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Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing's Syndrome
Abstract
CONTEXT: Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations. OBJECTIVE: Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS. DESIGN AND SETTING: 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. PARTICIPANTS: 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). INTERVENTION: Mifepristone was administered at doses of 300-1200 mg daily. MAIN OUTCOME MEASURES: 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. RESULTS: In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P < 0.0001). 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). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). Mean weight change was -5.7 ± 7.4% (P < 0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P < 0.001) in women and -8.44 ± 5.9 cm (P < 0.001) in men. Overall, 87% (P < 0.0001) had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women. CONCLUSIONS: Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.
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“Overt adrenal insufficiency is rare under treatment with mifepristone (326).”
From Adrenocortical carcinoma (2014) · cites this paper as [326]
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BackgroundMethodPotential functional and pathological side effects related to off-target pharmacological activity
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“The progestin effect of PR ligands can be assayed by the standard McPhail test (endometrial changes assessed after treatment of estrogen-primed rabbits) or more contemporary methods that assess in vitro transcriptional activity(167,168) Mifepristone is a PR ligand with pure antagonist activity that also has antiglucoc…”
MethodCOVID-19 and the Endocrine System: A Comprehensive Review on the Theme
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“After 24 weeks of mifepristone treatment, fasting plasma glucose and HbA1c decreased, respectively, from 8.3 ± 4.1 to 5.8 ± 2.1 mmol/L and from 7.43 ± 1.52 to 6.29 ± 0.99%, leading to a reduction in the number of antidiabetic medications the patients were taking (99).”
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BackgroundAn individualized approach to the management of Cushing disease
Fleseriu, M., Varlamov, E., Hinojosa-Amaya, J. M., Langlois, F., & Melmed, S. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00868-7 · Cited by 59
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“fepristone is a glucocorticoid-receptor antagonist shown to produce clinical and metabolic benefits in patients with Cushing’s disease over 6 months [123].”
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“This often necessitates the use of spironolactone and/or potassium replacement (103).”
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Glucocorticoid Withdrawal Syndrome following treatment of endogenous Cushing Syndrome
He, X., Findling, J. W., & Auchus, R. J. (2022) · Pituitary · doi:10.1007/s11102-022-01218-y · Cited by 68
Self-citationFleseriu, M., Molitch, M., Gross, C., Schteingart, D., Vaughan, T. B., & Biller, B. (2013) · Endocrine Practice · doi:10.4158/ep12149.ra · Cited by 55
Self-citationDebono, M., Chadarévian, R., Eastell, R., Ross, R. J. M., & Newell-Price, J. D. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060984 · Cited by 60
“These data support recent findings in a study in patients with overt Cushing’s syndrome where an improvement in insulin AUC and HOMA-IR was shown in the combined diabetes mellitus/impaired glucose tolerance and hypertension groups [12].”
BackgroundResultAcute stress is detrimental to heart regeneration in zebrafish
Sallin, P., & Jaźwińska, A. (2016) · Open Biology · doi:10.1098/rsob.160012 · Cited by 61
Future directions in the diagnosis and medical treatment of adrenocortical carcinoma
Creemers, S. G., Hofland, L. J., Korpershoek, E., Franssen, G. J. H., van Kemenade, F. J., de Herder, W. W., & Feelders, R. A. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0452 · Cited by 61
“Mifepristone, a glucocorticoid receptor antagonist, is another treatment modality for excess cortisol levels (Fleseriu et al. 2012).”
BackgroundVarlamov, E. V., Langlois, F., Vila, G., & Fleseriu, M. (2021) · European Journal of Endocrinology · doi:10.1530/eje-20-1309 · Cited by 58
Self-citationHu, P., Oomen, C. A., van Dam, A., Wester, J., Zhou, J., Joëls, M., & Lucassen, P. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046224 · Cited by 58
“We nevertheless decided to use this drug, to allow easy comparison with earlier studies in rats and men [11,12,13,14,35,36,51,52,53,54,55,56,57].”
Treatment of Cushing's disease: a mechanistic update
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Self-citationGlucocorticoid excess and COVID-19 disease
Guarnotta, V., Ferrigno, R., Martino, M., Barbot, M., Isidori, A. M., Scaroni, C. M., Ferrante, A., Arnaldi, G., Pivonello, R., & Giordano, C. S. D. S. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-020-09598-x · Cited by 59
Mifepristone for Management of C ushing's Syndrome
Morgan, F. H., & Laufgraben, M. J. (2013) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1202 · Cited by 56
“In the patients with Cushing’s disease, magnetic resonance imaging demonstrated stability of the pituitary tumor, with the exception of one patient with an aggressive tumor.(37) Limitations of this multicenter study include a relatively high dropout rate, lack of a placebo group, short study duration, and open-label d…”
BackgroundMethodInfluentialCurrent management of Cushing's disease
Tritos, N. A., & Biller, B. M. K. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12975 · Cited by 56
Self-citationStructural insights into glucocorticoid receptor function
Frank, F., Ortlund, E. A., & Liu, X. (2021) · Biochemical Society Transactions · doi:10.1042/bst20210419 · Cited by 55
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“The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome demonstrated improvement in diabetes and hypertension in 60% and 40% of CS patients, respectively [249].”
BackgroundMethodKeller-Wood, M., Feng, X.-D., Wood, C., Richards, E., Anthony, R., Dahl, G., & Tao, S. (2014) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00530.2013 · Cited by 51
Therapeutic Strategies for the Treatment of Severe Cushing’s Syndrome
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“Mifepristone binds to GR with an 18-fold higher affinity than cortisol [53], resulting in a loss of negative feedback effects at the HPA by cortisol, leading to an increase in ACTH secretion in CD with a concomitantly increased cortisol production [23].”
Impact of Adrenal Steroids on Regulation of Adipose Tissue
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“tion in glycated hemoglobin (HbA1c) and fasting plasma glucose levels in patients with endogenous CS treated over a 6-month period (the SEISMIC study) (74).”
Cushing's disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment.
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Simeoli, C., Auriemma, R. S., Tortora, F., Leo, M. D., Iacuaniello, D., Cozzolino, A., Martino, M. C. D., Pivonello, C., Mainolfi, C. G., Rossi, R., et al. (2015) · Endocrine · doi:10.1007/s12020-015-0557-2 · Cited by 50
Fallo, F., Dalmazi, G. D., Beuschlein, F., Biermasz, N. R., Castinetti, F., Elenkova, A. P., Faßnacht, M., Isidori, A. M., Kaštelan, D., Korbonits, M., et al. (2022) · Journal of Hypertension · doi:10.1097/hjh.0000000000003252 · Cited by 48
“However, in larger cohorts of Cushing’s syndrome patients, hypertension was an adverse event of treatment with ketoconazole alone, metyrapone alone, or with their combination in 48% of the cases overall [189], with osilodrostat in 12% [171], and with mifepristone in 24% [190].”
BackgroundResetting the Stress System with a Mifepristone Challenge
Dalm, S., Karssen, A. M., Meijer, O. C., Belanoff, J. K., & de Kloet, E. R. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0614-5 · Cited by 47
Hypertension and Cardiovascular Mortality in Patients with Cushing Syndrome
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Quality of Life in Patients With Cushing's Disease
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“Twenty-four-week treatment with mifepristone in CS has also been shown to improve the mental and physical scores of SF-36 and depression, measured by BDI-II (48).”
MethodWang, J., Chen, J., Wan, L., Shao, J., Lu, Y., Zhu, Y., Ou, M., Yu, S., Chen, H., & Jia, L. (2014) · The AAPS Journal · doi:10.1208/s12248-013-9559-2 · Cited by 47
“mifepristone, may be a good candidate for further investigation for the following reasons: (1) The patentable metapristone is the primary metabolite of mifepristone.”
InfluentialEGFR Induces E2F1-Mediated Corticotroph Tumorigenesis
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Cushing’s Syndrome Effects on the Thyroid
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“A clinical trial evaluating the safety and efficacy of mifepristone in endogenous CS found that eight of 42 patients had reversible increases in TSH during the treatment [73], which normalized six weeks after mifepristone discontinuation.”
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Modern management of mild autonomous cortisol secretion
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“Several large prospective studies are currently ongoing within the ENSAT community and in the United States.6,71 In the future, it is likely that in order to individualize therapy, a panel of multiple noninvasive biomarkers will be used to accurately diagnose patients with clinically relevant MACS.”
BackgroundInfluentialGlobal clinical response in C ushing's syndrome patients treated with mifepristone
Katznelson, L. J., Loriaux, D. L., Feldman, D., Braunstein, G. D., SCHTEINGART, D. E., & Gross, C. (2013) · Clinical Endocrinology · doi:10.1111/cen.12332 · Cited by 45
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Self-citation
Metadata
- Authors
- Fleseriu, M., Biller, B. M. K., Findling, J. W., Molitch, M. E., Schteingart, D. E., Gross, C., on behalf of the SEISMIC Study Investigators, The SEISMIC Study Investigators include, Auchus, R., Bailey, T., Biller, B. M. K., Carroll, T., Colleran, K., Fein, H., Findling, J. W., Fleseriu, M., Hamrahian, A., Katznelson, L., Kerr, J., Kipnes, M., Kirschner, L., Koch, C., Lerman, S., Lyons, T., McPhaul, M., Molitch, M. E., Schteingart, D. E., Vaughan, T. B., & Weiss, R.
- Affiliations
- Corcept Therapeutics (United States) (US)
- The University of Texas Southwestern Medical Center (US)
- AMCR Institute (US)
- Massachusetts General Hospital (US)
- Medical College of Wisconsin (US)
- Oregon Health & Science University (US)
- Cleveland Clinic (US)
- Northwestern University (US)
- The Ohio State University Wexner Medical Center (US)
- University of Mississippi Medical Center (US)
- University of Michigan (US)
- University of Alabama at Birmingham (US)
- University of Chicago (US)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-06-01
- Volume
- 97
- Issue
- 6
- Pages
- 2039-2049
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2021271765
- Semantic Scholar
- 40d98664c0987b1bdf2cbb43dbea52247bf04f70
- Cited by
- 479
- References
- 45
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 22 · 2023: 28 · 2022: 33 · 2021: 29 · 2020: 30 · 2019: 41 · 2018: 35 · 2017: 35 · 2016: 38 · 2015: 45 · 2014: 39 · 2013: 39 · 2012: 16
- FWCI
- 35.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- mifepristone, Cushing's syndrome, glucocorticoid receptor antagonist, type 2 diabetes, impaired glucose tolerance, hypertension, glycemic control, HbA1c, insulin resistance, blood pressure, weight loss, waist circumference, adverse events, drug safety, quality of life, depression, cognitive function
- MeSH terms
- Adult, Antihypertensive Agents, Blood Glucose, Blood Pressure, Body Composition, Body Weight, Cushing Syndrome, Diabetes Mellitus, Type 2, Female, Hormone Antagonists, Humans, Hydrocortisone, Hypertension, Male, Middle Aged, Quality of Life, Quinolines, Receptors, Glucocorticoid, Urea, Mifepristone, Glucose Intolerance
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