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Cushing disease caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma leads to hypercortisolaemia with high mortality due to metabolic, cardiovascular, immunological, neurocognitive, haematological and infectious conditions. The disorder is challenging to diagnose because of its common and heterogenous presenting features and the biochemical pitfalls of testing levels of hormones in the hypothalamic-pituitary-adrenal axis. Several late-night salivary cortisol and 24-h urinary free cortisol tests are usually required as well as serum levels of cortisol after a dexamethasone suppression test. MRI might only identify an adenoma in 60-75% of patients and many adenomas are small. Therefore, inferior petrosal sinus sampling remains the gold standard for confirmation of ACTH secretion from a pituitary source. Initial treatment is usually transsphenoidal adenoma resection, but preoperative medical therapy is increasingly being used in some countries and regions. Other management approaches are required if Cushing disease persists or recurs following surgery, including medications to modulate ACTH or block cortisol secretion or actions, pituitary radiation, and/or bilateral adrenalectomy. All patients require lifelong surveillance for persistent comorbidities, clinical and biochemical recurrence, and treatment-related adverse effects (including development of treatment-associated hypopituitarism). In this Review, we discuss challenges in the management of Cushing disease in adults and provide information to guide clinicians when planning an integrated and individualized approach for each patient., (© 2023. Springer Nature Limited.)

The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed., (© 2023. The Author(s).)

Background: Silent corticotroph adenomas (SCAs) are a rare subtype of non-functional pituitary adenoma. While it has been suggested that they are more aggressive and recur more frequently following excision, there is limited literature on the optimum treatment strategy for these tumors, especially regarding the role of radiation therapy in incompletely resected tumors., Method: We assimilated data from 62 SCAs and 238 other non-functional adenomas (ONAs), defined according to the WHO 2017 criteria that incorporates transcription factor analysis. We compared their clinicoradiological characteristics, such as hormonal levels, tumor configuration, size, and invasiveness. For 52 SCAs and 205 ONAs with serial follow-up imaging, we studied outcomes for progression after subtotal resection with or without radiation therapy or recurrence after gross total resection. Kaplan Meier analysis for recurrence or progression was used to determine the need for a differential treatment strategy for SCAs compared with other non-functional adenomas specifically concerning the role of radiotherapy., Results: Patients with SCAs present at a younger age than ONAs (43.9 years vs. 48.2 years, p = 0.014), with larger (14.9 cc vs. 9.7 cc, p = 0.006) and more invasive adenomas (61.2% vs. 45.8%, p = 0.021). Overall, SCAs are more likely to recur or progress (48.7 vs. 15.7%, p < 0.001) following excision than ONAs, with significantly poorer event-free survival (Log rank test p < 0.001). Early adjuvant radiotherapy provides favorable outcomes among SCAs with postoperative residual tumor, on par with ONAs. Multivariate analysis identified male gender (HR: 2.217; p = 0.017), MIB index ≥ 3% (HR: 2.116; p = 0.012), and SCA tumor pathology (HR: 3.787; p < 0.001) as factors predicting recurrence., Conclusions: Based on the results of this retrospective, single-center review of 300 non-functional adenomas, we conclude that silent corticotroph adenomas are an aggressive subtype of non-functional pituitary adenomas that are larger, more likely to be invasive, and tend to recur more frequently after a subtotal excision compared with other non-functional adenomas. A gross total resection must be attempted whenever possible and earlier adjuvant radiation is recommended when re-surgery for residual tumor is difficult., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Nelson's syndrome (NS) is a condition which may develop in patients with Cushing's disease after bilateral adrenalectomy. Although there is no formal consensus on what defines NS, corticotroph tumor growth and/or gradually increasing ACTH levels are important diagnostic elements. Pathogenesis is unclear and well-established predictive factors are lacking; high ACTH during the first year after bilateral adrenalectomy is the most consistently reported predictive parameter. Management is individualized and includes surgery, with or without radiotherapy, radiotherapy alone, and observation; medical treatments have shown inconsistent results. A subset of tumors demonstrates aggressive behavior with challenging management, malignant transformation and poor prognosis., Competing Interests: Disclosure The authors have nothing to disclose. This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing's syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2-3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.

Context: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era., Objective: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS., Patients, Design, and Setting: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis., Results: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor., Conclusions: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The prevalence of sellar masses (SMs) is reported in Europe and North America but only limited data are available from the Middle East and North Africa (MENA) region., Objectives: Assess the prevalence and characteristics of SMs in Al Ain city, United Arab Emirates., Design: Retrospective, descriptive multicenter study., Setting: Three endocrine centers in Al Ain., Patients and Methods: All patients diagnosed with SMs in the city of Al Ain, Emirate of Abu Dhabi, between 2011 and 2016 were evaluated. Cases were identified using ICD 9 and 10 codes and demographic and clinical data were collected. The prevalence rate was calculated for patients alive and residing in Al Ain city until 31 December 2016., Main Outcome Measures: Clinical presentations and prevalence rate., Sample Size: 272., Results: The mean (SD) age on presentation was 40.8 (14.3) years (range: 6-114 years, median: 40.0). The 170 (61.8%) females and 128 (46.5%) were native citizens of the United Arab Emirates. Two hundred and forty five (90%) patients had pituitary adenomas (PAs) while 27 (10%) had non-pituitary sellar lesions. The four most common SMs were prolactinoma (n=139, 51.1%), nonfunctioning adenoma (NFA) (n= 69, 25.4%), somatotroph adenoma (n=32, 11.8%) and craniopharyngioma (n=15, 5.5%). Patients with prolactinoma, corticotroph adenoma, and Rathke's cleft cyst had small sellar masses (<1 centimeter) while the majority of patients with other SMs had macroadenomas. Hypogonadism and growth hormone deficiency was present in 41.8% and 20.5% of the patients, respectively. Of 268 patients with available data, 82 patients underwent surgery while 25 patients received radiotherapy. At the end of 2016, 197 patients were residing in Al Ain city. The overall prevalence of SMs was 25.7/100 000 with PAs constituting most of these masses (n=177) for a prevalence of 23.1/100 000., Conclusions: This is the first study of SMs in the United Arab Emirates and the MENA region. Prolactinoma and NFA were the two most common SMs. Further studies are needed to explore the reasons for the lower prevalence of SMs in our region compared with other countries., Limitations: Retrospective design, relatively small sample size., Conflict of Interest: None.

Crooke's cell adenoma (CCA) is an aggressive subtype of corticotroph adenoma; however, CCA is associated with a high incidence of low expression of methyl guanine methyl transferase (MGMT), suggesting that temozolomide (TMZ) treatment might be effective for this tumor type. The case of a 56-year-old woman with Cushing's disease caused by a pituitary CCA is presented. At the age of 38 years, the patient presented to our hospital with polyuria and a visual field defect. MRI and laboratory studies showed a 4.5-cm-diameter pituitary tumor with plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels of more than 500 pg/mL and 40 μg/dL, respectively. At 39 years of age, the patient underwent a craniotomy, and her plasma ACTH and cortisol levels decreased to less than 200 pg/mL and 10 μg/dL, respectively; however, these hormone levels increased gradually to 3,940 pg/mL and 70 μg/dL, respectively, by the time the patient was 56 years old. Histopathological re-examination of the previously resected specimen showed that the pituitary tumor was MGMT-negative CCA. TMZ treatment after the second operation decreased the plasma ACTH levels from 600-800 pg/mL to 70-300 pg/mL. No signs of recurrence were observed in the seven years following these treatments with added prophylactic radiation therapy. These clinical findings suggest that TMZ treatment to patients with CCA accompanied with elevated ACTH may be good indication to induce lowering ACTH levels and tumor shrinkage.

Pituitary tumors are a heterogeneous group of lesions (usually benign) and proper understanding of the anatomy, physiology, and pathology of the hypothalamic/pituitary region is essential to make an accurate diagnosis and define the essential treatment options (i.e., surgery, medical therapies, and radiotherapy, alone or in combination). Surgery is the primary treatment for acromegaly, Cushing disease, thyroid-stimulating hormone-secreting adenomas, resistant prolactinomas, and nonfunctioning pituitary adenomas causing mass effect. Medical and radiation therapy are reserved in cases in which surgery is not possible or does not provide a complete cure. In the last decades, tremendous innovations (i.e., targeted drugs and refined surgical tools and techniques) have expanded the treatment strategies for pituitary adenomas. We herein report the current indications for and depiction of the surgical techniques in pituitary surgery, review current medical treatments, and provide a glimpse of future possibilities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cushing's disease (CD) is the most common etiology of Cushing's syndrome (CD) due to corticotroph pituitary adenoma, which are in most cases small (80-90% microadenomas) and in about 40% cannot be visualized on imaging of the sella. First-line treatment for CD is transsphenoidal surgery (TSS) with the aim of complete adenoma removal and preservation of pituitary gland function. As complete adenoma resection is not always possible, surgical failure is a common problem. This can be the case either due to persistent hypercortisolism after first TSS or recurrence of hypercortisolism after initially achieving remission. For these scenarios exist several therapeutic options with their inherent characteristics, which will be covered by this review., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Pituitary carcinomas are rare and aggressive neoplasms that despite current treatment regimens continue to have a poor prognosis. Adrenocorticotrophic hormone pituitary tumors have been shown to alter their clinical manifestations with conversion to Cushing disease and silent types., Case Description: The purpose of this paper is to present the first documented case of an adrenocorticotrophic hormone-secreting pituitary adenoma with Cushing disease that differentiated into a silent corticotroph pituitary carcinoma with metastases to distant sites in the central nervous system., Conclusions: This patient was later treated with radiotherapy, temozolomide, and bevacizumab, with 8 years of progression-free survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

One of today's challenges in endocrinology is the treatment of Cushing's disease: Although pituitary surgery has the potential to 'cure' the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be 'default options'. This 'personal view' tries to shed some light on the inescapable difficulties of the current treatments of Cushing's disease and to provide some optimistic view for the future where the pituitary adenoma should be the 'reasonable obsession' of a successful therapeutist., (© 2018 European Society of Endocrinology.)

Objective: Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients., Methods: Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes., Results: Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224)., Conclusion: Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD., Abbreviations: BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Objective: Treatment alternatives for persistent and recurrent Cushing disease (CD) include pituitary surgical re-intervention, radiation therapy (RT), pharmacotherapy, and bilateral adrenalectomy (BA). The decision of which of these alternatives is better suited for the individual patient rests on clinical judgment and the availability of resources. This retrospective cohort study was performed at a referral center to evaluate the long-term efficacy of different secondary interventions for persistent and recurrent CD., Methods: We evaluated the hospital charts of 84 patients (77 female, median age 34 years, median follow up 6.3 years) with CD diagnosed, treated, and followed at our multidisciplinary clinic according to a pre-established protocol., Results: Of the 81 patients who were initially treated with transsphenoidal surgery (TSS), 61.7% had a long-lasting remission, 16% had persistent disease, and 22% achieved remission but relapsed during follow-up. The most frequently used secondary treatment was pituitary re-intervention, followed by ketoconazole, RT, and BA. Early remissions were observed in 66.6% of the re-operated and in 58.3% of the radiated patients; long-lasting remission was achieved in 33.3% and 41.6% of these patients, respectively. Nelson syndrome developed in 41.6% of the patients who underwent BA. Upon last follow-up, 88% of all the patients are in remission, and 9.5% are biochemically controlled with ketoconazole., Conclusion: The efficacy of treatment alternatives for recurrent or persistent CD varies considerably among patients and multiple interventions are often required to achieve long-lasting remission., Abbreviations: ACTH = adrenocorticotrophic hormone; BA = bilateral adrenalectomy; CBG = cabergoline; CD = Cushing disease; CV = coefficient of variation; DXM = dexamethasone; IQR = interquartile range; RT = radiation therapy; SRS = stereotactic radiosurgery; TSS = transsphenoidal surgery; UFC = urinary free cortisol; ULN = upper limit of normal.

Objective: Our aim was to review short- and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome., Methods: We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution., Results: BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour., Conclusion: BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism., (© 2015 European Society of Endocrinology.)

Purpose: Data on real-world treatment patterns for Cushing's disease (CD) are limited. We used a novel graphical technique to analyze treatment patterns in CD patients in the United States., Methods: Two combined US claims databases were used to identify CD patients with claims with Cushing's syndrome diagnosis and either benign pituitary adenoma or hypophysectomy and newly-treated in 2008 (no treatment in prior 6 months). Patients were followed from first treatment day until end of enrollment or 12/31/2010. We compared summary statistics with a novel graphical methodology that simultaneously displays individual color-coded patient treatment histories., Results: Among 228 newly-treated CD patients, 180 (78.9%) had surgery as first observed treatment, 42 (18.4%) had pharmacotherapy, and 6 (2.6%) had radiotherapy. In 42 patients who had pharmacotherapy as first treatment, dopamine agonists were used as first pharmacotherapy in 24 (57.1%), ketoconazole in 17 (40.5%), and mitotane in one patient (2.4%). In 180 patients with surgery as first treatment, 15 (8.3%) later had radiotherapy and 14 (7.8%) had pharmacotherapy. In 42 patients who had pharmacotherapy as first treatment, 10 (23.8%) later had surgery and 2 (4.8%) had radiotherapy. Mean duration of first pharmacotherapy varied: 369.5 days for dopamine agonists, 157.1 for ketoconazole, and 30.0 for mitotane., Conclusions: This study addresses a need for US data on real-world treatment patterns for CD patients. The majority of CD patients undergo surgery as initial therapy. Patients using pharmacotherapy had limited persistence with treatment. Neither reasons for discontinuation of therapy nor the impact of a recent FDA warning on potentially fatal liver toxicity from ketoconazole could be assessed.

Introduction: Cushing's syndrome is associated with a number of clinical manifestations and co-morbidities which may not resolve even after long-term remission leading to excessive mortality., Materials and Methods: This review summarizes the main manifestations of Cushing's syndrome (active or in remission) with particular focus on data from recently published literature., Conclusion: Obesity and metabolic alterations, hypertension and cardio/cerebrovascular complications, hypercoagulability/thromboembolism, neuropsychiatric, muscle/skeletal and immune consequences remain the most challenging. Cardiovascular consequences and immunosuppression determine the main causes of death in Cushing's syndrome necessitating early intervention when possible.

Introduction: Cushing's syndrome (CS) is a rare disease characterized by a collection of signs and symptoms, also common in the general population without elevated cortisol secretion. During the last years more patients with CS are identified earlier and with milder disease. Many of these patients are diagnosed during screening efforts performed for certain or isolated complaints like weight gain, diabetes mellitus (DM), hypertension, osteoporosis, elevated white blood cell counts and more., Methods: In this review article the most popular screening test performed in the studies cited was the 1-mg dexamethasone suppression test., Conclusions: Cushing is not frequent enough to support the use of routine screening in patients with morbid obesity and type 2 DM. Also only 1% of hypertensive patients have secondary hypertension due to CS. However, screening should be considered in young patients with resistant DM and/or hypertension. Among patients with osteoporosis and vertebral fractures up to 5% were diagnosed with subclinical hypercortisolism; most of these had adrenal adenoma. Screening for CS is important in subjects with adrenal incidentaloma, and many studies show a high prevalence (~10%) of Cushing or subclinical CS in these patients.

Introduction: Cushing's disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality., Methods: Here we review the comorbidities associated with Cushing's disease and their impact on quality of life and mortality., Results: Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbidity and a poor quality of life. Normalization of cortisol levels leads to significant improvement in comorbidities but long-term data regarding complete resolution are lacking and need further study., Conclusion: Early diagnosis and treatment of hypercortisolemia, aggressive management of comorbidities along with long-term follow-up is crucial for the optimal recovery of these patients.

Introduction: Cushing syndrome (CS) of any etiology (adrenal, pituitary or ectopic) impacts negatively on health-related quality of life (QoL), especially in active hypercortisolism but also after endocrine cure. Both generic questionnaires like the short-form 36 health survey -SF-36- and the derived SF-12, or the Hospital Anxiety and Depression Scale (HADS), and disease-specific measures like the CushingQoL and the Tuebingen CD-25 questionnaires have provided information on the impact of CS on patients perceived health., Materials and Methods: Studies published since January 2013 until November 2014 on QoL in patients with CS were identified, reviewed and summarized., Conclusions: Treatment of CS improves patients perceived QoL, but it often takes many months and often never normalizes. In parallel to persistent QoL impairment in cured CS, brain and cerebellar volume are reduced. Depression, anxiety and cognitive dysfunction are common. Pediatric patients with CS also present worse QoL than normal children, as well as additional issues like delayed growth and pubertal development, next to abnormal body composition, psychological and cognitive maturation. Fluoxetine has been suggested as a neuroprotectant and antidepressant for patients with CS, although no prospective studies are yet available. The CushingQoL questionnaire has been mapped to well-validated instruments like SF-36 or EQ-5D, and therefore may be used in cost-utility and other health economy studies.

Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

Cushing syndrome is the constellation of signs and symptoms caused by protracted exposure to glucocorticoids. The most common cause of Cushing syndrome in children and adolescents is exogenous administration of glucocorticoids. Presenting features commonly include weight gain, growth retardation, hirsutism, obesity, striae, acne and hypertension. Almost invariably, linear growth is severely diminished, a factor which may be useful in differentiating between childhood obesity and Cushing syndrome. Diagnostic approaches are based on distinguishing between adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent etiologies, and consideration of the most likely diagnosis by age. Treatment modality is dependent upon etiology. After cure, important components of care include attention to linear growth, pubertal progression and body composition.

The aim of this study was to review the literature published and the most important papers presented to meetings on Cushing's disease from October 2011 to September 2012. The selection has been performed according to the authors' criteria. Articles have been classified into five groups: quality of life and perception of the disease, clinical features and pathophysiology, comorbidity conditions, diagnosis, and treatment. The results and conclusions of each publication are discussed., (Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.)

Background: Silent corticotrophic adenomas (SCAs) stain adrenocorticotropic hormone (ACTH)+ without causing Cushing disease. SCAs are reportedly more aggressive, but information comes from small series., Objective: To determine whether SCAs behave more aggressively than hormone-negative adenomas (HNAs), and characterize SCA ACTH production alterations., Methods: SCAs (n = 75) and HNAs (n = 1726) diagnosed at our institution from 1990 to 2011 were retrospectively reviewed. RT-PCR was used to compare expression of ACTH-producing factors., Results: SCA patients exhibited comparable sex and age as HNA patients (P = .7-.9). SCAs exhibited comparable size as HNAs (2.2 vs 2.0 cm, P = .2), with cavernous sinus invasion in 30% of SCAs vs 18% of HNAs (P = .03). SCA patients had higher mean preoperative serum ACTH (46 vs 19 ng/L; P = .005; normal = 5-27 ng/L), but comparable serum cortisol (13 vs 12 μg/dL; normal = 4-22 μg/dL; P < .05) as HNA patients. SCAs were gross totally resected 59% of the time, vs 53% for HNAs (P = .8). Kaplan-Meier 3-year progression/recurrence rates were 34% for strongly ACTH-positive Type I SCAs, 10% for weakly ACTH-positive Type II SCAs, and 6% for HNAs (P < .001 SCA vs HNA; P < .001 Type I vs HNA; and P = .08 Type II vs HNA). Expression of ACTH precursor pro-opiomelanocortin was 900-fold elevated in SCAs and 1300-fold elevated in Cushing disease-causing adenomas (CDCAs) vs HNAs (P < .001). Transcription of PC1/3, which cleaves pro-opiomelanocortin into ACTH, was 30-fold higher in CDCAs than SCAs (P = .02)., Conclusion: In the largest series to date, SCAs exhibited comparable size, but increased cavernous sinus invasion and progression/recurrence vs HNAs. SCAs exhibit deficient pro-opiomelanocortin to ACTH conversion. Close follow-up is warranted for SCAs.

Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

Background: Pituitary carcinomas are rare and challenging clinical entities. Because of the paucity of cases, there is limited information in the literature on how best to diagnose and treat pituitary carcinomas., Methods: We review the literature and describe a woman who presented with an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma that later evolved into a carcinoma with intracranial metastases., Results: A 39-year-old woman presented at age 27 with classic findings of Cushing's syndrome and a pituitary macroadenoma. Her initial treatment was transsphenoidal surgery, during which we confirmed an ACTH-secreting pituitary neoplasm. For 5 years, she was asymptomatic before her first recurrence. During the next 6 years, she underwent four transsphenoidal surgeries and two craniotomies. After each surgery, there was some reduction in the size of the macroadenoma but the residual tumor mass would rapidly enlarge. Immunochemical staining was positive for ACTH, and a stain for Ki-67 antigen showed a high mitotic index. Eleven years after her initial presentation, magnetic resonance imaging revealed bilateral hippocampal and tempero-occipital masses. The patient's health continued to deteriorate, largely from complications of severe hypercortisolemia, and she died from sepsis. At postmortem, the hippocampus and tempero-occipital lobe masses proved to be a pituitary tumor with positive ACTH staining., Conclusions: Pituitary carcinomas are rare, may present many years after diagnosis of a primary pituitary adenoma, and should be suspected in patients with persistent or recurrent disease. Reliable histopathologic ways to distinguish between carcinoma and adenoma are difficult because the features of hypercellularity, nuclear pleomorphism, and mitotic figures are not always helpful., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: While pituitary adenomas are common, pituitary carcinomas are rare. It is unclear whether pituitary carcinomas arise de novo or evolve from adenomas., Methods: We studied the clinical characteristics and tissue samples from eight pituitary surgeries and the autopsy from a patient with pituitary carcinoma. A 16-year-old female patient was diagnosed with an aggressive Crooke cell macroadenoma. Following transsphenoidal surgery, clinical signs of Cushing disease quickly reappeared. During the 14-year course of the illness, eight pituitary surgeries, three courses of extracranial irradiation and two (90) Yttrium-DOTATOC treatments were undertaken. A bilateral adrenalectomy was performed. The patient died of metastatic disease and uncontrolled hypercortisolism due to an adrenal remnant. A systematic morphologic study (histologic staining, electron microscopy) of all available surgical and autopsy specimens was undertaken., Results: Brisk mitotic activity, high Ki-67 and p53 immunolabelling were present in the pituitary samples from the onset. High proportion of tumour cells showed irregular nuclei and large nucleoli, and gradual increase in MGMT staining was observed. The tumour remained of Crooke cell type throughout the course. Autopsy disclosed a postirradiation sarcoma in the pituitary area., Conclusions: The question whether pituitary carcinomas arise de novo or transform from an adenoma cannot be answered at present with certainty., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: To analyze the therapeutic results of intervention and the factors affecting the outcome of patients with Cushing's disease (CD) cared for at the All Indian Institute of Medical Science (AIIMS), New Delhi., Design: Patients with Cushing's disease treated at a teritiary care centre from January 2000 to December 2009 were prospectively studied., Results: Ninety-seven patients received treatment for CD during this period. Mean duration of follow-up was 3.4 ± 2.2 (mean ± SD) years. Eighty-one patients (83.5%) underwent transsphenoidal surgery (TSS) as the primary treatment modality. Fifty-four patients (66.7%) went into remission after initial TSS; ten (18.5%) of them relapsed after a mean follow-up period of 2.9 ± 2.1 (mean ± SD) years. Histopathologic examination of resected tissue showed corticotroph adenoma in 48 of the 54 (88.9%) who went into remission and 17 of the 27 (63.0%) who did not go into remission after the initial TSS. Sixteen patients with severe hypercortisolism underwent bilateral adrenalectomy (BA) as a life-saving measure which was followed by pituitary surgery 6 to 12 months later. Five patients including one with a large macroadenoma required three or more procedures to achieve eucortisolism., Conclusion: Fifty-four out of 81 (66.7%) of our patients with CD had remission following initial TSS, ten of whom relapsed later on. Sixteen patients unerwent BA as a life-saving procedure. Factors affecting outcome were, age, gender, low dose dexamethasone suppression test cortisol value and histologic confirmation of corticotroph adenoma.

The corticotrophinoma, causing pituitary dependent hypercortisolism, represents the highest percentage of pituitary tumours in the dog. The mechanism by which it develops is currently unknown and two theories are postulated: the hypothalamic and the monoclonal. It is not clear either what factors are involved in the tumour genesis; nevertheless, firm candidates are the Rb1 gene, proteins p27, p21 and p16, as are also defects in the glucocorticoid receptor and Nur77/Nurr1. The role of BMPs remains to be evaluated in greater depth. Although at present the chosen treatment in human is surgical, there are various pharmacological treatments already in use that have favourable results and others, still under research, also showing promising results., (Copyright 2009 Elsevier Ltd. All rights reserved.)

According to epidemiological studies, the prevalence of pituitary adenomas is 16.5% and the majority of them are "incidentalomas". The symptoms of pituitary disorders are often non-specific; disturbances of pituitary function, compression symptoms, hypophysis apoplexy or accidental findings may help the diagnosis. The hormonal evaluation of pituitary adenomas is different from the algorithm used in the disorders of peripheral endocrine organs. The first-line therapy of prolactinomas are the dopamine agonists, and the aims of the treatment are to normalize the prolactin level, restore fertility in child-bearing age, decrease tumor mass, save or improve the residual pituitary function and inhibit the relapse of the disease. The available dopamine agonists in Hungary are bromocriptine and quinagolide. In case of tumors with good therapeutic response, medical therapy can be withdrawn after 3-5 years; hyperprolactinemia will not recur in 2/3 of these patients. Neurosurgery is the primary therapy of GH-, ACTH-, TSH-producing and inactive adenomas. In the last decades, significant improvement has been reached in surgical procedures, resulting in low mortality rates. Acromegalic patients with unresectable tumors have a great benefit from somatostatin analog treatment. The growth hormone receptor antagonist pegvisomant is the newest modality for the treatment of acromegaly. The medical therapy of Cushing's disease is still based on the inhibition of steroid production. A new, promising somatostatin analog, pasireotide is evaluated in clinical trials. The rare TSH-producing tumor can respond to both dopamine agonist and somatostatin analog therapy. The application of conventional radiotherapy has decreased; radiotherapy is mainly used in the treatment of invasive, incurable or malignant tumors. Further studies are needed to elucidate the exact role of radiosurgery and fractionated stereotaxic irradiation in the treatment of pituitary tumors.

Background: Pituitary carcinomas are rare neuroendocrine tumors affecting the adenohypophysis. The hallmark of these lesions is the demonstration of distant metastatic spread. To date, few well-documented cases have been reported in the literature., Case Presentation: Here, we report the case of a fatal pituitary carcinoma evolving within two years from an adrenocorticotrophic hormone (ACTH)-secreting macroadenoma and review the global literature regarding this rare neuroendocrine tumor., Conclusion: Pituitary carcinomas are extremely rare neoplasms, representing only 0.1% to 0.2% of all pituitary tumors. To date, little is understood about the molecular basis of malignant transformation. The latency period between initial presentation of a pituitary adenoma and the development of distal metastases marking carcinoma is extremely variable, and some patients may live well over 10 years with pituitary carcinoma.

Pituitary adenomas are being recognized and diagnosed with increasing frequency. One of the most common forms of pituitary lesion is the clinically non-functioning pituitary adenoma (NFPA), which is often diagnosed incidentally. The vast majority of pituitary adenomas are sporadic, but familial adenomas can occur in the multiple pituitary adenoma type 1 syndrome, in Carney complex or in familial isolated pituitary adenoma. Distinguishing NFPA from prolactinomas can occasionally cause a differential diagnostic problem due to the 'stalk effect'. NFPA often show hormone synthesis on tissue immunostaining without causing clinical symptoms. Most often these are silent gonadotroph adenomas, with silent corticotroph or somatotroph adenomas occurring less frequently. It is unclear why these silent adenomas do not release hormones at a clinically recognizable level, although it is probable that there is a continuum between fully functional and completely silent adenomas. Another intriguing feature of NFPAs is the lack of clinical response to somatostatin analogues, despite the presence of somatostatin receptors and an often good response in the in vitro setting. Temozolomide has been successfully used for the treatment of a few aggressive pituitary adenomas, and the response to this drug could be influenced by the expression of the DNA repair enzyme O-6-methylguanine DNA methyltransferase. The early diagnosis, prediction of long-term outcome and treatment of NFPAs remain a challenge for endocrinologists., (Copyright 2009 S. Karger AG, Basel.)

Aggressive pituitary tumors are rare the pathogenesis is not well established. The development of pituitary tumor after apoplexy has also been rarely reported. We describe the sequential development of Cushing's disease, apoplexy and aggressive pituitary tumor in the same patient. A 31-year old male presented with eutopic ACTH dependent Cushing's syndrome which failed initial pituitary surgery. He underwent subsequent bilateral adrenalectomy for control of hypercortisolism. An episode of pituitary apoplexy then occurred which was followed by the development of a null-cell pituitary tumor. This second tumor exhibited an aggressive behavior with invasion into the surrounding structures and systemic spread clinically. This case provides important evidence for the hypotheses of the pathogenesis of aggressive pituitary tumors which could have arisen from surviving adenoma cells following apoplexy or as a de novo development of pituitary carcinoma from cells which were not part of the original adenoma. This is the first report of a transformation of Cushing's disease to an aggressive and invasive null cell tumor after pituitary irradiation, apoplexy and surgery.

Silent corticotroph pituitary adenomas (SCA) are defined as pituitary adenomas showing positive staining for adrenocorticotrophic hormone in immunohistochemical studies, but not associated with perioperative clinical or laboratory features of hypercortisolaemia. They account for 1.1-6% of surgically removed pituitary adenomas. Currently, two distinct pathologic subtypes of SCA are recognised. Their pathogenesis remains unclear. They present with local mass effects (headache, visual deterioration, cranial nerve palsies, endocrine dysfunction). The lack of manifestations of cortisol excess has not been conclusively explained. In surgical series, most tumours are macroadenomas with suprasellar extension present in 87-100% of the cases; this is in contrast to Cushing's disease, which is mostly attributed to microadenomas. Surgery remains the main therapeutic approach. Attempts to identify predictors of recurrence have not been successful. Management and follow-up protocols should be planned taking into account their potential aggressive behaviour, particularly upon recurrence. The development of florid pituitary Cushing's syndrome and local recurrence followed by metastatic disease (occasionally outside the central nervous system) have been rarely reported.

Pituitary tumors are the most common intracranial neoplasms. They are commonly encountered by the gynecologist during an evaluation for galactorrhea, menstrual disturbances, or infertility. Although the majority of these tumors are benign, their impact on the endocrine and nervous system can be striking. The availability of neuroimaging techniques has allowed for more rapid diagnosis, affording earlier treatment. This review is intended to describe the common pituitary tumors seen by the gynecologist, and their impact on reproduction and fertility in the female patient.

Several new therapeutic options both medicinal and surgical, have emerged for the treatment of Cushing's syndrome. In Cushing's disease caused by an adrenocorticotropin (ACTH) secreting pituitary adenoma, the introduction ofendoscopic pituitary surgery offers better visualization of the sella than does the traditional explorative surgery. However, at present it is unclear whether this will result in a better outcome. New drugs under investigation include universal somatostatin analogues such as SOM230, and a combination of a somatostatin analogue and dopamine agonist known as dopastatin. These agents may also be effective for the medicinal treatment of ectopic ACTH-secretion. Treatment with radioactive-labelled somatostatin-analogues such as 177lutetium octreotate is another option for these patients. The primary treatment for ACTH-independent Cushing's syndrome is laparoscopic adrenalectomy. In rare cases of bilateral adrenal hyperplasia, medicinal treatment aimed at new regulatory pathways of cortisol secretion can be applied.

Adrenalectomy is a radical therapeutic approach to control hypercortisolism in some patients with Cushing's disease. However it may be complicated by the Nelson's syndrome, defined by the association of a pituitary macroadenoma and high ACTH secretion after adrenalectomy. This definition has not changed since the end of the fifties. Today the Nelson's syndrome must be revisited with new to criteria using more sensitive diagnostic tools, especially the pituitary magnetic resonance imaging. In this paper we will review the pathophysiological aspects of corticotroph tumor growth, with reference to the impact of adrenalectomy. The main epidemiological data on the Nelson's syndrome will be presented. More importantly, we will propose a new pathophysiological and practical approach to this question which attempts to evaluate the Corticotroph Tumor Progression after adrenalectomy, rather than to diagnose the Nelson's syndrome. We will discuss the consequences for the management of Cushing's disease patients after adrenalectomy, and will also draw some perspectives.