대한생식의학회지 : 제 35 권제 4 호 2008 과배란유도시혈중 AMH 와난소반응성과의상관관계 ; 예측인자로서의효용성 관동대학교의과대학제일병원산부인과 안영선 김진영 * 조연진 김민지 김혜옥 박찬우 송인옥 궁미경 강인수 Correlation of Basal AMH & Ovarian Response in IVF Cycles; Predictive Value of AMH Young Sun Ahn, Jin Yeong Kim *, Yun Jin Cho, Min Ji Kim, Hye Ok Kim, Chan Woo Park, In Ok Song, Mi Kyoung Koong, Inn Soo Kang Department of Obstetrics & Gynecology, Cheil General Hospital, Kwandong University, College of Medicine, Seoul, Korea Objectives: The aim of this study was to evaluate the usefulness of Anti-müllerian hormone (AMH) as a predictive marker for ovarian response and cycle outcome in IVF cycles. Methods: From Jan., to Aug., 2007, 111 patients undergoing IVF/ICSI stimulated by short or antagonist protocol were selected. On cycle day 3, basal serum AMH level and FSH level were measured. The correlation between basal serum AMH or FSH, and COH outcome was analyzed and IVF outcome was compared according to the AMH levels. To determine the threshold value of AMH for poor- and hyper- response, ROC curve was analyzed. Results: Serum AMH showed higher correlation coefficient (r=0.792, p<0.001) with the number of retrieved mature oocyte than serum FSH (r=-0.477, p<0.001). According to ovarian response, FSH and AMH leves showed significant differences among poor, normal, and hyperresponder. For predicting poor ( 2 oocytes) and hyperresponse ( 17 oocyets), AMH cut-off values were 0.5 ng/ml (the sensitivity 88.9% and the specificity 89.5%) and 2.5 ng/ml (sensitivity 85.7%, specificity 87.0%), respectively. According to the AMH level, patients were divided into 3 groups: low ( 0.60 ng/ml), normal (0.60~2.60 ng/ml), and high AMH ( 2.60 ng/ml). The number of retrieved mature oocytes was significantly higher (2.7±2.2, 8.1±4.8, 16.5±5.7) and total gonadotropin dose was lower (3530.5±1251.0, 2957.1±1057.6, and 2219.2±751.9 IU) in high AMH group (p<0.001). There was no significant difference in fertilization rates and pregnancy rates (23.8%, 34.0%, 37.5%) among the groups. Conclusions: Basal serum AMH level correlated better with the number of retrieved mature oocytes than FSH level, suggesting its usefulness for predicting ovarian response. However, IVF outcome was not significantly different according to the AMH levels. Serum AMH level presented good cut-off value for poor- or hyper-responders, therefore it could be useful in prediction of cycle cancellation, gonadotropin dose, and OHSS risk in IVF cycles. [Korean. J. Reprod. Med. 2008; 35(4): 309-317.] Key Words: Anti-müllerian hormone, Ovarian response, Controlled ovarian hyperstimulation 체외수정시좋은결과를얻기위해서는, 과배란 주관책임자 : 김진영, 우 ) 100-380 서울특별시중구묵정동 1-19, 제일병원산부인과 Tel: (02) 2000-7549, Fax: (02)2000-7790 e-mail: jinkim223@yahoo.co.kr 현소속 : 인천서울여성병원산부인과 유도전에 ovarian reserve를평가하는것이많은도움이될수있다. 여성의나이에따라난소의난포 pool과난자의질의저하, 즉 ovarian reserve가감소되는데, 그감소정도는개인에따라차이가있어 ovarian reserve를반영할수있는여러지표들이사 - 309 -
과배란유도시혈중 AMH 와난소반응성과의상관관계 ; 예측인자로서의효용성 대한생식의학회지 용되어왔다. 대표적으로혈중 FSH이나 inhibin B 등이 ovarian reserve의지표로이용되고있으나, 이러한지표들은난포의성장단계나크기차이에따라영향을받을수있고, 그변화는생식능력의감소에비하여늦게나타날수있으며, 월경주기에따른변화가심하여 ovarian reserve를판단하는데제한이있는것으로알려져있다. 1 혈액학적지표이외에초음파검사를통한 antral follicle count, ovarian stromal blood flow, ovarian volume 등도 ovarian reserve를판단하는데이용되고있으나, 2~5 이또한측정의편차가심하고추가적검사가필요하다는단점이있다. Antimüllerian hormone ( 항뮬러리안호르몬, AMH) 은남성태아의고환분화시기부터 Sertoli cell에서분비되어 Müllerian duct의퇴화를유도하는호르몬으로, 여성에서는사춘기때증가되어폐경기까지발현되는데, 난소의 preantral 또는 antral follicle의 granulosa cell에서생성된다, 6~9 AMH의생리적기능은아직명확하지않으나, follicle의 recruitment와 selection의조절역할을하는것으로생각된다. 10 혈중 AMH 농도는 antral follicle의개수와밀접한연관이있고, 11 생리주기에따른수치변화가거의없이가장안정된결과를보이며, 체외수정시채취되는난자수와밀접한연관이있어, 최근 ovarian reserve를반영하는좋은지표로제시되고있다. 12 한편 HCG 투여일의혈중 AMH 수치가배아의 quality 및착상율과관련된다는결과도보고된바있다. 13 이에저자들은체외수정을위한과배란유도시혈중기저 AMH 수치와난소반응성과의상관관계를채취된성숙난자의개수로분석하여, AMH의난소반응예측인자로서의효용성및체외수정결과와의관련성을알아보고자하였다. 연구대상및방법 1. 연구대상 2007년 1월부터 2007년 8월까지본원에서과배 란유도및체외수정을시행하는 27세이상 47세이하의 111명의환자를대상으로전향적연구로진행하였다. 이전에편측난소절제술을받았거나, FSH 수치가 20 miu/ml 이상의심한난소기능저하, 고프로락틴혈증이나갑상선기능이상등의내분비질환이있는경우, 1개월이내에경구용피임약등의호르몬제재를투여받은경우, 2 cm 이상크기의난소낭종을가진환자는대상에서제외하였다. 본연구는본원의 IRB (Institutional review board) 를통과하였으며, 모든환자에서시술전환자의동의를얻었다. 2. 과배란유도환자들은생리주기제2~3일에방문하여혈중 AMH 및 FSH 및 estradiol (E 2 ) 를측정하였으며, 질식초음파상난소낭종을포함한골반내이상유무를확인하고, 기저 E 2 수치가 40 pg/ml 미만인경우과배란유도를시작하였다. 환자의나이와이전주기의반응을고려하여성선자극호르몬의용량을결정하였다. 혈중기저 AMH와 FSH 측정시 GnRH agonist의효과를배제하기위하여, GnRH antagonist나 GnRH agonist flare up 요법을이용하여과배란유도를하였다. GnRH-agonist flare up 요법은월경주기 2일부터 Buserelin acetate (Superfact, Hoechst, Germany) 를하루 0.5 mg씩피하주사하였으며, 성선자극호르몬제는 recombinant FSH (Gonal-F, Serono, Switzerland, 또는 Puregon, Organon, Netherland) 을사용하였다. GnRH antagonist 요법은우성난포의직경이 14 mm 이상이거나혈중 E 2 농도가 150 pg/ml 이상인날부터 Cetrorelix acetate (Cetrotide, Serono, Switzerland) 를하루 0.25 mg씩 hcg 투여일까지피하주사하였다. 성선자극호르몬의용량은각각의난포의성장및혈중 E 2 농도에따라조절하였으며, 초음파검사상우성난포의직경이 18 mm 이상인경우 hcg (Pregnyl, Organon, Netherlands) 10,000 IU를근주하였다. hcg 투여후, 36시간후에질식초음파유도하에난자채취를시행하였다. - 310 -
제 35 권제 4 호, 2008 안영선 김진영 조연진 김민지 김혜옥외 4 인 채취된난자중성숙난자의수와혈중 AMH 및 FSH와의상관관계를분석하였고, 채취된성숙난자의평균갯수 ± 2SD을기준으로 2개이하의성숙난자가나온경우를저반응군 (poor responder), 3개에서 16개까지를정상반응군 (normal responder), 17개이상을과반응군 (hyper responder) 으로구분하여, 각군간의과배란유도결과를비교하였다. AMH level에따른체외수정결과는 AMH 수치에따라 25% (0.6 ng/ml) 미만, 25~75% (0.6~2.6 ng/ ml), 75% (2.6 ng/ml) 이상으로나누어비교하였다. 또한난소저반응군과고반응군의예측을위한임계치 (threshold value) 를분석하였다. 3. AMH 및 FSH의측정생리주기 2~3일째채혈된혈액은 1시간이내에 Serum을분리하여 -80 에동결보관되었다. Serum AMH는 MIS/AMH ELISA DSL -10-14400 kit (Diagnostic Systems Laboratories, Texas, USA) 를사용하여 ELISA (Enzyme-Linked Immunosorbent Assay) 로분석하였다. 분석의 sensitivity는 0.017 ng/ml이었으며, intra-assay coefficient of variance는 3.4%, inter-assay coefficient of variance는 6.5% 였다. FSH의측정은 immunoradiometric assay (Adaltis, Italia S.P.A, Reno-(BO), Italy) 로측정하였으며, sensitivity는 0.25 miu/ml이었고, intra-assay coefficient of variance는 3.8%, inter-assay coefficient of variance는 5.8% 였다. 4. 통계분석각각의결과는평균 ± 표준편차로표기하였고, SPSS version 12를이용하여통계학적분석을하였다. Pearson's correlation coefficient 를이용한상관분석및 linear regression 분석을이용하였다. 각군의평균값의비교는 ANOVA, 분율의비교는 χ 2 test를시행하였고, p value < 0.05를통계적으로유의하다고판정하였다. 난소저반응군과고반응군의예측을위한임계치 (threshold value) 를구하기위해서 ROC (Receiver Operating Characteristic) curve 분석을이용하였다. 결과과배란유도후채취된성숙난자의개수와혈중기저 AMH 또는 FSH 수치와의상관분석에서 FSH는유의한음의상관관계 (r=-0.477, p<0.001) 를보이고있었으며, AMH는 FSH보다상관정도가더 Number of retrieved mature oocytes 30 20 10 Number of retrieved mature oocytes 30 20 10 0 0 0.0 5.0 10.0 15.0 20.0 25.0 30.0 Basal FSH (miu/ml) r = -0.477 (p<0.001) 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 Basal AMH (ng/ml) r = 0.792 (p<0.001) Figure 1. Correlation between the number of retrieved mature oocytes and AMH or FSH - 311 -
과배란유도시혈중 AMH 와난소반응성과의상관관계 ; 예측인자로서의효용성 대한생식의학회지 높은양의상관관계 (r=0.792, p<0.001) 를나타내었다 (Figure 1). 채취된성숙난자갯수에따라저반응군 (2개이하 ), 정상반응군 (3~16개), 과반응군 (17개이상 ) 으로나누어각군에서환자특성과과배란유도결과를비교하였다 (Table 1). 세군에서나이는과반응군에서적었고 (38.2± 3.6, 36.0±4.0, 33.4±3.7, p=0.002), 각군에서 AMH level은 0.36±0.24, 1.73±1.29, 4.14±1.17 (p<0.001), FSH level은 11.6±4.3, 9.0±2.7, 6.8±1.5 (p<0.001) 로반응군간유의한차이를보였으며, 또한 hcg 투여 Table 1. Outcome of COH according to the ovarian response Poor responder ( 2) Normal responder (3~16) Hyper responder ( 17) No. of patients 19 74 18 Age (yrs) 38.2±3.6 a 36.0±4.0 a 34.0±4.0 b 0.002 Infertility duration(yrs) 3.9±3.1 4.3±2.9 4.0±2.9 NS Body Mass Index (kg/m 2 ) 21.2±3.5 21.4±3.1 21.0±3.3 NS Day 3 AMH (ng/ml) 0.36±0.24 a 1.73±1.29 b 4.14±1.17 c <0.001 Day 3 FSH (miu/ml) 11.6±4.3 a 9.0±2.7 b 6.8±1.5 c <0.001 HCG day E 2 (pg/ml) 505.3±373.0 a 1610.3±924.1 b 2822.3±1470.4 c <0.001 Total dose of Gonadotropin (IU) 3228.9±1204.8 a 3042.6±1118.7 a 2031.3±629.1 b <0.001 COH duration (days) 10.7±3.1 9.6±1.7 9.4±1.7 NS No. of retrieved mature oocytes 1.3±0.8 a 7.6±3.5 b 20.6±3.7 c <0.001 Values are Mean ± SD, a vs. b <0.05, b vs. c <0.05 P Figure 2. Threshold values of AMH for poor & hyper responders - 312 -
제 35 권제 4 호, 2008 안영선 김진영 조연진 김민지 김혜옥외 4 인 일의 E 2, gonadotropin 용량도유의한차이를보였다 (Table 1). 이러한 AMH와채취된성숙난자갯수와의높은상관정도를바탕으로, ROC curve 분석을통해저반응군과과반응군에대한임계치를분석한결과, AMH level 0.50 ng/ml으로하였을때, sensitivity 88.9%, specificity 89.5% 로저반응군을예측할수있었고, ROC AUC (area under the curve) 가 0.96으로높은신뢰도를보였으며, sensitivity 88.9%, specificity 89.5%, PPV (positive predictive value) 61.6%, NPV (negative predictive value) 97.7% 였다. 과반응군은 AMH 임계치 2.50 ng/ml에서 sensitivity 85.7%, specificity 87.0%, ROC AUC 0.93, sensitivity 85.7%, specificity 87.0%, PPV 60.0%, NPV 96.4% 로역시높은예 측도를보였다 (Figure 2). AMH level에따라 3 군 (low AMH: 25% 이하, 0/60 ng/ml, normal AMH: 25~75% (0.60~2.60 ng/ml), high AMH: 75% 이상, 2.60 ng/ml) 으로구분하여과배란유도결과를분석하였다. AMH level이높을수록채취된성숙난자의개수는 2.8±2.5, 8.1±4.8, 16.5±5.7로각군간유의하게증가되었으며, 투여된성선자극호르몬의양은유의하게감소하였다. FSH는 low AMH와 normal AMH군간에차이가없었고, high AMH군에서는유의하게낮았다 (Table 2). 세군간에성숙난자의비율 (72%, 81.9%, 84.2%), 수정율 (77.9%, 73.1%, 74.5%), 이식주기당임신율 (23.8%, 34.0%, 37.5%) 은유의한차이가없었다 (Table 3). Table 2. Outcome of COH according to the AMH levels Variables Low AMH ( 0.60 ng/ml) Normal AMH (0.60~2.60 ng/ml) High AMH ( 2.60 ng/ml) No. of patients 27 56 28 Age (yr) 37.5±4.1 a 36.5±3.9 a 33.4±3.3 b <0.001 Infertility duration (yr) 4.2±3.5 4.6±3.1 3.5±1.8 NS Body Mass Index (kg/m 2 ) 22.6±3.5 21.0±3.0 20.8±3.0 NS Day 3 AMH (ng/ml) 0.33±0.16 a 1.46±0.60 b 4.24±1.09 c <0.001 Day 3 FSH (miu/ml) 10.6±4.4 a 9.3±2.7 a 7.2±1.7 b <0.001 HCG day E 2 (pg/ml) 581.0±446.0 a 1652.3±905.0 b 2548.3±1328.8 c <0.001 Total dose of Gonadotropin (IU) 3530.5±1251.0 a 2957.1±1057.6 b 2219.2±751.9 c <0.001 COH duration (days) 10.7±2.7 a 9.5±1.7 b 9.5±1.6 b 0.02 No. of retrieved mature oocytes 2.8±2.5 a 8.1±4.8 b 16.5±5.7 c <0.001 Values are mean ± SD, a vs. b <0.05, b vs. c <0.05 Table 3. IVF outcome according to the AMH level Variables Rate of mature oocyte (%) (per total retrieved oocytes) Low AMH ( 0.60 ng/ml) Middle AMH (0.60~2.60 ng/ml) High AMH ( 2.60 ng/ml) 72 (72/100) 81.9 (422 /515) 84.2 (462/549) NS Fertilization rate (%) 77.9 73.1 74.5 NS Clinical pregnancy rate (%) per transfer 23.8 (5/21) 34.0 (17/50) 37.5 (9/24) NS P P - 313 -
과배란유도시혈중 AMH 와난소반응성과의상관관계 ; 예측인자로서의효용성 대한생식의학회지 고찰여성의나이가증가함에따라 ovarian reserve의감소로인해임신가능성이감소하게된다. 최근난소기능의새로운지표로서연구되고있는 AMH 는태령 36주경부터난소의 granulosa cell에서생성되기시작하며, 여성에서주로사춘기이후 preantral follicle 및 early antral follicle에서분비되어폐경직전까지분비되는것으로 antral follicle 단계이후로는그분비가감소된다. 7~9 기능은명확지않으나난포발달과정중초기난포 recruitment나우성난포를 selection하는과정에서역할을하여, primodial follicle에서 primary follicle로의성장을억제하는기능을하는것으로알려지고있다. 10,14,15 AMH가난소기능을반영하는데있어 antral follicle 수나, 난소과자극주기에서성장난포의수및채취되는난자수와밀접한관계가있다고보고된바있으며, 9,11,12,16 또한생리주기에따른수치변화가거의없어난소의 small follicel의상태를안정적으로반영하는것으로생각된다. 17,18 본연구에서도기저 AMH 수치가채취되는성숙난자수와밀접한상관관계를가지며 FSH보다더강한상관성을보여난자수의예측에더유용할것으로생각되었다. 특히배란유도과정중과반응의징후가있는경우성선자극호르몬제용량을감소시켜투여하게되므로, 채취된난자보다실제난소의 small follicle의 pool은더높은상관관계를보일수있다. Nelson 등은 AMH가나이나 FSH와비교하여난자수의예측과그에따른 live birth rate을예측하는데보다밀접한상관성이있고, 특히과반응군을저반응군이나정상반응군과구분지어예측하는데더정확한지표가된다고보고하였다. 즉, FSH는저반응과정상반응군은구분하지만과반응군을구분지어예측하기어려우며, 반대로 AMH는저반응군과정상반응군간에 overlap이상당히있어, 과반응군을예측하는데더유용한것으로보고하였다. 19 본연구에서도 low AMH군과 normal AMH군에서난자수 가평균 2.7개및 8.1개로차이가있었으나두군간 FSH는차이가없어, 난소반응성을구분지어예측하는데 AMH가더유용할것으로생각된다. 실제로 FSH만으로는예기치못한과반응을예측하기어려운경우가있다. 사용된성선자극호르몬제용량도 AMH가높을수록유의하게적었는데, 따라서과배란유도전에환자의 AMH 수치에따라미리적정용량을계획하는데도움이될것이다. 기저 FSH level은 poor response를예측하는좋은지표로널리이용되고있으며, 20 본연구에서도 FSH 또한채취난자수에따라 poor, normal, hyper responder로구분하여, 각군간유의한차이 (11.6± 4.3, 9.0.±2.7, 6.8±1.5, p<0.001) 를보였다. Bancsi 등은난소반응성을예측하는데있어단독인자로는 antral follicle count가가장좋으나, 이를측정하는데있어초음파상의해석문제나초음파시술자의주관적차이가있을수있으며, inhibin B나, antral follicle count, FSH 등의여러인자들의조합으로예측정도를높일수있다고하였다. 21 또한 Kwee 등은기존 ovarian reserve test 방법과 AMH를비교하여 poor response의예측에는 AMH, FSH, CCCT, antral follicle count가유사하였고, hyper response의예측에는 antral follicle count가가장좋은것으로보고하면서, 그러나생리주기에관계없이측정할수있는장점이있어실질적으로쉽게적용할수있는단독인자로서 AMH의우수성이제시되고있다. 9,12,22 본연구에서성숙난자의수에의한저반응군과고반응군의 cut-off value를예측하기위한 AMH의 ROC curve 분석결과, 저반응군예측은 AMH의임계치 0.50 ng/ml에서 sensitivity 88.9%, specificity 89.5%, PPV (positive predictive value) 61.6%, NPV (negative predictive value) 97.7% 로높은신뢰성을보였고, 과반응군의예측을위해서는 AMH 임계치를 2.50 ng/ml로하여높은예측도를보였다. 이는다른연구결과와유사하여, La Marca 등은저반응군의 cut off value 0.50 ng/ml에서 sensitivity 85.0%, specificity 82.3% 를보고하였고, 23 Seifer 등은 AMH level을 1.0 ng/ml로하였을때 6개이하의난 - 314 -
제 35 권제 4 호, 2008 안영선 김진영 조연진 김민지 김혜옥외 4 인 자채취그룹을예견하는데좋은결과를얻었다고하였다. 24 한편 AMH level이난자의양적인지표이외에난자 quality나수정률, 임신률등과의관련성이제기되고있는데. 높은 AMH가임신율증가와관련되고, 25 기저 AMH와채취된난자의질과연관성이있으며, 26 hcg 투여일의 AMH level이 2.7 ng/ml 이상시에배아의질 (quality) 이향상된다는보고도있다. 13 반면, Smeenk 등은이러한임신율향상은난자의수증가에기인한효과이고독립적으로난자의질이나, 임신율을예측하는인자는아닌것으로보고하였다. 27 본연구에서도기저 AMH level에따라구분된각군간에성숙난자의비율이나수정률, 임신률에유의한차이는없었다. 추후수정란의등급이나 AMH 수치를세분하여분석해볼필요가있을것으로생각된다. 결론적으로, AMH에따라난자의질이나임신율등에차이는없었으나, 과배란시채취되는난자수를예측하는면에서는 FSH보다밀접한상관성을가지고있어매우유용한지표로생각된다. 따라서기저 AMH로난소저반응군이나고반응군을예측하여과배란유도시주기의취소나환자별로적정한용량결정및과반응군을예측하고, 난소과자극증후군의위험을감소시키는데도움이될것으로사료된다. 참고문헌 1. Kwee J, Elting MW, Schats R, Bezemer PD, Lambalk CB, Schoemaker J. Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment results of a prospective randomized study. Hum Reprod 2003; 18: 1422-7. 2. Bukulmez O, Arici A. Assessment of ovarian reserve. Curr Opin Obstet Gynecol 2004; 16: 231-7. 3. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a metaanalysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005; 83: 291-301. 4. Wallace WH, Kelsey TW. Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography. Hum Reprod 2004; 19: 1612-7. 5. Jarvela IY, Sladkevicius P, Kelly S, Ojha K, Campbell S, Nargund G. Quantification of ovarian power Doppler signal with three-dimensional ultrasonography to predict response during in vitro fertilization. Obstet Gynecol 2003; 102: 816-22. 6. Behringer RR, Finegold MJ, Cate RL. Mullerian inhibiting substance function during mammalian sexual development. Cell 1994; 79: 415-25. 7. Lee MM, Donahoe PK, Hasegawa T, Silverman B, Crist GB, Best S, et al. Müllerian inhibiting substance in humans normal levels from infancy to adulthood. J Clin Endocrinol Metab 1996; 81: 571-6. 8. Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Antimüllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age, J Clin Endocrinol Metab 2004; 89: 318-23. 9. van Rooij IA, Broekmans FJ, te Velde ER, Bancsi LF, de Jong FH, Themmen AP. Serum antimüllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17: 3065-71. 10. Durlinger AL, Kramer P, Karels B, de Jong FH, Uilenbroek JT, Grootegoed JA, et al. Control of primordial follicle recruitment by anti-mullerian hormone in the mouse ovary. Endocrinology 1999; 140: 5789-96. 11. Gruijters MJ, Visser JA, Durlinger AT, Themmen AF. Antimüllerian hormone and its role in ovarian function. Mol Cell Endocrinol 2003; 15: 85-90. 12. Fanchin R, Schonauer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-müllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003; 18: 323-7. 13. Silberstein T, MacLaughlin DT, Shai I, Trimarch JR, Lambert- Messerlian G, Seifer DB, et al. Mullerian inhibiting substance levels at the time of HCG administrarion in IVF cycles predict both ovarian reserve and embryo morphology. Hum Reprod 2006; 21: 159-63. 14. Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian function: The role of anti-mullerian hormone. Reproduction - 315 -
과배란유도시혈중 AMH 와난소반응성과의상관관계 ; 예측인자로서의효용성 대한생식의학회지 2003; 124: 601-9. 15. Visser JA, dejong FH, Laven JSE, Themmen APN. Anti- Mullerian hormone: a new marker for ovarian function. Reproduction 2006; 1: 1-9. 16. Van Rooij IA, Broekmans FJ, tevelde ER, Fauser BC, Bansci LF, de Jong FH, et al. Serum anti-mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17: 3065-71. 17. Cook CL, Siow Y, Taylor S, Fallat ME. Serum mullerianinhibiting substance levels during normal menstrual cycles. Fertil Steril 2000; 73: 859-61. 18. La Marca A, Stabile G, Carducci Artenisio A, Volpe A. Serum anti-mullerain hormone throughout the human menstrual cycle. Hum Reprod 2006; 21: 3103-7. 19. Nelson SM, Yates RW, Fleming R. Serum anti-mullerian hormone and FSH: predictioin of live birth and extremes of response in stimulated cycles-implications for individualization of therapy. Hum Reprod 2007; 22: 2414-21. 20. Jurema MW, Bracero NJ, Garcia JE. Fine tuning cycle day 3 hormonal assessment of ovarian reserve improves in vitro fertilization outcome in gonadotropin-releasing hormone antagonist cycles. Fertil Steril 2003; 80: 1156-61. 21. Bancsi LF, Broekmans FJ, Eijkemans MJ, de Jong FH, Habbema JD, te Velde ER. Predictors of poor ovarian response in in vitro fertilization a prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77: 328-36. 22. Kwee J, Schats R, McDonnell J, Themmen A, de Jong F, Lambalk C. Evaluation of anti-mullerian hormone as a test for the prediction of ovarian reserve. Fertil Steril 2008; 90: 737-43. 23. La Marca A, Giulini S, Tirelli A, Bertucci E, Marsella T, Xella S, et al. Anti-mullerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Hum Reprod 2007; 22: 766-71. 24. Seifer DB, MacLaughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum mullerian-inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002; 77: 468-71. 25. Eldar-Geva T, Ben Chetrit A, Spitz IM, Rabinowitz R, Markowitz E, Mimoni T, et al. Dynamic assays of inhibin B, anti-mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome. Hum Reprod 2005; 20: 3178-83. 26. Ebner T, Sommergruber M, Shebl O, Schreier-Lechner E, Tews G. Basal level of anti-mullerian hormone is associated with oocyte quality in stimulate cycles. Hum Reprod 2006; 21: 2022-6. 27. Smeenk JM, Sweep FC, Zielhuis GA, Kremer JA, Thomas CM, Braat DD. Antimullerian hormone predicts ovarian responsiveness, but not embryo quality or pregnancy, after in vitro fertilization or intracyoplasmic sperm injection. Fertil Steril 2007; 87: 223-618. - 316 -
제 35 권제 4 호, 2008 안영선 김진영 조연진 김민지 김혜옥외 4 인 = 국문초록 = 목적 : 체외수정을위한과배란유도시난소반응성의예측인자로서항뮬러리안호르몬 (AMH) 의효용성을 FSH와비교하여알아보고, 체외수정결과와의관계도알아보고자하였다. 연구방법 : 2007년 1월부터 2007년 8월까지단기요법이나 GnRH antagonist 요법을이용하여체외수정을시행하는 111 명을대상으로, 생리주기 3일째혈중 AMH 및 FSH를전향적으로측정하였다. 과배란유도후채취된난자개수와 AMH 또는 FSH의상관관계를분석하였고, 채취된난자수및 AMH 수치에따라과배란유도결과와체외수정결과를비교하였다. 저반응군및과반응군의예측을위한 AMH의임계치를알아보기위해 ROC curve 분석을시행하였다. 결과 : AMH는채취된성숙난자수와밀접한양의상관관계를나타냈으며 (r=0.792, p<0.001), FSH (r=-0.477, p<0.001) 보다더높은상관관계를보였다. 난소반응성에따라저반응군 ( 성숙난자수 2), 정상반응군 (3~16), 과반응군 ( 17) 으로나누어 AMH와 FSH 수치는유의한차이를보였으며, 저반응군 ( 채취된성숙난자수 2) 및과반응군 ( 채취된성숙난자수 17) 을예측하는데 ROC curve 상 AMH의임계치는각각 <0.50 ng/ml (sensitivity 88.9%, specificity 89.5%), 및 2.60 ng/ml ((sensitivity 85.7%, specificity 87.0%) 였다. AMH level에따라 low AMH group ( 0.60 ng/ml), normal AMH group (0.60~2.60 ng/ml), high AMH group으로구분하여, 각군간채취된성숙난자수와 (2.7±2.2, 8.1±4.8, 16.5±5.7, p<0.001), 투여된성선자극호르몬제의용량에 (3530.5±1251.0, 2957.1±1057.6, 2219.2±751.9 IU, p<0.001) 유의한차이를보였다. 성숙난자의비율과수정율에유의한차이는없었으며임신율도 23.8%, 34.0%, 37.5% 로각군간유의한차이는없었다. 결론 : 혈중기저 AMH는과배란유도시채취되는성숙난자수와높은상관관계가있어난소반응성의예측인자로서유용할것으로생각된다. AMH 수치에따라체외수정결과에는차이가없었으나, 저반응군및과반응군의예측에유용하여체외수정시주기의취소나, 환자별적정용량의결정및난소과자극증후군의위험을감소시키는데도움이될것으로사료된다. 중심단어 : 항뮬러리안호르몬 (AMH), 난소과자극, 난소반응 - 317 -