CLINICAL OBSTETRICS AND GYNECOLOGY
`Volume 39, Number 2, PP 506-510
`Publishers
`© 1996, Lippincott-Raven
`
`Mifepristone:
`Treatment of Cushing's
`Syndrome
`
`OLIVER SARTOR, MD" and
`GORDON B. CUTLER, Jr. MDt
`"Louisiana State University Medical Center
`Shreveport, Louisiana
`tNational
`Institute of Child Health and Human Development,
`National
`Institute oj Health
`Bethesda, Maryland
`
`Cushing's syndrome is mediated by glu-
`cocorticoid
`receptors
`and results
`from
`chronic exposure to excessive endogenous
`or exogenous glucocorticoids.
`If endoge-
`nous glucocorticoids are present in excess,
`this surplus is a consequence of excessive
`production
`rather
`than inadequate
`de-
`struction. Although the adrenal cortex is
`the sole source of endogenous glucocor-
`ticoid production, pathologic elevation of
`glucocorticoid secretion may result from
`an autonomously
`functioning
`adrenal
`cortex or from an excessive production of
`adrenocorticotrophin
`hormone (ACTH).
`Although ACTH is ordinarily
`derived
`from the anterior pituitary, pathologic se-
`cretion of ACTH (and its variants) may
`be derived either from the pituitary or an
`ectopic source.
`
`Correspondence: Oliver Sartor, MD, Section of He-
`matology/Oncology, Department of Medicine, LSUMC,
`1501 King's Highway. Shreveport, LA 71130.
`
`The treatment of endogenous Cushing's
`syndrome requires diagnosis of the patho-
`physiologic source, with subsequent
`treat-
`ment being directed toward the underlying
`problem. Surgical extirpation of the under-
`lying cause is the treatment
`of choice,
`whether the cause is an adrenal neoplasm,
`a pituitary adenoma, or an ectopic ACTH-
`secreting tumor. In some cases, however,
`the underlying cause may not be amenable
`to a surgical resection. Examples include
`pituitary tumors that have involved the
`cavernous sinus, occult or metastatic ec-
`topic ACTH-secreting tumors, and meta-
`static adrenocortical
`carcinoma.
`In such
`cases, the clinician may be confronted with
`considering complete removal of the adre-
`nal glands, pituitary irradiation, or phar-
`macologic therapy to blunt cortisol secre-
`tion or action. Additionally, pharmacologic
`therapy of endogenous Cushing's syndrome
`also may be indicated under other condi-
`tions (i.e., acute psychiatric problems de-
`
`CLINICAL OBSTETRICS AND GYNECOLOGY
`
`VOLUME 39
`
`NUMBER 2
`
`JUNE 1996
`
`506
`
`1
`
`TEVA1009
`
`

`

`Mifepristone:Treatment of Cushing'sSyndrome
`
`501
`
`veloping as a consequence of glucocorticoid
`excess or life-threatening opportunistic in-
`fection).
`Several pharmacologic means exist for
`control of excessive glucocorticoid secre-
`tion. These inelude metyrapone, aminoglu-
`tethimide, mitotane, ketoconazole, or mi-
`fepristone (RV 486; Roussel-Velaf, Ro-
`mainville, France). All of these therapeutic
`agents, except mifepristone, operate by de-
`creasing adrenal steroid secretion. Mifepri-
`stone functions as a glucocorticoid antag-
`onist by binding to glucocorticoid receptors.
`It actions and use will be covered in more
`detail.
`
`Mifepristone as a
`Glucocorticoid Antagonist and
`Agonist
`Mifepristone (RV 486 or RV 38486) was
`originally developed by Roussel-Velaf as an
`antiprogestin, and this antihormonal action
`has been the primary focus of most elinical
`studies. The activity of mifepristone as a
`glucocorticoid antagonist, however, was
`recognized early in the stages of drug de-
`velopment with the first report of antiglu-
`cocorticoid activity by Philibert et al. in
`1981.1 After demonstration of the antiglu-
`cocorticoid activity in primates.' studies in
`humans were initially reported in 1984 by
`Bertagna and colleagues.' In the Bertagna
`studies,
`antiglucocorticoid
`activity was
`demonstrated
`by a marked increase in
`plasma cortisol and lipotropin after admin-
`istering 400 mg of mifepristone to "normal"
`men. In addition, mifepristone administra-
`tion was associated with a dose-dependent
`blockade of dexamethasone-induced corti-
`sol suppression. Thus mifepristone was
`shown to act as an anti-glucocorticoid by
`antagonizing the negative feedback on the
`pituitary of endogenous and exogenous
`glucocorticoids. Reports of mifepristone's
`application in patients with glucocorticoid
`excess followed shortly thereafter (vide in-
`fra).
`
`com-
`receptor-binding
`Like many
`pounds, mifepristone
`exhibits mixed an-
`tagonist/agonist
`activity.
`In a carefully
`conducted trial examining the glucocor-
`ticoid agonist-like activity ofmifepristone
`in humans, plasma ACTH responses and
`cortisol responses were monitored in the
`presence and absence of corticotropic
`re-
`leasing hormone stimulation
`in patients
`with primary adrenal
`insufficiency after a
`brief period (36 hours) of glucocorticoid
`deprivation. Vnder
`these circumstances,
`oral mifepristone
`administration
`(20 mgt
`kg) resulted in a partial suppression of the
`corticotropic
`releasing hormone-induced
`ACTH response.'
`These data
`strongly
`suggest that mifepristone exerts some ag-
`onistic effect at the glucocorticoid recep-
`tor. The glucocorticoid agonist potency of
`mifepristone
`in these experiments was
`calculated to be approximately
`11250th
`the activity of cortisol (on a weight basis).
`In a subsequent
`series of experiments
`in
`primates, mifepristone was unable to pro-
`vide adequate agonist activity to prevent
`fatal adrenal
`insufficiency in adrenalec-
`tornized-monkeys." Thus, although glu-
`cocorticoid agonist activity is detectable
`in sensitive assays, glucocorticoid antag-
`onism is the predominant
`action. How-
`ever, glucocorticoid
`antagonism in pa-
`tients occurs at higher doses in patients
`than does progesterone
`antagonism,
`and
`women who have received mifepristone
`as an anti progestin in early pregnancy
`typically report no ill effects due to glu-
`cocorticoid antagonism.
`Mifepristone
`exerts its glucocorticoid
`antagonism by occupying glucocorticoid
`receptors, thereby blocking in a competitive
`fashion agonist-induced transcriptional ac-
`tivation. The affinity of mifepristone for the
`glucocorticoid receptor
`is approximately
`three-fold higher than that for dexametha-
`sone.' The mechanism whereby mifepri-
`stone acts at the glucocorticoid receptor is
`distinct from its action at the progesterone
`receptor. First,
`the progesterone receptor
`typically exists in two isoforms (of varying
`
`2
`
`

`

`508
`
`SARTOR AND CUTLER
`
`length and varying actions), whereas the
`glucocorticoid receptor
`typically exists in
`only one isoform. In the antagonism of pro-
`gesterone receptors, mifepristone
`avidly
`binds to the receptor and operates primarily
`at a post-DNA binding step. In glucocorti-
`coid antagonism, mifepristone has at least
`two mechanisms of action. Although it also
`can act at a post-DNA binding step after
`binding to the receptor, binding of mife-
`pristone to cytosolic glucocorticoid recep-
`tors has the additional effect of blocking
`translocation of glucocorticoid receptors to
`the nucleus' The end result is that mife-
`pristone-bound glucocorticoid receptors are
`relatively segregated from DNA binding,
`and even when DNA binding occurs, tran-
`scriptional activation is significantly di-
`minished in comparison to agonist-bound
`receptors.
`The clinical pharmacology of mifepri-
`stone is described elsewhere in this publi-
`cation. Mifepristone is readily absorbed af-
`ter oral ingestion with a bioavailability ex-
`ceeding 30%. Peak drug levels are typically
`reached in 1-2 hours, and the drug has a
`half-life of more than 20 hours. Mifepri-
`stone is highly protein bound, extensively
`metabolized, and primarily excreted in the
`bile. Mifepristone metabolites also exhibit
`
`a prolonged half-life and biologic activity,":
`Treatment of Cushing's
`Syndrome With Mifepristone
`The first report of mifepristone treatment
`of Cushing's syndrome was a case report
`published in 1985" In this report, a patient
`with inoperable ectopic ACTH secretion
`secondary to a metastatic carcinoid tumor
`was treated in a step-dose fashion starting
`at 5 mg/kg/day by mouth and escalating by
`5 mg/kg every 1-2 weeks. The maximum
`dose of mifepristone administered was 20
`mg/kg/day. Before mifepristone treatment,
`the patient failed to respond to therapy with
`metyrapone and had many manifestations
`of uncontrolled Cushing's
`syndrome,
`in-
`cluding altered cognitive status, diminished
`
`libido, muscle weakness, round facies, dor-
`socervical fat pads, central obesity, weight
`gain, hypertension, hypokalemic alkalosis,
`abnormal glucose tolerance test results, in-
`creased urinary nitrogen excretion,
`in-
`creased urinary and plasma cortisol, and
`increased ACTH. During therapy with mi-
`fepristone, all objective manifestations of
`Cushing's improved except for total body
`weight, plasma and urinary cortisol, and
`plasma ACTH. During mifepristone ther-
`apy, the circulating ACTH level increased
`further. All psychological measures also
`improved according to the patient's report
`and psychiatric interviews. The patient was
`treated for a total of 10 weeks without rec-
`ognized side effects. After this time, limited
`drug availability prevented further
`treat-
`ment, and the patient
`received a bilateral
`adrenalectomy. This important case report
`demonstrated
`the feasibility of
`treating
`Cushing's syndrome patients with mifepri-
`stone.
`The next report of mifepristone admin-
`istered to patients with Cushing's described
`3 days treatment
`in seven patients." Five
`patients had been diagnosed with pituitary-
`dependent Cushing's syndrome (Cushing's
`disease); two patients had ectopic secretion
`of ACTH. In each of the five patients with
`Cushing's disease, 3 days of mifepristone
`(400 mg/day) were associated with marked
`increases in urinary cortisol, which per-
`sisted for 3-4 days after drug discontinua-
`tion. Plasma cortisol, urinary 17-hydroxy-
`steroids, and plasma lipotropin also were
`increased, but to a lesser extent. These data
`suggest that mifepristone antagonized the
`glucocorticoid mediated
`suppression
`of
`ACTH secretion at the level of the pituitary
`tumor. One patient developed nausea and
`headaches;
`another
`developed
`lethargy.
`Each of these patients were treated with
`dexamethasone and improved within min-
`utes according to the report. In the two pa-
`tients with ectopic ACTH-secreting tumors,
`no significant changes were noted in glu-
`cocorticoid secretion suggesting lack of glu-
`
`3
`
`

`

`Mifepristone: Treatment oj Cushing's Syndrome
`
`509
`
`cocorticoid feedback inhibition on ectopic
`ACTH-secreting tumors.
`and col-
`These studies by Bertagna
`leagues'? helped to highlight two important
`potential problems of treating patients with
`pituitary-dependent
`Cushing's
`syndrome
`with mifepristone. Blockade of glucocorti-
`coid action results in increased cortisol se-
`cretion, probably as a result of decreased
`feedback of glucocorticoids on the pituitary.
`This decreased feedback leads in turn to in-
`creased ACTH secretion and increases cor-
`tisol, which competes with mifepristone at
`the glucocorticoid receptor. Previous stud-
`ies have shown that hyperplastic adrenals
`can vigorously respond
`to even small
`changes in ACTH, and this appeared to
`have occurred in these patients. Secondly,
`because there is no acceptable rapid bio-
`chemical measurement
`to monitor gluco-
`corticoid action (as opposed to secretion),
`titration of mifepristone dosing may be
`problematic. A particular concern is that
`excessive receptor blockade may produce
`symptoms of adrenal
`insufficiency despite
`high cortisol levels.
`In the largest series reported to date, II
`patients with Cushing's syndrome due to
`inoperable adrenal cancer or inoperable
`"ectopic" ACTH-secreting neoplasms were
`treated with mifepristone." Doses varied
`from 5 to 22 mg/kg/day, and treatment du-
`rations varied from 4 weeks to 12 months.
`Seven of the II patients demonstrated
`marked improvement
`in the syndrome as
`manifested by improvement
`in the Cush-
`ingoid phenotype, psychiatric status, hy-
`pertension, and carbohydrate intolerance.
`In this study, three patients discontinued
`mifepristone because of possible signs or
`symptoms of adrenal insufficiency. One ad-
`ditional patient developed an unrelated
`medical complication
`and discontinued
`treatment for reasons unrelated to the drug.
`Nausea was the most common complaint;
`two of the three male patients developed
`gynecomastia, and one male patient devel-
`oped impotence. Of note, one of the pa-
`tients who developed Addisonian symp-
`
`toms had a significant decrease in cortisol
`secretion for
`reasons that were unclear.
`From these data, the authors conclude that
`mifepristone has clinical use in the treat-
`ment of a subset of patients with Cushing's
`syndrome whose cortisol secretion depends
`on non-pituitary sources. Clinical manifes-
`tations of adrenal insufficiency may be en-
`countered in a substantial minority of pa-
`tients, and (again) management was com-
`plicated by a lack of reliable biochemical
`markers of glucocorticoid action.
`In a more recent report, two patients with
`acute psychosis and high elevations of cor-
`tisol were treated with treated with mife-
`pristone." In the first case, a 43-year-old
`with adrenal
`cancer and psychosis was
`treated with 800 mg/day of mifepristone
`and all mental
`abnormalities
`resolved
`within 24 hours. After 5 days, hypoglycemic
`episodes appeared and the mifepristone
`dose was decreased to 400 mg/day without
`additional complications. A second patient,
`also with inoperable adrenal cancer and
`psychosis, was treated with 400 mg/day mi-
`fepristone with complete disappearance of
`psychiatric
`symptoms within 24 hours.
`Other signs and symptoms of Cushing's
`improved during the remaining 2 months
`of the patient's life and the patient did not
`develop Addisonian-type complications.
`
`Summary
`Mifepristone is a potent antagonist of glu-
`cocorticoid and progesterone receptors. It
`is the only drug administered to humans
`with these actions. Exploration of mifepri-
`stone in the treatment of Cushing's syn-
`drome is in its infancy. The cases reviewed
`in this report comprise the entire medical
`literature. Development and availability of
`mifepristone has been severely restricted
`because of controversy
`surrounding
`its
`ability to function as an "abortion pill." As
`the political controversy abates, increasing
`studies of this drug may be anticipated in
`patients with glucocorticoid excess.
`
`4
`
`

`

`510
`
`SARTOR AND CUTLER
`
`have highlighted
`the authors
`Although
`trials with the drug,
`they also
`therapeutic
`note that diagnostic
`uses in cases of gluco-
`corticoid
`excess may be of interest. Some
`cases of endogenous Cushing's
`syndrome
`are difficult
`to diagnosis
`and a glucocorti-
`coid antagonist may be as useful as a glu-
`cocorticoid
`agonist
`(such as dexametha-
`sone)
`in the dynamic
`evaluation
`of glan-
`dular
`function.
`In particular, mifepristone
`might be useful
`in distinguishing
`pituitary
`from occult
`ectopic ACTH-secreting
`tn-
`mars.
`surround-
`One of the primary problems
`in cases of
`ing the use of mifepristone
`Cushing's
`syndrome
`is the long half-life of
`the drug and the necessity to titrate doses
`carefully in a manner
`that avoids signs and
`symptoms
`of glucocorticoid
`deficiency.
`Biochemical markers
`reflecting
`the "glu-
`cocorticoid
`status"
`of a patient would be
`useful
`for dose adjustment
`and monitoring
`and would improve the risk to benefit
`ratio
`for mifepristone
`treatment
`of Cushing's
`syndrome.
`
`References
`I. Philibert D, Deraedt R, Teutsch G. RU486:
`A potent antiglucocorticoid
`in vivo. Tokyo,
`Japan:
`International Congress
`of Pharma-
`cology, 1981 (Abstract 1463).
`2. Healy DL, Chrousos GP, Sculle HM, Gold
`PW, Hodgen GD. Pituitary and adrenal re-
`sponses to the antiglucocorticoid steroid
`analog RU 486 in primates. J Clin Endo-
`crinol Metab. 1983;57:863-865.
`3. Bertagna X, Bertagna C, Luton JP, Husson
`JM, Girard F. The new steroid analog RU
`486 inhibits glucocorticoid
`action in man.
`J Clin Endocrinol Metab. 1984;59:25-~8.
`4. Laue L, Chrousos GP, Loriaux DL et al. The
`and anti progestin steroid
`antiglucocorticoid
`RU 486 suppresses the adrenocorticotropin
`
`response to ovine corticotropin releasing
`in man. J Clio Endocrinol Metab.
`hormone
`1984;66:290-293.
`5. Laue L, Galluci W, Loriaux DL, Udelsman
`R, Chrousos GP. The antiglucocorticoid
`and
`antiprogestin
`steroid RU 486:
`its glucocor-
`ticoid agonist effect is inadequate
`to prevent
`in primates. J Clio En-
`adrenal
`insufficiency
`docrinol Metab. 1988;67:602-606.
`6. Beck CA, Estes PA, Bona BJ, Muro-Cacho
`CA, Nordeen SK, Edwards DP. The steroid
`antagonist RU486 exerts different effects on
`the glucocorticoid
`and progesterone
`recep-
`tors. Endocrinology. 1993;133:728-740.
`7. Kawai S, Nieman LK, Brandon DD,
`et a1.
`of the antiglu-
`Pharmacokinetic
`properties
`and anti progesterone
`cocorticoid
`steroid
`RU486 in man. J Pharmacol Exper Thera-
`peut.1987;241:401-406.
`8. Chang-hai H, Yong-en S, Zhi-hou Y, et al.
`Pharmacokinetic
`study of orally adminis-
`tered RU 486
`in non-pregnant
`women.
`Contraception. 1989;40:449-460.
`9. Nieman LK, Chrousos GP, Kellner C, et al.
`Successful
`treatment of Cushing's
`syndrome
`with the glucocorticoid
`antagonist RU 486.
`J Clin Endocrinol Metab. 1985;61:536-540.
`10. Bertagna X, Bertagna C, Laudat MH, Hus-
`son JM, Girard F, Luton JP. Pituitary-ad-
`renal response to the antiglucocorticoid
`ac-
`tion of RU 486 in Cushing's syndrome. J
`Clin Endocrinol Metab. 1986;63:639-643.
`II. Chrousos GP, Laue L, Nieman LK, Udets-
`man R, Kawai S, Loriaux DL. Clinical ap-
`plications ofRU 486, a prototype glucocor-
`In: Bau-
`ticoid and progesterone
`antagonist.
`lieu EE, Segal SJ, eds. The Antiprogestin
`Steroid RU 486 and Human Fertility Con-
`trol. New York: Plenum Press. 1989;273-
`284.
`12. van der Lely AJ, Foeken K, van der Mast
`RC, Lamberts SWJ. Rapid reversal of acute
`psychosis in the Cushing's syndrome with
`cortisol-receptor
`antagonist
`mifepristone
`(RU 486). Ann Intern Med. 1993;114:
`143-144.
`
`5
`
`

`

`CLINICAL OBSTETRICS AND GYNECOLOGY (ISSN 0009-9201)
`A Quarterly Publication
`Copyright © 1996 by Lippincott-Raven Publishers. All rights reserved. No part of this book may be used or
`reproduced in any manner whatsoever without permission except in the case a/brief quotations embodied in critical
`articles and reviews. Printed in the United States of America. For information
`address Medical Department,
`Lippincott-Raven
`Publishers, 227 East Washington Square, Philadelphia, Pennsylvania
`19106.
`Library of Congress Card No. 73-18786
`
`In view of The Copyright Revision Act of 1976, effective January I, 1978, all manuscript considered for publication
`in CLINICAL OBSTETRICS AND GYNECOLOGY must be accompanied by a release that contains the following
`language: "In consideration
`a/Lippincott-Raven
`Publishers
`taking action in reviewing
`and editing my submission,
`the author(s)
`undersigned
`hereby
`transfers,
`assigns.
`or otherwise
`conveys
`all copyright
`ownership
`to Lippincott-
`Raven Publishers
`in the event
`that such work is published
`by Lippincott-Raven
`Publishers."
`
`Authorization to photocopy items for internal or personal use or the internal or personal use of specific clients
`is granted by Lippincott-Raven
`Publishers,
`for libraries and other users registered with the Copyright Clearance
`Center (CCC), provided that
`the base fee per copy is paid directly to CCC, 222 Rosewood Drive, Danvers, MA
`01923.
`0009-9201/96
`
`The authors and publishers have exerted every effort to ensure that drug selection and dosage set forth in this
`text are in accord with recommendations
`and practice at the time of publication. However,
`in view of ongoing
`research, changes in government
`regulations, and the constant
`flow of information
`relating to drug therapy and
`drug reactions,
`the reader is urged to check the package insert for each drug for any change in indications and
`dosage, and for added warnings and precautions. This is particularly important when the recommended agent is
`a new and/or
`infrequently employed drug.
`
`CLINICAL OBSTETRICS AND GYNECOLOGY (ISSN 0009-9201) is published quarterly by Lippincott-Raven
`Publishers, 12107 Insurance Way, Hagerstown, MD 21740. Business offices are located at 227 East Washington
`Square, Philadelphia, PA 19106. © Copyright 1996 by Lippincott-Raven
`Publishers. Printed in the U.S.A.
`Second class postage paid at Hagerstown, Maryland, and at additional mailing offices. Statements or opinions
`reOect the views of the author(s) and are not
`the opinion of
`expressed in Clinical Obstetrics
`and Gynecology
`Lippincott-Raven
`Publishers unless so stated. Rapid medical changes make it mandatory that any health care
`provider check package inserts before prescribing to patients.
`
`Subscription information, orders, or changes of address: (except Japan) 12107 Insurance Way, Hagerstown, MD
`21740, or call 1-800-638-3030;
`in Maryland, call collect 301~714-2300.
`In Japan, contact
`Igaku-Shoin, Ltd, 1-
`28-36 Hongo, Bunkyo-ku, Tokyo 113, Japan.
`
`Annual subscription rates: U.S. $119.00 individual, $223.00 institution; Canada and Mexico $159.00 individual,
`$259.00 institution; The Canadian GST tax of 7% will be added to the subscription price of all orders shipped
`to Canada. Lippincott-Raven
`Publishers' GST identification
`number
`is 130876246; all other countries except
`Japan, $173.00 individual, $273.00 institution (prices include $14.00 air freight delivery; air freight delivery
`occurs within 7-21 days worldwide).
`International
`subscriptions must be prepaid. Single copies $65.00. (Rates
`are subject to change.) In Japan.contact
`Igaku-Shcin, Ltd, 1-28-36 Hongo, Bunkyo-ku, Tokyo 113, Japan. Copies
`will be replaced without charge if the publisher
`receives a request within 60 days of the mailing date in the U.S.
`or within 5 months in other countries.
`
`Send address changes to CLINICAL OBSTETRICS AND GYNECOLOGY,
`POSTMASTER:
`Hagerstown, MD 21741.
`@l Text printed on acid-free paper.
`
`P.O. Box 1550,
`
`6
`
`

`

`Clinical Obstetrics
`and Gynecology
`
`June 1996 / Volume 39 / Number 2
`
`7
`
`