Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone

Maria Fleseriu; James W. Findling; Christian A. Koch; Sven Martin Schlaffer; Michael Buchfelder; Coleman Gross

doi:10.1210/jc.2014-1843

Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone

Maria Fleseriu, James W. Findling, Christian A. Koch, Sven Martin Schlaffer, Michael Buchfelder, Coleman Gross

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

Abstract

Context: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood.

Objective: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients.

Design and Setting: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study.

Patients: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study.

Interventions: Mifepristone (300-1200 mg) was administered once daily.

Main Outcome Measures: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment.

Results: A ≥2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 ± 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI.

Conclusions: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable overtime. Corticotroph tumor progression and regression may occur overtime, but patients may have significant increases in ACTH levels without evidence of tumor growth.

Original language	English (US)
Pages (from-to)	3718-3727
Number of pages	10
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	99
Issue number	10
DOIs	https://doi.org/10.1210/jc.2014-1843
State	Published - Oct 1 2014

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Endocrinology
Clinical Biochemistry
Biochemistry, medical

Access to Document

10.1210/jc.2014-1843

Cite this

Fleseriu, M., Findling, J. W., Koch, C. A., Schlaffer, S. M., Buchfelder, M., & Gross, C. (2014). Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. Journal of Clinical Endocrinology and Metabolism, 99(10), 3718-3727. https://doi.org/10.1210/jc.2014-1843

Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. / Fleseriu, Maria; Findling, James W.; Koch, Christian A. et al.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 10, 01.10.2014, p. 3718-3727.

Research output: Contribution to journal › Article › peer-review

Fleseriu, M, Findling, JW, Koch, CA, Schlaffer, SM, Buchfelder, M & Gross, C 2014, 'Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone', Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 10, pp. 3718-3727. https://doi.org/10.1210/jc.2014-1843

@article{91bbe11e33c04443acd910b1ac75678c,

title = "Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone",

abstract = "Context: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood.Objective: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients.Design and Setting: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study.Patients: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study.Interventions: Mifepristone (300-1200 mg) was administered once daily.Main Outcome Measures: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment.Results: A ≥2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 ± 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI.Conclusions: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable overtime. Corticotroph tumor progression and regression may occur overtime, but patients may have significant increases in ACTH levels without evidence of tumor growth.",

author = "Maria Fleseriu and Findling, {James W.} and Koch, {Christian A.} and Schlaffer, {Sven Martin} and Michael Buchfelder and Coleman Gross",

note = "Publisher Copyright: Copyright {\textcopyright} 2014 by the Endocrine Society.",

year = "2014",

month = oct,

day = "1",

doi = "10.1210/jc.2014-1843",

language = "English (US)",

volume = "99",

pages = "3718--3727",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "The Endocrine Society",

number = "10",

}

TY - JOUR

T1 - Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone

AU - Fleseriu, Maria

AU - Findling, James W.

AU - Koch, Christian A.

AU - Schlaffer, Sven Martin

AU - Buchfelder, Michael

AU - Gross, Coleman

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Context: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood.Objective: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients.Design and Setting: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study.Patients: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study.Interventions: Mifepristone (300-1200 mg) was administered once daily.Main Outcome Measures: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment.Results: A ≥2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 ± 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI.Conclusions: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable overtime. Corticotroph tumor progression and regression may occur overtime, but patients may have significant increases in ACTH levels without evidence of tumor growth.

AB - Context: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood.Objective: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients.Design and Setting: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study.Patients: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study.Interventions: Mifepristone (300-1200 mg) was administered once daily.Main Outcome Measures: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment.Results: A ≥2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 ± 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI.Conclusions: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable overtime. Corticotroph tumor progression and regression may occur overtime, but patients may have significant increases in ACTH levels without evidence of tumor growth.

UR - http://www.scopus.com/inward/record.url?scp=84907662217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907662217&partnerID=8YFLogxK

U2 - 10.1210/jc.2014-1843

DO - 10.1210/jc.2014-1843

M3 - Article

C2 - 25013998

AN - SCOPUS:84907662217

SN - 0021-972X

VL - 99

SP - 3718

EP - 3727

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 10

ER -

Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this