deamino-arginine-vasopressin and Pituitary-ACTH-Hypersecretion

Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret.. The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis.. This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis.. Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test.. The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Diagnosis, Differential; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion

Alcohol-induced hypercortisolism (AIH) is underrecognized and may masquerade as neoplastic hypercortisolism [Cushing syndrome (CS)] obscuring its diagnosis.. In order to characterize AIH, we performed a chart review of eight patients (4 males and 4 females; 2014-2022) referred for evaluation and treatment of neoplastic hypercortisolism - six for inferior petrosal sinus sampling, one due to persistent CS after unilateral adrenalectomy, and one for pituitary surgery for Cushing disease (CD). Five underwent dDAVP stimulation testing.. All eight patients had clinical features of hypercortisolism and plasma ACTH levels within or above the reference interval confirming hypothalamic-pituitary mediation. All had abnormal low-dose dexamethasone suppression test and increased late-night salivary cortisol. Only one had increased urine cortisol excretion. In contrast to CD, the 5 patients tested had blunted or absent ACTH and cortisol responses to desmopressin. Two had adrenal nodules and one had abnormal pituitary imaging. Most patients underreported their alcohol consumption and one denied alcohol use. Elevated blood phosphatidyl ethanol (PEth) was required in one patient to confirm excessive alcohol use. All patients had elevations of liver function tests (LFTs) with AST>ALT.. AIH is an under-appreciated, reversible cause of non-neoplastic hypercortisolism that is indistinguishable from neoplastic CS. Incidental pituitary and adrenal imaging abnormalities as well as under-reporting of alcohol consumption further confound the diagnosis. Measurement of PEth helps to confirm an alcohol use disorder. Elevations of LFTs (AST>ALT) and subnormal ACTH and cortisol responses to dDAVP help to distinguish AIH from neoplastic hypercortisolism.

Topics: Adrenocorticotropic Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Ethanol; Female; Humans; Hydrocortisone; Male; Pituitary ACTH Hypersecretion; Pituitary Diseases

The aim of this study was to evaluate the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin for pediatric Cushing’s disease (CD).. We reviewed studies performed in children that evaluated the accuracy of BIPSS with desmopressin.. All included studies were case series of children with adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. The overall accuracy of BIPSS before stimulation was 84.1% (37/44), and after stimulation it was 92.3% (36/39). The overall lateralizing accuracy of BIPSS was 50.0%.. Considering that available evidence is limited, it appears that BIPSS with desmopressin stimulation is accurate for the diagnosis of pediatric CD, but its lateralizing accuracy is probably not suitable for pediatric clinical practice.

Topics: Adrenocorticotropic Hormone; Child; Cushing Syndrome; Deamino Arginine Vasopressin; Humans; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion

The treatment of choice for Cushing's disease (CD) is trans-sphenoidal surgery (TSS). However, TSS is not always curative and, even when curative it is associated with a substantial rate of recurrence. Published recurrence rates vary between 5 and 20%; half of these recurrences appear within 5-years and the remaining half within or even after 10 years post-surgery. A low or undetectable cortisol in the immediate post-op period is regarded as the best criterion of remission. However, low post-op cortisol levels do not accurately predict long-term remission. Moreover, there are no other robust predictors providing certainty about the long-term outcomes. Interestingly, several studies have shown that the desmopressin test performed in the early post-op period may have some promise in predicting more precisely the risk of recurrence. In view of the lack of robust ways to predict long-term outcomes, current guidelines suggest that every patient in remission should be monitored for the possibility of recurrence. The methods used to detect recurrence are similar to those used to assess the cortisol secretory status and include assessment of: (i) abnormal circadian rhythm by late night salivary cortisol (LNSC) or midnight serum cortisol; (ii) impaired cortisol feedback by the dexamethasone suppression test and; (iii) increased 24-h bioavailable cortisol by urinary free cortisol. The timing of evaluation begins when HPA axis recovers, and then annually or sooner in case of clinical suspicion. Currently LNSC is regarded as the earliest and most sensitive biochemical alteration in detecting recurrence; a major caveat for LNSC, however, is its great variability. In practice, the diagnosis of recurrence is a challenge due to the fact that recurrence is usually a slow process with apparent clinical manifestations that may be delayed and alterations of classical biomarkers that may be delayed as well.

Topics: Biomarkers; Deamino Arginine Vasopressin; Dexamethasone; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary ACTH Hypersecretion; Pituitary-Adrenal System; Recurrence; Retrospective Studies

Inferior petrosal sinus sampling (IPSS) offers a means of differentiating between Cushing disease and Cushing syndrome with lower false-positive and false-negative rates relative to traditional techniques. However, consolidated data on efficiency reflecting contemporary use is lacking. We present a comprehensive meta-analysis of IPSS as a means of diagnosing ACTH-cortisol axis derangements via both CRH and desmopressin-stimulated techniques.. Searches of 7 electronic databases from inception to December 2020 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. Outcomes were pooled by random-effects meta-analyses of proportions where possible. We performed a meta-analysis of sixty-eight unique publications, assessing each technique for positive predictive value (PPV), false positive rates, and overall changes in practice patterns over time.. A total of 68 studies satisfied all criteria, with 3685 (3471, 94.2% confirmed) and 332 (285, 85.8% confirmed) patients tested for Cushing's disease and syndrome, respectively. Pooled analyses demonstrated an overall PPV of 89.3% (95%CI[83.6%, 94.0%]) in CRH stimulation diagnosis of Cushing disease. In desmopressin stimulation, our analyses demonstrated an overall PPV of 96.5% (95%CI[94.5%, 98.1%]) in diagnosis of Cushing disease. There was a significant decline in the use of CRH-stimulation IPSS in diagnosis of both Cushing disease (p = 0.0055) and Cushing syndrome (p = 0.013). Concurrently, there was a significant increase in the use of desmopressin-stimulation IPSS in diagnosis of both pathologies (p < 0.0001).. Our findings demonstrate significant changes in practice patterns with respect to IPSS stimulation technique. Our pooled analyses demonstrate improved diagnostic performance in desmopressin stimulation procedures relative to CRH stimulation procedures. Further multi-institutional studies with special attention to acquiring quality data for sensitivity, specificity, and other critical analyses are necessary to truly evaluate this promising technique.

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Diagnosis, Differential; Humans; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Predictive Value of Tests

The aim of this study was to review the literature published and the most important papers presented to meetings on Cushing's disease from October 2011 to September 2012. The selection has been performed according to the authors' criteria. Articles have been classified into five groups: quality of life and perception of the disease, clinical features and pathophysiology, comorbidity conditions, diagnosis, and treatment. The results and conclusions of each publication are discussed.

Topics: ACTH-Secreting Pituitary Adenoma; Deamino Arginine Vasopressin; Endomyocardial Fibrosis; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Hypophysectomy; Neoplasm Proteins; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prognosis; Quality of Life; Somatostatin; Thrombophilia

Because of the variability in the clinical expression of Cushing's syndrome, different biochemical tests and imaging techniques must be used for effective diagnosis and treatment. The clinical history is important to assess the general impact of hypercortisolism on organs and systems, as well as to guide suspicion toward more aggressive entities such as overt ectopic ACTH syndrome or to detect an iatrogenic etiology of Cushing's syndrome. The screening phase relies on tests that are sensitive but not specific, such as urinary free cortisol, nocturnal salivary cortisol and 1 mg dexamethasone suppression, which still require established assessment criteria. Confirmation can be obtained by repeating urinary cortisol, 2 mg/day dexamethasone suppression, both alone and combined with corticotropin releasing hormone (CRH), to exclude pseudoCushing states. ACTH dependency can be easily explored by ACTH measurements, but the differential diagnosis between pituitary and ectopic Cushing's disease is difficult and may require invasive procedures such as inferior petrosal sinus sampling. Sophisticated imaging and isotopic techniques play a significant role in locating the source of ACTH in ectopic syndromes but are not always effective. In general, biochemical and imaging tests should be combined in order to assess different mechanisms and perspectives of the syndrome. Rigorous methodology is essential to obtain accurate results, allowing a correct diagnosis and improving therapeutic performance in this devastating disease.

Topics: ACTH Syndrome, Ectopic; Adenoma; Adrenal Cortex Neoplasms; Adrenocorticotropic Hormone; Circadian Rhythm; Corticotropin-Releasing Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Dexamethasone; Diagnosis, Differential; Diagnostic Imaging; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Pituitary-Adrenal System; Saliva

Topics: ACTH Syndrome, Ectopic; Adrenal Cortex Function Tests; Adrenocorticotropic Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Diagnosis, Differential; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Pituitary Neoplasms

Recurrence of Cushing's disease (CD) after transsphenoidal surgery (TSS) occurs in about 25% of cases. Twenty percent of patients with immediate postsurgical corticotroph deficiency will present late recurrence.. The aim of the study was to evaluate a coupled dexamethasone desmopressin test (CDDT) as a predictor of recurrence of CD.. We conducted a prospective bicenter study (Marseille and Grenoble, France).. We studied 38 patients treated by TSS for CD with a mean follow-up of 60 months.. We evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose dexamethasone suppression test and CDDT 3 to 6 months after surgery and then yearly.. After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH. Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol. Basal values were observed after low-dose dexamethasone suppression test. Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence.. Ten patients presented recurrence. ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in three of 28 patients in remission (100% sensitivity, 89% specificity). The test became positive in eight of 10 patients with recurrence 6-60 months before classical markers of hypercortisolism. Six patients with immediate postsurgical corticotroph deficiency presented recurrence. All of them presented CDDT positivity during the 3 yr after surgery, and recurrence 6 to 60 months after CDDT positivity.. CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 yr after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Biomarkers; Deamino Arginine Vasopressin; Dexamethasone; Diagnostic Techniques, Endocrine; Early Diagnosis; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Postoperative Complications; Prognosis; Recurrence; Sensitivity and Specificity; Young Adult

The differential diagnosis between Cushing's disease (CD) and ectopic ACTH syndrome (EAS) is complex, and bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold-standard test. However, BIPSS with corticotropin-releasing hormone (CRH) stimulation is rarely available.. This retrospective cohort study aimed to assess the accuracy of the inferior petrosal sinus to peripheral ACTH gradient (IPS:P) before and after desmopressin stimulation for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), applying different cutoff values.. A total of 50 patients (48 with CD and 2 with EAS) who underwent BIPSS were included in this study. The sensitivity and specificity of IPS:P in BIPSS before and after desmopressin stimulation were evaluated. Various cutoff values for IPS:P were examined to determine their diagnostic accuracy.. Using the traditional IPS:P cutoff, the sensitivity was 85.1% before stimulation, 89.6% after stimulation, and a combined sensitivity of 91.7%. Applying cutoff values of IPS:P >1.4 before and >2.8 after stimulation, the sensitivity was 87.2% and 89.6%, respectively, with a combined sensitivity of 91.7%. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values of 1.2 before stimulation and 1.57 after stimulation, resulting in a sensitivity of 93.6% and 93.8%, respectively, with a combined sensitivity of 97.9%. Specificity remained at 100% throughout all analyses. Among the 43 patients who responded positively to stimulation, 42 (97.7%) did so within the first three minutes, and all 43 (100%) did so within the first five minutes. None of the assessed clinical variables predicted the ACTH response to stimulation in BIPSS with statistical significance.. ACTH stimulation with desmopressin during BIPSS improves the accuracy of IPS:P, making it a valuable tool for investigating ACTH-dependent Cushing's syndrome. Considering the low risk of complications, we recommend the use of desmopressin stimulation during BIPSS for the differential diagnosis of ACTH-dependent CS.

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Humans; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Retrospective Studies

This single-center retrospective cohort study aimed to describe the findings and validity of Bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of patients with ACTH-dependent Cushing's syndrome (CS).. Eleven patients underwent BIPSS due to equivocal biochemical tests and imaging results. Blood samples were taken from the right inferior petrosal sinus (IPS), left IPS, and a peripheral vein before and after stimulation with desmopressin (DDAVP). ACTH and prolactin levels were measured. The diagnosis was based on the ACTH ratio between the IPS and the peripheral vein. Also, lateralization of pituitary adenoma in patients with Cushing's disease (CD) was predicted. No significant complications were observed with BIPSS.. Based on the pathology report, eight patients had CD, and three had ectopic ACTH syndrome (EAS). Unstimulated BIPSS resulted in a sensitivity of 87.5%, specificity of 100%, PPV of 100%, NPV of 75%, and accuracy of 91%. Stimulated BIPSS resulted in a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and accuracy of 100%. However, pituitary magnetic resonance imaging (MRI) had a lower diagnostic accuracy (sensitivity:62.5%, specificity:33%, PPV:71%, NPV:25%, accuracy:54%). BIPSS accurately demonstrated pituitary adenoma lateralization in 75% of patients with CD.. This study suggests that BIPSS may be a reliable and low-complication technique in evaluating patients with ACTH-dependent CS who had inconclusive imaging and biochemical test results. The diagnostic accuracy is improved by DDAVP stimulation. Pituitary adenoma lateralization can be predicted with the aid of BIPSS.

Topics: Adenoma; Adrenocorticotropic Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Diagnosis, Differential; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Retrospective Studies

To clarify the characteristics of Cushing's disease (CD) patients who respond to the desmopressin (DDAVP) test and its underlying mechanisms.. Forty-seven patients with CD who underwent DDAVP testing were included. Patients were divided into two groups: DDAVP test (+) (adrenocorticotropic hormone [ACTH] levels increased by ≥ 1.5-fold during the DDAVP test) and DDAVP test (-) (ACTH levels increased by < 1.5-fold). AVP receptor expression levels in these tumors were quantified using quantitative RT-PCR and immunohistochemistry. AVP receptor promoter activity was analyzed using a dual-luciferase reporter assay system.. Females (96.9%) and USP8 mutants (85.7%) were more prevalent in the DDAVP test (+) than in the DDAVP test (-). Indeed, the ACTH and cortisol responsiveness to DDAVP was greater in USP8 mutation positive tumors than that in USP8 wild type tumors (3.0-fold vs. 1.3-fold, 1.6-fold vs. 1.1-fold, respectively). Responsiveness to DDAVP was correlated with the expression levels of AVPR1B, but not with those of AVPR2. Comparably, Avpr1b promoter activity was enhanced by the overexpression of mutant USP8 compared to the wild type.. We found that the responsiveness of ACTH to DDAVP in CD was greater in tumors with USP8 mutations. The present data suggest that USP8 mutations upregulate the AVPR1B promoter activity. Additionally, we showed that the DDAVP test can predict the presence of USP8 mutations.

Topics: Adrenocorticotropic Hormone; Deamino Arginine Vasopressin; Endopeptidases; Endosomal Sorting Complexes Required for Transport; Female; Humans; Hydrocortisone; Mutation; Pituitary ACTH Hypersecretion; Promoter Regions, Genetic; Receptors, Vasopressin; Ubiquitin Thiolesterase

Differentiating the etiology of ACTH-dependent Cushing's syndrome (CS) has remained challenging due to the limited accuracy of noninvasive assays. Nowadays, bilateral inferior petrosal sinus sampling (BIPSS) with corticotropin-releasing hormone (CRH) is the gold standard method in the diagnostic work-up of complex CS. However, this method is as yet far from being widespread. The limited utility of this method could be due to many factors such as limited availability of an experienced interventionist, limited availability of CRH, and cost of the procedure. So far, very few studies have been conducted using desmopressin instead of CRH. In this study, we report the use of BIPSS with desmopressin as a diagnostic tool in a series of patients with suspected Cushing's disease (CD) and equivocal imaging in a tertiary referral center in Iran.. A total of 13 patients with ACTH-dependent CS and no significant lesions in their pituitary MRI participated in this retrospective case series. All patients underwent BIPSS with desmopressin, and, following centralization of CS, transsphenoidal surgery (TSS) was carried out and diagnosis of CD was confirmed using standard methods.. Of the 13 patients with confirmed CD (by pathology or biochemical response after surgery), eight (61.5%) were female, with a median age of 32 years (IQR: 26-41). The median duration of disease was 24 months (IQR: 11-48). During BIPSS, all patients had a central-to-peripheral gradient greater than 2 under basal conditions. This central-to-peripheral gradient did not increase to > 3 after desmopressin administration in two of these patients. Based on the gradient after BIPSS, the sensitivity of this modality in the diagnosis of CD was 100%. Eight of the 13 patients had right lateralization in both BIPSS and TSS; therefore, the accuracy rate of lateralization by BIPSS was 61.5%. No complications occurred after BIPSS, the exception being the development of groin hematoma in one patient.. No significant benefits of adding desmopressin to BIPSS were observed. The sensitivity of BIPSS in the diagnosis of CD was high, whereas it has moderate accuracy in tumor lateralization.

Topics: Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Female; Humans; Iran; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Retrospective Studies

Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI.. Multicentre retrospective study.. Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses.. Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively).. The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

Topics: Adult; Antidiuretic Agents; Deamino Arginine Vasopressin; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Postoperative Complications; Predictive Value of Tests; Recurrence; Retrospective Studies

Transsphenoidal surgery (TSS) is the treatment of choice in Cushing's disease. However, recurrence rates are substantial and currently there are no robust predictors of late prognosis. As accumulating evidence challenge the accuracy of the traditionally used early postoperative cortisol values, alternative tests are required. The study of Cambos et al., published in a recent issue of the European Journal of Endocrinology, adds to the existing data that support a role of the desmopressin test as an early and reliable predictive marker in successfully TSS-treated patients. However, despite these promising data, the use of this test is hampered by the fact that it can be applied only in patients with a documented preoperative positive test. Moreover, the lack of robust criteria to define positive postoperative responses represents another major limitation.

Topics: Adrenocorticotropic Hormone; Biomarkers; Deamino Arginine Vasopressin; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Postoperative Period; Recurrence

To analyze the bilateral and simultaneous petrosal sinus sampling (BIPSS) in a subgroup of children and adolescents with ACTH-dependent Cushing's syndrome (ADCS) METHODS: Retrospective study in a tertiary reference center. From 1993 and 2017, 19 children and adolescents (PED) were submitted to the BIPSS, median age of 14 years (range 9-19 years), 53% were males, 18 had Cushing's disease (CD) and one had ectopic ACTH syndrome (EAS). All procedures were performed with 10 µg of intravenous desmopressin.. The catheter positioning was successful in all cases. The central ACTH gradient was met in 17/19 cases. At baseline, central gradient occurred in 16/19 (84%) with gradient values of 7.2 ± 6.0. After stimulation, there was an increase in the center-periphery gradient values (33.6 ± 44.3). In one case, central gradient was defined only after stimulation. Two cases presented without a central gradient; one case of CD with a false-negative and one EAS case. Lateralization occurred in all cases with a central gradient. Confirmation of the tumor location presumed by the procedure with the surgical description occurred in 60% of the cases. The BIPSS in this PED subgroup of ADCS presented a sensitivity of 94.4% and specificity of 100%. There were no complications of the procedure.. In a series of children and adolescents with ADCS, BIPSS was safe and highly accurate in defining the central to peripheral ACTH gradient using desmopressin as secretagogue. Nevertheless, there was a limited value of the ACTH-gradient between the petrosal sinuses for the tumor location.

Topics: Adolescent; Adult; Child; Cushing Syndrome; Deamino Arginine Vasopressin; Female; Humans; Male; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Retrospective Studies; Young Adult

Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results. However, IPSS is an invasive procedure and its availability is limited.. To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD.. Retrospective study.. Two university hospitals.. A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016.. Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results.. Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD. The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively. CT scan identified 67% EAS at presentation with no false-positives. The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan. The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan. Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended.. In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome.

Topics: ACTH Syndrome, Ectopic; Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Aged, 80 and over; Algorithms; Deamino Arginine Vasopressin; Decision Support Techniques; Diagnosis, Differential; Female; Humans; Hydrocortisone; Magnetic Resonance Imaging; Male; Middle Aged; Neuroendocrine Tumors; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Pituitary Function Tests; Pituitary Gland; Predictive Value of Tests; Retrospective Studies; Tomography, X-Ray Computed; Young Adult

We investigated the expression of vasopressin receptor 2 and 3 on corticotrophin tumor cells, their role in regulating ACTH secretion, and their potential therapeutic implications.. We retrospectively assessed 52 hospitalized patients with pathologically confirmed ACTH-secreting tumors. The expression of vasopressin receptor 2 and 3 was explored via qualitative and quantitative immunohistochemistry analyses. The role of vasopressin receptors in regulating ACTH secretion was further studied in the AtT-20 cell line.. Among 50 cases of pituitary corticotrophin adenoma, 31 were vasopressin receptor 2 positive, 38 were vasopressin receptor 3 positive, and 24 were both vasopressin receptor 2 and 3 positive. Two patients with ectopic ACTH syndrome were vasopressin receptor 3 positive, and one was also vasopressin receptor 2 positive. In 12 patients who underwent bilateral inferior petrosal sinus sampling before surgery, the central ACTH increment ratio after desmopressin stimulation was correlated with vasopressin receptor 2 but not with vasopressin receptor 3 staining intensity. In an. Both vasopressin receptor 2 and 3 are expressed in ACTH-secreting tumors. Vasopressin receptor 2 rather than vasopressin receptor 3 is the primary receptor that seems to mediate the ACTH response in corticotrophin tumors. A vasopressin receptor 2 antagonist can inhibit ACTH secretion induced by desmopressin in AtT-20 cells.

Topics: ACTH Syndrome, Ectopic; Adolescent; Adrenocorticotropic Hormone; Adult; Antidiuretic Hormone Receptor Antagonists; Cell Line, Tumor; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Pituitary ACTH Hypersecretion; Receptors, Vasopressin; Retrospective Studies; Tumor Cells, Cultured; Young Adult

Bilateral inferior petrosal sinus sampling (BIPSS) is useful for differential diagnosis of adult Cushing's disease (CD) but may not be so reliable in pediatric cases. The purpose of this study was to evaluate the sensitivity of BIPSS before and after desmopressin stimulation in pediatric CD, and to explore related factors of false-negative results and meanings of sampling lateralization.. We retrospectively analyzed 16 pediatric CD patients who underwent 17 BIPSS procedures from 2006 to 2017. CD was diagnosed if inferior petrosal sinus (IPS) to peripheral adrenocorticotropic hormone (ACTH) ratio was >2 at baseline or >3 after desmopressin stimulation. Sampling lateralization was yielded if interpetrosal sinus gradient was >1.4. Magnetic resonance imaging (MRI) was conducted. All the patients underwent surgery and the diagnosis was confirmed.. The sensitivity was 64.7% (11/17) at baseline and 83.3% (10/12) after desmopressin stimulation. After stimulation, BIPSS reached its best sensitivity at 3 min. Sampling lateralization rate was 62.5% and 63.6% before and after stimulation, and the accordant rate with actual tumor lateralization was 50.0% and 42.9%, respectively. The accuracy of MRI in predicting the tumor lateralization was 80.0%. Sampling lateralization rate (81.8% in true-positive, 20.0% in false-negative, p = 0.036) and ACTH at dominant IPS (p = 0.001) was lower among false-negative patients.. The sensitivity of BIPSS in pediatric CD was low at baseline, but increased after desmopressin stimulation. Sampling lateralization cannot accurately indicate the tumor lateralization, but the absence of sampling lateralization with low ACTH at IPS is a hint of false-negative cases in BIPSS.

Topics: Adolescent; Child; Deamino Arginine Vasopressin; Female; Humans; Magnetic Resonance Imaging; Male; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Retrospective Studies; Young Adult

Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin.. We retrospectively analysed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or nonsuppressed high-dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients.. Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery.. IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH.

Topics: ACTH Syndrome, Ectopic; Adult; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Retrospective Studies; Software

To describe findings and outcomes of 331 bilateral inferior petrosal sinus sampling (BIPSS) procedures performed in 327 patients evaluated for Cushing disease (CD).. The radiology department's electronic database was searched to identify all BIPSS procedures (1990-2013). Electronic medical records were used to identify demographics, laboratory, procedural, surgical and pathologic findings.. A total of 331 BIPSS procedures were performed in 327 patients (254 F, 73 M), mean age 41 (range 7-81) years. The overall technical success rate was 88% for bilateral cannulation, though nearly two-thirds of the technical failures had unilateral sampling that diagnosed CD. Of the 331 BIPSS procedures, 40 were performed without, and 291 with stimulation by Acthrel or desmopressin. Sensitivity was 89-94% for unstimulated BIPSS, 96% for stimulated BIPSS, and 77% for MRI. BIPSS lateralization was accurate in about half of patients, compared with 75% accuracy for MRI. Mean inferior petrosal sinus (IPS):peripheral adrenocorticotropic hormone ratio was 17.3 (SE 1.8) at baseline, and 99.2 (SE 14.8) at 3 min, with decreasing values over time. All patients with follow-up after surgical resection for centralizing BIPSS were reported to be cured, with cortisol levels significantly decreased from 19 to 4 μg/dL (p<0.0001). Complications from BIPSS were rare, including groin hematoma (2.5%), but no thromboembolic complications were seen.. BIPSS remains the 'gold standard' for diagnosing CD. Stimulation with Acthrel or desmopressin is key to increasing specificity. When only one IPS can be successfully cannulated, results may still be diagnostic. BIPSS findings cannot be used to accurately lateralize lesions within the pituitary.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Aged, 80 and over; Angiography, Digital Subtraction; Cerebral Angiography; Child; Deamino Arginine Vasopressin; Female; Humans; Hydrocortisone; Magnetic Resonance Imaging; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Postoperative Complications; Reproducibility of Results; Treatment Outcome; Young Adult

Cushing's disease (CD) has a significant relapse rate after successful transsphenoidal surgery (TSS). Many CD patients respond aberrantly to the desmopressin test (DT). Disappearance of this response after surgery may suggest complete removal of abnormal corticotrophs and a lower possibility of recurrence.. The utility of postoperative DT to predict long-term outcome compared to the widely used postoperative cortisol level.. Retrospective analysis.. Tertiary hospital.. Seventy-three patients underwent TSS and postoperative DT; 51 had sustained remission, defined as normal dexamethasone suppression and urinary free cortisol at 6 months. After excluding 12 patients with short follow-up, negative or no preoperative DT, we analyzed 39 patients.. Measurements of morning cortisol at 1-2 weeks and DT within 6 months after TSS.. Recurrence or remission at latest follow-up.. Mean follow-up was 63 ± 50 months. Recurrence occurred in seven patients. In logistic regression analysis, postoperative cortisol levels were not associated with remission. Apart from the percentage increment of cortisol, all other DT criteria (peak cortisol, peak ACTH, absolute cortisol increment [ΔCort], absolute ACTH change, and percentage absolute ACTH change) were significant predictors of outcome. In receiver operating characteristic analysis, the ΔCort had the best diagnostic performance. ΔCort <7.4 μg/dL had a sensitivity of 97% to detect remission. Comparison of Kaplan-Meier curves showed that ΔCort <7.4 μg/dL was associated with remission, whereas ΔCort ≥7.4 μg/dL had a hazard ratio of recurrence of 24.7 (95% confidence interval, 10.6-448.5) at 60 months (median).. Loss of desmopressin response indicates favorable prognosis and, if used in addition to basal cortisol levels, improves the accuracy of the postoperative assessment of CD.

Topics: Adult; Antidiuretic Agents; Deamino Arginine Vasopressin; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; Outcome Assessment, Health Care; Pituitary ACTH Hypersecretion; Predictive Value of Tests; Prognosis; Recurrence

Bilateral inferior petrosal sinus sampling (BIPSS) following corticotropic-releasing hormone (CRH) stimulation is the current gold standard technique in the diagnosis of Cushing disease. However, as a result of CRH shortage, desmopressin (DDAVP) has been used instead for BIPSS. We present the experience of a single tertiary care center using the modified BIPSS protocol and compare the results obtained with DDAVP with those obtained with CRH.. Using the radiology department's electronic database, BIPSS procedures performed at our institution using DDAVP and CRH were identified. Electronic medical records and imaging studies were reviewed and the clinical history, demographic data, endocrine test results, complications of BIPSS, and patient outcomes were recorded. BIPSS data were analyzed for centralization and lateralization of pituitary adrenocorticotropic hormone (ACTH) source. We identified 20 BIPSS cases (16 women, mean age 38 years) performed using DDAVP between 2012 and 2013.. The 20 cases demonstrated conventional inferior petrosal sinus anatomy and were successfully cannulated bilaterally. Of these, 18 met the criteria for both centralization and lateralization. A total of 18 patients underwent trans-sphenoidal tumor resection; one patient was lost to follow-up and one is still being followed. There were no complications resulting from the use of DDAVP, specifically no thromboembolic events. Calculated sensitivity for BIPSS with DDAVP was 94.5%. There was also no significant difference in the biochemical results produced by BIPSS using either DDAVP or CRH. All 18 patients demonstrated an ACTH-secreting adenoma on pathology review.. DDAVP is a safe alternative to CRH, producing comparable diagnostic results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Young Adult

Prolactin may reduce false-negative results in diagnosing Cushing's disease (CD) during inferior petrosal sinus sampling (IPSS). Prolactin normalization could improve the accuracy of IPSS in predicting adenoma lateralization in CD. However, none of the previous studies had involved the use of desmopressin during IPSS. Our objective was to examine the utility of prolactin measurement during IPSS with desmopressin stimulation. We conducted a retrospective analysis of 40 patients (including 31 females) with ACTH-dependent Cushing's syndrome who underwent IPSS between 2010 and 2013. Thirty-eight CD patients were partitioned into true positive (n = 35) and false negative (n = 3). The proportion of improper IPSS venous sampling defined by corresponding IPS:P (inferior petrosal sinus to peripheral) prolactin ratio <1.8 was significantly different between two groups (P = 0.004). Applying a prolactin-normalized ACTH IPS:P ratio >0.8 cutoff could increase the sensitivity of IPSS to 38/38 (100 %). Among the 31 patients with histopathologically proven adenoma localization, correct prediction of adenoma lateralization was obtained in 14/31 (45 %) patients by a peak intersinus ACTH gradient of ≥1.4 in baseline and was not improved by desmopressin stimulation. Left-right intersinus gradients of unilateral prolactin-adjusted ACTH IPS:P ratios could increase the correct prediction of adenoma lateralization to 20/31 (65 %) in baseline and 24/31 (77 %) (P = 0.006) after desmopressin stimulation, respectively. Prolactin is helpful to adjust negative results of IPSS with desmopressin stimulation. It may improve the accuracy in predicting adenoma lateralization in CD as well.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adult; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Prolactin

To analyse the performance of the desmopressin (DDAVP) test in the diagnosis of Cushing's disease (CD).. This was a prospective cohort study of 124 patients with suspected hypercortisolism who were recruited from an outpatient endocrinology clinic and investigated for Cushing's syndrome (CS). The ACTH and cortisol responses to the DDAVP test were assessed to determine patient diagnosis and test the procedure's diagnostic accuracy.. A total of 68 patients had CD, while 56 had suspected CS. According to ROC analysis, an ACTH peak of 71·8 pg/ml (15·8 pmol/l) following DDAVP administration was able to diagnose CD with a specificity of 94·6% and a sensitivity of 90·8%, a negative predictive value (NPV) of 89·9% and a positive predictive value (PPV) of 95·3%. An absolute ACTH increment ≥37 pg/ml (8·1 pmol/l) over baseline had a sensitivity of 88·0%, specificity of 96·4%, NPV of 87·0% and PPV of 95·3% in diagnosing CD. Only 2 of 56 cases without CD had an absolute ACTH increment ≥37 pg/ml (8·1 pmol/l) over baseline. The DDAVP test was superior to other clinical instruments in diagnosing CS.. The DDAVP test could be a useful additional tool to diagnose CD in patients with suspected CS.

Topics: Adrenocorticotropic Hormone; Adult; Brazil; Cohort Studies; Deamino Arginine Vasopressin; Diagnosis, Differential; Diagnostic Techniques, Endocrine; Female; Hormone Antagonists; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Prospective Studies; Reproducibility of Results

Predicting the outcome of patients operated on for Cushing's disease (CD) is a challenging task. Our objective was to assess the accuracy of immediate postsurgical plasma cortisol, desmopressin test and the coupled dexamethasone-desmopressin test (CDDT) as predictors of outcome.. Sixty-seven patients with initial remission and a minimal postsurgical follow-up greater than 18 months were included in this retrospective bicentre study.. Follow-up included 3-6 months followed by yearly 24-h urinary-free cortisol, ACTH and cortisol plasmatic levels, a 1-mg overnight dexamethasone suppression test (1-mg DST), desmopressin test and the CDDT. ROC curves were performed to define the optimal threshold of immediate postsurgical cortisol level and 3- to 6-month desmopressin test and CDDT, as predictors of final outcome in comparison with classical biological markers of recurrence.. Eleven patients presented recurrence. The patient's median follow-up was 52 months (range, 18-180). As early predictors of outcome, immediate postsurgical plasma cortisol level <35 nmol/l predicted the lack of recurrence with 93% negative predictive value (NPV), whereas predictive positive value (PPV) was 25%. During the follow-up, the CDDT was more precise than the desmopressin test in predicting the lack of recurrence (100% NPV) when performed in the first 3 years after surgery. Positivity of the CDDT was defined based on ROC curves by ACTH and cortisol increments >50%. The CDDT was highly reproducible, as the same response was observed every year in 91% of the patients.. Adding the CDDT the first 3 years after surgery to immediate postsurgical cortisol evaluation should allow obtaining an optimal follow-up management of patients operated for Cushing's disease.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Deamino Arginine Vasopressin; Dexamethasone; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Postoperative Period; Predictive Value of Tests; Recurrence; Remission Induction; Retrospective Studies; ROC Curve; Young Adult

A 32-year-old Chinese woman with rapid weight gain and progressive edema was found to have typical Cushingoid features. Her endocrine data were consistent with a diagnosis of ACTH-dependent Cushing's syndrome. To differentiate ectopic ACTH syndrome (EAS) from Cushing's disease (CD), various dynamic endocrine and imaging tests were performed. Her ACTH response was negative to corticotropin-releasing hormone (CRH) and positive to desmopressin. Magnetic resonance imaging of the pituitary showed no mass lesion. Computed tomography scan of the chest revealed a large mass (21 × 15 mm) in the anterior mediastinum, where positron emission tomography showed accumulation of [(18)F] fluorodeoxyglucose. Selective venous sampling showed marked step-up in ACTH level in the internal thoracic vein but not in the cavernous sinus after CRH stimulation. These data are compatible with the diagnosis of EAS. The resected tumor was pathologically consistent with thymic neuroendocrine tumor (NET) positive for ACTH by immunohistochemistry and abundant V1b receptor gene expression by RT-PCR. Postoperatively, her circulating ACTH/cortisol levels became normalized, and responded to stimulation with CRH but not with desmopressin. Her Cushingoid appearance gradually disappeared, and she was free from recurrence 5 years after surgery. This is a rare case of desmopressin-responsive EAS caused by thymic NET with predominant V1b gene expression, which was successfully localized by imaging modalities combined with selective venous sampling.

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Gene Expression; Humans; Hydrocortisone; Neuroendocrine Tumors; Pituitary ACTH Hypersecretion; Positron-Emission Tomography; Receptors, Vasopressin; Thymus Neoplasms; Tomography, X-Ray Computed

To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case.. Laboratory tests included morning and midnight serum cortisol levels, 24h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques.. A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results.. Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.

Topics: ACTH-Secreting Pituitary Adenoma; Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Deamino Arginine Vasopressin; Female; Humans; Hydrocortisone; Hypophysectomy; Magnetic Resonance Imaging; Periodicity; Phenotype; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured

Desmopressin is a synthetic agonist of vasopressin receptors (AVPRs). The desmopressin stimulation test is used in the diagnosis and postsurgery prognosis of Cushing disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in patients with CD are poorly understood.. The objectives of this study were to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release and to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD.. A total of 8 normal pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning pituitary adenomas, 17 somatotropinomas, and 3 prolactinomas were analyzed for AVPR expression by quantitative real-time RT-PCR. Primary cultures derived from corticotropinomas, nonfunctioning pituitary adenomas, somatotropinomas, prolactinomas, and NPs were treated with desmopressin, and ACTH secretion/expression, [Ca(2+)]i kinetics, and AVPR expression and/or proliferative response were evaluated. The relationship between AVPR expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin tests was assessed.. Desmopressin affects all functional parameters evaluated in corticotropinoma cells but not in NPs or other pituitary adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b antagonist completely blocked desmopressin stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas.. The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.

Topics: Adenoma; Adrenocorticotropic Hormone; Aged; Deamino Arginine Vasopressin; Humans; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Function Tests; Pituitary Gland; Pituitary Neoplasms; Prognosis; Receptors, Vasopressin

Activation of the hypothalamic-pituitary-adrenal axis has been reported in some patients with the obstructive sleep apnea syndrome (OSAS). In current study, we investigated whether OSAS affect the screening test for subclinical Cushing's disease using 0.5 mg overnight dexamethasone suppression test (DST) in Japanese obese diabetic patients with OSAS. Among Japanese obese patients with type 2 diabetes mellitus who had been hospitalized in our department, we selected 20 patients with moderate to severe untreated OSAS (apnea-hypoxia index, AHI, of ≥15 events/hour). All patients underwent 0.5 mg DST. The same test was repeated in patients with positive response of it within a few days after continuous positive airway pressure (CPAP) therapy. We found that five patients showed positive response of DST (25%). Three of these patients continued to use CPAP, and they showed normal response of DST after CPAP therapy. Serum cortisol after 0.5 mg DST measured before CPAP therapy correlated significantly with fasting serum cortisol level (r=0.764, p<0.0001), but not with various clinical parameters, including AHI (p=0.784), body mass index (p=0.984), waist circumference (p=0.957), HbA1c (p=0.261), fasting plasma glucose (p=0.420) and HOMA-IR (p=0.500). Our study show that OSAS causes a pseudo-Cushing's syndrome in obese patients with type 2 diabetes mellitus, which phenomena can be reversed by CPAP therapy.

Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Adult; Body Mass Index; Continuous Positive Airway Pressure; Cushing Syndrome; Deamino Arginine Vasopressin; Dexamethasone; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Hydrocortisone; Japan; Male; Middle Aged; Obesity; Overweight; Pituitary ACTH Hypersecretion; Pituitary Gland; Severity of Illness Index; Sleep Apnea, Obstructive

In more than one third of patients with Cushing's disease, pituitary MRI does not identify a microadenoma. The diagnostic approach should be as rigorous as possible in patients with ACTH-dependent Cushing's syndrome, to obtain a definitive diagnosis. Improved pituitary MRI techniques, including dynamic sequences, optimal T1-weighted spin-echo MRI protocol, MRI technique of spoiled gradient recalled acquisition in the steady state, and using a 3-tesla magnet, improved the tumor detection rate, parallel to the performance of endocrine dynamic tests (CRH stimulation, desmopressin stimulation and high-dose dexamethasone suppression tests). When a pituitary tumor is not convincingly identified, inferior petrosal sinus sampling remains the gold standard for diagnosis, and recently, new approaches (simultaneous prolactin measurement) could improve its sensitivity and specificity. Transsphenoidal surgery is the first-line treatment, with remission rates similar to those of patients with preoperative positive MRI. However, medical therapies play an important role after surgical failure or in a search for the onset of a visible tumor, especially with development of new drugs targeting the pituitary gland.

Topics: Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Dexamethasone; False Negative Reactions; Humans; Magnetic Resonance Imaging; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Remission Induction; Sensitivity and Specificity

In this technical note, the use of desmopressin to stimulate pituitary adrenocorticotropic hormone secretion in place of the commercially available corticotropin releasing hormone (CRH) in bilateral inferior petrosal sinus sampling is described. Although the use of CRH is the standard of practice, it is currently unavailable in the USA and desmopressin provides reliable results with no additional observed side effects.

Topics: Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Humans; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion

There is no consensus on the remission criteria for Cushing's disease or on the definition of disease recurrence after transsphenoidal surgery, and comparison of the different published series is therefore difficult. A long-term recurrence rate of Cushing's disease ranging from 2%-25% has been reported. Predictors of long-term remission reported include: 1) adenoma-related factors (aggressiveness, size, preoperative identification in MRI), 2) surgery-related factors, mainly neurosurgeon experience, 3) clinical factors, of which dependence on and duration of glucocorticoid treatment are most important, and 4) biochemical factors. Among the latter, low postoperative cortisol levels, less than 2 mcg/dL predict for disease remission. However, even when undetectable plasma cortisol levels are present, long-term recurrence may still occur and lifetime follow-up is required. We report the preliminary results of the first 20 patients with Cushing's disease operated on at our hospital using nadir cortisol levels less than 2 mcg/dl as remission criterion.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adolescent; Adrenal Insufficiency; Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Combined Modality Therapy; Deamino Arginine Vasopressin; Dexamethasone; Female; Follow-Up Studies; Glucocorticoids; Hormone Replacement Therapy; Humans; Hydrocortisone; Hypophysectomy; Male; Metyrapone; Middle Aged; Neoplasm Recurrence, Local; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Postoperative Complications; Remission Induction; Retrospective Studies; Saliva; Secretory Rate; Young Adult

Cushing's disease (CD) has an uncertain prognosis because patients achieving remission after transsphenoidal pituitary neurosurgery (TSS) may relapse. We aimed to identify factors predicting relapse, focusing on desmopressin (DDAVP) and corticotropin-releasing hormone (CRH) tests after surgery.. Fifty-seven patients with CD (mean age 36 years) after TSS experienced remission (24 cases), late relapse (LR) (15 cases), or persistent disease (18 cases).. The median time to relapse was 40 months. ACTH levels increased after both DDAVP and CRH stimulation, with a significantly higher response in the late recurrence group, showing this to be an indicator of increased risk of relapse. In the logistic regression model, a rise in ACTH >9 pg/ml after DDAVP and >36·7 pg/ml after CRH showed a sensitivity of 93% and 73%, respectively, a specificity of 82% and 76% in LR group. The area under the curve was 0·91 for DDAVP, 0·80 for CRH and 0·95 for DDAVP+CRH test, i.e. the combined tests performed better than each test alone, but not to a statistically significant degree. A response to both tests resulted in a positive predictive value (PPV) of 100%, while no response to either test in a negative predictive value (NPV) of 100%.. ACTH hyper-responsiveness to DDAVP stimulation proved a valuable indicator of relapsing patients with high sensitivity and specificity; in selected cases when a clear high increment of ACTH level is not evident, the CRH test might be used as additional tool to confirm the risk of future relapses.

Topics: Adolescent; Adult; Aged; Area Under Curve; Computer Simulation; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Female; Humans; Male; Middle Aged; Pituitary ACTH Hypersecretion; Predictive Value of Tests; Prognosis; Recurrence; Remission Induction; Treatment Outcome; Young Adult

Most patients with Cushing's disease (CD) respond to corticotrophin-releasing hormone (CRH) or desmopressin with increased corticotrophin (ACTH) and cortisol levels. Although the vasopressin receptor subtype located on normal corticotrophs is the V3 receptor (V3R), desmopressin is a selective V2 receptor (V2R) agonist and it is unclear whether corticotrophinomas exhibit aberrant V2R expression. Furthermore, no studies have determined the relationship between the in vivo response of CD patients to desmopressin and vasopressin receptor expression, or between the response to CRH and CRH receptor (CRHR) expression. Therefore, the aim of this study was to investigate the expression of vasopressin receptors (V1R, V2R, and V3R) and CRHR on corticotroph tumours and its possible relation to the in vivo response.. A prospective study of 29 patients with CD.. Patients underwent desmopressin and CRH stimulation tests before surgery. The expression of vasopressin receptors and CRHR on corticotrophinomas was determined by immunocytochemistry.. Most of the corticotrophinomas exhibited abundant expression of V1R, V3R, and CRHR, whereas the expression of V2R varied greatly and was lower in macroadenomas than in microadenomas. Both the percentage increment of ACTH and net area under the curve (AUC) of ACTH in the desmopressin stimulation test were found to be correlated with tumour volume. After adjustment for tumour volume, a positive correlation was found between the percentage increment of ACTH and the degree of V2R expression, but not between that of V1R or V3R. No relationship between the level of expression of CRHR on tumour tissues and the percentage increment or netAUC of ACTH to CRH was observed in CD patients.. We concluded that V2R was expressed on corticotrophinomas and that the level of its expression correlated well with the ACTH response to desmopressin in CD patients, although abundant expression of V1R and V3R was also found in almost all corticotroph tumours. Further studies are needed to elucidate the role of these receptors in the pathogenesis of CD.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Aged, 80 and over; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Female; Fluorescent Antibody Technique; Humans; In Situ Hybridization; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prospective Studies; Receptors, Vasopressin

Diagnosis of mild Cushing's disease (CD) can be difficult in pregnant women, because its clinical and biochemical features can be erroneously interpreted as consequence of the gestation. Corticotropin releasing hormone (CRH) and desmopressin (DDAVP) tests are currently used to confirm CD, but data concerning adrenocorticotropic hormone (ACTH) response during pregnancy are lacking. A woman with mild cushingoid features was evaluated during the first trimester of gestation. Serum cortisol was normal at morning, but increased at midnight and incompletely suppressed by 1-mg dexamethasone overnight administration. Also 24-h urinary free cortisol levels were mildly elevated. She delivered vaginally a healthy newborn at the 39th week of an uneventful pregnancy. After delivery, an ACTH-secreting microadenoma was surgically removed. During the first trimester of gestation and after delivery, human CRH (h-CRH) and DDAVP-stimulated ACTH peaks were higher than those measured in 22 healthy premenopausal women. While the ACTH/h-CRH peak was intermediate between those measured in the healthy women and in 9 CD female patients, ACTH/DDAVP peak was in the range of CD patients and dramatically higher than those of healthy women. However, ACTH increase after h-CRH was significantly higher after delivery than during gestation (p < 0.003), while ACTH responses to DDAVP were similar. In pregnant women with mild cushingoid features, h-CRH and DDAVP tests are useful to confirm the diagnosis of CD. Mild hypercortisolism can be well tolerated, but cardiovascular and metabolic parameters should be monitored carefully.

Topics: Adrenalectomy; Adult; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Live Birth; Pituitary ACTH Hypersecretion; Pregnancy; Pregnancy Complications; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Desmopressin is a known haemostatic agent and is also being used, albeit at lower doses, during the diagnostic work-up of Cushing's syndrome, a condition characterized by excess cortisol concentrations and frequent thromboembolic events. No study has yet evaluated whether administration of desmopressin for diagnostic purposes induces significant, adverse changes in endothelial cell markers in these patients.. Administration of desmopressin to patients with Cushing's disease induces changes in endothelial cell markers comparable with those observed in obese and normal weight subjects. It follows, that desmopressin testing does not induce disease-specific untoward changes in coagulatory markers in patients with endogenous hypercortisolism and its use in this context appears safe.. Desmopressin, a vasopressin analogue, is used for various clinical purposes, including haemostasis and, in recent times, the diagnostic work-up of patients with Cushing's syndrome, a condition associated with a known prothrombotic profile. We decided to evaluate whether and to what extent a diagnostic dose of desmopressin induces significant changes in endothelial parameters in patients with Cushing's disease (CD) and obese and normal weight controls.. Twelve patients with CD, 10 obese and five normal weight controls were studied. Von Willebrand antigen (VWF:Ag), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were measured at baseline and up to 4 h after 10 µg desmopressin i.v.. Desmopressin 10 µg transiently increased VWF:Ag and t-PA and decreased PAI-1 in all subjects. The magnitude of the VWF:Ag and t-PA increases after desmopressin was comparable in the three groups (VWF:Ag peak-to-basal ratio 1.9 ± 0.17, 1.5 ± 0.11 and 1.8 ± 0.13 and t-PA peak-to-basal ratio 1.6 ± 0.18, 1.6 ± 0.20 and 1.8 ± 0.24 for CD, obese and controls, respectively, all NS). The PAI-1 decrease observed in patients with CD was comparable with obese (0.7 ± 0.07 and 0.6 ± 0.09, NS) and controls (0.7 ± 0.07 vs. 0.4 ± 0.09, P= 0.08).. Administration of desmopressin to patients with CD for diagnostic purposes induces a transitory increase in VWF:Ag counterbalanced by a decrease in PAI-1 and increase in t-PA. The magnitude of these changes is largely comparable with that observed in obese and normal weight controls. Our data show that testing with desmopressin does not induce disease-specific changes in endothelial markers in patients with CD.

Topics: Body Weight; Case-Control Studies; Deamino Arginine Vasopressin; Fibrinolysis; Humans; Pituitary ACTH Hypersecretion; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator; von Willebrand Factor

We recently proposed a new and effective way of interpreting human corticotrophin-releasing hormone (hCRH) and desmopressin (DDAVP) tests, for the differential diagnosis between Cushing's disease (CD) and pseudo-Cushing state (PC), based on the simultaneous analysis of ACTH and cortisol.. The study had the aims of comparing the diagnostic performance of the two tests and determining whether carrying out both tests was more beneficial than carrying out only one.. We studied 30 CD, 18 PC and 12 control (CT) subjects: in these patients, hCRH test, DDAVP test, 24-h urinary free cortisol, serum cortisol after overnight 1-mg dexamethasone suppression test and serum cortisol circadian rhythm were performed.. The hCRH test and the DDAVP test showed an identical and excellent diagnostic performance (sensitivity 96·6% and specificity 100% for both tests); moreover, the hCRH and DDAVP tests showed almost perfect diagnostic agreement (κ = 0·93; P < 0·05) with a significantly higher number of concordant diagnoses (58 cases of 60) than those resulting from all other possible combinations among the studied tests. Interestingly, there were no subjects in whom both hCRH and DDAVP tests gave a simultaneous misdiagnosis.. Our study indicates that the hCRH and DDAVP tests have similar diagnostic performance and present excellent agreement, without giving simultaneous misdiagnosis in any subject. Because of these characteristics, the use of both tests offers the physician a valuable tool for those cases of hypercortisolism which are difficult to interpret.

Topics: Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Female; Humans; Hydrocortisone; Male; Pituitary ACTH Hypersecretion

GH-producing pituitary adenomas frequently co-produce other certain anterior pituitary hormones, such as prolactin (PRL). In contrast, GH-producing adenomas which express all of corticotropin-releasing factor (CRF), urocorin1 (Ucn1) and urocortin3 (Ucn3) have not been reported. A 39-year-old woman was admitted for evaluation of the pituitary tumor. The diagnosis of acromegaly was confirmed by elevated serum GH and IGF-I levels, and the absence of GH suppression by oral glucose tolerance test. ACTH response to desmopressin (DDAVP) was observed (plasma ACTH levels increased from 13.9 to 50.4 pg/ml at 90 min). Although it is known that ACTH response to DDAVP is considerably useful for the diagnosis of ACTH-dependent Cushing's syndrome, the diagnosis of Cushing's disease was not supported by the criteria. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistological examination confirmed a GH- and PRL-producing adenoma, whereas ACTH was negative. ACTH response to DDAVP disappeared after tumor removal. To determine the cause of preoperative ACTH response to DDAVP, we examined expression of CRF family peptides and vasopressin V1b receptor in the pituitary adenoma by immunohistochemistry. Immunohistochemistry revealed positive immunostaining for CRF, Ucn1, Ucn3 and vasopressin V1b receptor in the adenoma. These observations raised the possibility that DDAVP caused an ACTH response, perhaps via the paracrine effects of tumor-derived CRF and Ucn1. When ACTH response to DDAVP is observed in patients with pituitary tumor, not only the direct effect of DDAVP on ACTH secretion, but also a possible involvement of CRF and/or urocortins expressed in the pituitary adenoma, should be considered.

Topics: Acromegaly; Adenoma; Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Human Growth Hormone; Humans; Immunohistochemistry; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Receptors, Vasopressin; Urocortins

The desmopressin (DDAVP) test has been proposed to discriminate Cushing's disease (CD) from pseudo-Cushing states (PC); however, current information on its value is scarce and contradictory.. The aim of the study was to assess the ability of the DDAVP test in distinguishing between these conditions, with emphasis on subjects with mild hypercortisolism.. We conducted a retrospective/prospective study at the Division of Endocrinology, Polytechnic University of Marche, Ancona, Italy.. The study included 52 subjects with CD, 28 with PC, and 31 control subjects (CT).. We performed the DDAVP test and standard diagnostic procedures for the diagnosis of Cushing's syndrome.. The diagnosis/exclusion of CD was measured.. Interpretation of the DDAVP test based on percentage and absolute increment of cortisol and ACTH did not afford acceptable values of both sensitivity (SE) and specificity (SP). CD diagnosis based on simultaneous positivity for basal serum cortisol greater than 331 nmol/liter and absolute ACTH increment greater than 4 pmol/liter and its exclusion in subjects negative for one or both measures yielded an SE of 90.3% and an SP of 91.5%. The approach was also highly effective in distinguishing PC from: 1) CD with moderate values of urinary free cortisol (SE, 86.9%; SP, 92.8%); 2) CD with moderate values of serum cortisol after dexamethasone suppression (SE, 86.6%; SP, 92.8%); and 3) CD with moderate values of midnight serum cortisol (SE, 100%; SP, 92.8%).. Interpretation of the DDAVP test through a combination of parameters allowed effective discrimination of CD from PC, even in subjects with mild hypercortisolism.

Topics: Adult; Analysis of Variance; Area Under Curve; Cushing Syndrome; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Humans; Hydrocortisone; Male; Pituitary ACTH Hypersecretion; Prospective Studies; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Statistics, Nonparametric

Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing's disease (CD).. In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargement.. Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 age and sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin.. Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin.. Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

Topics: Adrenal Gland Neoplasms; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Female; Ghrelin; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion

Topics: Adrenocorticotropic Hormone; Adult; Deamino Arginine Vasopressin; Female; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Recurrence; Risk Factors

Patients with Cushing's disease (CD) often show an ACTH and cortisol response to desmopressin (DDAVP).. We tested whether persistence of a positive response to DDAVP after successful surgery identifies patients at risk of CD recurrence.. We prospectively included all CD patients who had a positive response to DDAVP before successful surgery from 1995 through 2007.. The study was performed at a university hospital.. One hundred seventy-four patients with CD, 148 women and 26 men, mean age 36.1 +/- 0.8 yr, were studied. The median follow-up after surgery was 58 months (interquartile range 22-93 months).. DDAVP test was performed immediately before and after surgery.. An ACTH and cortisol increment of at least 30 and 20% above baseline, respectively, were considered as a positive response to DDAVP. The risk of CD recurrence was analyzed according to the postoperative hormonal response to DDAVP.. Recurrence of CD occurred in 19 patients (10.9%). The recurrence-free survival at 5 yr was 89.8% [95% confidence interval (CI) 84.2-95.4]. Patients with a positive ACTH response had a 5-yr recurrence-free survival of 82.6% (95% CI 70.6-94.6%) as compared with 94.0% (95% CI 88.2-99.8%; P < 0.01) in patients without it. Multivariate analysis showed that persistence of a positive ACTH response to DDAVP was significantly associated with CD recurrence.. Positive ACTH response to DDAVP after surgery is associated with an increased risk of CD recurrence. However, the specificity and predictive value of this finding are low.

Topics: Adrenocorticotropic Hormone; Adult; Deamino Arginine Vasopressin; Female; Humans; Hydrocortisone; Male; Pituitary ACTH Hypersecretion; Postoperative Period; Prospective Studies; Recurrence

To evaluate the role of non-invasive dynamic tests in the diagnosis and differential diagnosis of Cushing's syndrome (CS).. We studied laboratory features of 74 patients with endogenous CS, subdivided as follows: 46 (62.1%) with Cushing's disease (CD), 21 (28.3%) with an adrenal tumor, and 7 (9.5%) with ectopic ACTH syndrome (EAS).. In 100% of cases of CS we found serum cortisol levels greater than 1.8 microg/dl after low-dose dexamethasone suppression tests (LDDST), as well as elevation of midnight serum or salivary cortisol. However, urinary free cortisol was normal in 11.5% of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and invariably increased in EAS. After the 8-mg overnight dexamethasone suppression test (HDDST), serum cortisol suppression >50% was observed in 79.5% of cases of CD and in 28.6% of subjects with EAS, whereas cortisol suppression >80% was only found in CD. After stimulation with CRH or desmopressin an ACTH rise > or =35% occurred in 86.5% of individuals with CD and 14.3% of those with EAS, whereas an ACTH rise > or =50 achieved 100% specificity. Moreover, the combination of serum cortisol suppression >50% after HDDST and an ACTH increase > or =35% after the administration of CRH or desmopressin only occurred in CD.. Our findings demonstrate that LDDST had 100% sensitivity for the diagnosis of CS and that HDDST and stimulation tests with CRH or desmopressin may be very useful for confirmation of CS etiology when analyzed together or when more stringent cut-offs are used.

Topics: ACTH Syndrome, Ectopic; Adrenal Gland Neoplasms; Corticotropin-Releasing Hormone; Cushing Syndrome; Deamino Arginine Vasopressin; Dexamethasone; Diagnosis, Differential; Humans; Hydrocortisone; Magnetic Resonance Imaging; Pituitary ACTH Hypersecretion; Pituitary Gland; Predictive Value of Tests; Retrospective Studies; Saliva; Sensitivity and Specificity

In the early postoperative period of Cushing's disease patients, desmopressin may stimulate ACTH secretion in the remnant corticotrophic tumour, but not in nontumour suppressed cells.. The aim of this study is to evaluate the serum cortisol responses to desmopressin after pituitary surgery, establishing an optimal cut-off for absolute increment (Delta) of serum cortisol (F) suitable to predict recurrence risk.. Retrospective case record study.. Fifty-seven Cushing's disease patients submitted to pituitary surgery and desmopressin stimulation in the early postoperative with a long-term follow-up (20-161 months) were studied.. Serum cortisol levels after desmopressin test (10 microg i.v.) 15-30 days after adenomectomy were used to determine DeltaF (absolute increment of F: F peak - F baseline). Sensitivity and specificity of DeltaF were calculated and a ROC curve was performed to establish an optimal cut-off for DeltaF to predict recurrence risk.. Fifteen patients had immediate postoperative failure (basal F > 165 nmol/l; 6 microg/dl) and one patient was lost during the follow-up. Forty-one patients achieved initial remission and were followed-up. Five of 11 patients who recurred had DeltaF > 193 nmol/l (7 microg/dl), but none of 30 patients who remained in prolonged remission showed DeltaF > 193 nmol/l after postoperative desmopressin stimulation.. Persistence of cortisol response (DeltaF > 193 nmol/l) to desmopressin in the early postoperative period can help to identify Cushing's disease patients with initial remission who present risk for later recurrence.

Topics: Adolescent; Adult; Aged; Antidiuretic Agents; Child; Deamino Arginine Vasopressin; Diagnostic Techniques, Endocrine; Female; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Postoperative Complications; Postoperative Period; Prognosis; Recurrence; Retrospective Studies; Risk Factors; Young Adult

The etiological diagnosis of ACTH-dependent Cushing's syndrome is often a problem. In fact, no endocrine or radiological examination can conclusively distinguish the ectopic from the pituitary source of disease. The aim of our study was to evaluate the role of stimulation and suppression endocrine tests in the diagnostic and therapeutic approach of patients with Cushing's disease (CD) and negative pituitary magnetic resonance imaging (MRI), considering their post-surgical outcome in comparison with patients with CD and positive MRI.. We retrospectively analyzed 31 patients (25 women and 6 men, median age 40 +/- 15 years) with a confirmed diagnosis of CD who underwent transsphenoidal pituitary surgery by the same neurosurgeon between 2001 and 2005. Preoperative endocrine assessment included corticotropin-releasing hormone (CRH), desmopressin (dDAVP), and overnight 8 mg dexamethasone suppression tests (8-DST) in all patients. Fifteen patients had a normal pituitary MRI and sixteen had a clearly evident pituitary microadenoma. Bilateral inferior petrosal sinus sampling (BIPSS) was performed in patients with discordant biochemical results or with signs and symptoms highly suggestive of an ectopic source of ACTH. Post-surgical median follow-up was 38.4 +/- 22.0 months.. Among patients with negative MRI, 60% had concordant positive endocrine tests and underwent neurosurgery without other examinations. BIPSS was performed in three other patients prompted by discordant endocrine tests (negative dDAVP) and in two patients with clinical suspicion of ectopic disease. Among patients with positive MRI, 87% underwent neurosurgery without BIPSS that was performed in two patients because of negative concomitant response to dDAVP and CRH tests. A pituitary adenoma, confirmed by pathological examination, was found in 40 and 81% of patients with negative and positive MRI respectively (P<0.05), corticotroph hyperplasia resulted more frequent in the group with negative MRI. Remission rate was not different between patients with negative and positive MRI (73 and 75% respectively; P=0.61) and between patients with negative MRI who did not undergo BIPSS and patients with positive MRI (P=0.56). The recurrence rate was also similar between groups (P=0.64), but higher, although not statistically different (P=0.07) in patients with corticotroph hyperplasia at histology.. An accurate evaluation of presurgical endocrine tests results enabled us to reduce the number of BIPSS in patients with a negative MRI without any fallout on their post-surgical outcome. In the hands of an expert pituitary surgeon, the outcome after surgeryand the subsequent recurrence rate are much the same in patients with negative or positive MRI.

Topics: Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Decision Trees; Dexamethasone; Female; Follow-Up Studies; Glucocorticoids; Humans; Hydrocortisone; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Predictive Value of Tests; Preoperative Care; Remission Induction; Retrospective Studies; Treatment Outcome

Although bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation is the most accurate procedure for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), 4-15% of patients with Cushing's disease (CD) fail to demonstrate diagnostic gradients. Preliminary data suggest that a more potent stimulation by the combined administration of CRH plus desmopressin during BIPSS may provide some diagnostic advantage. A crucial issue, however, is whether such an amplified stimulation may affect the specificity of the procedure, and this was the main aim of the present study.. We investigated the diagnostic accuracy of BIPSS performed by CRH plus desmopressin stimulation.. A retrospective analysis was conducted at a single tertiary care center.. Fifty-four patients were admitted for the investigation of ACTH-dependent CS. CD was diagnosed in 47 patients; occult ectopic ACTH syndrome (oEAS) was histologically confirmed in seven patients.. All patients underwent BIPSS with CRH plus desmopressin administration. Additional noninvasive tests included CRH test, high-dose dexamethasone suppression test, desmopressin test, and pituitary magnetic resonance imaging.. Gradients of inferior petrosal sinus (IPS) to peripheral (IPS/P) ACTH were calculated before and after stimulation with CRH plus desmopressin.. The sensitivity for a basal IPS/P gradient greater than 2 was 61.7%, with 100% specificity and a diagnostic accuracy of 66.7%. After stimulation with CRH plus desmopressin, receiver operating characteristic (ROC) curve analysis showed that a cutoff gradient of more than 2 offers the best test performance. In total, 46 of 47 patients with CD had an IPS/P gradient greater than 2, but none of the patients with oEAS, resulting in a sensitivity of 97.9%. The specificity was 100%, diagnostic accuracy was 98.2%, and the positive and negative predictive values were 100 and 87.5%, respectively. A subgroup of 18 patients (16 with CD and two with oEAS) had contradictory responses to routine tests with CRH and/or high-dose dexamethasone suppression test; sensitivity, specificity, and accuracy of BIPSS in this subgroup were 100%.. The application of a combined stimulation with CRH plus desmopressin during BIPSS is associated with a high sensitivity but no loss of specificity.

Topics: ACTH Syndrome, Ectopic; Adult; Antidiuretic Agents; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Retrospective Studies; Sensitivity and Specificity

Cushing's syndrome (CS) is rare in children. Information on bilateral inferior petrosal sinus sampling (BIPSS) in children with CS is limited. In the procedure CRH is always used to stimulate ACTH values. In addition, growth failure is the main complication of pediatric CS, mainly due to a profound GH suppression that persists for a few months after cure of the disease. Early treatment with recombinant GH after CS cure may partly reverse this phenomenon. We report herein a case of Cushing's disease (CD) in a 7-yr-old child, presenting with severe growth failure. No pituitary adenoma was shown on magnetic resonance imaging and a BIPSS using desmopressin allowed the identification of a central to peripheral (C/P) gradient; however transphenoidal surgery (TSS) did not cure the disease thus requiring the performance of bilateral adrenalectomy. After cure of the disease, a partial catch up of the growth delay occurred without any GH treatment. Our case reinforces the fact that BIPSS can be performed safely in very young children with CD. It also suggests for the first time that the use of desmopressin during the procedure gives the same information as CRH, as well as confirming the fact that the success of TSS is poor in very young children. Finally, it suggests that growth failure in children with CS can be partially reversed after surgical cure of the disease without any GH treatment and that the high IGF-I observed during corticosteroid replacement therapy is due to a state of IGF-I resistance.

Topics: Adrenalectomy; Antidiuretic Agents; Child; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Humans; Male; Petrosal Sinus Sampling; Pituitary ACTH Hypersecretion; Sphenoid Sinus

At present no single test is considered of absolute value in identifying patients successfully operated for Cushing's disease who are at risk for recurrence. The present report describes the first two patients in whom ACTH/cortisol abnormal responses to desmopressin disappeared after cure and then clearly reappeared during long-term follow-up several months before the clinical and hormonal features of hypercortisolism became manifest. The case histories of 2 young women are reported. The diagnosis of Cushing's disease was made on the basis of clinical features and standard hormonal criteria. Both patients, showing abnormal ACTH/cortisol rises after desmopressin test, underwent pituitary adenomectomy by transsphenoidal surgery and after operation plasma ACTH and serum cortisol levels were 0.2 and 0.4 pmol/l and 56 and 32 nmol/l, respectively. During the follow-up both patients underwent desmopressin (10 microg iv), ovine CRH (1 microg/kg iv) and 1 mg dexamethasone tests at 1, 6, 12, 24 months after surgery. In these two cases the ACTH/cortisol response to desmopressin normalized following pituitary adenomectomy, concomitantly with the normalization of all the other clinical and hormonal parameters. Subsequently abnormal rises after the synthetic AVP analogue administration appeared: paradoxical ACTH/cortisol increments after desmopressin occurred 24 and 6 months before any other hormonal or clinical sign of recurrence of hypercortisolism. As desmopressin may be able to stimulate ACTH/cortisol release in Cushing's disease, but not in normal subjects, we suggest that it can have a role in early identifying successfully operated Cushing's patients at risk for recurrence.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Dexamethasone; Female; Follow-Up Studies; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Recurrence; Time Factors