{"paper_id":"91cb312c-16bb-4f35-a359-5afe187cdd4d","body_text":"TurkiyeKlinikleriJMed Sci2011;31(6) 1351 \nTherapeuticEfficiencyofTibolonein \naRatEndometriosisModel \nAA BB SS   TTRR AA CC TT  OO bb  jjeecc  ttii  vvee:: This study ai med to eva lu a te the the ra pe u tic ef fi ci ency of ti bo lo ne in an \nex pe ri men tal rat mo del of in tra-ab do mi nal en do met ri o sis. MM aa  ttee  rrii  aall  aanndd  MM eett  hhooddss:: In this ex pe ri -\nmen tal study, in tra-ab do mi nal en do met ri o sis was in du ced in 30 fe ma le rats sur gi cally. Fo ur we eks \naf ter this pro ce du re, la pa ro tomy was per for med again. The di men si ons of the en do met ri o sis fo ci we -\nre re cor ded and right af ter, the ope ra ti on was comp le ted. Rats we re ran domly di vi ded in to thre e \ngro ups and sub se qu ently, the tre at ment was star ted. In the first gro up (n= 8), a sing le do se of 1 cc \n0.9% NaCl was in jec ted sub cu ta ne o usly. In the se cond gro up (n= 8), in tra mus cu lar in jec ti on of 1 mg \nle up ro lid ace ta te was ad mi nis te red. In the third gro up (n= 8), 1 mg/kg/day of ti bo lo ne was gi ven by \nga va ge. At the end of 4- we eks of drug ad mi nis tra ti on, la pa ro tomy was per for med to all rats. The \ndi men si ons of the en do met ri o sis fo ci we re re cor ded. Af ter wards, all the rats we re sac ri fi ced. The \ndif fe ren ces in the are as of en do met ri o tic imp lants and ad he si on sco res we re com pa red bet we en the \ngro ups. \nRR ee  ssuullttss:: The di men si ons of the en do met ri o sis fo ci in the gro ups tre a ted with le up ro lid (p< \n0.05) and ti bo lo ne (p< 0.05) we re sig ni fi cantly di mi nis hed compared to that of the con trol gro up. \nNo sta tis ti cally sig ni fi cant dif fe ren ces we re fo und bet we en the tre at ment gro ups. \nCC oonncc  lluu  ssii  oonn:: In a \nrat en do met ri o sis mo del, ti bo lo ne has a si mi lar ef fi ci ency as that of le up ro lid ace ta te, an agent used \nfor con ven ti o nal me di cal tre at ment of en do met ri o sis. With its an dro ge nic and pro ges ta ge nic cha -\nrac te ris tics, ti bo lo ne de ser ves at ten ti on as an al ter na ti ve agent in the me di cal tre at ment of en do -\nmet ri o sis in hu man. \nKKeeyy  WW oorrddss::  Rats; endometriosis; gonadotropin-releasing hormone; tibolone \nÖÖZZEETT  AA mm aaçç:: Bu ça lış ma da ka rın içi en do met ri o zis li de ney sel sı çan mo de lin de ti bo lon un te ra pö tik \net kin li ği nin de ğer len di ril me si amaç lan dı. GGee  rreeçç  vvee  YY öönn  tteemm   lleerr:: Bu de ney sel ça lış ma da, 30 di şi sı çan -\nda ka rın içi cer ra hi en do met ri o zis mey da na ge ti ril di. Bu iş lem den dört haf ta son ra tekrar  la pa ro to -\nmi ya pıl dı. En do met ri o zis odak la rı nın bo yut la rı kay de dil di he men ar dın dan ope ras yon ta mam lan dı. \nSı çan lar rast ge le üç gru ba ay rıl dı ve da ha son ra te da vi baş lan dı. Bi rin ci gru ba (n= 8), NaCl 1 cc %0.9 \ntek doz ola rak cilt al tı na en jek te edil di. İkin ci gru ba (n= 8), le up ro lid ase tat 1 mg in tra mus kü ler \nola rak uy gu lan dı. Üçün cü gru ba (n= 8), ti bo lon 1mg/kg/gün ola rak ga vaj ile ve ril di. Dört haf ta ilaç \nalı mı nın son ra sın da tüm sı çan la ra la pa ro to mi ya pıl dı. En do met ri o zis odak la rı nın bo yut la rı kay de -\ndil di. Da ha son ra tüm sı çan lar öl dü rül dü. Grup lar ara sın da en do met ri o tik imp lant lar ve adez yon \nsko ru alan la rın da ki fark lı lık lar kar şı laş tı rıl dı. \nBB uull  gguu  llaarr:: Le up ro lid (p< 0.05) ve ti bo lon (p< 0.05) ile \nte da vi grup la rın da en do met ri o zis odak la rı nın bo yut la rı kon trol gru bu na gö re an lam lı ola rak azal -\nmış tı. Te da vi grup la rı ara sın da is ta tis tik sel ola rak an lam lı fark yok tu. \nSS oo  nnuuçç:: Sı çan en do met ri o zis \nmo de lin de, ti bo lon un en do met ri o zis te da vi sin de kon van si yo nel tıb bi te da vi nin bir aja nı olan le up -\nro lid ase ta ta ben zer bir et kin li ği var dır. An dro je nik ve pro ges ta je nik özel lik le ri ile ti bo lon in san \nen do met ri o zis te da vi sin de al ter na tif bir ajan ola rak dik kat çek mek te dir. \nAA nnaahh  ttaarr  KKee  llii  mm ee  lleerr:: Sıçanlar; endometriyozis; gonadotropin salgılatıcı hormon; tibolon \nTTuurrkkiiyyee  KKlliinniikklleerrii  JJ  MM eedd  SS ccii  2200 1111;;3311((66 ))::11335511--55\nYavuz ŞİMŞEK, MD,a\nTemel CEYHAN, MD,b\nYusuf ÜSTÜN, MD,b\nTayfun İDE,c\nŞevki ÇELEN, MD,a\nE rdoğan AKAR,c\nYusuf ŞİRİN,c\nSemih KALELİ, MD d\naDepartment of High Risk Pregnancy,\nDr. Zekai Tahir Burak \nEducation and Research Hospital,\nbDepartment of \nObstetrics and Gynecology,\ncExperimental Animals Surgical \nResearch Center,\nGülhane Military Medicinal Faculty,\nAnkara \ndDepartment of \nObstetrics and Gynecology,\nİstanbul Universty \nCerrahpaşa Faculty of Medicine, \nİstanbul\nGe liş Ta ri hi/Re ce i ved: 15.06.2010 \nKa bul Ta ri hi/Ac cep ted: 24.01.2011 \nYa zış ma Ad re si/Cor res pon den ce: \nYavuz ŞİMŞEK, MD \nDr. Zekai Tahir Burak \nEducation and Research Hospital,\nDepartment of High Risk Pregnancy,\nAnkara,\nTÜRKİYE/TURKEY \ndryavuzsimsek@yahoo.co.uk \ndoi:10.5336/medsci.2010-19821 \nCop yright © 2011 by Tür ki ye Kli nik le ri \nORİJİNAL ARAŞTIRMA   \n\nn do met ri o sis is a chro nic di se a se cha rac te ri -\nzed by the pre sen ce of the en do met ri al gland \nand stro ma out of the en do met ri al ca vity . It \nis ma inly a di se a se of the wo men of rep ro duc ti ve \nage and its es ti ma ted in ci den ce is 1 0 %. 1,2 V a ri o us \nthe o ri es on its eti o logy such as ret rog ra de mens tru -\na ti on and di rect imp lan ta ti on, vas cu lar in va si on, \nlack of im mu ne res pon se, and ge ne tic fac tors ha ve \nbe en pro po sed. Ho we ver, the exact eti o logy has not \nbe en de fi ned yet .1-4 \nEn do met ri o sis is an es tro gen de pen dent di se a -\nse. The se fo ci in vol ve es tro gen re cep tors and es tro -\nge nic sti mu la ti on in cre a ses the de ve lop ment of \nen do met ri o sis fo ci .1,2 \nVa ri o us agents [pro ges tins , go na dot ro pin re -\nle a sing hor mo ne ana logs (GnRHa) , com bi ned oral \ncon tra cep ti ves, da na zol] used in the me di cal tre -\nat ment of en do met ri o sis show the ir ef fects by an -\nti-es tro ge nic ac ti vity .5 The tre at ment of en do met - \nri o sis was in ves ti ga ted in ear li er stu di es with a rat \nm o del using GnRHa a nd go na dot ro pin re le a sing \nhor mo ne an ta go nists and va ri o us agents such as \npen to xiphy lli ne, doxyc ycli ne ,and le va mi zol. 5-9 \nGnR H ana lo gu es are be ing used ef fec ti vely in the \ntre at ment of en do met ri o sis and the re is a con sen -\nsus in the cur rent li te ra tu re that the se agents are \nef fec ti ve. 5,9 The use of GnRHa with monthly in -\njec ti ons or in jec ti ons with 3-month in ter vals in hi -\nbits ova ri an es tro gen synthe sis and forms a \nhypo es tro ge nic en vi ron ment, thus di mi nis hing \nthe en do met ri o sis fo ci .5,10 \nTi bo lo ne is a mo le cu le that has a se lec ti ve \nre gu la tory ef fect on the es tro gen re cep tors .11 It \nis ra pidly me ta bo li zed and con ver ted in to thre e \nac ti ve me ta bo li tes. Thre e alp ha hydroxyl (OH) and \n3-be ta-OH me ta bo li tes show an es tro ge nic ac ti vity \non the bo nes, va gi na, and cen tral ner vo us \nsystem. 11,12 De l ta-4 me ta bo li te, ho we ver, has pro -\nges ta ge nic and an dro ge nic cha rac te ris tics and in -\nhi bits the pro li fe ra ti on of en do met ri al cells .11,12 It \nis ma inly used as an al ter na ti ve to the post me no -\npa u sal hor mo ne the rapy. This study ai med to eva -\nlu a te and com pa re the ef fects of ti bo lo ne and \nGnRHa on an ex pe ri men tal en do met ri o sis mo del \nin the rats .\nMATERIAL AN D METHODS \nThe pre sent study was con duc ted at the Ex pe ri -\nmen tal Ani mals La bo ra tory of the sur gery de part -\nment of Gul ha ne Mi li tary Me di cal Aca demy ,\nbet we en the July 04, 2 009 and Sep tem ber 18, 2009. \nThe ap pro val of the ins ti tu ti o nal et hics com mit te e \nwas ob ta i ned be fo re the study and all the pro ce du -\nres on the ani mals we re con duc ted in ac cor dan ce \nwith the di rec ti ons of ‘Gu i de for the Ca re and Use of \nLa bo ra tory Ani mals ’. The study was per for med on \n30 fe ma le Swiss-Al bi no rats that we ig hed 200-250 \ngrams, we re in the pro es trus pha se and non-preg -\nnant . The rats we re kept in ste el ca ges in a cli ma -\nte-con trol led en vi ron ment un der ad li bi tum fe e ding \ncon di ti ons and pro vi ded with ac cess to day light bet -\nwe en 06:00 am  and 6 :00 pm . The study had three \npha ses, the de ta ils of which are pre sen ted be low: \nPHA SE I \nThe en do met ri o sis mo del in the rats was for med by \nthe met hod pre vi o usly des cri bed by Ver non and \nWil son :13 \nAll the rats we re ad mi nis te red 100 mg/kg of \nke ta min hydroch lo ri de (Ke ta lar ® fla kon) for anest -\nhe si a . The tric ho tomy of the ab do mi nal re gi on was \nma de by elec tric ra zor. A mid li ne in ci si on of 3 cm \nwas ma de af ter di sin fec ti on of the ab do men with \nio di ne whi le the rats we re in su pi ne po si ti on. The \ncu ta ne o us, sub cu ta ne o us and musc le tis su es we re \nse pa ra ted and thus, the pe ri to ne al ca vity was ac ces -\nsed. A 15 mm seg ment of the right ute ri ne corn was \nre mo ved. This cylin dri cal seg ment was ope ned with \nlon gi tu di nal in ci si on and the en do met ri al la yer was \nex po sed. The en do met ri al fa ce of the re mo ved seg -\nment was su tu red with a sing le su tu re to me sen tery \nusing non-ab sor bab le su tu re ma te ri al (No:4/0 silk \nsu tu re ). The la yers of the ab do men we re con se cu ti -\nvely clo sed, and the pro ce du re was en ded. \nPHA SE II \nTwenty-eight days af ter the first ope ra ti on, the rats \nun der went a se cond la pa ro tomy un der ste ri le con -\ndi ti ons as des cri bed abo ve. The in tra -ab do mi nal en -\ndo met ri o tic fo ci and ad he si ons we re ob ser ved. The \nlength and width of the imp lants we re me a su red \nand the sur fa ce are a of the imp lants was cal cu la ted . \nTurkiye Klinikleri J Med Sci 2011;31(6) 1352 \nŞimşek ve ark. Kadın Hastalıkları ve Doğum \n\nThe ad he si ons we re clas si fi ed ac cor ding to the \nsco ring system of Bla u er, which was used pre vi o -\nusly in rat en do met ri o sis mo dels 14,15 as fol lows: \nAD HE SION SCO RE \n0: No ad he si on \n1: Thin ad he si ons \n2: Thick ad he si on in one are a \n3: Wi des pre ad thick ad he si ons \n4: Ad he si ons of the in ter nal or gans to the ab -\ndo mi nal wall \nThe ab do men was clo sed and the pro ce du re \nwas en ded . Thre e rats with no sus pec ted en do met -\nri o sis fo ci mac ros co pi cally and three rats that di ed \nin the first pha se we re exc lu ded from the study. The \nre ma i ning 24 rats we re di vi ded in to three gro ups. \nThre e days af ter the se cond pha se, the rats in \nthe first gro up (the con trol gro up , n= 8) we re in -\njec ted with 1 cc of 0.9% NaCl. \nThe rats in the se cond gro up (n= 8) we re ad mi -\nnis te red 1 mg in tra mus cu lar le up ro lid ace ta te (Luc -\nrin De pot- 3M ®, Ab bott), as was used in pre vi o us \nstu di es as the tre at ment do se .5,9 \nThe rats in the third gro up (n= 8) we re gi ven \n1 mg/kg/day of ti bo lo ne (Li vi al ® tab let, Or ga non )\nfor four we eks with ga va ge . The do se of ti bo lo ne \nwas cal cu la ted ba sed on the re com men da ti ons by \nGe naz za ni et al. with the the ra pe u tic do se ran ge \n(0.2-2 mg/g/day) ar ran ged for fe ma le rats .16 \nPHA SE II I \nAll rats we re sac ri fi ced by cer vi cal dis lo ca ti on and \nwe re sub jec ted to la pa ro tomy pro ce du re as de fi ned \near li er. The are a of the en do met ri o tic fo ci and in -\ntra -ab do mi nal ad he si ons we re re cor ded .\nThe chan ges in the are a of en do met ri o sis fo ci \nof all gro ups we re me a su red and com pa red . The in -\ntra -ab do mi nal ad he si on sco res we re al so com pa -\nred. \nSTA TIS TI CAL ANALY SIS \nThe da ta we re eva lu a ted using SPSS 15.0 prog ram. \nA ll the da ta we re ex pres sed as me an va lu es. The in -\nter gro up com pa ri sons we re ma de wit  pa i red sam -\np le t test . A  p va lu e <0.05 was con si de red as \nsta tis ti cally sig ni fi cant. \nRESULTS \nD u ring the study three rats di ed and anot her three \nrats with no sus pec ted en do met ri o sis fo ci mac ros -\nco pi cally we re exc lu ded from the study. The study \nwas comp le ted with 24 rats. \nIn the se cond pha se, the me an are a of en do -\nm et ri o tic fo ci and in tra -ab do mi nal ad he si on sco res \namong the gro ups we re si mi lar (Tab le 1). En do -\nm et ri o tic fo ci we re mac ros co pi cally ob ser ved as \ncystic or vas cu lar le si ons . At the end of the tre at -\nm ent, the are a of the en do met ri o tic fo ci and ad he -\nsi on sco res we re fo und to dec re a se in all thre e \ngro ups (Fi gu re 1). In Gro ups 2 and 3, the re duc ti on \nwas mo re mar ked com pa red to that in the con trol \ngro up and the difference was sta tis ti cally sig ni fi -\ncant (p< 0. 05) (Tab le 2). \nDISCUSSION \nN o vel tre at ment met hods of en do met ri o sis, a chro -\nnic di se a se with unc le ar eti o logy, are fre qu ently \nused in ex pe ri men tal rat, mi ce, mon key, and rab bit \nm o dels. One of the se met hods was used by Ver non \nand Wil son for the first ti me in a rat en do met ri o -\nsis mo del be ca u se rats are inex pen si ve and ha ve a \nshort 4-day mens tru al cycle, short lu te al pha se of \nthe cycle, and pre do mi nant es trus pha se .13,17 \nGnRHa  is wi dely used in the me di cal tre at -\nm ent of en do met ri o sis with a pro ven ef fi ci ency .18- \nTurkiye Klinikleri J Med Sci 2011;31(6) 1353 \nGynecology and Obstetrics Şimşek et al \nArea of endometriotic foci (mm 2) Adhesion score \nPre Post P value Pre Post P value \nControl (n= 8)36.6 ± 11.5 28.8 ± 7.8 0.070 3.1 ± 0.8 1.6 ± 0.5 0.005 \nLeuprolid (n= 8)35.2 ± 9.9 9.3 ± 8.9 0.003 2.8 ± 0.8 1 ± 1.06 0.004 \nTibolone (n= 8)33.1 ± 12.1 15.3 ± 8.2 0.000 2.5 ± 0.9 1.1 ± 1.1 0.001 \nTABLE 1: Pre- and posttreatment area of endometriotic foci and adhesion scores in the three groups.\n\n20 In the use of GnRHa , FSH and LH sec re ti on from \nthe hypoph ysis are tem po ra rily in cre a sed . Ho we -\nver, with its sup raph ysi o lo gi cal do se, ago nis tic ac -\nti vity is sus ta i ned, re cep tors are down-re gu la ted, \nand  hypoph ysis-go nad axis is in hi bi ted. In con se -\nqu en ce of inac ti va ti on of the oral form , it is used \nin the form of sub cu ta ne o us or in tra mus cu lar in -\njec ti ons. GnRHa has be en shown to in du ce at rophy \nin the en do met ri o tic fo ci, in cre a se the ac ti vity of \npe ri to ne al na tu ral kil ler cells, and re du ce the le vels \nof  pe ri to ne al IL-6, IL-1 β, TNF  α, and Ca- 125 in rat \nen do met ri o sis mo dels .21,22 In our study, post tre at -\nm ent mac ros co pic chan ges and ad he si on sco res we -\nre eva lu a ted in a rat en do met ri o sis mo del. Pa ral lel \nto the fin dings in the li te ra tu re, the gro up that re -\nce i ved GnRHa tre at ment had sig ni fi cant re duc ti -\nons in the are as of the en do met ri o tic fo ci and \nad he si on sco res com pa red to the rats in the con trol \ngro up .5-7,21 Ho we ver, in ad di ti on to the high costs, \nit car ri es the risk of os te o po ro sis when used for \nlong pe ri ods of ti me. A d di ti o nally, GnRHa tre at -\nm ent pro du ces se ve ral tro ub le so me si de ef fects be -\nca u se of its strong an ti es tro ge nic ef fects, and \nre lap se might oc cur af ter the ces sa ti on of tre at -\nment. Du e to the se re a sons, al ter na ti ve tre at ment \nop ti ons are be ing in ves ti ga ted. \nTi bo lo ne is a ste ro id mo le cu le from the gro up \nof mo le cu les that act as es tro ge nic ac ti va tor re gu la -\ntor in se lec ti ve tis su es .11 It has an es tro ge nic ac ti -\nvity in the cen tral ner vo us system, bo ne, and \nge ni tal tis su es, whi le it does not have such ef fects in \nthe bre ast tis su e and en do met ri um , so it is ma inly \nused for the ma na ge ment of cli mac te ric symptoms \nin post me no pa u sal wo men .11,23 Ti bo lo ne in the en -\ndo met ri um is ir re ver sibly con ver ted to its ∆-4 iso -\nm er that binds to both pro ges te ro ne and an dro gen \nre cep tors. 11 Ti bo lo ne and its ∆-4 iso mer in du ce es -\ntro gen inac ti va ting enz ymes 17 β- hydroxy ste ro id \ndehy dro ge na se and sul fot rans fe ra se, in hi bit sul fa -\nta se and en han ce lo cally the de ac ti va ti on of bi o lo -\ngi cally ac ti ve es tro ge nic me ta bo li tes. 11,12 Nu me ro us \nstu di es ha ve shown that to ac hi e ve add-back tre at -\nm ent of en do met ri o sis, the use of ti bo lo ne in cre a se \nthe bo ne mi ne ral den sity, re du ces an ti-es tro ge nic \nsi de-ef fects, however do es not af fect the de ve lop -\nm ent of en do met ri o sis fo ci .24-26 \nIn the me no pa u sal pe ri od, the use of ti bo lo ne \nhas be en shown to in du ce en do met ri al at rophy .27 \nEt tin ger et al., in ves ti ga ted the en do met ri al ef fects \nof ti bo lo ne in 3519 post-me no pa u sal pa ti ents, and \nthey emp ha si zed the neg li gib le ef fect of ti bo lo ne \non en do met ri al pro li fe ra ti on for ma ti on in the first \nthree ye ars of its use .28 On the ot her hand, li te ra -\ntu re re ve als en do met ri o sis de ve lop ment with ti bo -\nlo ne used for post me no pa u sal hor mo ne tre at ment \nin some ca ses .29 To the best of our know led ge, the \npri mary ef fi ci ency of ti bo lo ne in en do met ri o sis tre -\nat ment has not be en stu di ed to da te in a rat en do -\nTurkiye Klinikleri J Med Sci 2011;31(6) 1354 \nŞimşek ve ark. Kadın Hastalıkları ve Doğum \nFIGURE 1: Comparison of delta values (postreatment-pretreatment) of areas \nof endometriotic foci among the three groups.\nControl (n= 8) Leuprolid acetate (n= 8) Tibolone (n= 8) p value \nAreas of endometriotic foci (mm 2) 8 (-3-30) 25.5 (3-54) 16.5 (9-30) 0.018* \nAdhesion scores 1 (0-3) 2 (0-4) 1.5 (0-2) 0.683 \nTABLE 2: Comparison of delta values (posttreatment -pretreatment) of areas of endometriotic foci and \nadhesion scores among the three groups.\n*p<0.05 when comparison between control vs leuprolid acetate groups and control vs tibolon groups.\n\nmet ri o sis mo del. The re fo re, our study might be \ncon si de red as the first to in ves ti ga te the re la ti ons -\nhip bet we en ti bo lo ne and en do met ri o sis in a rat \nmo del. In our study, ti bo lo ne ca u sed a reg res si on \nin the en do met ri o tic fo ci in the early pe ri od as with \nGnRHa use. The are as of en do met ri o tic fo ci we re \nsig ni fi cantly re du ced in the gro up of rats that re -\nce i ved ti bo lo ne (Gro up-3) when com pa red to the \nrats in the con trol gro up (The me an are as of en do -\nmet ri o tic fo ci we re 33. 1 mm 2 and 15.3 mm 2, res -\npec ti vely) . The le vel of the reg res si on in the \nen do met ri o tic fo ci was si mi lar to the one that ob -\nta i ned with GnRHa tre at ment. Ad di ti o nally, af ter \na 4-we ek tre at ment pe ri od, the ad he si on sco res of \nthe rats we re sig ni fi cantly smaller com pa red to the \nsco res of the rats in the con trol gro up. The pri mary \naim of this study was the de ter mi na ti on and eva -\nlu a ti on of mac ros co pic ap pe a ran ce and ad he si ons \nsco res . Ho we ver, the reg res si on in the en do met ri -\no tic fo ci was not his to pat ho lo gi cally gra ded, which \nis a li mi ta ti on of our study. \nIn conc lu si on, the pre li mi nary in for ma ti on ob -\nta i ned in this study sug gests that des pi te es tro ge nic \nef fects, ti bo lo ne can be used as an al ter na ti ve agent \nin the tre at ment of en do met ri o sis du e to its an dro -\nge nic and pro ges ta ge nic bi o ac ti ve pro ducts . Ho we -\nver, our fin dings ne ed to be con fir med by furt her \nde ta i led stu di es with his to pat ho lo gic cor re la ti ons. \nTurkiye Klinikleri J Med Sci 2011;31(6) 1355 \nGynecology and Obstetrics Şimşek et al \n1. Vignali M, Infantino M, Matrone R, Chiodo I,\nSomigliana E, Busacca M, et al. Endometriosis: novel\netiopathogenetic concepts and clinical perspectives.\nFertil Steril 2002;78 (4): 665-78.\n2. 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