[1021-972XK85/6103-D§38$02.00jo
`Journal ol‘Clinical Endocrinology and Metabolism
`Copyright© 1985 by The Endocrine Society
`
`Vol. 61, No. 3
`Printed in US A.
`
`Successful Treatment of Cushing’s Syndrome with the
`Glucocorticoid Antagonist RU 486*
`
`LYNNETTE K. NIEMAN, GEORGE P. CHROUSOS, CHARLES KELLNER,
`IRVING M. SPITZ, BRUCE C. NISULA, GORDON B. CUTLER,
`GEORGE R. MERRIAM, C. WAYNE BARDIN, AND D. LYNN LORIAUX
`
`Developmental Endocrinology Branch, National Institute of Child Health and Human Development (LICN,
`G.P.C., B.C.N., G.B.C., GEM” D. LL); the Biological Psychiatry Branch, National Institute of Mental
`Health (CK), National Institutes ofHeultk, Bethesda, Maryland 20205,- and the Population Council (Lil/1.3.,
`Cid/.13.). New York, New York 00000
`
`ABSTRACT. A patient with Cushing’s syndrome due to ec-
`topic ACTH secretion was treated successfully with the new
`glucocorticoid antagonist RU 486 [ITB—hydroxy-llfi-(Il-dimeth‘
`ylamino phenylHTor-ll-propynyl]estra-4,9-dien-3-one]. This
`compound is a lQ-nor steroid with substitutions at positions C11
`and C]? which antagonizes cortisol action competitively at the
`receptor level. Oral RU 486 was given in increasing doses of 5,
`10, 15, and 20 mg/kg-day for a 9-week period. Treatment eficacy
`was monitored by assessment of clinical status and by measuring
`several glucocorticoid-sensitive variables, including fasting blood
`sugar, blood sugar 120 min after oral glucose administration,
`
`and plasma concentrations of TSH, corticosteroid-binding glob-
`ulin, LH, testosterone-estradiol-binding globulin, and total and
`free testosterone. With therapy, the somatic features of Cush-
`ing's syndrome [buffalo hump, central obesity, and moon faeies)
`ameliorated, mean arterial blood pressure normalized, suicidal
`depression resolved, and libido returned Al! biochemical gluco-
`corticoid—sensitive parameters normalized. No side-effects of
`drug toxicity were observed. We conclude that RU 486 may
`provide a safe, well tolerated, and effective medical treatment
`for hypercortisolism. (J Ctin Enrica-inc! Metab 61: 536, 1.985)
`
`HE CURRENTLY available treatments for Cush-
`
`ing's syndrome caused by metastatic ACTH-pro-
`ducing tumors or adrenal cancer are often unsatisfactory.
`Surgical resection of the tumor, when feasible, may be
`only partially or temporarily effective in controlling
`Cushing’s syndrome. Medical therapy with adrenolytic
`agents lo,p’—DDD) or steroidogcnic enzyme inhibitors
`[aminoglutethimide or metyrapone) is frequently asso-
`ciated with toxic side-effects (1—5}.
`A clinically applicable glucocorticoid antagonist is, in
`theory, an attractive alternative treatment for hypercor-
`tlSOliSm and has been sought for many years {6}. The
`recently discovered compound RU 486 [lTfi—hydroxy-
`1113- (4 -dimethylamino phenyl)1 701- (1 -propynyl)estra~
`4,9-dien-3-one], a 19-nor steroid with a high affinity for
`the rat glucocorticoid receptor with no agenist effects in
`citro or in viva, is a potent competitive glucocorticoid
`antagonist in rodents (7), nonhuman primates [8, 9), and
`man (IO—12).
`
`Received March 15, 1935.
`Address requests for reprints to: Dr. Nieman, National Institutes of
`Health, Building 10, Room 1014262, Bethesda, Maryland 20205.
`' Presented in part at the Seventh International Congress of Endo-
`crinology. Quebec, Canada, July 1984.
`
`536
`
`We report here the successful treatment with RU 486
`of a 25-yr—old man with Cushing’s syndrome caused by
`the ectopic secretion of ACTH. During therapy,
`the
`somatic features of Cushing’s syndrome (cervical fat pad,
`central obesity, and moon facies)
`improved, suicidal
`depression cleared, and glucocorticoid-sensitive meas-
`ures, such as elevated fasting and postabsorptive blood
`sugar, normalized. The drug was tolerated well, and no
`side-effects were noted during therapy or after its discon-
`tinuation.
`
`Case Report
`
`The patient was in excellent health until the fall of 1981
`when he noted loss of strength, short term memory, and atten-
`tion span. In the spring of 1982, because these symptoms
`worsened, be discontinued his weight-lifting regimen. He com-
`plained of increasing anxiety and depression. In September
`1982, he stopped working because of these cognitive and psy-
`chological changes. Treatment with antidepressants was initi-
`ated. His depression deepened, however, and led to two suicide
`attempts. At that time, he had moon facies, hypertension, and
`diabetes, and was evaluated for Cushing’s syndrome. Both
`serum and urinary cortisol levels were elevated, and 17-hydrox-
`ycorticosteroid excretion increased during a standard 2- and 8—
`mg dexamethasone suppression test {13).
`An intrathoracic mass lesion was found and was resected in
`
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`ANTIGLUCOCORTICOlD THERAPY
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`537
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`March 1983. The lesion was not contiguOus with a bronchus.
`Microscopic and immunohistochemical examination of the
`specimen showed a carcinoid tumor with granules that stained
`with anti-ACTH serum. Immediately after surgery, plasma
`cortisol levels were normal. Insulin and antihyperbensive and
`antidepressant medications were discontinued, and the pa-
`tient’s Symptoms improved. By May 1983, h0wever, his symp~
`toms recurred, and his urinary cortisol excretion rate was about
`500 ugfday. He was given metyrapone, but had only transient
`clinical improvement.
`In August 1983, he was admitted to the NIH. He complained
`of disorientation. diminished memory and cognitive ability,
`impotence, a 20—“) weight gain over 3 yr, and long-standing
`muscle weakness. He had a ruddy round face. His blood pres;
`sure was 18:0[120 mm Hg, and his pulse was 90 beats/min. He
`was anxious and depressed. He performed calculations slowly.
`The thoracotomy scar was hyperpigmented. Computerized axial
`tomograms of the chest revealed multiple lung nodules. He had
`hypokalernic alkalosis (serum potassium, 1.9 meqfliter; bicar-
`bonate, 33 meg/liter; chloride, 94 meq/liter; sodium, 147 Inqu
`liter).
`His medications, including maprotiline hydrochloride (Lu-
`diomil), trifloroperazine (Stelazine), benztropin mesylate (Co-
`gentin), and metyrapone (1 g/day} were stopped before labo»
`ratory evaluation. He became withdrawn, severely depressed,
`and complained that he felt unable to think clearly. Ludiomil
`was reinitiated because of suicidal ideation, and his depressive
`symptoms and cognition improved. Potassium supplements
`were given {20-120 meqfday). Treatment with increasing doses
`of RU 486 for 9 weeks caused marked improvement
`in all
`biochemical and clinical parameters of hypercortisolism {see
`Results].
`
`Materials and Methods
`
`Protocol
`
`The protocol for the therapeutic use of RU 486 was approved
`under an investigational exemption for new drugs by the Na-
`tional Center for Drugs and Biologics, DHHS, and by the
`NICHHD Clinical Research Committee (83-CH-87). The pa-
`tient participated in the study after giving informed consent.
`All tests were performed at the NIH Clinical Center.
`RU 486 was formulated into 50—mg tablets by Rousselv
`UCLAF (Paris, France]. A single oral dose of 6 mg/kg RU 486
`given at midnight has been found to prevent morning adrenal
`suppression caused by 1 mg dexemethasone (11). Accordingly,
`the initial oral daily dose was 5 nag/kg and increased in 5 mg}
`kg increments every 1 or 2 weeks to a maximum of 20 mg/kg-
`day {see Fig. 1}.
`.
`A number of clinical and biochemical glucocorticoid-sensi-
`tive measures were monitored to evaluate treatment efficacy.
`Clinical measures included blood pressure and body weight.
`The patient’s mood was assessed daily by a self-report ques-
`tionnaire and three times a week by psychiatric interviews {14).
`Metabolic and hormone measures included urinary excretion
`of nitrogen and fasting and postabsorptive blood sugar, which
`are elevated by hypercortisolism, and plasma concentrations of
`corticosteroid-binding globulin (CBG) (15), testosterone-estra-
`
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`FIG. 1. The effect of RU 486 treatment on glucocorticoid-sensitive
`variables. A, Two hour post-OG'I'I‘ {oral glucose tolerance test] and
`fasting blood sugar levels were elevated before RU 486 therapy and fell
`to normal levels during treatment. The serum TSH concentration was
`initially subnorrnal and rose progressively. CBG concentrations also
`rose into the normal range. Mean daily blood pressure decreased during
`RU 486 therapy. B, Plasma concentrations of LH, total testosterone.
`and free testosterone were initally depressed; all normalized with RU
`486 therapy. TeBG capacity showed similar increases. Shaded areas
`represent the upper (u.|.|.ll or lower (Ll—Ll} normal range.
`
`diol-binding globulin (TeBGJ, testosterone {16. 17), LH {16,
`17), and TSH (18, 19), which are suppressed by hypermrtisoh
`15m.
`
`Plasma ACTH and plasma and urinary cortisol levels also
`were measured frequently. Metabolic and hormonal measure-
`ments were made on one to three morning blood samples drawn
`before therapy and during the final week of each dose interval.
`Standard oral glucose tolerance tests were performed after 3
`days of ingestion of a IOU-g carbohydrate diet using a loll-g
`glucose challenge. Creatinine, blood urea nitrogen (BUN),
`serum glutamic oxaloacetic acid-transaminase (SGOT), and
`serum glutamic pyruvic acid-transaminase (SGPT) measure-
`ments were monitored throughout treatment as indices of drug
`toxicity. Serial electrocardiograms and chest x-rays were done
`for a similar purpose.
`
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`538
`
`Assays
`
`Plasma testosterone (20), LH (21}, ACTH (22], steroid bio—
`synthetic intermediates (pregnenolone, 17-hydroxypregneno-
`lone, 17-hydroxyprogesterone, and 11-deoxycortisol} (20, 23),
`plasma and urinary cortisol (23), and serum 'I‘SH (24) were
`measured by RIA as previously described. CBC and TeBG were
`measured using a solid phase Concanavalin A-Sepharose assay
`(25). The free testosterone concentration was calculated from
`the measured levels of total hormone and binding proteins
`(albumin and TeBG) {25}. Plasma glucose concentrations were
`measured with a Cobas bioanalyzer; SGOT, SGPT, BUN, cre-
`atinine and albumin concentrations were measured with an
`Autoanalyzer (Beckman, Palo Alto, CA).
`Using a previously described method for separation of bound
`from free hormone (25}, competitive binding assays were done
`to exclude displacement by RU 486 of testosterone or cortisol
`from their plasma binding proteins, an action that might result
`in spurious changes in hormone concentrations. Increasing
`concentrations of RU 486 or unlabled hormone were added to
`samples with known amounts of radioactively labeled hormone
`and binding globulin. RU 486 did not displace cortisol from
`CBG or testosterone from TeBG in concentrations ranging
`from 10"0—10'5 M.
`
`Results
`
`All glucocorticoid-sensitive clinical and biochemical
`parameters were initially abnormal in this patient, and
`each became normal during treatment with RU 486
`despite continued marked hypercortisolism.
`The physical stigmata of Cushing’s syndrome, includ-
`ing supraclavicular and dorsocei-vical fat pads and central
`obesity, regressed considerably by the conclusion of ther-
`apy. This change in fat distribution was not associated,
`however, with achange in total body weight, which varied
`between 85 and 89 kg both before and during RU 486
`treatment. Maximum daily systolic and diastolic blood
`pressures decreased steadily during treatment with RU
`486, from 200/120 mm Hg before therapy, to 140/90 mm
`Hg at its conclusion (Fig. 1A). The hypokalemic alkalosis
`resolved, serum potassium ranged from 3.9—4.6 meg/liter,
`and serum bicarbonate ranged from 25—29 meq/liter
`following discontinuation of potassium after the sixth
`week of RU 486 therapy.
`Both subjective and objective psychological measures
`improved during RU 486 therapy. When the daily dose
`of RU 486 was increased to 15 mg/kg, Ludiomil therapy
`was stopped (fourth week of therapy}. The patient’s
`depression continued to improve, and he reported in-
`creasing attention span, libido, and sense of wellbeing.
`This subjective improvement was corroborated by self-
`rating questionnaires and psychiatric interviews.
`Plasma glucose levels were initially 140 mg/dl in the
`fasting state (normal, <105 mg/dl) and 268 mg/dl 2 h
`after ingestion of 100 g glucose (normal, (140 mg/dl', Fig.
`1A]. The fasting blood sugar level became normal while
`
`NIEMAN ET AL.
`
`JCE& Muses
`Volfii-Nofi
`
`the patient was taking RU 486 in a dose of 10 mg/kg-
`day, and the 2 h pastoral glucose tolerance test blood
`sugar level normalized when he was taking 20 rag/kg
`(Fig. 1A). Serum TSH concentration was initially sub-
`normal ((0.18 nU/ml) and rose progressively to 1.5 ,uU/
`ml during treatment (normai, 0.54.5 ,uU/ml; Fig. 1A).
`CBC-binding capacity increased from 7.4 rig/d1 (normal,
`12.2—20 rig/d1) to 16.8 ,ug/dl (Fig. 1B).
`Plasma LH levels rose during treatment with RU 486
`from 9.4 to 23.2 mIU/ml (normal, 6—26 mIU/ml; Fig.
`1B). Similarly, plasma total and free testosterone con-
`centrations and TeBG-binding capacity increased from
`subnormal to normal levels during therapy with RU 486
`(Fig. 13}. The total testosterone concentration was ini—
`tially 73 ng/dl (normal, 20041000 rig/d1} and rose to 842
`ng/dl when the patient was taking 20 mg/kg-day RU
`486. TeBG capacity increased frOm 0.063 ,ug/dl (normal,
`0.2—1.0 pg/dl) to 1.02 pg/dl at the conclusion of therapy.
`Free testosterone increased from 3.5 ng/dl (normal, 5—
`30 ngfdl) to 1?.4 ng/dl.
`Twenty-four hour urinary nitrogen excretion fell from
`22 g/day (normal, 12—20 g/day} before treatment to 5 g/
`day at its conclusion. No abnormalities in serum creati-
`nine, BUN, SGOT, or SGPT, urinalysis, electrocardi—
`ogram, chest radiography, or physical examination were
`found during or after therapy. The patient experienced
`no adverse subjective effects.
`In contrast to the marked improvement in these glu-
`cocorticoid—sensitive parameters, urinary cortisol,
`plasma cortisol, and ACTH levels remained significantiy
`elevated throughout the treatment with RU 486. 6-50
`gel chromatography revealed that 85% of ACTH immu-
`noreactivity was in the same fractions as ACTH—(L39).
`Before initiation of RU therapy, the mean plasma ACTH
`concentration was 165 :r. 7.6 (1513:) pg/ml (n = 5); during
`treatment, it was 241 i 14 pg/ml (n = 14; normal, 8—15
`pg/ml}. The range of plasma cortisol concentration was
`29-495 ,ug/dl (mean t SE, 43.5 i 3.3 pig/(fl; n = 7) before
`and 13.8—56.5 rig/d1 {mean 1 SE, 31.8 i 2.0 rig/d1; n =
`27) during RU 486 administration (normal, 8—18 pg/dl).
`Mean daily urinary cortisol excretion rates also were
`elevated, ranging between 514 and 11,592 pg/day (mean
`t SE, 4865 i 1159 rig/24 h; n = 11) before therapy.
`During therapy, urinary cortisol excretion was similar
`and ranged between 106 and 8072 Jug/day (mean t SE,
`1175 i 327 rig/24 h; n = 27; normal, 20~95 rig/24 h).
`Plasma steroid precursor concentrations during ther-
`apy were within the normal range or mildly elevated.
`Pregnenolone was 124 ng/dl (normal, <250), 17-hydrox-
`ypregnenolone was 135 ng/dl (normal, <250), 17-hydrox-
`yprogesterone was 706 ng/dl (normal, (200), and 11—
`deoxycortisol was 431 ng/dl (normal, (200).
`No side-effects occurred during RU 486 treatment. In
`the 10th week, because limited availability of RU 436
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`ANTIGLUCOCORTICOID THERAPY
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`539
`
`prevented further treatment, the patient underwent a
`bilateral adrenalectomy 48 h after discoritinuation of
`therapy and during supplemental glucocorticoid therapy.
`Tissue vascularity was normal at the time of surgery,
`and his postoperative course and wound healing were
`satisfactory.
`
`Discussion
`
`The glucocorticoid antagonist RU 486 ameliorated the
`clinical and biochemical features of hypercortisoiism in
`this patient. Treatment with RU 486 was associated with
`redistribution of body fat and resolution of severe depres—
`sion, hyperglycemia, and hypertension, obviating the
`need for a variety of medications which he previously
`required. Several hormonal disorders typical of hyper-
`cortisolism (suppressed plasma levels of TSH, LH, tes-
`testerone, CBG, and TeBG) also reverted to normal
`during RU 486 therapy (15, 19}.
`The satisfactory response to RU 486 administration
`despite persistent marked elevation of serum and urinary
`cortisol levels is consistent with studies of its mechanism
`of action in vitro and in animals. RU 486 interacts with
`
`the glucocorticoid receptor and thereby blocks the effects
`of cortisol (7). The mild decline in plasma and urinary
`cortisol during therapy might be due to an additional
`effect of RU 486 to diminish adrenal steroidogenesis
`directly via enzyme inhibition or a result of spontaneous
`fluctuation in the severity of the syndrome. No major
`block occurred, however, in the enzymes 36-hydroxyste-
`roid dehydrogenase-A5,A"-isomerase,21-hydroxy1ase, 17-
`hydroxylase, or ll-hydroxylase, as suggested from the
`levels of measured steroid precursors in the patient’s
`plasma.
`Although RU 486 was an effective therapy in our
`patient with Cushing’s syndrome due to ectopic ACTH
`secretion, control may be more difficult to achieve in
`patients with hypercortisolism of pituitary origin (Cush-
`ing’s disease). Previous studies in nonhuman primates
`and normal subjects suggest that the dose of RU 486
`necessary to achieve normal glucocorticoid status in
`Cushing’s syndrome will depend on the plasma free cor-
`tisol concentration and the presence of cortisol feedback.
`In nonhuman primates and normal men and women,
`doses of RU 486 greater than 5 mg} kg cause an increase
`in both plasma cortisol and ACTH levels, presumably by
`antagonizing cortisol feedback at the pituitary or hypo-
`thalamus (8—12). In patients with Cushing‘s disease in
`whom cortisol feedback is present, ACTH levels may
`increase, perhaps in an exaggerated manner, as is often
`the case with ACTH reSponses to CRH (22) or metyra-
`pone (26). Nevertheless, high doses of a glucocorticoid
`antagonist may overcome the reserve of the pituitary
`adrenal axis in patients with Cushing’s disease and thus
`
`alleviate the texic effects of hypercorticolism on tissues.
`If this were true, then an antigiucocorticoid could be used
`for preparation of patients for surgery.
`The lack of side-effects or toxicity associated with RU
`486 administration in our patient contrasts markedly
`with the morbidity that characterizes the other medicai
`treatments for hypercortisolism. Although the incidence
`of side-effects cannot be established until additional
`
`patients are studied, the present experience suggests that
`RU 486 therapy may be tolerated better than other
`currently available medical treatments of hypercortisol-
`ism. Greater toierance may yield greater efficacy, since
`the avaiiable medical treatments often cannot be given
`in fully effective doses because of their sideaeffects.
`One potential problem with RU 486 is that overtreat-
`ment might cause glucocorticoid insufficiency. Since glu-
`cocorticoid insufficiency cannot be assessed through
`measurement of adrenal steroids during RU 486 therapy,
`we suggest that patients be given RU 486 in gradually
`increasing doses in concert with careful evaluation for
`signs and symptoms of adrenal insufficiency.
`Currently, the major drawback of RU 486 is that it is
`costly to synthesize and not available in quantities suf-
`ficient for extensive clinical study. Despite these prob-
`lems, RU 486 holds promise as a safe, well tolerated, and
`effective medical therapy for hypercortisolism that mer-
`its further clinical evaluation.
`
`Acknowledgments
`We would like to thank Ms. Penny Colbert, Mary Hall, and Mary
`Beth McCole for their assistance in typing this manuscript.
`
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