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Plurihormonal pituitary adenomas are rare forms of pituitary adenomas that express more than one hormone. The most common association is with growth hormone (GH) and prolactin. Cosecretion of GH and adrenocorticotrophic hormone (ACTH) is rare with only 25 reported cases in literature. Most presented with features of GH excess, and only four presented with Cushing’s disease. We report a case of a woman in her 30s with recurrent plurihormonal pituitary macroadenoma cosecreting GH and ACTH, diagnosed during workup for polycystic ovarian syndrome, and both times presenting uniquely with Cushing’s disease. Biochemical testing showed GH excess and hypercortisolism. She underwent transsphenoidal surgery twice and immunohistochemistry showed positive staining for GH and ACTH on both occasions. We aim to raise more awareness of this rare type of pituitary adenoma, shed light on the importance of recognising rare presentations and highlight the necessity of rigorous follow-up given morbidity and potentially higher mortality risk.

Objective This extended evaluation (EE) of the SONICS study assessed the effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing's syndrome. Design/Methods SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at months 9 and 12 (relative to the start of maintenance). For pituitary MRI in patients with Cushing's disease, a threshold of ≥2 mm denoted change from baseline in the largest tumor diameter. Results Sixty patients entered EE at month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, BMI, abdominal girth, hirsutism, CushingQoL, and Beck Depression Inventory-II scores improved from the study baseline at months 9 and 12. Forty-six patients completed month 12; four (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal, Fridericia-corrected QT interval >460 ms, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and month 12 or follow-up, the largest tumor diameter was stable in 27 (87%) patients, decreased in one, and increased in three (largest increase 4 mm). Conclusion In the first long-term levoketoconazole study, continued treatment through a 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Background Many patients with Cushing’s disease (CD) require long-term medical therapy to control their hypercortisolism. In the core phase of a Phase II study (LINC 2; NCT01331239), osilodrostat normalized mean urinary free cortisol (mUFC) in 78.9% of patients with CD. Here, we report long-term efficacy and safety data for osilodrostat following completion of an optional extension to LINC 2. Methods Adult patients with CD were enrolled in a 22-week prospective Phase II study. Patients with mUFC ≤ upper limit of normal (ULN) or receiving clinical benefit at week 22 could enter the optional extension. The proportion of complete (mUFC ≤ ULN) or partial (mUFC > ULN but ≥ 50% decrease from baseline) mUFC responders was assessed over time. Results Sixteen of 19 enrolled patients entered the extension. Median (range) osilodrostat exposure from baseline to study end was 5.4 years (0.04–6.7); median (range) average dose was 10.6 mg/day (1.1–47.9). Overall response rate (complete and partial mUFC responders) was consistently ≥ 50%. Sustained control of most cardiovascular-related parameters was observed during the extension. The long-term safety profile was consistent with that reported during the core phase. Testosterone levels (females) decreased towards baseline levels during long-term follow-up, with no new or worsening cases of hirsutism during the extension. Conclusions In the longest prospective study of a steroidogenesis inhibitor to date, osilodrostat provided sustained reductions in mUFC for up to 6.7 years of treatment, with no new safety signals emerging during the extension. These findings support osilodrostat as an effective long-term treatment for patients with CD.

Endoscopic endonasal surgery is the main transsphenoidal approach for pituitary surgery in many centers; however, few studies compare the endoscopic and microscopic surgical approaches with regard to long-term follow-up. This single-center study aimed to compare the 2 techniques over 15 years.Medical records and magnetic resonance images from 40 patients with primary transsphenoidal surgery for Cushing's disease at Sahlgrenska University Hospital between 2003 and 2018 were reviewed. 14 patients who underwent microscopic surgery and 26 patients who underwent endoscopic surgery were included in this study.In the microscopic group, 12 of 14 patients achieved endocrine remission, compared to 19 of 26 patients in the endoscopic group (n. s.). Three patients in each group developed a late recurrence. Complications were seen in 5 patients in the microscopic group and in 8 patients in the endoscopic group (n. s.). No serious complications, such as carotid artery damage, cerebrovascular fluid leakage, epistaxis, or meningitis, occurred in any group. The postoperative hospital stay was shorter in the endoscopic than in the microscopic group.Endoscopic endonasal surgery for Cushing's disease showed no difference in remission, recurrence, and complication rates compared to the microscopic approach. The endoscopic group had a shorter postoperative hospital stay than the microscopic group, which in part may be due to the minimal invasiveness of the endoscopic approach.

Background Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD. Methods We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated. Results Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis. Conclusion Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

The aim of this article is to report a case of iatrogenic Cushing's disease associated with a delayed inflammatory response due to a facial dermal filler procedure.A case report according to CARE guidelines was performed. A delayed inflammatory reaction due to dermal filler injection resulted in iatrogenic Cushing's disease in a patient with no comorbidities or allergies.Prolonged use of glucocorticoids can cause adverse effects, such as iatrogenic Cushing's disease. Dermal fillers have a very low incidence of complications, but these need to be discussed with patients. Drugs used to treat delayed inflammatory reaction include antibiotics, antihistamines, steroids, and intralesional hyaluronidase. Reversal of dermal fillers should be explained to the patient and included in the written consent.Due to patient non-compliance and possible adverse effects of steroid medications, physicians should consider limiting their prescriptions of steroid medications to no more than 2 weeks and require frequent follow-up to discuss hyaluronidase if the condition returns off of steroid medication. In addition, it may be advisable to only treat with one filler brand, especially in the same session as this may be a risk factor.

Objective Endogenous hypercortisolism predisposes to impaired immune function and infections. To date, however, it is unknown whether there is a subtype-specific pattern in white blood cell (WBC) and WBC differential (WBCD) count. Methods A retrospective monocentric cohort study was carried out in patients with overt endogenous Cushing’s syndrome (CS) or adrenal incidentalomas and autonomous cortisol secretion (ACS), with WBC/WBCD analysis at initial diagnosis and after biochemical remission. Cut-offs were obtained by receiver-operating characteristics analysis. Results In total, 253 patients were analyzed (Cushing’s disease (CD); n = 88; ectopic CS (ECS), n = 31; cortisol-producing adrenal adenomas (CPA), n = 40; ACS, n = 45; adrenocortical carcinomas (ACC), n = 49). Total leukocytes and neutrophils correlated positively with serum cortisol after 1-mg dexamethasone (r = 0.314 and r = 0.428), while a negative correlation was observed for lymphocytes and eosinophils (r = −0.374 and r= −0.380) (each P P Conclusion Most immune cells correlate with the degree of hypercortisolism and differ among CS subtypes. WBCD changes are already identified 3 months after remission from endogenous hypercortisolism.

Objective In Cushing’s disease (CD), detection of an adenoma by MRI is challenging. The aim of this study is to compare real-life MRI in the initial diagnostic workup of CD with high-quality MRI performed in a tertiary center for pituitary diseases. Design and methods We retrospectively analyzed 139 patients with CD who underwent primary transsphenoidal surgery (TSS) in our department and had both an MRI conducted at a different institution (external MRI; extMRI) and an MRI conducted at our institution (internal MRI; intMRI). Preoperative interpretation of MRI was performed independently by an external radiologist (extRAD), an internal neuroradiologist (intRAD) and a pituitary surgeon (SURG). Intraoperative detection of an adenoma and endocrinological remission provided proof of the true adenoma localization in 105 patients. Results Interpretation of extMRI by extRAD and SURG was concordant in only 64% (89/139) of cases, while 74.1% (103/139) concordance was observed for interpretation of intMRI by intRAD and SURG. Based on extMRI, the true localization of the adenoma was correctly predicted in only 46.7% of the patients by extRAD and in 65.7% by SURG. In contrast, the sensitivity to correctly identify the adenoma on intMRI was 80.0% for intRAD and 94.3% for SURG. Conclusion Both the quality of MRI and the reader’s experience are paramount for detection of microadenomas in CD. Every effort should be made to perform high-quality initial MRI according to current standards and to ensure rating by an expert in pituitary imaging.

Endogenous Cushing’s syndrome (CS) is a rare endocrine condition frequently caused by a tumor resulting in elevated cortisol levels. Cushing’s disease (CD) caused by an adrenocorticotropic hormone–secreting pituitary adenoma is the most common form of endogenous CS. Medical therapy for CD is mostly used as second-line treatment after failed surgery or recurrence and comprises several pituitary-directed drugs, adrenal steroidogenesis inhibitors, and a glucocorticoid receptor blocker, some of which are US Food and Drug Administration (FDA)–approved for this condition. The recent Pituitary Society consensus guidelines for diagnosis and management of CD described osilodrostat, an oral inhibitor of 11β-hydroxylase, as an effective, FDA-approved medical therapy for CD. Because clinical experience outside clinical trials is limited, we provide here a review of published data about osilodrostat and offer example case studies demonstrating practical considerations on the use of this medication. Recommendations regarding osilodrostat are provided for the following situations: specific assessments needed before treatment initiation; monitoring for adrenal insufficiency, hypokalemia, and changes in QTc; the potential value of a slow up-titration in patients with mild disease; managing temporary treatment cessation for patients with CD who have acquired coronavirus disease 2019; monitoring for increased testosterone levels in women; exercising caution with concomitant medication use; considering whether a higher dose at nighttime might be beneficial; and managing cortisol excess in ectopic and adrenal CS. This review highlights key clinical situations that physicians may encounter when using osilodrostat and provides practical recommendations for optimal patient care when treating CS, with a focus on CD.

An increased risk of ocular hypertension was seen in Cushing's disease.Systemic steroid use is a significant risk factor for increased intraocular pressure (IOP). The incidence of ocular hypertension may rise to 30%-40% of the general population due to topical or systemic glucocorticoid usage. However, the incidence of ocular hypertension in endogenous hypercortisolemia, as well as the ophthalmological outcomes after endocrine remission due to surgical resection, remain unknown.The IOP, visual field, and peripapillary retinal nerve fiber layer thickness were documented in all patients with Cushing's disease (CD) admitted to a tertiary pituitary center for surgery from January to July 2019. Patients with acromegaly and patients with nonfunctioning pituitary adenoma (NFPA) during the same study period served as controls. We calculated the odds ratio (OR), identified the risk factors of developing ocular hypertension, and presented postoperative trends of the IOP.A total of 52 patients (38.4±12.4 y old) with CD were included. The IOP was higher in patients with CD (left 19.4±5.4 mm Hg and right 20.0±7.1 mm Hg) than in patients with acromegaly (left 17.5±2.3 mm Hg and right 18.6±7.0 mm Hg, P =0.033) and patients with NFPA (left 17.8±2.6 mm Hg and right 17.4±2.4 mm Hg, P =0.005). A total of 21 eyes (20.2%) in patients with CD were diagnosed with ocular hypertension compared with 4 eyes (4.7%) in the acromegaly group and 4 eyes (4.5%) in the NFPA group. The OR of developing ocular hypertension in patients with CD was 5.1 [95% confidence interval (CI), 1.3-25.1, P =0.029] and 6.6 (95% CI, 1.8-30.3, P =0.007) when compared with the 2 control groups. Among patients with CD, those with a higher urine-free cortisol were more likely to develop ocular hypertension (OR=19.4, 95% CI, 1.7-72.6). The IOP decreased at 1 month after surgery in patients with CD, and the change was sustained for 3 months after surgery.An increased risk of ocular hypertension was seen in CD and suggests that endogenous hypercortisolemia should be considered as part of the glaucoma assessment. This result warrants the discretion of both ophthalmologists and neuroendocrinologists.

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.

To limit the role of bilateral inferior petrosal sinus sampling (BIPSS) in distinguishing between Cushing disease (CD) and ectopic Cushing syndrome (ECS), recent reports have proposed a noninvasive approach based on a combination of biochemical testing and radiological imaging as an alternative to the conventional invasive strategy (CIS). However, this strategy requires further validation. The current study aimed to evaluate 2 limited invasive protocols (LIP-1 and LIP-2) in limiting the role of BIPSS while maintaining a diagnostic accuracy similar to that of CIS.This was a single-center study conducted on individuals with corticotropin-dependent Cushing syndrome. The LIPs were based on performing high-dose dexamethasone suppression (50% cut-off in first [LIP-1] and80% in second [LIP-2]) and magnetic resonance imaging of the sella in all individuals and selective use of computed tomography of the chest and abdomen before BIPSS. These LIPs were evaluated for limiting the use of BIPSS, their accuracy, and cost in comparison to CIS.Of the 206 individuals, 114 (97 of CD and 21 of ECS) were eligible for the current study. Using LIP-1, LIP-2, and CIS, BIPSS could have been avoided in 62.3%, 35.9%, and 25.4% of individuals, respectively. The positive predictive value for CD using LIP-1 and LIP-2 was 98.9% and 100%, respectively. The cost per patient evaluated using LIP-1, LIP-2, and CIS was $602.21, $966.81, and $1107.78, respectively.LIPs represent an equally accurate, less invasive, and more cost-effective alternative to the CIS for distinguishing between CD and ECS.

Exposure to cortisol excess in Cushing’s disease (CD) results in increased cardiovascular morbidity and reduces survival, with cardiovascular disease being a leading cause of death. At diagnosis, a significant number of patients have adverse cardiovascular profiles (e.g., obesity, diabetes or impaired glucose tolerance, dyslipidemia, hypertension, cardiac abnormalities and vascular disease). Remission of hypercortisolemia reduces but does not completely eliminate the cardiovascular complications; hazard ratios for myocardial infarction and stroke are high during long-term monitoring, highlighting the long-lasting effects of hypercortisolism and the importance of the timely diagnosis and successful management of this condition. Data on mortality of patients in remission are not consistent but in a multicenter study, an increased all-cause and circulatory mortality in patients with CD in remission for at least 10 years has been demonstrated. Cardiovascular morbidity requires particular focus and effective management during the care of patients with CD, from their presentation until long-term follow up.

Cushing’s disease is a rare, but devastating condition, caused by corticotroph tumors. It rarely manifests as syndrome and very few isolated cases present with germline mutations. Instead, the vast majority of corticotroph tumors are sporadic monoclonal neoplasms. At present, the major recurrent somatic driver mutations are found in the USP8 gene, which encodes for a deubiquitinase that rescues proteins regulating ACTH synthesis. Almost half of functional corticotroph tumors carry somatic USP8 mutations that associate with a distinct transcriptomic and clinical profile. Other genes mutated in a small fraction of corticotroph tumors include the deubiquitinase encoding gene USP48 and the glucocorticoid receptor expressing NR3C1. Recent reports on somatic TP53 and ATRX mutations in corticotroph macroadenomas and carcinomas indicate that within specific patient subpopulations they are not as rare as assumed.

Cushing's syndrome and Cushing's disease cause various metabolic disorders associated with high cortisol levels. Some reports have shown that Cushing's syndrome is complicated with dissecting aortic aneurysm and aortic dissection after long-term exposure to high cortisol levels. We herein report a rare case of aortic dissection complicated with Cushing's disease. Aortic dissection may occur even under relatively short periods of high cortisol conditions. This case suggests that hypercortisolemia should be treated as soon as possible in order to prevent aortic dissection in subjects with Cushing's disease.

This brief review is devoted mainly to publications in the last 5 years dealing with health-related quality of life (QoL) after a diagnosis of endogenous hypercortisolism, due to pituitary-dependent Cushing’s disease (CD) or any other cause of Cushing syndrome (CS). Despite improvement after treatment, persistent physical morbidity, neurocognitive problems like worse executive capacity and memory as well as stress intolerance, depressive symptoms and more anxiety, lead to long-term impairment of QoL.

Management of Cushing’s disease is informed by dedicated imaging of the sella and parasellar regions. Although magnetic resonance imaging (MRI) remains the investigation of choice, a significant proportion (30–50%) of corticotroph tumours are so small as to render MRI indeterminate or negative when using standard clinical sequences. In this context, alternative MR protocols [e.g. 3D gradient (recalled) echo, with acquisition of volumetric data] may allow detection of tumors that have not been previously visualized. The use of hybrid molecular imaging (e.g. 11C-methionine positron emission tomography coregistered with volumetric MRI) has also been proposed as an additional modality for localizing microadenomas.

Itsenko–Cushing’s disease is a rare, multisystem disease characterized by the presence of endogenous central hypercortisolism due to an ACTH-secreting brain tumor. The frequency of Itsenko-Cushing’s disease in adulthood is 0.7–2.4 per 1 million population, and only 10% of all cases occur in childhood. The age of onset of the disease in children is on average 12.0–14.8 years. A typical manifestation of the disease in children, along with obesity and arterial hypertension, is a decrease in growth rates. The gold standard for diagnosing central hypercortisolism is MRI of the brain, however, the effectiveness of this method in children is only 50%. The main method of treatment is neurosurgical transnasal transsphenoidal removal of endosellar pituitary adenoma, which makes it possible to achieve remission in more than 65% of cases. This article describes a clinical case of Itsenko–Cushing’s disease in a 6.5-year-old child with obesity, arterial hypertension, atypically «high» stature, average velocity and non-visualizable corticotropinoma. The article presents the stages of diagnostic search, the complexity of differential diagnosis and surgical treatment, the results of follow-up after the treatment and a brief review of the literature.

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.

Context Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks’ open-label osilodrostat). Results Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P Conclusion Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.

[Context] Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse., [Objectives] This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas., [Methods] A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years’ follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery., [Results] Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P, [Conclusion] This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas., This work was supported by the Junta de Andalucía (Nos. P20_00442, PEER-0048-2020, A-0006-2017, A-0055-2018, C-0015-2014, RC-0006-2018; postdoctoral grant DOC_01584, and BIO-0139); Ministry of Science and Innovation (Nos. PID2019-105564RB-I00 and PID2019-105201RB-I00); Instituto de Salud Carlos III, cofunded by the European Union (ERDF/ESF, “Investing in your future”; Nos. PI13/02043; PI16/00175, PI21/01012, and Sara Borrell programme CD19/00255); Spanish Ministry of Universities (predoctoral contract FPU16-05059); a GETNE2019 research grant; and CIBERobn. CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain.

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 patients and 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 nucleus and 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.

Pasireotide, which has a high affinity for somatostatin receptor (SSTR) 5, has attracted attention as a new treatment for refractory Cushing's disease. The patient was a 28-year-old man. He had refractory Cushing's disease and underwent multiple surgeries, radiotherapy, and medication therapy. An examination of the adenoma by immunohistochemistry revealed a low SSTR5 expression. An USP8 mutation was not detected by reverse transcription polymerase chain reaction. Although we administered pasireotide, it was ineffective. While a further investigation is necessary, the analysis of SSTR5 expression may support the prediction of the efficiency of pasireotide for Cushing's disease. We report this case as a useful reference when considering whether or not to use pasireotide for refractory corticotroph adenomas.

OBJECTIVE A systematic review was performed to provide objective evidence on the use of stereotactic radiosurgery (SRS) in the management of secretory pituitary adenomas and develop consensus recommendations. METHODS The authors performed a systematic review of the English-language literature up until June 2018 using the PRISMA guidelines. The PubMed (Medline), Embase, and Cochrane databases were searched. A total of 45 articles reporting single-institution outcomes of SRS for acromegaly, Cushing’s disease, and prolactinomas were selected and included in the analysis. RESULTS For acromegaly, random effects meta-analysis estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rates were 97.0% (95% CI 96.0%–98.0%), 44.0% (95% CI 35.0%–53.0%), and 17.0% (95% CI 13.0%–23.0%), respectively. For Cushing’s disease, random effects estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rate were 92.0% (95% CI 87.0%–95.0%), 48.0% (95% CI 35.0%–61.0%), and 21.0% (95% CI 13.0%–31.0%), respectively. For prolactinomas, random effects estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rate were 93.0% (95% CI 90.0%–95.0%), 28.0% (95% CI 19.0%–39.0%), and 12.0% (95% CI 6.0%–24.0%), respectively. Meta-regression analysis did not show a statistically significant association between mean margin dose with crude endocrine remission rate or mean margin dose with development of any new hypopituitarism rate for any of the secretory subtypes. CONCLUSIONS SRS offers effective tumor control of hormone-producing pituitary adenomas in the majority of patients but a lower rate of endocrine improvement or remission.

Background Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear. Methods A total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays. Results A novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETs in vitro and in vivo. Conclusion Our studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing’s disease.

Background Quantification of salivary cortisol is one of the highly sensitive and specific screening parameters for Cushing’s syndrome (CS). However, only late-night salivary cortisol is part of the standard screening procedure. In this study, we aimed to analyze salivary cortisol day profiles in patients with different types of CS to test whether specific patterns might be relevant for diagnosis and subtyping. Material and Methods Among 428 patients including those with confirmed Cushing’s syndrome (N=111, of those 75 with Cushing’s disease, 27 patients with adrenal CS and nine patients with ectopic CS), autonomous cortisol secretion (N=39) or exclusion of CS (control group, N=278) salivary cortisol was measured five times a day. Results At each of the five time points, salivary cortisol was significantly higher in patients with CS compared to the control group (p≤0.001). Using the entire profile instead of one single salivary cortisol at 11 p.m. improved diagnostic accuracy (85 vs. 91%) slightly. Patients with ACTH-dependent CS had higher salivary cortisol levels than patients with adrenal CS. Also, morning cortisol was significantly higher in patients with ectopic CS than in patients with Cushing’s disease (p=0.04). Nevertheless, there was a strong overlap between diurnal profiles, and the diagnostic yield for subtyping was low. Discussion The study results show that using diurnal salivary cortisol profiles for CS diagnosis results in a limited increase in diagnostic accuracy. With significant differences between Cushing subtypes, cortisol profiles are not useful in everyday clinical practice for subtyping of CS.

Patients who were followed up for CD and treated with pasireotide between 2014-2020 at Cerrahpaşa Medical Faculty, were evaluated retrospectively. The efficacy and adverse effects of pasireotide were evaluated in this study.Thirty-two patients were evaluated. The mean duration of treatment was 26.5 [range, 12.0-37.0] months. The 24-h urinary free cortisol (UFC) decreased 46% during the treatment and normalized in 37.5% of patients. A significant decrement was found between pretreatment and last follow-up UFC (p = 0.001). Plasma ACTH decreased by 21%. A significant decrement was found between pre-treatment and the 3rd month, 6th month, and last follow-up ACTH levels (p = 0.014, p = 0.017, and p = 0.017, respectively). Serum cortisol levels decreased by 18% and a significant decrement was found between pretreatment and the 3rd month, and between pretreatment and the last follow-up (p = 0.034 and p = 0.013, respectively). While fasting blood glucose at the 3rd month was significantly higher than pretreatment fasting blood glucose, no significant difference was found between pretreatment fasting blood glucose and 6th month and last follow-up fasting blood glucose. Although there was a significant difference between pretreatment HbA1c levels and the HbA1c levels at the 3rd month (5.9% vs. 6.6% p = 0.007), 6th month (5.9% vs. 6.7% p = 0.003), and the last follow-up (5.9% vs. 7.1% p = 0.001), in the last follow-up, the majority (77%) of patients had adequate glycemic control (HbA1c ≤ 7.0 %)./AbstractTextAbstractText Label="RESULTS"The authors declare that there is no conflict of interest.Pasireotide treatment is an alternative treatment in CD, remission is obtained in the first months of treatment, and continues for an extended period. Although hyperglycemia is the most common adverse effect, it can be successfully controlled.

Resume La remission spontanee de la maladie de Cushing est un evenement extremement rare. Nous decrivons un cas representatif et proposons une revue systematique des cas precedemment rapportes dans la litterature. Presentation de cas : une femme de 51 ans diagnostiquee avec la maladie de Cushing a subi un traitement unique avec de la metyrapone pendant neuf mois. Deux mois apres l’arret du traitement, elle a ete admise pour une insuffisance renale aigue. Apres encore quatre mois, en juin 2020, il n’y avait aucun signe d’hypercortisolisme, que ce soit cliniquement ou biochimiquement, ou d’hypocortisolisme, chez notre patient. Un an plus tard, elle est toujours en remission. Cas rapportes dans la litterature : sur 23 patients (dont notre cas), 87 % etaient des femmes avec un âge median de 32 ans. Parmi ceux qui avaient des tumeurs radiologiquement visibles, 10 patients avaient des microadenomes (44 %), tandis que 7 patients avaient des macroadenomes (30 %). Le delai moyen entre le diagnostic et la remission spontanee etait de 5 mois, plus court dans les macroadenomes (1 mois) que dans les microadenomes (13,5 mois). Avant la remission spontanee, les traitements etaient : l’absence de traitement (65 %), les inhibiteurs steroidiens (22 %), la surrenalectomie bilaterale et l’autotransplantation surrenale (5 %), la surrenalectomie bilaterale partielle (4 %), la chirurgie hypophysaire incomplete (4 %). L’apoplexie tumorale hypophysaire etait l’evenement incrimine le plus frequent (91 %), documente radiologiquement chez 43 % des patients. La periode moyenne de remission au cours du suivi etait de 28 mois, les remissions allant de 6 a 130 mois. Une recidive de la maladie de Cushing est survenue chez 39 % (n = 9) des patients. Bien que plusieurs mecanismes responsables de ce phenomene aient ete proposes, l’apoplexie tumorale hypophysaire cliniquement manifeste ou infra-clinique, cette derniere se presentant parfois de maniere atypique, semble etre l’evenement incrimine le plus frequent. Les medecins doivent en etre conscients, et un suivi regulier est obligatoire en raison de son imprevisibilite.

Background Nowadays, the endoscopic endonasal approach to sellar and parasellar region tumors is a common technique in neurosurgery, and surgical nuances, complications, and management strategies are shared in a multidisciplinary setting between neurosurgeons and ear, nose, and throat surgeons. Due to the heterogeneity of its variations, the role of the anterior nasal packing in endoscopic endonasal approach to the skull base surgery (EESBS) has not yet been unanimously accepted and no consensus or guidelines on its use exist. Materials and Methods A survey containing 10 questions about indications, management advantages, and pitfalls of the use of anterior nasal packing in EESBS was created by using an online open-source tool (SurveyMonkey). The questionnaire was sent to 39 Italian neurosurgical departments, which routinely adopt the endoscopic endonasal approach. Results Almost half of 39 selected centers (19; 48.7%) answered our survey. The main results can be summarized as 1) anterior nasal packing after EESBS is considered useful by 84% of participants, 2) prevention of epistaxis is the principal indication for anterior nasal packing, 3) the type of approach and skull base reconstruction influence the use of anterior nasal packing, and 4) nasal discomfort is considered the principal negative aspect of nasal packing. Conclusions Our study identified that anterior nasal packing is commonly adopted in certain conditions, namely when extensive nasal dissection is performed. Furthermore, the choice to adopt or not the anterior nasal packing should be tailored taking in account specific conditions, such as acromegaly and Cushing disease. It represents an important factor in reducing postoperative sinonasal complications of EESB.

Cushing's disease (CD) is the most frequent form of endogenous hypercortisolism. Management of this devastating condition relies on pituitary surgery, while effective pharmacological treatment mainly focus on periphery targeting pharmaceuticals. Approved tumour-targeting drugs are limited to dopamine agonists and somatostatin analogues with frequently low efficacy and substantial side effects. Discoveries on the genetics and pathophysiology of corticotroph tumorigenesis brought forward new potential pharmacological targets. Compounds such as retinoic acid although promising in preclinical studies, are not as efficient in the clinic. Others, such as, silibinin, gefitinib and roscovitine are effective in preclinical models, but their efficacy and safety still needs to be determined in patients with CD.

Funder: Wellcome Trust Institutional Strategic Support Fund, University of Cambridge, Management of Cushing's disease is informed by dedicated imaging of the sella and parasellar regions. Although magnetic resonance imaging (MRI) remains the investigation of choice, a significant proportion (30-50%) of corticotroph tumours are so small as to render MRI indeterminate or negative when using standard clinical sequences. In this context, alternative MR protocols [e.g. 3D gradient (recalled) echo, with acquisition of volumetric data] may allow detection of tumors that have not been previously visualized. The use of hybrid molecular imaging (e.g. 11C-methionine positron emission tomography coregistered with volumetric MRI) has also been proposed as an additional modality for localizing microadenomas.

Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic. (Rev Invest Clin. 2022;74(5):244-57).

ObjectiveThe first-line treatment for Cushing’s disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%, even in those with real initial remission. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and the treatment response to ketoconazole in Cushing’s disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital.Patients and methodsThis was a retrospective cohort of Cushing’s disease patients with active hypercortisolism who used ketoconazole at any stage of follow-up. Patients who were followed up for less than 7 days, who did not adhere to treatment, or who were lost to follow-up were excluded.ResultsOf the 172 Cushing’s disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, five of whom (15%) had also undergone radiotherapy; seven used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years. A total of 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to nine others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Only four patients had serious adverse effects that warranted discontinuation. There were 20 confirmed episodes of hypokalemia among 10/33 patients (30%).ConclusionKetoconazole effectively controlled hypercortisolism in 66% of Cushing’s disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out. Hypokalemia is a frequent metabolic effect not yet described in other series, which should be monitored during treatment.