The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease

Fukuoka, Hidenori; Shichi, Hiroki; Yamamoto, Masaaki; Takahashi, Yutaka

doi:10.3390/ijms21239132

Cited by 27 publications

(22 citation statements)

References 157 publications

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“…Indeed, Mu Y-M et al showed that the GRα mRNA levels in the adenomas in patients who showed no response to the 8-mg dexamethasone suppression test were significantly lower than those in the adenomas in patients who showed suppression [ 40 ]. Glucocorticoid receptors may not only contribute to regulation of the ACTH production but also to the control of cortocotropinoma growth via the MAPK pathway [ 41 , 42 ]. The more aggressive behavior of silent corticotropinomas and the development of pituitary macroadenoma in Nelson syndrome [ 43 ] may confirm the hypothesis of the involvement of glucocorticoids in the negative regulation of corticotropinoma growth.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Approach to Predicting the Outcomes of Transsphenoidal Endoscopic Adenomectomy in Patients with Cushing’s Disease

Kuritsyna

Tsoy

Cherebillo

et al. 2022

JPM

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Persistent and recurrent hypercortisolism after transsphenoidal endoscopic surgery (TSS) is considered to be an urgent issue prompting the search for Cushing’s disease (CD) remission predictors. The goal was to find a combination of predictors that can forecast the remission of CD after TSS. A total of 101 patients with CD who had undergone TSS were included. One year after surgery, CD remission status was evaluated. Preoperative pituitary magnetic resonance imaging (MRI) data, preoperative results of a high-dose dexamethasone suppression test (HDDST) and morning serum cortisol level collected 24 h after TSS (24 h MSeC) were compared in patients with and without remission of hypercortisolism. Remission one year after TSS was confirmed in 63 patients. CD remission predictors one year after TSS were: adenoma size ≥ 3 mm in the absence of invasive growth and the suppression of serum cortisol ≥ 74% in the HDDST, 24 h MSeC ≤ 388 nmol/L. A total of 38 patients had three favorable values of detected predictors; all of them had CD remission one year after TSS. With long-term follow-up, 36 of them remained in remission. Patients who had no one favorable predictor had no remission of hypercortisolism one year after TSS. Our data confirmed the prospects of using a combination of selected predictors to forecast CD remission after TSS.

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Section: Discussionmentioning

confidence: 99%

A Comprehensive Approach to Predicting the Outcomes of Transsphenoidal Endoscopic Adenomectomy in Patients with Cushing’s Disease

Kuritsyna

Tsoy

Cherebillo

et al. 2022

JPM

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“…A main characteristic of the pathogenesis of pituitary ACTH-secreting adenomas is an impaired ACTH suppression by GC negative feedback, potentially caused by different molecular abnormalities. It was reported that ACTH-secreting pituitary tumors show enhanced 11HSD2 gene expression but suppressed 11HSD1 gene expression, suggesting a partial or weak GC resistance [ 30 ]. Other mechanisms possibly underlying GC resistance may be due to abnormalities in the activation and function of GR.…”

Section: Pathophysiology Of Pituitary and Adrenal Mild Hypercortisolismmentioning

confidence: 99%

“…Additionally, Brg1, which belongs to the SWitch/Sucrose NonFermentable proteins (a group of proteins that regulate the way DNA is packaged) and histone deacetylase 2 have been shown to be important for the proopiomelanocortin gene expression. Loss of either Brg1 or histone deacetylase 2 can lead to GC resistance in ACTH-secreting adenomas, since Brg1 stabilizes the interaction between GR and histone deacetylase 2 to suppress proopiomelanocortin gene transcription [ 30 ]. In summary, increased expression of the 11HSD2 gene, HSP90 or Testicular receptor 4, and loss of expression of Brg1gene or CABLES1 gene are thought to contribute to the pathogenesis of ACTH-secreting pituitary tumors by reducing the GC negative feedback system.…”

Section: Pathophysiology Of Pituitary and Adrenal Mild Hypercortisolismmentioning

confidence: 99%

“…The above mentioned mechanisms and other factors, including arginine vasopressin and interleukin-1β, interleukin-6 and leukemia inhibitory factor, which have been recently described as having a potential role in the pathogenesis of ACTH-secreting adenomas, have been discussed in a comprehensive review by Fukuoka and coauthors [ 30 ].…”

Section: Pathophysiology Of Pituitary and Adrenal Mild Hypercortisolismmentioning

confidence: 99%

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Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Favero

Cremaschi

Parazzoli

et al. 2022

IJMS

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Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

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“…However, the mechanism of ACTHomas is still unclear. 2 The pituitary adenoma invasion is an important factor associated with the clinical prognosis. Endothelial cell derivedsecreted factor epidermal growth factor-like domain 7 (EGFL7), plays an important role in angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

EGFL7-blocking antibody inhibit pituitary adenoma proliferation and invasion

Liu¹,

Wang²,

Gao³

et al. 2022

JNSK

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Objective: To study the effect of EGFL7-blocking monoclonal antibody inhibiting the proliferation and invasion of mouse adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) AtT-20 cells. Methods: After treated with different concentration of EGFL7-blocking monoclonal antibody for 24, 48, 72 h, the proliferation of AtT-20 cells was determined by MTS. Simultaneously, ACTH secretion of AtT-20 cells by ELISA and the mRNA expression of invasion related genes such as E-cadherin, snail, MMP-2 and MMP-9 by Real-time PCR were detected. Results: EGFL7-blocking monoclonal antibody could effectively inhibit the proliferation and ACTH secretion of AtT-20 cells in a dose-dependent and time-dependent manner. At the same time, EGFL7-blocking monoclonal antibody significant down-regulated the mRNA level of snail, MMP-2 and MMP-9 in AtT-20 cells. Conclusion: EGFL7-blocking monoclonal antibody could inhibit mouse pituitary adenoma AtT-20 cells proliferation and invasion.

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The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease

Cited by 27 publications

References 157 publications

A Comprehensive Approach to Predicting the Outcomes of Transsphenoidal Endoscopic Adenomectomy in Patients with Cushing’s Disease

A Comprehensive Approach to Predicting the Outcomes of Transsphenoidal Endoscopic Adenomectomy in Patients with Cushing’s Disease

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

EGFL7-blocking antibody inhibit pituitary adenoma proliferation and invasion

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