MULTIPLE SCLEROSIS (MS) is a chronic inflammatory

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1 X/01/$03.00/0 Vol. 86, No. 4 Th Journl of Clinicl Enocrinology & Mtbolism Print in U.S.A. Copyright 2001 by Th Enocrin Socity Combin Trtmnt with Corticostrois n Moclobmi Fvors Normliztion of Hypothlmo- Pituitry-Arnl Axis Dysrgultion in Rlpsing- Rmitting Multipl Sclrosis: A Rnomiz, Doubl Blin Tril FLORIAN THEN BERGH, TANIA KÜMPFEL, ANNETTE GRASSER, RAINER RUPPRECHT, FLORIAN HOLSBOER, AND CLAUDIA TRENKWALDER Dprtmnt of Nurology, Mx Plnck Institut of Psychitry, Munich, Grmny ABSTRACT Hyprrsponsivnss of th hypothlmo-pituitry-rnl (HPA) xis in multipl sclrosis (MS), n utoimmun inflmmtory iss of th cntrl nrvous systm, is prsumbly u to iminish corticostroi rcptor function. It probbly influncs th immun rspons, but its clinicl significnc is not clr. Similr HPA ysrgultion occurs in prssion n is rvrsibl with succssful ntiprssnt trtmnt. W conuct oubl blin, plcbocontroll tril to vlut th nuronocrin ffct of cotrtmnt with th ntiprssnt moclobmi s n junct to orl corticostrois in MS. Twnty-on ptints with finit rlpsing-rmitting MS (11 fmls, g yr; Expn Disbility Sttus Scl scor of nurologicl impirmnt, ) in cut rlps wr trt with plcbo (n 13) or 300 mg moclobmi (rvrsibl monomin oxis A inhibitor; n 8) for 75 ys. All rciv orl fluocortolon from y 7 on, n th os ws tpr until y 29. Effcts wr Rciv July 10, Rvision rciv Octobr 10, Rrvision rciv Dcmbr 15, Accpt Dcmbr 28, Arss ll corrsponnc n rqusts for rprints to: Dr. Florin Thn Brgh, Ntionl Institut of Nurologicl Disss n Strok, Lbortory of Molculr Biology, Ntionl Instituts of Hlth, 36 Convnt Driv, Room 3C11, Bths, Mryln E-mil: [email protected]. vlut using th combin xmthson-crh tst n cliniclly on ys 1, 30, n 75. At bslin, th HPA xis ws milly ctivt, comprbly for trtmnt groups [r unr th curv for cortisol (AUC-Cort), rbitrry units in th moclobmi group vs in th stroi lon group; mn SEM]. In group of hlthy controls with comprbl mogrphic chrctristics, th AUC-Cort ws Moclobmi cotrtmnt rsult in normliztion of th HPA xis rspons, whrs th HPA systm hyprrspons ws mintin with strois lon (AUC-Cort on y 30, vs ; on y 75, vs ). Th chng in Expn Disbility Sttus Scl ws comprbl for both groups. Although corticostrois lon h no ffct on th HPA rspons using th xmthson-crh tst, trtmnt with moclobmi combin with corticostrois fvors normliztion of th HPA rspons in rlpsing-rmitting MS. (J Clin Enocrinol Mtb 86: , 2001) MULTIPLE SCLEROSIS (MS) is chronic inflmmtory iss of th cntrl nrvous systm tht usully bgins in young ulthoo n follows rlpsing cours of cntrl nrvous systm ysfunction with complt or incomplt rmissions, vntully ling to prmnnt impirmnt in mny ptints (1). Although thr is no known singl cus of th isorr, thr is mpl vinc tht it is T lymphocyt-pnnt utoimmun procss tht is probbly triggr by xognous vnts such s infctions (2). Th vrious componnts of th immun rspons tht r implict in th pthognsis of MS r primrily controll by intrinsic fbck loops. Howvr, th immun systm is lso influnc xtrinsiclly, notbly by th nocrin systm. Mchnisms of mutul intrctions hv bn bst chrctriz for th glucocorticostrois, which gnrlly ct in n immunosupprssiv wy (3, 4) n whos scrtion is rgult by th hypothlmo-pituitry-rnl (HPA) xis. In ition, nocrinologiclly ctiv pptis n cytokins, scrt by clls of th immun systm, xrt vrious ffcts on th HPA xis, for xmpl, incrs scrtion of ACTH n cortisol uring cut inflmmtory rctions (for rviws, s Rfs. 5 n 6). Thrfor, stuying nocrin function my provi itionl insight into th pthognsis of n furthr thrputic strtgis for MS. Although rlir rports on th rgultion of th HPA systm in MS yil vribl rsults (7 9), rcnt litrtur mor consistntly shows hyprctivity of th HPA xis unr bsl conitions (10), in ynmic tsting (10 14), or postmortm (15 17). Using th combin xmthson-crh tst (Dx-CRH tst), w prviously show hyprctivity of th HPA systm in MS ptints, which ws significntly corrlt to th clinicl cours of MS (12, 18). As yt, howvr, littl is known bout th tim cours of HPA xis ctivity n its rltion to thrputic intrvntions. It is concivbl, for xmpl, tht chronic hyprscrtion of cortisol ls to snsitiztion of immun clls towr th ffcts of corticostrois, mking stroi miction for cut rlps lss ffctiv. In th rt, suscptibility to xprimntl llrgic ncphlomylitis, n niml mol of MS, is rlt to th immunogntic bckgroun n th ntign us for immuniztion (19). In ition, HPA systm ctivity hs lso bn shown to influnc th cours of xprimntl llrgic ncphlomylitis (20 23), lthough its 1610 Th Enocrin Socity. Downlo from prss.nocrin.org by [${iniviulusr.isplynm}] on 20 Novmbr t 23:44 For prsonl us only. No othr uss without prmission.. All rights rsrv.

2 NEUROENDOCRINE EFFECT OF MOCLOBEMIDE AS ADJUNCT TO CORTICOSTEROIDS IN MS 1611 rol in trmining iss suscptibility in iffrnt rt strins is controvrsil (24). Nuronocrin fbck hs lso bn stui in ptints with ffctiv isss in th srch for th nurobiologicl bsis of moo isorrs. Hyprctivity of th HPA systm is on of th most consistnt finings in mjor prssion (rviw in Rfs. 25 n 26). Th Dx-CRH tst in prss ptints yils rsults similr to thos in MS (27 29). Intrstingly, succssful trtmnt with ntiprssnts is ssocit with ruction or normliztion of HPA hyprctivity (28, 30, 31). Animl xprimnts hv shown tht ntiprssnts incrs glucocorticoi rcptor mssngr ribonuclic ci in th hypothlmus (32), n tht mitriptylin (33) n th rvrsibl inhibitor of monomin oxis A, moclobmi (34), both incrs th mount of glucocorticoi rcptors in th rt hypothlmus. On of th mchnisms of ction of ntiprssnts my thrfor b th rstortion of th isturb fbck rgultion of th HPA systm. W hypothsiz tht u to HPA xis ctivtion n ccompnying subclinicl hyprcortisolism, th trgt tissus (notbly clls of th immun systm) my pt to stroi ffcts n b lss suscptibl to stroi miction in MS ptints. Rstoring norml HPA xis function by comiction (with n ntiprssnt) my thrfor improv th thrputic ffct of such miction. In th first stp w wnt to trmin whthr HPA systm ysrgultion ws fix or coul b moifi n to ssss th tolrbility of combin trtmnt. W thrfor conuct oubl blin, plcbo-controll tril to vlut th ffct of cotrtmnt with th ntiprssnt moclobmi s n junct to orl corticostrois in MS. Tril sign Subjcts n Mthos As th comiction w chos moclobmi ovr mitriptylin, bcus th lttr hs nticholinrgic si-ffcts, vrsly ffcting blr function, which is oftn impir in MS. Ptints wr trt with moclobmi or plcbo for 6 ys bfor strois wr ; th intrvl ws introuc to llow for incrs synthsis of glucocorticoi rcptors, ccoring to prvious t from niml xprimnts (34). Th tril inclu ptints with rlpsing-rmitting or chronic progrssiv MS. In this rport w prsnt t for rlpsing-rmitting MS only; th stuy is ongoing in chronic progrssiv ptints (s blow). Th tril ws sign s oubl blin, plcbo-controll, clinicl tril. It ws pprov by th thics committ of th Mx Plnck Institut of Psychitry n ws conuct ccoring to th Dclrtion of Hlsinki. For n ovrviw of th tril sign, s Fig. 1. To b inclu in th tril, ptints h to hv cliniclly finit MS ccoring to Posr s critri (35) n cliniclly rlvnt rlps (fin s nw or rcurring nurologicl ysfunction lsting for t lst 48 h in th bsnc of fvr, intrcurrnt infction, or othr fctors possibly cusing impir nurologicl functioning) with n iniction for trtmnt with corticostrois. Exclusion critri wr mjor prssion [ccoring to th Dignostic n Sttisticl Mnul of Mntl Disorrs III (36)] or othr psychitric isss, fmily history of ffctiv isorrs in first gr rltiv, or trtmnt with psychoctiv or othr cntrlly cting mictions, corticostrois, immunosupprssnts, or immunomoulting substncs within th lst 6 months. All ptints gv writtn inform consnt. Upon inclusion in th tril, ptints wr xmin cliniclly [y 0; incluing scoring nurologicl isbility ccoring to Kurtzk s Expn Disbility Sttus Scl (EDSS) (37)], n prssiv symptoms wr scor using th Hmilton prssion (HAMD) scor (38). Nuronocrinologicl ssssmnt ws prform using th combin Dx- CRH tst on y 1 (s blow). From y 2 until th n of th tril, ptints rciv ithr 300 mg moclobmi ily or plcbo in inticl cpsuls. All ptints rciv orl fluocortolon strting on y 7 t 100 mg ily; th os ws tpr ovr 22 ys (100, 80, 60, n 40 mg for 3 ys ch, n 20 n 10 mg for 5 ys ch, rspctivly), togthr with rnitiin (300 mg ily). On y 30, 1 y ftr th lst os of fluocortolon (10 mg), th clinicl vlution n Dx-CRH tst wr rpt. Ptints continu to tk th stuy miction (moclobmi or plcbo) n wr gin xmin cliniclly n by th Dx-CRH tst on y 75, i.. 6 wks ftr csstion of stroi trtmnt. Subjcts Figur 2 givs n ovrviw of th mtho of subjct slction. Scrning for this tril inclu ll ptints mitt for corticostroi trtmnt (n 138). Of ths, 98 wr xclu bcus thy mt xclusion critri; in most css, corticostroi trtmnt coul not b ly ccoring to stuy protocol on clinicl grouns, or prior ntiprssnt miction coul not b xclu with sufficint crtinty. Th rmining 40 ptints (who h rlpsing-rmitting or chronic-progrssiv MS) wr conscutivly ssign to th stuy miction. This procur follow rnomiz, blin trtmnt ssignmnt, which h bn provi bfor th strt of th tril by th institut s biomtricin. Although our primry intrst ws to xmin th ffct of moclobmi on th HPA ctivity of ll MS ptints, w itionlly wnt to invstigt this ffct within spcific clinicl subgroups such s rlpsing-rmitting, sconry, n primry progrssiv ptints. Thrfor, w rcruit t lst ight ptints pr trtmnt rm for ch of th formntion groups n prform th nlysis in th first group of FIG. 1. Dsign of th tril. Th Enocrin Socity. Downlo from prss.nocrin.org by [${iniviulusr.isplynm}] on 20 Novmbr t 23:44 For prsonl us only. No othr uss without prmission.. All rights rsrv.

3 1612 THEN BERGH ET AL. JCE&M 2001 Vol. 86 No. 4 t 1430 h n kpt ptnt by norml slin infusion. Bloo ws tkn t 15-min intrvls btwn 1500 n 1630 h for trmintion of plsm concntrtions of cortisol n ACTH. At 1502 h, 100 g synthtic humn CRH (CLINALFA, Läuflingn, Switzrln) ws injct s n iv bolus. Dtrmintion of plsm hormon concntrtions Bloo ws rwn into prchill tubs contining thylnimin ttrctt n Trsylol n cntrifug, th plsm ws tkn off, frozn, n stor t 80 C until msurmnt. Cortisol n ACTH concntrtions wr trmin using commrcil RIAs (ImmuChm Cortisol, ICN Biomicls, Inc., Cost Ms, CA; RIA-ACTH, Nichols Institut Dignostics, Sn Jun Cpistrno, CA), with n intrssy cofficint of vrition of lss thn 8% n n intrssy cofficint of vrition of lss thn 4%. FIG. 2. Flow chrt of subjct slction n trtmnt ssignmnt. PLC, Plcbo; MOC, moclobmi; FLUO, fluocortolon. S Subjcts n Mthos for tils. TABLE 1. Clinicl chrctristics of th stuy popultion Chrctristic Plcbo fluocortolon Trtmnt ptints mting this rquirmnt (rlpsing-rmitting MS). Twntyon ptints with rlpsing-rmitting MS wr inclu. Tbl 1 givs th mogrphic n clinicl chrctristics of th ptints ccoring to trtmnt rm. For bttr ssssmnt of th nuronocrin prmtrs, th vlus wr compr with th rsults of Dx-CRH tsts obtin prviously in 27 hlthy controls with comprbl mogrphic chrctristics (18). Tbl 1 givs mogrphic chrctristics of th control subjcts. Nuronocrinologicl ssssmnt Moclobmi fluocortolon Hlthy controls No Ag (yr) Sx (f/m) 7/6 4/4 10/17 Diss urtion EDSS HAMD No. of prvious rlpss No. of prvious stroi courss Vlus r th mn SEM. Th Dx-CRH tst ws prform s prviously scrib (12). Ptints wr prtrt with 1.5 mg xmthson, orlly, t 2300 h th night bfor th tst. On th y of th tst, n iv cnnul ws insrt Dt nlysis For sttisticl nlysis, th following curv inictors of th plsm hormon concntrtions in th Dx-CRH tst wr us: mximum concntrtion (Mx-Cort n Mx-ACTH), iffrnc btwn bslin n mximum ftr humn CRH injction ( -Cort n -ACTH), n th r unr th tim cours curv ccoring to th trpzoi rul (AUC-Cort n AUC-ACTH). In n xplortory mnnr, th EDSS scor ws nlyz s n inictor of th clinicl ffct of th trtmnts. Group iffrncs with rspct to th clinicl n nuronocrin prmtrs wr sttisticlly tst for significnc by two-fctoril multivrit nlysis of covrinc. Group ws btwn-subjcts fctor with thr lvls (MS ptints with plcbo, MS ptints with moclobmi, n controls), tim ws within-subjct fctor with thr lvls (bslin, y 30, n y 75), n g n sx wr th covrits. If significnt min or intrction ffcts wr foun, univrit F tsts wr prform to intify th vribls with significnt contributions to ths ffcts. For ths vribls, tsts with contrsts wr subsquntly crri out to loct th group or tim pirs with significnt iffrncs. Vlus wr lso compr with th rsults obtin prviously in 27 hlthy controls. As th nominl lvl of significnc, 0.05 ws ccpt. A postriori tsts (univrit F tsts n tsts with contrst) wr prform t ruc lvl of significnc (just ccoring to Bonfrroni procur) to kp th typ I rror lss thn or qul to Dt r givn s th mn sm unlss stt othrwis. Rsults Of th 21 rlpsing-rmitting ptints rnomiz, 13 rciv plcbo plus fluocortolon, n 8 rciv moclobmi plus fluocortolon. Dmogrphic n clinicl chrctristics wr not rlvntly iffrnt btwn th 2 trtmnt groups, xcpt for slightly highr mn HAMD scor in th moclobmi group ( vs in th plcbo group). This iffrnc rsult from singl ptint with HAMD scor of 19 in th vrum group, whrs ll othr ptints h scors blow 3. This lttr, low rng of HAMD scors is quivlnt to no mor thn minor symptoms of prss moo (.g. occsionl concrns, mil slp isturbnc); thus, ptints wr symptomtic by this msur. Th nuronocrinologicl ssssmnt t bslin rvl xggrt cortisol scrtion in th combin Dx- CRH tst in both trtmnt groups (Fig. 3, lft, Dy 1) compr with hlthy controls. Both groups thus isply ysrgultion of th hypothlmo-pituitry-rnl systm, with comprbl gr of ysrgultion. Th mn morning cortisol plsm concntrtion ws norml in ll subjcts. Covrinc nlysis i not rvl significnt ffcts of th covrits g n sx on th concntrtions of ny of th hormons. In contrst, tim s wll s group by tim xrt significnt influnc on th cortisol concntrtions s both min n intrction ffcts [multivrit nlysis of covri- Th Enocrin Socity. Downlo from prss.nocrin.org by [${iniviulusr.isplynm}] on 20 Novmbr t 23:44 For prsonl us only. No othr uss without prmission.. All rights rsrv.

4 NEUROENDOCRINE EFFECT OF MOCLOBEMIDE AS ADJUNCT TO CORTICOSTEROIDS IN MS 1613 TABLE 2. Clinicl n nuronocrin prmtrs bfor, immitly ftr, n 6 wks ftr orl fluocortolon trtmnt ccoring to trtmnt group FIG. 3. Plsm cortisol concntrtion in th Dx-CRH tst bfor (lft), immitly ftr (cntr, Dy 30) n 6 wks ftr (right, Dy 75) trtmnt with fluocortolon n plcbo (n 13; F) or fluocortolon n moclobmi (n 8; f)., Th cortisol rspons in 27 hlthy controls stui prviously. nc, Wilks multivrit tst of significnc; ffct of tim: F(6, 40) 3.173; P 0.012; ffct of group by tim: F(12, 80) 1.98; P 0.037]. Ths ffcts, spcilly th intrction ffct, wr shown (or nforc) for lmost ll curv inictors (univrit F tsts, P 0.05). W thrfor proc to nlyz for ch of th curv inictors th simpl ffcts (contrsts) mong th thr groups t ch tim point n vic vrs for th thr tim points within ch group. Tsts with contrsts rvl th following rsults. Nuronocrinologicl follow-up in th group trt with plcbo n fluocortolon rvl tht th tim cours of th plsm cortisol concntrtion chng littl on y 30 (1 y ftr th n of stroi miction; Fig. 3, cntr, Dy 30) s wll s on y 75. Corticostrois lon thus i not substntilly ltr HPA systm ysrgultion. In contrst, whn fluocortolon ws combin with moclobmi, cortisol scrtion in th Dx-CRH tst on y 30 ws lowr thn in th rfrnc popultion n ws inistinguishbl from tht in controls on y 75 (Fig. 3, right, Dy 75). Combin moclobmi n fluocortolon thus l to normliztion of HPA xis ctivity. Th nuronocrin inictors r list in Tbl 2. It ws furthr foun tht th AUC-Cort ws significntly iffrnt from tht in th rfrnc popultion in both ptint groups t bslin. At follow-up, AUC-Cort in th moclobmi group ws not iffrnt from tht in controls t both ssssmnts. In th plcbo group, trn (P 0.067) towr HPA systm hyprctivity ws rtin t th finl visit. Th trtmnt ws wll tolrt in both groups. Siffcts inclu trnsint mil nus uring th first 3 5 ys of stuy rug trtmnt s wll s slp isturbnc uring th first wk of th combin miction. Ths si-ffcts wr mor common in th moclobmi group, lbit not significntly. Although th si-ffcts gnrlly subsi within ys, on ptint (moclobmi group) complin of insomni for lmost th ntir prio of stroi miction. Thr ws no iniction tht combin trtmnt ggrvt ny othr known si-ffcts of moclobmi or fluocortolon. Group/prmtr Plcbo fluocortolon Moclobmi fluocortolon Hlthy controls n Bslin EDSS NA HAMD NA Bsl ND cortisol (145 34) (129 24) Mx Cortisol b b ( ) ( ) ( ) Dltmx Cortisol c ( ) ( ) ( ) AUC Cortisol b b Mx ACTH ( ) ( ) ( ) Dltmx ACTH ( ) ( ) ( ) AUC ACTH Dy 30 EDSS HAMD Mx Cortisol c ( ) ( ) Dltmx Cortisol ( ) ( ) AUC Cortisol c Mx ACTH ( ) ( ) Dltmx ACTH ( ) ( ) AUC ACTH Dy 75 EDSS HAMD Mx Cortisol c ( ) ( ) Dltmx Cortisol ( ) ( ) AUC Cortisol c Mx ACTH ( ) ( ) Dltmx ACTH ( ) ( ) AUC ACTH Hormon plsm concntrtions r givn in Systèm Intrntionl units, n convntionl units r givn in prnthss. AUC vlus wr clcult from convntionl units ccoring to th trpzoil rul. nmol/l (ng/ml). b Significntly iffrnt from controls (P 0.05). c Mrginlly significnt iffrnc from controls (P 0.1). Arbitrry units. pmol/l (pg/ml) Th thrputic ffct of corticostroi trtmnt on nurologicl impirmnt ws similr in both groups, with mn ructions of th EDSS on y 30 of points (moclobmi group) n (plcbo group) n comprbl furthr improvmnt until y 75. Th HAMD scor ws mor mrkly ruc in th moclobmi group; howvr, th mn chng ws smll, s xpct from th gnrlly low scors t bslin. Th on ptint with HAMD scor of 19 rciv moclobmi n improv to HAMD scor of 10. Th Enocrin Socity. Downlo from prss.nocrin.org by [${iniviulusr.isplynm}] on 20 Novmbr t 23:44 For prsonl us only. No othr uss without prmission.. All rights rsrv.

5 1614 THEN BERGH ET AL. JCE&M 2001 Vol. 86 No. 4 Discussion Th min finings of this plcbo-controll tril in rlpsing-rmitting MS r 1) mil hyprctivity of th HPA systm, which is 2) not substntilly chng in th cours of orl trtmnt with corticostrois, but 3) cn b ssntilly normliz by combin trtmnt with moclobmi n corticostrois. This combin trtmnt rgimn ws wll tolrt n qully ffctiv s corticostrois lon. Tim cours of HPA xis ysrgultion in multipl sclrosis Dysrgultion of th HPA systm in MS ptints hs bn monstrt in numbr of stuis (10 14, 18). Among th tsts mploy to t, th combin Dx-CRH tst ws spcilly snsitiv t tcting HPA xis hyprctivity (18), n w thrfor chos it s th min msur for nuronocrinologicl ssssmnt in this tril. Th mil gr of cortisol hyprscrtion ws comprbl to th rng w (12, 18) n othrs (14) h obsrv in rlpsing-rmitting MS in rlir invstigtions. W bliv tht it rflcts isturbnc of ngtiv fbck t th lvl of th hypothlmus or pituitry, whr th ministr xmthson supprsss HPA systm ctivity, mit vi th glucocorticoi, n prtly th minrlocorticoi rcptor. An bnormlly low numbr or ltr function of ths rcptors coul xplin this phnomnon. Th origin of th HPA xis ysrgultion in MS is currntly unclr, n stuying its tim cours my contribut to unrstning this phnomnon. Among functionl isturbncs, ctivtion of hormon scrtion, for xmpl by cytokins or inflmmtory mitors my b involv (5, 6), which woul b consistnt with normliztion upon trtmnt with ntiinflmmtory gnts. Altrntivly, it my mrly rflct ntomicl mg to th cntrl nrvous systm, s it ws foun to corrlt with th gr of nurologicl impirmnt (18). In this lttr cs, HPA xis ysrgultion woul b xpct to hrly rspon to trtmnt. Our prsnt rsults rgu in fvor of functionl rthr thn structurl isturbnc, s th rspons of th HPA systm cn b ffctivly mnipult pning on th choic of trtmnt. Th stroi rgimn w us i not prouc substntil supprssion of th HPA xis, s ssss by th Dx-CRH tst 1 y ftr th n of trtmnt. This pprs contrictory to th usully obsrv pttrn of HPA systm own-rgultion upon xognous stroi ppliction. Th slow tpring from 100-mg to 10-mg ily os, n th 1-y intrvl bfor th Dx-CRH tst probbly llow for sufficint rcovry of HPA systm rctivity. Thr r thr prvious stuis on th ctivity of th HPA xis in th contxt of stroi trtmnt for MS rlps (39 41). All of ths stuis focus on concrns bout nocrinologicl sfty n wr thrfor sign to primrily tct possibl subnorml HPA systm ctivity. Miro t l. (39) prform ACTH stimultion n mtyrpon tsts immitly ftr csstion of thrpy. Thy show tht orl corticostrois (prnison, tpr from 1 mg/kg) i not rsult in gross supprssion of cortisol scrtion n conclu tht thy wr nocrinologiclly sf. No bslin vlus r rport. Wnning t l. (40) n Lvic t l. (41) invstigt ptints trt with iv mthylprnisolon (500 mg ily for 5 ys n 1000 mg ily for 7 ys, rspctivly), n thir rsults r thrfor not irctly comprbl to ours. Ths stuis tct subnorml bsl cortisol lvls up to 5 ys ftr csstion of trtmnt (40), but only trnsintly ruc ACTH n cortisol rsponss to iv CRH (40) or insulin-inuc hypoglycmi (41) for 1 3 ys. Ths stuis o not commnt on th phnomnon of ovrctivity of th HPA systm, n th follow-up prio ws t most 3 wks ftr stroi trtmnt (41). It is thrfor ifficult to compr ths trils with our prsnt work. Most importntly, howvr, orl trtmnt i not supprss HPA systm rsponsivnss (39), s ws th cs in our sris. Moifiction of HPA systm ctivity n possibl clinicl ffcts Essntilly norml rctivity of th HPA xis ws chiv by combintion of strois n moclobmi. As strois lon h no comprbl ffct, th influnc on th HPA systm is lrgly ttributbl to moclobmi. Th most probbl mchnism of this influnc is n incrs in glucocorticoi rcptor (GR) contnt in th hypothlmus, thus rstoring th usul lvl of HPA supprssion by xognous xmthson. Piffr t l. monstrt tht ntiprssnts o incrs th mount of GR mssngr ribonuclic ci in th hypothlmus in hlthy rts f mitriptylin (32). Biochmicl n phrmcologicl stuis confirm th incrs in GR protin, n bhviorl tsting inict n ttnution of HPA xis rctivity to stblish strssors with both moclobmi (34) n mitriptylin (33). A highr numbr of GRs coul xplin how th fbck inhibition by xmthson is improv, rflct by iminish cortisol scrtion compr with bslin. Th mor pronounc ffct on lowring cortisol scrtion compr with ACTH scrtion inicts tht th chronic stimultion of th rnl glns is iminish, but my lso b th rsult of itionl priphrl ffcts. Anothr possibl xplntion might, of cours, b tht th physicl n psychologicl strss ssocit with nurologicl impirmnt l to HPA ctivtion, n tht it rsolv sconry to clinicl improvmnt. Howvr, this sms unlikly bcus th trtmnt groups h vry similr clinicl cours, but bhv iffrntly with rspct to nuronocrin rgultion. Still, th smpl siz is smll, n th influnc of unrcogniz confouning ffcts cnnot b xclu. In th prsnt ptint group, th ffcts of moclobmi cotrtmnt on HPA systm ysrgultion wr mort. Sttisticlly, significnt iffrnc compr with controls ws prsnt t bslin, n HPA ovrctivity prsist until th finl visit in ptints rciving fluocortolon lon. With moclobmi cotrtmnt, no iffrnc from controls ws tct t follow-up ssssmnts. Dirct comprison of th two trtmnt groups i not, howvr, rsult in iffrncs rching sttisticl significnc. W think tht this filur to show significnt group iffrncs in th irct comprison is prtly u to th smll smpl siz. Furthr, this stuy compriss ptints with rlpsing-rmitting MS only, th group with th milst gr of HPA xis ctivtion (18). Although our stuy smpl ws too smll to tct clin- Th Enocrin Socity. Downlo from prss.nocrin.org by [${iniviulusr.isplynm}] on 20 Novmbr t 23:44 For prsonl us only. No othr uss without prmission.. All rights rsrv.

6 NEUROENDOCRINE EFFECT OF MOCLOBEMIDE AS ADJUNCT TO CORTICOSTEROIDS IN MS 1615 iclly rlvnt iffrncs in th ffcts of th two trtmnts, this ws not th primry gol of th stuy. Th iffrnc is xpct to b subtl n woul rquir lrgr numbrs of ptints to b tct. This is lso vint from rcnt stuy compring iffrnt rgimns of stroi trtmnt in MS (42). In ition, possibl clinicl bnfit of normlizing HPA xis rsponsivnss woul probbly b vint with long-trm thrpy only. Th mn prssion scors (HAMD) my sm unxpctly low in chroniclly ill popultion. Strict xclusion of ptints who mt critri for mjor prssion n ttribution of somtic symptoms to MS rthr thn prssion hv probbly contribut to ths low scors. Chronic hyprscrtion of cortisol, s suggst by th known HPA xis hyprctivity in MS, ls to trgt tissu pttion, mking th tissus lss snsitiv to th ffcts of strois, mong othrs in th immun systm. Morovr, rcnt vinc (43) suggsts tht in g rts, hyprcortisolism is crucil fctor limiting th prolifrtion of nurl stm clls in th hippocmpus, n tht ruction of corticostroi lvls rstors norml formtion of nurons vn in ult mmmls. Although this hs not bn prospctivly stui in MS, th ysrgultion of th HPA systm my thrfor contribut to th pthognsis of th iss, n its normliztion my b bnficil. Our prsnt t monstrt tht th HPA systm ysrgultion cn b moifi by phrmcologicl intrvntion. Furthr invstigtion is rquir to trmin whthr th obsrv nocrinologicl chngs influnc th clinicl outcom in th long trm. Rfrncs 1. Compston DAS, McAlpin s multipl sclrosis, 3r E. Lonon: Churchill Livingston. 2. Hohlfl R Biotchnologicl gnts for th immunothrpy of multipl sclrosis: principls, problms n prspctivs. Brin. 120: Prrillo JE, Fuci AS Mchnisms of glucocorticoi ction on immun procsss. Annu Rv Phrmcol Toxicol. 19: Boumps DT, Chrousos GP, Wilr RL, Cupps TR, Blow JE Glucocorticoi thrpy for immun-mit isss: bsic n clinicl corrlts. Ann Intrn M. 119: Bsovsky HO, l Ry A Immun-nuro-nocrin intrctions: fcts n hypothss. Enocr Rv. 17: Turnbull AV, Rivir CL Rgultion of th hypothlmic-pituitryrnl xis by cytokins: ctions n mchnisms of ction. Physiol Rv. 79: Ktlr CJ, Dlmott P Rsults of rnl n pituitry stimultion tsts in ptints with multipl sclrosis. Act Nurol Scn. 48: Mi E, Summr K Srum cortisol lvls of multipl sclrosis ptints uring ACTH trtmnt. J Nurol. 220: Snyr BD, Lktu DJ, Do RP ACTH-inuc cortisol prouction in multipl sclrosis. Ann Nurol. 10: Michlson D, Ston L, Gllivn E, t l Multipl sclrosis is ssocit with ltrtions in hypothlmic-pituitry-rnl xis function. J Clin Enocrinol Mtb. 79: Rr AT, Lowy MT, Mltzr HY, Antl JP Dxmthson supprssion tst bnormlitis in multipl sclrosis: rltion to ACTH thrpy. Nurology. 37: Grssr A, Möllr A, Bckmun H, Yssouriis A, Holsbor F Htrognity of hypothlmic-pituitry-rnl systm rspons to combin xmthson-crh tst in multipl sclrosis. Exp Clin Enocrinol Dib. 104: Wi T, Lightmn SL Th nuronocrin xis in ptints with multipl sclrosis. Brin. 120: Fssbnr K, Schmit R, Mossnr R, t l Moo isorrs n ysfunction of th hypothlmic-pituitry-rnl xis in multipl sclrosis: ssocition with crbrl inflmmtion. Arch Nurol. 55: Rr AT, Mkowic RL, Lowy MT Arnl siz is incrs in multipl sclrosis. Arch Nurol. 51: Erkut ZA, Hofmn MA, Rvi R, Swb DF Incrs ctivity of hypothlmic corticotropin-rlsing hormon nurons in multipl sclrosis. J Nuroimmunol. 62: Purb JS, Rshr FC, Hofmn MA, t l Incrs numbr of corticotropin-rlsing hormon xprssing nurons in th hypothlmic prvntriculr nuclus of ptints with multipl sclrosis. Nuronocrinology. 62: Thn Brgh F, Kümpfl T, Trnkwlr C, Rupprcht R, Holsbor F Dysrgultion of th hypothlmo-pituitry-rnl xis is rlt to th clinicl cours of multipl sclrosis. Nurology. 53: Wkrl H, Kojim K, Lnns-Viir J, Lssmnn H, Linington C Animl mols. Ann Nurol. 36:S47 S McPh IA, Antoni FA, Mson DW Spontnous rcovry of rts from xprimntl llrgic ncphlomylitis is pnnt on rgultion of th immun systm by nognous rnl corticostrois. J Exp M. 169: Bolton C, Flowr RJ Th ffcts of th nti-glucocorticoi RU on stroi-mit supprssion of xprimntl llrgic ncphlomylitis (EAE) in th Lwis rt. Lif Sci. 45: Mson D, McPh I, Antoni F Th rol of th nuronocrin systm in trmining gntic suscptibility to xprimntl llrgic ncphlomylitis in th rt. Immunology. 70: Rr AT, Thpr M, Jnsn MA A ruction in srum glucocorticois provoks xprimntl llrgic ncphlomylitis: implictions for trtmnt of inflmmtory brin iss. Nurology. 44: Stffrl A, Linington C, Holsbor F, Rul JMHM Suscptibility n rsistnc to xprimntl llrgic ncphlomylitis: rltionship with hypothlmic-pituitry-rnl xis rsponsivnss in th rt. Enocrinology. 140: Holsbor F, Spnglr D, Husr I Th rol of corticotropin-rlsing hormon in th pthognsis of Cushing s iss, norxi nrvos, lcoholism, ffctiv isorrs n mnti. Prog Brin Rs. 93: Owns MJ, Nmroff CB Th rol of corticotropin-rlsing fctor in th pthophysiology of ffctiv n nxity isorrs: lbortory n clinicl stuis. Cib Foun Symp. 172: von Brlbn U, Holsbor F Cortisol rspons to combin xmthson-humn-corticotropin-rlsing hormon chllng in ptints with prssion. J Nuronocrinol. 1: Husr I, Yssouriis A, Holsbor F Th combin xmthson/crh tst: rfin lbortory tst for psychitric isorrs. J Psychitr Rs. 28: Moll S, Yssouriis A, Hubr J, Holsbor F Corticostroi rcptor function is crs in prss ptints. Nuronocrinology. 65: Brn N, Rul JMHM, Holsbor F Do ntiprssnts stbiliz moo through ctions on th hypothlmic-pituitry-rnocorticl systm? Trns Nurosci. 18: Husr IJ, Schwigr U, Gotthrt U, t l Pituitry-rnl-systm rgultion n psychopthology uring mitriptylin trtmnt in lrly prss ptints n norml comprison subjcts. Am J Psychitry. 153: Piffr A, Villux S, Brn N Antiprssnt n othr cntrlly cting rugs rgult glucocorticoi rcptor mssngr RNA lvls in rt brin. Psychonuronocrinology. 16: Rul JM, Stc I, Sor M, Holsbor F Chronic trtmnt of rts with th ntiprssnt mitriptylin ttnuts th ctivity of th hypothlmic-pituitryrnocorticl systm. Enocrinology. 133: Rul JM, Lbur MS, Grigoriis DE, D Souz EB, Holsbor F Hypothlmic-pituitry-rnocorticl xis chngs in th rt ftr long-trm trtmnt with th rvrsibl monomin oxis-a inhibitor moclobmi. Nuronocrinology. 60: Posr CM, Pty DW, Schinbrg L, t l Nw ignostic critri for multipl sclrosis: guilins for rsrch protocols. Ann Nurol. 13: Amricn Psychitric Assocition Dignostic n sttisticl mnul of mntl isorrs, 3r E. Wshington DC: Amricn Psychitric Assocition. 37. Kurtzk JF Rting nurologic impirmnt in multipl sclrosis: n xpn isbility sttus scl (EDSS). Nurology. 33: Hmilton M Dvlopmnt of rting scl for primry prssiv illnss. Br J Consult Clin Psychol. 6: Miro J, Amo JA, Psqur C, Lopz Corovill JJ, Brcino J Assssmnt of th hypothlmic-pituitry-rnl xis function ftr corticostroi thrpy for MS rlpss. Act Nurol Scn. 81: Wnning GK, Witholtr H, Schnur G, Mullr PH, Knuth S, Rnn W Rcovry of th hypothlmic-pituitry-rnl xis from supprssion by short-trm, high-os intrvnous prnisolon thrpy in ptints with MS. Act Nurol Scn. 89: Lvic Z, Micic D, Nikolic J, t l Short-trm high os stroi thrpy os not ffct th hypothlmic-pituitry-rnl xis in rlpsing multipl sclrosis ptints. Clinicl ssssmnt by th insulin tolrnc tst. J Enocrinol Invst. 19: Brns D, Hughs RA, Morris RW, t l Rnomis tril of orl n intrvnous mthylprnisolon in cut rlpss of multipl sclrosis. Lnct. 349: Cmron HA, McKy RDG Rstoring prouction of hippocmpl nurons in ol g. Nt Nurosci. 2: Th Enocrin Socity. Downlo from prss.nocrin.org by [${iniviulusr.isplynm}] on 20 Novmbr t 23:44 For prsonl us only. No othr uss without prmission.. All rights rsrv.