Pediatric Macrocorticotropinoma: Do They Differ from Microcorticotropinoma?

INTRODUCTION: Cushing's disease (CD) due to macrocorticotropinoma (MC) in children and adolescents is a rare entity with limited information regarding its characteristics. The objective of the study is to describe the clinical, biochemical, imaging, management, outcome, and genetic characteristics of children and adolescents with CD due to MC and compare them with those of microcorticotropinoma (mc). METHODS: This retrospective study was conducted at a single tertiary care center. Thirty-two patients with CD and MC (maximum tumor dimension ≥10 mm on imaging) and 65 patients with mc (<10 mm on imaging) aged ≤20 years at presentation were enrolled. RESULTS: Nineteen girls and 13 boys with MC presented at a median (IQR) age of 14.5 (12.0-17.9) years. Patients with MC had higher body mass index-standard deviation score (BMI-SDS) (3.70 ± 2.60 vs. 2.59 ± 2.01, p = 0.04), more frequent neuro-ophthalmic symptoms (25% vs. 9% p = 0.04) and short stature (59% vs. 34%, p = 0.049) but less frequent livid striae (53% vs. 77%, p = 0.01), hypokalemia (12% vs. 36%, p = 0.04), and lower cortisol (nmol/L) to corticotropin (pmol/L) ratio (41.20 vs. 55.74, p = 0.04) than those with mc. The remission (59% vs. 64%, p = 1.0) and relapse (53% vs. 37%, p = 0.26) rates after first-line surgery and remission rate after radiotherapy (RT) were comparable between the two cohorts, whereas time to remission after RT (27 vs. 13 months, p = 0.05) was longer in the MC group. A patient with MC had a pathogenic germline variant in CDH23. CONCLUSION: In this large monocentric series of pediatric CD, frequent mass effect symptoms and short stature, higher BMI-SDS, less frequent livid striae, and hypokalemia with lower effective cortisol secretion characterize the MC cohort. The outcomes of surgery and RT were similar between the groups except for a longer time to remission after RT in the MC cohort. Germline variants are rare (4%) in pediatric MC.

Different patient versus provider perspectives on living with Cushing's disease.

CONTEXT: Patients with Cushing's disease (CD) face challenges living with and receiving appropriate care for this rare, chronic condition. Even with successful treatment, many patients experience ongoing symptoms and impaired quality of life (QoL). Different perspectives and expectations between patients and healthcare providers (HCPs) may also impair well-being. OBJECTIVE: To examine differences in perspectives on living with CD between patients and HCPs, and to compare care goals and unmet needs. DESIGN: Memorial Sloan Kettering Pituitary Center established an annual pituitary symposium for pituitary patients and HCPs. Through anonymous pre-program surveys distributed at the 2020 and 2022 symposia, patients and HCPs answered questions related to their own sense, or perception of their patients' sense, of hope, choice, and loneliness in the context of living with CD. PARTICIPANTS: From 655 participants over two educational events, 46 patients with CD and 116 HCPs were included. Median age of both groups was 51 years. 78.3% of the patients were female vs. 53.0% of the HCPs. RESULTS: More patients than HCPs reported they had no choices in their treatment (21.7% vs. 0.9%, P < 0.001). More patients reported feeling alone living with CD than HCPs' perception of such (60.9% vs. 45.5%, P = 0.08). The most common personal care goal concern for patients was 'QoL/mental health,' vs. 'medical therapies/tumor control' for HCPs. The most common CD unmet need reported by patients was 'education/awareness' vs. 'medical therapies/tumor control' for HCPs. CONCLUSIONS: CD patients experience long term symptoms and impaired QoL which may in part be due to a perception of lack of effective treatment options and little hope for improvement. Communicating experiences and care goals may improve long term outcomes for CD patients.

Problem-solving therapy can reduce psychological distress in patients with Cushing's disease: a randomized controlled trial.

OBJECTIVE: To evaluate the effects of online group problem-solving therapy (PST) for reducing negative problem orientation (NPO), psychological distress, and increasing quality of life in patients with Cushing's disease (CD). METHODS: In this randomized trial, we allocated 55 eligible patients to either PST (n = 28) or treatment as usual (TAU) (n = 27) groups. The analyses primarily relied on intent-to-treat (ITT) principle and were repeated with intervention completers (per-protocol analyses). Social problem-solving inventory-revised short form, Beck Depression Inventory (BDI), General Health Questionnaire-12 (GHQ-12), Perceived Stress Scale (PSS), The Satisfaction with Life Scale, and Cushing's Quality of Life scale were used. Pre-test, post-test, and follow-up measures were obtained. Linear mixed models were used to compare PST and treatment as usual (TAU) groups across time. RESULTS: Of the total 55 patients with CD, the mean age was 46 ± 12 years, 49 patients (89%) were female, and 41 patients (74.5%) were in remission. The patients within the PST and TAU groups were similar in terms of age, sex, and disease activity. ITT analyses showed a greater reduction of NPO scores in patients who received PST as compared to patients who received usual care (df = 45.9, p = 0.029, Cohen's d = 0.47). The decrease in NPO was sustained at follow-up (mean difference: - 2.2, p = 0.007). Results of the ITT analyses revealed no superior benefits of the intervention for psychological distress. However, per-protocol analyses demonstrated that PST provided a greater decrease in BDI, PSS, and GHQ-12 scores. CONCLUSION: PST may decrease NPO and improve the psychological well-being of patients with CD.

Quality of life impairment after a diagnosis of Cushing's syndrome.

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.

Determinants of Clinical Behavior and Prognosis in Cushing's Disease: A Quest for Useful Biomarkers.

Abstract: 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).

Successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia.

We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.

Patient-Centered Outcomes with Pituitary and Parasellar Disease.

Over the last 2 decades, advances in the diagnosis and management of pituitary diseases have made it possible to attain an endocrine "cure" in a large proportion of patients. In other words, tumors can be excised or controlled with drugs, mass effects of the lesion on surrounding structures can be solved, and pituitary deficiencies can be substituted with all relevant hormones. While this is considered a satisfactory outcome for health care providers, patients often suffer from an aftermath of prior endocrine dysfunction exposure, with irreversible effects, both physically and psychologically, which have a great impact on their everyday life. Diagnostic delay, often of several years, adds a negative impact on health perception. This affects their social, professional, and family domains and determines their future life. Understanding that this may occur is important, and health care providers should offer information to prepare the patient for this difficult journey, especially in the case of acromegaly, Cushing disease, or hypopituitarism. In order to maintain a good quality of life (QoL) in the long-term, patients need to adapt to this new situation, something that may be difficult, since they often cannot continue with all the activities and rhythm they used to do. Depression is often the consequence of maladaptation to the new situation, leading to impaired QoL.

Current management of Cushing's disease.

Cushing's disease (CD) is caused by a pituitary tumour that secretes adrenocorticotropin (ACTH) autonomously, leading to excess cortisol secretion from the adrenal glands. The condition is associated with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission. Transsphenoidal pituitary surgery (TSS) remains the mainstay of treatment for CD but requires considerable neurosurgical expertise and experience in order to optimize patient outcomes. Up to 90% of patients with microadenomas (tumour below 1 cm in largest diameter) and 65% of patients with macroadenomas (tumour at or above 1 cm in greatest diameter) achieve endocrine remission after TSS by an experienced surgeon. Patients who are not in remission postoperatively or those who relapse may benefit from undergoing a second pituitary operation. Alternatively, radiation therapy to the sella with interim medical therapy, or bilateral adrenalectomy, can be effective as definitive treatments of CD. Medical therapy is currently adjunctive in most patients with CD and is generally prescribed to patients who are about to receive radiation therapy and will be awaiting its salutary effects to occur. Available treatment options include steroidogenesis inhibitors, centrally acting agents and glucocorticoid receptor antagonists. Several novel agents are in clinical trials and may eventually constitute additional treatment options for this serious condition.

Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing's disease.

PURPOSE: Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing's disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. METHODS: After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing's disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. RESULTS: Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. CONCLUSIONS: HSRT is an appropriate treatment approach for refractory Cushing's disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.

Successful reduction of ACTH secretion in a case of intractable Cushing's disease with pituitary Crooke's cell adenoma by combined modality therapy including temozolomide.

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.

Cushing's Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century.

Cushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients - the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.

LONG-TERM OUTCOME OF THE DIFFERENT TREATMENT ALTERNATIVES FOR RECURRENT AND PERSISTENT CUSHING DISEASE.

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.

BIOCHEMICAL CONTROL DURING LONG-TERM FOLLOW-UP OF 230 ADULT PATIENTS WITH CUSHING DISEASE: A MULTICENTER RETROSPECTIVE STUDY.

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.

Diagnosis and Treatment of Pituitary Adenomas: A Review.

IMPORTANCE: Pituitary adenomas may hypersecrete hormones or cause mass effects. Therefore, early diagnosis and treatment are important. OBSERVATIONS: Prevalence of pituitary adenomas ranges from 1 in 865 adults to 1 in 2688 adults. Approximately 50% are microadenomas (<10 mm); the remainder are macroadenomas (≥10 mm). Mass effects cause headache, hypopituitarism, and visual field defects. Treatments include transsphenoidal surgery, medical therapies, and radiotherapy. Prolactinomas account for 32% to 66% of adenomas and present with amenorrhea, loss of libido, galactorrhea, and infertility in women and loss of libido, erectile dysfunction, and infertility in men; they are generally treated with the dopamine agonists cabergoline and bromocriptine. Growth hormone-secreting tumors account for 8% to 16% of tumors and usually present with enlargement of the lips, tongue, nose, hands, and feet and are diagnosed by elevated insulin-like growth factor 1 levels and growth hormone levels; initial treatment is surgical. Medical therapy with somatostatin analogues, cabergoline, and pegvisomant is often also needed. Adrenocorticotropic hormone (ACTH)-secreting tumors account for 2% to 6% of adenomas and are associated with obesity, hypertension, diabetes, and other morbidity. Measurement of a late-night salivary cortisol level is the best screening test but petrosal sinus sampling for ACTH may be necessary to distinguish a pituitary from an ectopic source. The primary treatment of Cushing disease (hypercortisolism due to ACTH-producing adenomas, which is the cause in approximately 65% of the cases of hypercortisolism) is adenoma resection and medical therapies including ketoconazole, mifepristone, and pasireotide. Hyperthyroidism due to thyroid-stimulating hormone-secreting tumors accounts for 1% of tumors and is treated with surgery and somatostatin analogues if not surgically cured. Clinically nonfunctioning adenomas account for 15% to 54% of adenomas and present with mass effects; surgery is generally required, although incidentally found tumors can be followed if they are asymptomatic. CONCLUSIONS AND RELEVANCE: Patients with pituitary adenomas should be identified at an early stage so that effective treatment can be implemented. For prolactinomas, initial therapy is generally dopamine agonists. For all other pituitary adenomas, initial therapy is generally transsphenoidal surgery with medical therapy being reserved for those not cured by surgery.

Long-term outcomes of children treated for Cushing's disease: a single center experience.

PURPOSE: Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients. METHODS: Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2). RESULTS: Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients. CONCLUSIONS: The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.

Fractures in pituitary adenoma patients from the Dutch National Registry of Growth Hormone Treatment in Adults.

PURPOSE: The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing's disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA). METHODS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated. RESULTS: At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy. CONCLUSIONS: During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms.

The development and validation of the Leiden Bother and Needs Questionnaire for patients with pituitary disease: the LBNQ-Pituitary.

BACKGROUND: Patients report persisting impairment in quality of life (QoL) after treatment for pituitary disease. At present, there is no questionnaire to assess (a) whether patients with pituitary disease are bothered by these consequences, and (b) their needs for support. OBJECTIVE: To develop and validate a disease-specific questionnaire for patients with pituitary disease which incorporates patient perceived bother related to the consequences of the disease, and their needs for support. METHODS: Items for the Leiden Bother and Needs Questionnaire for patients with pituitary disease (LBNQ-Pituitary) were formulated based on results of a recent focus group study (n = 49 items). 337 patients completed the LBNQ-Pituitary and six validated QoL questionnaires (EuroQoL-5D, SF-36, MFI-20, HADS, AcroQol, CushingQoL). Construct validity was examined by exploratory factor analysis. Reliabilities of the subscales were calculated with Cronbach's alphas, and concurrent validity was assessed by calculating Spearman's correlations between the LBNQ-Pituitary and the other measures. RESULTS: Factor analyses produced five subscales (i.e., mood problems, negative illness perceptions, issues in sexual functioning, physical and cognitive complaints, issues in social functioning) containing a total of 26 items. All factors were found to be reliable (Cronbach's alphas all ≥.765), and the correlations between the dimensions of the LBNQ-Pituitary and other questionnaires (all P ≤ .0001) demonstrated convergent validity. CONCLUSIONS: The LBNQ-Pituitary can be used to assess the degree to which patients are bothered by the consequences of the pituitary disease, as well as their needs for support. It could also facilitate an efficient assessment of patients' needs for support in clinical practice. We postulate that paying attention to needs for support will lead to optimal patient care (e.g., improvement in psychosocial care), and positively affect QoL.

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.

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.

Clinical and biochemical manifestations of Cushing's.

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.