Document yr8rbM7p0pVEx1eq45Jrp0xgV
ELSEVIER
Epidemiologic Evidence for Uterine Growth Factors in the Pathogenesis of Ovarian Cancer
DANIEL W. CRAMER, MD, ScD, AND HUIJUAN XU, MPH
ABSTRACT wToo4agwmww0ttuhvv5r.foohheom6eoaa4vmooswreisaovtltiapxeahrohartadaghenisbaanolecmei1lddouwpdfue-ca.imsf3leianhnhcattn)tnoyaoeiaotth.nodecdtteecttoreAehuhetssahrnfhaorste.eitpevdoatphmdhTadraorrytestaarhonswshmsttyttttauiaoeeeoessectlcrr(ucmcicseheeOiiotcnauhxciamenhvRartcptacnisogelnoohnf,umteanfs=ihedrarwsuctyyeofhmsebtrfeios0mdeeeoe2rsorc.trc0o3c4swhotfo.titdo;y5vhauoemodgraA09teerbfsiirbno5eaanmipwgirnen%nlnnraeoseooeilnteviormaiEdg(etxaoCersOhraiperssdsryal.intihoRto,aaidelsoycOuanet0wspinaag=rmat.voc1esnihtef(taipirrdhoopo0renuottdanrl.ochcm6lhmdelateel1i;osvb1arts9imitettu9r.yoho0oaw9tat5uynewl)enb5too%.rsirede;ooeflgo5Ayoeprimopw:Cnc(rrl3(OvrttaeeOahuil1wavplod,Rslob0riRryrhio0iua)aia-aoou3vh.gltn4==mreens1yhlldrso4iyptcigt0otd0n-feeithiac.rh.sarel96eco1tvierdti;gs;uniao.ocec0nltd9uen9ao)iodup5gs,f5tminuiwcahi%ca%otrtyathnaenpgaanedsdoc,erbCltoidrrisowmwcdyanoletar,euflooinaistnfp0dbmrotheinoecee.avo-d3etinclamlrtanvoccroltirpoueinliocwevgeacpftdaiaranisaicn1nuotrrutarth.iolicclr1eoesyaeugaer)snmnnd,nesevttpurusacwicuyatadntecluaatomitriewm(ienbnlmeCirasoclogeoniineennlusrhort)rndehgsess,tf, fkaecytowrso.rds: Ovarian neoplasia, hysterectomy, tubal ligation, mucinous tumors, growth
INTRODUCTION Mecutoltmipyle(setvuednieswhiathvoeusut grgeemstoevdatlhaotftuobvaalrileigs)atimonayorphryostteecrt booasogfepfmeaeeinrrenaestdptityroobopnvypesao,vrosiaiefasndunhaeocilfnarifzmecnaclcuotteidnodrianu(nl1ego-e1ftfco2ftoeh)cc.neltVf.ooosaDuvurnariaoedrtiuaieonssfgfirt,anohttmaeetrhsfptceewrmreetotiaeamlntpeiierontenrgovasficeohstfu,ufasecvolchyert bcoinmepdletotedexcaamsei-nceotnhtreoalssstoucdiiaetsioonf obvetawrieaenncoanvcaeriraanrecacnocmer oearnuesdditniustbeparrplorlpeigotaastetiidoo.nnso. rAhnysetxeprelacntoamtioynannodttporeinvvioeusstilgyacteonvsairdi METHODS Bcaentwceerernec1e9n7t8lyanddiag1n9o8s1e,2d1i5n whoosmpietnalws iinththepeigthreelaitaelroBvoasrtioann
mv2a2nae1rdRFAndLretGdoMcoodymefnreinOevgdetsewibchsdcosoeartloAleeoOdptSgurrbyicgAicshnusEtvotseaeptotrnnireld2i,duqc2eBeusGm,,eoya1isBsonn9ttslo9edoos4tcngot;oG,oy:lanMyoDCc,ngcAaeeyMencn.p.oitABteeleolrrdi0,gWg2NyBh1.aro1EmiCvg5per.hiaamdanmembdmeeWrairo,nloIMdo,mgWD1ye9n,o9C'Ssm4ecH.enDont,es'spOr,HibtDaosltse,epHptirataiarcrlts-, 6551A99v5enbuyeEolsfetvhieerASmcieernicceasI,nNc.ew York, NY 10010
athreeasawmereehionsteprivtailesw, e2d35awbooumteanvwaritiehtyepoitfhreislikalfaocvtaorrisa.nFcroamn cerwereinterviewedbetween 1984and 1987. Slidesoftumor seppeitchiemlieanlsowvaerrieanrecvaienwceerdcaonndfirtmheedh.iTstuompaothrsoloofgbiocrtdyeprelinoef mwearleigsnealencctyedwferroemintchluedgeedn.eIrnalbpoothpusltuatdiioens,acnodntmroaltcsuhbejdecbtys a2g1e5 caonndtrporlescuinbcjetcotsfirnestihdeenficresttsotucdayseanpdat2ie3n9tsin; tthheerseecwoenrde study. Informed consent was obtained from subjects under protocols approved at the participating hospitals. Women wwehroe ehxacdluhdaedd aashcyosntetrroelctsoumbjyecwtsibthutbwotohmoevnawriehsorheamdohvaedd a hysterectomy and were certain that at least one ovary had been retained were included. Further details on study m(1e3t-h1o8d).s are discussed in other articles about these studies
While a variety of risk factors have been investigated esboarnhaaicnvniaootntsdadinoeodr.bm4driseaee5ty(nepat4OonioocclRerrlaoctodsneont)oudcntefkrbedxofoarruaarlloimtconsmltuiuvei4gbntadt5aejhra.e0trieticiaIiowsnntonesneno.tcshwmoCatouirnersefdcrutnteriuedueewrbdesbpaaeiao(atsltslhrnesestorlde,euimcgpabraigbaiiadotnetothjtiereuvhoeyddsenldit-wabaecaosyldiitrttoraehleihvoxsdspygakperrristoefsiistaoatsfeieacunrrcrretrhecoerecenyartcogcosnsodertmcfeemsdoesr)ysrr,
SSDI 1014074-277-29779(974/)9050/0$998.5-E0
!AuElyP 1V9o9i5.: 53,1N0o-3. 144
UTERINE FACTORS AND OVARCIAraNmCerAaNnCd EXRu 311
TABLE 1. General characteristics of cases and controls from combined ovarian cancer studies
Variable
Case n
Reference age (yf < 40 40-49 50-59 60-69 > 70
Ever married No Yes
Religion Catholic Protestant Jewish Other
Education < college > college
Parity None 1-2 >3
Oral contraceptive use No Yes
Talc use No Yes
89 11802320 56 86 364 244 1622114 318 132 161 139 150 349 101 249 201
`'CAPl,g*ceo0an.tf0id3di.eangcneosinistefrovralc.ases and at interview for controls.
%
19.8 18.4 26.7 22.7 12.4 19.1 80.9 54.2 27.6 13.6 4.7 70.7 29.3 35.8 30.9 33.3 77.6 22.4 55.3 44.7
Control n
91 86 116 101 60 50 404 260 136 44 14 328 126 85 162 207 312340 300 154
%
20.0 18.9 25.6 22.2 13.2 11.0 89.0 57.3 30.0 93..17 72.2 27.8 341558...767 2781..64 66.1 33.9
O(9d5d%s rCatli)o
1 0.5 (0.4-0.8)
1 1.0 (0.7-1.3) 1.5 (1.0-2.3) 1.6 (0.8--3.2)
1 1.1 (0.8-1.4)
1 0.4 (0.3-0.6) 0.4 (0.3-0.5)
1 0.7 (0.5-1.0)k
1 1.6 (1.2--2.1)
RESULTS Tdeambloeg1rasphhoiwc sorrisrekpfroordouvcatirviaenvcaarinacbelersatshsoact ihaatevde wbeitehnssehvoewranl tliiidongetaebntretiaioccrniatslwkainifntadhcattogohveresaadrfsiioassrtonrocibicvauaatnitroiicoanennrb.cetoTatwnhtceheeeerncoachsroyensmttgerirgoroehluctgtpocrmoowunyapfsoo. urnTnteuhdaberorlayerl was a slight but not significant excess ofwomen with Jewish drchphtooaoeraiayanrffoflntidgofdtltTigecuhievsiberaecnbeoauenybrshuatrnbelseiwaislcejalegelcdwnepic2eborgreiteceeanamsslaravnchtetblenpiik,ooecyodmcasgwronuseororroer,srcoceplrdtciaccuteerkthatueoanretislenaoronldierytckhnsdeipcyeloaantiaaaloosvlnoycmttntesisifernehtttooiroaobnoagunpotfvutnsughelisteetnsuraiwsod.aotvbtueovthChnevabioaeooelajarruoenralsihmcisface.lgbaetcanTsoapeddcas.tdheaosecieteneetoanaiisrntnetplptmhercncaaoapewettaitcrrrsinirreeaoehhrwpsnrtntyiyeiehttatisssicsdstevkttdh,tee,i,eiaerrvrotsfbnebeoegi.vcudccueaetitCthtoneocfrafnaiimomtnetavhscnaconyeeyyelt fctuionbndafiilndgelingwcaeatsiionnnteorotvrastlah(tyiCsstlti)ecra0el.cl6ytotmosigy1n.3iwf)i.acsaAnmtp(orOoretRecat=ipvpea0re.e9ffn;etc9t5f%oorf
women who had either hysterectomy or tubal ligation more than 20 years prior to the age at diagnosis or interview (OR = 0.6; 95% Cl, 0.3 to 1.2).
Table 3 shows the risks for ovarian cancer associated with tubal ligation or hysterectomy in various subgroups of case patients and control subjects. The protective effect was more apparent in subjects 50 years and older, parous subjects, and subjects who had not used talc in their pelvic hygiene. The odds ratio in the latter group associated with prior hysterectomy or tubal ligation was 0.6 (95% Cl, 0.4 to 1.0).
Table 4 examines the odds ratios for tubal ligation or hysterectomy among women with various histologic types of ovarian cancer. A history of pelvic surgery was most frequently observed among women with undifferentiated twuommoersn, 6w(i2th0%m)uocfi3n0o,uasntdumleaosrtsfroefqutheentolyvaorbys,er3ve(d4.2am%o) nogf 72. Referenced against the 14.8% frequency of prior pelvic surgery observed in all control subjects, the odds ratio for a mucinous epithelial ovarian tumor associated with prior tubal ligation or hysterectomy was 0.3 with a 95% confi dence interval of 0.1 to 1.0 after adjusting for parity.
312 CUrTaEmReIrNaEndFAXuCTORS AND OVARIAN CANCER
JAulEyP1V99o5i.: 53,10N-o3.144
TABLE 2. Odds ratios of hysterectomy and tubal ligation for the risk of ovarian cancer from the combined data
Variable
n
No operation Tubal ligation HTuysbtaelrelcigtoamtioyn or hysterectomy Age (y) at first operation
< 35 35-44 >45 Recency of last operation (y) < 10 10-19 >20
398 16 36 52 18 22 12 10 26 16
*fcAThdrjueestecdonftorrolpsahriatyd b(0o,t>h t1u).bal ligation and hysterectomy. Cl, confidence interval.
Case_________ % 883..46 8.0 11.6
4.0 4.9 2.7 2.2 5.8 3.6
________ Contro1________ n%
387 23
85.2 5.1
47
(>lh
10.4 14.8
20
31
4.4 6.8
16 3.5
12 2.6
2278
5.9 6.2
Odds ratio* (95% Cl)
1 00..98 ((00..45--11..73)) 0.9 (0.6-1.3)
U (0.6-2.1) 0.8 (0.4--1.4) 0.8 (0.4-1.8)
1.0 (0.4-2.3) U (0.6-2.0) 0.6 (0.3-1.2)
DISCUSSION Overall, in this study, we found a nonsignificant deficit of cMasoerepaatpiepnatrsenwthporohtaedcthioand hoyf sptreiroercthoymstyeroercttoumbayl loigr attuiobna.l lhmwiaghudaoctiihnohaonadudostnnhtooeuvtmsauuorsrireagsdneroctyafaln2tchc0eeinororwtvhmaaesroioyrrb.ehsAyeygrelvitaeherndsoeuap,gmraehovnnidtohguewwssoleoymm,dewaentnoawwm, ihbetonhy tahteiomnseblvetews,edeon nportiocrleahrylysteesretacbtolimshythoervtaulbidailtyloigfaatnioanssaoncdi o(tai1svv-sae1or2coi)aif.anetOixcouiansnrtbicdneeigtsrw,cduieatsetsinasi.ompnAroiworderiolplpzefeeolrnvcsiuuscsatussoudinvrigeeesevxrriypeelwpaanonedrdatteoiindovnatashripetarhnpoaetcteraschnptacievveceer been offered for this possible association.
Biases that may pertain in epidemiologic studies, such asrecall bias, generally leadto an excessofcasepatients with the exposure rather than a deficiency, which is observed for the hysterectomy and tubal ligation association. Confound ing might explain this association, ifthere were some factor that protected against ovarian cancer but increased risk for hysterectomy or tubal ligation. The most obvious of such factors would be childbearing. High parity decreases the risk for ovarian cancer and most certainly is associated with the decision to have a tubal ligation. High parity has also been found to increase the risk for hysterectomy in both cohort (19) and cross-sectional studies (20). Parity is clearly the most important confounder that must be controlled for in investigating the association between ovarian cancer and hysterectomy or tubal ligation. Virtually all studies that
TvaAriBouLsEsu3b.gOrodudpss roafticoassefsoranpdelvciocnstruorlgsery (hysterectomy or tubal ligation) for the risk of ovarian cancer by
Subgroups
Pelvic surgery
Case n%
Control n%
Age < 50 y Age > 50 y Parity 0 Parity > 1 Nontalc user Talc user
No Yes YYNNeeooss YNeos YNNeoos Yes
153 89.0
19 11.0
213453529
8181..19 945..46
246 85.1
43 14.9
22245 12747
89116030....6400
12525 232 4851 306364 24528 13159
87.6 12.4 83.8 9165..23 824..97 811476...100 8172..73
CPl, -co0n.f0id4e. nce interval.
Odds ratio (95% Cl)
1
0.9 (0.15-1.7)
0.7 1.2
((00..144--41..01))
1
0.8 (0.6-1.3)
0.6 (0.114-1.0)*
1.1 (0.6-2.1)
AJuElyP 1V9o9l5.:53,1N0-o3. 144
UTERINE FACTORS AND OVARCIAraNmCerAaNnCdEXRu 313
ThiAstBolLogEic4t.ypOedodrsgrraatidoeso(Of oRvsa)rfioanr pcrainocreprelvic surgery (hysterectomy or tubal ligation) associated with
Group
All controls Cancer type
Serous Mucinous Endometrioid Clear cell Undifferentiated Other Cancer grade Borderline Malignane
"kAP d*ju0s.t0e6d. for parity (0, > 1).
Total 386
231 72 46 31 30 41
103 348
Surgery n%
67 14.8
28 3
12.1 4.2
6 13.0
4 12.9
6 20.0
5 12.2
9 43
8.7 12.4
OR (95% Cl)"
0.9(0.5-1.41 0.3 (0.1-1.0)` 1.0 (0.4-2.5) 1.4 (0.5-4.6) 1.8 (0.7--4.6) 1.0 (0.4-2.6) 0.8 (0.4-1.6) 0.9 (0.6-1.4)
oinvvaersiatingactaendcethr ehaavsesaodcijautsitoend fboertwpaereinty paenldvitchesuarsgseorcyiatainodn hftegsoafcaefcmrsseeWttcoyepttrn,eheoiirfaasnsofstnigrshdaitoteynefpvtsddfhrtae.eeucrcOrdiosteailsrscnlluaepittoalcoctglmhasceuenotysecrhnseettoaoarr(tra3sbrcv,otiueiusn2skpt1butt)tafaoihpovlleirreslzoriutaegupustasopibioestesaineoclliisdtntoltiailftgtmehntahiaoetisigetvtohahtipnhdetceeeroolrnverppnciprrhfseooroypetttuseesoetneccredsmtntriiueetvvigcrteea. tfaeundrdtharetermthpoervotaiplmoosefeoodvfatphreiaelvst iwcthisitushrspgcerrereymemnailanigygnleaefnaftedccttoonwdtohitueiloddnisal.egaTndohsetioys tyheearsgraefatteersot pperroatteicotnioanndbewinagnionbgsewrivtehdtiimnethsienciemsmuergdeiaryte. Although this was observed in some studies (3, 11), it was ncloloogtsTicesuserbentanhisneiisgn,fettwomheeaelxnmepoalttarjeoancratithtt.iyaoTtnohsfhutyshstsuatedtturiheebscaatvlionemecfalyfulmudoeionrnrgceteutsohbboaivslrioolvinugaesga.btiiniooanl caonndtaomvairnieasn.tsAalrtehonuoglhonmgaernyabvleagtionarel accohnttahme ipnealvnitcs ccaovuiltdy bofiaoocnhipttnitiheepnvvylnooarsaptgeaaeptnCiehtdiarrnrrfee(iiiiioarti1msaasnnethtnptk3onnhsedtnsito.,ats.eettuwstncuur1Ahecdaparna8modoamyurn)clmo,u.ipt,pcohkottlattHeteraedenhhtr(nlcltioeg2,eecynhltwn3ewipueaptva)atthessrhhredoouwfveoooaetebttestithometeenfoershfecmr,cecaeagotrwtlrHllcidaeioeoovevvthnncsaveeeuootiauindsawrtslefreaakrinefezipftaiclfidtfehaeeenthheivndcalsctcysvievaattstogtihcrsloahconmcinieygfeurefospcipniaasprunnetuekeenenerarldlepaygldmgvatlvyeoeeitatnictacianrrngcymoeyoyltssiepccnswtiuebnooeeauo,cireeosslnfrnnghassgraheoiaanakoteasnyrhrfnnedvrynyg(yireit2admsisuwepic2rewmrpbira)(napdao.1iaguaseaotn2Tpstelsh,mmor)eoncehctlaiaasidoloauefgntiegniorannxasadddeetrll,
tHtouobtwahleelvioegrva,taitrohyne, wrreeedsruueclnteiondtgeosibtnrsoedgrevecnerdeleabvsyeeldosthehseetrrrsoegpneoonrrtehpdarovfodeluclocowtniosininsg. tent effects of hysterectomy been seen on gonadotropins pealafrnfteodevcrisytoteoucrfsholatyiundbghuaeonlsrclCmoignaoastnttiidaeonenlreaevcodehnls(eo2(xv23p4a)lr-sai2uan6gna)g.tiecNosantenevcdeefomrrtrhraieystlhkeo.esfsf,eprtrhaoentecocitrthicveuer outvmdhoitroreelerWvrveccoeedoteosdlunyvtcpichanfereerrodinooapstmavonrofaaustcttreerihiicroareetcpnnhueouoacllftvaftaeuitgnrcittuorcehossnereu.wirrnraTegtpefhheatageretfryhrarreo.ocetwtuHguoibesttryhneasisrnelttfieschanlirricaseegettcaoatgtrhstroeirisaonamotancgwynhawtederhovesobiitneudfvhaltleiieedconmrtuocorrisevuernlsdapyatruhttiireeceaneddest gmg(2rru7oos,ww2cl8ttehh).iffnTaachcatteoovsrrae-srImi,aeraatyeyndopinfrccosoldpuleuodccneieeyeds-psdbitduiymeriruunmtlgeaarteliisngntergroosfwuatrstcohtaomfnraa-dcI,topoarrren,sgdimnnshaounaolvctihyne poarreancrdioncerienffeecetfsfeocntsthate duitsetrainnte seipteisthoelniuemstroorgetrno-psehnosbitliavset teluoto(haiwadiaun3spvolbnseotab0tspawpesdrTmtu-aperodeee3eeylhmrradgne2v.evl.bernedi)uegaOIygb,tn.ornctnoyao,-ibfTdigaotdnsnasipeaprnhneeoeocoramrrteprnmacuiwertsveeootshgwweosiauntuncnhatitadtodnugoduiaetseometfmbslnrmnasanttifscehhnccootr(eytonrtemeerrthrnoisusvbamaroatgpetmasiothtadtpnrrtiuefupoooiaigifgr,ostrtttwpnrhehpoehetnSatucectrrmesitrheoiltmtrpeeinhilobpcalrvonreefovoaaolloetatyirstgauercndfotsktrnrleuoteiemyduodoafotmrsnifrwornaamae(iiiton2snaclsrtfliuhr9e)tadtuoynsem)mctirot,fgalecihdabyirnfroatcmdcoeeeihotneh.htumseeouugirmyecrigrecsoitrossnmhilhottnnuenuemgiesasolvonortmrdttpeaansuirftccytnrdabopsrioeteatteelrrboegimqttserkteumisdmnugoooetmmsaeinlyfntotmynnohiotaoimhccudoaonnturyyoesrstrr;t
314 CUrTaEmReIrNaEndFAXCu TORS AND OVARIAN CANCER
JAulEyP1V99o5i.: J3.10N-o3.M4
pgsohromywleettmhic.uPtceairnraeotnuotsmhteautsimc. aoHlrlsyo,wmSeacvyuelarl,ryisg(e3iv3fe)rnormetvhigeeewrsmemdacelevllilnsdueanmscmbeeotrhnoao-tf mewterirueleIldccnibtnaoecosmounnaesyncctleuouesmsrxsiapootrulnryabs,.nawianlteitlohirgenisaptfosioeorrrtnieoafsupo,rrrcohfotiaenvncdactirienviagemneaufcnsfatedncatcflsueoorrftbphaerenircodorsnothusfyifddesyr swtheeveepsroraoulprecoxespeolfaiusntatehtriaiontneps.grorAotewnctothivofenalcmatonardys bsdypeehrciyvuseltaeftrirveocemtoerxmepmylaoonrvafatrliooomnf lmfabciaiygncroaetositodtnuiroutsslnecitkr.yitenirpouWleynptshett.oieoFoffunuidsnrruetiothcpthfiheeeatrnrtfhidaroseecpnsoteuoencoartuesrrurlctapothhetroeraoovitgnntahrerrteeaihsaagtesncrirtohohocwneltiehrtohceeofupfflooiauatvvchttiaeateoorrrliniriienaasselnbadygtrcuierratmoeunmwcboctetlurahysrl would likely be informative.
This study was supported by grant ROl CA 42008 from the National Cancer Institute.
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