European Journal of Endocrinology (2009) 160 1003–1010
`
`ISSN 0804-4643
`
`CLINICAL STUDY
`Merits and pitfalls of mifepristone in Cushing’s syndrome
`F Castinetti, M Fassnacht1, S Johanssen1, M Terzolo2, P Bouchard3, P Chanson4, C Do Cao5, I Morange, A Pico´ 6,
`S Ouzounian3, J Young4, S Hahner1, T Brue, B Allolio1 and B Conte-Devolx
`Service d’Endocrinologie, diabe`te et maladies me´taboliques, et Centre de reference des maladies rares d’origine hypophysaires DEFHY, Hoˆpital de la Timone,
`Marseille 13005, France, 1Endocrine and Diabetes Unit, Department of Medicine I, University Hospital, University of Wu¨rzburg, Josef-Schneider-Strasse
`2, 97080 Wuerzburg, Germany, 2Dipartimento di Scienze Cliniche e Biologiche, Medicina Interna I, Orbassano 10043, Italy, 3Service d’Endocrinologie,
`Hoˆpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, FR-75571 Paris Cedex 12, France, 4Assistance Publique-Hoˆpitaux de Paris, Service
`d’Endocrinologie et des Maladies de la Reproduction, Hoˆpital de Biceˆtre, and Universite´ Paris Sud 11, and INSERM U693, F-94275 Le Kremlin-Biceˆtre,
`France, 5Clinique Endocrinologique Marc Linquette, CHU, 59037 Lille-Cedex, France and 6Servicio de Endocrinologı´a y Nutricio´n, Hospital General
`Universitario de Alicante, Alicante 03010, Spain
`
`(Correspondence should be addressed to F Castinetti who is now at Laboratory of Dr Sally Camper, Department of Human Genetics, University of Michigan,
`4109 Catherine Street, Ann Arbor, Michigan 48109, USA; Email: fredcast@umich.edu)
`
`Abstract
`
`Objective: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients
`with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness
`and tolerability of mifepristone in Cushing’s syndrome (CS).
`Design: Retrospective study of patients treated in seven European centers.
`Methods: Twenty patients with malignant (nZ15, 12 with adrenocortical carcinoma, three with
`ectopic ACTH secretion) or benign (nZ5, four with Cushing’s disease, one with bilateral adrenal
`hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose
`of 400 mg/day (200–1000). Median treatment duration was 2 months (0.25–21) for malignant CS,
`and 6 months (0.5–24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of
`adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated.
`Results: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia.
`Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5
`patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week.
`Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20
`patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure
`levels in 3/20 patients.
`Conclusion: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close
`monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency.
`Mifepristone provides a valuable treatment option in patients with severe CS when surgery is
`unsuccessful or impossible.
`
`European Journal of Endocrinology 160 1003–1010
`
`Introduction
`
`Cushing’s syndrome (CS) is a rare but serious disease
`with significant morbidity and mortality due to
`cardiovascular, metabolic, and infectious complications
`(1, 2). Transsphenoidal surgery is the treatment of
`choice for Cushing’s disease (CD) and is usually followed
`by pituitary irradiation or by bilateral adrenalectomy if
`surgery has failed (3). In malignant CS, surgery remains
`the first-line treatment in adrenocortical carcinoma
`(ACC) and ectopic ACTH secretion (EAS) while
`chemotherapy and/or radiotherapy are reserved for
`advanced disease (4, 5). Medical management of
`hypercortisolism can thus be used in four circum-
`stances: during the period required for localization of
`the ACTH source, in preparation for surgery, following
`
`radiation therapy to bridge its delayed efficacy or in
`metastatic disease as part of a multimodal approach.
`Several drugs have been advocated, each having
`advantages and drawbacks. For example, o,p0-dichloro-
`diphenildichloroethane is effective in controlling cortisol
`excess in about 50–80% of cases, and also has
`antitumoral effects due to its adrenolytic activity (6).
`However, maximum efficacy is delayed and the drug is
`frequently poorly tolerated due to a narrow therapeutic
`window (7, 8). Other drugs like ketoconazole or
`metyrapone may act more rapidly but are often only
`partially effective and associated with significant
`adverse events (e.g., serious hepatotoxicity, hyperten-
`sion or hypokalemia)
`(9, 10).
`In cases of drug
`intolerance or unresponsitivity, an alternative medical
`treatment should be useful.
`
`q 2009 European Society of Endocrinology
`
`DOI: 10.1530/EJE-09-0098
`Online version via www.eje-online.org
`
`Downloaded from Bioscientifica.com at 11/19/2018 08:15:24PM
`via free access
`
`1
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`1004
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`F Castinetti and others
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`EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
`
`Mifepristone is the first and only available glucocorti-
`coid receptor antagonist (11, 12). It was discovered in
`the early 1980’s (13), but due to its strong antiprogestin
`activity it has mainly been used as a contragestive pill.
`Owing to the controversy related to this use of
`mifepristone,
`there is presently limited experience
`concerning the use of mifepristone in hypercortisolism.
`To date only 21 patients (including two children) were
`reported to have been treated with mifepristone, mostly
`for short periods (14–19). Most of these cases were
`published as case reports, except for one study including
`10 patients (20). However, four of these patients were
`treated for !10 days due to adverse effects, although
`these adverse events may have been unrelated to
`mifepristone therapy. Moreover, only 12 patients were
`treated with mifepristone for CS for more than 2 weeks.
`All of these patients showed rapid regression of clinical
`signs of cortisol excess suggesting that mifepristone
`could become a valuable treatment option in poorly
`controlled hypercortisolism. Adverse events included
`nausea and fatigue, which could be attributed to
`adrenal insufficiency in three cases. These scarce data
`also drew attention to the limitations of biochemical
`parameters for follow-up as the blockade of glucocorti-
`coid receptors by mifepristone may lead to variable
`increase in plasma ACTH and consequently cortisol
`concentrations (12, 16). Thus, the diagnosis of both
`persistent hypercortisolism and adrenal insufficiency is
`difficult and largely based on clinical assessment and
`close follow-up.
`Owing to the lack of sufficient clinical data on
`mifepristone in cases of glucocorticoid excess, we
`decided to evaluate retrospectively the use of mifepris-
`tone as a treatment of CS in seven European centers.
`We report here the results of mifepristone therapy in
`20 patients. Owing to the various etiologies of CS,
`we divided this group into malignant and benign CS.
`We tried to define the efficacy and adverse events of
`mifepristone to better define the potential role of this
`drug in endogenous glucocorticoid excess.
`
`Patients and methods
`
`We retrospectively evaluated the effectiveness and
`tolerability of mifepristone. We included in our study
`20 patients with CS who had been treated with
`mifepristone (Mifegyne, Exelgyn Laboratories, Paris,
`France; Mifepristone, HRA Pharma, Paris, France).
`These patients were followed in seven European
`nZ4, Paris
`nZ1,
`centers:
`France
`(Marseille
`Le Kremlin-Bicetre nZ2, Lille nZ1), Germany (Wu¨ rzburg,
`nZ9), Italy (Orbassano nZ2), and Spain (Alicante,
`nZ1). Mifepristone was used on a compassionate basis
`after all patients had given their written informed
`consent; they had previously received detailed infor-
`mation on the potential side effects and benefits of
`mifepristone. Patient charts were retrospectively
`
`www.eje-online.org
`
`analyzed in detail for changes in clinical status, adverse
`events, and changes in standard biochemical and
`hormonal parameters.
`The diagnosis of CS was based on the combination of
`clinical features of hypercortisolism and biochemical
`assessment according to recommended guidelines (21).
`The study population comprised 13 females (including
`five post-menopausal women) and seven males, with a
`mean age of 48.5 years (range 20–63) at the time of
`diagnosis of CS (Table 1). None of them presented cyclic
`CS. Mifepristone was initiated due to the lack of efficacy
`(nZ6) or limited tolerance (e.g. hepatotoxicity) (nZ7)
`of previous medical
`treatments,
`increase in liver
`enzymes due to metastatic disease leading to contra-
`indication for adrenostatic drugs (nZ3) or as additional
`symptomatic therapy in combination with metyrapone
`or etomidate (nZ2). In these two patients, metyrapone
`and etomidate were considered as only partially
`effective, and the dose was not modified during
`mifepristone treatment. In addition, mifepristone was
`given to two patients with CD as first adjunctive
`treatment after unsuccessful transsphenoidal surgery
`(nZ2). All patients had undergone complete clinical
`and hormonal evaluation prior to mifepristone treat-
`ment. In all centers, efficacy and adverse events of
`mifepristone were assessed every 15–30 days by careful
`clinical evaluation (clinical signs of hypercortisolism,
`psychiatric symptoms, clinical signs, and symptoms
`suggestive of adrenal
`insufficiency, blood pressure)
`or earlier if justified by the patient’s condition. Every
`15–30 days biochemical follow-up included control of
`serum electrolytes, liver enzymes, and kidney function.
`In diabetic patients, frequent glycemic controls were
`performed with modification of diabetes treatment, if
`necessary. TSH levels were measured after 3–6 months
`of
`treatment or in case of clinical evidence of
`hypothyroidism, as one case of Hashimoto thyroiditis
`has been described previously during mifepristone
`therapy (20). Random samples of ACTH and serum
`cortisol concentrations were taken in monthly intervals
`(during outpatient visits). Owing to its antiprogestin
`effects, mifepristone has been reported to induce
`endometrial hyperplasia (22). Accordingly, transvaginal
`ultrasound examination was performed in a patient of
`our series treated for 18 months, as previously
`recommended. All adverse events occurring during
`treatment were recorded with special attention to the
`problems of adrenal insufficiency and hypokalemia.
`
`Results
`
`the 20 patients treated with
`Individual data of
`mifepristone for CS are given in Table 1. Mifepristone
`was initiated at a median dose of 400 mg/day (range
`200–1000). The initial dose was decided by each
`investigator and varied with the severity of clinical
`signs of hypercortisolism. The median maximal dose
`
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`EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
`
`Mifepristone in Cushing’s syndrome
`
`1005
`
`Table 1 Individual data of the 20 patients treated by mifepristone.
`
`Etiology
`
`Sex/age
`
`Surgery
`
`Anticortisolic drugs
`
`Clin. signs Psy. signs Hypertension HypoK
`
`Diab.
`
`Previous treatments
`
`Pre-mifepristone
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`ACC
`
`EAS
`
`CD
`
`BAH
`
`M/63
`F/39
`F/52
`F/52
`F/45
`F/63
`M/20
`F/47
`F/38
`F/44
`M/64
`M/52
`M/55
`F/43
`F/38
`M/45
`M/56
`F/50
`F/45
`F/52
`
`Y
`Y
`Y
`Y
`Y
`N
`Y
`Y
`N
`Y
`Y
`N
`N
`N
`Y
`Y
`Y
`N
`N
`N
`
`Mitotane
`Mitotane
`Mitotane
`Mitotane
`Mitotane, ketoconazole
`Mitotane, ketoconazole
`Mitotane, ketoconazole
`Mitotane, ketoconazole
`Mitotane, metyrapone
`Mitotane, metyrapone
`Mitotane, metyrapone
`Mitotane, etomidate
`Etomidate, metyrapone
`Ketoconazole
`Ketoconazole
`Ketoconazole
`Ketoconazole
`None
`None
`Ketoconazole
`
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`C
`
`C
`K
`K
`K
`K
`K
`K
`K
`K
`K
`K
`C
`K
`C
`K
`K
`K
`C
`K
`K
`
`C
`C
`C
`C
`K
`C
`C
`C
`K
`K
`K
`K
`K
`C
`C
`K
`K
`K
`K
`C
`
`C
`C
`K
`K
`K
`K
`C
`K
`K
`K
`K
`C
`C
`C
`C
`K
`K
`C
`K
`C
`
`C
`K
`K
`C
`K
`K
`C
`K
`K
`K
`K
`C
`C
`C
`K
`K
`K
`K
`K
`C
`
`Etiology: ACC, adrenocortical carcinoma; CD, Cushing’s disease; BAH, bilateral adrenal hyperplasia; EAS, ectopic ACTH secretion. Sex/age: F, female;
`M, male; age in years. Previous treatment: surgery, Y when surgery was performed before mifeptsotone, N when no surgery was performed. Pre-mifepristone,
`clinical or biochemical signs before mifepristone treatment; clin. signs, clinical signs of hypercortisolism (hirsutism, bruising, facial fullness, edema, truncal
`obesity); psy. signs, psychiatric signs or cognitive deficit; hypertension, high blood pressure level (O140/90 mmHg); hypoK, low serum potassium level
`(!3.5 mmol/l); diab., diabetes; for each criterion, C is marked when the criterion was reported, K when the criterion was absent.
`
`during the treatment was 600 mg/day (400–2000).
`The maximal dose was decided by each investigator
`according to clinical efficacy and tolerance (mainly
`blood potassium level, signs of adrenal insufficiency).
`The median duration of treatment was 2.5 months
`(5 days to 24 months). Efficacy and adverse events of the
`treatment are reported in Table 2.
`
`Mifepristone in malignant CS
`
`Effectiveness and adverse events in patients with
`ACC Twelve patients received mifepristone for advanced
`ACC. Nine of them were treated unsuccessfully by
`surgery, cytotoxic chemotherapy, and/or mitotane,
`two were treated by chemotherapy and mitotane only,
`and one received only mitotane for a few days, which
`was then stopped due to a sharp increase in liver
`enzymes (patient no. 12, Table 1). Anticortisolic drugs
`including ketoconazole (nZ4), metyrapone (nZ3) or
`etomidate (case no. 12), had been used without sufficient
`response or were stopped due to poor tolerance. The
`median starting dose of mifepristone was 400 mg/day
`(200–1000 mg) with a median maximal dose of
`600 mg/day (400–2000) and a median duration of
`treatment of 2 months (5 days to 6 months).
`In eight patients (66%),
`the clinical signs of
`hypercortisolism improved rapidly within the first
`month. In these cases, both patient and attending
`physician judged the treatment as success. However, in
`most cases symptoms did not disappear completely.
`
`Psychiatric symptoms improved within the first week in
`one of
`two affected patients and blood pressure
`decreased in four of seven patients with hypertension
`(57%). Cessation of insulin treatment and switch to
`oral drugs was possible in one out of four patients
`with diabetes mellitus. In three out of four patients with
`low serum potassium prior to mifepristone, hypokale-
`mia worsened during mifepristone treatment requiring
`high doses of supplemental potassium (up to 16 g/day),
`spironolactone (up to 100 mg/day), and, in case no. 12,
`cessation of mifepristone within 1 week of treatment.
`In patient no. 1, low serum potassium concentrations
`remained unchanged during mifepristone. Three other
`patients presenting initially with normal serum
`potassium concentrations developed moderate to severe
`hypokalemia during treatment with mifepristone. Thus,
`7 out of 12 patients (58.3%) experienced significant
`problems with serum potassium during mifepristone
`treatment.
`Mifepristone treatment was stopped due to death or
`tumor progression (nZ8),
`lack of significant benefit
`(nZ2), and uncontrolled severe hypokalemia (nZ1).
`None of the patients died because of adverse effects
`of mifepristone. Patient no. 9 is still on treatment after
`3 months with clinical signs of hypercortisolism
`improved despite tumor progression.
`
`Effectiveness and adverse events in patients with
`EAS A total of
`three patients were treated with
`mifepristone for metastatic EAS (thymic carcinoma
`nZ1, small cell
`lung cancer nZ2). All had been
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`www.eje-online.org
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`1006
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`F Castinetti and others
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`EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
`
`Table 2 Efficacy and adverse events of mifepristone in the 20 patients of the series.
`
`Dose
`initial/final
`
`Duration
`(months)
`
`Clin.
`signs
`
`Psy.
`signs
`
`Hypertension HypoK Diab.
`
`Adr.
`Ins.
`
`Reason for cessation of
`mifepristone treatment
`
`During mifepristone treatment
`
`6
`2.5
`3
`3
`1
`2
`1
`2
`3
`2
`1.5
`0.25
`
`1
`2
`18
`12
`24
`0.5
`
`3
`6
`
`Y
`Y
`Y
`Y
`4
`4
`Y
`4
`Y
`Y
`Y
`4
`
`Y
`Y
`Y
`Y
`Y
`4
`
`Y
`Y
`
`Y
`K
`K
`K
`K
`K
`K
`K
`K
`K
`K
`4
`
`K
`Y
`K
`K
`K
`Y
`
`K
`K
`
`Y
`4
`Y
`Y
`K
`4
`Y
`4
`K
`K
`K
`K
`
`Y
`[
`[
`K
`K
`K
`
`[
`K
`
`4
`[
`[
`[
`[
`K
`[
`[
`K
`K
`K
`[
`
`[
`[
`[
`K
`K
`4
`
`[
`4
`
`Y
`K
`K
`4
`K
`K
`4
`K
`K
`K
`K
`4
`
`Y
`Y
`K
`K
`K
`K
`
`K
`Y
`
`[
`[
`
`[
`
`Death (tumor progression)
`Death (tumor progression)
`Death (tumor progression)
`Death (tumor progression)
`No significant benefit
`No significant benefit
`Death (tumor progression)
`Death (tumor progression)
`Ongoing treatment
`Tumor progression
`Death (tumor progression)
`Uncontrolled hypokalemia, cessa-
`tion after 1 week of treatment
`Tumor progression, hypokalemia
`Bilateral adrenalectomy
`Ongoing treatment
`Bilateral adrenalectomy
`Radiosurgical treatment efficacy
`Neurosurgical treatment made
`possible due to psychosis
`improvement
`Ongoing treatment
`Bilateral adrenalectomy
`
`Etiology
`
`ACC
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`
`13 EAS
`14
`15
`16 CD
`17
`18
`
`1000/1000
`400/400
`400/600
`400/600
`400/2000
`600/600
`600/1200
`400/1200
`400/600
`200/600
`200/400
`600/600
`
`400/600
`600/600
`400/800
`400/800
`600/1200
`600/600
`
`19
`20 BAH
`
`600/600
`600/600
`
`Etiology: ACC, adrenocortical carcinoma; CD, Cushing’s disease; BAH, bilateral adrenal hyperplasia; EAS, ectopic ACTH secretion. Dose: mg/day. In the
`column « during mifepristone treatment, 4 when the criterion was unchanged, [ if the criterion appeared or was worsened during the treatment, K if the
`criterion was still absent, Y if the criterion decreased or disappeared with the treatment; Adr. Ins., clinical signs during the treatment were evocative of adrenal
`insufficiency (C), or no sign of adrenal insufficiency was present (K); note that patients 2, and 14 presented severe fatigue during the treatment.
`
`unsuccessfully treated by surgery. The median starting
`dose was 400 mg/day (400–600 mg) with a median
`maximal dose of 600 mg/day (600–800 mg), and
`a median duration of
`treatment of
`two months
`(1–21 months). Patient no. 13 was treated concomi-
`tantly with metyrapone, making it difficult to correctly
`interpret the results. Clinical signs of hypercortisolism
`improved in all patients. One patient with severe psychosis
`showed rapid improvement during the first week after
`initiation of mifepristone. Two patients who presented
`with high blood pressure and low serum potassium
`experienced worsening of hypokalemia and hypertension
`during mifepristone treatment and required high doses
`of spironolactone (up to 400 mg/day) and potassium
`supplementation (up to 20 g/day). Severe hypokalemia
`was also observed in the remaining patient who had
`moderately lowered serum potassium prior to therapy.
`In two patients with diabetes mellitus at diagnosis,
`insulin doses could be rapidly decreased allowing good
`glycemic control with reduced insulin doses or a switch
`to oral antidiabetic drugs. Mifepristone was eventually
`stopped due to tumor progression and/or profound
`hypokalemia (nZ2). The third patient (patient no. 15)
`with metastatic thymic carcinoma is still on treatment. In
`this patient, withdrawal of mifepristone after cytotoxic
`chemotherapy worsened clinical signs and symptoms
`of hypercortisolism and, therefore, treatment with
`mifepristone was reinitiated. Presently, she has no
`clinical signs of hypercortisolism. Moderate hypokalemia
`
`and elevated blood pressure levels are well controlled by
`spironolactone and potassium administration after 21
`months of treatment.
`
`Mifepristone in benign CS
`
`Effectiveness and adverse events in patients with CD
`Four patients with CD were treated with mifepristone
`in our centers. Two of them underwent unsuccessful
`transsphenoidal surgery, in one followed by gamma-
`knife radio surgery. The third patient
`(no. 18)
`presented with severe psychosis making surgery
`impossible. The fourth patient
`(no. 19) had no
`pituitary adenoma image on magnetic resonance
`imaging and ketoconazole was poorly tolerated. The
`median starting dose of mifepristone was 600 mg/day
`(300–600 mg), median maximal dose 700 mg/day
`(600–1200), and median duration of treatment was
`9 months (0.5–24 months).
`Clinical signs of hypercortisolism improved rapidly in
`three out of
`four patients (75%). The patient with
`psychosis showed rapid improvement of psychiatric
`symptoms within the first week of treatment. None of
`the patients had hypertension. However, patient no. 19
`developed high blood pressure and severe hypokalemia
`during mifepristone. In one patient (no. 18), low serum
`potassium remained unaffected by the treatment with
`mifepristone. In all patients, ACTH and cortisol levels
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`EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
`
`Mifepristone in Cushing’s syndrome
`
`1007
`
`increased during mifepristone (up to three times of
`pretreatment levels).
`Mifepristone was eventually stopped in three patients
`because of bilateral adrenalectomy (nZ1), eventual
`efficacy of gamma-knife radio surgery (nZ1), and
`neurosurgical treatment after regression of psychosis
`(nZ1). Patient no. 19 is still on treatment six months
`after initiation of mifepristone therapy.
`
`Effectiveness and adverse events in a patient with
`bilateral adrenal hyperplasia This patient was
`treated with mifepristone (600 mg/day) because of
`severe clinical signs of hypercortisolism, intolerance to
`ketoconazole, and refusal of bilateral adrenalectomy.
`Signs of hypercortisolism and hypertension improved
`progressively during the first three months of treatment.
`Hypokalemia was present before initiation of mifepris-
`tone and remained unchanged during treatment.
`Metformin treatment could be stopped after one
`month of treatment, and HbA1c decreased from 7.1 to
`6.4% after six months of mifepristone. Eventually, the
`patient underwent bilateral adrenalectomy after six
`months of treatment with mifepristone.
`
`Adrenal insufficiency during mifepristone
`treatment
`
`Three of our 20 patients presented clinical signs
`suggestive of adrenal
`insufficiency (fatigue, nausea,
`and vomiting). All were treated by dexamethasone
`followed by a reduction of mifepristone dose to 50% of
`the last dosage prior to adrenal insufficiency. Patients
`received 1 mg dexamethasone/400 mg mifepristone as
`recommended previously (23). Two patients reported
`extreme fatigue, but no other clinical signs of adrenal
`deficiency (patients nos 3 and 14). Their treatment was
`not modified.
`
`Other potential adverse effects of mifepristone
`
`One non-diabetic patient had a transient episode of
`hypoglycemia. No increase in liver enzymes or altera-
`tions in thyroid function or kidney function was
`observed in relation to mifepristone treatment. In the
`female patient (patient no. 15) who received mifepris-
`tone for 18 months, no endometrial hyperplasia was
`observed.
`
`Discussion
`
`The antiglucocorticoid activity of mifepristone is well
`established in vitro (14). However, in long-term studies
`mifepristone has been mainly used as an anti-progestin
`in meningioma, myoma or other progesterone-
`dependent diseases
`(24, 25).
`It
`is used as an
`antiglucocorticoid in patients with hypercortisolism
`
`and was hampered by the controversy related to its
`use for inducing abortion leading to legal restrictions in
`several countries. Accordingly, as shown in Table 3,
`only 21 patients (including two children) have been
`treated by mifepristone for CS (14, 15, 17, 20, 22,
`26–29). Thus, our study of 20 patients doubles the
`database of mifepristone treatment for CS and, there-
`fore, allows a better appreciation of its effectiveness and
`adverse effects.
`Our study clearly indicates that mifepristone has
`significant potential
`to improve clinical signs and
`symptoms related to CS. Of note, all four patients not
`benefitting from mifepristone suffered from very
`advanced ACC (the fifth patient, who presented rapid
`regression of psychosis signs, was only treated for
`15 days). In general, most of our patients were heavily
`pretreated and, in most cases, anticortisolic drugs had
`failed to control CS or were not tolerated. An important
`advantage of mifepristone is the rapid onset of its action
`making it especially helpful for patients presenting with
`psychosis. In three out of four patients, psychosis signs
`indeed disappeared within one week of therapy.
`Our study highlights two main challenges in the
`treatment of patients with CS with mifepristone:
`hypokalemia and adrenal insufficiency. In our study,
`55% patients presented relevant hypokalemia. The
`percentage of hypokalemia in our study is higher than
`the 20% previously reported (16). In CS, hypokalemia is
`directly related to glucocorticoid excess as massive
`hypercortisolemia leads to incomplete renal
`inacti-
`vation of cortisol by 11-b-dehydrogenase, and hence
`mineralocorticoid excess (30). As mifepristone blocks
`only glucocorticoid action,
`the mineralocorticoid
`activity of cortisol excess is not affected by mifepristone
`treatment,
`thus leading to hypokalemia. On the
`contrary, mifepristone may lead to an increase of
`plasma ACTH and consecutively of cortisol levels in
`some patients with CS, particularly with CD due to
`alterations in negative feedback. Other mechanisms
`that probably contributed to the higher incidence of
`hypokalemia in our study may be related to the fact that
`in many patients adrenostatic therapy was stopped prior
`to mifepristone treatment because of drug intolerance.
`Thus, in these patients, increase in cortisol concen-
`trations could be related to cessation of adrenostatic
`therapy or tumor progression, leading to hypercortiso-
`lism and severe hypokalemia. Furthermore, even if this
`mechanism seems less likely, it has been shown that
`progesterone acts as an anti-mineralocorticoid and the
`antiprogestin activity of mifepristone may have reduced
`this anti-mineralocorticoid action of endogenous pro-
`gesterone further enhancing mineralocorticoid excess
`(31). In many of our cases, profound hypokalemia was
`thus probably multifactorial. However, the fact that
`severe hypokalemia was observed even with the use of
`spironolactone and potassium supplementation draws
`attention on the fact that hypokalemia may become
`a treatment limiting side-effect of mifepristone, mainly
`
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`
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`via free access
`
`5
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`

`

`1008
`
`F Castinetti and others
`
`EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
`
`Table 3 Efficacy and adverse effects of mifepristone in the 21 patients of the literature.
`
`Sex/age Etiology
`
`Dose
`
`Duration
`
`Clinical
`improvement Adverse effects
`
`References
`
`1
`2
`3
`
`4
`5
`
`6
`
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`
`18
`19
`20
`21
`
`F/45
`F/32
`F/NA
`
`M/62
`M/43
`
`ACC
`ACC
`ACC
`
`ACC
`ACC
`
`5–22 mg/kg
`400
`30–20 mg/kg
`
`400
`800–400
`
`M/36
`
`EAS
`
`5–22 mg/kg
`
`M/42
`F/63
`F/55
`F/46
`M/25
`F/2
`F/43
`F/38
`F/38
`M/51
`F/14
`
`NA
`NA
`NA
`NA
`
`EAS
`EAS
`EAS
`EAS
`EAS
`EAS
`EAS
`EAS
`AA
`CD
`NCS
`
`NA
`NA
`NA
`NA
`
`5–22 mg/kg
`5–22 mg/kg
`5–22 mg/kg
`800–1600
`5–20 mg/kg
`25–100 thrice/day
`600
`800
`5–22 mg/kg
`400–2000
`400
`
`NA
`NA
`NA
`NA
`
`2
`2
`4
`
`9
`0.5
`
`10
`
`12
`4
`2.25
`0.3
`2.25
`2
`2
`10
`1.5
`18
`8
`
`!1
`!1
`!1
`!1
`
`Yes
`Yes
`Yes
`
`Yes
`Yes
`
`Yes
`
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`
`NE
`NE
`NE
`NE
`
`Vaginal bleeding, hypoglycemia,
`water retention
`
`Hypoglycemic episodes, increase in
`eosinophils
`Hashimoto thyroiditis, gynecomastia,
`impotence, inhibition of cortisol
`synthesis
`Nausea, gynecomastia
`Adrenal insufficiency
`
`Hypokalemia, myelemia
`
`Nausea
`Severe hypokaliemia, adrenal crisis
`Endometrial hyperplasia, transient
`rash, Hashimoto’s thyroiditis
`Hypotension
`Pneumocystis carinii pneumonia
`Severe nausea, prostration
`Nausea, inhibition of cortisol
`synthesis
`
`(20)
`(29)
`(18)
`
`(19)
`(29)
`
`(20)
`
`(20)
`(20)
`(20)
`(15)
`(28)
`(14)
`(17)
`(17)
`(18)
`(26)
`(22)
`
`(20)
`(20)
`(20)
`(20)
`
`Etiology: ACC, adrenocortical carcinoma; CD, Cushing’s disease; AA, adrenal adenoma; EAS, ectopic ACTH secretion; NCS, normocortisolemic Cushing’s
`syndrome; NA, not available. Dose: mg/day. Duration: months. Clinical improvement: NE, not available. Adapted from ref. (16).
`
`in patients with most severe forms of CS. In these
`cases, a combination of mifepristone with anticortisolic
`drugs may ameliorate treatment-induced hypokalemia.
`Of note that hypokalemia was rapidly reversible (within
`48 h) after cessation of mifepristone treatment.
`The other important aspect in the management of
`patients receiving mifepristone is the risk of adrenal
`insufficiency. During mifepristone treatment, adrenal
`insufficiency can only be assessed by clinical obser-
`vation, as cortisol and ACTH concentrations are either
`elevated or not altered by mifepristone treatment.
`As outlined above, high cortisol
`levels may cause
`overstimulation of mineralocorticoid receptors leading
`to low serum potassium concentrations and even
`elevated blood pressure levels further hindering the
`assessment of adrenal insufficiency. Key clinical features
`are weakness, fatigue, nausea, vomiting, and hypogly-
`cemic episodes. In our series, three patients presented
`clinical signs suggestive of adrenal insufficiency leading
`to therapeutic problems. This result is quite similar to
`previous reports. Out of 19 adult patients with CS
`described previously, there were five events of adrenal
`insufficiency based on clinical assessment (16). Admin-
`istration of dexamethasone led to rapid reversal and was
`highly effective in treatment of mifepristone-induced
`adrenal
`insufficiency. Dexamethasone is superior to
`intravenous hydrocortisone because of its high affinity
`
`to the glucocorticoid receptor and its lack of miner-
`alocorticoid activity (23). However, it should be given
`for at least two days because of the prolonged half-life of
`mifepristone (90 h). Monitoring of patients with CS
`receiving mifepristone is demanding and requires
`particular attention to detect and treat adrenal
`insufficiency. Careful education of the patients is also
`mandatory.
`The median dosage to control CS in our study was
`lower than reported previously. This may be related to
`different formulations of the drug, or because of different
`levels of cortisol secretion. Based on our study,
`it
`seems that most of the patients can be controlled with
`a daily dose of 400–800 mg and that a daily dose
`above 1000 mg is probably not more effective but may
`be associated with higher toxicity. We therefore,
`recommend to start with a daily dosage of 200–400 mg
`and to increase the dose according to clinical efficacy
`(e.g. blood pressure) and tolerance (blood potassium
`level, signs of adrenal insufficiency). In patients in whom
`rapid improvement is needed (e.g. psychosis), it seems
`reasonable to increase the dosage every three days by
`200 mg. In all other patients, dosage adjustments in
`every two weeks may be preferable.
`The potential risks and benefits of mifepristone have
`to be weighed against alternative treatment options.
`In comparison with mifepristone, the main advantage of
`
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`
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`
`6
`
`

`

`EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
`
`Mifepristone in Cushing’s syndrome
`
`1009
`
`adrenostatic drugs for CS is the possibility to monitor
`cortisol concentration, whereas during mifepristone
`cortisol concentration provides no guidance for treat-
`ment. However, most of the time, other anticortisolic
`drugs also expose patients to frequent and/or severe side
`effects without superior efficacy (27). Ketoconazole has
`been shown to be highly useful in the treatment of CS
`(9). However, serious and life-threatening hepatotoxi-
`city has been described (32). Moreover, ketoconazole is
`no longer available in some European countries (e.g.
`Germany). Metyrapone, an inhibitor of 11-b-hydroxylase,
`is not easily available in several European countries
`and may also be associated with significant side
`effects (10). Etomidate induces profound inhibition of
`11-b-hydroxylase also in non-hypnotic doses. However,
`it can only be used intravenously and, therefore, is not
`well-suited for long-term treatment (33). Similarly, the
`use of mitotane is not without difficulties. It has a
`narrow therapeutic window and it often takes several
`weeks to months to reach plasma target
`levels.
`Numerous side effects of mitotane have been reported,
`and a significant percentage of patients may not tolerate
`long-term mitotane therapy due to gastrointestinal
`and/or neurotoxic adverse events (6–8, 27). Thus,
`treatment with mifepristone may be of a significant
`value in the medical
`treatment of CS in a high
`percentage of cases.
`Our study has several limitations: it is a multicenter
`and retrospective report suffering from the classical
`drawbacks of this type of investigations. Secondly, in
`some patients, mainly with adrenal carcinoma, mife-
`pristone was combined with adrenostatic drugs or
`chemotherapy. However, this concomitant treatment
`was not altered during mifepristone treatment. Third,
`due to its mechanism of action, biochemical evalua