Case Report
`
`
`
`Marina Basina, MD; Hau Liu, MD, MBA, MPH;
`Andrew R. Hoffman, MD; David Feldman, MD
`
`ABSTRACT
`
`Objective: We describe a girl with Cushing disease for
`
`whom surgery and radiation treatments failed and the sub-
`sequent clinical course with mifepristone therapy.
` Methods: We present the patient’s clinical, biochemi-
`cal, and imaging findings.
`
`Results: A 16-year-old girl presented with classic
`Cushing disease. After transsphenoidal surgery, Cyberknife
`radiosurgery, ketoconazole, and metyrapone did not control
`her disease, and she was prescribed mifepristone, which
`was titrated to a maximal dosage of 1200 mg daily with
`subsequent symptom improvement. Mifepristone (RU486)
`is a high-affinity, nonselective antagonist of the glucocor-
`ticoid receptor. There is limited literature on its use as an
`off-label medication to treat refractory Cushing disease.
`Over her 8-year treatment with mifepristone, her therapy
`was complicated by hypertension and hypokalemia requir-
`ing spironolactone and potassium chloride. She received
`a 2-month drug holiday every 4 to 6 months to allow for
`withdrawal menstrual bleeding with medroxyprogester-
`one acetate. Urinary cortisol, serum cortisol, and cortico-
`tropin levels remained elevated during mifepristone drug
`
`Submitted for publication December 25, 2011
`Accepted for publication February 21, 2012
`From the Stanford University School of Medicine, Division of Endocrinology,
`Stanford, California.
`Address correspondence to Dr. Marina Basina, Stanford University School
`of Medicine, Division of Endocrinology, Stanford, CA 94305-5103. E-mail:
`mbasina@stanford.edu.
`Published as a Rapid Electronic Article in Press at http://www.endocrine
`practice.org on March 22, 2012. DOI:10.4158/EP11391.CR
`To purchase reprints of this article, please visit: www.aace.com/reprints.
`Copyright © 2012 AACE.
`
`holidays. While on mifepristone, her signs and symptoms
`of Cushing disease resolved. Repeated magnetic resonance
`imaging demonstrated stable appearance of the residual
`pituitary mass. Bilateral adrenalectomy was performed,
`and mifepristone was discontinued after 95 months of
`medical therapy.
`
`Conclusions: We describe the longest duration of
`mifepristone therapy thus reported for the treatment of
`refractory Cushing disease. Mifepristone effectively
`controlled all signs and symptoms of hypercortisolism.
`Menstruating women who take the drug on a long-term
`basis should receive periodic drug holidays to allow for
`menses. The lack of reliable serum biomarkers to monitor
`the success of mifepristone therapy requires careful clini-
`cal judgment and may make its use difficult in Cushing
`disease. (Endocr Pract. 2012;18:e114-e120)
`
`Abbreviations:
`ACTH = corticotropin; MRI = magnetic resonance
`imaging
`
`INTRODUCTION
`
`Cushing syndrome refers to the clinical manifesta-
`
`tions related to chronic exposure to excessive glucocor-
`ticoids and is associated with significant morbidity and
`mortality due to cardiovascular, metabolic, and infec-
`tious complications (1). Cushing disease, due to a corti-
`cotropin (ACTH)-producing pituitary tumor, accounts for
`approximately 70% of the cases of endogenous Cushing
`syndrome. The initial treatment of Cushing disease is usu-
`ally transsphenoidal surgery, but failure to achieve a cure
`is common and patients with recurrent or residual disease
`require additional treatment. Secondary therapies can
`include repeated surgery; external beam irradiation; or
`medical treatment with steroidogenic enzyme inhibitors
`(ie, metyrapone; ketoconazole; aminoglutethimide, which
`is no longer available in the United States; and etomidate,
`which is available in only an intravenous form and requires
`
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`close monitoring) or adrenolytic drugs (mitotane), which
`are usually only partially effective and are often associated
`with significant adverse effects. Drugs that inhibit ACTH
`release are currently in development (2).
`
`An additional therapeutic option is to use a gluco-
`corticoid receptor antagonist. Mifepristone (RU486) is a
`high-affinity, nonselective antagonist of the glucocorti-
`coid receptor, but owes its clinical application as an abor-
`tifacient to its ability to block the progesterone receptor
`(3). In early studies, mifepristone was shown to bind to
`the human glucocorticoid receptor with high affinity and
`without stimulating glucocorticoid activity (4,5). The anti-
`glucocorticoid effect is dose-dependent and requires much
`higher doses than required for its antiprogestin activity (6).
`Mifepristone blocks both the central actions of cortisol (its
`negative feedback to inhibit corticotropin-releasing hor-
`mone and ACTH secretion) and its peripheral activity (7).
`In healthy persons, long-term administration of mifepris-
`tone was observed to produce persistent elevation of serum
`ACTH and cortisol levels, but the response to corticotro-
`pin-releasing hormone and the circadian rhythm of ACTH
`and cortisol secretion were not affected (8). No clinical
`symptoms of adrenal insufficiency were observed when
`mifepristone was given to healthy volunteers for 8 days at a
`dosage of 200 mg daily (9). In an early study, patients with
`Cushing disease demonstrated significant increases in uri-
`nary cortisol excretion after receiving 400 mg of mifepris-
`tone for 3 consecutive days, and 2 of the 5 patients devel-
`oped clinical signs of adrenal insufficiency that required
`dexamethasone administration. However, patients with
`Cushing syndrome from nonpituitary causes experienced
`no significant change in hormone secretion (10).
`
`Since the original report in 1985 (11), mifepristone has
`been used in a relatively small number of patients as an
`off-label medication to treat Cushing disease, usually as a
`temporary bridge to control the disease while awaiting the
`delayed effect of pituitary radiation therapy. As a result,
`there is a limited experience with the use of mifepristone
`in the control of hypercortisolism regarding the optimal
`dose, duration of use, and clinical monitoring, includ-
`ing the recognition of adverse effects. Since mifepristone
`blocks central nervous system and pituitary glucocorticoid
`receptors, feedback relationships within the hypothalamic-
`pituitary-adrenal axis are abrogated. As a result, circulat-
`ing concentrations of ACTH and cortisol are elevated
`during mifepristone therapy, and the response to treat-
`ment can only be judged by clinical assessment and not
`by biochemical measures of cortisol or ACTH levels (12).
`There are no known independent biomarkers that can be
`used as surrogate measurements to help guide therapy. To
`date, the literature includes approximately 50 patients with
`Cushing disease who have been treated with mifepristone
`(13). In most patients, the treatment was of short duration.
`One study included 10 patients, 4 of whom were treated
`for fewer than 10 days (14). Published reports describe a
`
` e115
`
`median duration of therapy as short as 5 days and as long
`as 24 months (13). Currently, mifepristone is being used
`in a clinical trial to gain US Food Drug Administration
`approval for use in treating Cushing disease.
`
`In this article, we describe a case of mifepristone treat-
`ment in a girl with Cushing disease who was treated for a
`duration of 8 years with complete resolution of all clinical
`signs and symptoms of Cushing syndrome. The prolonged
`use of mifepristone in female patients raises a number of
`concerns related to menstrual function and fertility.
`
`CASE REPORT
`
`A 16-year-old girl presented to her pediatrician in
`
`June 2000 with an 8-month history of amenorrhea, 18.2-kg
`weight gain (from 52.7 to 70.9 kg), purple stretch marks on
`her shins, and severe fatigue. Menarche commenced at age
`13 years, and she had regular menses until they stopped
`abruptly with the onset of her symptoms.
`
`Physical examination revealed a young woman with
`the classic appearance of Cushing disease. Most striking
`were the severe striae on the thighs, shins, and abdomen.
`Acne and hirsutism were not present. Initial laboratory
`studies included an elevated serum ACTH concentration
`of 102 pg/mL, elevated urinary free cortisol excretion of
`390 mg/24 h, nonsuppressible cortisol level after an over-
`night dexamethasone test (actual value not available), and
`an elevated dehydroepiandrosterone sulfate concentration
`of 3171 mg/dL (reference range, 30-300 mg/dL) (Table 1,
`Fig. 1). Cushing disease was presumptively diagnosed, and
`magnetic resonance imaging (MRI) of the pituitary gland
`showed a 1.5-cm enhancing mass with possible extension
`into the right cavernous sinus.
`
`The patient underwent transsphenoidal surgery on June
`21, 2000, but complete tumor removal was not possible
`because of cavernous sinus invasion. Pathologic examina-
`tion revealed an ACTH-secreting pituitary adenoma. ACTH
`staining was confirmed in fine granular secretory material
`of the cytoplasm of the tumor cells. Thyrotropin and pro-
`lactin staining were negative. Postoperatively, ACTH and
`cortisol levels transiently normalized. By September 2000,
`at age 17 years, her menses became regular again and her
`body weight decreased to 52.7 kg. Follow-up MRI done in
`September 2000 showed postoperative changes with sur-
`gical defect in fat packing in the right aspect of pituitary
`fossa; the remainder of the gland was normal. Another MRI
`study in April 2001 did not reveal any clinically signifi-
`cant change compared with MRI findings from September
`2000.
`
`In 2001, approximately 1 year after surgery, men-
`strual irregularity returned. Repeated MRI performed in
`September 2001 revealed a new 9 × 4-mm right sellar and
`parasellar mass with extension into the right cavernous
`sinus, encasing, but not narrowing, the right carotid artery.
`ACTH and cortisol levels were significantly elevated
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`Date
`6/1/2001
`10/1/2001
`1/1/2002
`2/1/2002
`3/1/2002
`
`4/1/2002
`
`5/1/2002
`
`6/1/2002
`
`7/1/2002
`
`8/1/2002
`
`9/1/2002
`
`10/1/2002
`
`1/1/2003
`
`2/1/2003
`
`5/1/2003
`
`7/1/2003
`
`8/1/2003
`1/1/2003
`5/1/2004
`7/1/2004
`12/1/2005
`5/1/2006
`1/1/2007
`6/1/2007
`3/1/2008
`9/1/2008
`11/1/2008
`6/1/2009
`7/1/2009
`10/1/2009
`4/1/2010
`
`Table 1
`Timeline of Clinical Laboratory Values and Medication Usage
`
`Serum cortisol
`(reference range,
`4-26 mg/dL)
`35
`…
`64.7
`…
`58.4
`
`Urinary cortisol
`(reference range,
`3.5-45 mg/24 h)
`390
`187
`1221
`2016
`255.3
`
`ACTH (reference
`range, 10-60 pg/
`mL)
`102
`…
`…
`…
`…
`
`Potassium
`(reference range,
`3.5-4.9 mEq/L)
`3.9
`…
`…
`3.8
`3.7
`
`47.9
`
`29.8
`
`54.1
`
`112
`
`125
`
`…
`
`143
`
`38.8
`
`…
`
`41.6
`
`…
`
`52.1
`…
`…
`…
`…
`…
`30
`27.4
`…
`20.8
`25.8
`22
`…
`…
`16.2
`
`193.6
`
`400
`
`518
`
`3009
`
`…
`
`5161.9
`
`…
`
`932.7
`
`1017.5
`
`…
`
`…
`
`2029.1
`552
`228
`…
`158
`56.4
`205.8
`188.5
`109.1
`248.7
`268.3
`256.6
`103.4
`167
`686
`
`…
`
`98
`
`…
`
`…
`
`…
`
`…
`
`…
`
`55
`
`…
`
`109
`
`…
`
`74
`…
`…
`…
`…
`…
`43
`85
`85
`43
`…
`66.1
`…
`43
`57
`
`…
`
`3.3
`
`3.2
`
`3.2
`
`3.3
`
`…
`
`3
`
`…
`
`…
`
`3.4
`
`3.2
`
`3.6
`…
`…
`…
`…
`…
`4.5
`…
`…
`…
`…
`…
`…
`4.5
`4.5
`
`Medication, dosage
`…
`…
`…
`Ketoconazole, 400 mg
`Ketoconazole, 600 mg;
`metyrapone, 500 mg
`Ketoconazole, 800 mg;
`metyrapone, 1000 mg
`Ketoconazole, 1200 mg;
`metyrapone, 1500 mg
`Mifepristone, 200 mg;
`aldactone, 25 mg
`Mifepristone, 400 mg;
`aldactone, 50 mg
`Mifepristone, 800 mg;
`aldactone, 100 mg
`Mifepristone, 1200 mg;
`aldactone, 200 mg
`Mifepristone holiday;
`medroxyprogesterone,
`10 mg for 6 days
`Mifepristone holiday;
`2nd course of
`medroxyprogesterone
`Mifepristone, 400 mg;
`aldactone, 150 mg
`Mifepristone, 400 mg;
`aldactone 150 mg
`Mifepristone, 400 mg;
`aldactone 100 mg
`Mifepristone, 200 mg;
`KCl mEq
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Mifepristone holiday
`Off mifepristone
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` e117
`
`Fig. 1. Timeline of urinary cortisol and serum corticotropin (ACTH) levels. Composite picture of the patient’s course over 100
`months. The left axis shows the patient’s 24-hour urinary free cortisol level and the right axis shows the patient’s ACTH levels
`over time. Note the units have been log transformed. The letters on the graph indicate the therapy: A denotes times during
`which the patient was not treated; B denotes when the patient was treated with ketoconazole; C denotes when the patient was
`treated with ketoconazole and metyrapone; and D denotes when the patient was treated with mifepristone. The upper limits of
`normal were 45 mg/24 h for urinary free cortisol and 60 pg/mL for ACTH.
`
`(Table 1, Fig. 1). Repeated pituitary surgery was not
`attempted because of the invasion into the cavernous sinus
`and around the carotid artery. Cyberknife radiosurgery was
`performed. A total dose of 2100 cGy was administered in
`3 fractions of 700 cGy each in November 2001, which tar-
`geted the 9 × 16 × 11-mm tumor in the lateral sella and
`cavernous sinus.
`
`In 2002, the patient continued to gain weight and to
`have irregular menses. Medical therapy with ketoconazole
`was initiated and the dosage was titrated to a maximum of
`1200 mg daily. Symptoms and signs of active Cushing dis-
`ease persisted, and metyrapone was added several months
`later. Despite receiving the maximum dosage of both medi-
`cations, she continued to gain weight and to develop new
`striae; urinary free cortisol and ACTH remained elevated
`(Table 1, Fig. 1). The development of severe alopecia led
`to decreasing the dosages of both medications.
`
`In June 2002, ketoconazole and metyrapone were
`discontinued and treatment with mifepristone (obtained
`from the Population Council) was started under US Food
`and Drug Administration IND #61254 for off-label use.
`The symptoms of Cushing disease improved markedly on
`mifepristone within the first few months of treatment. The
`
`patient was initially prescribed a dosage of 200 mg daily,
`then the dosage was titrated up to 1200 mg daily. After 2
`to 3 months, the dosage was gradually lowered to 200 mg
`daily due to hypokalemia; clinical improvement continued
`even as the dosage was decreased. A clinically significant
`reduction in the striae on her lower extremities was noted,
`and she reported improved energy and weight loss back to
`her baseline weight of 52.3 to 52.7 kg.
`
`The treatment course was initially complicated by
`hypertension and hypokalemia, presumably due to high
`cortisol levels activating the mineralocorticoid receptor.
`Spironolactone and potassium chloride replacement ther-
`apy were added approximately 3 months after initiation of
`mifepristone with normalization of potassium and blood
`pressure. In January 2003, it was noted that the patient had
`not had a menstrual period since initiation of mifepristone
`therapy 7 months earlier. Transabdominal ultrasonogra-
`phy was performed, which showed that the endometrial
`thickness was 1.7 cm with a small amount of fluid with in
`the endometrial cavity. To induce a menstrual period, the
`patient was given a drug holiday for 2 months along with 2
`courses of oral medroxyprogesterone acetate, thus leading
`to withdrawal menstrual bleeding. During the interruption
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`e118
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`of mifepristone therapy, measurement of ACTH, corti-
`sol, and urinary free cortisol was performed to monitor
`the course of her disease (Table 1, Fig. 1). Repeated MRI
`showed stable appearance of the residual pituitary mass.
`
`The patient remained on mifepristone therapy until
`November 2009 for a total duration of 95 months with
`a drug holiday every 4 to 6 months to allow menses and
`measurement of cortisol and ACTH. During this treatment
`period, all clinical signs and symptoms of Cushing syn-
`drome completely resolved. Urinary free cortisol, random
`serum cortisol, and ACTH concentrations were monitored
`and were shown to remain abnormally elevated during the
`drug holiday periods with a gradual decline in the levels
`over the 8 years of therapy (Table 1, Fig. 1). Findings on
`annual pituitary MRI remained stable with no significant
`change in tumor size. There were no signs or symptoms of
`adrenal insufficiency at any time point during the course
`of mifepristone treatment, and we observed no clinically
`significant skin hyperpigmentation.
`that
`
`The medical
`team eventually concluded
`Cyberknife therapy was not going to cure the Cushing
`disease in this patient. In light of the fact that she could
`not become pregnant while receiving mifepristone, we
`proceeded with bilateral adrenalectomy and discontinued
`mifepristone after 95 months of medical therapy. During
`the 8 months between the time that the mifepristone was
`discontinued and before she underwent adrenalectomy,
`she continued to have regular menstrual cycles and did not
`redevelop any clinical stigmata or symptoms of Cushing
`syndrome. However, serum ACTH and cortisol and urinary
`free cortisol all remained elevated. Laparoscopic bilateral
`adrenalectomy was performed on July 29, 2010, and the
`patient was prescribed replacement cortisol and fludrocor-
`tisone therapy. She has remained well with regular men-
`ses since surgery, without signs or symptoms of recurrent
`Cushing disease or Nelson syndrome.
`
`DISCUSSION
`
`Our report is unique because we describe the lon-
`
`gest duration of mifepristone use to treat Cushing disease
`refractory to other therapies including transsphenoidal
`surgery, Cyberknife radiosurgery, and medical modalities.
`Previously published case reports have described a mean
`duration of mifepristone use of 11 months (0-24 months),
`compared with 8 years of therapy in this patient.
` Mifepristone appears to be a very effective drug for
`rapidly controlling the signs and symptoms of hypercor-
`tisolism. Up to 85% of previously described patients with
`Cushing disease showed improvement in clinical signs
`(weight loss, improvement in skin symptoms) during
`the first month of therapy, and approximately 50% had a
`decrease in blood pressure and an improvement in glycemic
`control (15). Before mifepristone treatment, the patient we
`describe had gained weight and had developed clinically
`
`significant skin findings with wide distribution of striae
`over her body, especially on the lower extremities. Both
`striae and weight gain markedly improved soon after ini-
`tiation of mifepristone treatment, and they resolved almost
`completely after the first year of therapy. Interestingly, the
`patient remained asymptomatic for 8 months after discon-
`tinuation of mifepristone and before she underwent bilat-
`eral adrenalectomy, even in the presence of laboratory find-
`ings suggestive of persistent Cushing disease.
`
`The reported adverse effects of mifepristone include
`hypertension and hypokalemia. Mifepristone blocks glu-
`cocorticoid receptors, leaving mineralocorticoid receptors
`susceptible to occupancy and stimulation by the high cor-
`tisol levels, causing a syndrome of apparent mineralocor-
`ticoid access. The cortisol excess exceeds the ability of the
`enzyme 11b-hydroxysteroid dehydrogenase 2 to inactivate
`it (16). The mineralocorticoid activity driven by cortisol
`occupancy of mineralocorticoid receptors leads to hypo-
`kalemia and elevated blood pressure despite improved
`symptoms of hypercortisolism. Both of these expected
`adverse effects were observed in the patient we describe,
`and she was treated with high dosages of potassium and
`spironolactone. Surprisingly, both potassium and spirono-
`lactone requirements decreased gradually over the course
`of the treatment, and she did not require either of these
`medications in the last few years of mifepristone therapy.
`This reduction in adverse effects is no doubt due in part
`to decreased cortisol levels. However, because her urinary
`free cortisol levels remained elevated, we speculate that her
`improvement in hypokalemia may possibly include devel-
`opment of mineralocorticoid receptor resistance because
`of chronic high cortisol or mifepristone levels occupying
`the receptor or increased capacity of 11b-hydroxysteroid
`dehydrogenase 2 activity.
`
`One of the difficulties with monitoring mifepristone
`therapy is the absence of reliable biochemical markers to
`guide dosage adjustment. Both ACTH and cortisol lev-
`els increase during the treatment; therefore, the dosage is
`adjusted on the basis of the clinical response alone.
`
`An additional point of interest is that we were able to
`decrease the mifepristone dosage gradually from 1200 mg
`daily to a maintenance dosage of 200 mg daily on the basis
`of the patient’s clinical response. The reduced dosage was
`maintained until the medication was discontinued before
`adrenalectomy without any recurrence of clinical signs or
`symptoms of Cushing disease, despite very elevated levels
`of urinary free cortisol.
`
`There are at least 2 possible explanations for the con-
`tinued clinical improvement and decrease in urinary free
`cortisol in the setting of a decrease in mifepristone dosage.
`The latter can be explained by partial resolution of her pri-
`mary disease as a delayed effect of Cyberknife radiosur-
`gery with some reduction in cortisol excess over the years.
`Clinical improvement may also have been due to down-
`regulation of her glucocorticoid receptors with prolonged
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`mifepristone therapy that permitted a reduced drug dosage
`to adequately block her glucocorticoid receptors and there-
`fore allowed her to be symptom-free on a lower dosage.
`Persistently elevated levels of ACTH and cortisol mea-
`sured during the mifepristone holidays, as well as lack of
`change on pituitary MRI, argue against a complete cure
`of her Cushing disease from the Cyberknife radiation, but
`apparently there was a partial reduction in cortisol excess.
`Although we are aware of no data from previous reports
`indicating that the second hypothesis is correct, some data
`suggest that glucocorticoid agonists down-regulate their
`receptor (17); therefore, this is a plausible effect of mife-
`pristone or the prolonged high levels of cortisol occupy-
`ing the glucocorticoid receptor. This phenomenon may be
`explored in larger clinical trials.
`
`Another important point that was encountered in our
`case, which has also been previously described in the liter-
`ature, is an endometrial thickening effect of mifepristone.
`Mifepristone’s ability to block the progesterone recep-
`tor allows for its main clinical use as a contragestive pill.
`Continuous use of mifepristone in a menstruating woman
`therefore leads to unopposed estrogen action on the endo-
`metrium, raising concern about the development of endo-
`metrial thickening and its inherent risk for endometrial
`carcinoma. Thus, menstruating women who are using the
`drug on a long-term basis should receive periodic drug hol-
`idays to permit a natural or progestin-stimulated sloughing
`of the endometrium. This effect of mifepristone is being
`clinically studied as a potential treatment option for uterine
`leiomyomata and endometriosis (18).
`
`As in our patient, long-term treatment with progester-
`one receptor modulators, a class of drugs to which mifepris-
`tone belongs, may be associated with endometrial thicken-
`ing seen on ultrasonography, which was initially thought
`to be due to endometrial hyperplasia. However, recent
`reports have detailed a new pattern of histology not previ-
`ously encountered in clinical practice. Therapy with mife-
`pristone and other progesterone receptor modulators shows
`a specific histologic finding of cystic glandular dilatation
`often associated with both admixed estrogen (mitotic) and
`progestin (secretory) epithelial effects (19). Endometrial
`thickening seen on ultrasonography is due to cystic glan-
`dular dilatation and is not due to endometrial hyperplasia.
`In 2006, during the National Institutes of Health–spon-
`sored workshop on the subject of “Progesterone Receptor
`Modulators and the Endometrium,” a panel of 7 experi-
`enced gynecologic pathologists designated a new term to
`describe these novel endometrial changes as progester-
`one receptor modulator–associated endometrial changes.
`Eighty-four endometrial specimens from women receiving
`progesterone receptor modulators were examined, but no
`overtly premalignant lesions were found (20).
`
` e119
`
`CONCLUSION
`
`The patient we describe received mifepristone therapy
`
`for the longest duration thus far reported to treat either
`Cushing disease or any other condition. There are various
`expected adverse effects of this medication (and other pro-
`gesterone receptor modulators) that require further inves-
`tigation in prospective trials of long duration. However,
`mifepristone has the ability to rapidly reverse the symp-
`toms and signs of Cushing disease with relative safety
`during prolonged treatment. Unlike other forms of medi-
`cal therapy, such as ketoconazole, mifepristone does not
`cause hepatic dysfunction. The lack of reliable biomarkers
`to judge the success of mifepristone therapy and the risk of
`adrenal insufficiency make the routine use of this therapy
`in Cushing disease complex, and careful monitoring of
`clinical responses is required. In patients with Cushing dis-
`ease for whom surgery and radiation therapy have failed,
`the drug is a useful approach for bridge therapy, and, as
`demonstrated in our patient, it can induce long-term remis-
`sion. Mifepristone can reverse Cushing disease, allowing
`adrenalectomy, when necessary, to be performed electively
`in a noncushingoid state. The drug appears to be a welcome
`addition to the array of options to treat Cushing syndrome,
`and its eventual role will be determined by the outcomes of
`larger long-term studies that are currently ongoing.
`
`ACKNOWLEDGMENT
`
`The authors thank Dr. Coleman Gross for providing
`
`valuable suggestions and helping with the literature search.
`
`DISCLOSURE
`
`
`
`The authors have no multiplicity of interest to disclose.
`
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