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The differential diagnosis of ACTH-dependent Cushing's disease (CS) is challenging. The gold standard approach bilateral inferior petrosal sinus sampling (BIPSS) is expensive and invasive, while other noninvasive tests, like the high-dose dexamethasone suppression test (HDDST), provide unsatisfactory diagnostic accuracy. This study aimed to find a new noninvasive practical approach with higher diagnostic accuracy to differently diagnose ACTH-dependent CS, which can be used in centers where BIPSS cannot be applied.264 Cushing's disease (CD) patients and 47 ectopic ACTH secretion syndrome (EAS) patients were analyzed in this single-center retrospective study (2011-2021). The multivariate logistic model was used to construct the scoring model.Female (adjusted OR 3.030, 95%CI 1.229-7.471), hypokalemia (0.209, 0.076-0.576), ACTH (0.988, 0.982-0.994), MRI pituitary lesion positive (8.671, 3.521-21.352), and HDDST positive (2.768, 1.139-6.726) have a strong association with the differential diagnosis of ACTH-dependent CS and were included in the final multivariable logistic regression model. A -14-to-14-point noninvasive scoring model was built on the model. The AUC of the noninvasive scoring model was 0.915 (95% CI 0.869-0.960), significantly higher than the AUC of HDDST (0.756, 95% CI 0.685-0.825, P = 0.004). The optimal cutoff of the model was ≥0 to diagnose CD. The sensitivity of the noninvasive scoring model was 91.3% (95% CI 87.3%-94.1%), and the specificity was 80.9% (95% CI 67.5%-89.6%). When the model's sensitivity was 100.0%, the cutoff was ≥ -10 with a specificity of 19.2%; when the model's specificity was 100.0%, the cutoff was ≥ 13 with a sensitivity of 22.7%.We developed a noninvasive scoring model to distinguish CD and EAS in ACTH-dependent CS patients with higher diagnostic utility than HDDST in the same cohort. The noninvasive scoring model might be applied in areas where BIPSS is unavailable, the CRH is hard to obtain, or the desmopressin stimulation is not widely applied. It also provided a triage tool for selecting patients that might benefit the most from a further BIPSS test.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's disease (CD). However, the reported remission rates of patients who received TSS vary widely between different studies, and the predictors of surgical outcomes remain controversial. The present study analyzed the early outcome of TSS in a large population of patients with CD at a single center, and identified potential predictors of initial remission of TSS in patients with CD.The clinical features and surgical outcomes of CD patients who underwent TSS between 1988 and 2018 at Peking Union Medical College Hospital (PUMCH) were collected and analyzed from their medical records.Of the 1604 CD patients who underwent TSS at PUMCH between February 1988 and October 2018, 1106 patients had complete medical data and pathological results. After surgery, the overall postoperative initial remission rate was 72.5, and 27.5% of patients maintained persistent hypercortisolism. The initial remission rate of patients with preoperative noninvasive adenoma based on MRI (77.1%), intraoperative noninvasiveness (72.5%), microadenoma (74.3%), pathological confirmation (76.4%), and first TSS (73.9%) was significantly higher than that in patients with preoperative invasive adenoma (53.0%), intraoperative invasiveness (60.7%), macroadenomas (65.9%), pathologically negative (49.7%), and repeat TSS (56.0%), respectively (all P 0.05). The initial remission rate in patients with pseudocapsule-based extracapsular resection (88.1%), MRI-visible adenoma (74.2%) was higher than that in patients without pseudocapsule-based extracapsular resection (77.1%), and with MRI-negative results (64.5%), respectively, but did not reach statistical significance (All P 0.05). Striking, there was no significant differences in initial remission rates between patients who underwent selective adenomectomy and enlarged adenomectomy (P 0.05). Whereas, the initial remission rates in patients who underwent partial hypophysectomy only was 51.0%, which was much lower than that in patients underwent selective adenomectomy and enlarged adenomectomy (P 0.05).The TSS is a safe and effective procedure for the treatment of CD. Whereas, preoperative invasiveness based on MRI, intraoperative invasiveness, macroadenomas pathologically negative, and repeat TSS are related to lower initial remission rates.

Gonadal and sexual disturbances are commonly encountered in patients with Cushing's disease. Nevertheless, the prevalence of hypogonadism in male Cushing's disease, the risk factors as well as the recovery time have been scarcely reported. Therefore, we aimed to explore the prevalence of hypogonadism at baseline and its determinants. In addition, the recovery time of hypogonadism and risk factors for unrecovered gonadal axis in male Cushing's disease with biochemical remission were investigated.We reviewed medical records of males with Cushing's disease managed between 2010 and 2020. Fifty-two male patients were enrolled according to the criteria. Each case attained biochemical remission after transsphenoidal surgery. Demographic details, clinical features, 24-hour UFC, hormonal profile [serum PRL, FSH, LH, TT, ACTH, cortisol, TT4/FT4, TT3/ FT3, TSH and IGF-1] were measured at baseline and during follow-up. The maximal tumor diameter on MRI was recorded at diagnosis.Hypogonadotropic hypogonadism was observed in thirty-nine patients (75%) at diagnosis. Total testosterone was negatively correlated with ACTH and 24-hour UFC. Midnight serum ACTH level at diagnosis was significantly associated with hypogonadism after adjusting for confounding factors. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months. Seven patients were persistently hypogonadal during the follow-up (≥1 year), mainly due to the hypopituitarism as a complication of the therapies such as surgery.Hypogonadotropic hypogonadism is frequent in male Cushing's disease, but it is reversible in most cases within one-year follow-up after remission.

Purpose Recurrence after pituitary surgery in Cushing’s disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. Methods We systematically screened the literature regarding recurrent and persistent Cushing’s disease using the MESH term Cushing’s disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number Results and conclusions Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient.

Posterior pituitary tumors are rare nonneuroendocrine neoplasms originating in the neurohypophysis that lack hormonal secretory capacity. Surprisingly, these tumors are relatively frequently associated with adenohypophyseal syndromes of hormonal hypersecretion such as Cushing's disease and acromegaly. Fifteen cases of posterior pituitary tumor associated with hypercortisolism have been reported to date, 13 of them were pituicytomas (Pi) and 2 were granular cell tumors (GCT). Six patients with posterior pituitary tumor associated with acromegaly have been reported (4 Pi and 2 GCT). The main forms of clinical presentation and the possible pathophysiological mechanisms of this association are reviewed.

Adrenal incidentalomas (AI) are discovered after work-up unrelated to adrenal gland diseases; up to 30% of AI show subclinical endogenous cortisol excess (SH), frequently associated to hypertension, obesity, metabolic disorders and increased incidence of cardiovascular events (CVEs). We analysed 628 AI patients divided into two groups: 471 non-functional adrenal adenoma (NFA) and 157 SH. All patients underwent complete examinations, 24-h ambulatory blood pressure monitoring, biohumoral parameters and vascular damage markers, such as c-IMT and ankle brachial index. After long-term follow-up, we registered newly onset of CVEs such as myocardial infarction (MI), percutaneous stenting and surgical bypass (PTA/CABG), stroke, overall/cardiovascular mortality. Moreover, SH patients underwent to surgical (SSH) or pharmacological treatment (MSH). SH patients showed higher prevalence of metabolic syndrome, diabetes mellitus, and previous CVEs respect NFA at baseline. After follow-up MSH group showed higher recurrence of major CV events compared with NFA and SSH (RR 2.27 MSH vs NFA for MI; RR 2.30 MSH vs NFA for PTA/CABG; RR 2.41 MSH vs NFA for stroke). In SSH there was a significant reduction of the number of antihypertensive medications needed to reach target blood pressure levels (2.3 ± 1.0 to 1.5 ± 0.4 drugs). None differences were found in SH patients, distinguished in relation to cortisol plasma levels after dexamethasone suppression test (1.8–5 µg/dL, above 5 µg/dL). SH is linked to relevant cardiovascular and metabolic alterations, leading to worsen clinical outcomes. In eligible patients, adrenalectomy is valid and safe option to treat SH, reducing cardiometabolic abnormalities.

Pregnancy is associated with the activation of the hypothalamus-pituitary-adrenal axis, which can cause a misdiagnosis of Cushing's syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence rate in Cushing's disease (CD) patients.This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14-45), PS remission, a follow-up of ≥6 months (median of 122 months, 6-402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing's syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA).Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses.There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data.

Cushing’s disease (CD) is a rare endocrine condition caused by a corticotroph pituitary tumor that produces adrenocorticotropic hormone. The current state of knowledge of CD treatment is presented in this article including factors that can be helpful in predicting remission and/or recurrence of the disease. The primary goals in CD treatment are quick diagnosis and effective, prompt treatment as the persistent disease is associated with increased morbidity and mortality. Cooperation of a team consisting of experienced pediatrician/adult endocrinologist, neuroradiologist, transsphenoidal neurosurgeon and (if necessary) radiotherapist contribute to the best treatment effects.

Purpose To estimate the prevalence of USP8, USP48, and BRAF mutations in patients with Cushing's disease (CD) from the Indian subcontinent, and determine their genotype-phenotype correlation. Methods We prospectively recruited 46 patients with CD who underwent surgery between September 2015 and July 2019 at our institute. Fresh frozen tumour tissue was obtained in all patients. Using Sanger sequencing, the presence of somatic USP8 mutations was documented and the frequency of USP48 and BRAF mutations in USP8 wild-type corticotroph adenomas was determined. Clinical, hormonal, and surgical data were then compared between USP8-, USP48- and BRAF-variant carriers and patients with wild-type tumours. Results Signature USP8 mutations were detected in 17 (37%) patients. Of the 29 USP8 wild-type adenomas, 4 (13.8%) harboured USP48 mutations, one of them being a splice-site mutation that has previously not been described. BRAF mutations were not found in any of the 29 patients. Corticotroph adenomas with USP8 mutations had a higher incidence of Crooke's hyaline change than wild-type tumours (70.6 vs. 37.9%, p = 0.032). Adenomas with USP48 mutations had a higher rate of cavernous sinus invasion than their wild-type counterparts (50 vs. 4%, p = 0.042). No other significant phenotypic difference could be established between mutant and wild-type tumours. Conclusions The prevalence of USP8 mutations in our series of patients with CD was 37%. The prevalence of USP48 mutations in USP8 wild-type adenomas was 13.8%, including a novel splice-site mutation. BRAF mutations were not found in any USP8 wild-type tumour. USP8-mutants showed significantly more Crooke's hyaline change and USP48-mutants were more likely to demonstrate cavernous sinus invasion.

In patients with ACTH-dependent Cushing's syndrome (CS), the differentiation between Cushing's disease (CD) and ectopic ACTH secretion (EAS) can often be challenging. The traditionally used biochemical tests have limited diagnostic accuracy and imaging modalities may fail to detect the culprit lesion. Inferior petrosal sinus sampling (IPSS) was introduced more than 3 decades ago as a test with optimal diagnostic accuracy and has since become the gold standard in the differential diagnosis between CD and EAS. However, several, albeit rare, pitfalls may limit its diagnostic accuracy and awareness is needed to avoid incorrect interventions. Moreover, it is an invasive and demanding procedure, available in a limited number of centers worldwide. This review aims to critically present the usefulness and pitfalls of IPSS and define strategies for its optimal place in the contemporary management of CS.

PURPOSE: It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition.METHODS: Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC).RESULTS: At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND.CONCLUSIONS: These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.

The most common etiology of Cushing’s syndrome (CS) is an ACTH-producing pituitary adenoma (pitCS), reported as 2–3 times more frequent than primary adrenal CS (adrCS). We aimed to analyze and compare features of patients with pitCS and adrCS. A retrospective file review of 196 consecutive patients (age 46.8 ± 15.6 years, 76% female) diagnosed with CS in 2000–2017 and followed for 5.2 ± 4.2 years; 109 (55.6%) had pitCS and 76 (38.8%) adrCS. Epidemiologic, clinical and biochemical factors were compared between and within the pitCS and adrCS groups. The relative proportion of pitCS to adrCS (1.4) was lower than previously reported and gradually decreased during the study years to only 1.2 in 2012–2017. The most common reason for CS screening was weight-gain in the pitCS group (48.6%) and adrenal incidentaloma in the adrCS group (39.5%). The pitCS patients were diagnosed at younger age (42.5 ± 15.1 vs. 51.6 ± 15.1 years, p

Pituitary surgery represents the first-line treatment for most patients with Cushing’s disease (CD). In the case of surgery failure, additional treatment options are required. Pasireotide has shown favourable results in the first-line treatment of patients with CD, who are not candidates for surgery or in the second-line when surgery has failed. The aim of the current study is to compare the effects of surgery and pasireotide treatment in a cohort of patients with CD, and to evaluate the differences in response rate in terms of hormonal and clinical control, and improvement of metabolic complications

In MRI-negative cases Cushing's disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission.Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent twoThe mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas.The results of the current study suggest that oCRH-stimulation may lead to increased

Purpose: Patients affected by Cushing’s disease often have important comorbidities directly linked to hypercortisolism that might enhance the operative risk. We report the safety of transsphenoidal surgery in patients affected by Cushing’s disease as compared with patients with nonfunctioning pituitary adenoma. Methods: We have retrospectively analyzed 142 patients with Cushing’s disease and 299 patients with nonfunctioning pituitary adenoma who underwent transsphenoidal surgery performed by a single experienced neurosurgeon between September 2007 and December 2014. For all of them, an intraoperative computerized anesthetic record for the automatic storage of data was available. Results: The intraoperative vital parameters and the frequency of drugs administered during anesthesia were comparable between Cushing’s disease and nonfunctioning pituitary adenoma groups. The duration of surgery was similar between the two groups (41.2 ± 11.8 vs. 42.9 ± 15.6 min), while the duration of anesthesia was slightly shorter in Cushing’s disease patients (97.6 ± 18.1 min) than in nonfunctioning pituitary adenoma patients (101.6 ± 20.6 min, p = 0.04). The total perioperative mortality rate was 0.2% (0% in Cushing’s disease vs. 0.3% in nonfunctioning pituitary adenoma). Cushing’s disease patients had surgical and medical complication rates of 3.5% each, not different from those occurring in nonfunctioning pituitary adenoma. The postoperative incidence of diabetes insipidus (10.6%) and isolated hyponatremia (10.6%) in Cushing’s disease patients was significantly higher than in nonfunctioning pituitary adenoma patients (4.4 and 4.1%; p = 0.02 and p = 0.01, respectively). Conclusions: In a large series of unselected and consecutive patients with Cushing’s disease, transsphenoidal surgery performed by one dedicated experienced neurosurgeon had a reasonably low risk of complications. In particular, despite the higher burden of comorbidities typically associated with hypercortisolism, medical complications are rare and no more frequent than in patients with nonfunctioning pituitary adenoma. © 2016 Springer Science+Business Media New York

Purpose 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. Methods 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. Results 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. Conclusions 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.

Introduction: Cushing’s disease (CD) is characterized by procoagulative profile. Treatment with cortisol-reducing medications might normalize the coagulation impairment potentially eliminating the risk of thromboembolic complications. Aim: The aim of this prospective study is to evaluate the effectiveness of 6–12 months of treatment with pasireotide (Signifor®, Novartis) 600 µg twice daily on coagulative factors in 21 patients (16 females, mean age 46 ± 12.2 years) with CD. Biochemical, hormonal (urinary free cortisol, UFC; late night salivary cortisol, LNSC; ACTH) and coagulative parameters as Protrombin time (PT), aPTT, factors VIII, IX and XI, antithrombin III, protein C, protein S, fibrinogen, were evaluated at baseline and during therapy. Results: UFC showed a significant reduction from baseline (3.2 ± 1.8 vs. 1.0 ± 0.8, p < 0.0001) with normalization in 13/21 (61.9%) and in 7/16 (43.8%) at 6 and 12 months, respectively. On the same way LNSC returned to normal in 5/11 at 6 months, showing a trend to reduction (8.6 ± 5 vs. 4.1 ± 2.9), even though without statistical significance (p = 0.07). Throughout the treatment period there was an increase in serum glycaemia (5.5 ± 2.3 vs. 6.8 ± 2.3 mmol/L, p = 0.09), with a concomitant significant increase in HbA1c after 6 months (40.7 ± 8.4 vs. 50.7 ± 12.3 mmol/mol, p = 0.006). Regarding coagulative parameters, no differences were found neither in clotting nor in anticoagulant factors during therapy. No patients developed thrombotic complication during treatment. Conclusions: Pasireotide resulted an effective treatment in controlling hypercortisolism in more than half of CD patients with partial restoration also of circadian cortisol secretion. No significant improvements were observed on clotting factors; this fact might depend on persistence of typical alteration of CD, such as obesity and hypertension, and reflects also on the worsening in glucide metabolism induced by the drug. Clinical implications of persistent procoagulative impairment while on medical therapy should be considered.

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 ratio1.8 was significantly different between two groups (P = 0.004). Applying a prolactin-normalized ACTH IPS:P ratio0.8 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.

Octreotide (OCT) is ineffective in patients with Cushing's disease (CD) due to the cortisol-induced down-regulation of somatostatin receptor subtype 2 which was shown to be reversible in vitro by using anti-glucocorticoid mifepristone. This study aimed to verify, in vivo, if mifepristone can modulate response to acute OCT administration in patients with CD. Three men and two postmenopausal women (age 52.5 ± 2 years) with CD were enrolled in the study. OCT (100 μg, s.c.) was administered alone on the first day (OCT-only), and it was then given after mifepristone administration (2 × 200 mg, p.os, 12 and 1 h before OCT), 3 days later (OCT-mif). ACTH and cortisol levels were measured before OCT administration and every 60 min thereafter for 6 h. Baseline ACTH and cortisol values, nadir values and percentage decrements (Δn) were compared during both tests. Mean ACTH-Δn did not differ significantly during the two tests. Both tests induced a30 % decrease in plasma ACTH in three patients (#1, 2 and 3) and a50 % decrease in the other two cases (#4 and 5). Cortisol decreased in patients #4 and 5, during both tests. ACTH-Δn did not correlate with morning cortisol nor with urinary free cortisol values. Patients #4 and 5 with the highest ACTH-Δn had the lowest cortisol values after 1 mg of dexamethasone. Brief mifepristone pre-treatment does not modify ACTH and cortisol response to acute OCT administration in CD. However, OCT seems to be more effective in patients with partially preserved cortisol inhibitory feedback.

Cushing’s disease (CD) is associated with significant morbidity and mortality, and therefore requires early intervention applying effective treatment. Transsphenoidal surgery is clearly the first-line therapy, with remission rates between 65 and 90 % in microadenomas, but somehow lower rates \65 % in macroadenomas. Second-line therapies include repeated surgery, various forms of medical treatment, radiation, and ultimately bilateral adrenalectomy. Several compounds have demonstrated some efficacy to lower cortisol excess in CD. They can be divided by their approaches targeting either the underlying corticotropic adenoma, the adrenal gland, or the peripheral glucocorticoid receptor. Unfortunately, there is no clear consensus for any of these second-line options, when and in which order they should be applied. Larger studies comparing several lines of treatment in a randomized fashion are hindered by the rarity of the disease. However, considering the relevant recurrence rates of CD after surgery [1], combined approaches applied simultaneously or in succession are necessary in many patients. To improve morbidity and mortality, those treatment options need to be analyzed with respect to their efficacy to normalize biochemical excess, tumor proliferation, and clinical consequences of the disease including quality of life. As none of the currently available treatment options except for surgery and potentially radiation is able to cure CD, side effects especially during long-term therapy are of special interest. An important addition to the medical therapy of CD stems from studies investigating compounds targeting the underlying corticotropic pituitary adenoma. Although these tumors are usually small, the ERCUSYN study documented macroadenomas in 21 % of patients with CD (11 % with extrasellar extension) [2]. Pasireotide (SOM230) is a multireceptor ligand somatostatin analog with particular high affinity to the somatostatin receptor subtype 5 strongly expressed in corticotropic adenomas. In a recent phase III, randomized, double-blind, multicenter trial, 15 and 26 % of patients with CD (for the 600 and 900 lg doses, respectively, given subcutaneously bid) normalized their UFC at 6 months [3], with concurrent improvements in clinical symptoms [4, 5] and relevant reduction in tumor volume. Those effects were sustained for a period of over 24 months [6]. A subsequent report on eight patients treated with pasireotide for at least 6 months in a single center study as part of the phase III trial also indicated relevant tumor shrinkage [7]. Such antiproliferative effect may be useful in the medical management of Nelson’s syndrome, as demonstrated in a recent case report [8]. Therefore, pasireotide may be especially considered in patients with relevant tumor mass and/or tumor progress, potentially also after bilateral adrenalectomy. Before pasireotide is started, patients should be informed about the most common (frequency[10 %) side effects: diarrhea, nausea, abdominal pain, fatigue, cholelithiasis, injection side reactions, and hyperglycemia. Most resemble those well known for other somatostatin analogs, so that physicians will feel familiar to cope with them. However, the rate of hyperglycemia is clearly increased, as demonstrated in the phase III trial, with the mean HbA1C increasing from 5.8 % in both the 600 and 900 lg groups at baseline to 7.2 and 7.4 %, respectively, at month 6. Therefore, patients should be monitored for & Stephan Petersenn stephan.petersenn@endoc-med.de

Cushing's disease (CD) is a severe endocrine condition caused by an adrenocorticotropin (ACTH)-pro- ducing pituitary adenoma that chronically stimulates adrenocortical cortisol production and with potentially serious complications if not or inadequately treated. Active CD may produce a fourfold increase in mortality and is associated with significant morbidities. Moreover, excess mortality risk may persist even after CD treatment. Although predictors of risk in treated CD are not fully understood, the importance of early recognition and ade- quate treatment is well established. Surgery with resection of a pituitary adenoma is still the first line therapy, being successful in about 60-70 % of patients; however, recur- rence within 2-4 years may often occur. When surgery fails, medical treatment can reduce cortisol production and ameliorate clinical manifestations while more definitive therapy becomes effective. Compounds that target hypo- thalamic-pituitary axis, glucocorticoid synthesis or adre- nocortical function are currently used to control the deleterious effects of chronic glucocorticoid excess. In this review we describe and analyze the molecular basis of the drugs targeting the disease at central level, suppressing ACTH secretion, as well as at peripheral level, acting as adrenal inhibitors, or glucocorticoid receptor antagonists. Understanding of the underlying molecular mechanisms in CD and of glucocorticoid biology should promote the development of new targeted and more successful therapies in the future. Indeed, most of the drugs discussed have been tested in limited clinical trials, but there is potential ther- apeutic benefit in compounds with better specificity for the class of receptors expressed by ACTH-secreting tumors. However, long-term follow-up with management of per- sistent comorbidities is needed even after successful treatment of CD.

Patients with Cushing disease (CD) are at increased risk of venous thromboembolism (VTE). It was surmised, but not conclusively shown that the risk is related to plasma hypercoagulability secondary to the glucocorticoids effect. This study is aimed at detecting hypercoagulability in patients with CD. Case-control study of 48 CD patients and controls enrolled at two Italian clinics for whom we assessed the thrombin-forming-potential in the presence of optimal activation of protein C obtained by adding into the assay system its main endothelial activator, thrombomodulin. These experimental conditions mimic more closely than any other test the in vivo situation. We observed enhanced thrombin-generation in CD patients, as shown by the modification of thrombin-generation parameters [i.e., shortened lag-time and time-to-peak, increased thrombin peak and endogenous thrombin potential (ETP)]. Moreover, the ETP ratio (with/without thrombomodulin), recognized as an index of hypercoagulability, was increased in patients as compared to controls. We attempted to explain such hypercoagulability by measuring both procoagulant and anticoagulant factors, and some other non-coagulation parameters (i.e., neutrophil extracellular traps (NET), recently associated with the VTE risk and/or increased hypercoagulability. We showed that the hypercoagulability in patients with CD is associated with increased levels of factor VIII and NET-related variables. We detected plasma hypercoagulability in patients with CD and found experimental explanation for its occurrence. Whether this hypercoagulability can entirely explain the occurrence of VTE in patients with CD should be investigated by ad-hoc clinical trials. However, until these studies will be available the evidence supports the concept that patients with CD are candidates for antithrombotic prophylaxis.

Successful treatment of Cushing syndrome causes transient or permanent adrenal insufficiency deriving from endogenous hypercortisolism-induced hypothalamus-pituitary-adrenal-axis suppression. We analyzed pre-treatment factors potentially affecting the duration of adrenal insufficiency. We conducted a retrospective analysis on patients successfully treated for Cushing disease (15 patients) who underwent transsphenoidal surgery, and nonmalignant primary adrenal Cushing syndrome (31 patients) who underwent unilateral adrenalectomy, divided into patients with overt primary adrenal Cushing syndrome (14 patients) and subclinical primary adrenal Cushing syndrome (17 patients). Epidemiological data, medical history, and hormonal parameters depending on the etiology of hypercortisolism were collected and compared to the duration of adrenal insufficiency. The median duration of follow-up after surgery for Cushing disease and primary adrenal Cushing syndrome was 70 and 48 months, respectively. In the Cushing disease group, the median duration of adrenal insufficiency after transsphenoidal surgery was 15 months: younger age at diagnosis and longer duration of signs and symptoms of hypercortisolism before diagnosis and surgery were associated with longer duration of adrenal insufficiency. The median duration of adrenal insufficiency was 6 months for subclinical primary adrenal Cushing syndrome and 18.5 months for overt primary adrenal Cushing syndrome. The biochemical severity of hypercortisolism, the grade of hypothalamus-pituitary-adrenal-axis suppression, and treatment with ketoconazole before surgery accounted for longer duration of adrenal insufficiency. In patients with Cushing disease, younger age and delayed diagnosis and treatment predict longer need for glucocorticoid replacement therapy after successful transsphenoidal surgery. In patients with primary adrenal Cushing syndrome, the severity of hypercortisolism plays a primary role in influencing the duration of adrenal insufficiency after unilateral adrenalectomy.

The main objective of this article is to study the psychosocial profile of patients of Cushing disease (CD) in a developing country setting. Eighteen patients with CD underwent a cross-sectional assessment regarding their socio-demographic and clinical profile, life events, social support, coping, dysfunction, quality of life, and psychiatric morbidity. Twenty-two demographically group-matched healthy participants (free from psychological morbidity) acted as the control group. The CD group had predominance of females (71.5%) with mean age at onset of 20.38 (range 8-38) years, and mean duration of illness of 65.33 (range 4-260) months. Six subjects (i.e., GHQ positive group) scored positive on the General Health Questionnaire-12 giving a psychological morbidity rate of 33.33%, with one having an ICD-10 diagnosis. There was no difference between GHQ positive and GHQ negative groups on number of life events, social support, quality of life and dysfunction. However, GHQ positive group used significantly more of internalizing coping strategies. Psychological morbidity occurs in a significant percentage of patients with CD. Presence of psychological morbidity is associated with internalizing coping strategies.

Cushing’s disease (CD), caused by an adrenocorticotropin-secreting pituitary adenoma, leads to hypercortisolemia and causes serious morbidity and increased mortality when suboptimally treated. Currently, the genetic events have rarely been reported in this disease. Recently, the recurrent activating mutations in the gene encoding ubiquitin-specific protease 8 (USP8) in CD have been independently reported by two teams. These hotspot mutations sustain epidermal growth factor receptor (EGFR) signaling and expand the pathogenic role of USP8 in corticotroph adenoma. This review summarizes current knowledge of USP8 and its substrate EGFR in cancer therapy and possible application of them in CD.

The purpose of this study was to review therapeutic outcomes and comorbidities of patients with Cushing's disease (CD) in a single center. We conducted a retrospective study of 33 patients with CD undergoing transsphenoidal surgery from January 2007 to February 2014 (27 females and 6 males, median age 38 years, range 18-71 years). The diagnosis of Cushing's syndrome was established on the basis of the patient's history, characteristic clinical features, and laboratory data including an elevated 24-h urinary free cortisol level, lack of serum cortisol suppression after dexamethasone suppression tests and an elevated midnight cortisol level. In 28/33 patients, the tumor was visualized on MR of the sellar region, while in 5 it was diagnosed using an inferior petrosal sinus sampling. Out of the 33 patients, 10 had macroadenoma and the remaining 23 had microadenoma. Twenty-one patients (63.6 %) had hypertension, 17 (51.5 %) dyslipidemia, and 7 (21.2 %) had type 2 diabetes or impaired glucose tolerance. The median follow-up period was 28 months. Remission after transsphenoidal surgery was achieved in 78.8 % of patients, while 7 patients failed to achieve disease remission. Those patients were treated with second-line treatment modalities (second operation, radiotherapy, bilateral adrenalectomy, and/or ketoconazole). One patient rejected all the treatment modalities after surgery. Cumulative remission after all the treatment modalities was achieved in 87.9 % patients. Patients with Cushing's disease should be managed in centers with much experience due to high patient load. In our Center, the remission of the disease has been achieved in 78.8 % of the patients following transsphenoidal surgery. Multimodal treatment which included radiotherapy and medical treatment led to biochemical remission of the disease in 87.9 % of patients.

Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing’s disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1–9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 μg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 μg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 ± 24.3 and 48.1 ± 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term.

The purpose was to review the use of mifepristone in the treatment of Cushing’s syndrome (CS) in the context of other recently published studies. We review the use of mifepristone, as published in the recent Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC). We also review the multiple case reports and case series of mifepristone use in CS. A review of other medications used in the treatment of Cushing’s disease (CD), including pasireotide and cabergoline also provides context for the discussion of the role of mifepristone in the treatment of CD. The results show that the treatment of CD has been primarily surgical with medical therapy reserved for adjuvant therapy when primary treatment fails or other therapies require time for optimal efficacy. Two recent large prospective studies, using pasireotide and mifepristone provide new clinical insights to the medical treatment of CD in particular. Mifepristone has been used to treat excessive cortisol production by blocking the action of cortisol at the level of the glucocorticoid receptor. Until recently, the majority of clinical experience with mifepristone on the treatment of excess cortisol was derived from case reports and small case series. Based on the SEISMIC study, mifepristone was FDA approved for hyperglycemia associated with CS. In conclusion the role of mifepristone in the treatment of CD remains one of adjuvant therapy. Its place among other choices for medical therapy has yet to be firmly established and an evidenced-based approach toward the use of novel medications in the treatment of CD has not been made. Selection of medication depends on drug approval and availability in individual countries and requires cautious assessment of potential adverse effects, consideration of patient comorbidities, and efficacy.

Adrenocorticotropin (ACTH) producing macroadenomas and pituitary apoplexy are unusual in Cushing’ s disease. A 20-year-old man who had been diagnosed Cushing’ s disease 2 months ago, presented with sudden headache, nausea, and vomiting. His serum cortisol level was 0.4 μg/dl and ACTH level was 23.9 pg/ml. Magnetic resonance imaging of the pituitary gland disclosed a hemorrhage in the pituitary macroadenoma (22 × 19 mm). He was treated with IV methylprednisolone immediately and then the symptoms were relieved within the first day of the treatment. The hemorrhagic lesion was resected by transsphenoidal surgery successfully. Impaired secretion of pituitary hormones may be seen after the pituitary apoplexy. We communicate a case with pituitary apoplexy of an ACTH secreting pituitary macroadenoma, causing acute glucocorticoid insufficiency.

We aimed to investigate the aortic function and to evaluate the relationship between aortic stiffness and systolic and diastolic functions of the left ventricle in patients with Cushing’s disease (CD). Fourteen women and one man with newly diagnosed CD, and 17 control cases were enrolled in this study. All subjects underwent echocardiography and systolic and diastolic aortic measurements were noted from M-mode aortic root. Aortic elastic parameters, aortic strain, and distensibility were calculated. Left ventricle functions were measured using echocardiography including, two-dimensional, M-mode, conventional Doppler, and tissue Doppler imaging. Aortic strain (7.4 ± 1.9 vs. 12.3 ± 2.4%; P < 0.001), and aortic distensibility (3.2 ± 1.1 × 10−6 vs. 5.6 ± 1.4 × 10−6 cm2 dyn−1; P < 0.001) were significantly decreased in patient group compared with control group. Mitral E velocity and the ratio of E/A were significantly lower and deceleration time of E was significantly prolonged in patients with CD. We also observed that patients with CD had markedly lower early diastolic myocardial peak velocity (Em) and Em/Am ratio and higher Tei index than in control group. Aortic elastic parameters are deranged in patients with CD and there is a significant correlation between left ventricular parameters determined by tissue Doppler echocardiography and aortic elastic parameters in these patients. We think that patients with CD should also be evaluated with aortic stiffness known to be an early marker for atherosclerosis.