See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/11841749
`
`Successful long-term treatment of refractory
`Cushing’s disease with high-dose mifepristone
`(RU 486). J Clin Endocrinol Metab
`
`ARTICLE in JOURNAL OF CLINICAL ENDOCRINOLOGY &AMP METABOLISM · SEPTEMBER 2001
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`0013-7227/01/$03.00/0
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`The Journal of Clinical Endocrinology & Metabolism 86(8):3568–3573
`Copyright © 2001 by The Endocrine Society
`
`Successful Long-Term Treatment of Refractory Cushing’s
`Disease with High-Dose Mifepristone (RU 486)
`
`JAMES W. CHU, DWIGHT F. MATTHIAS, JOSEPH BELANOFF*, ALAN SCHATZBERG*,
`ANDREW R. HOFFMAN, AND DAVID FELDMAN
`Departments of Medicine (J.W.C., D.F.M., A.R.H., D.F.) and Psychiatry (J.B., A.S.), Stanford University School of Medicine,
`Stanford, California 94305
`
`An extremely ill patient, with Cushing’s syndrome caused by
`an ACTH-secreting pituitary macroadenoma, experienced
`complications of end-stage cardiomyopathy, profound psy-
`chosis, and multiple metabolic disturbances. Initially treated
`unsuccessfully by a combination of conventional surgical,
`medical, and radiotherapeutic approaches, he responded dra-
`matically to high-dose long-term mifepristone therapy (up to
`25 mg/kg䡠d). Treatment efficacy was confirmed by the normal-
`ization of all biochemical glucocorticoid-sensitive measure-
`ments, as well as by the significant reversal of the patient’s
`heart failure, the resolution of his psychotic depression, and
`the eventual unusual return of his adrenal axis to normal. His
`
`18-month-long mifepristone treatment course was notable for
`development of severe hypokalemia that was attributed to
`excessive cortisol activation of the mineralocorticoid recep-
`tor, which responded to spironolactone administration. This
`case illustrates the efficacy of high-dose long-term treatment
`with mifepristone in refractory Cushing’s syndrome. The case
`also demonstrates the potential need for concomitant miner-
`alocorticoid receptor blockade in mifepristone-treated Cush-
`ing’s disease, because cortisol levels may rise markedly,
`reflecting corticotroph disinhibition, to cause manifestations
`of mineralocorticoid excess. (J Clin Endocrinol Metab 86:
`3568–3573, 2001)
`
`CHRONIC EXPOSURE TO excessive corticosteroids in
`
`Cushing’s syndrome (CS) leads to the development of
`multiple metabolic abnormalities, including glucose intoler-
`ance, dyslipidemia, hypertension, osteoporosis, and weight
`gain (1). Cushing’s disease (CD) accounts for approximately
`70% of cases of endogenous CS. The standard initial treat-
`ment of CD is transsphenoidal adenomectomy, which
`achieves cure rates of 70–80% (1). Pituitary macroadenomas
`(size ⬎ 1 cm) are more difficult to cure than microadenomas
`(size ⬍ 1 cm). Patients suffering residual or recurrent disease
`undergo repeat transsphenoidal hypophysectomy, external
`beam pituitary irradiation, medical adrenolytic therapy, or
`surgical adrenalectomy to control the hyperadrenocorticism
`(1, 2). However, no particular therapy is completely satis-
`factory. Repeat transsphenoidal surgery results in high re-
`lapse rates, therapeutic effects from pituitary radiotherapy
`are delayed, the steroidogenic enzyme inhibitors for chem-
`ical adrenalectomy (metyrapone, mitotane, aminoglutethim-
`ide, ketoconazole) are often limited by severe toxicity and
`inadequate cortisol suppression, and surgical approaches to
`accomplish total adrenalectomy may not fully extirpate ad-
`renocortical tissue (1, 2). Adrenalectomy also carries the risk
`of rapid residual pituitary corticotroph growth, i.e. Nelson’s
`syndrome.
`We describe a patient with refractory CD and multiple
`medical comorbidities who exhausted conventional thera-
`pies but was successfully treated with high-dose mifepris-
`tone (RU 486), a glucocorticoid receptor (GR) antagonist (3),
`
`Abbreviations: 11␤HSD, 11␤-hydroxysteroid dehydrogenase; BPRS,
`brief psychiatric rating scale; CD, Cushing’s disease; CS, Cushing’s
`syndrome; GR, glucocorticoid receptor; LVEF, left ventricular ejection
`fraction; LVH, left ventricular hypertrophy; MR, mineralocorticoid re-
`ceptor; MRI, magnetic resonance imaging.
`
`as a bridge until the therapeutic effects of delayed radiation
`therapy became manifest. Not only did the patient’s hypo-
`thalamic-pituitary-adrenal axis return to normal, but his
`multiple medical problems all dramatically reversed. During
`mifepristone therapy, the patient, in addition, required spi-
`ronolactone, a mineralocorticoid receptor (MR) antagonist,
`to ameliorate cortisol-induced MR activation, a result of el-
`evated serum cortisol produced by mifepristone-induced
`corticotroph disinhibition.
`
`Case Report
`The patient was a 51-yr-old African-American retired me-
`chanic who was diagnosed with diabetes mellitus type 2 and
`hypertension, 6 yr before his evaluation at our institution.
`One year before admission, he developed recurrent syncope.
`Transthoracic echocardiography showed severe left ventric-
`ular hypertrophy (LVH) and left ventricular ejection fraction
`(LVEF) of 20%. Coronary angiography revealed an isolated
`60% occlusion of the left anterior descending artery that
`underwent percutaneous transluminal angioplasty and
`stenting. In the 6 months before admission, the patient was
`treated, at three other hospitals, for recurrent upper and
`lower extremity abscesses. Several incision and drainage pro-
`cedures did not yield any microbial etiology. An increased
`frequency of syncopal episodes, concomitantly with New
`York Heart Association functional class IV symptoms, led to
`the patient’s referral for evaluation of cardiac transplantation
`at our facility.
`At the time of arrival at our institution, the patient’s med-
`ications included digoxin, captopril, carvedilol, hydralazine,
`isosorbide, and insulin. Physical examination showed a
`wheelchair-bound man, with rounded facies, appearing
`chronically ill and acutely in distress. His blood pressure was
`
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`Chu et al. (cid:127) Mifepristone Therapy of Cushing’s Disease
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`The Journal of Clinical Endocrinology & Metabolism, August 2001, 86(8):3568–3573 3569
`
`130/82, pulse was 92 and regular, height was 1.78 m, and
`weight was 80 kg. The patient was somnolent and unable to
`provide any medical history. He was extremely weak and
`had striking muscular atrophy of the extremities. There were
`no abdominal striae, but there was palpable hepatomegaly
`and prominent pedal edema. He had fluctuant, warm, red,
`tender lesions involving the right upper and left lower extrem-
`ities. When the patient tried to stand, he developed syncope.
`During the subsequent hospitalization, chest radiography
`showed diffuse cardiomegaly, an electrocardiogram re-
`vealed LVH with secondary repolarization abnormality, and
`a repeat echocardiogram demonstrated LVEF of 22%, con-
`centric LVH, and left ventricular enlargement. The patient’s
`cardiomyopathy was deemed out of proportion to the iso-
`lated coronary atherosclerosis. Cryptococcus neoformans was
`cultured from the extremity abscesses, serum Cryptococcus
`antigen titers were positive (1:512), urine and sputum cul-
`tures revealed Candida albicans, and a left toe skin culture
`grew Trichophytum rubrum. The patient was started on flucy-
`tosine and fluconazole to treat the cryptococcosis. His gly-
`cemic control was poor, despite using more than 100 U insulin
`per day. Retinal examination showed diabetic retinopathy, and
`urine studies revealed proteinuria.
`To screen for possible CS, a low-dose (1 mg) dexametha-
`sone overnight suppression test was performed, demonstrat-
`ing a nonsuppressed serum cortisol (1493 nm). ACTH-
`dependent CS was diagnosed by finding concomitant ele-
`vated ACTH (81 pm) and serum cortisol levels (⬎828 nm).
`High-dose (8 mg) dexamethasone did not suppress the cor-
`tisol (1294 nm). CRF levels were undetectable. Magnetic res-
`onance imaging (MRI) revealed a cystic 2 ⫻ 1-cm pituitary
`mass (Fig. 1). Formal visual field testing was negative. Com-
`puted tomography of the adrenal glands showed bilateral
`hyperplasia. Despite failure of the high-dose dexamethasone
`suppression (including a repeat test using 32 mg dexameth-
`asone), the patient was diagnosed with CD (4) but was
`deemed too ill to undergo confirmatory inferior petrosal
`sinus sampling. The patient’s antifungal regimen was
`changed to include ketoconazole, because this imidazole de-
`
`rivative can inhibit steroidogenesis (5). However, ketocon-
`azole was incompletely effective, and metyrapone was started,
`but the latter was abruptly discontinued after coincident de-
`velopment of atrial arrhythmias, requiring cardioversion.
`During the patient’s transsphenoidal adenomectomy, all
`visible traces of a soft cystic tumor were removed, but in-
`vasion of adjacent structures precluded complete surgical
`extirpation. A postoperative MRI scan confirmed residual
`tissue in the sella turcica. Histopathological analysis revealed
`a necrotic adenoma. A predominant pituitary cell type was
`unidentifiable by immunohistochemistry, because all immu-
`nostaining was inadequate because of the necrotic state of the
`specimen. Postoperatively, ACTH and cortisol levels de-
`clined but remained abnormally elevated (Fig. 2). Ketocon-
`azole was reinstituted at 1200 mg/d to inhibit steroidogen-
`esis. One month later, the patient underwent 3-dimensional
`conformal external beam radiotherapy, receiving 5040 cGy to
`the pituitary bed in 28 fractions over 6 wk. On ketoconazole,
`the patient developed extreme nausea and elevated
`transaminases (ALT 228 IU/L), necessitating a change to
`mitotane therapy (2 g/d) for 2 months. His ACTH remained
`more than 18 pm; and serum cortisol, more than 773 nm. His
`gonadal axis declined: total testosterone, 1.9 nm (normal,
`12.1–24.9); free testosterone, 0.01 nm (normal, 0.04–0.11); and
`FSH, less than 1 IU/L (normal, 1.55–9.74). He was started on
`im testosterone therapy.
`On psychiatric evaluation, the patient was severely de-
`pressed, with a 21-item Hamilton depression rating scale score
`of 27 (normal, ⬍5). Although he denied symptoms of overt
`psychosis, his brief psychiatric rating scale (BPRS) was 38 (nor-
`mal, ⬍18). He showed significant cognitive impairment, as
`indicated by grossly diminished scores on multiple aspects of
`the paragraph recall test and the Stroop color-word test.
`
`Materials and Methods
`
`Serum cortisol was measured using the IMMULITE competitive im-
`munoassay (Diagnostic Products Corp., Los Angeles, CA), whereas
`ACTH was determined by ARUP Laboratories (Salt Lake City, UT) using
`a chemiluminescent immunoassay. Other measurements were per-
`
`FIG. 1. Brain MRI images of a 51-yr-old man with CD. Sagittal T1-weighted (left panel) and coronal T1-weighted postgadolinium (right panel)
`MRIs of the brain demonstrate a cystic pituitary mass measuring approximately 2 ⫻ 1 cm.
`
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`3570 The Journal of Clinical Endocrinology & Metabolism, August 2001, 86(8):3568–3573
`
`Chu et al. (cid:127) Mifepristone Therapy of Cushing’s Disease
`
`FIG. 2. Adrenal axis function in a man
`with CD treated with mifepristone.
`Note that measurements of serum cor-
`tisol are expressed in ␮g/dl (1 ␮g/dl ⫽
`27.59 nM), and those of ACTH are ex-
`pressed in ng/L (1 ng/liter ⫽ 0.22 pM). A,
`Transsphenoidal resection of pituitary
`adenoma; B, start of external beam ra-
`diotherapy; C, end of external beam ra-
`diotherapy; D, medical adrenolytic
`therapy; E, acute adrenocortical insuf-
`ficiency.
`
`formed in the Stanford Clinical Laboratory using standard procedures.
`Bone mineral densitometry was assessed by dual-x-ray absorptiometry
`employing a Hologic, Inc. (Bedford, MA) QDR 4500 apparatus. Neu-
`ropsychiatric testing used the Hamilton depression rating Scale
`(HAMD-21), brief psychiatric rating scale, Stroop color-word test, and
`paragraph recall test, as reported previously (6).
`
`Results
`The patient remained extremely ill, and it was anticipated
`that the radiotherapy would not show benefit for at least 1
`yr. Chemical adrenalectomy had been unsuccessful, and the
`patient’s cardiac status was considered too tenuous to un-
`dergo adrenalectomy, even via a laparoscopic approach.
`Given the lack of feasible effective therapies, the patient was
`initiated on mifepristone at 400 mg/d (⬃6 mg/kg䡠d). This
`was done with his informed consent, permission from the
`human subjects committee, and an Investigational New
`Drug approval from the Food and Drug Administration. It
`was hoped that mifepristone, begun 5 months after diagnosis
`of CD, would control the hypercortisolism until the radio-
`therapy took effect.
`During the initial 8 months of mifepristone treatment, the
`dose was gradually increased to a maximum of 2000 mg/d
`(⬃25 mg/kg䡠d) in response to continued signs of hypercor-
`tisolism (Fig. 2). It was recognized that the fluctuating, but
`
`persistently elevated, serum ACTH and cortisol could not
`accurately reflect therapeutic efficacy, because mifepristone
`antagonizes the hypercortisolemic effects at the receptor
`level, not by altering corticosteroid production (7). Severe
`hypokalemia (potassium ⬍ 3 mm) developed, requiring
`high-dose potassium replacement and initiation of spirono-
`lactone therapy. However, clinical findings attributable to CS
`slowly improved, and the mifepristone dosage was titrated
`downwards over the following 10 months. The accompany-
`ing fall in ACTH and cortisol concentrations likely repre-
`sented delayed effects of radiotherapy, although spontane-
`ous improvement could not be ruled out (8). In month 10 of
`mifepristone therapy, at 800 mg/d (⬃10 mg/kg䡠d), the
`patient experienced an episode of suspected adrenocortical
`insufficiency, manifested by weakness, orthostatic hypoten-
`sion, and hypoglycemia (serum glucose ⬃1.1 mm, not on
`antidiabetic drugs), which necessitated dexamethasone
`bolus therapy and mifepristone dose reduction, to which he
`responded.
`By month 18 of mifepristone therapy, the patient’s overall
`appearance was markedly improved, and he now walked
`unassisted. The ACTH had fallen (⬍8.8 pm), and the serum
`cortisol was not only suppressible, by low-dose dexameth-
`asone to 30 nm, but was also normally responsive to exog-
`
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`Chu et al. (cid:127) Mifepristone Therapy of Cushing’s Disease
`
`The Journal of Clinical Endocrinology & Metabolism, August 2001, 86(8):3568–3573 3571
`
`enous corticotropin (from 433 to 1112 nm). Presuming an
`intact hypothalamic-pituitary-adrenal axis, the mifepristone
`dose was tapered and discontinued.
`Of the severe metabolic, cardiovascular, and neuropsy-
`chiatric dysfunction (Table 1) associated with CD, the most
`remarkable improvement in this patient was his transfor-
`mation from a wheelchair-bound heart-transplant candidate
`to an active individual walking 1–2 miles a day. The echo-
`cardiographic finding of a marked increase in LVEF, to 35–
`40%, corroborated this observation. The multiple fungal in-
`fections did not recur after cessation of antifungal agents. The
`severe insulin resistance abated, and glycemic control re-
`mained in a desirable range without the use of antidiabetic
`medications. The marked hypertriglyceridemia regressed
`without therapy. Markers of bone turnover and bone mineral
`density improved. The hypokalemia resolved, and the blood
`pressure has been well controlled, with the remaining anti-
`hypertensives consisting of carvedilol and furosemide to
`treat the congestive heart failure. Other medications in-
`cluded levothyroxine [to treat mild hypothyroidism; FT4,
`10.2 pm (normal, 9.0–25.7); TSH, 7.22 U/L (normal, 0.4–4.0)],
`im testosterone, and digoxin.
`The patient’s neuropsychiatric status improved dramati-
`cally. His elevated BPRS score, indicating psychosis, entirely
`resolved; and his mood normalized. His cognition improved
`substantially, with dramatic correction in all aspects of the
`Stroop color-word and paragraph recall tests. After recovery,
`the patient revealed that he had been far more psychotic than
`he had admitted at the onset of mifepristone treatment, de-
`scribing previous visual hallucinations and feelings of being
`observed by unseen people. He had not initially acknowl-
`
`edged these symptoms because he thought that he would
`“sound crazy” (which indicates preserved insight).
`
`Discussion
`17␤-hydroxy-11␤-(4-dimethylaminophenyl)-17␣-(1-
`propynyl)-estra-4,9-dien-3-one, also known as RU 38486,
`RU 486, or mifepristone is a potent antagonist of both glu-
`cocorticoid and progestin receptors (3). Its clinical proper-
`ties yield an effective contraceptive, as well as abortifacient;
`and it may have potential benefit in treating CS, unresect-
`able meningioma and leiomyoma, refractory endometriosis,
`metastatic breast cancer, and even psychotic depression (6,
`9). We describe a patient with a pituitary macroadenoma,
`causing refractory CD, associated with multiple severe
`physiologic derangements that regressed after amelioration
`of hypercortisolism. Mifepristone was used successfully to
`antagonize the effects of hypercortisolism while awaiting
`the delayed remission induced by pituitary irradiation. Our
`report, describing the highest dose of mifepristone achieved
`for the longest duration reported in a patient with CS,
`coincides with the recent approval of mifepristone for usage
`in the United States, and it supports the utility of this
`therapy in managing hypercortisolism.
`Previous reports have described clinically therapeutic
`mifepristone usage in more than 14 patients with CS (10, 11).
`A potential adverse effect experienced by these and other
`patients treated with high-dose mifepristone for long periods
`involves episodes of possible adrenal insufficiency that can-
`not be confirmed biochemically but that resolve after exog-
`enous glucocorticoid administration and mifepristone
`
`TABLE 1. Hormonal, metabolic, cardiovascular, and neuropsychiatric indices at diagnosis of Cushing’s disease and before, during, and
`after mifepristone therapy
`
`Index
`
`At initial
`diagnosis
`
`At start of
`mifepristone
`therapy
`
`During
`mifepristone
`therapy
`
`After
`mifepristone
`therapy
`
`Normal values
`
`2.9–11.4
`
`166–580
`⬍138
`0
`
`0.99–2.39
`
`age-dependent
`age-dependent
`4–6%
`
`⬍5.18
`⬎0.91
`⬍3.37
`⬍2.26
`3.5–5.0
`
`0
`
`⬎50%
`
`⬍5
`18
`
`Hormonal
`ACTH (pM)
`Serum cortisol (nM)
`Fasting
`After dexamethasone, 1 mg
`Exogenous insulin use (U/d)
`Metabolic
`Serum osteocalcin (nM)
`Bone mineral density (g/cm2)
`Left total hip
`Lumbar spine (1–4)
`Hemoglobin A1c (%)
`Serum cholesterol (mM)
`Total
`HDL
`LDL
`Fasting triglycerides (mg/dl)
`Potassium (mM)
`Cardiovascular function
`New York Heart Association
`functional class
`Estimated left ventricular
`ejection fraction
`Neuropsychiatric function
`27
`—
`21-Item Hamilton-D score
`38
`—
`BPRS score
`HDL, High-density lipoprotein; LDL, low-density lipoprotein; —, not available.
`
`20
`
`1076
`—
`70
`
`0.80
`
`—
`—
`10.4
`
`8.11
`0.91
`—
`4.83
`4.2
`
`IV
`
`—
`
`81
`
`949
`1493
`115
`
`—
`
`—
`—
`11.5
`
`—
`—
`—
`—
`4.0
`
`IV
`
`19%
`
`28
`
`1402
`—
`40
`
`6.43
`
`0.795
`0.977
`7.7
`
`7.17
`0.54
`—
`5.48
`3.0
`
`II–III
`
`30%
`
`18
`20
`
`6
`
`320
`30
`0
`
`7.66
`
`0.822
`0.989
`6.9
`
`5.28
`0.85
`3.52
`2.00
`4.4
`
`I
`
`35–40%
`
`8
`18
`
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`3572 The Journal of Clinical Endocrinology & Metabolism, August 2001, 86(8):3568–3573
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`Chu et al. (cid:127) Mifepristone Therapy of Cushing’s Disease
`
`dose reduction (cited within Refs. 3 and 11). The difficult
`monitoring of therapeutic efficacy stems from the lack of a
`biomarker of GR activity. Because mifepristone antagonizes
`the GR of the pituitary corticotrophs, as well as that of pe-
`ripheral tissues, its administration causes disinhibition of
`ACTH release, with consequently increased levels of ACTH
`and serum cortisol (7). Thus, patients undergoing mifepris-
`tone treatment may manifest seemingly paradoxical findings
`of elevated circulating ACTH and cortisol concentrations
`accompanying symptoms of adrenocortical insufficiency. In
`our patient’s case, the additional inhibition of MR by spi-
`ronolactone may have further contributed to the symptoms
`that suggested adrenal insufficiency.
`Notable aspects of this patient’s case include the pro-
`nounced, yet reversible, cardiac failure, as well as the severe
`hypokalemia. These clinical effects may be attributable to
`abnormal overactivation of MR. In physiological settings, the
`enzyme 11␤-hydroxysteroid dehydrogenase (11␤HSD) con-
`verts cortisol, an avid GR- and MR-binding glucocorticoid,
`to its 11-keto analog (cortisone), a non-GR, non-MR-binding
`glucocorticoid (12). This conversion protects the MR from
`cortisol, thereby maintaining the in vivo specificity of MR
`activation by aldosterone, which circulates in concentrations
`100-1000 times less than that of cortisol. However, in CS,
`where the capacity of 11␤HSD to guard the MR is over-
`whelmed or impaired, illicit cortisol overstimulation of MR
`leads to hypokalemic alkalosis and hypertension (13). Be-
`cause mifepristone inhibits cortisol binding to GR, but not to
`MR, and causes ACTH disinhibition to further exacerbate
`endogenous hypercortisolism (which is likely to have pro-
`voked hypokalemia in this case), we treated this patient, in
`addition, with the MR antagonist spironolactone. The com-
`bination therapy was intended to prevent deleterious effects
`of cortisol- mediated receptor activation by achieving dual
`blockade of GR and MR.
`The end-stage heart failure that dramatically improved,
`after the amelioration of glucocorticoid excess, raises the
`question of whether the cardiomyopathy was directly caused
`by hypercortisolism (14, 15). Patients with endogenous CS
`are commonly affected by severe LVH out of proportion to
`the degree of concomitant hypertension (14, 15), and this
`LVH frequently leads to heart failure. Are such adverse car-
`diovascular findings in CS mediated by cortisol activation at
`the GR and/or at the MR level? MRs have been reported to
`occur not only in kidney epithelium but also in myocardium,
`and increased cardiac fibrosis is seen in endomyocardial
`biopsies from CS patients (14), reminiscent of the fibrosis and
`other abnormalities attributed to aldosterone-associated MR
`activation in congestive heart failure (16). The same processes
`contributing to the progression of heart failure are effectively
`attenuated or reversed by antialdosterone therapy (17, 18).
`Thus, it is possible that the cardiomyopathy of CS may result
`from cortisol-mediated overstimulation of myocardial MR,
`just as the features of apparent mineralocorticoid excess in CS
`may result from cortisol-mediated overactivation of renal
`epithelial MR, with both abnormal findings being manifested
`in the setting of overwhelmed or defective 11␤HSD activity.
`The patient’s marked elevation in serum cortisol and
`ACTH was nonsuppressible after high-dose dexamethasone;
`this is consistent with other reports of pituitary macroad-
`
`enomas causing CD and does not necessarily denote an ec-
`topic ACTH syndrome (4). Furthermore, it can be postulated
`that the hormonally aggressive behavior of the patient’s mac-
`roadenoma potentiated not only the cardiomyopathy but
`also the hypokalemia and hypertension, the latter two find-
`ings of which are much more commonly observed in CS
`patients with ectopic ACTH-secreting tumors (13). A striking
`clinical result of this case is the reappearance of an ostensibly
`normal hypothalamic-pituitary-adrenal axis, at the patient’s
`most recent evaluation; this result is uncommonly reported,
`given that the treatment of refractory CD tends to render
`patients adrenocortical-deficient.
`The association between hypercortisolism and neuropsy-
`chiatric symptoms has been known for decades, with an
`estimated prevalence of psychiatric dysfunction of more than
`40% in patients with CS (19). Psychosis and cognitive im-
`pairment are noted less commonly than depression, but this
`may stem from the use of inappropriate detection techniques.
`If suitable tests to reveal psychosis and impaired cognition
`are used, it is possible that the symptoms of patients with CS
`would best be classified as psychotic major depression or
`major depression with cognitive impairment. Our patient’s
`features of depression improved markedly after treatment of
`CS, although he exhibited residual insomnia and anxiety.
`However, the psychosis totally abated, and cognition nor-
`malized. Interestingly, the recognition of the link between
`adrenal axis dysfunction and affective disorders has led to
`successful use of mifepristone in treating psychotic depres-
`sion, as detailed in a separate report (6).
`In conclusion, an improved understanding of the interac-
`tions between glucocorticoids, mineralocorticoids, receptors,
`and end-organ effects, in conjunction with the rational ap-
`plication of receptor antagonists, can lead to directed therapy
`of the numerous morbidities associated with severe CS. In
`this report, combination use of mifepristone and spirono-
`lactone allowed the dramatic reversal of cardiovascular, met-
`abolic, and neuropsychiatric abnormalities in a patient with
`refractory CD.
`
`Acknowledgments
`
`Received January 9, 2001. Accepted March 13, 2001.
`Address all correspondence and requests for reprints to: David Feld-
`man, M.D., Division of Endocrinology, Room S-005, Stanford University
`School of Medicine, Stanford, California 94305-5103. E-mail: feldman@
`cmgm.stanford.edu.
`This work was supported in part by NIH Grants DK-07217-24 (to
`J.W.C.), RO1-MH50604 (to A.S.), DK-42482 (to D.F.), and Human Health
`Service Grant MO1-RR00070, General Clinical Research Centers,
`National Center for Research Resources.
`* J.B. and A.S. have a financial interest in Corcept Therapeutics Inc.,
`a pharmaceutical company that is testing antiglucocorticoid treatment
`for psychiatric disorders.
`
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