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Endocrine Care |
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
Address all correspondence and requests for reprints to: David Feldman, M.D., Division of Endocrinology, Room S-005, Stanford University School of Medicine, Stanford, California 94305-5103.
Abstract
An extremely ill patient, with Cushing’s syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg·d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, 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 receptor, 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 mineralocorticoid receptor blockade in mifepristone-treated Cushing’s disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.
CHRONIC EXPOSURE TO excessive corticosteroids in Cushing’s syndrome (CS) leads to the development of multiple metabolic abnormalities, including glucose intolerance, dyslipidemia, hypertension, osteoporosis, and weight gain (1). Cushing’s disease (CD) accounts for approximately 70% of cases of endogenous CS. The standard initial treatment 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 satisfactory. Repeat transsphenoidal surgery results in high relapse rates, therapeutic effects from pituitary radiotherapy are delayed, the steroidogenic enzyme inhibitors for chemical adrenalectomy (metyrapone, mitotane, aminoglutethimide, ketoconazole) are often limited by severe toxicity and inadequate cortisol suppression, and surgical approaches to accomplish total adrenalectomy may not fully extirpate adrenocortical 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 therapies but was successfully treated with high-dose mifepristone (RU 486), a glucocorticoid receptor (GR) antagonist (3), as a bridge until the therapeutic effects of delayed radiation therapy became manifest. Not only did the patient’s hypothalamic-pituitary-adrenal axis return to normal, but his multiple medical problems all dramatically reversed. During mifepristone therapy, the patient, in addition, required spironolactone, a mineralocorticoid receptor (MR) antagonist, to ameliorate cortisol-induced MR activation, a result of elevated serum cortisol produced by mifepristone-induced corticotroph disinhibition.
Case Report
The patient was a 51-yr-old African-American retired mechanic 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 ventricular 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 procedures 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 medications 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 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 extremities. When the patient tried to stand, he developed syncope.
During the subsequent hospitalization, chest radiography showed diffuse cardiomegaly, an electrocardiogram revealed LVH with secondary repolarization abnormality, and a repeat echocardiogram demonstrated LVEF of 22%, concentric LVH, and left ventricular enlargement. The patient’s cardiomyopathy was deemed out of proportion to the isolated coronary atherosclerosis. Cryptococcus neoformans was cultured from the extremity abscesses, serum Cryptococcus antigen titers were positive (1:512), urine and sputum cultures revealed Candida albicans, and a left toe skin culture grew Trichophytum rubrum. The patient was started on flucytosine and fluconazole to treat the cryptococcosis. His glycemic 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) dexamethasone overnight
suppression test was performed, demonstrating a nonsuppressed serum
cortisol (1493 nM). ACTH- dependent CS was diagnosed by
finding concomitant elevated ACTH (81 pM) and serum
cortisol levels (>828 nM). High-dose (8 mg) dexamethasone
did not suppress the cortisol (1294 nM). CRF levels were
undetectable. Magnetic resonance imaging (MRI) revealed a cystic 2
x 1-cm pituitary mass (Fig. 1
). Formal
visual field testing was negative. Computed tomography of the adrenal
glands showed bilateral hyperplasia. Despite failure of the high-dose
dexamethasone suppression (including a repeat test using 32 mg
dexamethasone), 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 derivative can
inhibit steroidogenesis (5). However, ketoconazole
was incompletely effective, and metyrapone was started, but the latter
was abruptly discontinued after coincident development of atrial
arrhythmias, requiring cardioversion.
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).
Ketoconazole was reinstituted at 1200 mg/d to inhibit steroidogenesis.
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.
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Materials and Methods
Serum cortisol was measured using the IMMULITE competitive immunoassay (Diagnostic Products Corp., Los Angeles, CA), whereas ACTH was determined by ARUP Laboratories (Salt Lake City, UT) using a chemiluminescent immunoassay. Other measurements were performed 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. Neuropsychiatric 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 undergo 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·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 radiotherapy 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·d) in
response to continued signs of hypercortisolism (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
spironolactone therapy. However, clinical findings attributable to CS
slowly improved, and the mifepristone dosage was titrated downwards
over the following 10 months. The accompanying fall in ACTH and
cortisol concentrations likely represented delayed effects of
radiotherapy, although spontaneous improvement could not be ruled out
(8). In month 10 of mifepristone therapy, at 800 mg/d
(10 mg/kg·d), the patient experienced an episode of suspected
adrenocortical insufficiency, manifested by weakness, orthostatic
hypotension, 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 dexamethasone to 30 nM, but was also normally responsive to exogenous 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 neuropsychiatric
dysfunction (Table 1) associated with CD,
the most remarkable improvement in this patient was his transformation
from a wheelchair-bound heart-transplant candidate to an active
individual walking 1–2 miles a day. The echocardiographic finding of a
marked increase in LVEF, to 35–40%, corroborated this observation.
The multiple fungal infections did not recur after cessation of
antifungal agents. The severe insulin resistance abated, and glycemic
control remained 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 antihypertensives consisting of carvedilol and
furosemide to treat the congestive heart failure. Other medications
included 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.
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Discussion
17ß-hydroxy-11ß-(4-dimethylaminophenyl)-17
-(1propynyl)-estra-4,9-dien-3-one,
also known as RU 38486, RU 486, or mifepristone is a potent antagonist
of both glucocorticoid and progestin receptors (3). Its
clinical properties yield an effective contraceptive, as well as
abortifacient; and it may have potential benefit in treating CS,
unresectable 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 cannot be confirmed biochemically but that resolve after exogenous glucocorticoid administration and mifepristone dose reduction (cited within Refs. 3, 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 peripheral tissues, its administration causes disinhibition of ACTH release, with consequently increased levels of ACTH and serum cortisol (7). Thus, patients undergoing mifepristone 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 spironolactone may have further contributed to the symptoms that suggested adrenal insufficiency.
Notable aspects of this patient’s case include the pronounced, 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 11ß-hydroxysteroid dehydrogenase (11ßHSD) converts 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 11ßHSD to guard the MR is overwhelmed or impaired, illicit cortisol overstimulation of MR leads to hypokalemic alkalosis and hypertension (13). Because mifepristone inhibits cortisol binding to GR, but not to MR, and causes ACTH disinhibition to further exacerbate endogenous hypercortisolism (which is likely to have provoked hypokalemia in this case), we treated this patient, in addition, with the MR antagonist spironolactone. The combination 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 cardiovascular 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 11ßHSD 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 macroadenomas causing CD and does not necessarily denote an ectopic ACTH syndrome (4). Furthermore, it can be postulated that the hormonally aggressive behavior of the patient’s macroadenoma potentiated not only the cardiomyopathy but also the hypokalemia and hypertension, the latter two findings 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 neuropsychiatric 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 impairment 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 normalized. Interestingly, the recognition of the link between adrenal axis dysfunction and affective disorders has led to successful use of mifepristone in treating psychotic depression, as detailed in a separate report (6).
In conclusion, an improved understanding of the interactions between glucocorticoids, mineralocorticoids, receptors, and end-organ effects, in conjunction with the rational application of receptor antagonists, can lead to directed therapy of the numerous morbidities associated with severe CS. In this report, combination use of mifepristone and spironolactone allowed the dramatic reversal of cardiovascular, metabolic, and neuropsychiatric abnormalities in a patient with refractory CD.
Footnotes
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.
1 J.B. and A.S. have a financial interest in Corcept Therapeutics
Inc., a pharmaceutical company that is testing antiglucocorticoid
treatment for psychiatric disorders. 
Abbreviations: 11ßHSD, 11ß-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 receptor; MRI, magnetic resonance imaging.
Received January 9, 2001.
Accepted March 13, 2001.
References
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