Volumetric MRI analysis of hippocampal subregions in Cushing's disease: A model for glucocorticoid neural modulation

2011 ◽  
Vol 26 (1) ◽  
pp. 64-67 ◽  
Author(s):  
T. Toffanin ◽  
F. Nifosì ◽  
H. Follador ◽  
A. Passamani ◽  
F. Zonta ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Neuronal Damage ◽  
Differential Sensitivity ◽  
Cushing's Disease ◽  
In Vivo Model ◽  
Limbic Structure ◽  
Post Surgery ◽  
Significant Difference ◽  
Acth Secreting

AbstractSeveral preclinical studies have demonstrated neuronal effects of glucocorticoids on the hippocampus (HC), a limbic structure with anterior–posterior anatomical and functional segmentation. We propose a volumetric magnetic resonance imaging analysis of hippocampus head (HH), body (HB) and tail (HT) using Cushing's disease (CD) as model, to investigate whether there is a differential sensitivity to glucocorticoid neuronal damage in these segments. We found a significant difference in the HH bilaterally after 12 months from trans-sphenoidal surgical selective resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary micro-adenomas. This pre–post surgery difference could contribute to better understand the pathopysiology of CD as an in vivo model for stress-related hypercortisolemic neuropsychiatric disorders.

scholarly journals Corticotrophin-releasing activity of desmopressin in Cushing's disease: lack of correlation between in vivo and in vitro responsiveness

2003 ◽  
Vol 177 (3) ◽  
pp. 373-379 ◽  
Author(s):  
F Pecori Giraldi ◽  
E Marini ◽  
E Torchiana ◽  
P Mortini ◽  
A Dubini ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Pituitary Adenomas ◽  
Receptor Gene ◽  
Normal Subjects ◽  
Cushing's Disease ◽  
Receptor Antagonists ◽  
Releasing Effect ◽  
Acth Secreting

Desmopressin (DDAVP), an arginine vasopressin analogue, markedly stimulates ACTH secretion in patients with Cushing's disease, in contrast to its minimal effect in normal subjects. However, little is known about the mechanisms underlying this action and it appeared to be of interest to evaluate the effect of DDAVP on ACTH-secreting pituitary adenomas in vitro, in comparison with its effect in the same patients in vivo. Pituitary adenomas from 14 patients with Cushing's disease were incubated with DDAVP, corticotrophin-releasing hormone (CRH) and DDAVP together with vasopressin receptor antagonists or CRH. Incubation with DDAVP induced a modest dose-dependent increase in ACTH concentrations which appeared maximal at 10 nM. CRH stimulated ACTH to a greater extent compared with DDAVP and potentiated the effect of DDAVP alone. The DDAVP-induced ACTH increase appeared blunted by vasopressin V(2) and V(3) receptor antagonists. V(3) receptor gene expression was detected by RT-PCR in all adenoma samples except for two which were not responsive to DDAVP in vitro but responsive to the peptide in vivo. Surprisingly, no difference in the in vitro ACTH secretory response was observed between in vivo DDAVP-responsive (ACTH peak>150% baseline) and -unresponsive (ACTH peak<120% baseline) patients, suggesting that the pituitary adenoma is not the sole mediator of the ACTH-releasing effect of DDAVP. In conclusion, the marked stimulatory effect of DDAVP observed in patients with Cushing's disease appears to be mainly dependent on an extrapituitary action, possibly the inhibition of a corticotrophin release-inhibitory factor.

scholarly journals Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

2015 ◽  
Vol 173 (4) ◽  
pp. M73-M83 ◽  
Author(s):  
Marily Theodoropoulou ◽  
Martin Reincke ◽  
Martin Fassnacht ◽  
Masayuki Komada
Keyword(s):  
Cushing’S Disease ◽  
Growth Factor Receptor ◽  
Pituitary Tumors ◽  
Cushing's Disease ◽  
Tumor Subtypes ◽  
Important Regulator ◽  
Epidermal Growth ◽  
Acth Secreting

Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Paediatric Cushing's disease

2015 ◽  
Vol 173 (1) ◽  
pp. R35-R45 ◽  
Author(s):  
Helen L Storr ◽  
Martin O Savage
Keyword(s):  
Early Diagnosis ◽  
Clinical Diagnosis ◽  
Cushing’S Disease ◽  
Therapeutic Strategy ◽  
Cushing's Disease ◽  
Significant Morbidity ◽  
Endocrine Disease ◽  
Definition Of ◽  
Acth Secreting ◽  
Biochemical Features

Cushing's disease (CD) is the commonest form of ACTH-dependent Cushing's syndrome and is a rare clinical diagnosis in paediatric and adolescent patients. CD is caused by an ACTH-secreting pituitary corticotroph adenoma and is associated with significant morbidity in children; therefore, early diagnosis and treatment are critical for optimal therapeutic outcome. This review highlights the key clinical and biochemical features of paediatric CD and appraises current practices in diagnosis and management. A close liaison with adult endocrinology colleagues, particularly, for interpretation of investigations and definition of therapeutic strategy is strongly advised.

scholarly journals Outcome of endoscopic vs microsurgical transsphenoidal resection for Cushing’s disease

2018 ◽  
Vol 7 (1) ◽  
pp. R26-R37 ◽  
Author(s):  
Nidan Qiao
Keyword(s):  
Recurrence Rate ◽  
Cushing’S Disease ◽  
Meta Analysis ◽  
Cushing's Disease ◽  
Recurrence Rates ◽  
Microscopic Surgery ◽  
Significant Difference ◽  
Comprehensive Search ◽  
Definition Of

Introduction It is unclear whether the proportions of remission and the recurrence rates differ between endoscopic transsphenoidal surgery (TS) and microscopic TS in Cushing’s disease (CD); thus, we conducted a systematic review and meta-analysis to evaluate studies of endoscopic TS and microscopic TS. Methods We conducted a comprehensive search of PubMed to identify relevant studies. Remission and recurrence were used as outcome measures following surgical treatment of CD. Results A total of 24 cohort studies involving 1670 adult patients were included in the comparison. Among these studies, 702 patients across 9 studies underwent endoscopic TS, and 968 patients across 15 studies underwent microscopic TS. Similar baseline characteristics were observed in both groups. There was no significant difference in remission between the two groups: 79.7% (95% CI: 73.1–85.0%) in the endoscopic group and 76.9% (95% CI: 71.3–81.6%) in the microscopic group (P = 0.485). It appears that patients who underwent endoscopic surgery experience recurrence less often than patients who underwent microscopic surgery, with recurrence proportions of 11.0% and 15.9%, respectively (P = 0.134). However, if follow-up time is taken into account, both groups had a recurrence rate of approximately 4% per person per year (95% CI: 3.1–5.4% and 3.6–5.1%, P = 0.651). Conclusions We found that remission proportion and recurrence rate were the same in patients who underwent endoscopic TS as in patients who underwent microscopic TS. The definition of diagnosis, remission and recurrence should always be considered in the studies assessing therapeutic efficacy in CD.

Differential response to myocardial reperfusion injury in eNOS-deficient mice

2002 ◽  
Vol 282 (6) ◽  
pp. H2422-H2426 ◽  
Author(s):  
Brent R. Sharp ◽  
Steven P. Jones ◽  
David M. Rimmer ◽  
David J. Lefer
Keyword(s):  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
In Vivo Model ◽  
Pcr Analysis ◽  
Inos Mrna ◽  
Mrna Levels ◽  
Wild Type ◽  
Significant Difference ◽  
Deficient Mice

Two strains of endothelial nitric oxide synthase (eNOS)-deficient (−/−) mice have been developed that respond differently to myocardial ischemia-reperfusion (MI/R). We evaluated both strains of eNOS−/− mice in an in vivo model of MI/R. Harvard (Har) eNOS−/− mice ( n = 12) experienced an 84% increase in myocardial necrosis compared with wild-type controls ( P < 0.05). University of North Carolina (UNC) eNOS−/−( n = 10) exhibited a 52% reduction in myocardial injury versus wild-type controls ( P < 0.05). PCR analysis of myocardial inducible NO synthase (iNOS) mRNA levels revealed a significant ( P < 0.05) increase in the UNC eNOS−/− mice compared with wild-type mice, and there was no significant difference between the Har eNOS−/− and wild-type mice. UNC eNOS−/− mice treated with an iNOS inhibitor (1400W) exacerbated the extent of myocardial necrosis. When treated with 1400W, Har eNOS−/− did not exhibit a significant increase in myocardial necrosis. These data demonstrate that two distinct strains of eNOS−/− mice display opposite responses to MI/R. Although the protection seen in the UNC eNOS−/− mouse may result from compensatory increases in iNOS, other genes may be involved.

Octreotide exerts different effects in vivo and in vitro in Cushing's disease

1994 ◽  
Vol 130 (2) ◽  
pp. 125-131 ◽  
Author(s):  
Günter K Stalla ◽  
Steffi J Brockmeier ◽  
Ulrich Renner ◽  
Chris Newton ◽  
Michael Buchfelder ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Cushing’S Disease ◽  
Cushing's Disease ◽  
Dependent Manner ◽  
Acth Secretion ◽  
Adenoma Cell ◽  
Cortisol Levels ◽  
Corticotropic Adenoma

Stalla GK, Brockmeier SJ, Renner U, Newton C, Buchfelder M, Stalla J, Müller OA. Octreotide exerts different effects in vivo and in vitro in Cushing's disease. Eur J Endocrinol 1994;130:125–31. ISSN 0804–4643 The effect of the long-acting somatostatin analog octreotide (SMS 201-995) on adrenocorticotropin (ACTH) secretion was studied in five patients with untreated Cushing's disease in vivo and in six human corticotropic adenoma cell cultures in vitro. For the in vivo study, 100 μg of octreotide sc was given 30 and 180 min after cannulation of the cubital vein and 100 μg of corticotropin-releasing hormone (CRH) was injected iv at 210 min. Serum ACTH and cortisol levels were measured for 390 min. In vivo, octreotide had no significant effect either on basal or CRH-stimulated ACTH levels and did not influence cortisol levels. The in vitro studies were conducted with corticotropic adenoma cell cultures derived from adenoma tissue obtained from six patients with Cushing's disease. In four of six cell cultures, octreotide (1 nmol/l–1 μmol/l) inhibited basal ACTH secretion in a dose-dependent manner. The inhibition ranged from 70 to 92% for 1 nmol/l octreotide to 14–46% for 1 μmol/l octreotide as compared to controls (100%). In three of three octreotide-responsive adenoma cell cultures investigated, CRH-stimulated ACTH secretion was suppressed by octreotide. Hydrocortisone pretreatment in vitro abolished the inhibitory effect of octreotide on ACTH secretion in one octreotide-responsive corticotropic adenoma cell culture. In conclusion, we showed that octreotide in most cases could inhibit the ACTH release from human corticotropic adenoma cells in vitro but had no suppressive effect on ACTH levels of patients with Cushing's disease in vivo. This discrepancy could be due to a somatostatin receptor down-regulation by cortisol at the hypercortisolemic state in vivo. Günter K Stalla, Max-Planck-Institute of Psychiatry, Clinical Institute, Kraepelinstr. 10, D-80804 Munich, Germany

Immunochistochemical characteristics of blood vessels in non-visualized and visualized on MRI pituitary adenoma in patients with Cushing’s disease

2016 ◽  
Vol 62 (5) ◽  
pp. 65-66
Author(s):  
Patimat M. Khandaeva ◽  
Iya A. Voronkova ◽  
Zhanna E. Belaya ◽  
Lyudmila Y. Rozhinskaya ◽  
Aleksandr V. Vorontsov ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Blood Vessels ◽  
Cushing’S Disease ◽  
Pituitary Tumor ◽  
Pituitary Tumors ◽  
Average Diameter ◽  
Cushing's Disease ◽  
Retrospective Evaluation ◽  
Acth Secreting ◽  
Microvessels Density

Backgraund. Regardless of improvements in MRI, up to 20% of ACTH-secreting pituitary tumors are only identified at surgical exploration.Aim: to estimate whether there is any difference in blood vessels and the subsequent ability to uptake contrast agent in visualized microadenoma as compared to non-visualized on MRI ACTH-secreting pituitary tumors.Materials and methods. retrospective evaluation of ACTH-positive pituitary tumors from patients with Cushing’s disease (n=39) with either non-visualized pituitary tumor on MRI (n=17) or pituitary tumor less then 25 mm (n=22). MRI was performed using Siemens Magnetom Harmony 1.0T with gadolinium. Selected tumors were stained with anty-СD34 antibody (clone QBEnd/10, RTU, Leica) and anty-D2-40 antibody (clone D2-40, RTU, Dako). We evaluated the microvessels density and measured the diameter of larger and smaller vessel.Results. The microvessels density were not different in subject with visualized (123 [77;136]) and non-visualized (112 [110,0;126,5]) pituitary adenomas as well as number of slit-shaped vessels (32 [5;50] in visualized vs 25 [5;50] in non-visualized pituitary adenoma). The diameter of these vessels also did not differ: the diameter of the largest vessels in patients without visualization 53 µm [32,5;63,5] vs 33 µm [30,0;51,5], the average diameter of the blood vessels 15 µm [14,5-26,0] against 13 µm [12;14].Conclusions. The diameter and microvessels density in ACTH-producing pituitary adenoma does not affect the visualization of adenoma on MRI in patients with Cushing 's disease.

scholarly journals Cyclic Cushing's disease with misleading inferior petrosal sinus sampling results during a trough phase

2015 ◽  
Vol 38 (2) ◽  
pp. E7 ◽  
Author(s):  
Vivien Bonert ◽  
Namrata Bose ◽  
John D. Carmichael
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Adrenocorticotropic Hormone ◽  
Diagnostic Testing ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Inferior Petrosal Sinus ◽  
Inferior Petrosal Sinus Sampling ◽  
Acth Secreting ◽  
Transsphenoidal Resection

Diagnosing Cushing's syndrome is challenging and is further hampered when investigations are performed in a patient with cyclic Cushing's syndrome. A subset of patients with Cushing's syndrome exhibit periods of abnormal cortisol secretion with interspersed normal secretion. Patients can have periods of clinical improvement during these quiescent phases or remain symptomatic. Initial diagnostic testing can be challenging because of the unpredictable durations of the peak and trough phases, and it is especially challenging when the diagnosis of cyclic Cushing's syndrome has not yet been determined. Here, the authors present the case of a patient with Cushing's disease with a pathology-proven adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma and whose initial inferior petrosal sinus sampling (IPSS) results were deemed indeterminate; further studies elucidated the diagnosis of cyclic Cushing's syndrome. Repeat IPSS was diagnostic of a central source for ACTH secretion, and the patient was treated successfully with transsphenoidal resection. Literature concerning the diagnosis and management of cyclic Cushing's syndrome is also reviewed.

scholarly journals Mutation and Expression Analysis of Corticotropin-Releasing Factor 1 Receptor in Adrenocorticotropin-Secreting Pituitary Adenomas1

1998 ◽  
Vol 83 (9) ◽  
pp. 3327-3331
Author(s):  
K. D. Dieterich ◽  
E. D. Gundelfinger ◽  
D. K. Lüdecke ◽  
H. Lehnert
Keyword(s):  
Expression Analysis ◽  
Cushing’S Disease ◽  
Pituitary Adenomas ◽  
Messenger Rna ◽  
Corticotropin Releasing Factor ◽  
Cushing's Disease ◽  
Receptor Regulation ◽  
R Gene ◽  
Acth Secreting

The present study was designed to investigate a possible role of CRF1 receptors (CRF1-R) in the pathogenesis of Cushing’s disease. ACTH-secreting pituitary adenomas and nonsecreting pituitary adenomas have been analyzed for mutations in the CRF1-R gene by PCR and sequencing and been compared with the sequences of normal anterior pituitaries. No mutations affecting the CRF1-R protein have been found in all tumors analyzed. However, we found a significant overexpression of the CRF1-R messenger RNA in ACTH-secreting pituitary adenomas vs. inactive adenomas and normal pituitaries. We conclude that mutations of the CRF1-R are unlikely to be involved in Cushing’s disease. We suggest that the overexpression of the CRF1-R messenger RNA may be related to a disturbed receptor regulation in ACTH-secreting pituitary adenomas.

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