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1 Poor r esponder Cl omi phene Ci t r at e Cont r ol l ed Ovar i an Hyper s t i mul at i on Ji H ong S ong, M.D., Mi Ky oung Koong, M.D. D ep artm ent of Obs tetrics and Gy necology, Colleg e of M edicine, S ungky unkwan Univers ity, Sam sung Cheil H osp ital & W om en 's H ealthcare Center, S eoul, K orea = Abs t r act = Ef f i cacy o f c l omi phene c i t r at e s t i mu l a t e d cyc l e i n poor r e s ponder s i n i n v i t ro f e r t i l i z at i on The pur pose of t hi s s t udy i s compar e IVF cyc l e out come i n poor r esponder s bet ween c l omi phene c i t r at e (CC) s t i mul at ed and cont r ol l ed ovar i an hyper s t i mul at i on (COH) pr ot ocol. A t ot a l of 94 pat i ent s r espondi ng poor l y i n pr evi ous IVF cyc l es (es t r adi ol < 600 pg/ ml or l es s t han 3 oocyt es r et r i eved ) subsequent l y under went e i t her COH (COH gr oup : 122 cycl es, 68 pat i ent s ) or CC- s t i mul at ed cycl es (CC gr oup : 43 cyc l es, 26 pat i ent s ). CC was admi ni s t er ed for f i ve consecut i ve days s t ar t i ng on cyc l e day 3 at a dose of 100 mg da i l y. Ser i a l t r ansvagi na l ul t r asound exami nat i on was done fr om cyc l e day 8. Ur i ne was col l ect ed 3-4 t i mes be for e hcg i nj ect i on for t he det ect i on of LH sur ge. The hcg - 1 -

2 was admi ni s t er ed when ser um es t r adi ol r eached gr eat er t han 150 pg/ ml and mean fol l i c l e di amet er > 16 mm. In COH gr oup, ovar i an s t i mul at i on was done us ing shor t pr ot ocol (GnRH-a/ FSH/ HMG/ hcg). No di f fer ence in age or number of t r ans fer r ed embryos was found bet ween CC gr oup and COH gr oup. COH gr oup had s i gni f i cant l y (p<0. 05) hi gher mean peak l eve l of E2 ( vs pg/ ml ) and gr eat er number of r et r i eved oocyt es ( vs ) t han CC gr oup. CC gr oup had t r ans fer r ed embr yos ( ) compar ed wi t h ( ) i n COH gr oup. However, CC gr oup had hi gher pr egnancy r at e t han COH gr oup per r et r i eva l [26. 9% (7/ 26 ) vs 6. 2% (6/ 97)], or per t r ans fer [31. 8% (7/ 22 ) vs 7% (6/ 86 )]. Al t hough cyc l e cance l l at i on r at e i n CC gr oup (48. 8%) was hi gher t han t hat of COH gr oup (21. 3%), t he pr egnancy r at e per cyc l e i n CC gr oup was s t i l l hi gher (16. 3%) t han COH gr oup (4. 9%). In addi t i on, i mpl ant at i on r at e i n CC gr oup was 17. 5% (7/ 40 ), whi ch was s i gni f i cant l y (p<0. 01) hi gher t han 3. 9% (7/ 180 ) i n COH gr oup. These dat a sugges t t hat oocyt e and embr yo qua l i t y ar e l ower i n COH cyc l es of poor r esponder s t han CC cyc l es. We sugges t t hat c l omi phene c i t r at e s t i mul at ed IVF cyc l e may be mor e e f f i c i ent t han COH IVF cyc l e i n poor r esponder s i n t er ms of l ower cos t s and hi gher pr egnancy per for mance. Key Wor ds : Poor r esponder, IVF-ET, Cl omi phene c i t r at e, Cont r ol l ed ovar i an hyper s t i mul at i on. 1987, GnRH agoni s t. poor r esponder - 2 -

3 (Jenki ns et al, 1991),, (Gi dl eg Bai r d et al, 1986 ). poor r esponder,, (Kar ande et al, 1996; Dor et al, 1995). cl omi phene ci t r at e (CC), poor r esponder CC. poor r esponder cont r ol l ed ovar i an hyper s t i mul at i on (COH) cl omi phene Ci t r at e poor r esponder 224.,,,. Poor r esponder s hcg i nj ect i on es t r adi ol (E2 ) 600 pg/ ml 3. poor r esponder , CC. 2 E2, LH, FSH, 3Cm E2 l evel 50 pg/ ml - 3 -

4 . 2. CC mg CC, 8 E2 14mm ur i ne LH. 16 mm hcg 10, 000 IU. ur i ne LH. GnRH-a shor t pr ot ocol. 2 GnRH-a super fact 0. 5mg, 3 FSH FSH HMG. 3 16mm E2 hcg 10, 000 IU, hcg 34., chi - squar e t es t St udent ' s t - t es t p< COH CC ( 0. 8 ), ( 0. 4 ) (p=0. 95, t - t es t ), , CC LH sur ge 26% (11/ 43 ). COH CC hcg - 4 -

5 E , pg/ ml, , (p<0. 05, t - t es t )(Tabl e 1). 2. COH CC 6. 2% (6/ 97), 26. 9% (7/ 26 ), 7% (6/ 86 ), 31. 8% (7/ 22 ) COH CC, 3. 9% (7/ 180 ), 17. 5% (7/ 40 ) CC (p<0. 01, chi - squar e t es t ). poor r esponder CC COH,, (Tabl e 2 ). CC,, (t <0. 05, t - t es t )(Tabl e 3 ). Tabl e 1. Char act er i s t i cs of CC ver sus COH cyc l e CC COH p-va l ue No. of cyc l es Age * NS E2 on hcg day (pg/ ml ) p<0. 05 Spont aneous LH surge 11 (26%) 2 (1. 6%) No. r et r i eved oocyt es p<0. 05 No. of good embr yo NS No. t r ans fer r ed embr yos NS * Val ues ar e mean SEM. NS : not s igni f i cant - 5 -

6 Tabl e 2. Compar i son of cyc l e out come CC COH p-va l ue n (%) n (%) No. of cyc l e s t ar t ed Cance l l at i on of OPU 17 (40 ) 25 (20 ) NS No. of ET cyc l e 22 (51) 86 (70 ) NS PR per cyc l e s t ar t ed 7/ 43 (16. 3 ) 6/ 122 (4. 9 ) <0. 05 PR per r et r i eva l 7/ 26 (26. 9 ) 6/ 97 (6. 2 ) <0. 01 PR per t r ans fer 7/ 22 (31. 8 ) 6/ 86 (7. 0 ) <0. 01 Impl ant at i on r at e 7/ 40 (17. 5) 7/ 180 (3. 9 ) <0. 01 PR : pregnancy rate Tabl e 3. Response t o c l omi phene c i t r at e s t i mul at i on i n pr egnant and nonpr egnant cyc l es Pr egnant Not pr egnant (n=7) (n=36 ) Age No. of oocyt e r et r i eval 2. 0* No. of t r ans fer r ed embr yos 1. 89* Val ues ar e mean SEM. * p<

7 1978. poor r esponder. fol l i cul ar r ecr ui t ment (Sat hanandan et al, 1989 ) cl eavage r at e (Ryssel ber ge et al, 1989 ). 2 hmg (Van-Hoof f et al, 1993 ), l ong (Dor et a l, 1992 ), shor t (Kar ande et a l, 1996; Tasder mi r et a l, 1996 ), ul t r ashor t (Ser af i ni et al, 1988 ) pr ot ocol GnRH-a, GnRH-a,, (McKenna et al, 1989 ). Poor r esponder ovar i an s t i mul at i on pr ot ocol,,, hmg (Jenki ns et al, 1991), ass i s t ed hat chi ng (Cohen et al, 1992; School cr af t et al, 1994 ) embr yo damage. pr ot ocol poor r esponder. CC (St enkampf et al, 1992; Houl t et al, 1992; Kel l ow et al, 1981), (Li ndhei m et al, 1997; Se i be l et a l, 1995; Daya et a l, 1995; Houl t et a l, 1992 ) poor r esponder, Li ndhei m poor r esponder (Li ndhei m et al, 1997)

8 poor r esponder, cl omi phene ci t r at e, cl omi phene ci t r at e E2,,,,,., endomet r i al r ecept i vi t y. CC. (St enkampf et al, 1992; Sei bel et al, 1995). poor r esponder CC, poor r esponder 224. poor r esponder s hcg i nj ect i on E2 600 pg/ ml 3. poor r esponder , CC. 1. COH CC 36. 2, 37. 3, ,

9 2. CC LH sur ge 26% (11/ 43 ). 3. COH CC hcg E , pg/ ml, , COH CC 6. 2% (6/ 97), 26. 9% (7/ 26 ), 7%(6/ 86 ), 31. 8%(7/ 22 ) COH CC % (7/ 180 ), 17. 5% (7/ 40 ) CC. 6. CC,,., poor ovar i an r esponder COH CC, cl omi phene ci t r at e

10 Cohen J, Al ikani M, Trowbr idge J, Rosenwaks Z: Implant at ion enhancement by se l ect i ve as s i s t ed hat chi ng us i ng zona dr i l l i ng of human embryos wi t h poor pr ognos i s. Hum Repr od 1992, 7, Daya S, Gunby J, Hughes EG, Col l i ns JA, Sagl e MA, YoungLa i EV Nat ur a l cycl es i n vi t r o fer t i l i zat i on : Cos t ef fect i veness anal ys i s and fact or s i nf l uenc i ng out come. Hum Repr od 1995, 10, Dor J, Se i dman DS, Amuda i E, Bi der D, Levr an D, Mashi ach S: Adj uvant gr owt h hor mone t her apy i n poor r esponder s t o i nvi t r o fer t i l i zat i on : A pr ospect i ve r andomi zed pl acebo-cont r ol l ed doubl e bl i nd s t udy. Hum Repr od 1995, 10, Houl t UJ, de Cr espi gny LC, OHer l i t hy C, Spe i r s AL, Lopat a A, Paul son RJ, Sauer MV, Frances MM, Macaso TM, Lobo RA: In vi t ro fer t i l i zat i on i n uns t i mul at ed cyc l es : The Uni ver s i t y of Sout her n Ca l i for ni a exper i ence. Fer t i l St er i l 1992, 57, J enki ns JM, Davi es DW, Devonpor t H, Ant hony FW, Gadd SC, Wat son RH, Mas son GM: Compar i son of poor r esponder s wi t h good r esponder s us i ng s t andar d buser e l i n/ human menopausa l gonadot r opi n r egi me for i n vi t r o fer t i l i zat i on. Human Repr od 1991, 6, Gi dl ey-ba i r d AA, O' ne i l LC, Si mos i ch MJ, Por t er RN, Pi k IL, Saunder s DM. Fa i l ur e of i mpl ant at i on i n human i n vi t r o fer t i l i zat i on and embr yo t r ans fer pat i ent s : t he e f fect s of a l t er ed pr oges t er one/ es t r adi ol r at i os i n human and mi ce. Fer t i l St er i l 1986, 45,

11 Karande VC, Rinehat t J, Mi l ler EC, Pret t DE, Morr i s R, Levrant S, Rao Ba l i n M, Br i cks i n M, Gl e i cher N: The va l ue of s t i mul at i on poor r esponder s us i ng f l ar e pr ot ocol i n cyc l es wi t h l ow basa l FSH concent r at i ons dur i ng IVF. 12t h Annua l Meet i ng of t he EHSRE, Maas t r i cht, Be l gi um. Hum Repr od 1996, 11, 200. Ke l l ow G, j ohns t one I, Robi nson HP: Ul t r asound cont r ol of c l omi phene/ human chor i oni c gonadot r ophi n s t i mul at ed cyc l es for oocyt e r ecover y and i n vi t r o fer t i l i zat i on. Fer t i l St er i l 1981, 36, Li ndhe i m SR, Vi da l i A, Di t kof f E, Sauer MV: Poor r esponder s t o ovar i an hyper s t i mul at i on may bene f i t fr om an at t empt at nat ur a l -cyc l e oocyt e r et r i eva l. J Repr od Med 1997, 14, McKenna KM, Fos t er P, McBa i n J, Mar t i n M, J ohns t on WI : Combi ned t r eat ment wi t h gonadot r opi n r e l eas i ng hor mone agoni s t and gonadot r ophi ns i n poor r esponder s hyper s t i mul at i on for i n vi t r o fer t i l i zat i on : Cl i ni ca l and endocr i ne r esul t s. Aus t NZ J Obs t et Gynecol 1989, 29, Rys se l ber ge M, Pui s sant f, Bar l ow P, Lej eune B, De l vi gne A, Ler oy F: Fer t i l i t y pr ognos i s i n IVF t r eat ment of pat i ent s wi t h cance l l ed cyc l es. Hum Repr od 1989, 4, Sat hanandan M, War ner s GM, Ki r by CA, Pet r ucco OM, Mat t hews CD: Adj uvant l eupr ol i de i n nor ma l, abnor ma l, and poor r esponder s t o cont r ol l ed ovar i an hyper s t i mul at i on for i n vi t r o fer t i l i zat i on/ gamet e i nt r a fa l l opi an t r ans fer. Fer t i l St er i l 1989, 6,

12 School cr a f t WB, Schl enker T, Gee M, J ones GS, J ones HW: As s i s t ed hat ching in t he t r eat ment of poor pr ognos i s in vi t r o fer t i l i zat i on candi dat es. Fer t i l St er i l 1994, 62, Se i be l MM, Kear man M, Ki es s l i ng A: Par amet er s t hat pr edi ct succes s for nat ur a l cyc l e i n vi t r o fer t i l i zat i on-et. Fer t i l St er i l 1995, 63, Ser a f i ni P, St one B, Ker i n J, Bat zof i n J, Qui nn P, Mar r s RP: An a l t er nat i ve appr oach t o cont r ol l ed ovar i an hyper s t i mul at i on i n Poor r esponder s : pr e- t r eat ment wi t h gonadot r ophi n r e l eas i ng hor mone ana l ogue. Fet i l St er i l 1998, 49, St enkampf MP, Kr et zer PA, McEl r oy E, Conway-Myer s BA: A s impl i f i ed appr oach t o i n vi t r o fer t i l i zat i on. J Repr od Med 1992, 37, Tasdermir M, Tasdermir I, Kodama H, Fukuda J, Tanaka T: Shor t prot ocol of gonadot r opi n r e l eas i ng hor mone agoni s t admi ni s t r at i on gave bet t er r esul t s i n l ong pr ot ocol poor r esponder s i n IVF-ET. J Obs t et Gynecol Res 1996, 1, Van-Hoof f NH, Al ber da AT, Hur sman GJ, Ze i l maker GH, Leer ent ve l d RA: Doubl i ng t he human menopausa l gonadot r opi n dose i n t he cour se of an IVF t r eat ment cyc l e i n l ow-r esponder s i n i n vi t r o fer t i l i zat i on t r eat ment. J As s i s t Repr od Genet 1992, 9,

13 2 ( 25 ) Korean J Med Hist Dec 2004 ISSN X * ( ) ( ) ( ). 1) ( ) ( ) ( ) ( ) ( ) 2) ( ) 3) 1990 ( ) 4) * 1) ( ) C

13 2 ( 25 ) Korean J Med Hist Dec 2004 ISSN X * ( ) ( ) ( ). 1) ( ) ( ) ( ) ( ) ( ) 2) ( ) 3) 1990 ( ) 4) * 1) ( ) C 13 2 ( 25 ) 2004 12 Korean J Med Hist 13 198 218 Dec 2004 ISSN 1225 505X * 1 11 1( ) ( ) ( ). 1) ( ) ( ) ( ) ( ) ( ) 2) ( ) 3) 1990 ( ) 4) * 1) ( ) CD- ROM 2) 1962 p 204 2000 p 18 3) 1966 p 330-1 198 5)

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