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Register Now! 2nd annual WAPO eSummit March 19 & 20, 2021 World Alliance of Pituitary Organizations represents the voice of 37 patient advocacies around the globe. This event is also translated into Español, there’s something for everyone! The World Alliance of Pituitary Organizations (‘WAPO’) represents the voice of 37 patient advocacies around the globe. We seek to empower and improve the Quality of Life of Pituitary Patients, by sharing knowledge and inform you about treatment choices. By registering to the WAPO eSummit 2021, you will have a unique opportunity to learn about the latest medical research, raise questions and dialogue with international experts on the pituitary gland! Get involved and register in one of the provided languages. We are looking forward to meeting you! For more information visit the link below. https://web.cvent.com/event/aaf5e35f-793d-49ff-9f4b-138f155dbbc2/summary?fbclid=IwAR0-ah0tkUnx7HmBkQlEoIMOEBvQOGxnvz_XP7fC7BDKhEKkuBhgXfVQL04

~ RECORLEV® (levoketoconazole) New Drug Application is Supported by Previously-Reported Positive and Statistically Significant Results from the Phase 3 SONICS and LOGICS Studies ~ ~ Nearly 40 Percent of Prescription-Treated Endogenous Cushing’s Syndrome Patients in the U.S. Are Not Well-Controlled, Underscoring Need for New, Safe and Effective Pharmaceutical Options to Help Regulate Cortisol Levels ~ ~ If Approved Following a Projected 10-Month Review Cycle, RECORLEV is Anticipated to Launch in First Quarter of 2022 ~ DUBLIN, Ireland and TREVOSE, Pa., March 02, 2021 (GLOBE NEWSWIRE) -- Strongbridge Biopharma plc, (Nasdaq: SBBP), a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs, today announced that it submitted a New Drug Application (NDA) for RECORLEV® (levoketoconazole) for the treatment of endogenous Cushing’s syndrome to the U.S. Food and Drug Administration (FDA). The submission is supported by previously reported positive and statistically significant results of the SONICS and LOGICS trials: two Phase 3 multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat adults with endogenous Cushing’s syndrome. “The submission of the New Drug Application for RECORLEV® (levoketoconazole) represents not only a significant milestone for Strongbridge but also for the Cushing’s syndrome community as a whole. As an organization focused on developing treatments for underserved rare disease patient populations, we are one step closer to helping address the needs of the estimated 8,000 Cushing’s syndrome patients in the U.S. who are treated with prescription therapy, many of whom, as we learned in our market research, are not well-controlled with current therapies,” said John H. Johnson, chief executive officer of Strongbridge Biopharma. “We look forward to working with the FDA through their review of our application, and we are actively preparing for the potential launch of RECORLEV in the first quarter of 2022, if approved.” RECORLEV, the pure 2S,4R enantiomer of the enantiomeric pair comprising ketoconazole, is a next-generation steroidogenesis inhibitor being investigated as a chronic therapy for adults with endogenous Cushing’s syndrome. Two Phase 3 studies have demonstrated substantial evidence of efficacy and safety in a combined study population of 166 patients that was representative of the adult drug-treated U.S. population with Cushing’s syndrome. The SONICS study met its primary and key secondary endpoints, demonstrating a statistically significant rate of mean urinary free cortisol normalization after six months of maintenance therapy without a dose increase (detailed results here). LOGICS, a double-blind, placebo-controlled randomized-withdrawal study, which also had statistically significant primary and key secondary endpoints, confirmed that the long-term cortisol-normalizing efficacy demonstrated in SONICS was due to use of levoketoconazole specifically (detailed results here). The long-term open-label extension study, OPTICS, is contributing safety information to the NDA. “We want to thank the patients, their families, investigators, collaborators, and employees who have contributed to the RECORLEV clinical program leading to this important regulatory milestone,” said Fredric Cohen, M.D., chief medical officer of Strongbridge Biopharma. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. Strongbridge will host a conference call tomorrow, Wednesday, March 3, 2021 at 8:30 a.m. ET to discuss the Company’s fourth quarter and full-year 2020 financial results and recent corporate highlights, including the RECORLEV NDA submission. About Cushing’s Syndrome Endogenous Cushing’s syndrome is a rare, serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure - often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, and this often results in undesirable physical changes. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Women with Cushing's syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne. Additionally, the internal manifestations of the disease are potentially life threatening. These include metabolic changes such as high blood sugar, or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle and bone, and psychologic disturbances such as depression, anxiety and insomnia. Untreated, the five-year survival rate is only approximately 50 percent. About the SONICS Study SONICS is an open-label, Phase 3 study of RECORLEV as a treatment for endogenous Cushing’s syndrome that enrolled 94 patients at centers in North America, Europe and the Middle East. Following a screening phase, SONICS has three treatment phases: (1) Dose Titration Phase: Patients started RECORLEV at 150 mg twice daily (300 mg total daily dose) and titrated in 150 mg increments with the goal of achieving a therapeutic dose – a dose resulting in mUFC normalization – at which point titration was stopped; (2) Maintenance Phase: The dose was fixed and should not have been changed other than for safety reasons or loss of efficacy. At the end of the six-month maintenance phase, the mUFC response rate was measured; and (3) Extended Evaluation Phase: Patients continued on RECORLEV for another six months to evaluate long-term safety and tolerability and explore efficacy durability. About the LOGICS Study The Phase 3, multinational, double-blind, placebo-controlled, randomized-withdrawal study, LOGICS, randomized Cushing’s syndrome patients with baseline mean urinary free cortisol (mUFC) at least 1.5 times the upper limit of normal (ULN) following completion of a single-arm, open-label treatment phase of approximately 14 to 19 weeks, with RECORLEV individually titrated according to mUFC response. A total of 79 patients were dosed during the open-label titration-maintenance phase, 7 of whom had previously received RECORLEV during the SONICS study, and 72 who had not previously received RECORLEV. At study baseline, the median mUFC was 3.5 times the ULN, indicative of significant hypercortisolemia. A total of 44 patients (39 who had completed the titration-maintenance phase and five who directly enrolled from the SONICS study), were randomized to either continue RECORLEV (n=22) or to have treatment withdrawn by receiving a matching placebo regimen (n=22) for up to 8 weeks, followed by restoration to the prior regimen using blinded drug. Of the 44 patients randomized, 11 patients (25 percent) had previously received RECORLEV during the SONICS study. Patients who required rescue treatment with open-label RECORLEV during the randomized-withdrawal phase were considered to have lost mUFC response at the visit corresponding to their first dose of rescue medication. Patients who did not qualify for randomization were removed from open-label treatment prior to randomization and excused from the study. About RECORLEV RECORLEV® (levoketoconazole) is an investigational cortisol synthesis inhibitor in development for the treatment of patients with endogenous Cushing’s syndrome, a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure. RECORLEV is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor. RECORLEV has demonstrated in two successful Phase 3 studies to significantly suppress serum cortisol and has the potential to be a next-generation cortisol inhibitor. The Phase 3 program for RECORLEV includes SONICS and LOGICS: two multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, demonstrating a statistically significant normalization rate of urinary free cortisol at six months. The LOGICS study, which met its primary endpoint, is a double-blind, placebo-controlled randomized-withdrawal study of RECORLEV that is designed to supplement the long-term efficacy and safety information supplied by SONICS. The ongoing long-term open label OPTICS study will gather further useful information related to the long-term use of RECORLEV. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. About Strongbridge Biopharma Strongbridge Biopharma is a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs. Strongbridge’s rare endocrine franchise includes RECORLEV® (levoketoconazole), a cortisol synthesis inhibitor currently being studied in Phase 3 clinical studies for the treatment of endogenous Cushing’s syndrome, and veldoreotide extended release, a pre-clinical next-generation somatostatin analog being investigated for the treatment of acromegaly and potential additional applications in other conditions amenable to somatostatin receptor activation. Both RECORLEV and veldoreotide have received orphan drug designation from the FDA and the European Medicines Agency. The Company’s rare neuromuscular franchise includes KEVEYIS® (dichlorphenamide), the first and only FDA-approved treatment for hyperkalemic, hypokalemic, and related variants of primary periodic paralysis. KEVEYIS has orphan drug exclusivity in the United States. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the federal securities laws. The words “anticipate,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “project,” “target,” “will,” “would,” or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements of historical facts, contained in this press release, are forward-looking statements, including statements related to data from the LOGICS and SONICS studies, the potential advantages of RECORLEV, the anticipated timing for potential approval of a marketing authorization for RECORLEV and for the potential launch of RECORLEV, Strongbridge’s strategy, plans, outcomes of product development efforts and objectives of management for future operations. Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed in such statement, including risks and uncertainties associated with clinical development and the regulatory approval process, the reproducibility of any reported results showing the benefits of RECORLEV, the adoption of RECORLEV by physicians, if approved, as treatment for any disease and the emergence of unexpected adverse events following regulatory approval and use of the product by patients. Additional risks and uncertainties relating to Strongbridge and its business can be found under the heading “Risk Factors” in Strongbridge’s Annual Report on Form 10-K for the year ended December 31, 2019 and its subsequent Quarterly Reports on Form 10-Q, as well as its other filings with the SEC. These forward-looking statements are based on current expectations, estimates, forecasts and projections and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors. The forward-looking statements contained in this press release are made as of the date of this press release, and Strongbridge Biopharma does not assume any obligation to update any forward-looking statements except as required by applicable law. Contacts: Corporate and Media Relations Elixir Health Public Relations Lindsay Rocco +1 862-596-1304 lrocco@elixirhealthpr.com Investor Relations Solebury Trout Mike Biega +1 617-221-9660 mbiega@soleburytrout.com From https://www.biospace.com/article/releases/strongbridge-biopharma-plc-announces-submission-of-new-drug-application-for-recorlev-levoketoconazole-for-the-treatment-of-endogenous-cushing-s-syndrome-to-the-u-s-food-and-drug-administration/

Rosario Pivonello,a,b Rosario Ferrigno,a Andrea M Isidori,c Beverly M K Biller,d Ashley B Grossman,e,f and Annamaria Colaoa,b Over the past few months, COVID-19, the pandemic disease caused by severe acute respiratory syndrome coronavirus 2, has been associated with a high rate of infection and lethality, especially in patients with comorbidities such as obesity, hypertension, diabetes, and immunodeficiency syndromes.1 These cardiometabolic and immune impairments are common comorbidities of Cushing's syndrome, a condition characterised by excessive exposure to endogenous glucocorticoids. In patients with Cushing's syndrome, the increased cardiovascular risk factors, amplified by the increased thromboembolic risk, and the increased susceptibility to severe infections, are the two leading causes of death.2 In healthy individuals in the early phase of infection, at the physiological level, glucocorticoids exert immunoenhancing effects, priming danger sensor and cytokine receptor expression, thereby sensitising the immune system to external agents.3 However, over time and with sustained high concentrations, the principal effects of glucocorticoids are to produce profound immunosuppression, with depression of innate and adaptive immune responses. Therefore, chronic excessive glucocorticoids might hamper the initial response to external agents and the consequent activation of adaptive responses. Subsequently, a decrease in the number of B-lymphocytes and T-lymphocytes, as well as a reduction in T-helper cell activation might favour opportunistic and intracellular infection. As a result, an increased risk of infection is seen, with an estimated prevalence of 21–51% in patients with Cushing's syndrome.4 Therefore, despite the absence of data on the effects of COVID-19 in patients with Cushing's syndrome, one can make observations related to the compromised immune state in patients with Cushing's syndrome and provide expert advice for patients with a current or past history of Cushing's syndrome. Fever is one of the hallmarks of severe infections and is present in up to around 90% of patients with COVID-19, in addition to cough and dyspnoea.1 However, in active Cushing's syndrome, the low-grade chronic inflammation and the poor immune response might limit febrile response in the early phase of infection.2 Conversely, different symptoms might be enhanced in patients with Cushing's syndrome; for instance, dyspnoea might occur because of a combination of cardiac insufficiency or weakness of respiratory muscles.2 Therefore, during active Cushing's syndrome, physicians should seek different signs and symptoms when suspecting COVID-19, such as cough, together with dysgeusia, anosmia, and diarrhoea, and should be suspicious of any change in health status of their patients with Cushing's syndrome, rather than relying on fever and dyspnoea as typical features. The clinical course of COVID-19 might also be difficult to predict in patients with active Cushing's syndrome. Generally, patients with COVID-19 and a history of obesity, hypertension, or diabetes have a more severe course, leading to increased morbidity and mortality.1 Because these conditions are observed in most patients with active Cushing's syndrome,2 these patients might be at an increased risk of severe course, with progression to acute respiratory distress syndrome (ARDS), when developing COVID-19. However, a key element in the development of ARDS during COVID-19 is the exaggerated cellular response induced by the cytokine increase, leading to massive alveolar–capillary wall damage and a decline in gas exchange.5 Because patients with Cushing's syndrome might not mount a normal cytokine response,4 these patients might parodoxically be less prone to develop severe ARDS with COVID-19. Moreover, Cushing's syndrome and severe COVID-19 are associated with hypercoagulability, such that patients with active Cushing's syndrome might present an increased risk of thromboembolism with COVID-19. Consequently, because low molecular weight heparin seems to be associated with lower mortality and disease severity in patients with COVID-19,6 and because anticoagulation is also recommended in specific conditions in patients with active Cushing's syndrome,7 this treatment is strongly advised in hospitalised patients with Cushing's syndrome who have COVID-19. Furthermore, patients with active Cushing's syndrome are at increased risk of prolonged duration of viral infections, as well as opportunistic infections, particularly atypical bacterial and invasive fungal infections, leading to sepsis and an increased mortality risk,2 and COVID-19 patients are also at increased risk of secondary bacterial or fungal infections during hospitalisation.1 Therefore, in cases of COVID-19 during active Cushing's syndrome, prolonged antiviral treatment and empirical prophylaxis with broad-spectrum antibiotics1, 4 should be considered, especially for hospitalised patients (panel ). Panel Risk factors and clinical suggestions for patients with Cushing's syndrome who have COVID-19 Reduction of febrile response and enhancement of dyspnoea Rely on different symptoms and signs suggestive of COVID-19, such as cough, dysgeusia, anosmia, and diarrhoea. Prolonged duration of viral infections and susceptibility to superimposed bacterial and fungal infections Consider prolonged antiviral and broad-spectrum antibiotic treatment. Impairment of glucose metabolism (negative prognostic factor) Optimise glycaemic control and select cortisol-lowering drugs that improve glucose metabolism. Hypertension (negative prognostic factor) Optimise blood pressure control and select cortisol-lowering drugs that improve blood pressure. Thrombosis diathesis (negative prognostic factor) Start antithrombotic prophylaxis, preferably with low-molecular-weight heparin treatment. Surgery represents the first-line treatment for all causes of Cushing's syndrome,8, 9 but during the pandemic a delay might be appropriate to reduce the hospital-associated risk of COVID-19, any post-surgical immunodepression, and thromboembolic risks.10 Because immunosuppression and thromboembolic diathesis are common Cushing's syndrome features,2, 4 during the COVID-19 pandemic, cortisol-lowering medical therapy, including the oral drugs ketoconazole, metyrapone, and the novel osilodrostat, which are usually effective within hours or days, or the parenteral drug etomidate when immediate cortisol control is required, should be temporarily used.9 Nevertheless, an expeditious definitive diagnosis and proper surgical resolution of hypercortisolism should be ensured in patients with malignant forms of Cushing's syndrome, not only to avoid disease progression risk but also for rapidly ameliorating hypercoagulability and immunospuppression;9 however, if diagnostic procedures cannot be easily secured or surgery cannot be done for limitations of hospital resources due to the pandemic, medical therapy should be preferred. Concomitantly, the optimisation of medical treatment for pre-existing comorbidities as well as the choice of cortisol-lowering drugs with potentially positive effects on obesity, hypertension, or diabates are crucial to improve the eventual clinical course of COVID-19. Once patients with Cushing's syndrome are in remission, the risk of infection is substantially decreased, but the comorbidities related to excess glucocorticoids might persist, including obesity, hypertension, and diabetes, together with thromboembolic diathesis.2 Because these are features associated with an increased death risk in patients with COVID-19,1 patients with Cushing's syndrome in remission should be considered a high-risk population and consequently adopt adequate self-protection strategies to minimise contagion risk. In conclusion, COVID-19 might have specific clinical presentation, clinical course, and clinical complications in patients who also have Cushing's syndrome during the active hypercortisolaemic phase, and therefore careful monitoring and specific consideration should be given to this special, susceptible population. Moreover, the use of medical therapy as a bridge treatment while waiting for the pandemic to abate should be considered. Go to: Acknowledgments RP reports grants and personal fees from Novartis, Strongbridge, HRA Pharma, Ipsen, Shire, and Pfizer; grants from Corcept Therapeutics and IBSA Farmaceutici; and personal fees from Ferring and Italfarmaco. AMI reports non-financial support from Takeda and Ipsen; grants and non-financial support from Shire, Pfizer, and Corcept Therapeutics. BMKB reports grants from Novartis, Strongbridge, and Millendo; and personal fees from Novartis and Strongbridge. AC reports grants and personal fees from Novartis, Ipsen, Shire, and Pfizer; personal fees from Italfarmaco; and grants from Lilly, Merck, and Novo Nordisk. All other authors declare no competing interests. Go to: References 1. Kakodkar P, Kaka N, Baig MN. A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19) Cureus. 2020;12 [PMC free article] [PubMed] [Google Scholar] 2. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4:611–629. [PubMed] [Google Scholar] 3. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17:233–247. [PubMed] [Google Scholar] 4. Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The immune system in Cushing's syndrome. Trends Endocrinol Metab. 2020 doi: 10.1016/j.tem.2020.04.004. published online May 6, 2020. [PubMed] [CrossRef] [Google Scholar] 5. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020;80:607–613. [PMC free article] [PubMed] [Google Scholar] 6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094–1099. [PubMed] [Google Scholar] 7. Isidori AM, Minnetti M, Sbardella E, Graziadio C, Grossman AB. Mechanisms in endocrinology: the spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur J Endocrinol. 2015;173:R101–R113. [PubMed] [Google Scholar] 8. Nieman LK, Biller BM, Findling JW. Treatment of Cushing's syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:2807–2831. [PMC free article] [PubMed] [Google Scholar] 9. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing's disease. Endocr Rev. 2015;36:385–486. [PMC free article] [PubMed] [Google Scholar] 10. Newell-Price J, Nieman L, Reincke M, Tabarin A. Endocrinology in the time of COVID-19: management of Cushing's syndrome. Eur J Endocrinol. 2020 doi: 10.1530/EJE-20-0352. published online April 1. [PubMed] [CrossRef] [Google Scholar] From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282791/

About Who Should Attend: Individuals with Cushing’s disease and their caregivers. When: Thursday, March 4, 2021, 6 PM, Eastern Where: Virtual presentation via Zoom. Click the Zoom link for the online event or call one of the phone numbers below: 833-548-0276 (US Toll-free) 833-548-0282 (US Toll-free) 877-853-5257 (US Toll-free) 888-475-4499 (US Toll-free) Whether you log on via computer or telephone, you will be asked for the meeting ID and password. Meeting ID: 969 3392 7432 Passcode: 945590 Attendees will be muted until the end of the presentation, at which time we will take questions. There is no fee for this event. Contact Maggie Bobrowitz with any questions: Margaret.Bobrowitz@DignityHealth.org or (888) 726-9370.

The Journal of Clinical Endocrinology & Metabolism, dgab079, https://doi.org/10.1210/clinem/dgab079 Abstract Context Psychiatric symptoms are common in Cushing’s disease (CD) and seem only partly reversible following treatment. Objective To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. Design Nationwide longitudinal register-based study. Setting University Hospitals in Sweden. Subjects CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. Main outcome measures Data from the Swedish Prescribed Drug Register and the Patient Register. Results In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension. Conclusions Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health. Cushing’s syndrome, hypercortisolism, neuropsychiatry, depression, sleeping disorder Issue Section: Clinical Research Article Read more at https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab079/6132459?rss=1

https://doi.org/10.1002/jbmr.4033 ABSTRACT Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long‐term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide (PINP), alkaline bone phosphatase, CTX‐I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex‐, age‐, and body mass index (BMI)‐matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T‐score = −1.4 ± 1.1). Two years after successful surgery, the T‐score had improved in 78% of patients (mean T‐score 2 years postoperatively −1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX‐I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three‐ to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. Introduction Cushing's syndrome (CS) is a rare disease with approximately 0.7 to 2.4 new cases per 1 million per year.1 Osteoporosis and osteopenia are typical comorbidities of patients with endogenous and exogenous CS. Depending on the study, 60% to 80% of patients have evidence for a reduced bone mineral density2 characteristically affecting the entire skeleton.3 About 5% of all cases of secondary osteoporosis are caused by hypercortisolism.4 However, data from prospective, well‐powered studies are rare, and few risk factors that would predict bone health have been identified so far. Guidelines for the management of osteoporosis due to endogenous CS are still missing.5 In terms of risk assessment, the subtype of CS does not seem to influence osteoporosis risk,6 whereas the morning cortisol levels are negatively correlated with lumbar bone mineral density.6 The duration of endogenous Cushing's syndrome (or the duration of exogenous replacement therapy after successful surgery) obviously affects bone mineral density.7 Whether the T‐score is the best predictor for fracture risk is not quite clear.2 Another area of uncertainty is the natural course of osteoporosis and bone turnover markers once the diagnosis of Cushing's syndrome has been established. A number of studies have addressed this topic, but the interpretation of the results is hampered because of limited patient numbers, concomitant osteoanabolic treatment, or both.8-10 In‐depth insight on bone remodeling in CS might come from bone turnover marker studies. For example, the bone formation marker osteocalcin is suppressed in untreated CS,3 a consistent observation making it useful as a diagnostic marker for CS.2 Based on the paucity of data, the lack of evidence for treatment guidelines, and the pressing open questions regarding risk assessment and management of osteoporosis, we performed a sufficiently powered study to analyze the natural course of bone turnover and bone mineral density in a monocentric cohort of patients with endogenous Cushing's syndrome. To the best of our knowledge, this is the first such study, and the data obtained will be instrumental for clinicians who care for patients with Cushing's syndrome. Materials and Methods Patients This study was performed as part of the prospective German Cushing registry, which has included 450 consecutive patients referred to our department for suspected CS since 2012. Structure and general characteristics of the registry have been described in detail previously.11-14 All patients included in the registry underwent a standardized biochemical screening and clinical examination at time of diagnosis and a yearly follow‐up after treatment to treat comorbidities and diagnose recurrence of the disease early. In all patients, standard screening for CS with a 1 mg low‐dose overnight dexamethasone suppression test (LDDST), collection of 24‐hour urine (UFC), and sampling of midnight salivary cortisol were performed. When the diagnosis of CS was confirmed, further subtyping was based on plasma adrenocorticotropic hormone (ACTH), corticotropin‐releasing hormone (CRH) test, high‐dose dexamethasone suppression test, imaging, and inferior petrosal sinus sampling (in case of ACTH dependence). Final diagnosis was CS in 156 patients and exclusion of CS in the remaining 294 patients. Patients with excluded CS were a quite heterogenic group with lead symptoms such as obesity (73%), arterial hypertension (50%), or hirsutism (33%). Final diagnoses in these subjects were metabolic syndrome, polycystic ovary syndrome (PCOS), obesity, depression, or primary hyperaldosteronism. Patient selection is shown in Fig. 1. Figure 1 Open in figure viewerPowerPoint Patient selection. *Very young age; patient conducted densitometry in a different clinic/outpatient clinic; patient refused densitometry. CS = Cushing's syndrome; BMD = bone mineral density; BMI = body mass index. Bold text indicates actual cohort of the study. In our analysis, we excluded patients for whom no densitometry data were available (n = 63) and patients receiving pharmacologic treatment for osteoporosis following diagnosis (n = 4). Densitometry data were not available for multiple reasons (very young age, external densitometry in a different clinic, missing consent to perform densitometry). We matched the remaining 89 patients with 71 controls subjects selected from those subjects in whom CS was excluded. Matching was done according to sex, age, and body mass index (BMI). None of the patients and controls received specific osteoanabolic or antiresorptive treatment, but 47% of patients with CS received vitamin D supplementation after remission. At time of diagnosis, 11% of controls and 17% of patients with CS received vitamin D supplementation. Methods In patients with confirmed CS, a bone mineral densitometry was conducted. Bone mineral density (BMD) was determined at the lumbar spine and the femur (neck and total femur). If a reduced bone mineral density was diagnosed, a follow‐up densitometry was performed 2 years after surgery. If bone mineral density was normal initially or during follow‐up, only one further densitometry was performed 2 or 3 years after initial diagnosis. An improvement or decrease of bone mineral density was defined according to the least significant change (LSC = 2.8 × 1.8%).15 Accordingly, an alteration of more than 5.04% of BMD was rated as significant. A detailed fracture history was taken and X‐ray of the spine was performed when clinical suspicion for fractures was high. In all patients, blood samples (serum and plasma) were taken at time of diagnosis and also 1 and 2 years after successful transsphenoidal surgery or adrenalectomy. Blood was taken in the fasting state between 8:00 and 10:00 a.m. Samples were centrifuged within 20 minutes at 4°C and stored at −80° until assayed. Three bone formation markers and two bone resorption markers were measured: osteocalcin, intact procollagen I‐N‐propeptide (PINP), and bone alkaline phosphatase (BAP) as bone formation markers, and CrossLaps (CTX‐I) and tartrate‐resistant acid phosphatase (5b TrAcP5b) as bone resorption marker, on basis of published data demonstrating their usefulness in CS and primary osteoporosis.2, 16 Samples were measured at the Endocrine Laboratory of the Department of Internal Medicine IV on the iSYS automated analyzer (IDS‐iSYS, Boldon, UK) by well‐validated assays.17, 18 Published, method‐specific reference intervals are available from a large healthy population.19, 20 For the determination of osteocalcin, an N‐MID assay was used, as pre‐analytics are less critical in this assay.21 TrAcp 5b is a new marker, which, in contrast to CTX‐1, can also reliably be measured in the non‐fasting state.22 Statistical analysis In a priori power analysis, we calculated that a total sample size of 102 would be sufficient to identify significant differences between groups, assuming a medium effect size (0.5), a power of 1 – β = 0.80 and a type I error of α = 0.05, with 51 subjects having Cushing's syndrome and 51 subjects being control subjects after excluding Cushing's syndrome. For statistical analysis, SPSS 25 (IBM Corp., Armonk, NY, USA) was used. Clinical characteristics are shown as mean and standard deviation when data is normal distributed; otherwise as median and ranges. Because of the lack of normal distribution of bone turnover markers, nonparametric tests were used to test differences between groups. Differences between bone turnover markers at different times were tested by Friedman test. Multiple regression analysis was used to investigate differences between CS and the control group regarding bone turnover markers adjusted for sex, age, and BMI. Any p values < 0.05 were considered to indicate statistical significance. Results Patient characteristics The clinical and biochemical characteristics of the patient sample are summarized in Table 1. Sixty‐five percent of patients had pituitary CS, 28% adrenal, and 7% suffered from ectopic CS. Patients and controls were well‐matched regarding sex, age, and vitamin D levels and supplementation, but differed in terms of diabetes prevalence. Table 1. Clinical and Biochemical Baseline Characteristics of Patients with Cushing's Syndrome (CS) and Control Subjects in Whom CS Has Been Excluded CS at time of diagnosis (n = 89) CS excluded (n = 71) p Value Sex 66 women (74%), 23 men (26%) 53 women (75%), 18 men (25%) 0.94 Age (years) 44 ± 13 43 ± 14 0.56 BMI 30 ± 7 31 ± 6 0.11 Vitamin D (ng/mL) 24 ± 10 24 ± 12 0.59 Vitamin D supplementation 17% 11% 0.37 Diabetes mellitus 30% (26) 11% (7) 0.007 Morning serum cortisol (μg/dL) 18 (11.7–24.9) 8.4 (5.9–11.6) ≤0.001 LDDST (μg/dL) 14.7 (7.7–23.7) 1.0 (0.8–1.2) ≤0.001 UFC (μg/24 h) 587 (331–843) 140 (78–216) ≤0.001 ACTH (pg/mL) 47 (9–76) 13 (9–18) ≤0.001 Late‐night salivary cortisol (ng/mL) 7.9 (3.3–11.8) 1.2 (0.6–1.8) ≤0.001 Bone turnover markers Osteocalcin (ng/mL) 8 (5–13) 13 (10–17) <0.001 PINP (ng/mL) 35 (29–62) 52 (35–73) 0.025 BAP (μg/L) 23 (16–31) 17 (14–24) 0.006 CTX‐I (ng/mL) 0.28 (0.17–0.42) 0.23 (0.12–0.32) 0.033 TrAcP (U/L) 2.3 (1.7–3.4) 1.9 (1.3–2.4) 0.009 Date are shown as mean ± standard deviation or median and ranges. BMI = body mass index; LDDST = low‐dose dexamethasone suppression test; UFC = urinary free cortisol; ACTH = adrenocorticotropic hormone; PINP = intact procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance. Baseline evaluation At time of diagnosis, the mean levels of bone formation markers osteocalcin and intact PINP were significantly decreased compared with the controls, and the bone formation marker bone alkaline phosphatase was increased (Table 1; Fig. 2). Both bone degradation markers CTX and TrAcP were increased (Table 1). Taken together, this demonstrates increased bone resorption and decreased bone formation in florid CS. Results of multiple linear regression analysis comparing Cushing's syndrome patients and controls are shown in Table 2. Bone markers were similar in patients with a reduced bone mass versus those with a normal bone mass (data not shown). Figure 2 Open in figure viewerPowerPoint Bone turnover markers and bone mineral density at baseline and 1 and 2 years after remission. Boxplot = median and ranges of bone turnover marker in patients with Cushing's syndrome.Gray box = median and ranges of bone turnover markers in the control group.PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; TrAcP = tartrate‐resistant acid phosphatase; CTX‐I = CrossLaps. Table 2. Results of Multiple Linear Regression Analysis Comparing Cushing's Syndrome Patients Versus Controls Dependent variable Standardized regression coefficient and p value for group variable Unadjusted Adjusted for age, sex, and BMI Osteocalcin (ng/mL) −0.392, 0.006 −0.375, 0.010 PINP (ng/mL) −0.215, 0.204 −0.256, 0.145 BAP (μg/L) 0.404, 0.001 0.470, <0.001 CTX‐I (ng/mL) 0.111, 0.366 0.065, 0.616 TrAcP (U/L) 0.227, 0.014 0.186, 0.069 PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance. Overall, bone mineral density was decreased with an average lowest T‐score of −1.4 (±1.1). BMD was significantly lower (p = 0.001) at the femoral neck (T‐score = −0.9 ± 1.0) and the spine (T‐score = −1.0 ± 1.5) compared with the total femur (T‐score = −0.5 ± 1.2). Twenty‐eight patients (32%) had a normal bone mineral density, 46 (52%) osteopenia, and the other 15 patients (17%) osteoporosis with a T‐score lower than −2.5. Seventeen of the patients (19%) had a history of low‐trauma osteoporotic fractures (9 vertebral fractures, 8 nonvertebral fractures). The fractures took place shortly before diagnosis (58%) or more than 2 years before diagnosis of the CS (42%). Patients with osteoporotic fractures had a significantly lower T‐score than patients without fractures (T‐score = −1.9 ± 0.8 versus −1.3 ± 1.1, p = 0.03) but did not differ in the values of the bone turnover markers or standard biochemical screening. Subtype, age, or BMI also did not differ between groups. However, men were significantly at higher risk of having fractures than women (35% of men had fractures versus 14% of women, p = 0.03). Both severity of hypercortisolism and duration of CS did not contribute to fractures rates (data not shown), but UFC was significantly higher in patients with a T‐score lower than −1.5 (Table 3). Table 3. Biochemical Markers in Patients With Cushing's Syndrome With a T‐Score Lower Than −1.5 and Above −1.5 Shown in Median and Ranges Variable T‐score < −1.5 (n = 39) T‐score ≥ −1.5 (n = 42) p Values LDDST (μg/dL) 16.6. (10.3–28.3) 11.9 (6.1–21.9) 0.12 UFC (μg/24 h) 706 (410–906) 398 (285–787) 0.03 Late‐night salivary cortisol (ng/mL) 8.3 (3.5–13.6) 5.7 (2.9–11.7) 0.39 ACTH (pg/mL) 53 (16–73) 42 (6–82) 0.88 LDDST = low‐dose dexamethasone suppression test; UFC = urinary free cortisol; ACTH = adrenocorticotropic hormone. Bold numbers indicate statistical significance. One‐ and 2‐year follow‐up Surgical tumor resection leading to biochemical remission of CS resulted in a strong increase of bone formation markers tested at 1‐year follow‐up (Table 4; Fig. 2A, B). After 2 years, the markers had decreased slightly but remained elevated. Bone resorption markers were mildly increased at time of diagnosis, increased further at 1 year post‐surgery, and returned almost to normal levels at 2 years (Table 4; Fig. 2D, E). A follow‐up bone densitometry conducted in 40 patients showed a parallel increase of the T‐score of 0.6 ± 0.8 (Fig. 2F). In particular, BMD of the spine improved (Table 5). Table 4. Bone Turnover Markers and Bone Mass in Patients With Cushing's Syndrome at Time of Diagnosis and During 2 Years of Follow‐Up Time of diagnosis (n = 50) 1 year in remission (n = 45) 2 years in remission (n = 38) p (0 versus 1) p (0 versus 2) p (1 versus 2) T‐score −1.5 (−2.0 to −0.8) – −1.1 (−1.5 to −0.4) – <0.001 – Osteocalcin (ng/mL) 8 (5–13) 30 (14–60) 21 (13–31) <0.001 0.008 0.3 PINP (ng/mL) 35 (29–62) 117 (52–221) 69 (46–113) <0.001 0.1 0.1 BAP (μg/L) 23 (16–31) 26 (19–38) 22 (15–31) 0.2 0.4 0.1 CTX‐I (ng/mL) 0.28 (0.17–0.42) 0.51 (0.22–0.91) 0.25 (0.18–0.73) 0.01 0.1 0.04 TrAcP (U/L) 2.3 (1.7–3.4) 2.8 (1.8–4.0) 2.3 (2–3.2) 0.1 0.6 0.002 PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance. Table 5. Overview: T‐Scores, Z‐Scores, and BMD Values With Percent Changes (Mean and Standard Deviation) Variable CS at time of diagnosis CS 2 years in remission p Values, percent changes (↑) Femoral neck T‐score femoral neck −0.81 ± 0.97 −0.59 ± 0.86 0.06 Z‐score femoral neck −0.59 ± 0.98 −0.28 ± 0.79 0.02 BMD (g/cm2) femoral neck 0.91 ± 0.12 0.95 ± 0.12 0.16; 4% ↑ Femur T‐score femur −0.49 ± 1.11 −0.42 ± 1.04 0.67 Z‐score femur −0.40 ± 1.04 −0.37 ± 0.85 0.31 BMD (g/cm2) femur 0.95 ± 0.15 0.97 ± 0.14 0.77, 2% ↑ Spine T‐score spine −0.96 ± 1.56 −0.55 ± 1.25 <0.001 Z‐score spine −0.85 ± 1.53 −0.58 ± 1.14 <0.001 BMD (g/cm2) spine 1.08 ± 0.22 1.13 ± 0.15 0.001, 0.6% ↑ BMD = bone mineral density; CS = Cushing's syndrome. Bold numbers indicate statistical significance. In 78% of patients, bone mineral density improved after 2 years; in 45% of patients, T‐score improved more than 0.5. No clinical fractures occurred after successful treatment of the CS. There was no significant correlation between improvement of bone mineral density and any of the bone turnover markers. Discussion This study investigated for the first time to our knowledge a panel of bone formation and resorption markers in a large cohort of patients with CS over the long term. The unique and comprehensive data show that initially bone metabolism is characterized by decreased bone formation and increased bone resorption, in line with the classical action of glucocorticoids. Successful treatment of endogenous Cushing's syndrome leads to a strong activation of bone turnover, characterized by increased bone formation and bone resorption, a process that is continuous beyond year 2 after remission of CS, although at a reduced activity level. In parallel, bone mineral density increases in the majority of patients. Although 19% had low‐trauma fractures at baseline, none of the subjects experienced clinical fractures during follow‐up. In summary, these data give new insight into bone healing after remission of CS. They strongly suggest that an observational approach to the bone phenotype is justified as long as remission from CS is secured. Reversibility of osteoporosis and bone turnover markers Although established in osteoporosis research, bone turnover markers are not measured on a routine basis in patients with CS. However, it is a consistent result from different studies that osteocalcin is depressed in patients with CS. In fact, this finding is so reliable that it was even suggested to use osteocalcin in the diagnosis of CS.2 P1NP and procollagen carboxy‐terminal propeptide (P1CP) have also been studied in several studies, with contradictory results.23 In a retrospective study with 21 patients with CS, it was shown that osteocalcin is depressed; this applies also for PINP, whereas CTX is increased.24 Some studies already have focused on the reversibility of osteoporosis after treatment of CS. In the majority of patients, bone mineral density increased within 2 years after successful treatment8-10, 25 Hermus and colleagues showed in a study with 20 patients that bone mineral density did not change 3 or 6 months after surgery but increased thereafter in almost all patients.8 In a study with 68 patients, the patients were followed up for 4 years. Bone mineral density increased over lumbar spine and femur but decreased at the forearm.25 The authors concluded that bone minerals were redistributed from the peripheral to the axial skeleton. In our study, bone mineral density also improved in the majority of patients but remained reduced in some. We did not find any difference in bone turnover markers between patients with improvement and without improvement. Current treatment guidelines and treatment suggestions As observed in our study, bone formation markers increase significantly after surgical cure, whereas bone degradation markers are mildly elevated at baseline and increase slightly at 1 year, returning within the normal range at 2 years. So far, there is no international guideline on the treatment of osteoporosis induced by endogenous CS and very few controlled interventional studies. In an opinion paper, Scillitani and colleagues recommended to treat all patients with vitamin D and calcium but not with bisphosphonates.5 In a randomized open‐label study by Di Somma and colleagues,26 39 patients (18 patients with active CS and 21 patients with CS in remission) received alendronate or no medication. Patients with active CS also received ketoconazole to control hypercortisolism. Bone mineral density improved and serum levels of osteocalcin increased in patients who received alendronate to a greater extent than those receiving no alendronate. In a small study by the same research group,27 15 patients with CS (9 adolescent patients and 6 adults) were observed for 2 years after successful treatment, showing that osteocalcin levels and bone mineral density increased significantly. Strengths and limitations Although this study has several strengths, including the large prospective design and measuring a panel of bone formation and resorption markers, there are a few limitations. Some asymptomatic fractures may have been overlooked because an X‐ray was not taken systematically in each patient. Furthermore, a follow‐up bone densitometry was not available for all patients. Additionally, patients in the control group suffered from diabetes, overweight, arterial hypertension, or other diseases. Novel aspects and outlook This study analyzes for the first time in a comprehensive way bone turnover markers during the course of CS. The data show that cure from CS leads to increases in bone remodeling and bone mineral density, in line with spontaneous “bone healing.” Our data support a wait‐and‐watch strategy despite a high endogenous risk for additional fractures, based on the baseline assessment. This observation will influence future therapeutic strategies in patients with CS. Our data suggest that the phase immediately after remission from CS is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients. Both bone attachment and bone degradation markers increase significantly, leading to an increase in bone mass and to a reduced risk of osteoporotic fractures. This unconstrained increase in bone formation markers after remission should be considered before specific therapy is initiated. Our data do not favor specific pharmacologic interventions with bisphosphonates or denosumab during this phase of remodeling because they may disrupt the osteoblast‐mediated bone mass increase. Disclosures All authors state that they have no conflicts of interest. Acknowledgments This work is part of the German Cushing's Registry CUSTODES and has been supported by a grant from the Else Kröner‐Fresenius Stiftung to MR (2012_A103 and 2015_A228). Additionally, AR, FB, and MR received funding by the Deutsche Forschungsgemeinschaft (CRC/TRR 205/1 “The Adrenal Gland”). Furthermore, funds for this project were provided by the Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der Ludwig‐Maximilians‐Universität München eV to LB. The data are stored on the following repository: https://figshare.com/ and will be made accessible after publication of the article. Authors’ roles: LB served as the principal investigator in this work and was responsible for the study conception and design, the analysis and interpretation of the data, and the drafting of the manuscript. JF, SZ, AO, AR, GR and SB contributed to the collection and analysis of the data. MS, FB, MD, MB substantially contributed to the interpretation of the data and the drafting of the manuscript. RS contributed to the conceptual design of the study, the interpretation of data and the revision of the paper. MR contributed to the conceptual design of the study, the collection, analysis and interpretation of data, and the drafting and revision of the paper. All authors contributed to the critical revision of the manuscript and approved the final version for publication. From https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.4033

A retrospective cohort study was performed to compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Researchers examined 6,821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 6,7564 individually-matched controls (primary, 20366; secondary, 39134). It was shown that in adrenal insufficiency, mortality was elevated, particularly primary, even with individual matching, and was found early in the disease course. The data demonstrated that cardiovascular disease was the major cause but mortality from infection was also high. The adrenal crisis was a common contributor. The outcomes suggested that early education for prompt treatment of infections and avoidance of adrenal crisis hold the potential to decrease mortality. The Journal of Clinical Endocrinology & Metabolism, dgab096, https://doi.org/10.1210/clinem/dgab096 Abstract Context Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations. Objective To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Design Retrospective cohort study. Setting UK general practitioner database (CPRD). Participants 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcome measures All-cause and cause-specific mortality; hospital admission from adrenal crisis. Results With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 - 1.77]. HRs were greater in primary (1.83 [1.66 - 2.02]) than in secondary (1.52 [1.40 - 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 - 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 - 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years. Conclusion Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality. PDF available at https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab096/6141434?redirectedFrom=fulltext

Biomarkers in a majority of Cushing’s syndrome patients with surgically induced disease remission showed a high rate of bone turnover and greater bone mineral density one and two years later, a study reports. Before treatment, these patients were found to have greater bone degradation and poorer bone formation, as can be common to disease-related bone disorders. Researchers believe their work is the first study of its kind, “and the data obtained will be instrumental for clinicians who care for patients with Cushing’s syndrome.” The study, “The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2‐Year Follow‐Up Study,” was published in the Journal of Bone and Mineral Research. Two common co-conditions of Cushing’s syndrome are osteopenia, a loss of bone mass, and osteoporosis, in which the body makes too little bone, loses too much bone, or both. Studies suggest up to 80% of people with Cushing’s have evidence of reduced bone mineral density affecting the entire skeleton. However, few risk factors to predict bone health have been identified so far, and guidelines for osteoporosis management due to Cushing’s are lacking. Uncertainty as to the natural course of osteoporosis once a diagnosis of Cushing’s syndrome has been made is also still evident. Investigators at the University of Munich, reportedly for a first time, analyzed the natural course of bone mineral density and bone turnover (recycling) in a group of people with endogenous Cushing’s syndrome — which refers to the disease caused by excess cortisol in the bloodstream, often due to a tumor in the adrenal or pituitary glands. They examined medical records of 89 Cushing syndrome patients with a mean age of 44, of which 74% were women. Of these, 65% had pituitary Cushing’s (Cushing’s disease), 28% had adrenal, and 7% had ectopic Cushing’s, which is caused by tumors outside the adrenal or pituitary glands. A group of 71 age- and sex-matched healthy participants were included as controls. In all patients, blood samples were collected at the time of diagnosis (baseline) and one and two years after removing one or both adrenal glands or moving tumors affecting the pituitary gland. Blood samples were analyzed for biomarkers related to bone formation and degradation (resorption). At the study’s beginning, the mean levels of two bone formation markers, osteocalcin and intact PINP, were significantly decreased in patients compared with controls, whereas the bone formation marker alkaline phosphatase was increased. Both markers for bone degradation — called CTX and TrAcP — were also high, which demonstrated “increased bone resorption and decreased bone formation in [Cushing’s syndrome],” the team wrote. While bone markers were similar in participants with a reduced bone mass relative to those with a normal bone mass, bone mineral density was lower overall. Bone mineral density was significantly lower in the neck and spine compared with the femur (thigh bone). Normal bone mineral density was reported in 28 (32%) patients, while 46 (52%) had osteopenia, and the remaining 15 (17%) lived with osteoporosis. A history of low-trauma bone fractures due to osteoporosis occurred in 17 (19%) patients, taking place shortly before diagnosis in more than half of these (58%) people, and more than two years before a Cushing’s diagnosis in the remaining group (42%). Compared to patients without fractures, those with fractures had a significantly lower T‐score, a bone density measure that represents how close a person is to average peak bone density. While Cushing’s subtype, age, or body mass index (BMI, body fat based on height) did not differ between groups, men had a significantly higher risk of fractures than women (35% of men vs. 14% of women). Both disease severity and duration did not contribute to fractures rates, but urinary free cortisol (a circulating cortisol measure) was significantly higher in patients with a low T‐score. At the one year after tumor removal, which led to Cushing’s remission based on blood tests, a significant increase in bone formation markers was reported. These biomarkers decreased slightly at two years post-surgery, but remained elevated. At the beginning of the study, bone resorption markers were mildly increased, which rose further one year after surgery before returning almost to normal levels by two years. In parallel, bone density measures conducted in 40 patients showed a matching increase in T-score, particularly in the spine. After two years, bone mineral density improved in 78% of patients, and T-scores improved in 45% of them. No fractures occurred after Cushing’s treatment, and there was no significant correlation between bone turnover markers and better bone mineral density. “This study analyzes for the first time in a comprehensive way bone turnover markers during the course of [Cushing’s syndrome],” the researchers wrote. “Our data suggest that the phase immediately after remission from [Cushing’s syndrome] is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients.” These results “will influence future therapeutic strategies in patients” with Cushing’s syndrome, they added. Steve Bryson PhD Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone. From https://cushingsdiseasenews.com/2021/02/19/successful-cushings-surgery-leads-to-better-bone-density-study-finds/

Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition. Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison's disease, a condition where the body's immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone. Groundbreaking study The rarity of Addison's disease has until now made scanning of the whole genome for clues to the disease's genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world's two largest Addison's disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator). AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life. Knowing what predisposes people to develop Addison's disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye's lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future. ### Contact information: Professor at the University of Bergen, Eystein Husebye - Eystein.Husebye@uib.no - cell phone +47 99 40 47 88 Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system. From https://www.eurekalert.org/pub_releases/2021-02/tuob-nsi021221.php

Central hypothyroidism is prevalent in about 1 in 2 adults with Cushing’s syndrome, and thyroid function can be restored after curative surgery for most patients, according to study findings. “Our study findings have confirmed and greatly extended previous smaller studies that suggested a link between hypercortisolism and thyroid dysfunction but were inconclusive due to smaller sample size and short follow-up,” Skand Shekhar, MD, an endocrinologist and clinical investigator in the reproductive physiology and pathophysiology group at the National Institute of Environmental Health Sciences, NIH, told Healio. “Due to our large sample and longer follow-up, we firmly established a significant negative correlation between hypercortisolemia measures — serum and urinary cortisol, serum adrenocorticotropic hormone — and thyroid hormones triiodothyronine, free thyroxine and thyrotropin.” Shekhar and colleagues conducted a retrospective review of two groups of adults aged 18 to 60 years with Cushing’s syndrome. The first group was evaluated at the NIH Clinical Center from 2005 to 2018 (n = 68; mean age, 43.8 years; 62% white), and the second group was evaluated from 1985 to 1994 (n = 55; mean age, 37.2 years; 89% white). The first cohort was followed for 6 to 12 months to observe the pattern of thyroid hormone changes after surgical cure of adrenocorticotropic hormone-dependent Cushing’s syndrome. The second group underwent diurnal thyroid-stimulating hormone evaluation before treatment and during remission for some cases. Urinary free cortisol and morning thyroid hormone levels were collected for all participants. In the second group, researchers evaluated diurnal patterns of TSH concentrations with hourly measurements from 3 to 7 p.m. and midnight to 4 p.m. In the first group, adrenocorticotropic hormone and serum cortisol were measured. In the first cohort, seven participants were receiving levothyroxine for previously diagnosed primary or central hypothyroidism. Of the remaining 61 adults, 32 had untreated central hypothyroidism. Thirteen participants had free T4 at the lower limit of normal, and 19 had subnormal levels. There were 29 adults with subnormal levels of T3 and seven with subnormal TSH. Before surgery, 36 participants in the first group had central hypothyroidism. Six months after surgery, central hypothyroidism remained for 10 participants. After 12 months, the number of adults with central hypothyroidism dropped to six. Preoperative T3 and TSH levels were negatively associated with morning and midnight cortisol, adrenocorticotropic hormone and urinary free cortisol. In post hoc analysis, a baseline urinary free cortisol of more than 1,000 g per day was adversely associated with baseline and 6-month T3 and free T4 levels. In the second group, there were 51 participants not on thyroid-modifying drugs who had a thyroid function test 6 or 12 months after surgery. Before surgery, free T4 levels were subnormal in 17 participants, T3 levels were subnormal in 22, and TSH levels were in the lower half of the reference range or below in all but one participant. After surgery, two participants had below normal free T4, one had subnormal T3, and TSH levels were in the lower half of the reference range or below in 23 of 48 participants. Before surgery, there was no difference in mean TSH between daytime and nighttime. A mean 8 months after surgery, the second group had a normal nocturnal TSH surge from 1.3 mIU/L during the day to 2.17 mIU/L at night (P = .01). The nocturnal TSH increase persisted as long as 3 years in participants who had follow-up evaluations. “We found a very high prevalence of thyroid hormone deficiency that appears to start at the level of the hypothalamus-pituitary gland and extend to the tissue level,” Shekhar said. “Some of these patients may experience thyroid hormone deficiency symptoms, such as fatigue, depression, cold intolerance, weight gain, etc, as a result of systematic and tissue-level thyroid hormone deficiency. We also noted a strong correlation between hypothyroidism and hypogonadism, which implies that hypothyroid patients are also likely to suffer adverse reproductive effects. Thus, it is imperative to perform thorough thyroid hormone assessment in patients with Cushing’s syndrome, and thyroid hormone supplementation should be considered for these patients unless cure of Cushing’s syndrome is imminent.” Researchers said providers should routinely screen for hypothyroidism in adults with Cushing’s syndrome. Even after thyroid function is restored, regular follow-up should also be conducted. Further research is needed to investigate thyroid dysfunction in iatrogenic Cushing’s syndrome and the impact of these findings on euthyroid sick syndrome, Shekhar said. For more information: Skand Shekhar, MD, can be reached at skand.shekhar@nih.gov. From https://www.healio.com/news/endocrinology/20210208/thyroid-dysfunction-highly-prevalent-in-cushings-syndrome

The cancer medicine bexarotene may hold promise for treating Cushing’s disease, a study suggests. The study, “Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT‐20 cells,” was published in the Journal of Cellular and Molecular Medicine. Cushing’s disease is caused by a tumor on the pituitary gland, leading this gland to produce too much adrenocorticotropic hormone (ACTH). Excess ACTH causes the adrenal glands to release too much of the stress hormone cortisol; abnormally high cortisol levels are primarily responsible for the symptoms of Cushing’s. Typically, first-line treatment is surgical removal of the pituitary tumor. But surgery, while effective in the majority of cases, does not help all. Additional treatment with medications or radiation therapy (radiotherapy) works for some, but not others, and these treatments often have substantial side effects. “Thus, the development of new drugs for CD [Cushing’s disease] treatment is extremely urgent especially for patients who have low tolerance for surgery and radiotherapy,” the researchers wrote. Recent research has shown that a protein called testicular receptor 4 (TR4) helps to drive ACTH production in pituitary cancers. Thus, blocking the activity of TR4 could be therapeutic in Cushing’s disease. Researchers conducted computer simulations to screen for compounds that could block TR4. This revealed bexarotene as a potential inhibitor. Further biochemical tests confirmed that bexarotene could bind to, and block the activity of, TR4. Bexarotene is a type of medication called a retinoid. It is approved to treat cutaneous T-cell lymphoma, a rare cancer that affects the skin, and available under the brand name Targretin. When pituitary cancer cells in dishes were treated with bexarotene, the cells’ growth was impaired, and apoptosis (a type of programmed cell death) was triggered. Bexarotene treatment also reduced the secretion of ACTH from these cells. In mice with ACTH-secreting pituitary tumors, bexarotene’s use significantly reduced tumor size, and lowered levels of ACTH and cortisol. Cushing’s-like symptoms also eased; for example, bexarotene treatment reduced the accumulation of fat around the abdomen in these mice. Additional cellular experiments suggested that bexarotene specifically works on TR4 by changing the location of the protein. Normally, TR4 is present in the nucleus — the cellular compartment that houses DNA — where it helps to control the production of ACTH. But with bexarotene treatment, TR4 tended to go outside of the nucleus, leading to lower ACTH production. The researchers noted that other mechanisms may also be involved in the observed effects of bexarotene. “In summary, our work demonstrates that bexarotene is a potential inhibitor for TR4. Importantly, bexarotene may represent a new drug candidate to treat CD,” the researchers concluded. From https://cushingsdiseasenews.com/2021/02/05/bexarotene-cancer-drug-t-cell-lymphoma-acth-production/?preview_id=39289

Abstract Cushing's syndrome is a rare entity in children. Adrenal tumour is the common cause of this syndrome in young children, whereas, iatrogenic causes are more common among older children. We report a 4 year old male child diagnosed with Cushing syndrome due to a right adrenal adenoma; the child presented with obesity and increase distribution of body hair. After thorough investigation and control of hypertension and dyselectrolytemia, right adrenalectomy was performed. The patient had good clinical recovery with weight loss and biochemical resolution of Cushing's syndrome. 1. Introduction Cushing's syndrome (CS) is rarely encountered in children. The overall incidence of Cushing syndrome is approximately 2–5 new cases per million people per year. Only approximately 10% of the new cases each year occur in children [1]. Unlike in adults, a male-to-female predominance have been observed in infants and young toddlers [[1], [2], [3]]. Although iatrogenic causes are common in children above seven years of age, adrenal causes (adenoma, carcinoma or hyperplasia) are common in children of younger age [4]. We report a 4 year old boy diagnosed with Cushing syndrome caused by a right adrenal adenoma, who had presented with obesity and increase distribution of body hair. Right adrenalectomy was performed and clinical stabilization resulted in weight loss and biochemical resolution of Cushing's syndrome. (see Fig. 5) 2. Case report A 4 years old boy presented with complaints of excessive weight gain of 5 months duration and increase frequency of micturition and appearance of body hair for 4 months. There was no history of any other illness, medication or steroid intake. The child was first born at term by normal vaginal delivery and birth weight of 3 kg. Physical examination revealed a chubby boy with moon face, buffalo hump, protruding abdomen, increase body hair and appearance of coarse pubic hair (Fig. 1). His intelligent quotient (IQ) was appropriate for his age and sex. His younger sibling was in good health and other family members did not have any metabolic or similar problems. Download : Download high-res image (710KB) Download : Download full-size image Fig. 1. The child with moon face, protruded abdomen and coarse body hair. The patient's body length was 92cm (between -2SD to -3SD), weight 20kg (between 1 SD and 2 SD), weight for height >3SD, and BMI was 23.6 (BMI for age >3 SD). His blood pressure on right arm in lying position was 138/76 mm Hg (above 99th percentile for height and age). Investigations: Morning 8am serum cortisol level - 27.3 μg/dl (normal: 6–23 μg/dl). with a concurrent plasma ACTH level of < 5 pg/ml (n value < 46 pg/ml). His serum cortisol following low dose dexamethasone suppression test (1mg dexamethasone at 11pm) at 8 am next morning was 22.1 μug/dl and his 24 hours urine catecholamine fraction was within normal limit. HB % -- 10.3 gm/dl; LDDST -- 25 μg/dl; FBS -- 106 mg/dl. Serum Na+ - 140.6mmol/l; K+ - 2.83mmol/l; Ca+ - 8.7 mg/dl. S. Creatinine −0.3 mg/dl. Ultrasonography of abdomen revealed a heterogenous predominantly hypoechoic right supra renal mass. Contrast enhanced CT abdomen revealed well defined soft tissue density lesion (size −5.2 cm × 5.2 cm x 5.7cm) in right adrenal gland with calcifications and fat attenuations showing mild attenuation on post contrast study (Fig. 2). Download : Download high-res image (703KB) Download : Download full-size image Fig. 2. CECT shows right adrenal mass with calcification and mild attenuation on post-contrast study. The child was started on oral amlodipine 2.5mg 12hourly; after 5days blood pressure became normal. For hypokalemia oral potassium was given @20 meq 8 hourly and serum potassium value became normal after 4 days. Right laparoscopic adrenalectomy was planned. but due to intra operative technical problems it was converted to an open adrenalectomy with right subcostal incision. A lobulated mass of size 9 cm × 5 cm x 4 cm with intact capsule was excised. The tumour weighed 230 gm. There was no adhesion with adjacent organs, three regional nodes were enlarged but without any tumour tissue. Inferior vena cava was spared. Histopathology report was consistent with adrenal adenoma (Fig. 3) (see Fig. 4). Download : Download high-res image (427KB) Download : Download full-size image Fig. 3. Cut section of tumour shows fleshy mass with fatty tissue. Download : Download high-res image (618KB) Download : Download full-size image Fig. 4. Microphotograph (100 × 10) showing intact capsule and adrenal tumour cells, which are larger in size with nuclear pleomorphism, inconspicuous nucleoli, cytoplasm of the tumour cells are abundant, eosinophilic and vacuolated. Download : Download high-res image (593KB) Download : Download full-size image Fig. 5. Physical appearance 4 months after adrenalectomy. Post operative management: during post operative period hypokalemia and flaxuating blood sugar level was managed with oral potassium and oral glucose supplement. patient developed mild cough and respiratory distress on post op day 2, it was managed with salbutamol nebulization and respiratory physio therapy. Patient developed minor ssi and discharged on 10 th post operative day with oral prednisolone supplementation. Follow up: the patient was followed up 2week after discharge and then every monthly, the oral prednisolone was gradually tapered and completely withdrawn on 2nd month after surgery.The patient experienced no post-surgical complications. After 4 months of surgery he reduces 6 kgs of his body weight with BMI of 16.5 (between median and 1SD) & BP 100/74 mm hg (within normal range), the moon face, buffalo hump, central obesity disappeared, morning 8am serum cortisol level was found within normal range 14 μg/dl (n value 6–23 μg/dl). 3. Discussion Cushing's syndrome is caused by prolonged exposure to supraphysiological levels of circulating glucocorticoids, which may be endogenously or exogenously derived. During infancy, CS is usually associated with McCune-Albright syndrome; adrenocortical tumours most commonly occur in children under four years of age and Cushing's disease (ACTH dependent) is the commonest cause of CS after five years of age [5]. Primary adrenocortical tumours (ACTs) account for only 0.3–0.4% of all childhood neoplasms. Almost a third of these tumours manifests as Cushing syndrome and over 70% of the unilateral tumours in young children are often malignant [2,3,6,7]. There seems to be a bimodal incidence of these tumours, with one peak at under 5 years of age and the second one in the fourth or fifth decades of life. ACTs may be associated with other syndromes, such as, Li-Fraumeni syndrome, Beckwith-wiedemann syndrome, isolated hemihypertrophy, or even a germline point mutation of P53 tumour suppressor gene as reported in a series from Brazil [8]. In comparison to adult CS, growth failure with associated weight gain is one of the most reliable indicators of hypercortisolaemia in pediatric CS. The parents often fail to notice facial changes and growth failure and hence the diagnosis is often delayed. In one study, the mean time from appearing symptoms to diagnosis in 33 children with Cushing's disease was 2.5 years [5]. More recently the comparison of height and BMI SDS measurements provided a sensitive diagnostic discriminator in pediatric patients with CD and those with simple obesity [9]. In the present case, the parents observed noticeable changes in his face and presence of body hair, which made them to bring the child to medical attention. A review of 254 children on the International Pediatric Adrenocortical Tumour Registry identified virilization as the most common manifestation [10]. About 10% of the tumours can be non-functional at presentation, and approximately one third of pediatric patients present with hypertension. Majority of patients (192/254) in the Registry had localized disease and metastatic disease was found in less than 5% of cases. Older children with CS or mixed androgen and cortisol secreting adrenocortical tumours had a worse prognosis compared to younger children [10]. The present case had mild hypertension as well as dyselectrolytemia at presentation, which could be controlled with medication. He had a single adenoma confined to the adrenal gland and there was no evidence of malignancy. After surgical excision of the tumour and the right adrenal gland, the patient made rapid improvement in clinical condition and has been on follow up for last 7 months. 4. Conclusion Pediatric adrenocortical tumours (ACTs) are most commonly encountered in females and in children less than four years. But our case being an 4-year-old boy forms a rare presentation of endogenous Cushing's syndrome due to adrenal adenoma. Cushing's syndrome in this child was controlled after right adrenalectomy. Patient consent Informed written consent was taken. Funding No funding or grant support. Authorship All authors attest that they meet the current ICMJE criteria for authorship. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] M.A. Magiakou, G. Mastorakos, E.H. Oldfield, et al. Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy N Engl J Med, 331 (10) (1994), pp. 629-636 [PubMed: 8052272] [2] C. Tsigos, G.P. Chrousos Differential diagnosis and management of Cushing's syndrome Annu Rev Med, 47 (1996), pp. 443-461 [PubMed: 8712794] [3] D.N. Orth Cushing's syndrome N Engl J Med, 332 (12) (1995), pp. 791-803 [PubMed: 7862184] [4] C.J. Migeon, R. Lanes (fifth ed.)F. Lifshitz (Ed.), “Adrenal cortex: hypo and hyper_x0002_function,” in Pediatric Endocrinology, vol. 8, Informa Healthcare, London, UK (2007), p. 214 [5] L.F. Chan, H.L. Storr, A.B. Grossman, M.O. Savage Pediatric Cushing's syndrome: clinical features, diagnosis, and treatment Arq Bras Endocrinol Metabol, 51 (8) (2007), pp. 1261-1271, 10.1590/S0004-273 [6] C.A. Stratakis, L.S. Kirschner Clinical and genetic analysis of primary bilateral adrenal diseases(micro- and macronodular disease) leading to Cushing syndrome Horm Metab Res, 30 (6–7) (1998), pp. 456-463 [PubMed: 9694579] [7] W.L. Miller, J.J. Townsend, M.M. Grumbach, S.L. Kaplan An infant with Cushing's disease due to anadrenocorticotropin-producing pituitary adenoma J Clin Endocrinol Metabol, 48 (6) (1979), pp. 1017-1025 [8] R.C. Ribeiro, F. Sandrini, B. Figueiredo, G.P. Zambetti, E. Michalkiewicz, A.R. Lafferty, et al. An inherited P53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma Proc Natl Acad Sci U S A, 98 (16) (2001), pp. 9330-9335 [9] J.E. Greening, H.L. Storr, S.A. McKenzie, K.M. Davies, L. Martin, A.B. Grossman, et al. Linear growth and body mass index in pediatric patients with Cushing's disease or simple obesity J Endocrinol Invest, 29 (10) (2006), pp. 885-887 [10] E. Michalkiewicz, R. Sandrini, B. Figueiredo, E.C. Miranda, E. Caran, A.G. Oliveira-Filho, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the international pediatric adrenocortical tumor Registry J Clin Oncol, 22 (5) (2004), pp. 838-845 From https://www.sciencedirect.com/science/article/pii/S2213576620303833

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Researchers conducted this retrospective cohort study to investigate acute and life-threatening complications in patients with active Cushing syndrome (CS). Participants in the study were 242 patients with CS, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. In patients with benign pituitary CS, the prevalence of acute complications was 62%, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Infections, thromboembolic events, hypokalemia, hypertensive crises, cardiac arrhythmias and acute coronary events were complications reported in patients with benign CS. The whole spectrum of acute and life-threatening complications in CS and their high prevalence was illustrated in this study both before disease diagnosis and after successful surgery. Read the full article on Journal of Clinical Endocrinology and Metabolism.

Thyroid cancer survival rates are 84 percent for 10 years or more if diagnosed early. Early diagnosis is crucial therefore and spotting the unusual signs could be a matter of life and death. A sign your thyroid cancer has advanced includes Cushing syndrome. What is it? What is Cushing syndrome? Cushing syndrome occurs when your body is exposed to high levels of the hormone cortisol for a long time, said the Mayo Clinic. The health site continued: “Cushing syndrome, sometimes called hypercortisolism, may be caused by the use of oral corticosteroid medication. “The condition can also occur when your body makes too much cortisol on its own. “Too much cortisol can produce some of the hallmark signs of Cushing syndrome — a fatty hump between your shoulders, a rounded face, and pink or purple stretch marks on your skin.” In a study published in the US National Library of Medicine National Institutes of Health, thyroid carcinoma and Cushing’s syndrome was further investigated. The study noted: “Two cases of thyroid carcinoma and Cushing's syndrome are reported. “Both of our own cases were medullary carcinomas of the thyroid, and on reviewing the histology of five of the other cases all proved to be medullary carcinoma with identifiable amyloid in the stroma. “A consideration of the temporal relationships of the development of the carcinoma and of Cushing's syndrome suggested that in the two cases with papillary carcinoma these conditions could have been unrelated, but that in eight of the nine cases with medullary carcinoma there was evidence that thyroid carcinoma was present at the time of diagnosis of Cushing's syndrome. “Medullary carcinoma of the thyroid is also probably related to this group of tumours. It is suggested that the great majority of the tumours associated with Cushing's syndrome are derived from cells of foregut origin which are endocrine in nature.” In rare cases, adrenal tumours can cause Cushing syndrome a condition arising when a tumour secretes hormones the thyroid wouldn’t normally create. Cushing syndrome associated with medullary thyroid cancer is uncommon. The syndrome is more commonly caused by the pituitary gland overproducing adrenocorticotropic hormone (ACTH), or by taking oral corticosteroid medication. See a GP if you have symptoms of thyroid cancer, warns the NHS. The national health body added: “The symptoms may be caused by less serious conditions, such as an enlarged thyroid, so it's important to get them checked. “A GP will examine your neck and can organise a blood test to check how well your thyroid is working. “If they think you could have cancer or they're not sure what's causing your symptoms, you'll be referred to a hospital specialist for more tests.” Adapted from https://www.express.co.uk/life-style/health/1351753/thyroid-cancer-signs-symptoms-cushing-syndrome

A young healthcare worker who contracted COVID-19 shortly after being diagnosed with Cushing’s disease was detailed in a case report from Japan. While the woman was successfully treated for both conditions, Cushing’s may worsen a COVID-19 infection. Prompt treatment and multidisciplinary care is required for Cushing’s patients who get COVID-19, its researchers said. The report, “Successful management of a patient with active Cushing’s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia,” was published in Endocrine Journal. Cushing’s disease is caused by a tumor on the pituitary gland, which results in abnormally high levels of the stress hormone cortisol (hypercortisolism). Since COVID-19 is still a fairly new disease, and Cushing’s is rare, there is scant data on how COVID-19 tends to affect Cushing’s patients. In the report, researchers described the case of a 27-year-old Japanese female healthcare worker with active Cushing’s disease who contracted COVID-19. The patient had a six-year-long history of amenorrhea (missed periods) and dyslipidemia (abnormal fat levels in the body). She had also experienced weight gain, a rounding face, and acne. After transferring to a new workplace, the woman visited a new gynecologist, who checked her hormonal status. Abnormal findings prompted a visit to the endocrinology department. Clinical examination revealed features indicative of Cushing’s syndrome, such as a round face with acne, central obesity, and buffalo hump. Laboratory testing confirmed hypercortisolism, and MRI revealed a tumor in the patient’s pituitary gland. She was scheduled for surgery to remove the tumor, and treated with metyrapone, a medication that can decrease cortisol production in the body. Shortly thereafter, she had close contact with a patient she was helping to care for, who was infected with COVID-19 but not yet diagnosed. A few days later, the woman experienced a fever, nausea, and headache. These persisted for a few days, and then she started having difficulty breathing. Imaging of her lungs revealed a fluid buildup (pneumonia), and a test for SARS-CoV-2 — the virus that causes COVID-19 — came back positive. A week after symptoms developed, the patient required supplemental oxygen. Her condition worsened 10 days later, and laboratory tests were indicative of increased inflammation. To control the patient’s Cushing’s disease, she was treated with increasing doses of metyrapone and similar medications to decrease cortisol production; she was also administered cortisol — this “block and replace” approach aims to maintain cortisol levels within the normal range. The patient experienced metyrapone side effects that included stomach upset, nausea, dizziness, swelling, increased acne, and hypokalemia (low potassium levels). She was given antiviral therapies (e.g., favipiravir) to help manage the COVID-19. Additional medications to prevent opportunistic fungal infections were also administered. From the next day onward, her symptoms eased, and the woman was eventually discharged from the hospital. A month after being discharged, she tested negative for SARS-CoV-2. Surgery for the pituitary tumor was then again possible. Appropriate safeguards were put in place to protect the medical team caring for her from infection, during and after the surgery. The patient didn’t have any noteworthy complications from the surgery, and her cortisol levels soon dropped to within normal limits. She was considered to be in remission. Although broad conclusions cannot be reliably drawn from a single case, the researchers suggested that the patient’s underlying Cushing’s disease may have made her more susceptible to severe pneumonia due to COVID-19. “Since hypercortisolism due to active Cushing’s disease may enhance the severity of COVID-19 infection, it is necessary to provide appropriate, multidisciplinary and prompt treatment,” the researchers wrote. From https://cushingsdiseasenews.com/2021/01/15/covid-19-may-be-severe-cushings-patients-case-report-suggests/?cn-reloaded=1

Dr. Theodore Friedman will host a webinar on COVID-19 Vaccines for Endocrine Patients Dr. Friedman will discuss topics including: How do the vaccines work? What did the New England Journal of Medicine article say about the Pfizer vaccine? What are the different vaccine options? What are the side effects? Who should and shouldn’t get a vaccine? What about Dr. Friedman’s vaccine studies? Sunday • December 27 • 6 PM PST Click here on start your meeting or https://axisconciergemeetings.webex.com/axisconciergemeetings/j.php?MTID=m5085619c25d8a2417d9316b56fe7830b OR Join by phone: (855) 797-9485 Meeting Number (Access Code): 177 542 2496 Your phone/computer will be muted on entry. Slides will be available on the day of the talk here There will be plenty of time for questions using the chat button. Meeting Password: pcos For more information, email us at mail@goodhormonehealth.com

Update November 22, 2020 I have not updated my patients on the COVID-19 pandemic since March. Since the last update and as of today’s date, 12.2 million Americans have been infected with COVID-19 and 256,000 Americans have died. Several of Dr. Friedman’s patients have been infected with COVID-19. Many businesses have closed and there have been major economic loses. The response to the pandemic has unfortunately been politicized and I say unfortunately because the virus doesn’t distinguish based on victim’s political party. Please see Dr. Friedman’s Letter in the Los Angeles Jewish Journal https://jewishjournal.com/letters_to_the_editor/316110/letters-lockdown-vs-no-lockdown/. Dr. Friedman completely supports efforts to limit the spread of the virus, including wearing masks, social distancing, handwashing and staying at home. Listening to government officials including the CDC is crucial. Dr. Friedman agrees with data showing gatherings are much safer outside and encourages his patients to err on the side of safety and caution. Dr. Friedman is spearheading efforts at Charles R. Drew University to be a site for a vaccine study and after some delays, it looks like his University will be a site for the Sanofi vaccine in December 2020. Dr. Friedman is very excited about the promising results from the Moderna and Pfizer trials and thinks vaccines along with mask-wearing and social distancing will curtail the pandemic, hopefully in the latter half of 2021. He does think that COVID-19 will be with us for a long time. Dr. Friedman anticipates that changes due to COVID-19, including telemedicine and working from home will remain with us after the pandemic subsides. As mentioned in the March update, patients with endocrine problems such as Cushing’s syndrome, Addison’s Disease, hypopituitarism and diabetes have slightly impaired immune systems, making them potentially susceptible for a more severe infection by COVID-19. He would recommend those patients to be especially vigilant about mask-wearing/social distancing and to get a vaccine when it comes out. He advices his patients the following: Wear masks, social distancing, handwashing and staying at home as much as possible Use delivery services for groceries, food and medications. Wash hands frequently for 20 seconds and/or use hand sanitizer several times a day Avoid air travel, public gatherings and other public places as guided by local officials Quarantine if sick or exposed. Labcorp and Quest both introduced testing for COVID-19 using nasal swabs. Several other laboratories are also performing tests. Dr. Friedman recommends PCR testing and not rapid antigen testing. For those with symptoms of Coronavirus, he recommends seeing your primary care doctor for testing. Dr. Friedman is unable to provide requisitions or swabs for this testing that should be done by their primary doctor. While Dr. Friedman was initially enthusiastic about antibody testing, he is concerned about the quality of the tests and no longer recommends it. Labcorp and Quest are both still open and Quest has a new Peace of Mind program for lab services not related to COVID-19 and for patients who are 60 years of age or older, or have other conditions that put them at greater risk for COVID-19, in which patients can come to their nearby Quest location during the first hour of each day for VIP care. Dr. Friedman encourages people to get their hormone testing done and make their followup appointments. Many patients have requested extra supply of their medications. However, most insurances do not allow this and carefully monitor medication use. Dr. Friedman recommends patients to use a mail-order pharmacy and sign up for auto-refills so that they get a consistent supply of their medications. Except for patients sick with COVID-19, patients should not up-dose hydrocortisone Dr. Friedman has restarting in person visits on the last Tuesday of each month and continues to see patients via telemedicine on the other Tuesday nights. Please visit goodhormonehealth.com for more information or to schedule an appointment. Dr. Friedman’s staff will still be doing in person growth hormone stimulation tests on Tuesday night in an isolated and sanitized clinic setting. Dr. Friedman especially encourages patients to eat healthy and exercise (especially being outside) including walking, hiking, biking, aerobic videos yoga or pilates at home, during this stressful period. Dr. Friedman encourages patients to get their flu vaccine and the COVID-19 vaccine when available. Everyone should pray that the pandemic ends soon. Dr. Friedman wishes everyone to stay healthy

From message board member @sharm - Sharmyn McGraw: Hi All, I hope you can join us on Zoom this Saturday, Nov. 14, 2020 starting at 9:00 a.m. (PST). For those that can't make it, I will record the meeting and post it later on our Facebook page. I look forward to seeing you! Contact @sharm if you have questions or email her here: pituitarybuddy@hotmail.com

How stressed are you? Your earwax could hold the answer. A new method of collecting and analyzing earwax for levels of the stress hormone cortisol may be a simple and cheap way to track the mental health of people with depression and anxiety. Cortisol is a crucial hormone that spikes when a person is stressed and declines when they're relaxed. In the short-term, the hormone is responsible for the "fight or flight" response, so it's important for survival. But cortisol is often consistently elevated in people with depression and anxiety, and persistent high levels of cortisol can have negative effects on the immune system, blood pressure and other bodily functions. There are other disorders which involve abnormal cortisol, including Cushing's disease (caused by the overproduction of cortisol) and Addison's disease (caused by the underproduction of cortisol). People with Cushing's disease have abnormal fat deposits, weakened immune systems and brittle bones. People with Addison's disease have dangerously low blood pressure. There are a lot of ways to measure cortisol: in saliva, in blood, even in hair. But saliva and blood samples capture only a moment in time, and cortisol fluctuates significantly throughout the day. Even the experience of getting a needle stick to draw blood can increase stress, and thus cortisol levels. Hair samples can provide a snapshot of cortisol over several months instead of several minutes, but hair can be expensive to analyze — and some people don't have much of it. Andrés Herane-Vives, a lecturer at University College London's Institute of Cognitive Neuroscience and Institute of Psychiatry, and his colleagues instead turned to the ear. Earwax is stable and resistant to bacterial contamination, so it can be shipped to a laboratory easily for analysis. It also can hold a record of cortisol levels stretching over weeks. But previous methods of harvesting earwax involved sticking a syringe into the ear and flushing it out with water, which can be slightly painful and stressful. So Herane-Vives and his colleagues developed a swab that, when used, would be no more stressful than a Q-tip. The swab has a shield around the handle, so that people can't stick it too far into their ear and damage their eardrum, and a sponge at the end to collect the wax. In a small pilot study, researchers collected blood, hair and earwax from 37 participants at two different time points. At each collection point, they sampled earwax using a syringe from one ear, and using the new self-swab method from the other. The researchers then compared the reliability of the cortisol measurements from the self-swab earwax with that of the other methods. They found that cortisol was more concentrated in earwax than in hair, making for easier analysis. Analyzing the self-swabbed earwax was also faster and more efficient than analyzing the earwax from the syringe, which had to be dried out before using. Finally, the earwax showed more consistency in cortisol levels compared with the other methods, which were more sensitive to fluctuations caused by things like recent alcohol consumption. Participants also said that self-swabbing was more comfortable than the syringe method. The researchers reported their findings Nov. 2 in the journal Heliyon. Herane-Vives is also starting a company called Trears to market the new method. In the future, he hopes that earwax could also be used to monitor other hormones. The researchers also need to follow up with studies of Asian individuals, who were left out of this pilot study because a significant number only produce dry, flaky earwax as opposed to wet, waxy earwax. "After this successful pilot study, if our device holds up to further scrutiny in larger trials, we hope to transform diagnostics and care for millions of people with depression or cortisol-related conditions such as Addison's disease and Cushing syndrome, and potentially numerous other conditions," he said in a statement. Originally published in Live Science.