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ORIGINAL ARTICLE Korean J Obstet Gynecol 2012;55(5):315-324 http://dx.doi.org/10.5468/kjog.2012.55.5.315 pissn 2233-5188 eissn 2233-5196 ANTI-MÜLLERIAN HORMONE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME Si-Yeon You, MD, So Yun Park, MD, Ga Young Yang, MD, Kyung Ah Jeong, MD, PhD, Young Ju Kim, MD, PhD, Hye Won Chung, MD, PhD Department of Obstetrics and Gynecology, Ewha Womans University School of Medicine, Seoul, Korea Objective The aim of this study is to investigate the relationship between anti-müllerian hormone (AMH) and parameters related to polycystic ovary syndrome (PCOS). Methods We measured serum AMH levels in 100 women with PCOS by Rotterdam European Society for Human Reproduction and Embryology criteria. We conducted somatometry, blood test and transvaginal or transrectal ultrasound test. We compared and analyzed AMH and parameters in terms of insulin resistance according to PCOS related phenotypes. We divided phenotypes into four groups by polycystic ovarian morphology (PCOM) and hyperandrogenemia (total testosterone [TT], free testosterone [ft]). Results AMH levels ranged from 4.1 to 21.0 ng/ml and the mean level was 10.4 ± 4.1 ng/ml. Significant differences in parameters of insulin resistance were not observed among low (4 to 8 ng/ml), moderate (8 to 12 ng/ml), and high (>12 ng/ml) levels of AMH. Significant differences in AMH were not observed among groups according to PCOS related phenotypes. Weight, body mass index, waist-hip ratio, TT, ft, sex hormone binding globulin, 2-hour insulin and homeostasis model assessment of insulin resistance index were different significantly according to PCOS related phenotypes. TT, ovarian volume and follicle number were positively correlated with AMH. Conclusion Increased serum AMH levels in PCOS are correlated with TT and PCOM. Keywords: Anti-Müllerian hormone; Polycystic ovary syndrome; Testosterone; Polycystic ovarian morphology 다낭성난소증후군 (polycystic ovary syndrome) 은가임기여성들중 5%-10% 의유병률을보이는흔한내분비질환으로희발월경 (oligomenorrhea), 안드로겐과잉증, 초음파로진단되는다낭성난소형태 (polycystic ovarian morphology, PCOM) 소견을진단기준으로하며불임및대사증후군을동반하기쉬운질환이다 [1]. 이러한다낭성난소증후군환자에서나타나는호르몬의변화로는테스토스테론의증가, 황체형성호르몬 / 난포자극호르몬비의변화, 황체형성호르몬의증가등이있으나이들은월경주기에따라그수치가변화하므로진단기준으로사용하기에는단점이있다. 최근많은연구를통해알려진항뮐러관호르몬 (anti-müllerian hormone) 은월경주기에따른변화없이일정한수준을유지하므로다낭성난소증후군을포함한난소의기능평가도구로기대되고있다 [2-4]. 항뮐러관호르몬은 transforming growth factor β family에속하는 dimeric glycoprotein 으로 [5] 고환의 sertoli cell 에서만들어져자궁, 난 Received: 2012.1.29. Revised: 2012.3.18. Accepted: 2012.4.18. Corresponding author: Kyung Ah Jeong, MD, PhD Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 158-710, Korea Tel: +82-2-2650-2858 Fax:+82-2-2647-9860 E-mail: ogjeong@ewha.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2012. Korean Society of Obstetrics and Gynecology WWW.KJOG.ORG 315

KJOG Vol. 55, No. 5, 2012 관및질상부를이루게되는뮐러관의발달을방해하는역할을한다 [6]. 여자태아에서항뮐러관호르몬은임신 36주경태아의난소에서처음발견되는데, 원시난포 (primary follicle) 의과립막세포 (granulosa cell) 에존재한다 [7]. 항뮐러관호르몬발현은난포가자라는동안지속되어전방난포 (preantral follicle) 와작은방난포 (antral follicle) 시기의과립막세포에서최고치를보인다. 하지만방난포의직경이 8 mm 이상이되면항뮐러관호르몬의발현은줄어들고난포자극호르몬의존성장기 (follicular stimulating hormone [FSH]-dependent follicular growth) 에들어서면서거의없어지게된다 [8,9]. 항뮐러관호르몬은 primordial pool에서자라는난포의수를조절하며난포자극호르몬-민감성난포 (FSH-sensitive follicle) 중에서우성난포 (dominant follicle) 을선택하는역할을한다 [10]. Durlinger 등 [11] 의연구에따르면항뮐러관호르몬이없는쥐에서원시난포 (primordial follicle) 가 growing follicle로전환하는속도가빨라져 primordial pool의고갈이가속화되는것을볼수있었다. 또한난포내에서항뮐러관호르몬의농도가줄어들수록난포자극호르몬에대한한계치가낮아져더큰방난포는항뮐러관호르몬이없는상황에서더욱예민한반응을보였고이는우성난포의선택에영향을미치는것으로나타났다 [12]. 다낭성난소증후군이있는여성에서항뮐러관호르몬의농도가정상월경주기의여성에서보다 2-3배이상높으며 [13], 혈액내항뮐러관호르몬농도는난포의수가증가할수록높아지는것으로알려져있다 [14]. 또한다낭성난소증후군여성중에무월경의여성에서희발월경의여성보다높은수치의항뮐러관호르몬이측정되었으며고안드로겐혈증 (hyperandrogenemia) 이있는경우에정상안드로겐수치를보이는여성보다항뮐러관호르몬이높다고보고되었다 [15]. 즉, 항뮐러관호르몬농도는고안드로겐혈증, 희발월경또는무배란, 다낭성난소형태등다낭성난소증후군의특징적진단소견과비례하는것으로나타났다 [16,17]. 이에본연구에서는한국가임기여성에서다낭성난소증후군환자를대상으로항뮐러관호르몬을측정하여국내자료를마련함으로써진단과치료예측에이용하고자하였다. 따라서항뮐러관호르몬농도의범위에따른다낭성난소증후군의임상적, 생화학적특징및인슐린저항성과당대사관련지표를알아보고, 다낭성난소증후군환자들의다낭성난소형태와고안드로겐혈증에근거한표현형에따라분류하여항뮐러관호르몬과의상관관계를분석하였다. 의안드로겐과잉증과무배란이있는다른질환을배제한경우에진단하였다. 1) 희발월경 : 35일이상월경이없는경우, 또는 1년에 10회이하의월경을하는경우로정의하고, 2) 임상적또는생화학적안드로겐과잉증 : modified Ferriman Gallwey (FG) score 가 8점이상인경우로정의하며 [18] 생화학적고안드로겐혈증은혈중테스토스테론농도가정상월경주기를가진대조군의 95분위수이상인경우로정의하고, 3) 초음파에서확인되는다낭성난소형태소견은월경시작후 10일이내에시행한초음파로하나이상의난소부피가 10 cm 3 이상이거나 2-9 mm 크기의난포가 12개이상보이는경우로정의하였다 [19]. 1) 신체계측및진찰환자 100명을대상으로연령, 체질량지수 (body mass Index), 허리- 둔부둘레비 (waist-hip ratio), modified FG score를측정하였다. 신체계측은표준화된신장계측기와체중계측기를이용하여신장과체중을측정하였고표준화된줄자를이용하여허리둘레를측정하였다. 허리둘레측정위치는마지막늑골하단과배꼽상방의가장짧은둘레로정하였다. 다모증진단을위한검사는기존에널리사용되고있는 modified FG score 방법을이용하였는데이는신체 9부위 ( 입술위, 턱, 앞가슴, 상복부, 하복부, 상지, 하지, 등, 엉덩이 ) 에서종모 (terminal hair) 분포정도를 5단계즉, 0점에서 4점으로점수화하였다. 2) 혈액검사혈액검사는초기난포기, 즉생리시작 10일이내에적어도 8시간이상금식후채혈하였으며호르몬검사로총테스토스테론, 성호르몬결합글로불린 (sex hormone binding globulin) 을측정하였다. 항뮐러관호르몬은 enzyme-linked immunosorbent assay kit (Diagnostic Systems Laboratories Inc., Webster, TX, USA) 를사용하여측정하였다. 측정한계치는 0.01 ng/ml이었고 intra-assay, inter-assay 변동계수는 4%-5%, 7%-9% 였다. 인슐린저항성및당대사와관련하여공복시와식후 2시간의혈당및인슐린, homeostasis model assessment of insulin resistance (HOMA-IR) 지수를측정하였다. 본연구는 2010 년 7월부터 2011 년 5월까지이화여자대학교목동병원산부인과에서희발월경주호소로내원한여성중다낭성난소증후군을진단받은환자 100명을대상으로하였다. 다낭성난소증후군은 2003년 Rotterdam European Society for Human Reproduction and Embryology (ESHRE) 진단기준에따라다음의세가지진단기준중두가지또는그이상을만족하고쿠싱증후군, 선천성부신과증식등 3) 골반초음파검사고해상도의 7 MHz 질식탐촉자 (transvaginal transducer) (LOGIQ 500, General electric medical systems, Milwaukee, WI, USA) 를사용하여난소를최대한확대하여검사하였다. 난소의가장긴종단면 (longitudinal cross-section) 에서내측변연 (inner margin) 에서외측변연 (outer margin) 으로스캔하면서관찰한 2-9 mm 크기의난포의총수를난포개수로하였으며, 난소의부피는길이 (length) 넓이 (width) 두께 (thickness) 0.523로계산하였다 [20]. 성경험이없는여성은직장초음파 (transrectal sonogram) 를시행하였다. 좌우양측난소의부피와난포의개수를측정하였고각각평균값을계산하였다. 난소낭종 316 WWW.KJOG.ORG

Si-Yeon You, et al. Anti-Müllerian hormone in PCOS 등의병변이있는경우는대상자에서제외하였다. 4) 항뮐러관호르몬농도범위에따른분류다낭성난소증후군환자들에서측정된항뮐러관호르몬농도의평균을기준하고중앙값을참고하여그범위를저, 중등, 고농도의 3군으로분류하였으며임상적, 생화학적특징을비교하였다. 3군간의인슐린저항성및당대사관련지표의차이가나타나는지분석하였다. 5) 다낭성난소증후군의표현형에따른분류다낭성난소증후군환자들을초음파로관찰한다낭성난소형태와고안드로겐혈증에근거한표현형에따라 4군으로분류하였다. 1) 골반초음파소견에서다낭성난소형태를보이지만고안드로겐혈증을보이지않는군 (PCOM without hyperandrogenemia [HA]), 2) 고안드로겐혈증으로총테스토스테론 (total testosterone, TT) 은증가하고유리테스토스테론 (free testosterone, ft) 은정상인군 (HA with high TT), 3) 총테스토스테론과유리테스토스테론이둘다증가되어있는군 (HA with high TT and ft), 4) 총테스토스테론은정상이고유리테스토스테론만증가되어있는군 (HA with high ft) 의 4군으로분류하여비교하였다. 통계분석은 SPSS ver. 17.0 (SPSS Inc., Chicago, IL, USA) 을이용 하였다. 항뮐러관호르몬의농도범위에따라분류한 3군, 다낭성난소증후군의표현형에따라분류한 4군간의차이는 one-way analysis of variance 분석을사용하였고, 항뮐러관호르몬과다낭성난소증후군의여러변수들간의 Pearson 상관계수를분석하였다. 통계적유의성은 P-value 0.05 이하를기준으로하였다. 연구의대상이된다낭성난소증후군환자들의연령은평균 26.6 ± 4.0세로젊은가임기여성이었고체질량지수 22.78 ± 4.48 kg/ m 2, 허리-둔부둘레비 0.84 ± 0.07로, 세계보건기구 (World Health Organization, WHO) [21] 에서정의한비만 (obesity) 여성 ( 허리-둔부둘레비>0.85) 에해당되지않는정상범위였다. 평균총테스토스테론농도는 73.5 ± 21.0 ng/dl, 유리테스토스테론은 0.89 ± 0.39 ng/dl로측정되었고, 난소의평균부피는 12.5 ± 3.4 cm 3, 난포개수는 16.9 ± 5.6 개로 ESHRE 기준에따른다낭성난소증후군의진단기준에부합하였다 [19]. 항뮐러관호르몬검사를시행한결과, 평균 10.4 ± 4.1 ng/ml, 중앙값이 9.4 ng/ml로측정되었고최저치 4.1 ng/ml에서최고치 21.0 Table 1. Clinical and biochemical characteristics of polycystic ovary syndrome with low, moderate, and high levels of AMH Characteristic Total AMH 4 8 (L) AMH 8 12 (M) AMH >12 (H) P value No. 99 26 39 34 Age (yr) 26.6 ± 4.0 27.1 ± 4.9 26.5 ± 3.4 26.6 ± 3.9 NS Weight (kg) 59.6 ± 13.5 63.5 ± 14.2 58.1 ± 13.6 58.7 ± 12.9 NS BMI (kg/m 2 ) 22.8 ± 4.5 24.4 ± 4.7 22.1 ± 4.4 22.5 ± 4.3 NS WHR 0.84 ± 0.07 0.87 ± 0.07 0.82 ± 0.06 0.84 ± 0.07 0.026 AMH (ng/ml) 10.4 ± 4.1 6.0 ± 1.0 9.7 ± 1.2 14.5 ± 3.6 <0.0001 TT (ng/dl) 73.5 ± 21.0 66.2 ± 32.9 69.5 ± 16.9 83.6 ± 25.3 0.001 ft (ng/dl) 0.89 ± 0.39 0.93 ± 0.40 0.81 ± 0.39 0.96 ± 0.40 NS SHBG (nmol/l) 69.6 ± 29.3 60.6 ± 32.9 72.1 ± 29.7 73.4 ± 25.6 NS Fasting glucose (mg/dl) 88.3 ± 7.7 90.9 ± 7.6 87.2 ± 7.8 87.4 ± 7.4 NS 2 hour glucose (mg/dl) 100.6 ± 23.1 106.2 ± 27.4 97.3 ± 21.2 99.7 ± 21.9 NS Fasting insulin (μiu/ml) 9.8 ± 4.8 10.9 ± 5.8 9.9 ± 3.8 8.9 ± 4.8 NS 2 hour insulin (μiu/ml) 49.8 ± 43.5 60.7 ± 66.2 50.2 ± 31.7 40.8 ± 31.2 NS HOMA IR 2.2 ± 1.2 2.5 ± 1.6 2.2 ± 1.0 1.9 ± 1.1 NS OV (cm 3 ) 12.5 ± 3.4 11.9 ± 3.5 11.9 ± 2.3 13.7 ± 4.0 0.039 FN 16.9 ± 5.6 14.0 ± 3.1 16.3 ± 4.3 19.9 ± 7.0 <0.0001 AMH, anti Müllerian hormone; NS, non-signifi cance; BMI, body mass index; WHR, waist hip ratio; TT, total testosterone; ft, free testosterone; SHBG, sex hormone binding globulin; HOMA IR, homeostasis model assessment of insulin resistance index=(fasting insulin [μu/ml] fasting glucose [mg/dl])/405; OV, ovarian volume; FN, follicle number. WWW.KJOG.ORG 317

KJOG Vol. 55, No. 5, 2012 Table 2. The mean serum AMH levels of various polycystic ovary syndrome related phenotypes Phenotype No. Mean ± SD P value PCOM without HA 30 9.7 ± 3.8 0.16 HA (TT) 20 11.0 ± 2.4 HA (TT, ft) 37 11.2 ± 4.9 HA (ft) 12 8.6 ± 3.6 Total 99 10.4 ± 4.1 AMH, anti Müllerian hormone; SD, standard deviation; PCOM, polycystic ovarian morphology; HA, hyperandrogenemia; TT, total testosterone; ft, free testosterone. ng/ml의범위로나타났다. 항뮐러관호르몬농도의평균및중앙값을기준으로호르몬수치의정도에따라저 (4-8 ng/ml), 중등 (8-12 ng/ ml), 고농도 (>12 ng/ml) 의 3군으로분류하여임상적, 생화학적특징을비교하였다. 항뮐러관호르몬수치정도에따라분류한 3군간의유의한차이를보인다낭성난소증후군환자의특징은총테스토스테론, 난소부피, 난포개수였으며인슐린저항성및당대사관련지표의통계적인차이는나타나지않았다 (Table 1). 다낭성난소증후군환자들을다낭성난소형태와고안드로겐혈증에근거한표현형에따라분류한 1) 다낭성난소형태를보이지만고안드로겐혈증을보이지않는군 (PCOM without HA), 2) 고안드로겐혈증으로총테스토스테론은증가하고유리테스토스테론은정상인군 (HA [TT]), 3) 총테스토스테론, 유리테스토스테론이둘다증가되어있는군 (HA [TT, ft]), 4) 총테스토스테론은정상이고유리테스토스테론만증가되어있는군 (HA [ft]), 4군간의항뮐러관호르몬수치를비교한결과, 3) 총테스토스테론, 유리테스토스테론이둘다증가되어있는군에서항뮐러관호르몬이 11.2 ± 4.9 ng/ml로가장높게측정되었다. 1) 다낭성난소형태를보이지만고안드로겐혈증을보이지않는군과 4) 유리테스토스테론만증가되어있는군의항뮐러관호르몬농도는 2) 총테스토스테론만증가되어있는군과 3) 총테스토스테론, 유리테스토스테론이둘다증가되어있는군에비해낮았으나 4군간의항뮐러관호르몬의차이는통계적으로유의하지않았다 (Table 2). 다낭성난소증후군환자들의체중, 체질량지수, 허리-둔부둘레비, 총테스토스테론, 유리테스토스테론, 성호르몬결합글로불린, 식후 2시간인슐린, HOMA-IR 지수는다낭성난소증후군의표현형에따라분류한 4군간에통계적으로유의한차이를보였다. 인슐린저항성및당대사에관련된식후 2시간인슐린, HOMA-IR 지수는 3) 총테스토스테론, 유리테스토스테론이둘다증가되어있는군에서가장높았다. 공복인슐린수치 (11.2 ± 5.5 uiu/ml) 는표현형에따라통계적으로유의한차이를보이지는않았지만 (P = 0.056), 4군중, 3) 총테스토스테론, 유리테스토스테론이둘다증가되어있는군에서가장높게나타났다. 그외연령과공복및식후 2시간혈당, 난소부피와난포개수는 4군 간에서유의한차이를보이지않았다 (Table 3). 다낭성난소증후군환자들의임상적, 생화학적특징과항뮐러관호르몬과의상관관계를분석한결과, 총테스토스테론농도가항뮐러관호르몬과의미있는양의상관관계 (R = 0.463) 를보였고, 골반초음파로측정한난소의부피 (R = 0.222) 와난포의개수 (R = 0.535) 역시통계적으로의미있는양의상관관계로나타났다. 연령, 체중, 체질량지수, 허리-둔부둘레비와다낭성난소증후군환자들의호르몬수치중유리테스토스테론, 성호르몬결합글로불린및인슐린저항성및당대사관련지표인공복혈당과인슐린, 식후 2시간혈당과인슐린, HOMA-IR 지수는항뮐러관호르몬과유의한상관관계를보이지않았다 (Table 4). 무월경또는희발월경및고안드로겐혈증을보이는다낭성난소증후군여성에서는난포의개수및난소의부피가고인슐린혈증 (hyperinsulinemia) 이나제1형당뇨병과연관되어있다고보고되고있으므로정확한진단이매우중요한질환이다 [22-24]. 하지만진단기준에포함되는초음파에의한난소형태소견의정확도에대한문제점과월경주기에따른호르몬의변화로보다객관적이며일관된진단방법의마련이필요하다. 본연구에참여한한국가임기의다낭성난소증후군여성에서항뮐러관호르몬의농도는평균 10.4 ± 4.1, 중앙값 9.4 ng/ml로측정되었고, 정상대조군을대상으로하지못한한계가있었으므로다른연구결과를참고로하였다. 최근국내에서보고된정상월경을하는 20-31 세한국인여성의항뮐러관호르몬농도는평균 4.94 ± 0.17 ng/ml로중앙값이 4.20 ng/ml이었다 [25]. 즉다른연구들에서제시한정상월경여성의항뮐러관호르몬농도보다증가된소견을보여 [25,26] 다낭성난소증후군과항뮐러관호르몬의관련성을보고한이전연구들과유사한결과를보였다 [27,28]. 정상월경을하는여성에비해다낭성난소증후군환자에서항뮐러관호르몬수치가증가하는것이보고되었으며 [12,15], 이는다낭성난소의과립막세포 (granulosa cell) 에서항뮐러관호르몬의합성및분비 318 WWW.KJOG.ORG

Si-Yeon You, et al. Anti-Müllerian hormone in PCOS Table 3. Clinical and biochemical characteristics of polycystic ovary syndrome related phenotypes Characteristic Total Phenotype Mean ± SD P value Age (yr) 26.6 ± 4.0 PCOM without HA 27.4 ± 4.0 NS HA (TT) 25.6 ± 3.1 HA (TT, ft) 26.8 ± 4.6 HA (ft) 25.9 ± 3.9 Weight (kg) 59.6 ± 13.5 PCOM without HA 58.1 ± 10.8 0.009 HA (TT) 52.9 ± 7.6 HA (TT, ft) 62.1 ± 14.3 HA (ft) 67.9 ± 19.5 BMI (kg/m 2 ) 22.8 ± 4.5 PCOM without HA 22.2 ± 3.8 0.007 HA (TT) 20.4 ± 2.6 HA (TT, ft) 23.8 ± 4.7 HA (ft) 25.2 ± 6.2 WHR 0.84 ± 0.07 PCOM without HA 0.84 ± 0.07 0.006 HA (TT) 0.80 ± 0.06 HA (TT, ft) 0.86 ± 0.06 HA (ft) 0.85 ± 0.07 TT (ng/dl) 73.5 ± 21.0 PCOM without HA 53.2 ± 7.5 <0.0001 HA (TT) 79.0 ± 8.8 HA (TT, ft) 91.1 ± 19.4 HA (ft) 60.3 ± 4.3 ft (ng/dl) 0.89 ± 0.39 PCOM without HA 0.51 ± 0.11 <0.0001 HA (TT) 0.70 ± 0.12 HA (TT, ft) 1.25 ± 0.33 HA (ft) 1.07 ± 0.19 SHBG (nmol/l) 69.6 ± 29.3 PCOM without HA 86.9 ± 24.6 <0.0001 HA (TT) 92.9 ± 19.2 HA (TT, ft) 51.5 ± 17.1 HA (ft) 41.0 ± 25.7 Fasting glucose (mg/dl) 88.3 ± 7.7 PCOM without HA 86.8 ± 7.5 NS HA( TT) 87.1 ± 6.6 HA (TT, ft) 90.7 ± 7.7 HA (ft) 86.7 ± 8.7 2 hour glucose (mg/dl) 100.6 ± 23.1 PCOM without HA 96.9 ± 25.9 NS HA (TT) 96.1 ± 17.2 HA (TT, ft) 105.5 ± 21.8 HA (ft) 102.2 ± 28.3 Fasting insulin (μiu/ml) 9.8 ± 4.8 PCOM without HA 8.9 ± 3.4 NS HA (TT) 8.1 ± 2.2 HA (TT, ft) 11.2 ± 5.5 HA (ft) 10.9 ± 6.9 Continued WWW.KJOG.ORG 319

KJOG Vol. 55, No. 5, 2012 Table 3. Continued Characteristic Total Phenotype Mean ± SD P value 2 hr insulin (μiu/ml) 49.8 ± 43.5 PCOM without HA 40.5 ± 29.5 0.022 HA (TT) 31.8 ± 16.4 HA (TT, ft) 63.0 ± 52.6 HA (ft) 62.3 ± 58.7 HOMA-IR 2.2 ± 1.2 PCOM without HA 1.9 ± 0.9 0.044 HA (TT) 1.8 ± 0.5 HA (TT, ft) 2.6 ± 1.5 HA (ft) 2.4 ± 1.7 OV (cm 3 ) 12.5 ± 3.4 PCOM without HA 12.6 ± 3.7 NS HA (TT) 12.4 ± 2.8 HA (TT, ft) 12.8 ± 3.5 HA (ft) 11.1 ± 2.6 FN 16.9 ± 5.6 PCOM without HA 16.1 ± 5.0 NS HA (TT) 17.0 ± 5.3 HA (TT, ft) 18.2 ± 6.5 HA (ft) 14.6 ± 4.0 SD, standard deviation; HA, hyperandrogenemia; NS, non-signifi cance; TT, total testosterone; ft, free testosterone; BMI, body mass index; WHR, waisthip ratio; SHBG, sex hormone binding hormone; HOMA IR, homeostasis model assessment of insulin resistance index=(fasting insulin [μu/ml] fasting glucose [mg/dl])/405; OV, ovarian volume; FN, follicle number. Table 4. Correlation of AMH and studied variables Pearson s correlation coefficient P value Age (yr) 0.059 NS Weight (kg) 0.167 NS BMI (kg/m 2 ) 0.139 NS WHR 0.009 NS TT (ng/dl) 0.463 <0.0001 ft (ng/dl) 0.151 NS SHBG (nmol/l) 0.075 NS Fasting glucose (mg/dl) 0.091 NS 2 hour glucose (mg/dl) 0.078 NS Fasting insulin (μiu/ml) 0.150 NS 2 hour insulin (μiu/ml) 0.165 NS HOMA IR 0.160 NS OV (cm 3 ) 0.222 0.027 FN 0.535 <0.0001 AMH, anti Müllerian hormone; NS, non-significance; BMI, body mass index; WHR, waist hip ratio; TT, total testosterone; ft, free testosterone; SHBG, sex hormone binding hormone; HOMA IR, homeostasis model assessment of insulin resistance index=(fasting insulin [μu/ml] fasting glucose [mg/dl])/405; OV, ovarian volume; FN, follicle number. 가증가하기때문인것으로설명된다 [29]. 다낭성난소증후군환자와정상월경을하는여성에서중합효소연쇄반응을통해항뮐러관호르몬 mrna를측정하였을때, 다낭성난소증후군환자에서항뮐러관호르몬의발현이약 3배정도높았으며 [30], Pellatt 등 [31] 의연구에서는다낭성난소의과립막세포에서분비하는항뮐러관호르몬이정상난소의 75배정도증가되는것을알수있었다. 또한항뮐러관호르몬농도가증가할수록다낭성난소증후군의발병률이증가하여항뮐러관호르몬이 4 ng/ml 미만인환자에서는발병률이 21% 인반면, 항뮐러관호르몬농도가 11 ng/ml 이상일경우에는 80% 에서다낭성난소증후군이발생하였다. 항뮐러관호르몬농도가높은군에서는안드로겐과잉증, 무배란, 다낭성난소의초음파소견을보이는환자비율이증가하였으며, 총테스토스테론및안드로스테네디온이항뮐러관호르몬이낮은군에비해현저하게상승된다고보고되었다 [32]. 본연구에서는항뮐러관호르몬의평균및중앙값을기준으로그범위를저, 중등, 고농도의 3군으로분류하여각각의변수들과의연관성을분석하였으며, 허리-둔부둘레비, 총테스토스테론, 난소의부피와난포의개수가항뮐러관호르몬농도에따라통계적으로유의한차이가있는것으로나타났다. 총테스토스테론과난소의부피, 난포의개수는항뮐러관호르몬농도가 12 ng/ml를초과한고농도환자군에서가장높게나타나항뮐러관호르몬이다낭성난소증후군과관련되며호르몬수치의정도와연관되어있는것으로나타났다. 연구에모집된다낭성난소증후군환자들을초음파로관찰한다낭 320 WWW.KJOG.ORG

Si-Yeon You, et al. Anti-Müllerian hormone in PCOS 성난소형태와고안드로겐혈증에근거하여네가지표현형으로구분하였으며각각의군에서항뮐러관호르몬농도를비교하였을때, 다낭성난소의형태적인이상만있는환자보다고안드로겐혈증이있는경우에항뮐러관호르몬이높았고, 총테스토스테론과유리테스토스테론이모두증가한군에서항뮐러관호르몬수치가가장증가되어있었으나 4군간의통계적으로유의한차이를보이지는않았다. 다낭성난소증후군의표현형에따라분류한네가지환자군의임상적, 생화학적특성을분석한결과, 체중, 체질량지수, 허리-둔부둘레비, 총테스토스테론, 유리테스토스테론, 성호르몬결합글로불린, 식후 2시간인슐린, HOMA-IR 지수는다낭성난소증후군의표현형에따라통계적으로유의한차이를보였다. 인슐린저항성및당대사에관련된식후 2시간인슐린, HOMA-IR 지수는총테스토스테론, 유리테스토스테론이둘다증가되어있는군에서가장높았다. Pache와 Fauser [33] 은안드로겐치료를받은여성에서다낭성난소증후군에서보이는비배란성전방난포수의증가가나타남을보고하였다. 또한총테스토스테론농도와유리안드로겐지표가난포개수및난소부피와양의상관관계를보인연구 [34] 등을통하여안드로겐의증가가다낭성난소형태의발생에영향을주는것을알수있으며, 항뮐러관호르몬이고안드로겐혈증을보이는군에서높았던이번결과를통하여다낭성난소증후군과안드로겐 ( 테스토스테론 ), 항뮐러관호르몬사이에비례적관계가있음을유추해볼수있겠다. 고인슐린혈증은전방난포의성장을자극하여난포자극호르몬에대한과립막세포의민감도를증가시켜결과적으로난포의개수및난소의부피를증가시키는것으로알려져있다 [35]. Chen 등 [34] 의연구결과, 전방난포의개수와체질량지수, HOMA-IR 지수및테스토스테론농도가양의상관관계를보였으며, 항뮐러관호르몬과비만도, 인슐린저항성및테스토스테론농도가다낭성난소증후군여성에서난포개수및난소부피를결정하는중요한인자라는것이보고되었다. 이번연구에서도식후 2시간인슐린및 HOMA-IR 지수는총테스토스테론과유리테스토스테론이모두증가한군에서가장높게측정되었는데, 이는고안드로겐혈증의중증도와인슐린저항성이비례하는것으로볼수있다. 각각의변수들과항뮐러관호르몬의상관관계를알아본결과, 총테스토스테론및난소부피, 난포개수가통계적유의성을보였다. 총테스토스테론은상관계수 0.463으로양의상관관계를보였다. 안드로겐은난포의성장과정중 FSH-independent stage에작용하는것으로알려져있으며 [36] 고농도안드로겐치료를하는여성에서생식샘자극호르몬 (gonadotropin) 의감소및다낭성난소에해당하는난소의형태변화가관찰되었다 [37]. 이번결과는 Eldar-Geva 등 [38] 이항뮐러관호르몬의농도는안드로겐농도와관련이있고, 고안드로겐혈증이있는다낭성난소증후군여성에서정상안드로겐수치를보이는다낭성난소증후군여성보다높았음을보고한연구와일치하는결과를보였다. Catteau-Jonard 등 [30] 이다낭성난소증후군환자와정상월경여성을대상으로난포의크기와과립막세포의안드로겐수용체발현을조사한연구에서는, 다낭성난소증후군환자의작은크기의난포에서안 드로겐수용체의발현이가장높았음을알수있었고, 항뮐러관호르몬 type II 수용체의발현은안드로겐수용체의발현과긍정적인상관관계가있었다. 본연구에서난소의부피와난포의개수역시상관계수 0.222와 0.535로항뮐러관호르몬농도와양의상관관계를보였으며모든변수들중난포의개수가항뮐러관호르몬과가장비례적인관계를보였다. 하지만 Crisosto 등 [39] 의연구에서다낭성난소증후군여성의항뮐러관호르몬과식후 2시간인슐린이양의상관관계를보인것과달리본연구에서는인슐린과항뮐러관호르몬사이의유의한관련성은나타나지않았다. 항뮐러관호르몬과인슐린저항성사이의관련성에대한연구들이발표되었지만, 다낭성난소증후군여성중에인슐린저항성이있는군이그렇지않은군에비해항뮐러관호르몬수치가높았으며무월경여성에서희발월경여성보다높은항뮐러관호르몬수치가관찰되었다는연구 [40] 가있는가하면, 항뮐러관호르몬과체질량지수, HOMA-IR 지수사이에음의상관관계를보고한연구도있어 [34] 인슐린저항성과항뮐러관호르몬농도의관련성에대한추가적인연구가필요할것으로생각된다. 항뮐러관호르몬은폐경에가까워지면서그수치가감소하여폐경이후에는거의검출되지않는수준까지떨어지게되고 [41,42], van Rooij 등 [43] 의연구는항뮐러관호르몬수치가노화에따른난자 / 난포수의감소를반영한다는것을보여주었다. 하지만본연구에서환자의연령과항뮐러관호르몬농도사이에통계적으로유의한상관관계를보이지않은것은, 정상여성에서보다다낭성난소증후군환자에서는연령증가에따른항뮐러관호르몬감소영향이적다고추측할수있겠다. Pigny 등 [44] 의연구에따르면항뮐러관호르몬측정 (cut-off value 8.4 ng/ml) 은다낭성난소증후군의진단도구로서민감도 (67%) 및특이도 (92%) 가상대적으로높은것으로보고되었으며, Dewailly 등 [45] 은다낭성난소증후군진단시에항뮐러관호르몬수치 5 ng/ml를기준하여이값을넘을때, 다낭성난소증후군으로진단하는방법이민감도 (92%) 및특이도 (97%) 가높았다 (area under the curve = 0.973) 고제시하였다. 또한과체중의다낭성난소증후군여성이체중감량을했을때월경주기의회복과함께항뮐러관호르몬수치가감소되는것으로반영되었다 [46]. 본연구는가임기여성중다낭성난소증후군으로진단된환자 100 명을대상으로항뮐러관호르몬에대한국내자료를마련하고자하였으며다낭성난소증후군과관련된임상적, 생화학적특징들과의상관관계를알아본것으로, 총테스토스테론및초음파의난소형태변화와관련하여항뮐러관호르몬농도가연관되는것으로나타났다. 하지만연구의대상이환자군으로제한되었으므로향후정상월경여성에서의항뮐러관호르몬농도및안드로겐등과의비교가필요할것으로생각된다. 여러내분비적인질병의원인으로생각되는다낭성난소증후군의진단및치료가중요하게생각되고있지만, 현재사용되는 3가지진단기준의혼용으로인하여난소의형태적인이상과고안드로겐혈증등의여러가지검사를위한비용적인문제가발생하게되고월경주기 WWW.KJOG.ORG 321

KJOG Vol. 55, No. 5, 2012 에따른호르몬수치의변화때문에고안드로겐혈증을진단하기위해환자마다검사시기를맞추어야하는불편함을감수해야하며정확한정상치조차일관되어있지않은어려운실정이다. 앞으로항뮐러관호르몬수치가다낭성난소증후군의진단적도구로서의유용성이확립된다면환자의월경주기에관계없이보다편리하게측정하는단일검사로진단비용을오히려감소시킬뿐아니라치료예후에대한예측인자로도활용할수있을것으로기대된다. References 1. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet 2007;370:685-97. 2. La Marca A, Stabile G, Artenisio AC, Volpe A. Serum anti- Müllerian hormone throughout the human menstrual cycle. Hum Reprod 2006;21:3103-7. 3. Tsepelidis S, Devreker F, Demeestere I, Flahaut A, Gervy C, Englert Y. Stable serum levels of anti-müllerian hormone during the menstrual cycle: a prospective study in normo-ovulatory women. Hum Reprod 2007;22:1837-40. 4. Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, Te Velde ER, Broekmans FJ. Anti-Müllerian hormone levels in the spontaneous menstrual cycle do not show substantial fl uctuation. J Clin Endocrinol Metab 2006;91:4057-63. 5. Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction 2006;131:1-9. 6. Lee MM, Donahoe PK. Mullerian inhibiting substance: a gonadal hormone with multiple functions. Endocr Rev 1993;14:152-64. 7. Rajpert-De Meyts E, Jorgensen N, Graem N, Müller J, Cate RL, Skakkebaek NE. Expression of anti-müllerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. J Clin Endocrinol Metab 1999;84:3836-44. 8. Durlinger AL, Gruijters MJ, Kramer P, Karels B, Ingraham HA, Nachtigal MW, et al. Anti-Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology 2002;143:1076-84. 9. Weenen C, Laven JS, Von Bergh AR, Cranfi eld M, Groome NP, Visser JA, et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 2004;10:77-83. 10. Visser JA, Themmen AP. Anti-Müllerian hormone and folliculogenesis. Mol Cell Endocrinol 2005;234:81-6. 11. Durlinger AL, Kramer P, Karels B, de Jong FH, Uilenbroek JT, Grootegoed JA, et al. Control of primordial follicle recruitment by anti-müllerian hormone in the mouse ovary. Endocrinology 1999;140:5789-96. 12. Durlinger AL, Gruijters MJ, Kramer P, Karels B, Kumar TR, Matzuk MM, et al. Anti-Müllerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology 2001;142:4891-9. 13. Pigny P, Merlen E, Robert Y, Cortet-Rudelli C, Decanter C, Jonard S, et al. Elevated serum level of anti-müllerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab 2003;88:5957-62. 14. Rice S, Ojha K, Whitehead S, Mason H. Stage-specifi c expression of androgen receptor, follicle-stimulating hormone receptor, and anti-müllerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. J Clin Endocrinol Metab 2007;92:1034-40. 15. La Marca A, Orvieto R, Giulini S, Jasonni VM, Volpe A, De Leo V. Mullerian-inhibiting substance in women with polycystic ovary syndrome: relationship with hormonal and metabolic characteristics. Fertil Steril 2004;82:970-2. 16. Carlsen SM, Vanky E, Fleming R. Anti-Müllerian hormone concentrations in androgen-suppressed women with polycystic ovary syndrome. Hum Reprod 2009;24:1732-8. 17. Pellatt L, Rice S, Mason HD. Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high? Reproduction 2010;139:825-33. 18. Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol 1981;140:815-30. 19. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19-25. 20. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 2003;9:505-14. 21. World Health Organization. Waist circumference and waist-hip ration: Report of a WHO expert consultation, Geneva, 8-11 December 2008 [Internet]. Geneva: World Health Organization: c2012 [cited 2012 Apr 20]. Available from: http://whqlibdoc.who.int/publications/2011/9789241501491_eng.pdf. 22. Carmina E, Orio F, Palomba S, Longo RA, Lombardi G, Lobo RA. Ovarian size and blood flow in women with polycystic 322 WWW.KJOG.ORG

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KJOG Vol. 55, No. 5, 2012 the threshold values of follicle count on ultrasound and of the serum AMH level for the defi nition of polycystic ovaries. Hum Reprod 2011;26:3123-9. 46. Moran LJ, Noakes M, Clifton PM, Norman RJ. The use of anti- Müllerian hormone in predicting menstrual response after weight loss in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:3796-802. 다낭성난소증후군의항뮐러관호르몬에관한연구 이화여자대학교의학전문대학원산부인과학교실유시연, 박소연, 양가영, 정경아, 김영주, 정혜원 목적다낭성난소증후군 (polycystic ovary syndrome) 환자에서항뮐러관호르몬 (anti-müllerian hormone) 을측정하여다낭성난소증후군의임상적, 생화학적특징및관련지표와의상관관계를분석하고자하였다. 연구방법 Rotterdam European Society for Human Reproduction and Embryology기준에따라진단된 100명의다낭성난소증후군환자에서혈중항뮐러관호르몬을측정하였다. 신체계측, 혈액검사, 질식또는직장초음파검사를시행하였다. 다낭성난소형태 (polycystic ovarian morphology, PCOM) 와고안드로겐혈증에근거한표현형에따라 4군으로분류하여, 항뮐러관호르몬과인슐린저항성등의다낭성난소증후군관련지표들의상관성을비교분석하였다. 결과다낭성난소증후군의항뮐러관호르몬농도는 4.1-21.0 ng/ml 범위에있었으며평균 10.4 ± 4.1 ng/ml이었다. 항뮐러관호르몬농도의범위에따라분류한저 (4-8 ng/ml), 중등 (8-12 ng/ml), 고 (>12 ng/ml) 농도의 3군간의인슐린저항성관련지표들은차이가없었다. 다낭성난소증후군의표현형에따른분류에서항뮐러관호르몬의유의한차이는나타나지않았으나, 체중, 체질량지수, 허리-둔부둘레비, 총및유리테스토스테론, 성호르몬결합글로불린, 식후 2시간의인슐린과 homeostasis model assessment of insulin resistance 지수는다르게나타났다. 총테스토스테론과초음파로관찰한난소부피및난포개수는항뮐러관호르몬과양의상관관계가있었다. 결론다낭성난소증후군환자에서증가되어있는항뮐러관호르몬농도는총테스토스테론과다낭성난소형태의초음파소견과상관성이있었다. 중심단어 : 항뮐러관호르몬, 다낭성난소증후군, 테스토스테론, 다낭성난소형태 324 WWW.KJOG.ORG