scholarly journals Tumor shrinkage by metyrapone in Cushing's disease exhibiting glucocorticoid-induced positive feedback

2021 ◽  
Author(s):  
Yasutaka Tsujimoto ◽  
Hiroki Shichi ◽  
Hidenori Fukuoka ◽  
Masaaki Yamamoto ◽  
Itsuko Sato ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Positive Feedback ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
High Dose ◽  
Tumor Shrinkage ◽  
Feedback Systems ◽  
Cross Sectional

Abstract Context Paradoxical increases in serum cortisol in the dexamethasone suppression test (DST) have been rarely observed in Cushing’s disease (CD). Its pathophysiology and prevalence remain unclear. Case description A 62-year-old woman with suspected CD showed paradoxical increases in cortisol after both 1-mg and 8-mg DST (1.95-fold and 2.52-fold, respectively). The initiation of metyrapone paradoxically decreased plasma ACTH levels and suppressed cortisol levels. Moreover, the pituitary tumor considerably shrank during metyrapone treatment. Ex vivo experiments The resected tumor tissue was enzymatically digested, dispersed, and embedded into Matrigel as 3-D cultured cells. ACTH levels in the media were measured. In this tumor culture, ACTH levels increased 1.3-fold after dexamethasone treatment (p <0.01) while control tumor cultures exhibited no increase in ACTH levels, but rather 20–40% suppression (p <0.05). Clinical study A cross-sectional, retrospective, multicenter study that included 92 patients with CD who underwent both low dose- (LD) and high dose- (HD) DST from 2014 to 2020 was performed. Eight cases (8.7 %) showed an increase in serum cortisol after both LDDST and HDDST. Conclusions This is the first report of a patient with GC-driven positive-feedback CD who showed both ACTH suppression and tumor shrinkage by metyrapone. Our cohort study revealed that 8.7% of patients with CD patients possibly possess GC-driven positive feedback systems, thereby suggesting the presence of a new subtype of CD that is different from the majority of CD cases. The mechanisms exhibiting GC positive-feedback in CD and the therapeutic approach for these patients remain to be investigated.

scholarly journals Morning Serum Cortisol as a Predictor for the HPA Axis Recovery in Cushing’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Q. Cui ◽  
D. Liu ◽  
B. Xiang ◽  
Q. Sun ◽  
L. Fan ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Cushing’S Disease ◽  
Serum Cortisol ◽  
Cross Sectional Study ◽  
Cushing's Disease ◽  
Confirmatory Test ◽  
Acth Stimulation ◽  
Cross Sectional ◽  
Postoperative Course ◽  
Morning Serum Cortisol

Background. The suppressed hypothalamic-pituitary-adrenal (HPA) axis after successful surgery for Cushing’s disease (CD) will recover in almost all patients. We aimed to identify the predictive factors for HPA axis recovery in CD patients with postoperative remission. Design and Methods. This observational retrospective cross-sectional study enrolled 69 CD patients with postoperative remission in Huashan Hospital from 2015 to 2019. All subjects had a detailed clinical evaluation. The low-dose ACTH stimulation test (LDT) was conducted as the gold standard for assessing the HPA axis function. Results. Peak cortisol in LDT was found only to be positively correlative with morning serum cortisol (MSC) ( ρ = 0.451 , p < 0.001 ). The MSC was higher ( p < 0.001 ), and the median postoperative course was significantly longer ( p = 0.025 ) in the patients with the recovered HPA axis function compared with unrecovered patients. The AUC value of MSC for predicting the recovery of the HPA axis was 0.701, and the optimal cutoff was 6.25 μg/dl (sensitivity 85.19% and specificity 47.62%). Other useful cutoff values were 10.74 μg/dl (specificity 100%) and 4.18 μg/dl (sensitivity 100%). Besides, combined with the postoperative course, the AUC values were higher than MSC alone (0.935 vs. 0.701, p < 0.001 ). Conclusions. MSC is a viable first-step diagnostic predictor for HPA axis recovery in CD patients with postoperative remission. For the patients with cortisol levels between 4.18 and 10.74 μg/dl, a confirmatory test should be conducted. When the MSC level was 10.74 μg/dl or greater, the replacement therapy could be discontinued.

scholarly journals MON-905 A Case of Cushing’s Disease with Glucocorticoid Positive-Feedback

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hiroki Shichi ◽  
Hidenori Fukuoka ◽  
Yasutaka Tsujimoto ◽  
Masaaki Yamamoto ◽  
Tomoaki Nakamura ◽  
...  
Keyword(s):  
Primary Culture ◽  
Cushing’S Disease ◽  
Positive Feedback ◽  
Ex Vivo ◽  
Culture Method ◽  
Cushing's Disease ◽  
Plasma Acth ◽  
Paradoxical Response ◽  
Free Cortisol ◽  
Underlying Mechanisms

Abstract Background: Although paradoxical response of cortisol (F) during high dose dexamethasone (Dex) suppression test (DST) is observed in a part of ectopic ACTH syndrome, few reports have been shown in Cushing’s disease (CD). It suggests a presence of glucocorticoid (GC)-driven positive-feedback loop. However, the underlying mechanism remains elusive. Here we present a case of CD showing clear clinical and pathophysiological evidences of GC positive-feedback using ex vivo 3-dimensional (D) culture method. Case: A 62-year-old woman manifested typical Cushing’s symptoms, including moon face, central obesity, hypertension, hypokalemia, and vertebral fractures. Endocrinological data were consistent with a diagnosis of CD; morning plasma ACTH 299 pg/mL, serum F 28 μg/dL, midnight serum F 43 μg/dL, and 24hr urinary free cortisol 988 μg/day. CRH test showed a slight increase in plasma ACTH levels (1.4 fold), and pituitary MRI revealed a 14 mm macroadenoma invading into the left cavernous sinus. Interestingly, both 1 mg and 8 mg DST showed a paradoxical increase in serum cortisol levels (27.7→64.7μg/dL and 17.17→35.68μg/dL, respectively). These data indicated a presence of positive-feedback response to GC in the tumor. Indeed, after the initiation of metyrapone (1,000 mg/day) administration for the treatment of hypercortisolemia, plasma ACTH levels were decreased to 147.5 pg/mL accompanied with the decrease in serum F levels to 4.12 μg/dL. Moreover, pituitary tumor obviously shrank during the metyrapone treatment. Thereafter, we undertook transsphenoidal surgery and plasma ACTH and serum F levels decreased to 35.8 pg/mL and 7.6μg/dL, respectively. ex vivo studies: To prove the presence of the positive feedback response and explore the underlying mechanisms, we performed a primary culture experiment using the tumor and applied 3D culture method. The resected tumor tissue was enzymatically digested, dispersed and embedded into the Matrigel. Then cells were treated with Dex (0.1-10 nM), and ACTH concentrations were measured after 72 hrs. Interestingly, ACTH levels significantly increased by 10 nM Dex treatment at 72 h (129 %, p &lt;0.01), indicating a paradoxical response to Dex in the tumor ex vivo. Conclusions: To our knowledge, this is the first case of CD who showed clinically obvious GC positive-feedback that was proved by ex vivo 3D primary culture cell models. Notably, tumor shrinkage was observed during the metyrapone treatment, suggesting that GC positive-feedback mechanisms also involve tumor proliferation. Further investigation is required for elucidating the underlying mechanisms.

scholarly journals Prediction of the transsphenoidal endoscopic adenomectomy results in patients with cushing’s disease

2022 ◽  
pp. 152-161
Author(s):  
N. V. Kuritsyna ◽  
U. A. Tsoy ◽  
V. Yu. Cherebillo ◽  
A. A. Paltsev ◽  
A. I. Tsiberkin ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
Serum Cortisol Level ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Morning Serum Cortisol ◽  
Transsphenoidal Adenomectomy ◽  
Important Challenge ◽  
One Year

Introduction. Transsphenoidal adenomectomy (TSA) is the method of choice in the treatment of Cushing’s disease (CD), but remission of hypercorticism cannot be achieved in all patients. The search for predictors of CD remission after TSA remains to be an important challenge in the endocrinology today.Aim. To study the preoperative and postoperative data of patients with CD to identify the predictors of hypercorticism remission after TSA.Materials and methods. 101 patients with confirmed CD after TSA were included. One year after operation all patients were examined for the presence of hypercorticism remission and divided into two groups: with CD remission and its absence. In both groups’ preoperative pituitary magnetic resonance imaging (MRI) data, the results of preoperative high dose dexamethasone suppression test (HDDST) and the results of serum cortisol collected in the morning 2–3 days after surgery were compared.Results. One year after TSA, CD remission was confirmed in 63 patients (62.4%), whereas in 38 patients (37.6%) hypercortisolism persisted. Favorable predictors of CD remission were: the adenoma size > 3 mm without the invasive growth according to pituitary MRI (specificity 82.4%, sensitivity 82.8%), serum cortisol suppression ≥ 74% in preoperative HDDST (specificity 81.5%, sensitivity 86.3%), morning serum cortisol level in 2–3 days after surgery ≤ 388 nmol/l (specificity 79.3%, sensitivity 97.4%).Conclusions. Pituitary MRI data, the results of preoperative HDDST and morning serum cortisol in the 2–3 days after surgery can be used as predictors of CD remission.

scholarly journals Prognostic markers of remission of cushing's disease after transsphenoidal endoscopic adenomektomii.

2018 ◽  
Vol 95 (12) ◽  
pp. 1106-1111
Author(s):  
Natalia V. Gussaova ◽  
W. A. Choi ◽  
V. Yu. Cerebillo ◽  
A. A. Paltsev ◽  
A. V. Savello ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Serum Cortisol ◽  
Threshold Value ◽  
Optimal Threshold ◽  
Cushing's Disease ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Free Cortisol ◽  
One Year ◽  
Cortisol Suppression

Aim. To study the role of prognostic oral high-dose dexamethasone suppression test (HDDST) and pituitary MRI in the prognosis of Cushing’s disease (CD). remission after transsphenoidal endoscopic surgery (TSS). Material and methods. 59 patients with Cushing’s disease (9 men, 50 women, mean age 40 years (15-72) underwent TSS were included. Before the TSS HDDST and pituitary MRI were performed in all cases. Postoperative examination was done one year after surgery. Remission criteria were: combination of normal midnight serum cortisol levels, normal 24 hour urine free cortisol (UFC) excretion and serum cortisol suppression less than 50 nmol/l in 1-mg dexamethasone test or secondary adrenal insufficiency (the need for glucocorticoid replacement). The optimal threshold value of serum cortisol suppression in the HDDST for prediction of CD remission after TSS was calculated by ROC-analysis. Results. One year after surgery CD remission was confirmed in 39 patients, whereas in 20 patients hypercortisolism persisted. The optimal threshold value of serum cortisol suppression in the HDDST for prediction of CD remission after TSS was 72%. Test’s sensitivity and specificity were 82% and 84%, respectively. The probability of wrong prediction was 17% (p=0,0001). In our study, the results of TSS did not correlate with MRI adenoma size.

scholarly journals P34 Characteristics, diagnosis and management of Cushing’s disease - A systematic review and meta-analysis

BJS Open ◽  
2021 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
Chan Hee Koh ◽  
Danyal Z Khan ◽  
Ronneil Digpal ◽  
Hugo Layard Horsfall ◽  
Hani J Marcus ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Cushing’S Disease ◽  
Meta Analysis ◽  
A Priori ◽  
Pituitary Surgery ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
Diagnosis And Management ◽  
Over Time

Abstract Introduction The clinical practice and research in the diagnosis and management of Cushing’s disease remains heterogeneous and challenging to this day. We sought to establish the characteristics of Cushing’s disease, and the trends in diagnosis, management and reporting in this field. Methods Searches of PubMed and Embase were conducted. Study protocol was registered a-priori. Random-effects analyses were conducted to establish numerical estimates. Results Our screening returned 159 papers. The average age of adult patients with Cushing’s disease was 39.3, and 13.6 for children. The male:female ratio was 1:3. 8% of patients had undergone previous transsphenoidal resection. The ratio of macroadenomas: microadenomas:imaging-undetectable adenomas was 18:53:29. The most commonly reported preoperative biochemical investigations were serum cortisol (average 26.4µg/dL) and ACTH (77.5pg/dL). Postoperative cortisol was most frequently used to define remission (74.8%), most commonly with threshold of 5µg/dL (44.8%). Average remission rates were 77.8% with recurrence rate of 13.9%. Median follow-up was 38 months. Majority of papers reported age (81.9%) and sex (79.4%). Only 56.6% reported whether their patients had previous pituitary surgery. 45.3% reported whether their adenomas were macroadenoma, microadenoma or undetectable. Only 24.1% reported preoperative cortisol, and this did not improve over time. 60.4% reported numerical thresholds for cortisol in defining remission, and this improved significantly over time (p = 0.004). Visual inspection of bubbleplots showed increasing preference for threshold of 5µg/dL. 70.4% reported the length of follow up. Conclusion We quantified the characteristics of Cushing’s disease, and analysed the trends in investigation and reporting. This review may help to inform future efforts in forming guidelines for research and clinical practice.

scholarly journals Diagnosis and Multimodality Management of Cushing’s Disease: A Practical Review

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Gabriel Zada
Keyword(s):  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Patient Survival ◽  
Clinical Laboratory ◽  
Management Strategies ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
First Line ◽  
Stepwise Approach

Cushing’s Disease is caused by oversecretion of ACTH from a pituitary adenoma and results in subsequent elevations of systemic cortisol, ultimately contributing to reduced patient survival. The diagnosis of Cushing’s Disease frequently involves a stepwise approach including clinical, laboratory, neuroimaging, and sometimes interventional radiology techniques, often mandating multidisciplinary collaboration from numerous specialty practitioners. Pituitary microadenomas that do not appear on designated pituitary MRI or dynamic contrast protocols may pose a particularly challenging subset of this disease. The treatment of Cushing’s Disease typically involves transsphenoidal surgical resection of the pituitary adenoma as a first-line option, yet may require the addition of adjunctive measures such as stereotactic radiosurgery or medical management to achieve normalization of serum cortisol levels. Vigilant long-term serial endocrine monitoring of patients is imperative in order to detect any recurrence that may occur, even years following initial remission. In this paper, a stepwise approach to the diagnosis, and various management strategies and associated outcomes in patients with Cushing’s Disease are discussed.

scholarly journals Surgical management of pediatric Cushing's disease: an analysis of 15 consecutive cases at a specialized neurosurgical center

2010 ◽  
Vol 54 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Ricardo Santos de Oliveira ◽  
Margaret de Castro ◽  
Sonir Roberto Rauber Antonini ◽  
Carlos Eduardo Martinelli Júnior ◽  
Ayrton Custódio Moreira ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Transsphenoidal Surgery ◽  
Pediatric Patients ◽  
Serum Cortisol ◽  
Plasma Cortisol Level ◽  
Hormone Deficiency ◽  
Cushing's Disease ◽  
Specialized Center ◽  
Biochemical Cure

OBJECTIVE: The aim of this study was to review the results of surgery for pediatric patients with Cushing's disease who were less than 18 years old and underwent transsphenoidal surgery in a specialized center during a 25-year period. SUBJECTS AND METHODS: Retrospective study, in which the medical records, histology and pituitary imaging of 15 consecutive pediatric patients with Cushing's disease (mean age: 13 years) were evaluated by the same team of endocrinologists and a neurosurgeon from 1982 to 2006. Patients were considered cured when there was clinical adrenal insufficiency and serum cortisol levels were below 1. 8 µg/dL or 50 nmol/L after one, two, three, or seven days following surgery; they therefore required cortisone replacement therapy. Follow-up was for a median time of 11.5 years (range: 2 to 25 years). RESULTS: Clinical and biochemical cure was achieved in 9/15 patients (60%) exclusively after transsphenoidal surgery. Hypopituitarism was observed in four patients; growth hormone deficiency, in two; permanent diabetes insipidus, in one case. CONCLUSIONS: Cushing's disease is rare in children and adolescents. Transsphenoidal surgery is an effective and safe treatment in most of these patients. Plasma cortisol level < 1. 8 µg/dL following surgery is the treatment goal and is a good predictive factor for long-term cure of Cushing's disease.

scholarly journals Dynamics of Serum Cortisol Levels after Transsphenoidal Surgery in a Cohort of Patients with Cushing’s Disease

2004 ◽  
Vol 89 (3) ◽  
pp. 1131-1139 ◽  
Author(s):  
G. A. F. S. Rollin ◽  
N. P. Ferreira ◽  
M. Junges ◽  
J. L. Gross ◽  
M. A. Czepielewski
Keyword(s):  
Cushing’S Disease ◽  
Transsphenoidal Surgery ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
Cortisol Levels

scholarly journals Increased Prevalence of Anxiety-Associated Personality Traits in Patients with Cushing's Disease: A Cross-Sectional Study

2013 ◽  
Vol 97 (2) ◽  
pp. 139-145 ◽  
Author(s):  
C. Dimopoulou ◽  
M. Ising ◽  
H. Pfister ◽  
J. Schopohl ◽  
G.K. Stalla ◽  
...  
Keyword(s):  
Personality Traits ◽  
Cushing’S Disease ◽  
Cross Sectional Study ◽  
Cushing's Disease ◽  
Sectional Study ◽  
Cross Sectional

scholarly journals Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease

2010 ◽  
Vol 95 (6) ◽  
pp. 2699-2714 ◽  
Author(s):  
Jitske Tiemensma ◽  
Nieke E. Kokshoorn ◽  
Nienke R. Biermasz ◽  
Bart-Jan S. A. Keijser ◽  
Moniek J. E. Wassenaar ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Functioning ◽  
Cushing’S Disease ◽  
Cognitive Impairments ◽  
Verbal Learning ◽  
Cushing's Disease ◽  
High Dose ◽  
Gender And Education ◽  
Irreversible Effects

Abstract Context and Objective: Active Cushing’s disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushing’s disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushing’s disease. Design: Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning. Patients and Control Subjects: We included 74 patients cured of Cushing’s disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education. Results: Compared with NFMA patients, patients cured from Cushing’s disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushing’s disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushing’s disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushing’s disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients. Conclusions: Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushing’s disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.

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