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Background: Double pituitary adenomas are rare presentations of two distinct adenohypophyseal lesions seen in <1% of surgical cases. Increased rates of recurrence or persistence are reported in the resection of Cushing microadenomas and are attributed to the small tumor size and localization difficulties. The authors report a case of surgical treatment failure of Cushing disease because of the presence of a secondary pituitary adenoma., Observations: A 32-year-old woman with a history of prolactin excess and pituitary lesion presented with oligomenorrhea, weight gain, facial fullness, and hirsutism. Urinary and nighttime salivary cortisol elevation were elevated. Magnetic resonance imaging confirmed a 4-mm3 pituitary lesion. Inferior petrosal sinus sampling was diagnostic for Cushing disease. Primary endoscopic endonasal transsphenoidal resection was performed to remove what was determined to be a lactotroph-secreting tumor on immunohistochemistry with persistent hypercortisolism. Repeat resection yielded a corticotroph-secreting tumor and postoperative hypoadrenalism followed by long-term normalization of the hypothalamic-pituitary-adrenal axis., Lessons: This case demonstrates the importance of multidisciplinary management and postoperative hormonal follow-up in patients with Cushing disease. Improved strategies for localization of the active tumor in double pituitary adenomas are essential for primary surgical success and resolution of endocrinopathies.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified., Competing Interests: Declaration of interests MF has received grants to her institution from Novartis, Strongbridge, Novo Nordisk, Crinetics, Millendo, Ascendis, and Pfizer; personal honoraria for consulting and advisory boards from Crinetics, HRA Pharma, Novartis, Recordati, Strongbridge, Sparrow, Ascendis, Novo Nordisk, and Pfizer; and has served on the Board of the Pituitary Society. RA has received grants to his institution from Strongbridge Biopharma, Novartis Pharmaceuticals, and Corcept Therapeutics, and personal honoraria for consulting and advisory boards from Strongbridge Biopharma, Recordati Rare Diseases, Corcept Therapeutics, and Novartis Pharmaceuticals. IB has received grants and fees for consulting, advisory boards, and authorship to her institution from the National Institutes of Health (NIH), Strongbridge, Corcept, HRA Pharma, Sparrow Pharmaceutics, Adrenas Pharmaceutics, and Elsevier, and non-financial support to her institution from HRA Pharma. AB-S has received personal honoraria for advisory boards from Recordati. JB has received grants to his institution from Novartis, HRA Pharma, and Recordati, and personal honoraria for consulting, lectures, and meeting attendance from Novartis, HRA Pharma, Ipsen, and Recordati. NRB has served on the Board or as an advisor for European Neuroendocrine Association and the European Reference Network on Rare Endocrine Conditions. CLB has received grants and personal honoraria for lectures from Novartis and served on the Board or as an advisor for Sociedade Brasileira de Endocrinologia e Metabologia, Endocrine Society, and European Society of Endocrinology. MDB has received grants as principal investigator from Novartis. JDC has received grants to his institution from Novartis, Strongbridge, and Crinetics; personal honoraria for consulting and authorship from Recordati, Novo Nordisk, Corcept, and Merck Manual; and served on the Board or as an advisor for Pituitary Society, Endocrine Society, and American Association of Clinical Endocrinologists. FFC has served on the Board of the Pituitary Society. FC has received personal honoraria for consulting, lectures, and support for meeting attendance from Recordati Rare Diseases, Ipsen, and HRA Pharma. PC has received grants and honoraria to his institution for consulting and lectures from Novartis and Recordati. JF has received grants to his institution from Novartis and personal honoraria for consulting and advisory boards from Corcept, Recordati, and Novartis. MGa has received non-financial support from Novartis and Recordati and served on the Board or as an advisor for Pituitary Society and Brazilian Society of Endocrinology and Metabolism. EBG has received grants and personal honoraria for consulting, lectures, and advisory boards from Novartis, Corcept, Strongbridge, Bristol-Myers Squibb, Recordati, and HRA Pharma; and has served as an advisor for Cushing's Support & Research Foundation. AGi has received grants to his institution from Pfizer and personal honoraria for consulting and advisory boards from Abiogen, Novo Nordisk, and Recordati; and has served on the Board or as an advisor to European Society of Endocrinology and Glucocorticoid Induced Osteoporosis Skeletal Endocrinology Group. AGr has served as an advisor to Novartis and as an editor for Neuroendocrinology and Journal of Neuroendocrinology. MGu has received personal honoraria for consulting and lectures from Recordati Rare Diseases UK, HRA Pharma, and Ipsen; and is a Board member or advisor for UK Society for Endocrinology and European Society of Endocrinology. AGI has received grants to her institution from Recordati, Novartis, and Strongbridge; and personal honoraria for consulting from Recordati, HRA Pharma, and Strongbridge. UBK has received grants as co-investigator from Corcept; personal honoraria for consulting, advisory board, and lectures from Acerus Pharmaceuticals and Novo Nordisk; and serves as editor for Journal of Clinical Endocrinology and Metabolism and as Board member for Endocrine Society. NK has received personal honoraria for consulting from Recordati Rare Diseases and HRA Pharma, and has served as Board member or advisor for Pituitary Society, European Neuroendocrine Association, Endocrine Society, and European Society of Endocrinology. LK has received personal honoraria for consulting from Strongbridge and Recordati. DFK has received royalties from Mizuho. AL has received grants from Recordati and Corcept; personal honoraria for lectures, support for meeting attendance, and advisory boards from Pfizer, Ipsen, Corcept, and the European Journal of Endocrinology; royalties from UpToDate Endocrinology; and served as a Board member for International Society of Endocrinology. AM has received grants and personal honoraria for lectures or presentations and support for meeting attendance from Pfizer, Ipsen, Novartis, and Novo Nordisk, and served as a Council member for Endocrine Society of Australia. SM has received grants to his institution from US Food and Drug Administration and non-financial support from Cyclacel. MM has received grants to his institution from Corcept, Novartis, and Strongbridge; fees for expert testimony from Janssen and Corcept; and personal honoraria for advisory boards for Merck, Pfizer, Recordati, and Strongbridge. JN-P has received grants and honoraria to the institution for consulting and advisory boards from Diurnal Ltd and HRA Pharma, Recordati, and Novartis; and served as a Board member or advisor for Pituitary Foundation and Endocrine Society. LN has received royalties from UpToDate and support for meeting attendance from the NIH, and has served as a Board member for Endocrine Society. AMP has received grants to his institution from HRA Pharma and served as advisor for European Reference Network on Rare Endocrine Conditions and European Endocrine Society. SP has received personal honoraria for lectures and advisory boards from HRA Pharma, Recordati Pharma, Novartis Pharma, and Crinetics Pharmaceuticals. RP has received grants to his institution from Novartis, Pfizer, Ipsen, Shire, IBSA Farmaceutici, HRA Pharma, Cortendo AB, Corcept Therapeutics, and Merck Serono, and personal honoraria for consulting, lectures, support for meeting attendance, and advisory boards from Novartis, Shire, HRA Pharma, Cortendo AB, Pfizer, Recordati, IBSA Farmaceutici, and Crinetics Pharmaceuticals. HR has received personal honoraria for consulting from Cerium and non-financial support from Corcept. MR has received personal honoraria for consulting, lectures, and advisory boards from Novartis, Recordati, HRA Pharma, and Ipsen. RS has received grants to his institution from Corcept and Crinetics, and personal honoraria for consulting from Strongbridge, Corcept, HRA Pharma, and Sterotherapeutics. CS has received grants and personal honoraria for lectures from Pfizer, Novartis, Recordati Rare Diseases, and HRA Pharma. IS has received personal honoraria for consulting from Medison Pharma. CAS has received grants from Pfizer; personal honoraria for consulting and support for meeting attendance from Lundbeck Pharma and the NIH; holds patents on the genetics of PRKAR1A, PDE11A, and GPR101; and has served as a Board member or advisor for Society for Pediatric Research, Children's Inn at NIH, and Cushing's Foundation. AT has received grants to his institution from HRA Pharma, and personal honoraria for consulting, lectures, and support for meeting attendance from HRA Pharma, Recordati Rare Diseases, and Ipsen. YT has received personal honoraria for consulting and lectures from Novo Nordisk, Recordati Rare Diseases, Bohringer Ingelheim, and Sumitomo Dainippon Pharma. MT has served as an advisor to European Society of Endocrinology. ST has received grants to his institution from Strongbridge, Crinetics, and Novartis, and personal honoraria for lectures, advisory boards, and support for meeting attendance from Recordati, Pfizer, and Ipsen. EV has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting, lectures, and advisory boards from HRA Pharma, HRA Pharma Spain, and Recordati Rare Diseases. GV has received grants to her institution from Novartis, Recordati, and Corcept; personal honoraria and honoraria to the institution for consulting and lectures from HRA Pharma and Recordati; and served as an advisor for Cushing's Hub. SMW has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting and lectures from HRA Pharma and Recordati Rare Diseases. MCZ has served as a Board member for European Neuroendocrine Association. BMKB has received grants to her institution from Novartis, Opko, Strongbridge, and Millendo; personal honoraria for consulting from Aeterna Zentaris, Ascendis, Crinetics, Merck Serono, Novartis, Novo Nordisk, Recordati, Strongbridge, and Sparrow; and served as an advisor for Endocrine Society. MB, KH, PM, BS, EVV, and JW have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing., Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018., Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients)., Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.

Background: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11β-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease., Methods: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete., Findings: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase., Interpretation: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease., Funding: Novartis Pharma AG., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Mifepristone is a glucocorticoid and progesterone receptor blocker that can be used for patients with hyperglycemia and Cushing syndrome in whom surgery failed to achieve remission or who were ineligible for surgery. We report a case series of patients with Cushing disease (CD) and central hypothyroidism that presented with increased levothyroxine requirements during mifepristone therapy., Methods: Retrospective longitudinal case series of patients with CD and central hypothyroidism treated with mifepristone in a retrospective database at four pituitary centers in the United States., Results: Five patients with CD were found, all women, median age 50 (interquartile range 47 to 64.5). They received mifepristone because no adequate response or intolerance to other drugs was observed. Mifepristone initiation was associated with a decrease in free thyroxine levels, mandating a dose increase of a median 1.83 (1.71 to 3.5) times the initial dose of levothyroxine to achieve normal levels. Weight loss was seen in four of five patients, ranging from 3.2 to 42.6 kg in up to 54 months of follow-up., Conclusions: Although the mechanism behind the decrease in thyroid hormone level is unknown, intestinal malabsorption, decreased residual thyroid function and increased inactivation of T4 via deiodinases are all potential causes. Whereas therapies for hypercortisolism aim to decrease features of hypercortisolemia such as weight gain and depression, hypothyroidism can hamper these goals. This case series raises awareness on the importance of assessment of thyroid status in patients receiving mifepristone to optimize clinical outcomes., Competing Interests: Disclosure Summary: F.J.G. has nothing to disclose. J.F. is and investigator and consultant for Novartis and Corcept. K.C.J.Y received research grants to Barrow Neurologic Institute from Millendo, and Corcept, and consultant fee from Corcept. M.F. has had research support paid to university from Novartis, Millendo, Strongbridge, and Scientific Consultant Fee from Novartis and Strongbridge. L.B.N. has received honoraria as a consultant for Corcept Inc.All data generated or analyzed during this study are included in this published article.