A new therapeutic approach in the medical treatment of Cushing's syndrome: glucocorticoid receptor blockade with mifepristone. Hypokalemia was often associated with alkalosis and edema and generally responded to potassium replacement (10–420 mEq daily); all nonpituitary CS patients received potassium supplementation. is an employee of Corcept Therapeutics, Inc. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. DNA binding properties of glucocorticosteroid receptors bound to the steroid antagonist RU-486. In this review, we summarize the results of mifepristone reported in the literature as a treatment of Cushing's syndrome. In this review, we summarize the results of mifepristone reported in the literature as a treatment of Cushing's syndrome. Safety indicators of a novel multi supplement based on guarana, selenium, and L-carnitine: evidence from human and red earthworm immune cells. are consultants to and serve as investigators on research grants to their institutions from Novartis. 4B). Main outcome measures: Global clinical response in Cushing's syndrome patients treated with mifepristone. For patients with at least mild depression at baseline (BDI-II ≥ 14, n = 24), median BDI-II scores improved from 23 (range 14–49) to 12 (range 0–34) (P < 0.001). 22 Citations for Mifepristone. Long-term data are needed to further define the role of mifepristone in the medical treatment of CS. National Library of Medicine This likely explains the increased blood pressure, hypokalemia, edema, and alkalosis seen in some patients; nine of the 12 patients with increased blood pressure were prescribed spironolactone. Late recurrence of operated adrenocortical carcinoma: atrial natriuretic factor before and after treatment with mitotane. Privacy, Help They include direct glucocorticoid receptor antagonists such as mifepristone and synthesis inhibitors such as metyrapone, ketoconazole, and aminoglutethimide. Four (one adrenal cancer and three ectopic ACTH) of seven patients with nonpituitary CS experienced hypokalemia during treatment. Mifepristone, when used together with prostaglandin E1 (misoprostol), is used to end an early pregnancy (49 days or less since the last menstrual period began). Clinically significant improvement was seen in 87% of patients, according to well-defined criteria used by the DRB. Fleseriu M, Molitch ME, Gross C, Schteingart DE, Vaughan TB 3rd, Biller BM. Reversible decreases in high-density lipoprotein cholesterol (HDL-C) and increases in TSH were observed. Pharmacological properties of mifepristone: toxicology and safety in animal and human studies. Because high cortisol may not be completely inactivated by 11β-hydroxysteroid dehydrogenase type 2 in the kidney, excess cortisol may activate the mineralocorticoid receptor (41). Although the side effect profile over 6 months is well characterized and manageable with additional medications, the long-term efficacy and safety remain to be determined, particularly with regard to the need for potassium supplementation and/or mineralocorticoid receptor blockade and endometrial monitoring. Treatment began at 300 mg/d; if no significant clinical improvement was noted by the investigator, doses could be increased to 600 mg/d on d 14, 900 mg/d at wk 6, and 1200 mg/d at wk 10. Our findings indicate that mifepristone may act as a glucocorticoid antagonist to augment uNK cell-mediated cytotoxicity through the ERK pathway. Epub 2020 Dec 4. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women. In addition to the 21 C-HT patients, 19 C-DM patients had a diagnosis of HTN at study entry; 42.5% (17 of 40) of these had a reduction in DBP of at least 5 mm Hg at wk 24/ET compared with baseline, and 27.5% had reductions in antihypertensive medications (50% of patients with a diagnosis of HTN were taking at least two antihypertensive medications at baseline). Mifepristone is a progestational and glucocorticoid hormone antagonist. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, Merits and pitfalls of mifepristone in Cushing's syndrome. Mean data are shown. Secondary endpoint results were noteworthy: mifepristone significantly decreased body weight, waist circumference, and body fat and increased insulin sensitivity. Indirect evidence comes from in vitro studies showing that the glucocorticoid induced up‐regulation of CXCR4 on T cells is blocked by the GR antagonist mifepristone (RU486; refs. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. With the exception of a very aggressive tumor in one patient, there were no increases in tumor size, but it is important to note that the study duration was only 6 months. Dexamethasone doses for these episodes ranged from 2–8 mg daily in tapering amounts for 1–12 d. Vaginal bleeding was observed during the study in five premenopausal women. Drugs in the medical treatment of Cushing's syndrome. Three patients had a nonsustained improvement (median score of +1 decreased to 0 at wk 24 or ET). J Clin Endocrinol Metab. Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment. The use of mifepristone in CS has been explored in case reports and/or small retrospective studies (9, 12–25). Data are shown as mean ± sd. It is important to note that cortisol elevations that occur in CD could be misleading and render the diagnosis of AI difficult. Hirsutism: implications, etiology and management. Fleseriu M, Findling JW, Koch CA, Schlaffer SM, Buchfelder M, Gross C. J Clin Endocrinol Metab. Interruptions or reductions in mifepristone due to AEs, most commonly nausea (n = 6), occurred in 40% of patients; there were interruptions or reductions for protocol-specified events in four subjects (two for AI, one for severe hypokalemia, and one for vaginal bleeding). It does Mifepristone was administered at doses of 300-1200 mg daily. Mifepristone (also known as RU -486, a GR antagonist; Sigma-Aldrich, St. Louis, MO, USA) and spironolactone (an MR antago-nist;Sigma-Aldrich),solvedinpolyethyleneglycol(Sigma-Aldrich) andethanol(1:10dilution),were usedat concentrations of 100 and 75 mg/kg bodyweight, respectively, as previously described (30). 2014 Apr;80(4):562-9. doi: 10.1111/cen.12332. Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P < 0.001); fasting plasma glucose decreased from 149.0 ± 75.7 mg/dl (8.3 ± 4.1 mmol/liter) to 104.7 ± 37.5 mg/dl (5.8 ± 2.1 mmol/liter, P < 0.03). Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. Regulation of the EGFR Pathway by HSP90 Is Involved in the Pathogenesis of Cushing's Disease. eCollection 2020. Antidiabetic medications were reduced in seven of 15 patients. 2, 15 January 1991 (1991-01-15), page 143/144, XP002041041 ISSN: 0003-4819 CHU J W ET AL: "Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone … Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment. Pharmacotherapy. All drafts of the manuscript were written and reviewed by all the authors. Mean percent total body fat declined by 3.6% by wk 24 (P < 0.001). Front Endocrinol (Lausanne). 2). Surgery for Cushing's syndrome: an historical review and recent ten-year experience. Mifepristone effects on tumor somatostatin receptor expression in two patients with Cushing's syndrome due to ectopic adrenocorticotropin secretion. Twenty-two patients had a serum potassium level less than 3.5 mEq/liter (<3.5 mmol/liter), but only three experienced severe hypokalemia [≤2.5 mEq/liter (≤2.5 mmol/liter)] during mifepristone treatment, including one serious AE [potassium 2.1 mEq/liter (2.1 mmol/liter)]. Would you like email updates of new search results? Damage evaluation of HAp-coated porous titanium foam in simulated body fluid based on compression fatigue behavior. 1 … In the C-HT mITT cohort, eight of 21) patients (38.1% achieved the primary endpoint of at least 5 mm Hg decline in DBP (95% CI lower bound 21%, P < 0.05; Table 3). Approach to the patient with possible Cushing's syndrome. Endometrial thickening was reported as an AE in 10 women. 9 , 12 , 13 ). Of 12 patients taking insulin, five reduced their daily dose by at least half. Joseph L. Mayer. The dosing scheme allowing investigators to use their clinical judgment regarding increasing mifepristone based on benefit vs. tolerance produced heterogeneity in management, which is a limitation of the study. One patient was rated as being worse at the final visit (early termination at wk 10) than at baseline. Epub 2013 Feb 21. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Vet Intern Med. A comparison of current acne grading systems and proposal of a novel system. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary cushing syndrome. 2020 Oct 29;6(1):18. doi: 10.1186/s40842-020-00105-4. 2013 Mar;33(3):319-29. doi: 10.1002/phar.1202. Zhang C, Dong X, Mao W, Wang C, Ma B, Hu L, Chen R. Am J Transl Res. The most common doses among responders at wk 24/ET were 600 mg (40%) and 1200 mg (40%), followed by 300 mg (13.3%) and 900 mg (6.7%). 2021 Feb 15;13(2):684-695. eCollection 2021. CORT108297 is a second-generation glucocorticoid receptor antagonist which has no affinity for the PR and is proposed for a Phase IIa clinical trial in Veterans with PTSD. Hypokalemia occurred in patients with both ACTH-dependent and independent CS. Context: LELY VAN DER A-J ET AL: "RAPID REVERSAL OF ACUTE PSYCHOSIS IN THE CUSHING SYNDROME WITH THE CORTISOL-RECEPTOR ANTAGONIST MIFEPRISTONE (RU 486)" ANNALS OF INTERNAL MEDICINE, NEW YORK, NY; US, US, vol. Four patients (two responders) received spironolactone during the study; one nonresponder was on spironolactone at entry and remained on a stable dose throughout the study. Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS. MRIs were stable at wk 10 and 24 in all cases except one. Keywords: Mifepristone, Mifepristone supplier, Glucocorticoid, progesterone, antagonists, glucocorticoid, Receptors, RU486, RU38486, RU, 486, 38486, Progesterone, Receptor, 1479, Tocris Bioscience. Morbidity and mortality in patients with CD are related to cortisol excess and rarely to the ACTH-secreting pituitary tumor mass. Early research on steroidal ligands which led to the identification of the non-selective GR antagonist RU-486 (mifepristone) and the GR-selective steroid RU-43044 is reviewed as is subsequent work on related steroidal compounds. Disclosure Summary: B.M.K.B., J.W.F., and M.E.M. An antiglucocorticoid is a drug which reduces glucocorticoid activity in the body. 8600 Rockville Pike homeostatic model assessment of insulin resistance, Clayton RN , Raskauskiene D , Reulen RC , Jones PW, Lindholm J , Juul S , Jørgensen JO , Astrup J , Bjerre P , Feldt-Rasmussen U , Hagen C , Jørgensen J , Kosteljanetz M , Kristensen L , Laurberg P , Schmidt K , Weeke J, Biller BM , Grossman AB , Stewart PM , Melmed S , Bertagna X , Bertherat J , Buchfelder M , Colao A , Hermus AR , Hofland LJ , Klibanski A , Lacroix A , Lindsay JR , Newell-Price J , Nieman LK , Petersenn S , Sonino N , Stalla GK , Swearingen B , Vance ML , Wass JA , Boscaro M, Pivonello R , De Martino MC , De Leo M , Lombardi G , Colao A, Castinetti F , Conte-Devolx B , Brue T, Heikinheimo O , Kontula K , Croxatto H , Spitz I , Luukkainen T , Lähteenmäki P, Beaufrère B , de Parscau L , Chatelain P , Morel Y , Aguercif M , Francois R, Bertagna X , Bertagna C , Laudat MH , Husson JM , Girard F , Luton JP, Chrousos GP , Laue L , Nieman LK , Udelsman R , Kawai S , Loriaux DL, Nieman LK , Udelsman R , Loriaux DL , Chrousos GP, Nieman LK , Chrousos GP , Kellner C , Spitz IM , Nisula BC , Cutler GB , Merriam GR , Bardin CW , Loriaux DL, Chu JW , Matthias DF , Belanoff J , Schatzberg A , Hoffman AR , Feldman D, van der Lely AJ , Foeken K , van der Mast RC , Lamberts SW, Newfield RS , Spitz IM , Isacson C , New MI, Oosterhuis JK , van den Berg G , Monteban-Kooistra WE , Ligtenberg JJ , Tulleken JE , Meertens JH , Zijlstra JG, Cassier PA , Abou-Amara-Olivieri S , Artru P , Lapalus MG , Riou JP , Lombard-Bohas C, Donckier JE , Michel LA , Berbinschi A , De Coster PM , De Plaen JF , Ketelslegers JM , Buysschaert M, Bilgin YM , van der Wiel HE , Fischer HR , De Herder WW, Castinetti F , Fassnacht M , Johanssen S , Terzolo M , Bouchard P , Chanson P , Do Cao C , Morange I , Picó A , Ouzounian S , Young J , Hahner S , Brue T , Allolio B , Conte-Devolx B, de Bruin C , Hofland LJ , Nieman LK , van Koetsveld PM , Waaijers AM , Sprij-Mooij DM , van Essen M , Lamberts SW , de Herder WW , Feelders RA, Schernthaner G , Matthews DR , Charbonnel B , Hanefeld M , Brunetti P, Hatch R , Rosenfield RL , Kim MH , Tredway D, Ware JE , Kosinski M , Bjorner JB , Turner-Bowker DM , Gandek B , Maruish ME, Matthews DR , Hosker JP , Rudenski AS , Naylor BA , Treacher DF , Turner RC, Nieman LK , Biller BM , Findling JW , Newell-Price J , Savage MO , Stewart PM , Montori VM, Assié G , Bahurel H , Coste J , Silvera S , Kujas M , Dugué MA , Karray F , Dousset B , Bertherat J , Legmann P , Bertagna X, Porterfield JR , Thompson GB , Young WF , Chow JT , Fryrear RS , van Heerden JA , Farley DR , Atkinson JL , Meyer FB , Abboud CF , Nippoldt TB , Natt N , Erickson D , Vella A , Carpenter PC , Richards M , Carney JA , Larson D , Schleck C , Churchward M , Grant CS, Mutter GL , Bergeron C , Deligdisch L , Ferenczy A , Glant M , Merino M , Williams AR , Blithe DL, Oxford University Press is a department of the University of Oxford. 126 Mifeprisone has high clinical … Because of its antiprogesterone effects, mifepristone has an impact on the endometrium characterized by thickening, with cystically dilated endometrial glands and features usually seen separately in normal proliferative and secretory endometrium (42). 2012; 97(6):2039-49 (ISSN: 1945-7197) Mifepristone, a glucocorticoid receptor antagonist, provides a novel approach to the treatment of hypercortisolism. Intervention: Seven patients discontinued mifepristone because of an AE; fatigue was the only cause of discontinuation for more than one patient (n = 2). It may also decrease quality of life (5, 37) and can result in an enlargement of an ACTH-secreting pituitary tumor in 15–20% of cases (38). Affiliations. This was a 24-wk, open-label, multicenter study of mifepristone administered as a single daily oral dose. Rapid reversal of acute psychosis in the Cushing syndrome with the cortisol-receptor antagonist mifepristone (RU 486). Cortisol, 11beta-hydroxysteroid dehydrogenases, and hypertension. ClinicalTrials.gov NCT00569582. Prevention and treatment information (HHS). Data are shown as mean ± se. Shen Y, Ji C, Jian X, Zhou J, Zhang Q, Qiao N, Zhang Y, Shou X, Zhou X, Ma Z. 4C). COVID-19 is an emerging, rapidly evolving situation. Glucocorticoid Receptor Antagonist Mifepristone, supplied by Millipore, used in various techniques. However, overall, there was no change in mean blood pressure from baseline to end of study. 2021 Jan 18;11:601984. doi: 10.3389/fendo.2020.601984. The mean change in HDL-C from baseline [62.3 ± 27.8 mg/dl (1.61 ± 0.72 mmol/liter)] to wk 24/ET was −14.2 ± 11.9 mg/dl (0.37 ± 0.31 mmol/liter) (P < 0.001); there were small declines in low-density lipoprotein cholesterol and triglycerides that were not statistically significant. Mifepristone is a progesterone and glucocorticoid antagonist that was approved as an abortifacient in many countries. When surgery fails to reverse hypercortisolemia, medical treatment can suppress cortisol overproduction and improve clinical manifestations. Data from longer-term use of mifepristone will be required to determine whether this risk is similar to that after bilateral adrenalectomy (38). Trial registration: Our previous studies demonstrated that mifepristone directly augments the cytotoxicity of human uterine natural killer (uNK) cells. Data are shown as mean ± sd. Bethesda, MD 20894, Copyright Mifepristone is the first and only available glucocorticoid receptor antagonist. Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. Late-night salivary cortisol increased 7.92-fold (1.43) at wk 16, and urinary free cortisol increased 7.70-fold (15.29) at wk 24/ET. and J.L.M. The mean baseline HbA1c of 7.43 ± 1.52% in the C-DM group decreased to 6.29 ± 0.99% at wk 24/ET (P < 0.001) (Fig. The treatment of Cushing's syndrome is far from perfect. Here, we scrutinized the notion that the morning decline in blood T‐cell numbers is mediated via GR‐induced up‐regulation of CXCR4 in humans. Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT). We evaluated the antagonistic effects of Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. Title: Glucocorticoid Receptor Antagonists VOLUME: 8 ISSUE: 9 Author(s):Robin D. Clark Affiliation:Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA. Patients with ectopic ACTH-secreting neoplasms or adrenocortical carcinoma often require control of hypercortisolism while waiting for definitive therapy or if definitive therapy is not feasible (39). A, Significant decreases in AUCglucose were observed in the C-DM cohort from baseline to each subsequent visit including wk 24/ET (P < 0.001). 2015 Oct 27;15:63. doi: 10.1186/s12902-015-0059-5. Mifepristone (oral, once daily dosing) is the only currently available drug falling under the glucocorticoid receptor antagonist category, Table 15.4. We conducted a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers. Brown DR, East HE, Eilerman BS, Gordon MB, King EE, Knecht LA, Salke B, Samson SL, Yuen KCJ, Yau H. Clin Diabetes Endocrinol. 126 Mifepristone is a glucocorticoid (and progestin) antagonist, which is approved in the United States for treatment of glucose intolerance in patients with CS with nonresectable tumors or who are not surgical candidates. Epub 2014 Jul 11. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. Clinical efficacy and safety of cefiderocol in the treatment of acute bacterial infections: a systematic review and meta-analysis of randomized controlled trials. Because mifepristone does not decrease cortisol production, measurement of this hormone should not be performed during treatment; careful monitoring by clinicians familiar with the mechanism of action of this unique agent is essential. Quality of life improved at wk 24/ET as measured by SF-36 mental composite scores (mean 40.0 ± 14.5 vs. 45.4 ± 12.5, P = 0.01) and physical composite scores (mean 34.9 ± 11.0 vs. 39.1 ± 10.8, P = 0.02). Ten women had AE of endometrial thickening, and abnormal vaginal bleeding occurred in five patients. Bioz Stars score: 99/100, based on 6 PubMed citations. During mifepristone treatment, 72% of the 43 patients with CD had at least a 2-fold increase in ACTH, cortisol, or both; 28% had smaller increases. Eight patients had undetectable TSH at baseline; of the remaining 42 patients, eight had increases in TSH above normal (three with TSH > 10 μU/liter, one with TSH of 32 μU/liter). This study was supported by Corcept Therapeutics. 2 and Table 3). Similar reductions in AUCglucose were observed in the C-DM ITT and completer populations. 3A). Purpose of review Mifepristone is the first and only available glucocorticoid receptor antagonist. IC 50 & Target IC50: 0.2 nM (progesterone receptor, in T47D cells), 2.6 nM (glucocorticoid receptor, in A549 cells) [1] Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials. Mifepristone, also known as RU-486, ... 1980, as part of a formal research project at the French pharmaceutical company Roussel-Uclaf for the development of glucocorticoid receptor antagonists, chemist Georges Teutsch synthesized mifepristone (RU-38486, the 38,486th compound synthesized by Roussel-Uclaf from 1949 to 1980; shortened to RU-486), which was discovered to also be a … This is the largest prospective multicenter trial of mifepristone and demonstrates effectiveness in treating the clinical and metabolic derangements associated with hypercortisolism. 2020 Dec 8;11:648. doi: 10.3389/fendo.2020.00648. Pituitary MRIs were obtained in 41 CD patients; 17 had visible tumors, 10 of which were macroadenomas, and the remaining 24 did not have demonstrable tumors after surgery. Similarly, interruptions or reduction in the dose of mifepristone to manage AE produced additional dosing pattern heterogeneity. Patients with ectopic ACTH secretion did not demonstrate increases in ACTH and cortisol in response to mifepristone. Keywords:Glucocorticoid receptor antagonist, GR antagonist, nuclear receptor, mifepristone Abstract: This review covers recent progress in the discovery of selective glucocorticoid receptor (GR) antagonists. We evaluated change in area under the curve for glucose on 2-h oral glucose test for C-DM and change in diastolic blood pressure from baseline to wk 24 for C-HT. Mifepristone (11 -[P-(dimethylamino)phenyl]-17 - hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) is a pro-gesterone receptor antagonist that has glucocorticoid re-ceptor antagonist activity at higher concentrations, with more than three times the binding affinity for the gluco-corticoid receptor than dexamethasone (10, 11). Design and setting: served as investigators on research grants to their institutions from Corcept Therapeutics, Inc. C.G. Endocrine clinical update: where are we in the therapeutic management of pituitary-dependent hypercortisolism. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress. Its relative binding affinity at the progesterone receptor is twice that of progesterone, its affinity at the glucocorticoid receptor is 3x that of dexamethasone, and more than 10 times that of cortisol (1). Eighteen of 25 C-DM patients (72%) had at least a 25% reduction from baseline in AUCglucose or a reduction in antidiabetic medication (95% CI = 50.6–87.9%). Mifepristone, when used together with prostaglandin E1 (misoprostol), is used to end an early pregnancy (49 days or less since the last menstrual period began). Changes in weight and body composition. Significant decreases in FPG and HbA1c occurred in the C-DM cohort, and more than half the hypertensive patients in both groups had either an improvement in DBP or a reduction in antihypertensive medication. Waist circumference decreased by −6.8 ± 5.8 cm (P < 0.001) in women and −8.4 ± 5.9 cm in men (P < 0.001) (Fig. Mifepristone (RU486) is a progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist with IC 50 s of 0.2 nM and 2.6 nM in in vitro assay. Sustained weight loss in patients treated with mifepristone for Cushing's syndrome: a follow-up analysis of the SEISMIC study and long-term extension. 3C). Read "A glucocorticoid antagonist, mifepristone affects anti‐Candida activity of murine neutrophils in the presence of prednisolone in vitro and experimental candidiasis of prednisolone‐treated mice in vivo, Pathogens and Disease" on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Although clinically significant AI is a potential side effect of glucocorticoid receptor antagonism (9), it was uncommon during this study. The two primary study endpoints were met: mifepristone significantly decreased AUCglucose during oGTT in patients with CS and T2DM or IGT and decreased DBP in a significant number of patients with CS and HTN. are consultants to Corcept Therapeutics, Inc. Mifepristone is a competitive glucocorticoid receptor antagonist and progesterone receptor antagonist that is associated with several treatment effects and adverse events that clinicians need to be aware of when considering its use. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). The overall clinical improvement response rate as assessed by the DRB in the mITT population was 87% (95% CI lower bound 76%, P < 0.0001); response rates were similar in the C-DM and C-HT cohorts (Table 3). It was initially mainly considered as a so-called 'contragestive' pill due to its antiprogestin activity. The SEISMIC Study Investigators include Richard Auchus, University of Texas Southwestern Medical Center, Dallas, TX; Timothy Bailey, AMCR Institute Inc., Escondido, CA; Beverly M. K. Biller, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Ty Carroll, Medical College of Wisconsin, Milwaukee, WI; Kathleen Colleran, University of New Mexico Health Sciences Center, Albuquerque, NM; Henry Fein, Sinai Hospital of Baltimore, Baltimore, MD; James W. Findling, Medical College of Wisconsin, Milwaukee, WI; Maria Fleseriu, Oregon Health & Science University, Portland, OR; Amir Hamrahian, Cleveland Clinic Foundation, Cleveland, OH; Laurence Katznelson, Stanford University Medical Center, Stanford, CA; Janice Kerr, University of Colorado Health Science Center at Fitzsimon, Aurora, CO; Mark Kipnes, Cetero Research/Diabetes and Glandular Disease Research, San Antonio, TX; Lawrence Kirschner, Ohio State University Medical Center, Columbus, OH; Christian Koch, University of Mississippi Medical Center, Jackson, MS; Sam Lerman, The Center for Diabetes and Endocrine Care, Hollywood, FL; Timothy Lyons, Oklahoma University Health Science Center, Oklahoma City, OK; Michael McPhaul, University of Texas Southwestern Medical Center, Dallas, TX; Mark E. Molitch, Northwestern University Feinberg Medical, Chicago, IL; David E. Schteingart, University of Michigan Medical Center, Ann Arbor, MI; T. Brooks Vaughan III, University of Alabama at Birmingham School of Medicine, Birmingham, AL; and Roy Weiss, The University of Chicago, Chicago, IL. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline. Four patients experienced progression of preexisting metastatic malignancy that resulted in death.