8 12
`
`TH E NEW ENG L AN D J OURNA L O F M EDI CI N E
`
`Sept. 2-1-, 198 7
`
`MEDICAL INTELLIGENCE
`
`DRUG THERAPY
`
`j o H N A. O AT ES, M.D., Editor
`A LAST AIR ].]. Wooo, M.D., Associate Editor
`
`THE USE OF KETOCONAZOLE AS AN
`INHIBITOR OF STEROID PRODUCTION
`
`NI CO LETTA SoN IN O, M .D.
`
`KETOCO N AZOLE is a n
`
`imid azole d erivative
`tha t is chemically rel ated to mi conazole (Fig. I).
`It is a n o ra l a ntim yco ti c agent with broad-spectrum
`activity a nd low toxi city. 1-3 The d rug is consid ered to
`represent a n importa n t innovati on in th e treatm en t of
`fun gal disease a nd has been used ex tensively in clini(cid:173)
`cal practice for the pas t f-ive years. The d evel()pm ent of
`gynecom as tia in som e pa ti ents treated fo r m ycosis first
`led to th e inves tigation of the drug's e!Tect on the pro(cid:173)
`'5 Thereaft er, ketoconazole
`duction of tes tosterone.4
`was shown to be a po tent inhibitor of gonad al a nd
`10 The
`adrena l steroid synth esis in vitro a nd in vivo. 5
`-
`finding of its importa nt endocrine eflects has a ro used
`a new interest in this agent. 11 E x tensive studies have
`been carried out to elu cid a te its m echa nism of action .
`In addi tion , there h ave been cl ini cal tri a ls to assess its
`th era peutic po tentia l. Because ketoconazole acts as a
`steroid inhibi to r with di!Terenti a l selectivity, it is a new
`thera peutic tool in th e m a nagem en t of condi tions in
`whi ch it is benefi cial to suppress gonad a l or adrena l
`hormone produ ction , such as pros ta te cance r a nd
`C ushing's syndrom e, res pecti vely.
`
`MEcHANISM oF AcTION
`K etoconazole inhibits the sy nth es is o f ergos terol in
`fun gi a nd of choles terol in m a mma li a n cells. 12·13 In
`addition , it in terferes with cy tochrom e P-450 enzy me
`na m ely, the tes ti s, 5 ova(cid:173)
`sys tem s in severa l organs -
`ry,6 adrenal gla nd ,7 kidney, I+ a nd li ver .15·16 Li ke other
`imid azole dru gs, it a ppears to in teract with cy to(cid:173)
`chro me P-450 a t the hem e iron site.17· 1!3
`
`Steroidogenesis
`The m os t sensitive site o f action in hum ans a ppea rs
`to be the C 17.20 lyase (Fig. 2), ex pl aining th e greater
`suppress ibili ty of tes tosterone secre tion , as co mpa red
`wi th cor tisol secretion , in hum a ns a fter a single d ose o f
`200 or 400 mg. 10·19 A simil a r finding has been reported
`
`From the Department of Biochemi stry , State Uni versity of New York at Buf(cid:173)
`fa lo, Buffalo, N. Y., and the Institute of Medical Semiotics, University of Padua,
`Padua, Italy. Address reprint requests to Dr. Soni no at the Institute ol' Medical
`Semiotics, Uni versity of Padua, via Ospedalc 105, 35 100 Padua , Italy.
`
`in m a le beagle d ogs. 20 I n hi bitio n o f C 11-2o lyase h as
`been d emo nstrated by a n in crease in ra tios o f precu r (cid:173)
`so r ( 17a- hydroxy proges tero ne or 17a, 20a-d ih ydroxy(cid:173)
`p rogeste rone or both ) to prod uct (and rosten ed io n e o r
`testos terone) both in v ivo 1!J·20 a nd in v itro. 1H·21-23 A ll
`in vitro studi es to tcs t C 1 7.20 I yase have used tes ti s
`p re pa rations, but clinica l d ata show tha t both go n a d a l
`a nd ad rena l a n d rogens decrease a fter ketocon azole
`admini stra ti on /·9 •2·1·25
`indi ca ting
`interferen ce w ith
`adrena l c l7-20 lyase as well ; the exte nt of this inhibi(cid:173)
`tio n has not been d e termin ed . Sin ce there is evid en ce
`th a t l 7a-h ydroxylase a nd C 17.20 lyase acti vities r es ide
`in a sing le enzy m e, it is no t surp ri sing that ke tocon a (cid:173)
`zole inhibi ts 17a-h yd roxy lase as well ( Fi g . 2) .21-23,:26
`C holes tero l sid e-cha in-cleavage bloc ka d e b y ke to (cid:173)
`conazole has been d emonstra ted in bo th tes ti c ul ar a nd
`ad rena l tiss ue prepa ra ti o n s .
`' 1 •~ 7 • 2 11 In vitro s tu d ies in
`1
`ra t tes ti cul a r mi crosom es h ave show n tha t c ho les te ro l
`sid e-cha in cleavage has a hig her sensiti vity to ketocon(cid:173)
`azole th a n does C 17.20 lyase. 27 A species-depe nd en t
`se nsitivity may acco un t fo r thi s fi nd ing. Ad ren ocorti(cid:173)
`cal s teroid biosy nthesis is a lso inhi bited at the 11 {3-
`hycl roxy lation J.J.,:29-31 a nd 18-h ycl roxy latio n s te ps. 31
`Ketoco nazole is m ore po tent in vitro tha n m etyrapon e
`in th e inhibitio n of both 11{3-hyclroxy lase a nd ch o les(cid:173)
`terol side-cha in cleavage (Fig. 2). 31
`T he e!Tects of ketoconazole on es troge n synth esis
`have no t been full y cl a rifi ed . ln contrast to in vitro
`•32 a nd tes(cid:173)
`findin gs tha t the agent inhibi ts ra t ovari a n 6
`'1 a rom a tase, in vi vo
`ti cul a r:33 a nd hum a n pl acenta l3
`stu d ies have shown
`th at the estradi ol: tes tos tero n e
`ra tio is increased in m en given ketoco nazo le. 35 -37 No
`da ta a re avail a bl e on es trogen levels in wom en dur(cid:173)
`in g trea tm en t. A n inhibi tory effect on oversecre ti o n o f
`es trogen by adrenal tum ors has been repor ted. 25·38
`It is of interes t th at mu ch hi gher concentra ti on s are
`req uired to a ffect cytochrom e P-4·50- clepencl ent en(cid:173)
`zy mes in ma mm a li a n tiss ues tha n to inhibi t funga l
`cy tochrom e P-4·50. 1!3·21·213 This m ay ex pl a in why en(cid:173)
`docrin e e!Tects beco m e evid ent in pa ti ents o nl y a t hig h
`cl oses. Concentra tions 12 times hig her th a n those suffi(cid:173)
`cient for a ntifungal ac ti vity a re need ed to inhi b it a n(cid:173)
`drogen syn th es is in tes ti s mi croso m es. C ho les teml
`sid e-cha in cleavage in tes tes a nd aclrena ls and a dren a l
`11{3-hyclroxy lase a re inhibi ted a t even hig her con(cid:173)
`centratio ns.39
`
`Steroid Transport and Action
`
`ln ad d ition to a direct action on multi p le en zym e
`sys tem s in d ifferent steroid ogen ic gla nd s, o th er m ech(cid:173)
`a ni sm s by w hi ch ketoco nazole m ay produ ce end ocrine
`ellects have bee n d escribed. A g lu cocorti coid a ntago(cid:173)
`ni st activity, whi ch acts by occ upying g lu cocor tico id
`recepto rs, has bee n observed in c ul tured he patom a
`cell s.'10 Disp lacem ent o f d ih ycl rotestos terone a nd , to a
`g reater exten t, es tra dio l fi·om sex-hor mon e-binding
`glo bulin by ketoconazo le is observed in vitro a t d rug
`conce n tra ti ons eq ui valent to those in pati en ts r eceiv(cid:173)
`in g hig h thera peu tic closes . 1·1 Co rtisol binding to corti(cid:173)
`cos tero id -bi ndin g globulin is no t a llected .'11 In no rm a l
`volunteers a nd in pa tients on a hi gh-close regim en ,
`
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`Page 1
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`

`
`Vo l. 3 17 No. 13
`
`MEDI CAL INTE LLIGENCE- SON INO
`
`8 13
`
`r:;J
`C~Cl
`
`Cl
`
`0
`I
`
`0
`I
`
`r-\
`0
`CH -0~ N N-~-CH
`~\......../
`
`3
`
`2
`
`Figure 1. Structure of Ketoconazole.
`
`a sig nifi cant elevati on of the es tradiol: testos terone ra(cid:173)
`tio (bo th to ta l and free hormone) occurs, 35•36 but th e
`percentages of bound and free fractions of both hor(cid:173)
`m ones a re not signifi can tly altered ; thus, the displace(cid:173)
`m ent of es tradiol from its binding globulin is not
`•35·36 The increased es tradiol:tes tos(cid:173)
`relevant in vivo. 8
`terone ra tio m ay be a n important factor in the devel(cid:173)
`opment of gynecom astia, 'f2 a principal side effect of
`th e drug. '~-,5,B, 35
`K etoconazole seems to have no direct effect a t the
`pituita ry level on the secreti on of either adrenocortico(cid:173)
`tropin43or lu teinizing hormone26 in ra t tissue studied
`in vivo a nd in vitro. This is in agreement with clinical
`fi ndings, as discussed below.
`
`has been found to be biphasic, with a n initial half-life
`of I to 3.3 hours16•49 and a terminal half-life of 8
`hours.48 •51 Pro tein-binding studi es have shown a high
`percentage of ketoconazole bound to plasma proteins,
`·7
`mainly albumin : 99 percent in hum an whole blood ,4
`and 93 and 91 percent in human serum a t serum con(cid:173)
`centrations of 50 and 25 t-tg per milliliter. 54 The drug
`is widely distributed in body fluid s, with d etectable
`concentrations in urin e, saliva, se bum, and cerum en
`after a 200-mg oral close.47 In a pa tient receiving 400
`mg per day, semen ketoconazole concentrations one
`and three hours a fter the dose were 0.9 and 0.25 t-tg per
`milliliter, indicating penetration into the genitouri(cid:173)
`nary tract.+' One study found th a t after an 800-mg
`close, ketoconazole was meas urable in the cerebros pi(cid:173)
`nal fluid . 55
`Ketoconazole is ex tensively meta bolized into inac(cid:173)
`tive compounds, primarily by the liver.47·48 M etabo(cid:173)
`lites and unchanged drug are excreted mostly in the
`feces, with very little excretion into the urin e. Al(cid:173)
`though renal impairment does not seem to cause accu(cid:173)
`mul ation of th e drug, hepatic ins ufficiency is a contra(cid:173)
`indication to its use, since the agent is meta bolized
`mainl y by th e liver and might worsen liver d amage by
`produ cing a toxic effect:17·'' 8
`In addition to its hepatotoxicity, ketoconazole's in(cid:173)
`terference with some mixed-function oxidase sys tems
`in liver microsomes 15•16·56 m ay h ave important non(cid:173)
`endocrine clinical effects tha t result from alterations in
`the hepa ti c meta bolism of the drug. Possible drug in(cid:173)
`teractions, whi ch are mos t likely due to interference
`with enzyme activities in liver mi crosomes, include
`potentia tion of oral anticoagul ants by ketoconazole,57
`markedly diminished serum concentra tions of both ri(cid:173)
`fampin and ketoconazole upon simulta neous adminis(cid:173)
`tration of those agents, 58 a d elay in the pos t-dose peak
`of ketoconazole concentra tion during long-term ad ~
`
`MINERALOCORTICOID
`
`GLUCOCORTICOID
`
`ANDROGEN
`
`17 OH
`
`17,20LYASE
`
`l3{J HSD
`
`17 OH
`PROGESTERONE ----11-+ 17·0H·PROGESTERONE
`
`l 21 OH
`
`17,20 LYASE
`1-- ANDROSTENEDIONE
`
`CHOLESTEROL
`~-SCC
`v~
`1 3/J HSD
`PREGNENOLONE ---•1-+• 1 7·0H·PREGNENOLONE---~ DEHYDROEPIANDROSTERONE
`13/J HSO
`l 21 OH
`l 17/J HSD
`::b 11 OH
`..
`d:: 18 OH
`...
`118 OH D
`
`PHARMACOLOGY
`The hormonal changes produced by the administra(cid:173)
`tion of ketoconazole a re d ose-dependent and fully re(cid:173)
`versible,5·7·8·10· 19·20·35•'fl,.1-3 with recovery from steroid-
`ogeni c blockad e 8 to I 6 hours after an oral dose. 7· 10
`A considera ble d egree of varia tion in the bioavailabil(cid:173)
`ity of the d rug has been observed in pharmacoki(cid:173)
`netic s tucli es :14>'f5
`In norm a l subj ects given a single oral close of 200 or
`400 m g of ketoconazole, the peak serum concentra(cid:173)
`tions occur a t two hours a nd are 3
`to 4 a nd 5 to 8 t-tg per milliliter,
`•16-4-s Higher serum
`respectively. 11
`levels are found in patien ts taking
`800 to I 200 mg per d ay.8·49 At eight
`hours, the drug is still m eas urable
`in serum , but it is undetectable a t
`24 hours. 35•'!6•1·7 Administra tion im(cid:173)
`m edi a tely after a meal results in
`lower serum levels than does ad(cid:173)
`minis tra tion during fas ting.46•'fB, 4·9
`G as tri c acidity is required for a b(cid:173)
`sorption, which may be impaired
`by a chlorhydria or antacid medi(cid:173)
`cation. 48 •50
`Serum or plasma levels of keto(cid:173)
`conazole have been d etermined by
`bioassay46•49·51 and by more sen(cid:173)
`sitive high-perform ance liquid chro(cid:173)
`matographic methods.52·53 Even a t
`high concentra tions the drug does
`not interfere wi th hormone radio(cid:173)
`immunoassays .5,10,35,'1I
`The serum clearance of th e drug
`
`11·DEOXYCORTICOSTERONE
`
`CORTICOSTERONE
`
`18·0 H·CORTICOSTERONE
`
`11·DEOXYCORTI SOL
`
`TESTOSTERONE
`
`4tOH
`
`CORTISOL
`
`ESTROGEN
`
`ALDOSTERONE
`
`Figure 2. Main Pathways of Adrenal Steroidogenesis.
`SCC denotes cholesterol side-chain cleavage, HSD hydroxysteroid dehydrogenase,
`OH hydroxylase, and OH D hydroxy dehydrogenase. Black bars indicate ketoconazole
`inhibition, and black-and-white bars metyrapone inhibition.
`
`WCK1040
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`

`
`8 14
`
`T H E NEW ENGL AND J OU RNAL Of MEDIC I NE
`
`Sept. 24, 1987
`
`ministration of phenytoin,'l9 accumulation of cyclo(cid:173)
`sporine during ketoconazole therapy ,·18 and inhibition
`of the disposition of m ethylprednisolone.59
`
`Side Effects
`The mos t common side effects a t the doses usually
`employed for fungal infection (200 to 400 mg per d ay)
`are gas trointes tinal reactions, pruritus, and alter(cid:173)
`ations in hepa tic function .15·47·48·56·60-62 About 10 per(cid:173)
`cent of patients have transient abnorma lities in liver
`fun ction,60·63 but the incidence of true hepatic injury
`seems to be very low (0.1 to 1.0 percent) .47·48·6° Fa tal
`hepatitis 6'~ and anaphylaxis65 have also been reported .
`The mechanism of liver d am age induced by ketocona(cid:173)
`zole is still unclear. It seems to involve an idiosyncrat(cid:173)
`ic type of reaction tha t does not d epend on the daily
`dose or the duration of treatment. H owever, an im(cid:173)
`mune hypersensitivity mechanism could not be ex(cid:173)
`cluded in some cases. Biochemical tests and assess(cid:173)
`ment for clinical signs of liver dysfun ction at periodic
`intervals (i.e., biweekly for the first two months and
`then monthly) a re therefore advised. No increased in(cid:173)
`cidence of hepa totoxicity has been reported in pa(cid:173)
`tients receiving prolonged high-dose treatment (800 to
`1200 mg per day) . In pa tients on a regimen of 200 to
`•5 is very rare. At high(cid:173)
`400 mg per day, gynecomas tia4
`er doses, endocrine effects, such as impairment of tes(cid:173)
`ticular fun ction 8 •66 and adrenal insufficiency,67-69 may
`occur. It is because ketoconazole produces such effec ts
`that it has been used to treat clinical conditions that
`may benefit from inhibi tion of either gonadal or ad re(cid:173)
`nal steroid production (see below).
`
`INHIBITION OF ANDROGEN PRODUCTION
`A substantial decrease in total and free tes tos terone
`and and ros tenedione levels occurs in normal men two
`I 5 19
`.
`00
`d
`f k
`hours after a smgle 2
`-mg ose o
`etoconazo e. '
`Recovery from suppression begins at 8 hours and is
`complete by 24 hours. There is a compensatory in(cid:173)
`crease in plasma luteinizing hormone and no change
`in cortisol levels, as compa red with values in persons
`receiving placebo, sugges ting tha t there is selective
`inhibition of C 17_20 lyase a t low d oses. 19 In patients
`receiving high or repeated doses on a long-term basis,
`end-organ effects of diminished tes tos terone levels be(cid:173)
`com e apparent, with marked individual variations.
`Large differences in m ean serum levels of both keto(cid:173)
`conazole and tes tos terone are found among patients
`receiving the same dosage; yet, an inverse correlation
`between ketoconazole and tes tos terone concentrations
`•37·70·71 During prolonged
`is consistently observed. 8
`treatment with 800 to 1200 mg per d ay in a single dose
`for progressive sys temic fungal disease, tes tos terone
`levels are subnormal over 24 hours in some cases, re(cid:173)
`sulting in reduced sperm counts (after four months),
`azoos permia, d ecreased libido, impotence, and gyne(cid:173)
`com as tia .8 Functional hypogonadism appears to be
`reversible upon drug withdrawal.
`Because of its ma rked effects on the androgen(cid:173)
`gonadotropin feedback sys tem in vivo, ketoconazole
`
`has been advocated for use in a test of gonad o tropin
`reserve in m en. 37 Additional stud ies are requi red to
`verify its feasibili ty and clinical usefuln ess. In th e fi rst
`tri al, nin e normal m en received four doses of ketocon(cid:173)
`azole (300, 600, 900, and 1200 mg per d ay); each d ose
`was given fo r one week. T he response to luteinizing
`hormone- releasing hormone was assessed befo re a nd
`after each week. Increases in lu tei nizing hormo ne a nd
`follicle-stimula ting hormone were m axima l a fter the
`dose of 900 mg per d ay. H owever, there was g reat
`variabili ty among subj ects in the levels of both gona(cid:173)
`dotropin and testosterone at each dose tes ted .37
`
`Therapeutic Use
`The potent inhibitory action of ketoconazole o n tes(cid:173)
`tos terone synthesis (Fig. 2) has been used with thera(cid:173)
`peutic benefit in th e ma nagem en t of pros ta te can(cid:173)
`cer.70-71- The drug acts very quickly and has th e
`advantage over other trea tm ents currently employed
`of also d ecreasing ad rena l a ndrogen produ ction . 72-H
`At divided doses of 400 mg every eight hours, w hich
`prevent androgen levels from returni ng to base line,
`castra te values are initially record ed. H owever, the
`rise in luteinizing hormone triggered by the fa ll in
`tes tos terone lead s to a p rogressive increase in tes tos(cid:173)
`terone levels.70-72 Nevertheless, striking clinical im(cid:173)
`provemen t is seen in ma ny pa tients; serum levels of
`pros ta tic acid phosphatase decrease and considerable
`pain relief and regression of so me lesions occurs,
`greatly reducing the need for a nalgesics. 71-74 Indeed ,
`clinical improvement seems to be be tter tha n wou ld b e
`expected on the bas is of tes tos terone levels over the
`long term . H owever, in add ition to impotence a nd
`gynecomas tia, severe gastroin tes tina l disturba nces75
`and signs of adrenal ins ufliciency71•72 m ay occur, re(cid:173)
`quiring dose reducti on and glu cocorti coid replace(cid:173)
`ment, respectively . Further hormonal assessm ent dur(cid:173)
`ing long-term treatment shows a consistent rise in
`proges terone, no changes in p rolactin and estradiol,
`and an increased es tradiol:tes tos terone ra tio. 35,70-72
`The proposal to use ketoconazole as a "sole treat(cid:173)
`ment" for pros tate cancer72 has been ques tioned be(cid:173)
`cause of several problems that have a risen in som e
`studi es: sustained redu ctions in tes tos terone levels
`cannot be maintained , la rge d iurnal flu ctua tions in
`serum testosterone occur in most patien ts, and com(cid:173)
`pliance with a high-dose regimen and strict eight-hour
`timing of doses is somewhat diffic ul t to obtain. 70·71 •75
`Nevertheless, good res ul ts are generally reported ,
`especially in patients previously castra ted or with
`cas tra te tes tos terone levels produ ced by administra(cid:173)
`tion of gonadotropin-releasing hormone a nalogues. In
`such pa tients, ketoconazole, by sup pressing adrenal
`androgen output, brings abo ut fu rther objective or
`subjective remissions.7 1·75 Indeed, a rationale for com(cid:173)
`bined treatment with ketoconazole and superactive
`analogues of gonadotropin-releasing horm one in this
`disease has been suggested by the more pronounced
`androgen suppression obtained wi th bo th drugs than
`with either alone, in studies in both huma ns75,76 and
`
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`
`Vol. 3 17 No. 13
`
`MEDICAL INTELLI GENCE- SONINO
`
`8 15
`
`l 77 I
`.
`amm a s.
`mp rovem ent has been reported in some
`patients in whom the combination drug treatment was
`introd uced a ft er other treatment methods had been
`used. 75 H owever, it has not been proved that the com(cid:173)
`bined treatment is more effective than ketoconazole
`alone, and further evidence is needed before it can be
`recommended.
`Successful th erapy with ketoconazole for up to 12
`months has been reported in three children (3.3 to 3.9
`years old) with precocious puberty and autonomous
`Leydig-cell hyperactivity with low basal and gonado(cid:173)
`tropin-releasing hormone- stimulated gonadotropin
`levels .78 Divided doses (up to 600 mg per day) were
`em ployed, with striking behavioral and clinical im(cid:173)
`provem ent. The growth rate and skeletal matura tion
`were both reduced, a nd low levels of tes tosterone and
`ad renal a ndrogens were maintained in the presence of
`high levels of 17a-hydroxy progesterone. Basal cortisol
`levels were in the norm al range for age. Similar results
`have been obtained in a nother child ( 4.2 years old),
`with gonadotropin-independ ent precocious puberty
`and tuberous sclerosis, who was also successfull y
`treated for six months with ketoconazole (600 mg per
`d ay) .79 In three older children (5.0 to 7.4 years of
`age), an "escape" phenomenon occurred after one to
`three months of continuous treatment with 600 mg per
`day, probably because of the onset of puberty-like
`pituitary fun ction . In these children, combined treat(cid:173)
`ment with ketoconazo le and a gonadotropin-releasing
`hormon e a nalogue restored hormona l levels to the
`prep uberta l ra nge. 80 No signs of liver dysfun ction or
`other side effects occurred in a ny child. In these pre(cid:173)
`liminary studi es, ketoconazole was a safe and effective
`inhibitor of testosteron e overprodu ction in children.
`However, the long-term safety of high-dose treatment
`with th e agent in children needs to be es tablished .
`Finally, because of its selective inhibition of andro(cid:173)
`gen production at low doses, 19 ketoconazole might be
`usefu l in the ma nagement of hirsutism . However, no
`clinical data on thi s iss ue are available at present,
`except lor reports of a few patients who had regression
`of their hirsuti sm while receiving ketoconazole for
`Cushing's syndrome38·81 a nd one pa tient with hirsut(cid:173)
`ism a nd polycystic ovary syndrome who had a striking
`improvem ent two months after starting ketoconazole
`therapy (200 mg twice daily) .82 On the other hand ,
`the effects on es trogen produ ction are still controver(cid:173)
`sial, and it is not known whether the drug allects hor(cid:173)
`monal cyclicity. Thus, the possible interference of ke(cid:173)
`toconazole with the hum an menstrual cycle should be
`evaluated .
`
`INHIBITION oF CoRTISOL PRooucTION
`Wh en ketoco nazo le is administered to s ubj ec ts
`with normal fun ction of the hypothalamic-pitui tary(cid:173)
`adrenal axis, the plasma cortisol response to adre(cid:173)
`nocorti cotropin is blunted for up to eight hours after a
`single dose of 400 or 600 mg_7,8,68,?l ,B3 However, ba(cid:173)
`sal cortisol levels a re not affected or are only slight(cid:173)
`ly lower, even during long-term high-dose treatment
`
`(up to 1200 mg per d ay). 7·70·72
`•78 Signs of adrenal
`insufficiency are uncommon,58·67-69·71 probably be(cid:173)
`cause of a compensatory rise in adrenocorticotropin
`70·72
`levels. 8
`•
`
`Therapeutic Use
`Because ketoconazole is ·a potent inhibitor of corti(cid:173)
`sol production, through the inhibition of both adreno(cid:173)
`cortical 11,8-hydroxylase and cholesterol side-chain
`cleavage (Fig. 2), it has been used in clinical trials of
`palliative treatm ent of Cushing's syndrome. Drug
`control of hypercortisolism is suita ble for patients un(cid:173)
`dergoing surgery , as well as for those treated with ex(cid:173)
`ternal pituitary radiation and those in whom more
`defi nitive treatment is delayed. 8·~
`In patients with an adrenal tumor or pituitary(cid:173)
`depend ent Cushing's disease, plasma cortisol levels
`are suppressed and the cortisol response to adrenocor(cid:173)
`tico tropin is blunted after administration of ketocona(cid:173)
`zole; inhibition of cortisol production by the drug has
`been confirmed in vitro in tiss ue slices of the excised
`tumors or hyperplastic adrenals. 30·85·86 Beneficial en(cid:173)
`docrine eflects of ketoconazole a t doses ranging from
`200 to 1000 mg per day have been observed in patients
`with Cushing's disease and in pa tients with either
`adrenal adenomas or carcinom as. 87 Increasing doses
`(from 400 to 1200 mg per day) have been used to
`reduce excess steroid effects in a pa ti ent with Cush(cid:173)
`ing's syndrome secondary to a fun ctioning adrenal(cid:173)
`rest tumor of the liver, 25 in a patient with prima(cid:173)
`ry adrenocorti cal micronodular adenomatosis,88 and
`in one with Cushing's syndrom e du e to ectopic pro(cid:173)
`du ction of adrenocorticotropin by a small-cell lung
`cancer,89 with improvement in clinical symptoms.
`Since ketoconazole interferes with C 17_20 lyase and
`is a more potent inhibitor of cholesterol side-chain
`cleavage activity, it can be expected that patients
`trea ted with the agent will be free of side effects such
`as mineralocorti coid excess or worsening of hirsutism,
`which may occur during treatment with metyrapone,
`which acts predominantly on 18- and 11,8-hydroxyl(cid:173)
`ases (Fig. 2). On the other hand , the antiandrogenic
`effects of ketoconazole may be disturbing in male pa(cid:173)
`tients. We used prolonged ketoconazole therapy (two
`to six months) in five patients with pituitary-depend(cid:173)
`ent Cushing's disease and recurrent hypercortisolism
`after transsphenoidal surgery. 81 A sixth patient was
`treated for two weeks before und ergoing bilateral ad(cid:173)
`rena lectomy. A dose of 400 mg every 12 hours was
`given during the first month and lowered thereafter,
`depending on individual responses. Urinary cortisol
`levels decreased to norma l in all patients, and rapid
`clinical improvements were observed.81 No patient
`had signs of drug toxicity. Fema le patients had regres(cid:173)
`sion of hirsutism, whereas in the only m ale patient,
`who was treated lo r four months, gyneco mastia devel(cid:173)
`oped. We are now treating additional patients with
`C ushing's disease with ketoconazole (600 mg per
`day). Drug doses necessary to m aintain cortisol levels
`within the norm al range in this condition are relatively
`
`WCK1040
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`

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`816
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Sept. 24, 1987
`
`lower than those employed to suppress testosterone in
`prostatic cancer and are well tolerated.
`Long-term administration of ketoconazole (3 to 13
`months with 600 to 800 mg per day) in other groups of
`patients with pituitary-dependent Cushing's disease
`has also resulted in decreased cortisol levels and im(cid:173)
`pressive clinical improvement,90•9 1 including regres(cid:173)
`sion of psychiatric symptoms. 90 It is noteworthy that
`unlike the findings in patients with an intact hypo(cid:173)
`thalamic-pituitary-adrenal axis, there was no marked
`increase in adrenocorticotropin levels during long(cid:173)
`term administration in any patient with Cushing's dis(cid:173)
`ease. Indeed, little changeBI or a decrease90 in plasma
`adrenocorticotropin concentrations was observed. In
`these patients, however, the adrenocorticotropin re(cid:173)
`sponse to corticotropin-releasing hormone during ad(cid:173)
`ministration of ketoconazole was unchanged 91 or even
`enhanced92 as compared with the pretreatment re(cid:173)
`sponse. This find ing argues against an additional in(cid:173)
`hibitory effect at the pituitary level and is in agree(cid:173)
`ment with the results of previous studies in an imals."13
`Although no conclusions can be drawn from the
`data available, long-term treatment with adrenal in(cid:173)
`hibitors might modify the sensitivity of the hypo(cid:173)
`thalamic-pituitary-adrenal axis in Cushing's disease,
`since unexpectedly low adrenocorticotropin levels
`have also been found during prolonged combined ad(cid:173)
`ministration of ;;etyrapone and aminoglutethimideY3
`One patient had marked regression of a functioning
`metastatic adrenal carcinoma while receiving pallia(cid:173)
`tive ketoconazole treatment. As in advanced prostate
`cancer, 71
`74 it is not known whether the drug acts on
`72
`•
`•
`tumor cells by more than one mechanism.
`
`OTHER EFFECTS
`
`Cholesterol
`Serum cholesterol levels were decreased after high(cid:173)
`dose ketoconazole treatment in patients with ad(cid:173)
`vanced prostate cancer. 72 •9·1· The inhibition of cho(cid:173)
`lesterol synthesis seems to be dose-dependent. 94
`However, the eflects of ketocon azole on cholesterol in
`humans need further evaluation with attention to po(cid:173)
`tential benefits and harm, since the consequences of
`an accumulation of cholesterol precursors are not
`known. 91'•95
`
`Vitamin D
`The inhibitory action of ketoconazole on kidney mi(cid:173)
`tochondrial 24-hyd roxylation of 25-hydroxyvitamin
`f
`f h
`D l'l· '' 7 l
`ld
`h
`·
`·
`·
`·-
`1as e
`to urt er mves tigation o
`t e euect
`cr
`of this agent on 25-hydroxyvitamin D metabolism.
`In cultured chick kidney cells, ketoconazole and mi(cid:173)
`conazole at therapeutic concentrations function as
`competitive inhibitors of both !-hydroxylase and
`24-hydroxylase activities. 96 These hydroxylases are
`a lso cytochrome P-450-dependent enzym es. After
`ketoconazol e administration to normal volunteers, a
`dose-depend ent reduction in serum I ,25-dihydroxy(cid:173)
`vitamin D levels with no change in serum levels of
`25-hydroxyvitamin D and parathyroid hormone was
`observed. 97 It is not known whether th e formation of
`
`25-hydroxyvitamin D by a cytochrome P-450 enzyme
`in liver mitochondria is a lso impaired.
`
`CoNCLUSIONS
`
`Recent research has ex tended the use of the anti(cid:173)
`mycotic agent ketoconazole to endocrine conditions.
`Crucial factors modulating the drug's effects are the
`dosage and timing of administration. R elatively low
`and single daily doses a re less likely to affect the endo(cid:173)
`crine system, whereas high or divided doses produce
`the maximum endocrine effects. As a potent testicular
`and adrenal steroid inhibitor with a predominant an(cid:173)
`tiandrogeni c action, ketoconazole is suitable for treat(cid:173)
`ment of prostatic carcinoma, especially in combina(cid:173)
`tion with gonadotropin-releasing hormone analogues.
`The latter agents prevent the compensatory increase
`in luteini zing hormone and the consequent stimula(cid:173)
`tion of testicu lar steroidogenesis that can overcome
`th e enzyme blockade induced by ketoconazole. It
`should be pointed out that the avai lable reports are
`still preliminary. International multi center studies are
`in progress to define the role of high-dose ketoconazole
`in the treatment of prostatic cancer. 98 Further studies
`will show whether ketoconazol e can be of value in the
`management of conditions of androgen excess, such as
`some forms of hirsutism and precocious puberty due
`to autonomous Leydig-cell hyperfunction.
`In addition, ketoconazole has proved to be useful in
`treating Cushing's syndrome of various causes be(cid:173)
`caus e of its ability to correct the severe complications
`of the disease quickly. Because of its differential selec(cid:173)
`tivity, the drug can be used as an alternative to steroid
`inhibitors that produce side eflects. Moreover, during
`prolonged treatment of pituitary-dependent Cush(cid:173)
`ing's disease with ketoconazol e, escape from adrenal
`inhibition does not seem to occur. However, the drug's
`interaction with the hypothalamic-pituitary-adrenal
`axis has not been fully clarified .
`
`I am indebted to Dr. Alexand er C. Brownie for his comments and
`suggestions and to M rs. Esther Olczak for assistance in th e prepara(cid:173)
`tion of the manuscript.
`
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`Vol. 3 17 No. 13
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`MED ICAL INTELLIGENCE- SON ! NO
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`8 17
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