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1 大韓不妊學會誌 : 第 32 卷第 4 號 2005 Kor. J. Fertil. Steril., Vol. 32, No. 4, 2005, 12 높은기저난포자극호르몬수치를가지는환자와고령환자의체외수정시술을위한과배란유도에서 GnRH Antagonist 다회투여법과 GnRH Agonist 장기요법의효용성에대한연구 포천중문의과대학교산부인과학교실, 차병원여성의학연구소 1 김지연 김낙근 윤태기 차선희 김유신 원형재조정현 차수경 1 정미경 1 최동희 Comparison of IVF-ET Outcomes between GnRH Antagonist Multiple Dose Protocol and GnRH Agonist Long Protocol in Patients with High Basal FSH Level or Advanced Age JY Kim, NK Kim, TK Yoon, SH Cha, YS Kim, HJ Won, JH Cho, SK Cha 1, MK Chung 1, DH Choi Department of Obstetrics and Gynecology, Pochon CHA University, College of Medicine, Seoul, Korea, 1 Fertility Center of CHA General Hospital Objectives: To compare the efficacy of GnRH antagonist multiple dose protocol (MDP) with that of GnRH agonist long protocol (LP) in controlled ovarian hyperstimulation for in vitro fertilization in patients with high basal FSH (follicle stimulating hormone) level or old age, a retrospective analysis was done. Methods: Two hundred ninety four infertile women (328 cycles) who were older than 41 years of age or had elevated basal FSH level (> 8.5 miu/ml) were enrolled in this study. The patients had undergone IVF-ET after controlled ovarian hyperstimulation using GnRH antagonist multiple dose protocol (n=108, 118 cycles) or GnRH agonist long protocol (n=186, 210 cycles). The main outcome measurements were cycle cancellation rate, consumption of gonadotropins, the number of follicles recruited and total oocytes retrieved. The number of fertilized oocytes and transferred embryos, the clinical pregnancy rates, and the implantation rates were also reviewed. And enrolled patients were divided into three groups according to their age and basal FSH levels; Group A - those who were older than 41 years of age, Group B - those with elevated basal FSH level (> 8.5 miu/ml) and Group C - those who were older than 41 years of age and with elevated basal FSH level (> 8.5 miu/ml). Poor responders were classified as patients who had less than 4 retrieved oocytes, or those with E 2 level < 500 pg/ml on the day of hcg injection or those who required more than 45 ampules of exogenous gonadotropin for stimulation. Results: The cancellation rate was lower in the GnRH antagonist group than in GnRH agonist group, 주관책임자 : 최동희, 우 ) 경기도성남시분당구야탑동 351 번지, 포천중문의과대학교분당차병원 Tel: (031) , Fax: (031) , artchoi83@medimail.co.kr

2 but not statistically significant (6.8% vs. 9.5%, p=ns). The amount of used gonadotropins was significantly lower in GnRH antagonist group than in agonist group (34.8±11.3 ampules vs. 44.1±13.4 ampules, p<0.001). The number of follicles > 14 mm in diameter was significantly higher in agonist group than in antagonist group (6.7±4.6 vs. 5.0±3.4, p<0.01). But, there were no significant differences in clinical pregnancy rate (24.5% in antagonist group vs. 27.4% in agonist group, p=ns) and implantation rate (11.4% in antagonist group vs. 12.0% in agonist group, p=ns) between two groups. Mean number of retrieved oocytes was significantly higher in GnRH agonist LP group than in GnRH antagonist MDP group (5.4±3.5 vs. 6.6±5.0, p<0.0001). But, the number of mature and fertilized oocytes, and the number of good quality (grade I and II) and transferred embryos were not different between two groups. In each group A, B, and C, the rate of poor response did not differ according to stimulation protocols. Conclusions: In conclusion, for infertile women expected poor ovarian response such as who are old age or has elevated basal FSH level, a protocol including a controlled ovarian hyperstimulation using GnRH antagonist appears at least as effective as that using a GnRH agonist, and may offer the advantage of reducing gonadotropin consumption and treatment period. However, much work remains to be done in optimizing the GnRH antagonist protocols and individualizing these to different cycle characteristics. Key Words: GnRH antagonist, GnRH agonist, Advanced age, Elevated basal FSH level 최근여성들의결혼과임신연령이증가면서고령으로인한생식력의감소때문에불임클리닉을찾는환자수가늘어나고있다. 따라서고령여성에서배란유도제에대한반응을예측하여적절한과배란유도방법을확립하는것이불임환자의치료에있어서더욱중요해지고있다. GnRH agonist는 1982년 Fleming 등에의해처음배란유도에사용된이후 1 체외수정을위한과배란유도에효과적으로사용되어왔다. GnRH agonist의작용기전은, 투여직후 flare effect를보인후뇌하수체의 GnRH 수용체의탈감작을일으켜혈중성선자극호르몬과성호르몬수치를감소시키는것인데, 이런기전을이용하여 GnRH 장기요법, 단기요법, 초단기요법등다양한배란유도방법이개발되어체외수정을위한과배란유도에이용되고있다. 특히 GnRH agonist 장기요법은조기 LH 급증을효과적으로예방하고회수되는난자수를증가시킴으로써체외수정을위한가장효율적인과배란유도방법으로자리잡게되었다. 2 그러나 GnRH agonist에의한뇌하수체의과잉억제가일어나과배란유도를위한외인성성선자극호르몬의투여량이증가되고따라서비용및치료기간이증가하는문제점이있다. 3 GnRH antagonist는 1990년대부터임상에서사용 되고있으며 agonist에비해 LH, FSH 억제효과가즉시나타나므로후기난포기에투여하여조기 LH 급증을예방할수있다. 따라서 GnRH agonist 대신 antagonist를저반응군환자에사용하면, 초기난포기에 GnRH agonist에의한억제를피할수있고초기의내인성성선자극호르몬을이용할수있다는장점이있다. 또한최근에인간의난소에서 GnRH 수용체가발견됨으로써 GnRH agonist가난소에직접적인억제를일으켜이러한기전이특히저반응군환자들에게서중요하게작용할수있을것이라고추정되고있어저반응군환자의과배란유도에 GnRH antagonist의사용이증가되고있는추세이다. 4,5 과배란유도를이용한체외수정시술주기에서저반응을보이는환자는 9~24% 로보고되고있다. 6 그런데실제저반응은배란유도제를투여하고난후에발견되는경우가많고현재배란유도에대한난소반응을정확하게예측할수있는검사가없어저반응군환자를찾아낼수있는선별검사법 (screening test) 이확립되어있지않은실정이다. 난소기능 ( 또는 ovarian reserve) 을알아보기위한여러가지검사법중, 월경주기제 2일또는 3일에측정된기저난포자극호르몬수치는가장주된선별검사법으로간주되고있는데, 이또한연구자마

3 다저반응군에서증가된기저난포자극호르몬수치를 7 miu/ml 이상에서 15 miu/ml 이상까지다양하게보고하고있어통일된기준값이존재하지않는다. 6 국내에서는김등 (1995년) 이월경주기제 2일또는 3일에측정된혈중기저 FSH 농도가난소반응의예측인자로유용하며, 그기준치는 8.5 miu/ml가적절하다고보고한바있다. 7 그외 41 세이상의나이도저반응군의예측인자의하나로생각되며, 이는 recruitment 가능한난포수의감소와난자질의저하때문으로생각되고있다. 6 본연구는저반응이예측되는높은기저난포자극호르몬수치 (>8.5 miu/ml) 을보이는환자와 41 세이상고령환자의체외수정시술에서 GnRH antagonist 다회투여법과 GnRH agonist 장기요법을사용하였을때과배란유도에대한난소반응을알아보고체외수정결과를비교해보고자하였다. 연구대상및방법 1. 연구대상본연구는 2002년 9월부터 2003년 9월까지포천중문의과대학차병원불임센터에불임을주소로내원하여체외수정시술을시행받은환자중기저난포자극호르몬수치가 8.5 miu/ml 를초과하거나 41세이상인환자를대상으로하였으며, GnRH antagonist 다회투여법이나 GnRH agonist 장기요법을사용하여체외수정시술을받은환자총 294명의 328 주기를후향적으로조사하였다. 2. 과배란유도및체외수정-배아이식 GnRH antagonist 다회투여법은월경주기 3일째부터외인성 FSH와 hmg를매일 300~450 IU을투여하기시작하였고우성난포의평균직경이 14 mm 에도달하면 GnRH antagonist인 Cetrorelix (Cetrotide, Serono, Germany) 0.25 mg을피하주사하기시작하여 hcg 투여일까지매일주사하였다. GnRH agonist 장기요법은이전월경주기의중기황체기부터 GnRH agonist인 buserelin acetate (Suprefact, Han Dok/Aventis Pharma) 0.3 mg을매일피하로주사하고월경이시작되면 3일째부터 0.15 mg으로감량투여하면서 FSH (Puregon, Organon Korea; GONAL- F, Serono Korea) 혹은 hmg (IVF-M, LG life Sciences) 300~450 IU를매일근육주사하기시작하였다 (Figure 1). GnRH antagonist와 agonist 군에서모두 3~4일간외인성 FSH와 hmg 투여후혈중 E 2 와질식초음파를통해난포성장을관찰하면서 FSH와 hmg 투여량을개인별로조절하였다. 평균직경이 18 mm 이상인난포가 2개이상초음파로관찰되면 hcg (Profasi, Serono) 10,000 IU를근육주사하였고 36시간후질식초음파를이용하여난자를회수하였다. 회수된난자는 10% synthetic serum substitute (Irvine Scientific Co., Santa Ana, CA) 가첨가된 preimplantation I 배양액에서 4~6시간배양한후 1~ /ml의정자농도가되게난자가있는배양접시에주입하거나정자직접주입술을시행하여수정을유도하였다. 16~20시간후전핵 (pronucleus) 형성유무로수정을확인한후 2일간더배양하여 4~8세포기에자궁내로이식하였다. 임신여부의확인은배아이식 12일후혈중 hcg를측정하여 10 miu/ml 이상이면일주일후질식초음파를시행하고태낭이보이는경우를임상적임신으로판정하였다. 3. 결과의관찰및통계검정대상환자에서주기취소율, 사용된고나도트로핀의양, 회수된난자와성숙난자의개수, 수정된난자와이식된배아의개수, 등급이우수한배아 (Grade I, II) 수를조사하였고임신율과착상율을확인하였다. 배아의등급은할구의크기가균일하고세포질내에세포파편이없는것을 grade I, 할구의크기가균일하고세포질내에세포파편이 10% 미만인것은 grade II, 세포파편은없으나할구의크기가균일하지않은것을 grade III, 할구의크기가균일하지않고세포질내에세포파편이 10% 이상인것은 grade IV, 할구가거의없고세포질내에세포파편이 50% 이상인것을 grade V라고하였다. 8 등급이우수한배아 (Grade I, II) 를선별하여자궁내이식하였고이식에사용되지않는여분의배아는동결보존시켰다. 또한대상환자를나이와기저난포자극호르몬수치에따라서세군으로나누어각군에서과배란유도에대한저반응비율을살펴보았다. A군은나

4 Figure 1. GnRH antagonist multiple dose protocol (MDP) and GnRH agonist long protocol, MCD; Menstrual Cycle Day. 이 41세이상인환자, B군은기저난포자극호르몬수치가 8.5 miu/ml를초과하는환자, C군은 41세이상이면서동시에기저난포자극호르몬수치가 8.5 miu/ml를초과하는환자로나누었다. 과배란유도후저반응의정의는채취된난자의수가 4개미만이거나 hcg 투여일의 E 2 가 500 pg/ml 미만이거나사용된고나도트로핀의양이 45앰플이상인경우로하였다. 각각의결과는평균 ± 표준편차로기술하였고, 통계적인분석에있어서평균값의비교를위해 Student's t-test, 분율의비교를위하여 χ 2 -test와 Fisher's exact test를사용하였으며, p 값이 0.05 미만인경우 에통계학적으로유의하다고판정하였다. 결과 GnRH antagonist 다회투여법을사용한군 108명, GnRH agonist 장기요법을사용한군 186명이었다. 대상환자의평균연령은 GnRH antagonist 군이 39.1±4.8세, GnRH agonist 군이 38.4±5.2세로두군간에유의한차이는없었다 (p=ns). 불임기간및체외수정시술의적응증도두군간에유의한차이는없었다. 기저난포자극호르몬수치는 GnRH antagonist 다회투여법을사용한군이 9.1 miu/ml,

5 GnRH agonist 장기요법을사용한군이 9.3 miu/ml 로역시두군간에유의한차이가없었다 (Table 1). GnRH antagonist 다회투여법을사용한군은 118 주기중 8주기에서, GnRH agonist 장기요법을사용한군은 210주기중 20주기에서시술이취소되어 GnRH antagonist 다회투여법을사용한군이낮은주기취소율을보였으나통계적인차이는없었다 (6.8% vs. 9.5%, p=ns). 주기취소의원인은조기배란에의한것이각각 2건 (2.7% vs. 0.9%, p=ns) 이고, 저난소반응에의한것이각각 6건과 18건 Table 1. Clinical characteristics of the patients GnRH antagonist MDP group GnRH agonist LP group p-value No. of patients No. of cycles Age (years) 39.1± ±5.2 NS Duration of infertility (years) 5.8± ±5.1 NS Basal FSH (miu/ml) 9.1± ±5.3 NS Infertility factors Tubal 25 (21.5%) 54 (26.5%) NS Male 29 (25.0%) 55 (26.9%) NS Other female only 15 (12.9%) 17 ( 8.3%) NS Multiple causes 27 (23.3%) 47 (23.0%) NS Unexplained 20 (17.2%) 31 (15.2%) NS Values are means ± SD, NS; not significant, MDP; multiple dose protocol, LP; long protocol Table 2. Comparison of results of controlled ovarian hyperstimulation and pregnancy outcome between GnRH antagonist MDP group and GnRH agonist LP group GnRH antagonist MDP group GnRH agonist LP group Cancellation rate (%) 8 (6.8) 20 (9.5) NS p-value Premature ovulation (%) 2 (1.7%) 2 (0.9%) NS Insufficient ovarian response (%) 6 (5.1%) 18 (8.6%) NS No. of FSH/hMG ampules 34.8± ±13.4 <0.001 Duration of gonadotropin administration (days) 8.7± ±2.1 <0.001 No. of follicles 14 mm on the day of hcg 5.0± ±4.6 <0.01 No. of oocytes 5.4± ±5.0 < No. of mature oocytes 3.9± ±3.2 NS No. of fertilized oocytes 4.1± ±2.9 NS No. of grade I,II embryos 1.5± ±0.8 NS No. of transferred embryos 2.7± ±1.1 NS Clinical pregnancy/ transfer (%) 27/110 (24.5) 52/190 (27.4) NS Implantation rate (%) 33/290 (11.4) 65/541 (12.0) NS Values are means ± SD, NS; not significant

Figure 2. Poor response rate according to age and FSH level in GnRH antagonist MDP group and GnRH agonist LP group. NS: not significant. (5.1% vs. 8.6%, p=ns) 으로두군간에유의한차이는없었다.

6 Figure 2. Poor response rate according to age and FSH level in GnRH antagonist MDP group and GnRH agonist LP group. NS: not significant. (5.1% vs. 8.6%, p=ns) 으로두군간에유의한차이는없었다. 사용된외인성고나도트로핀용량은 GnRH antagonist 다회투여법을사용한군은 34.8±11.3 앰플, GnRH agonist 장기요법을사용한군은 44.1±13.4 앰플로 antagonist 군에서 agonist 군에비해유의하게낮은결과를보였다 (p<0.001). 고나도트로핀투여기간도 GnRH antagonist 다회투여법을사용한군이 8.7±1.5일, GnRH agonist 장기요법을사용한군이 10.8±2.1일로 GnRH antagonist 다회투여법을사용한군에서유의하게짧은기간을보였다 (p<0.001). HCG 투여일에관찰된직경 14 mm 이상의난포개수는 GnRH antagonist 다회투여법을사용한군이 5.0±3.4개, GnRH agonist 장기요법을사용한군이 6.7±4.6개로 GnRH agonist 장기요법을사용한군에서유의하게높았다 (p<0.01). 그러나배아이식주기당임신률은 GnRH antagonist 다회투여군 (24.5%) 과 GnRH agonist 장기요법이군 (27.4%) 사이에통계적으로유의한차이를보이지않았고, 착상율도각각 11.4% 와 12.0% 로양군간에유의한차이가없었다 (Table 2). 양군간의과배란유도결과를비교해보면, 각군에서채취된난자의평균개수는 GnRH antagonist 다회투여법을사용한군이 5.4±3.5개, GnRH agonist 장기요법을사용한군이 6.6±5.0개로 GnRH agonist 장기요법을사용한군이유의하게많았다 (p<0.0001). 성숙난자수 (3.9±2.7 vs. 5.0±3.2) 와수정된난자수 (4.1±2.0 vs. 5.0±2.9) 도 GnRH agonist 장기요법을사용한군이 antagonist 다회투여군에비해많은경향을보였으나, 통계적으로유의한차이는없었다 (p=ns). 등급이우수한배아수 (1.5±0.6 vs. 1.6±0.8) 와이식된배아수 (2.7±1.0 vs. 3.0±1.1) 도양군간에차이를보이지않았다 (Table 2). 두군에서의나이와기저난포자극호르몬수치에따른저반응군의비율을비교해보면, A군의경우 GnRH antagonist 다회투여법을사용한군이 54.7%, GnRH agonist 장기요법을사용한군이 48.1%, B군의경우 GnRH antagonist 다회투여법을사용한군이 50.7%, GnRH agonist 장기요법을사용한군이 44% 환자에서저반응을나타내었으나 antagonist와 agonist 군간에통계적으로유의한차이는없었다. 41세이상이면서동시에기저난포자극호르몬수치가 8.5 miu/ml를초과하는 C군의경우는 antagonist 와 agonist 두군에서공히 78.9% 와 70% 의비교적높은저반응율를나타내었으나역시두군간에유의한차이는없었다 (Figure 2)

7 고찰 GnRH agonist가체외수정시술에이용되면서, 임신율이크게향상되었으나, 저반응군에서는 GnRH agonist에의한뇌하수체기능억제때문에외인성성선자극호르몬에대한난소반응이과도하게저하되어주기취소율이상당히높아지고, 성숙된난자회수를증가시키지못하면서비용과치료기간의증가를초래하였다. 7 따라서저반응군에서의과배란유도결과를향상시키기위해 GnRH agonist 투여의용량과기간을줄이기위한배란유도법들이제안되었으며, 9 그예로는성선자극호르몬단독요법, 크로미펜과성선자극호르몬병합요법, GnRH agonist flare-up protocol 등이있다. 10 최근에는저반응군환자에서 GnRH agonist가가지는부정적효과를극복하고임신율을향상시키기위해서 GnRH antagonist를이용한과배란유도법이도입되어사용되고있다. GnRH antagonist는 GnRH 수용체에서 native GnRH를경쟁적으로억제함으로써, GnRH agonist에서나타나는초기의자극효과없이단시간에내인성성선자극호르몬의유리를억제할수있고, GnRH agonist와달리수용체의탈감작이일어나지않기때문에 antagonist의사용이끝난후에는즉시정상적인기능을회복한다는장점을갖는다. 11,12 일반적으로사용되는 GnRH antagonist protocol에는일회투여법과다회투여법의두가지가있다. 일회투여법은 cetrorelix 3 mg을한번, 성선자극호르몬투여제 7일째에주사하는방법이고, 다회투여법은 cetrorelix 0.25 mg을성선자극호르몬제 5일째나 6일째투여하기시작하여이후매일동일한용량을 hcg 투여일까지피하주사하도록하는방법이다. GnRH antagonist를사용하여과배란유도후임신율이 GnRH agonist 군에비해유의하게감소한다는보고가있으며, 그이유는 GnRH antagonist가자궁내막에직접적인억제작용을나타내어착상에영향을줄수있기때문이라고하였다. 13 한편 Akman 등은 GnRH antagonist 다회투여법사용시 GnRH flare-up protocol에비해회수된난자의수는유의하게감소하였지만, 주기취소율과임신율및착상율은유의한차이가없음을보고 하였다. 5 본연구결과 GnRH antagonist 다회투여법을사용한군에서성장한난포와회수된난자수가유의하게적었으나임신율이나착상율에있어서는유의한차이를보이지않았다. 또한사용된성선자극호르몬의총량이 GnRH agonist 장기요법에비해통계학적으로유의하게적었다 (34.8±11.3 앰플 vs. 44.1±13.4 앰플, p<0.001). 성장난포의수가적은것과사용된성선자극호르몬의양이적게나타난것으로보아난소과자극증후군의발생가능성을줄일수있다는가능성을기대해볼수있다. 14 저반응군의개념은 1983년 Garcia 등에의해혈중최고에스트로겐농도 300 pg/ml 미만을보이는것으로처음정의되었다. 15 이후저반응군에대한정의를내리기위한시도가전개되어혈중최고 E 2 농도가 500 pg/ml이하, hcg 투여일의우성난포의수가 4개이하, 40세이상의환자, 생리주기 3일에측정한기저난포자극호르몬농도또는 clomiphene citrate challenge test를기준으로하였을때난소내난자의비축이감소를보이는경우등으로정의하였으나아직공통적으로사용할수있는명확한정의는없는상태다. 본연구에서는일반적으로나쁜예후를갖는다고예측되는 41세이상의연령과높은기저난포자극호르몬농도를보이는환자들을대상으로하여저반응율를비교해보았다. 그결과 GnRH antagonist 다회투여법을사용한군과 GnRH agonist 장기요법을사용한군에있어서실제적인저반응을보이는비율은 GnRH antagonist 를사용한군에서높았지만통계학적으로유의한차이는없었다. 이것은난소기능이감소되었다고예측되는고연령이나높은기저난포자극호르몬수치를가지는환자에서, GnRH agonist 사용할경우예상되는난포기초기의난소억제같은부작용을피하고과배란유도를위해 GnRH antagonist를사용하는것에대한근거가될수있을것같다. 또한이번연구에서고령이면서높은기저난포자극호르몬수치를같이가진환자의저반응율이과배란유도방법과관계없이높은수치 (78.7/70.0%) 를보였는데, 이러한결과는저반응이예측되는환자에서시술전과배란유도에대한저반응가능성을미리 counselling하는데에도참고가될수있을것이다

8 결론적으로고령이거나높은기저난포자극호르몬수치를보이는저반응이예측되는환자의체외수정을위한과배란유도에서 GnRH antagonist 다회투여법의사용은 GnRH agonist 장기요법과비슷한임신율, 착상율을보이면서, 동시에외인성고나도트로핀의투여량을감소시키고시술주기를단축시켜환자의신체적경제적부담을덜어줄수있는유용한치료방법으로사료된다. 또한저반응의비율도두군간에유의한차이가없었다. 향후여러예측인자들의조합으로과배란유도전에저반응을더정확히예측할수있다면, 고령이거나높은기저난포자극호르몬수치를보이는불임환자의치료에도움이될것으로생각한다. 참고문헌 1. Fleming R, Adam AH, Barlow DH, Black WP, MacNaughton MC, Coutts JR. A new systemic treatment for infertile women with abnormal hormone profiles. Br J Obstet Gynecol 1982; 89: Loumaye E. The control of endogenous secretion of LH by gonadotropin-releasing hormone agonists during ovarian hyperstimulation for in vitro fertilization and embryo transfer. Hum Reprod 1990; 5: Ben-Rafael Z, Lipitz S, Bider D, Maschiach S. Ovarian hyporesponsiveness in combined gonadotropinreleasing hormone agonist and menotropin therapy is associated with low serum follicle-stimulating hormone levels. Fertil Steril 1991; 55: Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Addition of GnRH antagonist in cycles of poor responders undergoing IVF. Hum Reprod 2000; 15: Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Comparison of agonistic flare-upprotocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod 2001; 16: Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 2003; 9: 김정훈, 조윤경, 목정은. 난소기능예측인자로서 Immunoradiometric Assay로측정된기초혈중난포자극호르몬농도의임상적유용성에관한연구. 대한산부회지 1995; 38: Erenus M, Souves C, Raj amahendr an P, Leung S, Fluker M, Gomel V. The effect of embryo quality on subsequent pregnancy rates after in vitro fertilization. Fertil Steril 1991; 56: Fasouliotis SJ, Simon A, Laufer N. Evaluation and treatment of low responders in assisted reproductive technology: A challenge to meet. J Assist Reprod Genet 2000; 17: Hugues JN, Cedrin DI. Revisiting gonadotrophinreleasing hormone agonist protocols and management of poor ovarian responses to gonadotrophins. Hum Reprod 1998; 4: 김문영, 정병준. GnRH Antagonist (Cetrotide) Short Protocol의임상적유용성에관한연구. 대한산부회지 2001; 28: Fluker MR. Gonadotropin-releasing hormone antagonists. Curr Opin Endocrinol Diabetes 2000; 7: Albano C, Felberbaum RE, Smitz J, Riethmuller- Winzen H, Engel J, Diedrich K, et al. Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)- antagonist ceterorelix and the LHRH-agonist buserelin. Hum Reprod 2000; 15: Olivennes F, Belaisch-Allart J, Emperaire JC, Dechaud H, Alvarez S, Moreau L, et al. Prospective, randomized, controlled study of in vitro fertilizationembryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). Fertil Steril 2000; 73: Garcia JE, Jones GS, Acosta AA, Wright G. HMG/ HCG follicular maturation for oocytes aspiration:

9 phase II, Fertil Steril 1983; 39: 이방현, 김정훈, 오영미. 체외수정시술을위한과배란유도에있어 GnRH Antagonist 다회투여법과 GnRH Agonist 장기요법의비교연구. 대한산부회지 2003; 46: 이은실, 김동환, 배도환. 저반응군환자에서 GnRH Antagonist를이용한과배란유도의효용성에관한연구. 대한산부회지 2003; 46: Borm G, Mannaerts B. The European Orgalutran Study Group. Treatment with the gonadotropinreleasing hormone antagonist Ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulation hormone is effective, safe and convenient: results of a controlled, randomized multicenter trial. Hum Reprod 2000; 15: Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung SY, Tier CC, et al. GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randommized controlled trial. Hum Reprod 2005; 20: Olivennes F, Kadhel P, Rufat P, Fanchin R, Fernandez H, Frydman R. Perinatal outcome of twin pregnancies obtained after in vitro fertilization: comparison with twin pregnancies obtained spontaneously or after ovarian stimulation. Fertil Steril 1996; 66: Scott RT, Hoffnab GE, Oehninger S, Muasher SJ. Intercycle variability of day 3 follicle stimulating hormone levels and its effect on stimulation quality in vitro fertilization. Fertil Steril 1990; 53: Van Rooij IA, Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Women older than 40 years of age and those with elevated folliclestimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization. Fertil Steril 2003; 79(3):

Microsoft Word - 8-송인옥.DOC

Microsoft Word - 8-송인옥.DOC 대한생식의학회지 : 제 34 권제 2 호 2007 저반응군의체외수정시술을위한과배란유도에있어 GnRH Antagonist 요법과 GnRH Agonist Flare Up 요법의효용성에관한연구 관동대학교의과대학제일병원산부인과 안영선 연명진 조연진 김민지 강인수 궁미경 김진영양광문 박찬우 김혜옥 차선화 송인옥 GnRH Antagonist Versus Agonist