. However, these phenomena can be turned into therapeutic advantage in severe cases of pituitary tumours. Therefore, unravelling the pituitary tumour microenvironment will allow a better understanding of the biology and behaviour of pituitary tumours and may provide further developments in terms of diagnosis and management of patients with aggressively growing or recurrent pituitary tumours.
MeSH term(s)	Humans ; Pituitary Neoplasms/diagnosis ; Pituitary Neoplasms/therapy ; Pituitary Neoplasms/metabolism ; Tumor Microenvironment ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Neoplasm Recurrence, Local ; Cytokines
Chemical Substances	Cytokines
Language	English
Publishing date	2023-04-15
Publishing country	Italy
Document type	Journal Article ; Review
ZDB-ID	432272-1
ISSN	1720-8386 ; 0391-4097 ; 1121-1369
ISSN (online)	1720-8386
ISSN	0391-4097 ; 1121-1369
DOI	10.1007/s40618-023-02089-1
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Zs.A 1480: Show issues

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Article ; Online: Genetic Testing in Hereditary Pituitary Tumors.

Akkuş, Gamze / Korbonits, Márta

Archives of medical research

2023 Volume 54, Issue 8, Page(s) 102920

Abstract: Genetic testing is becoming part of mainstream endocrinology. An increasing number of rare and not-so-rare endocrine diseases have an identifiable genetic cause, either at the germline or at the somatic level. Here we summerise germline genetic ... ...

Abstract	Genetic testing is becoming part of mainstream endocrinology. An increasing number of rare and not-so-rare endocrine diseases have an identifiable genetic cause, either at the germline or at the somatic level. Here we summerise germline genetic alterations in patients with pituitary neuroendocrine tumors (pituitary adenomas). These may be disorders with isolated pituitary tumors, such as X-linked acrogigantism, or AIP-related pituitary tumors, or as part of syndromic diseases, such as multiple endocrine neoplasia type 1 or Carney complex. In some cases, this could be relevant for treatment choices and follow-up, as well as for family members, as cascade screening leads to early identification of affected relatives and improved clinical outcomes.
MeSH term(s)	Humans ; Pituitary Neoplasms/diagnosis ; Pituitary Neoplasms/genetics ; Pituitary Neoplasms/pathology ; Adenoma/diagnosis ; Adenoma/genetics ; Adenoma/pathology ; Genetic Testing ; Mutation
Language	English
Publishing date	2023-11-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1156844-6
ISSN	1873-5487 ; 0188-4409 ; 0188-0128
ISSN (online)	1873-5487
ISSN	0188-4409 ; 0188-0128
DOI	10.1016/j.arcmed.2023.102920
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Article ; Online: Metabolic complications of glucocorticoids - Prevention by metformin.

Sanpawithayakul, Kanokporn / Korbonits, Márta

Annales d'endocrinologie

2023 Volume 84, Issue 4, Page(s) 483–497

Abstract: Glucocorticoid treatment is prescribed in 2 to 3% of the population for various diseases. Chronic exposure to excess glucocorticoid can lead to iatrogenic Cushing's syndrome, which is associated with increased morbidity, especially from cardiovascular ... ...

Abstract	Glucocorticoid treatment is prescribed in 2 to 3% of the population for various diseases. Chronic exposure to excess glucocorticoid can lead to iatrogenic Cushing's syndrome, which is associated with increased morbidity, especially from cardiovascular diseases and infections. While several 'steroid-sparing' drugs have been introduced, glucocorticoid treatment is still applied in a large number of patients. We have previously showed that the enzyme AMPK plays a key role in mediating the metabolic effects of glucocorticoids. While metformin is the most widely used drug for treatment of diabetes mellitus, its mechanism of effect is still debated. Among several effects, it stimulates AMPK in peripheral tissue, affects the mitochondrial electron chain, influences gut bacteria and stimulates GDF15. We have hypothesised that metformin will counteract the metabolic effects of glucocorticoids, even in patients without diabetes. Two double-blind placebo-controlled randomised clinical studies were conducted: in the first, glucocorticoid-naive patients started metformin treatment early together with the glucocorticoid treatment. While in placebo group glycaemic indices worsened, these sequelae were prevented in the metformin group, suggesting a beneficial effect of metformin on glycaemic control in non-diabetic patients receiving glucocorticoid treatment. In the second study, we treated patients already on established glucocorticoid therapy for a longer period with metformin or placebo. In addition to the beneficial effects on glucose metabolism, we observed significant improvement in lipid, liver, fibrinolysis, bone and inflammatory parameters, as well as fat tissue and carotid intima media thickness. Moreover, patients had a lower risk of developing pneumonia and a reduced number of admissions to hospital, representing financial advantage for the health service. We believe that the routine use of metformin for patients on glucocorticoid treatment would represent a key advantage in the care for this patient population.
MeSH term(s)	Humans ; Metformin/therapeutic use ; Glucocorticoids/adverse effects ; Hypoglycemic Agents/adverse effects ; AMP-Activated Protein Kinases/therapeutic use ; Carotid Intima-Media Thickness ; Diabetes Mellitus, Type 2/drug therapy ; Randomized Controlled Trials as Topic
Chemical Substances	Metformin (9100L32L2N) ; Glucocorticoids ; Hypoglycemic Agents ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2023-05-18
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	299-9
ISSN	2213-3941 ; 0003-4266
ISSN (online)	2213-3941
ISSN	0003-4266
DOI	10.1016/j.ando.2023.05.002
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Article ; Online: Pseudoacromegaly-A challenging entity in the endocrine clinic: A systematic review.

Marques, Pedro / Sapinho, Inês / Korbonits, Márta

Clinical endocrinology

2024

Abstract: Objective: Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion ... ...

Abstract	Objective: Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly. Design/patients: PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively. Results: Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI. Conclusions: Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.
Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.15053
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Zs.A 814: Show issues

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Article ; Online: Glucose and lipid metabolism abnormalities in Cushing's syndrome.

Salehidoost, Rezvan / Korbonits, Márta

Journal of neuroendocrinology

2022 Volume 34, Issue 8, Page(s) e13143

Abstract: Prolonged excess of glucocorticoids (GCs) has adverse systemic effects leading to significant morbidities and an increase in mortality. Metabolic alterations associated with the high level of the GCs are key risk factors for the poor outcome. These ... ...

Abstract	Prolonged excess of glucocorticoids (GCs) has adverse systemic effects leading to significant morbidities and an increase in mortality. Metabolic alterations associated with the high level of the GCs are key risk factors for the poor outcome. These include GCs causing excess gluconeogenesis via upregulation of key enzymes in the liver, a reduction of insulin sensitivity in skeletal muscle, liver and adipose tissue by inhibiting the insulin receptor signalling pathway, and inhibition of insulin secretion in beta cells leading to dysregulated glucose metabolism. In addition, chronic GC exposure leads to an increase in visceral adipose tissue, as well as an increase in lipolysis resulting in higher circulating free fatty acid levels and in ectopic fat deposition. Remission of hypercortisolism improves these metabolic changes, but very often does not result in full resolution of the abnormalities. Therefore, long-term monitoring of metabolic variables is needed even after the resolution of the excess GC levels.
MeSH term(s)	Adipose Tissue/metabolism ; Cushing Syndrome/complications ; Cushing Syndrome/metabolism ; Glucocorticoids/metabolism ; Glucose/metabolism ; Humans ; Insulin Resistance ; Lipid Metabolism/physiology
Chemical Substances	Glucocorticoids ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-08-18
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1007517-3
ISSN	1365-2826 ; 0953-8194
ISSN (online)	1365-2826
ISSN	0953-8194
DOI	10.1111/jne.13143
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Zs.A 2634: Show issues

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Article ; Online: AIP: A double agent? The tissue-specific role of AIP as a tumour suppressor or as an oncogene.

Haworth, Oliver / Korbonits, Márta

British journal of cancer

2022 Volume 127, Issue 7, Page(s) 1175–1176

Abstract: Aryl hydrocarbon receptor-interacting protein (AIP) is a co-chaperone to heat shock proteins and nuclear receptors. Loss-of-function heterozygote germline mutations lead to predisposition to growth hormone- or prolactin-secreting pituitary typically ... ...

Abstract	Aryl hydrocarbon receptor-interacting protein (AIP) is a co-chaperone to heat shock proteins and nuclear receptors. Loss-of-function heterozygote germline mutations lead to predisposition to growth hormone- or prolactin-secreting pituitary typically presenting in childhood. Based on these data AIP behaves as a tumour suppressor. However, previously in diffuse large B cell lymphoma and now in this new manuscript in the British Journal of Cancer on colorectal cancer, it seems that high expression of AIP is associated with tumour development and more aggressive disease. AIP, therefore, joins a distinguished group of proteins that can behave both as a tumour suppressor and as an oncogene.
MeSH term(s)	Germ-Line Mutation ; Growth Hormone ; Heat-Shock Proteins ; Humans ; Oncogenes/genetics ; Prolactin
Chemical Substances	Heat-Shock Proteins ; Prolactin (9002-62-4) ; Growth Hormone (9002-72-6)
Language	English
Publishing date	2022-09-05
Publishing country	England
Document type	Editorial
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-022-01964-7
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Uh III Zs.142: Show issues

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Article ; Online: Molecular genetic testing in the management of pituitary disease.

Coopmans, Eva C / Korbonits, Márta

Clinical endocrinology

2022 Volume 97, Issue 4, Page(s) 424–435

Abstract: Objective: Most pituitary tumours occur sporadically without a genetically identifiable germline abnormality, a small but increasing proportion present with a genetic defect that predisposes to pituitary tumour development, either isolated (e.g., aryl ... ...

Abstract	Objective: Most pituitary tumours occur sporadically without a genetically identifiable germline abnormality, a small but increasing proportion present with a genetic defect that predisposes to pituitary tumour development, either isolated (e.g., aryl hydrocarbon receptor-interacting protein, AIP) or as part of a tumour-predisposing syndrome (e.g., multiple endocrine neoplasia (MEN) type 1, Carney complex, McCune-Albright syndrome or pituitary tumour and paraganglioma association). Genetic alterations in sporadic pituitary adenomas may include somatic mutations (e.g., GNAS, USP8). In this review, we take a practical approach: which genetic syndromes should be considered in case of different presentation, such as tumour type, family history, age of onset and additional clinical features of the patient. Design: Review of the recent literature in the field of genetics of pituitary tumours. Results: Genetic testing in the management of pituitary disease is recommended in a significant minority of the cases. Understanding the genetic basis of the disease helps to identify patients and at-risk family members, facilitates early diagnosis and therefore better long-term outcome and opens up new pathways leading to tumorigenesis. Conclusion: We provide a concise overview of the genetics of pituitary tumours and discuss the current challenges and implications of these genetic findings in clinical practice.
MeSH term(s)	Adenoma/diagnosis ; Adenoma/genetics ; Genetic Testing ; Growth Hormone-Secreting Pituitary Adenoma/genetics ; Growth Hormone-Secreting Pituitary Adenoma/pathology ; Humans ; Molecular Biology ; Multiple Endocrine Neoplasia Type 1 ; Pituitary Neoplasms/diagnosis ; Pituitary Neoplasms/genetics ; Pituitary Neoplasms/pathology
Language	English
Publishing date	2022-03-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.14706
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Zs.A 814: Show issues

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Article ; Online: Beware of epistaxis: fatal pseudoaneurysm rupture 30 years after treatment of acromegaly.

Carreira, Ana / Muna, Solomon / Grossman, Ashley B / Korbonits, Márta

BMJ case reports

2024 Volume 17, Issue 4

Abstract: We present a fatal complication of treatment in a patient with early-onset acromegaly, treated with two transsphenoidal operations, radiotherapy, radiosurgery and pegvisomant. He was diagnosed in his 30s, and controlled from his 40s, with stable residual ...

Abstract	We present a fatal complication of treatment in a patient with early-onset acromegaly, treated with two transsphenoidal operations, radiotherapy, radiosurgery and pegvisomant. He was diagnosed in his 30s, and controlled from his 40s, with stable residual tumour within the left cavernous sinus. In his 60s, 30 years after surgery/radiotherapy and 14 years after radiosurgery, he developed recurrent episodes of mild epistaxis. A week later, he presented at his local hospital's emergency department with severe epistaxis and altered consciousness. He was diagnosed with a ruptured internal carotid artery (ICA) pseudoaneurysm, but unfortunately died before treatment could be attempted.ICA pseudoaneurysms are rare complications of surgery or radiotherapy and can present with several years of delay, often with epistaxis. This case highlights the importance of life-long monitoring in patients with previous pituitary interventions and early recognition of epistaxis as a herald sign of a potentially catastrophic event, thus leading to timely treatment.
MeSH term(s)	Male ; Humans ; Epistaxis/etiology ; Epistaxis/therapy ; Epistaxis/diagnosis ; Aneurysm, False/diagnostic imaging ; Aneurysm, False/etiology ; Aneurysm, False/therapy ; Acromegaly/complications ; Carotid Artery, Internal ; Pituitary Gland
Language	English
Publishing date	2024-04-19
Publishing country	England
Document type	Case Reports ; Journal Article
ISSN	1757-790X
ISSN (online)	1757-790X
DOI	10.1136/bcr-2023-258533
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