Active Cushing's Disease Research Articles

THU019 Osilodrostat As An Emergency Alternative For Hypercortisolism In A Patient With An Impaired Liver Function

Abstract Disclosure: M. Minasyan: None. A. Bogusławska: None. A. Gamrat: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None. Osilodrostat as an emergency alternative for hypercortisolism in a patient with an impaired liver function. A case presents a 34 year old woman with an active Cushing Disease, who underwent non-radical surgery of invasive pituitary adenoma in 2014 and CyberKnife radiotherapy in 2018. Patient demonstrates many complications of long lasting hypercortisolemia- poorly controlled diabetes mellitus, heart failure, hypertension, hypercholesterolemia, mental disturbances and severe hepatic impairment. Challenges in this case are aggravated by very difficult compliance. Due to elevated liver function tests, the patient couldn’t have started ketoconazole and relacorilant treatment. Because of non-controlled DM, pasireotide treatment was contraindicated in her case. She didn’t agree either for metyrapone treatment or for adrenalectomy. Finally osilodrostat has been implemented as the last-chance alternative given at the time of severe hepatic impairment. At the dose of 2x2mg we observe clinical improvement, normalisation of UFC, decrease of Hba1c and spectacular improvement of liver function. However the current data on use of osilodrostat in patients with hepatic impairment are limited, our case shows that osilodrostat can be an emergency alternative for severe hypercortisolism with impaired liver function. The mechanism of improvement of liver function may be indirect through decreasing the level of hypercortisolemia, however potential direct beneficial influence of osilodrostat on liver function seems to be an interesting subject worth further investigation. More studies on the link between hypercortisolemia, liver function and steroidogenesis inhibitors are needed. Presentation: Thursday, June 15, 2023

THU099 The Challenging Management Of Silent Corticotroph PitNET—From Very Aggressive To Mild Course Of Disease During Long Follow Up

Abstract Disclosure: A. Bogusławska: None. &. Kluczyński: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None. We present a case series of silent corticotroph PitNETs with various clinical outcomes. Case 1. A 33-year-old male admitted to Emergency Department (ED) due to severe headaches and vomiting- giant PitNET (39x33x55 mm) was visualized-debulking transsphenoidal surgery (TSS) was performed. Histopathology results showed silent adenoma subtype 1 (densely granulated), Ki67<1%. Due to rapid progression of PitNET- patient underwent two emergency TSS and stereotactic fractionated radiotherapy. Treatment with temozolomide, pasireotide, cabergoline, radiotherapy was introduced. After 18 months of combined therapy stable disease was observed. Implementation of pasireotide resulted in spectacular decrease of headaches (initially 9-10 to none /10 using NRS). Case 2. A 31-year-old male presented in our clinic due to headaches and bitemporal hemianopsia. In MRI PitNET was found (22x19x23mm) and active Cushing disease (CD) was diagnosed. TSS was performed in 2013. Histopathology results showed corticotroph PitNET with Crook cells. Postoperatively, PitNET progression (17x26x13mm) was observed with no overt CD. In 2022, due to worsening of headaches and vision loss, second TSS was performed. Histopathologists described corticotroph tumor with Crook cells with ATRX mutation of uncertain significance. Pasireotide implementation is planned. Case 3. A 47-yeard-old female was admitted to ED due to severe headache and nausea. In MRI pituitary tumor (20x17x20mm) with local invasion was found. The patient was operated and histopathology showed densely granulated corticotroph PitNET; ACTH(+), GH(+), Ki-67% was 3%, p53<5%, with single Crook cells. In follow-up, progression of PitNET was noted (31x32x30 mm) and the patient underwent proton therapy. Case 4. A 56-yeard old female after three TSS (2012,2017,2018) and craniotomy (2020) due to aggressive corticotroph PitNET with Ki67 <1%. In 2009 a pituitary tumour (9x10x13 mm) was found. Before last craniotomy, the tumour was 24x24x28mm. After neurosurgery, paresis of right III nerve and left hemiparesis occurred. Pasireotide implementation is planned. Case 5. A 70-year old female presented in 2015 with severe headaches/nausea. In MR PitNET (32x24x31mm) was found. The patient underwent TSS and histopathology showed corticotroph PitNET with Ki67<1%. Due to PitNET progression, second TSS and fractionated radiotherapy was performed (2017) however in last MRI (2022), tumor relapse was noted. Case 6/7: A 46-year-old and 50 year-old females were operated due to local symptoms of PitNET. Histopathology revealed silent corticotroph PitNET. In follow-up MRI after one year showed no progression of pituitary tumor. The management of silent corticotroph PitNETs is very challenging and individualized approach is required. Further multicenter studies to understand the pathophysiology and the course of silent corticotroph PitNETs are needed. Presentation: Thursday, June 15, 2023

The relations of circulating agouti-related peptide and leptin with altered sleep architecture in patients with active Cushing's disease: a pilot study.

To evaluate sleep architecture of patients with Cushing's disease (CD) and to explore whether agouti-related peptide (AgRP) and/or leptin play a permissive role in sleep alterations in patients with active CD. We performed polysomnography on 26 patients with active CD and age 26 age- and sex-matched control subjects. Blood samples were obtained from all participants for the analyzes of AgRP and leptin. The laboratory and sleep-related parameters were compared. The groups were similar in age, gender, and body mass index. The CD group had reduced sleep efficiency (71.6 ± 12.1% vs. 78.8 ± 12.6%, p = 0.042) and increased wake after sleep onset (WASO%) (24.7 ± 13.1% vs. 17.4 ± 11.6%, p = 0.040) as compared to control group. Seventeen patients with CD (65.4%) and 18 control subjects (69.2%) had obstructive sleep apnea. Serum AgRP (13.2 ± 7.4pg/ml vs. 9 ± 3.1, p = 0.029), leptin (59.5 mcg/l, [IQR] 32.6-94.6 vs. 25.3 mcg/l, [IQR] 12.9-57.5, p = 0.007) were higher in CD group. AgRP and leptin correlated negatively with total sleep time, sleep efficiency, stage N2 sleep (%), and positively with WASO%. In multiple regression analyses, serum cortisol (ß = - 0.359, p = 0.042) and AgRP (ß = - 0.481, p = 0.01) were significant predictor of sleep efficiency. AgRP was also significant predictor of WASO% (ß = 0.452 and p < 0.05). Active CD carries an increased risk of impaired sleep efficiency and continuity which may worsen health-related quality of life. Elevated circulating AgRP and, to a lesser extent, leptin may be associated with decreased sleep efficiency and continuity in patients with CD. Patients with CD who have subjective sleep symptoms should be screened with polysomnography.

Sustained hypercortisolemia after bilateral adrenalectomy in Cushing's disease

Abstract Introduction Cushing's disease caused by pituitary corticotropin (ACTH)-secreting tumors. These tumors are almost always benign and are usually microadenomas. In 30 to 40 percent, the microadenoma is so small that it is not detectable by magnetic resonance imaging (MRI). Primary therapy consists of transsphenoidal surgery or pituitary irradiation. Patients who fail this first approach can be treated either by repeat transsphenoidal surgery, medical therapy, radiotherapy, or, as a final resort, surgical or medical adrenalectomy. Clinical Case A 38-year-old male patient presented with headache and fatigue. The laboratory examinations reviewed ACTH depending Cushing's syndrome. A suspicious lesion in the pituitary with no contrast enhancement was observed in Sella MRI. Cavernous sinus sampling consistent with central sources. He was operated in 2018 for pituitary Cushing's disease. Reticulin framework disrupted compatible with adenoma but, ACTH could not be stained in immunohistochemical staining for technical reasons. Due to the high cortisol levels of the patient in the postoperative follow-up, the patient underwent bilateral adrenalectomy in 2019. Because of active Cushing's disease, patient was re-evaluated in 2022. In laboratory examinations, HGB 16.6 g/dL, WBC 6400 /uL, NEU 3200 /uL, PLT 228000 uL, cre 0.76 mg/dL, TSH 1.5 mIU/L, FT4 1.2 ng/dl, FSH 4.6 U/L, LH 7.98 U/L, PTH 23.7 ng/L, PRL 17 µg/L, Total Testosterone 571 ng/dl, Progesterone 0.06 µg/L, GH 0.04 ug/L, IGF1 83 µg/L were detected. Basal cortisol was 35 ug/dl and ACTH 67 ng/L. Cortisol with 1 mg of DST resulted in 28 ug/dl. 2 mg DST resulted in cortisol 38 ng/L. Free cortisol in the urine was found to be 281 mg/day (n&amp;lt;130 mg/day). Empty sella was observed in sella MR. No prominent contoured lesion was observed in the pituitary gland. Adrenal gland was not observed in the Abdominal MRI. No tumor was detected in Thorax CT. The patient's pasireotide 0.3 mg 1×1 treatment was continued. Metyropane 250 mg 2×1 was added to the treatment. Conclusion In Cushing's disease, the ACTH-secreting adenoma may be too small to be detected.

Growth hormone (GH) deficiency and GH replacement therapy in patients previously treated for Cushing's disease.

Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

Region-specific disturbed iron redistribution in Cushing's disease measured by magnetic resonance imaging-based quantitative susceptibility mapping.

Cushing's disease (CD) is most common endogenous Cushing's syndrome. This study aimed to assess iron alternations in deep grey matter in CD. A cross-sectional study was performed. In this study, 48 active CD patients, 39 remitted CD patientsand 52 healthy control (HC) subjects underwent magnetic resonance imaging. Quantitative susceptibility mapping (QSM). Decreased susceptibility values were found in the bilateral putamen, caudate, red nucleus, subthalamic nucleusand pulvinar nuclei of the thalamus (TL-PLV) in active and remitted patients with CD compared with HCs. Interestingly, in remitted patients with CD, altered susceptibility values were significantly correlated with altered brain volumes in TL-PLV, while TL-PLV may play an essential role as a general regulatory hub for adaptive and flexible cognition. Chronic exposure to hypercortisolism may be related to iron distribution and significantly correlated with altered brain volumes and clinical features in patients with CD.

Health-Related Quality of Life in Cushing Disease: Discrepancy Between Parent and Child Reports

Background: Previously we reported impairment in quality of life (QoL) measures in children with Cushing disease (CD) by parent proxy; however, little is known about QoL measures from the affected child’s perspective. Method: Prospective study of 48 (26 females, Age:11.5±3.0 yr.) children diagnosed with CD. Prior to treatment, the Child Health Questionnaire (CHQ) was used to assess QoL by parent (proxy) and child report. Results: In children with active CD, there was a discrepancy between parent and child responses for mental health and self-esteem subscales. Child responses were significantly lower than parent responses (lower scores indicate poorer function) for mental health (56 ± 2 vs. 67 ± 2, p<0.001) and self-esteem (32.8 ±3 vs. 60.5 ±3, p<0.001). No significant differences were found between parent vs.child report for other subscale scores of the CHQ. Conclusion: This is the first study to compare child vs. parent report of health-related quality of life children with active CD. Parent reports underestimated the impact of CD on quality of life measures for mental health and self-esteem. It is important for clinicians to obtain information about health-related quality of life from the child’s perspective in order to guide management and take precautionary measures to alleviate negative outcomes.

Disruption of Rich-Club Connectivity in Cushing Disease

Cushing disease (CD) is a rare clinical disease in which brain structural and function are impaired as the result of excessive cortisol. However, little is known whether rich-club organization changes in patients with CD, as visualized on resting-state magnetic resonance imaging (fMRI), can reverse to normal conditions after transsphenoidal surgery (TSS). In this study, we aimed to investigate whether the functional connectivity of rich-club organization is affected and whether any abnormal changes may reverse after TSS. In this study, 38 patients with active CD, 33 with patients with CD in remission, and 41 age-, sex-, and education-matched healthy control participants underwent resting-state fMRI. Brain functional connectivity was constructed based on fMRI and rich club was calculated with graph theory approach. We constructed the functional brain networks for all participants and calculated rich-club connectivity based on fMRI. We identified left precuneus, right precuneus, left middle cingulum, right middle cingulum, right inferior temporal, right middle temporal, right lingual, right postcentral, right middle occipital, and right precentral regions as rich club nodes. Compared with healthy control participants, rich-club connectivity was significantly lower in patients with active CD (P < 0.001). Moreover, abnormal rich-club connectivity improved to normal after TSS. Our results show rich-club organization was disrupted in patients with active CD with excessive cortisol production. TSS can reverse abnormal rich-club connectivity. Rich club may be a new indicator to investigate the outcomes of TSS and to increase our understanding of the effect of excessive cortisol on brain functional connectivity in patients with CD.

Detrimental effects of hypercortisolism on brain structure and related risk factors

Brain structural abnormalities are often observed on magnetic resonance imaging (MRI) scans of Cushing's syndrome patients, but the pathogenesis is not fully understood. To understand the relationship between brain structural abnormalities and potential risk factors in active Cushing's disease (CD) patients, a total of 101 treatment-naïve CD patients and 95 sex-, age- and education matched controls with non-functioning adenomas (NFA) underwent clinical evaluation and MRI investigation, and the relative risk factors were analyzed. 14 patients in sustained remission after transsphenoidal surgery were followed. Compared with the NFA subjects, the patients with CD had more cortical (P < 0.01) and subcortical atrophy (P < 0.01) and a higher prevalence of white matter hyperintensity (WMH) (P < 0.01). WMH severity in CD patients positively correlated with age (r = 0.532, P = 0.000), disease course (r = 0.257, P = 0.009), postprandial glucose (r = 0.278, P = 0.005), frequency of left ventricular hypertrophy (r = 0.398, P = 0.001) and hypothyroidism (r = 0.246, P = 0.014). The markers of cortical and subcortical atrophy (sylvian fissure ratio, bifrontal ratio, bicaudate ratio and third ventricle width) were positively associated with the progression of WMH in the CD patients. In the follow-up of 14 patients with CD, brain atrophy and WMH was partially reversible after correction of hypercortisolism. In conclusions, brain atrophy and WMH were more likely to appear in CD patients and were possibly partially reversible following correction of hypercortisolism.

Telomere Length Changes in Children With Cushing Disease: A Pilot Study

Changes in telomere length (TL) have been linked to certain diseases. Studies on the effect of cortisol on TL have not led to conclusive results. To determine whether TL is affected in pediatric patients with Cushing disease (CD) through an exploratory study. We studied 10 pediatric patients [mean age: 13.3 (2.6) years, 7 females], diagnosed and treated successfully for CD. TL was measured before and approximately 1 year after treatment. TL was compared with controls adjusting for age, and associations with disease characteristics were assessed. Adjusting for age, total lymphocyte TL of patients did not differ from controls during active disease (P = 0.13) but was shorter than controls at follow-up (P = 0.031). Total lymphocyte TL during active CD and at follow-up did not correlate with markers of hypercortisolemia. There was strong inverse correlation between TL during active disease and at follow-up with triglyceride levels at active disease (adjusted [Adj] R2 = 0.64; P = 0.02 and Adj R2 = 0.5; P = 0.036, respectively), suggesting that the higher the triglycerides, the shorter the TL in patients with CD. The change of TL between active disease and follow-up was positively correlated with systolic blood pressure (Adj R2 = 0.76; P = 0.006). In this pilot study, TL is shorter in children with hypercortisolemia, a difference that becomes detectable only after cure of CD. Triglycerides and blood pressure appear to be factors that are associated with TL in these patients. Further studies are required to confirm these results.

Impaired brain network architecture in Cushing's disease based on graph theoretical analysis.

To investigate the whole functional brain networks of active Cushing disease (CD) patients about topological parameters (small world and rich club et al.) and compared with healthy control (NC). Nineteen active CD patients and twenty-two healthy control subjects, matched in age, gender, and education, underwent resting-state fMRI. Graph theoretical analysis was used to calculate the functional brain network organizations for all participants, and those for active CD patients were compared for and NCs. Active CD patients revealed higher global efficiency, shortest path length and reduced cluster efficiency compared with healthy control. Additionally, small world organization was present in active CD patients but higher than healthy control. Moreover, rich club connections, feeder connections and local connections were significantly decreased in active CD patients. Functional network properties appeared to be disrupted in active CD patients compared with healthy control. Analyzing the changes that lead to abnormal network metrics will improve our understanding of the pathophysiological mechanisms underlying CD.

Safety and Efficacy of Subcutaneous Pasireotide in Patients With Cushing's Disease: Results From an Open-Label, Multicenter, Single-Arm, Multinational, Expanded-Access Study.

Introduction: The efficacy and safety of subcutaneous (sc) pasireotide have been evaluated in a Phase III trial. Here, we report safety and efficacy results from a multinational, expanded-access study of pasireotide sc in patients with Cushing's disease (CD) in a real-world setting (clinicaltrials.gov, identifier: NCT01582061).Methods: Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 μg twice daily (bid; EU countries) or 900 μg bid (non-EU countries; 600 μg bid in patients with impaired glucose metabolism). Pasireotide dose could be adjusted in 300 μg increments/decrements to a maximum of 900 μg bid or minimum of 300 μg bid for sustained urinary free cortisol (UFC) normalization/tolerability issues. Primary objective: document the safety of pasireotide sc in patients with CD. Key secondary objectives: assess the proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) and changes from baseline in clinical signs/symptoms and quality of life (QoL) to weeks 12, 24, and 48.Results: One hundred and four patients received pasireotide: female, n = 84 (80.8%); median duration of pasireotide exposure, 25.1 weeks; median (range) baseline mUFC, 321.2 nmol/24 h (142–10,920; 2.3 × ULN [1.0–79.2]). Forty (38.5%) patients completed the study. The most common reasons for premature discontinuation of pasireotide were unsatisfactory therapeutic effect (n = 26, 25.0%) and adverse events (AEs; n = 20, 19.2%). Drug-related grade 3/4 AEs or drug-related serious AEs (primary endpoint) were documented in 42 (40.4%) patients, most commonly diabetes mellitus (n = 12, 11.5%) and hyperglycemia (n = 8, 7.7%). All patients experienced ≥1 AE and most (n = 102; 98.1%) reported ≥1 drug-related AE; six (5.8%) patients discontinued treatment because of hyperglycemia-related AEs. At weeks 12, 24, and 48, respectively, 36/66 (54.5%), 22/46 (47.8%), and 9/21 (42.9%) evaluable patients had normalized mUFC levels. Clinical signs/symptoms and QoL were also improved.Conclusions: In an international, real-world, clinical-practice setting, pasireotide sc was generally well-tolerated (no new safety signals were identified), effectively reduced UFC (normalization in ~50% of evaluable patients) and improved clinical signs and QoL in patients with CD. While hyperglycemia-related AEs were common, consistent with previous studies, most were manageable, with <6% of patients discontinuing treatment because of these events.

Dysregulation of resting-state functional connectivity in patients with Cushing's disease.

To explore the anatomical distance-dependent functional connectivity patterns in patients with active phase of Cushing's disease (CD) and to evaluate the associations between hypercortisol exposure and regional normalized functional connectivity strengths (nFCSs). Based on the fMRI data in 32 CD patients and 32 healthy controls (HCs), we computed the nFCSs for each voxel in the brain and further divided them into long-range and short-range nFCSs. General linear models was used to investigate between-group differences in these nFCS metrics and the correlations between the nFCSs and clinical variables. Compared with HC, CD patients showed dysregulation of the nFCSs mainly in the default mode network. They showed an overall higher nFCS in bilateral parahippocampal cortex mainly owing to the disruption of long-range nFCS and a relatively lower nFCS in bilateral posterior cingulate cortex (PCC), bilateral lateral parietal cortex (LP), and right prefrontal cortex (PFC). In addition, their long-range nFCS was lower in the bilateral anterior cingulate cortex, PCC, and LP; short-range nFCS was lower in the bilateral PFC. Notably, the positive correlation between the nFCSs in their right parahippocampal cortex and serum cortisol levels at 08:00 remained significant after taking the anatomical distance into consideration. The discrepant functional connectivity patterns found in our study indicated a hypercortisol-associated, distance-dependent disruption of resting-state functional connectivity in patients with active CD. We provide novel insights into the impacts of hypercortisol exposure and the pathophysiologic mechanisms of CD, which may facilitate advances in CD intervention ultimately.

MON-LB078 Desmopressin Stimulated Salivary Cortisol as a Suplementary Tool in the Diagnosis of Cushing's Syndrome

The classic desmopressin test consists of serum cortisol and plasma ACTH measurements after intravenous administration of desmopressin. This test has been shown to have good accuracy in the context of exclusion of Cushing's syndrome in patients with non-tumoral hypercortisolism; with an equal or greater precision than the synthetic corticotrophin-releasing hormone (CRH) test. Meanwhile, salivary cortisol samples are independent of fluctuations in the serum transcortin, reflect the plasma free fraction (about 70%), and are not influenced by the alteration of salivary flow ; It has been largely employed in the evaluation of hypercortisolism states, however its role in the desmopressin test has not been fully evaluated. Aim: To compare salivary cortisol measurements during the desmopressin test in active Cushing’s disease as opposed to obese patients without clinical or biochemical evidence of hypercortisolism. Methods: Nineteen individuals, from endocrine outpatient clinics of an university were enrolled: 11 patients with active Cushing's disease and 8 obese individuals (BMI greater than 35kg / m2). Salivary cortisol plasma ACTH and serum cortisol were collected at baseline, 15, 30, 45, 60 and 120 minutes after IV administration of desmopressin (10 mcg). Salivary cortisol and plasma ACTH were performed by an electrochemiluminescence immunoassay, while serum cortisol was made by competitive immunoassay using direct chemiluminescence. Results: The groups were epidemiologic and clinical homogenous. In comparison to baseline, plasma ACTH, serum and salivary cortisol after desmopressin stimulation were significantly elevated at 45 (P<0,01) and 60 minutes (P<0,01) . The increment in salivary cortisol at 15 (P<0,01) and 30 minutes (P<0,01) was significantly different in patients with Cushing`s disease in comparison to obese patients. Salivary cortisol increased in comparison to baseline in patients with Cushing’s disease (range: 66 to 309%) mainly at 60 minutes, declining thereafter. A positive correlation between salivary and serum cortisol at 30, 45, 60,and 120 minutes was observed in patients with Cushing’s disease, particularly at 120 minutes (rho 0,90, p<0,01). In obese patients, salivary cortisol did not respond to desmopressin administration and there was no correlation between serum and salivary cortisol. Conclusion: Inclusion of the measurement of salivary cortisol to the desmopresin test may add value to its interpretation, combined with serum cortisol and plasma ACTH. Desmopressin stimulated salivary cortisol at 60 minutes could be used as an additional tool in differentiating Cushing`s disease from of non-tumoral hypercortisolism . Further studies in larger and more a diverse populations are needed to confirm the role of desmopressin -stimulated cortisol in the diagnosis of Cushing`s syndrome. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

The changes of standard DXA measurements and TBS depending on outcomes of neurosurgical treatment in patients with Cushing's disease

BACKGROUND: Patients with endogenous hypercortisolism have reduced bone mineral density (BMD) and trabecular bone score (TBS) that are the causes of secondary osteoporosis and low-traumatic fractures. It is well known that radical treatment (neurosurgery or radiosurgery) of Cushing’s disease leads to a decline of cortisol levels in all body fluids to normal values. However, it is still uncertain whether bone tissue structure, and particularly its microarchitecture, does recover in remission of the disease.&#x0D; AIMS: To evaluate an influence of hormone activity (presence or absence of remission) in patients with Cushing's disease on changes of bone structure measurements in accordance with DXA values (TBS, BMD, T- and Z-scores), as well as significance of such changes in 12 and 24 months after neurosurgical treatment.&#x0D; MATERIALS AND METHODS: In patients with confirmed active Cushing's disease (ACTH-producing pituitary adenoma) (n = 44) and in control group of healthy volunteers (n = 40), BMD in lumbar spine (L1-L4) and simultaneously TBS, in cut-off points before neurosurgical treatment (in both groups) and in 12 and 24 months after it (only in patients), were assessed. We diagnosed presence or absence of disease remission at cut-offs. All measurements were performed using a GE iDXA device (GE Healthcare Lunar, Madison, Wisconsin, USA). The TBS was calculated simultaneously from taken BMD scans, blinded to clinical outcome using TBS iNsight software v2.1 (Medimaps, Merignac, France). The activity of Cushing’s disease was evaluated using late-night salivary cortisol (LNSC, at 23:00). To determine the differences in DXA and TBS values before and after neurosurgical intervention depending on remission occurrence, covariate analysis (ANCOVA) was applied.&#x0D; RESULTS: There were found significant changes in TBS, BMD and T-score values in 12 months after neurosurgical treatment associated with presence or absence of disease remission (p = 0.039, 0.046 and 0.048, respectively). No differences in Z-score as well as in all measurements in 24 months, that might be associated with remission occurrence, were revealed. The gain in all DXA measurements (including TBS) during 24 months of observation period was statistically significant when analyzing data using Student’s paired t-test. However, the values corresponding to the age references had not been achieved for the specified time interval.&#x0D; CONCLUSIONS: Patients with Cushing’s disease have lower TBS values. In remission conditions TBS is getting significantly higher. The increase in BMD and TBS occurs during 24 months after achieving remission of Cushing’s disease but doesn’t lead to a full restoration of normal bone mass and microstructure throughout observation period of 24 months.

Active Cushing Disease Is Characterized by Increased Adipose Tissue Macrophage Presence.

Although glucocorticoids (GCs) have potent anti-inflammatory actions, patients with hypercortisolism due to Cushing disease (CD) have increased circulating proinflammatory cytokines that may contribute to their insulin resistance and cardiovascular disease. The mechanisms and tissues that account for the increased systemic inflammation in patients with CD are unknown. To determine whether chronic endogenous GC exposure due to CD is associated with adipose tissue (AT) inflammation in humans. Abdominal subcutaneous AT samples from 10 patients with active CD and 10 age-, sex-, and body mass index‒matched healthy subjects were assessed for macrophage infiltration and mRNA expression of proinflammatory cytokines. Using immunohistochemistry, AT samples were analyzed for the expression of vimentin, caspase, CD3, CD4, CD8, CD11c, CD20, CD31, CD56, CD68, and CD163. Quantitative PCR was used to assess the mRNA gene expression of arginase, CD11b, CD68, EMR-1, IL-6, IL-10, MCP-1, and TNF-α. Immunohistochemistry revealed higher mean percentage infiltration of CD68+ macrophages and CD4+ T lymphocytes, increased mean area of CD11c+ M1 macrophages, higher number of CD11c+ crownlike structures, and decreased vimentin in the AT of patients with active CD compared with controls. PCR revealed no differences in mRNA expression of any analyzed markers in patients with CD. Chronic exposure to GCs due to CD increases the presence of AT macrophages, a hallmark of AT inflammation. Hence, AT inflammation may be the source of the systemic inflammation seen in CD, which in turn may contribute to obesity, insulin resistance, and cardiovascular disease in these patients.

Quality of life is significantly impaired in both secretory and non-functioning pituitary adenomas.

To evaluate the quality of life (QoL) in patients with pituitary adenomas in comparison with healthy Mexican population QoL scores. Cross-sectional study using the short form 36 questionnaire (SF-36) in 175 patients with pituitary adenomas grouped by adenoma subtype and disease activity, and compared them with the healthy Mexican population normative QoL scores. A total of 44 patients with non-functioning pituitary adenomas (NFPA), 48 with acromegaly, 53 with prolactinomas and 30 with Cushing disease (CD) were enrolled in this study. Mental and physical components scores (MCS & PCS) of SF-36 questionnaire were lower in patients with active disease in all adenoma subtypes (P<0.03). A significant negative relationship between prolactin levels and MCS (r=-0.30, P<0.01) and PCS (r=-0.41, P<0.01) were found in prolactinomas. Patients with CD showed 24hours urine-free cortisol levels negatively correlated with MCS (r=-0.43, P<0.01) but not with PCS. No significant correlation was found between IGF-1 ULN and QoL scores in acromegaly. NFPA patients had lower QoL scores than patients with controlled CD, acromegaly or prolactinoma (P<0.02). Active CD and prolactinoma have lower QoL scores in comparison of NFPA (P<0.05). Having an adenoma, secretory or non-functioning, decrease QoL scores in comparison of results in the healthy Mexican population register. Using an adjusted-multivariate model, we confirmed that disease activity in all secretory adenomas is an independent risk factor, reducing SF-36 scores significantly. Activity in all secretory pituitary adenomas' patients decrease mental and physical QoL. However, independently of disease activity, secretory and NFPA significantly decrease QoL in comparison with healthy Mexican population QoL register.

Structural brain abnormalities in Cushing's syndrome.

Alongside various physical symptoms, patients with Cushing's disease and Cushing's syndrome display a wide variety of neuropsychiatric and cognitive symptoms, which are indicative of involvement of the central nervous system. The aim of this review is to provide an overview of the structural brain abnormalities that are associated with Cushing's disease and Cushing's syndrome and their relation to behavioral and cognitive symptomatology. In this review, we discuss the gray matter structural abnormalities found in patients with active Cushing's disease and Cushing's syndrome, the reversibility and persistence of these changes and the white matter structural changes related to Cushing's syndrome. Recent findings are of particular interest because they provide more detailed information on localization of the structural changes as well as possible insights into the underlying biological processes. Active Cushing's disease and Cushing's syndrome is related to volume reductions of the hippocampus and in a prefrontal region involving the anterior cingulate cortex (ACC) and medial frontal gyrus (MFG). Whilst there are indications that the reductions in hippocampal volume are partially reversible, the changes in the ACC and MFG appear to be more persistent. In contrast to the volumetric findings, changes in white matter connectivity are typically widespread involving multiple tracts.

Insulin sensitivity and secretion and adipokine profile in patients with Cushing's disease treated with pasireotide.

To evaluate the effect of pasireotide on β-cell and adipose function in patients with Cushing's disease (CD). Clinical and hormonal parameters, insulin secretion evaluated by HOMA-β and by the area under the curve (AUC2h) of C-peptide during a mixed meal tolerance test and insulin sensitivity, evaluated by the euglycaemic hyperinsulinaemic clamp, were evaluated in 12 patients with active CD, before and after 6 and 12months of pasireotide. In addition, a panel of adipokines including leptin (Ob), leptin/leptin receptor ratio (Ob/Ob-R ratio), adiponectin, resistin, visfatin, adipocyte fatty acid binding protein (AFABP) and non-esterified fatty acids (NEFAs) was evaluated at baseline and after 12months of pasireotide. During 12months of pasireotide treatment, a significant decrease in weight (p=0.004), BMI (p=0.008), waist circumference (p=0.009), urinary free cortisol (p=0.007), fasting insulinaemia (p=0.007), HOMA-β (p=0.015) and AUC2h c-peptide (p=0.017), concomitance with an increase in fasting glycaemia (p=0.015) and HbA1c (p=0.030), was found. With regard to adipokines, a significant decrease in Ob (p=0.039), Ob/Ob-R ratio (p=0.017) and AFABP (p=0.036) was observed concomitant with a significant increase in Ob-R (p=0.028) after 12months of pasireotide. 12months of treatment with pasireotide in CD is associated with an impairment of insulin secretion and an improvement of adipose function without any interference in insulin sensitivity.

Volumetric magnetic resonance imaging analysis in patients with short-term remission of Cushing's disease.

The data on patients with short-term remission of Cushing's disease (CD) might provide information that is not available from previous long-term remission studies. We aimed to investigate structural changes in the brain in these patients and to examine whether these changes were associated with clinical characteristics. A cross-sectional study was performed. Thirty-four patients with CD (14 with CD in short-term remission and 20 with active CD) and 34 controls matched for age, sex and education underwent clinical evaluation and magnetic resonance imaging brain scans. Biometric measurements, disease duration and remission duration data were collected. Grey matter volumes in the whole brain were examined using voxel-based morphometry (VBM). No differences were observed in the grey matter volumes of the medial frontal gyrus (MFG) and cerebellum between the patients with remitted CD and healthy controls, whereas patients with active CD had smaller grey matter volumes in these two regions compared with controls and patients with remitted CD. Furthermore, significant correlations were found between remission time and grey matter values in these regions in short-term remission patients with CD. Additionally, greater grey matter volumes in the bilateral caudate of short-term remission patients with CD were observed. Trends for structural restoration were found in CD patients with short-term remission. This finding was associated with the number of days elapsed since curative surgery and the current age of the patients. This study enhances our understanding of potential reversibility after the resolution of hypercortisolism in CD patients.