0021-972X/85/6103-0536$02.00/0
`Journal of Clinical Endocrinology and Metabolism
`Copyright© 1985 by The Endocrine Society
`
`Vol.6l, No 3
`Printed in U.s.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, N ational Institute of Child Health and Human Development (L.K.N.,
`G.P.C., B. C.N., G.B.C., G.R.M., D.L.L.); the Biological Psychiatry Branch, National Institute of Mental
`Health (C.K), National Institutes of Health, Bethesda, Maryland 20205; and the Population Council (!.M.S .,
`C. W. B.), New York, New York 00000
`
`ABSTRACT. A patient with Cushing's syndrome due to ec(cid:173)
`topic ACTH secretion was treated successfully with the new
`glucocorticoid antagonist RU 486 (17{j-hydroxy-ll{j-(4-dimeth(cid:173)
`ylamino phenyl) 17 a-(1-propynyl)estra-4,9-dien-3-one ]. This
`compound is a 19-nor steroid with substitutions at positions Cll
`and C17 which antagonizes cortisol action competitively at the
`receptor leveL Oral RU 486 was given in increasin g doses of 5,
`10,15, and 20 mg/kg ·day for a 9-week period. T reatment eficacy
`was monitored by assessment of clinical status and by measu.ri ng
`several glucocorticoid-sensitive variables, including fasting blood
`sugar, blood sugar 120 min after oral glucose administration,
`
`and plasma concentrations of TSH, corticosteroid-binding glob(cid:173)
`ulin, LH, testosterone-estradiol-binding globulin, and total and
`free testosterone. With therapy, the somatic features of Cush(cid:173)
`ing's syndrome (buffalo hump, central obesity, and moon faci e.~)
`ameliorated, mean arterial blood pres ure normalized, suicidal
`depression resolved, and libido re~ed. AU biochemical gluco(cid:173)
`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 Clin Endocrinol Metab 61: 536, 1985)
`
`T HE CURRENTLY available treatments for Cush(cid:173)
`
`ing's syndrome caused by metastatic ACTH-pro(cid:173)
`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 (o,p '-DDD) or steroidogenic enzyme inhibitors
`(aminoglutethimide or metyrapone) is frequentiy asso(cid:173)
`ciated with toxic side-effects (1-5).
`A clinically applicable glucocorticoid antagonist is, in
`theory, an attractive alternative treatment for hypercor(cid:173)
`tisolism and has been sought for many years (6). The
`recently discovered compound RU 486 [17,8-hydroxy-
`11,8-(4-dimethylamino phenyl) 17 a-(1-propynyl)estra-
`4,9-dien-3-one], a 19-rtor steroid with a high affinity for
`the rat glucocorticoid receptor with no agonist effects in
`vitro or in vivo, is a potent competitive glucocorticoid
`antagonist in rodents (7), nonhuman primates (8, 9), and
`man (10-12).
`
`Received March 15, 1985.
`Address requests for reprints to: Dr. Nieman, National Institutes of
`Health, Building 10, Room 10N262, Bethesda, Maryland 20205.
`* Presented in part at ·the Seventh International Congress of Endo(cid:173)
`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(cid:173)
`ures, such as elevated fasting and postabsorptive blood
`sugar, normalized. The drug was tolerated well, and rto
`side-effects were noted during therapy or after its discon(cid:173)
`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(cid:173)
`tion span. In the spring of 1982, because these symptoms
`worsened, he discontinued his weight-lifting regimen. He com·
`plained of increasing anxiety and depression. In September
`1982, he stopped workjng because of these cognitive and psy(cid:173)
`chological changes. Treat ment with antidepressants was initi(cid:173)
`ated. His depression deepened, however, and led to two suicide
`attempts. At that time, he had moon fac ies, hypertension, and
`diabetes, and was evaluated for Cushing's syndrome. Both
`serum and Uiinary cortisol levels were elevated, and 17-hydroJ·
`ycorticosteroid excretion increased during a standard 2- and 8.·
`mg dexamet hasone suppression test (13).
`.
`An intrathoracic mass lesion was found and was resected 111
`
`1
`
`TEVA1012
`
`

`

`ANTIGLUCOCORTICOID THERAPY
`
`537
`
`A.
`GIUCOM 2 Hr OGTT (mg/dl)
`
`B.
`LH(miU/ml)
`
`230
`
`Feeling GIUCOM (mg/dl)
`
`TeBG (~g/dl)
`
`CBG(~g/dl)
`
`FrM Teetoeterone (ng/dl)
`28
`
`NJarch i983. The lesion was not contiguous with a bronchus.
`~[icroscopic and immunohistochemical examination of the
`speci men showed a carcinoid tumor with granules that stained
`with anti-ACTH serum. Immediately after surgery, plasma
`cortisol levels were normal. Insulin and antihypertensive and
`011 tidepressant medications were discontinued, and the pa(cid:173)
`tient's symptoms improved. By May 1983, however, his symp(cid:173)
`toms recurred, and his urinary cortisol excretion rate was about
`500 !Lg/day. He was given metyrapone, but had only transient
`clinical improvement.
`In August 19.83, he was admitted to the NIH. He complained
`of disorientation, diminished memory and cognitive ability,
`impotence, a 20-lb weight gain over 3 yr, and long-standing
`!lluscle weakness. He had a ruddy round face. His blood pres(cid:173)
`sure was 180/120 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
`tomogra.ms of the chest revealed multiple lung nodules. He had
`hypokalemic alkalosis (serum potassium, 1.9 meqfliter; bicar(cid:173)
`bonate, 38 meq/ liter; chloride, 94 meqfliter; sodium, 147 meqf
`liter).
`His medications, including maprotiline hydrochloride (Lu(cid:173)
`diomil), trifloroperazine (Stelazine), benztropin mesylate (Co(cid:173)
`gentin), and metyrapone (1 g/day) were stopped before labo(cid:173)
`ratory evaluation. H e 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(cid:173)
`tional Center for Drugs and Biologics, DHHS, and by the
`NICHHD Clinical Research Committee (83-CH-87). The pa(cid:173)
`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 Roussel(cid:173)
`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 r:ng dexamethasone (11). Accordingly,
`the initial oral daily dose was 5 mg/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(cid:173)
`tive measures were monitored to evaluate treatment efficacy.
`Clinical :r;neasures included blood pressure and body Weight.
`The patient's mood was assessed daily by a self-report ques(cid:173)
`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-astra-
`
`Dose RU 486 (mg/kg/d)
`
`~~F
`
`I ~ I
`
`15
`
`45
`
`DoM RU 486 (mg/kg/d)
`
`~~F I ~.
`
`45
`
`75
`
`15
`75
`DAY OF ADIII.SSION
`FIG. 1. The effect of RU 486 treatment on glucocorticoid-sensitive
`variables. A, Two hour post-OGTT (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 subnormal and rose progressively. CBG concentrations also
`rose into the normal rarige. 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 (L..L..UJ) or l9wer (LLLJ) normal range.
`
`dial-binding globulin (TeBG), testosterone (16, 17), LH (16,
`17), and TSH (18, 19), which are suppressed by hypercortisol(cid:173)
`ism.
`Plasma ACTH and plasma and urinary cortjsol levels also
`were measured frequently. Metabolic and hormonal measure(cid:173)
`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 100-g carbohydrate diet using a 100-g
`glucose challenge. Creatinine, blood urea nitrogen (BUN)
`serum glutamic o:X:aloacetic acid-transaminase (SGOT), and
`serum glutamic pyruvic acid-transaminase (SGPT) measure(cid:173)
`ments were monitored throughout treatment as indices of drug
`toxicity. Serial electrocardiograms and chest x-rays were done
`for a similar purpose.
`
`2
`
`

`

`538
`
`Assays
`
`NIEMAN ET AL.
`
`Plasma testosterone (20), LH (21), ACTH (22), steroid bio(cid:173)
`synthetic intermediates (pregnenolone, 17-hydroxypregneno(cid:173)
`lone, 17-hydroxyprogesterone, and 11-deoxycortisol) (20, 23),
`plasma and urinary cortisol (23), and serum TSH (24) were
`measured by RIA as previously described. CBG 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(cid:173)
`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 <:hanges 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 hot displace cortisol from
`CBG or testosterone from TeBG in concentrations ranging
`from 10-10-10-5 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(cid:173)
`ing supraclavicular and dorsocervical fat pads and central
`obesity, regressed considerably by the conclusion of ther(cid:173)
`apy. This change in fat distribution was not associated,
`however, with a change 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. lA). The hypokalemic alkalosis
`resolved, serum potassium ranged from 3.9-4.6 meq/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(cid:173)
`creasing attention span, libido, and sense of wellbeing.
`This subjective improvement was corroborated by self(cid:173)
`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.
`lA). The fasting blood sugar level became normal while
`
`the patient was taking RU 486 in a dose of 10 mg/kg.
`day, and the 2 b postoral glucose tolerance test blood
`sugar level normalized when be was taking 20 mgjk
`(Fig. lA). Serum TSH concentration was initially sub~
`normal. ( <0.18 IL U /ml) and rose progressively to 1.5 J.LU;
`ml durmg treatment (normal, 0.5-4.5 .uU/ml; Fig. lA).
`CBG-binding capacity increased from 7.4 ,ug/dl (normal
`12.2- 20 ,ug/dl) to 16.8 J.Lg/ 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.
`lB). Similarly, plasma total and free testosterone con(cid:173)
`centrations and TeBG-binding capacity increased from
`subnormal to normal levels during therapy with RU 486
`(Fig. lB). The total testosterone concentration was ini(cid:173)
`t ially 73 ng/ dl (normal, 200-1000 ng/dl) and rose to 842
`ng/dl when the patient was taking 20 mg/kg.day RU
`486. TeBG capacity increased from 0.063 J.Lg/dl normal;
`0.2-1.0 J.Lg/dl) to 1.02 ,ug/dl at the conclusion of therapy:
`Free testosterone increased from 3.5 ng/dl (normal, 5-
`30 ng/dl) to 17.4 ng/dl.
`Twenty-four hour urinary nitrogen excretion fell from
`22 gjday (normal, 12-20 g/day) before treatment to 5 g/
`day at its conclusion. No abnormalities in serum creati(cid:173)
`nine, BUN, SGOT, or 'sGPT, urinalysis, electrocardi(cid:173)
`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(cid:173)
`cocorticoid-sensitive parameters, urinary cortisol,
`plasma cortisol, and ACTH levels remained significantly
`elevated throughout the treatment with RU 486. G-50
`gel chromatography revealed that 85% of ACTH immu(cid:173)
`noreactivity was in the same fractions as ACTH -(1-39).
`Before initiation ofRU therapy, the mean plasma ACTH
`concentration was 165 ± 7.6 (±SE) pg/ml (n = 5); during
`treatment, it was 241 ± 14 pg/ml (n = 14; normal, 8-15
`pg/ml). The range of plasma cortisol-concentration was
`29-49.5 J.Lg/dl (mean ± SE, 43.5 ± 3.3 J.Lg/dl; n = 7) before
`and 13.8-56.5 J.Lg/dl (mean ± SE, 31.8 ± 2.0 J.Lg/dl; n,;
`27) during RU 486 administration (normal, 8-18 J.Lg/dl).
`Mean daily urinary cortisol excretion rates also were
`elevated, ranging between 514 and 11,592 J.Lg/day (mean
`± SE, 4865 ± 1159 J.Lg/24 h; n = 11) before theraPY·
`During therapy, urinary cortisol excretion was similar
`and ranged between 106 and 8072 J.Lg/day (mean ± sE,
`1175 ± 327 J.Lg/24 h; n = 27; normal, 20-95 J.Lg/24 h).
`Plasma steroid precursor concentrations during ther(cid:173)
`apy were within the normal range or mildly elevated(cid:173)
`Pregnenolone was 124 ng/dl (normal, <250), 17-hydrol·
`ypregnenolone was 135 ng/dl (normal, <250), 17-hydrol·
`yprogesterone was 706 ng/dl (normal, <200), and 11-
`deoxycorlisol was 431 ng/dl (normal, <200).
`No side-effects occurred during RU 486 treatment. 1~
`the lOth week, because limited availability of RU 48
`
`3
`
`

`

`ANTIGLUCOCORTICOID THERAPY
`
`539
`
`reve11ted further treatment, the patient underwent a
`~jlateral adren~lectomy 48 h after disco~ti:~mation of
`therapy and durmg supplemental glucocortlc01d therapy.
`tfissue vascularity was normal at the time of surgery,
`~nd his postoperative course and wound healing were
`sfltisfactory.
`
`Discussion
`
`The glucocorticoid antagonist RU 486 ameliorated the
`clinical and biochemical features of hypercortisolism in
`thi - patient. Treatment with RU 486 was associated with
`redistribution of body fat and resolution of severe depres(cid:173)
`sion, hyperglycemia, and hypertension, obviating the
`need for a variety of medications which he previously
`required. Several hormonal disorders typical of hyper(cid:173)
`cortisolism (suppressed plasma levels of TSH, LH, tes(cid:173)
`tos erone, 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
`cor isol 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 3{3-hydroxyste(cid:173)
`roid dehydrogenase-115,.14-isomerase,21-hydroxylase, 17-
`hydroxylase, or 11-pydroxylase, 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(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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 toxic effects of hypercorticolism on tissues.
`If this were true, then an antiglucocorticoid 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 medical
`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(cid:173)
`ism. Greater tolerance may yield greater efficacy, since
`the available medical treatments often cannot be given
`in fully effective doses because of their side-effects.
`One potential problem with RU 486 is that overtreat(cid:173)
`ment might cause glucocorticoid insufficiency. Since glu(cid:173)
`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(cid:173)
`ficient for extensive clinical study. Despite these prob(cid:173)
`lems, RU 486 holds promise as a safe, well tolerated, and
`effective medical therapy for hypercortisolism that mer(cid:173)
`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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`
`5
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`CLINIC L
`NDOCRINOLO
`GMETABOLIS
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`1“
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`volume 61/l‘lumber 3/SEPTEMBER 1985
`JCEMAZ/ISSN 0021-972)!
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`g i I
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`SSUED MONTHLY FOR
`THE ENDOCRINE SOCIETY
`
`6
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`