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1 대한내분비학회지 : 제 21 권제 5 호 2006 원저 한국인다낭성난소증후군환자의아디포넥틴과그렐린유전자다형성 이화여자대학교의과대학내과학교실, 산부인과학교실 1 이혜진 변은경 박휘라 오지영 홍영선 성연아 정혜원 1 Adiponectin and Ghrelin Polymorphism in Korean Women with Polycystic Ovary Syndrome Hyejin Lee, Eun Kyung Byun, Hwi Ra Park, Jee-Young Oh, Youngsun Hong, Yeon-Ah Sung, Hyewon Chung¹ Departments of Internal Medicine and Obstetrics and Gynecology 1, Ewha Womans University College of Medicine ABSTRACT Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation, and this is a common disorder in premenopausal women. However, the pathogenesis is still uncertain. There has been no studies about PCOS-related genetic abnormalities in Korea. In this study, we examined the frequency of the adiponectin and ghrelin genotypes in Korean women with PCOS. Methods: Fifty four women with PCOS and 174 regular cycling healthy women were recruited for the study, and their reproductive hormones and metabolic profiles were measured. The polymorphisms of the ghrelin and adiponectin genes were analyzed. Results: The frequency of ghrelin gene polymorphism was not different between the women with PCOS and the controls. The frequency of the TG adiponectin genotype was higher and the frequency of the TT genotype was lower in the women with PCOS compared to the controls (P < 0.05). For the PCOS women with GG adiponectin genotype, their triglycerides levels were significantly higher compared to the PCOS women with the TT and TG genotypes even after adjusting for the BMI. Conclusion: Adiponectin gene polymorphism is associated with presence of PCOS and it is responsible for the dyslipidemia seen in PCOS. Yet further study is required to confirm the role of this genetic polymorphism in the susceptibility to PCOS and the associated metabolic features. (J Kor Endocrinol Soc 21:394~401, 2006) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: Adioponectin, Ghrelin, Polycystic ovary syndrome 서론 1) 고안드로겐혈증과배란이상이특징인다낭성난소증후군 (polycystic ovary syndrome, PCOS) 은가임여성의 5~10% 에서발생하는흔한내분비질환이나 [1,2] 그병인은아직정확하게밝혀져있지않으며통일된진단기준도없다. 1990년 National Institutes of Health (NIH) conference에서임상적고안드로겐증혹은고안드로겐혈증과만성적인무배접수일자 : 2006년 5월 17일통과일자 : 2006년 7월 31일책임저자 : 성연아, 이화여자대학교의과대학내과학교실 란이있으며, 고안드로겐증의다른원인질환이없을때 PCOS로진단할수있다고하였으나 [3], 2003년 European Society of Human Reproduction and Embryology (ESHRE) 에서는만성적인무배란, 임상적고안드로겐증이나고안드로겐혈증, 그리고초음파상다낭성난소의세가지중둘이상을만족하는경우를 PCOS로진단할것을권유하고있다 [4]. PCOS의병인은다양하고아직완전히규명되지않았는데, 높은가족력은이질환의병인에유전적인요인이관여함을시사한다 [5,6]. PCOS 환자의여자형제연구에서약 46% 가정상월경주기의고안드로겐혈증혹은 PCOS이었다 [7]. 또한 PCOS 환자의남자형제에서상염색체우성의유

2 - 이혜진외 6인 : 한국인다낭성난소증후군환자의아디포넥틴과그렐린유전자다형성 - 전양상을보이는조기남성형대머리가흔하고 [8], 혈중 dehydroepiandrosterone sulfate (DHEAS) 농도가증가되어유전적으로안드로겐과생성이있을가능성이보고되었다 [9]. PCOS의유전양상은아직확실하지않으나, 다유전자의이상에의한것으로생각된다. PCOS의병인으로생각되는스테로이드호르몬생성을조절하는경로 [10,11], 성선자극호르몬의작용을조절하는경로 [12], 인슐린신호전달체계경로 [13~15], 체중조절및에너지이용경로 [16] 에관여하는유전자들이 PCOS의병인후보유전자일가능성이있다 [17]. 그중인슐린저항성과비만에관여하는유전자로아디포넥틴, 그렐린을들수있으며, 특히그렐린은생식기능에도관여하는것으로보고되어있다 [18,19]. 본연구는 PCOS 병인후보유전자중아디포넥틴과그렐린의유전자다형성이 PCOS의유병과관련이있는지를규명하고자하였다. 대상및방법 1. 대상 PCOS 환자 54명과대조군 174명을대상으로하였다. PCOS의진단은 1990년 NIH conference에서정한진단기준에따라 [3], 고안드로겐혈증과연 8회미만의희소월경이있으며쿠싱증후군이나선천성부신과증식이없는경우로하였다. 대조군은 PCOS 환자와연령에필적한여성으로서월경주기가정상이고직계가족중당뇨병의병력이없는정상체중의여성으로하였다. 2. 방법 1) 신체계측과체지방측정모든대상자에서가능한가벼운복장으로신발을벗은상태에서표준화된신장계측기와체중계측기로신장및체중을측정하고, BMI는체중 (kg)/[ 신장 (m)] 2 으로계산하였다. 허리둘레와엉덩이둘레를측정하여허리 / 엉덩이둘레비 (waist to hip ratio, WHR) 를산출하였으며, 허리둘레는마지막늑골하단과배꼽상방의가장짧은둘레를측정하였고, 엉덩이둘레는엉덩이돌출부의가장긴둘레를측정하였다. 혈압은대상자를 5분이상충분히안정시킨후두차례측정하여평균값을구하였다. 내장지방및피하지방면적의측정을위해대상자의제대수준에서전산화단층촬영을하여 Hounsfield number -150 unit에서 -50 unit에속하는부위를합산하여총복부지방면적으로하고복부와배부의복막을경계로안쪽부위를측정하여내장지방면적 (visceral fat area, VFA) 으로하였다. 2) 혈액검사대조군은초기난포기에, PCOS 환자는임의로선정한날 에 8시간이상금식한후다음날아침공복상태에서혈액을채취하였다. 유리테스토스테론, DHEAS, 안드로스테네디온은상품화된키트를사용하여방사면역측정법으로측정하였고 (Diagnostic Products Co., Los Angeles, CA, USA), 성호르몬결합글로불린, 황체호르몬, 난포자극호르몬은방사면역계수법으로측정하였다 (Diagnostic Products Co., Los Angeles, CA, USA). 혈당은포도당분석기 (Backman Model Glucose Analyzer 2, CA, USA) 를이용하여포도당산화법으로측정하였고, 인슐린은상품화된방사면역키트 (Diagnostic Product Co., Los Angeles, CA, USA) 를이용하여측정하였다. 공복총콜레스테롤, 트리글리세리드, 고밀도지단백콜레스테롤은자동분석기 (Hitachi 7150 autochemistry analyzer, Japan) 를이용하여효소법으로측정하였다. 아디포넥틴농도는상품화된키트를이용하여방사면역측정법으로측정하였다 (Linco Research, Inc., St. Charles, MO, USA). 3) 유전자분석 (1) Genomic DNA 추출대상자의말초전혈 4.3 ml을 0.7 ml의 ACE (acid citrate EDTA) 용액이들어있는튜브에채혈하였다. EDTA 튜브에채취한 200 μl의혈액시료에서 QIA amp blood kit (QIAGEN Inc., Hilden, Germany) 을사용하여 genomic DNA를분리하였다. 분광광도계로 260 nm에서흡광도를측정하여 DNA의농도를측정한후중합효소연쇄반응전까지 -20 에보관하였다. (2) 중합효소연쇄반응가. 그렐린유전자 Preproghrelin Leu72Met 유전자다형성은 cysteine (C) 이 adenine (A) 으로치환된변이이다. 중합효소연쇄반응을위해시발체 (primer) 를아래와같이제작하였다. Forward primer: 5 -GCTGGGCTCCTACCTGAGC-3' Reverse primer: 5 -GGACCCTGTTACCTGCCAC-3' 추출한 genomic DNA 0.1 μg과양방향의시발체각각 10 nm, 5 mm의 dntp, Taq DNA 중합효소 (Promega Co., Madison, WI, USA) 0.5 unit, 30 mm MgCl 2, 500 mm KCl, 200 mm Tris-HCl (ph 8.3) 을 20 μl의 PCR 혼합액에첨가하였다. 중합효소연쇄반응은 Gene Amp PCR system 9600 (Perkin-Elmer, Norwalk, USA) 을이용하였으며, 조건은 94 2분으로초기변성후 94 30초, 초, 72 30초를 30회반복하였고, 72 에서 7분간연장반응후종료하였다. 618 염기쌍의중합효소연쇄반응산물을제한효소인 BsrI (New England Biolabs Inc., Berverly, MA, USA) 을사용하여 65 에서 3시간동안반응시켰다. 반응물은 ethidium bromide (0.1 μg/ml) 를포함한 1.5%

3 대한내분비학회지 : 제 21 권제 5 호 2006 agarose 겔에서전기영동하였다. Gel blot을분석하였으며 blot의사진은 ultraviolet densitometry (Gel-Doc and Chemidoc system, Bio-Rad Laboratories, Hercules, CA, USA) 를사용하여출력하였다. 제한효소에의해절단되어 517 염기쌍과 101 염기쌍의두염기밴드가보이면 Leu/Leu 동형접합체로, 유전자변이로인하여제한효소에의해절단되지않은 618 염기쌍만보이는경우 Met/Met 동형접합체로, 이들염기밴드가모두보이는경우 Leu/Met 이형접합체로판독하였다. Amp PCR system 9600을이용하였으며, 조건은 94 2분으로초기변성후 94 30초, 60 30초, 72 30초를 35 회반복하였고, 72 에서 7분간연장반응후종료하였다. 327 염기쌍의중합효소연쇄반응산물을제한효소인 SmaI (New England Biolabs Inc., Berverly, MA, USA) 을사용하여 25 에서 12시간동안반응시켰다. 반응물은 ethidium bromide (0.1 μg/ml) 를포함한 2.0% agarose 겔에서전기영동하였다. Gel blot을분석하였으며 blot의사진은 ultraviolet densitometry를사용하여출력하였다. T 대립형 질을포함하고있는반응물은제한효소 Smal 에의해절단 나. 아디포넥틴유전자중합효소연쇄반응을위해시발체 (primer) 를아래와같이제작하였다. Forward primer: 5 -GAAGTAGACTCTGCTGAGATGG-3' Reverse primer: 5 -TATCAGTGTAGGAGGTCTGTGATG -3' 추출한 genomic DNA 0.1 μg과양방향의시발체각각 10 되지않아 372 염기쌍만을보이며, G 대립형질을포함하고있는산물은제한효소에의해절단되어 216 염기쌍과 156 염기쌍의 DNA절편을보인다. 372 염기쌍만을보이는경우를 TT 동형접합체로, 216 염기쌍과 156염기쌍의두염기밴드가보이면 GG 동형접합체로, 이들염기밴드가모두보이는경우에는 GT 이형접합체로판독하였다. nm, 5 mm 의 dntp, Taq DNA 중합효소 0.5 unit, 30 mm MgCl 2, 500 mm KCl, 200 mm Tris-HCl (ph 8.3) 을 20 μl 의 PCR 혼합액에첨가하였다. 중합효소연쇄반응은 Gene 4) 통계분석통계분석은 SPSS 11.0 프로그램 (SPSS Inc., Chicago, IL, Table 1. Clinical and biochemical characteristics in total subjects Control (n = 174) PCOS (n = 54) Age (yr) 26 ± 3 26 ± 5 Waist (cm) 68.7 ± ± 8.7 * BMI (kg/m 2 ) 21.0 ± ± 3.9 * Systolic blood pressure (mmhg) 114 ± ± 11 Diastolic blood pressure (mmhg) 75 ± 7 76 ± 9 Visceral fat area (cm 2 ) 36 ± ± 42 * Free testosterone (pg/ml) 0.8 ± ± 1.1 * SHBG (nmol/l) 66.2 ± ± 17.9 * DHEAS (μg/dl) ± ± 97.4 Androstenedione (ng/ml) 2.6 ± ± 1.3 * LH (IU/L) 4.6 ± ± 4.8 * FSH (IU/L) 4.1 ± ± 1.5 * Fasting glucose (mg/dl) 82.2 ± ± 7.9 * Postprandial 2 hr glucose (mg/dl) ± ± 27.8 * Fasting insulin (μu/ml) 7.0 ± ± 9.1 Postprandial 2 hr insulin (μu/ml) 24.0 ± ± 38.3 * Total cholesterol (mg/dl) 167 ± ± 33 Triglycerides (mg/dl) 52 ± ± 102 * HDL-cholesterol (mg/dl) 57 ± 8 54 ± 13 Adiponectin (ng/ml) 41.1 ± ± 15.9 Data are mean ± SD. DHEAS, dehydroepiandrosterone sulfate; FSH, follicle stimulating hormone; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; SHBG, sex hormone binding globulin. * P < 0.05 vs. control

4 - 이혜진외 6인 : 한국인다낭성난소증후군환자의아디포넥틴과그렐린유전자다형성 - USA) 을이용하였고측정치는평균과표준편차로표시하였 는환자 (205 ± 195 mg/dl) 에서 TT (78 ± 55 mg/dl) 및 다. 두군의평균을비교하기위하여대응표본 T 검정을실 TG 유전자형을가진환자 (79 ± 82 mg/dl) 에비해트리글 시하였고, 외생변수의효과를통제하기위하여공분산분석을사용하였다. 대조군과환자에서유전자다형성의빈도차 리세리드가증가되어있었다 (P < 0.05). 이들은 BMI를보정한후에도의미가있었다 (Table 3). 이를보기위해교차분석을실시하였다. 유의수준은 P 값을 0.05 미만으로하였다. 고 찰 결 과 본연구는한국 PCOS 환자에서인슐린저항성및비만과 1. 연구대상자의특징유리테스토스테론, 안드로스테네디온, 황체호르몬, 난포자극호르몬은 PCOS 환자에서대조군에비해증가되어있었고, 성호르몬결합글로불린은 PCOS 환자에서대조군에비해감소되어있었다. 공복혈당과당부하 2시간후혈당, 인슐린은 PCOS 환자에서대조군에비해상승되어있었다. 이들은 BMI를보정한후에도유의한차이를보였다 (P < 0.05). 트리글리세리드는 PCOS 환자에서대조군에비해높았으나 BMI를보정한후에통계적의의는없었다. 아디포넥틴농도는 PCOS 환자에서대조군에비해낮은경향을보였다 (P = 0.06)(Table 1). 2. 유전자형그렐린유전자형분포는 PCOS 환자에서 Leu/Leu 73.7%, Leu/Met 21%, Met/Met 5.3%, 대조군에서는 Leu/Leu 73.7%, Leu/Met 24.3%, Met/Met 2.0% 로서 PCOS 환자와대조군사이에차이가없었다. 아디포넥틴유전자형분포는 PCOS 환자에서 TT 34.2%, TG 57.9%, GG 7.9% 였고, 대조군에서 TT 56.7%, TG 40.3%, GG 4.0% 로 PCOS 환자에서대조군에비해 TT 유전자형의빈도가낮고 TG 유전자형의빈도가높았다 (Table 2). PCOS 환자에서아디포넥틴유전자형에따른생식호르몬과아디포넥틴농도의차이는없었으나, GG 유전자형이있 관련된유전자인아디포넥틴, 그렐린유전자다형성과그와관련된표현형을분석하여 PCOS와관련된유전자형을규명하고자하였다. PCOS의가족내호발경향은이질환의유전적소인을시사하고있으나, 그유전양식이나원인유전자는아직정확하게밝혀지지않았다. PCOS의병인과관련된스테로이드호르몬생성을조절하는유전자, 성선자극호르몬의작용을조절하는유전자, 인슐린신호전달체계에관여하는유전자, 체중조절에관련된유전자들이병인후보유전자로서의가능성이있을것이다. 그렐린은위장에서분비되는호르몬으로음식물섭취를촉진시켜체중증가와관련된다 [20]. 그렐린은 PCOS 환자에서감소되어있으며인슐린저항성과관련되어있는것이관찰되었고 [21], PCOS 환자에서안드로겐을감소시키는치료를한후그렐린농도가증가한다는보고도있었다 [22]. 그렐린유전자다형성과비만과의관련성은연구결과마다다양하게나타나일부연구에서는 preproghreiln Met72를포함한유전자다형성이비만을억제한다는결과를보였고 [23,24] 일부연구에서는관련성을입증하지못하였다 [25]. 본연구결과에서그렐린유전자형분포는 PCOS 환자와대조군사이에차이가없었다. 아디포넥틴은 apm1 유전자의산물로동맥경화증을억제하고, 염증반응을감소시키는작용을하는것으로알려져있다 [26~28]. 아디포넥틴은지방세포에서분비되지만, 비만한경우에혈중농도가감소되며체중감소시에혈중농도가증 Table 2. Frequencies of ghrelin and adiponectin genotype in control and women with polycystic ovary syndrome (PCOS) Control (%) (n = 174) PCOS (%) (n = 54) Ghrelin Leu/Leu Leu/Met Met/Met Adiponectin * TT TG GG * P < 0.05 by χ 2 test

5 대한내분비학회지 : 제 21 권제 5 호 2006 Table 3. Clinical and biochemical characteristics according to adiponectin genotype in women with polycystic ovary syndrome TT (n = 19) TG (n = 31) GG (n = 4) Age (yr) 28 ± 5 26 ± 4 29 ± 10 Waist (cm) 77 ± ± 7 73 ± 1 BMI (kg/m 2 ) 22.3 ± ± ± 3.9 Systolic blood pressure (mmhg) 116 ± ± ± 5 Diastolic blood pressure (mmhg) 76 ± ± 9 76 ± 5 Visceral fat area (cm 2 ) 65 ± ± ± 60 Free testosterone (pg/ml) 2.1 ± ± ± 0.5 SHBG (nmol/l) 38 ± ± ± 15 DHEAS (μg/dl) ± ± ± Androstenedione (ng/ml) 4.0 ± ± ± 1.1 LH (IU/L) 9.5 ± ± ± 4.4 FSH (IU/L) 4.9 ± ± ± 1.0 Fasting glucose (mg/dl) 86 ± 9 87 ± 7 86 ± 13 Postprandial 2 hr glucose (mg/dl) 119 ± ± ± 23 Fasting insulin (μu/ml) 7.9 ± ± ± 4.5 Postprandial 2 hr insulin (μu/ml) 27.6 ± ± ± 17.2 Total cholesterol (mg/dl) 183 ± ± ± 49 Triglycerides (mg/dl) 78 ± ± ± 195 * HDL-cholesterol (mg/dl) 56 ± ± ± 12 Adiponectin (ng/ml) 32.4 ± ± ± 10.4 Data are mean ± SD. DHEAS, dehydroepiandrosterone sulfate; FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin. * P < 0.05 vs. TT. P < 0.05 vs. TG. 가되어 [29], 아디포넥틴발현이지방세포에의해하향조절됨을생각할수있다 [27]. 아디포넥틴은인슐린감수성과관련되어있으며, 일본인과피마인디언을대상으로한연구에서아디포넥틴이인슐린저항성의지표와역상관관계를보이는것이관찰되었고이는 BMI를보정한후에도유의한관계를보였다 [30,31]. PCOS 환자를대상으로한연구에서비만한환자는아디포넥틴농도의감소를보였지만, 정상체중환자는인슐린저항성이있음에도혈중아디포넥틴농도가대조군과차이가없어혈청아디포넥틴농도는인슐린감수성자체보다비만도와관련되었다고보고되었다 [32,33]. 본연구결과역시 PCOS 환자가대조군에비해아디포넥틴농도가낮았으나, 정상체중군환자는대조군과유의한차이를보이지않았다. 이는아디포넥틴의혈중농도가인슐린감수성보다는지방조직의변화에더큰영향을받는다는것을생각할수있겠다. 본연구에서아디포넥틴농도는비만한 PCOS 환자에서정상체중 PCOS 환자와대조군에비해낮았으나, 체중을보정한후에는유의한차이가없었다. 아디포넥틴유전자는세개의엑손과두개의인트론으로 구성되어있으며, 유전자 3q27에위치하고있다 [34]. 아디포넥틴유전자변형은비만및인슐린감수성과관련되어있고 [35] 비만과인슐린저항성을특징으로하는 PCOS도아디포넥틴유전자변형과관련되어있을가능성이있다. 본연구에서는아디포넥틴유전자의뉴클레오타이드 94 (exon 2) 에서의 T-G 유전자다형성의분포를분석하였으며, PCOS 환자에서대조군에비해 TG형이유의하게높았고, TT형이유의하게낮았다. 아디포넥틴유전자형에따른호르몬및아디포넥틴농도의차이는없었으나, 아디포넥틴유전자의 GG 변이가있는환자에서 TT, TG 유전자형을가진환자에비해트리글리세리드가높았다. 반면정상대조군에서는아디포넥틴유전자형에따른임상양상의차이를볼수없었다. 따라서 PCOS 환자에서아디포넥틴유전자다형성이이상지혈증등과연관될가능성이있을것으로생각되었다. 아디포넥틴유전자다형성에대한연구는서로다른결과를보이는데, 대만인연구에서 G 대립형질의빈도가비만한환자에서낮고 [36], BMI가 G 대립형질과음의상관관계를보였으며, 일본인과중국인을대상으로한연구에서는 G 대립형질을

6 - 이혜진외 6인 : 한국인다낭성난소증후군환자의아디포넥틴과그렐린유전자다형성 - 가질때더인슐린감수성이좋았다 [37]. 반면서구인을대상으로한연구에서는 GG/GT변이가있는환자에서 BMI가증가되고인슐린감수성도감소되어있었다 [35]. 아디포넥틴 T45G 유전자다형성에대한연구에서는 PCOS 환자가대조군에비해유의하게 GG 변이형의빈도가높았고, G 대립형질을가진 PCOS 환자에서공복인슐린이낮고, 인슐린감수성지표가증가하는경향을보였다 [38]. 이렇게유전자다형성의빈도나임상상이차이를보이는것은연구대상환자들의인종이나대상수, PCOS 진단기준의다양성에기인할것으로생각된다. 결론적으로한국인 PCOS 관련유전자형분석에서아디포넥틴의유전자변형은 PCOS의유병과연관이있었고, 이상지혈증등대사이상과연관될가능성이있었다. 요약연구배경 : 고안드로겐혈증과만성무배란이특징인다낭성난소증후군은가임여성에서흔한내분비질환이나아직그병인은명확하지않으며, 국내다낭성난소증후군 (polycystic ovary syndrome, PCOS) 환자의유전적인소인이나원인에대한연구는없다. 저자들은본연구를통하여 PCOS 환자에서아디포넥틴과그렐린유전자다형성을분석하고자하였다. 방법 : 54명의 PCOS 환자와 174명의정상월경주기를가진건강한여성대조군을대상으로하였다. 생식호르몬과대사인자를측정하였고, 그렐린과아디포넥틴의유전자다형성을분석하였다. 결과 : 그렐린유전자형의분포는 PCOS 환자와대조군사이에차이가없었다. PCOS 환자에서대조군에비해아디포넥틴의유전자 TG형의빈도가유의하게높았고 TT형이유의하게낮았다. GG유전자형을가진 PCOS 환자에서트리글리세리드가 TT 나 TG 유전자형을가진환자에비해유의하게높았고이는 BMI를보정한후에도유의한차이를보였다. 결론 : PCOS 관련유전자형분석에서아디포넥틴의유전자변형은 PCOS의유병및이상지혈증등대사이상과연관되어있었으나향후보다많은수의 PCOS 환자를대상으로한연구가필요할것이다. 참고문헌 1. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapandi ED, Bartzis MI: A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal metabolic profile. J Clin Endocrinol Metab 84: , Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R: Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83: , Zawadski JK, Dunaif A: Diagnostic criteria for polycystic ovary syndrome; towards a rational approach. In: Dunaif A, Givens JR and Haseltine F ed. Polycystic Ovary Syndrome. pp , Blackwell Scientific, Boston, Rotterdam ESHRE/ASRAM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81: 19-25, Legro RS, Spielman R, Urbanek M, Driscoll D, Strauss JF 3rd, Dunaif A: Phenotype and genotype in polycystic ovary syndrome. Recent Prog Horm Res 53: , Givens JR: Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 17: , Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A: Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci. U S A 95: , Abbott DH, Dumesic DA, Franks S: Developmental origin of polycystic ovary syndrome-a hypothesis. J Endocrinol 174:1-5, Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A: Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 87: , Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Willianmson R: Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 6: , Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Willliamson R: Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 3: ,

7 대한내분비학회지 : 제 21 권제 5 호 Franks S: Polycystic ovary syndrome. N Engl J Med 333: , Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T: Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41: , Dunaif A, Xia J, Book CB, Schenker E, Tang Z: Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 96: , Ciaraldi TP, el-roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS: Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 75: , Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 36: , Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss JF 3rd, Spielman RS, Dunaif A: Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A 96: , Tena-Sempere M: Ghrelin: novel regulator of gonadal function. J Endocrinol Invest 28(suppl 5):26-29, Barreiro ML, Tena-Sempere M: Ghrelin and reproduction: a novel signal linking energy status and fertility? Mol Cell Endocrinol 29:1-9, Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR: Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992, Schofl C, Horn R, Schill T, Schlosser HW, Muller MJ, Brabant G: Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 87: , Gambineri A, Pagotto U, Tschop M, Vicennati V, Manicardi E, Crcello A, Cacciar M, De lasio R, Pasquali R: Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome. J Endocrinol Invest 26: , Ukkola O, Ravussian E, Jacobson P, Perusse L, Rankinen T, Tschop M, Heiman ML, Leon AS, Rao DC, Skinner JS, Wilmore JH, Sjostrom L, Bouchard C: Role of ghrelin polymorphism in obesity based on three different studies. Obes Res 10: , Miraglia del Giudice E, Santoro N, Cirillo G, Raimondo P, Grandone A, D'Aniello A, Di Nardo M, Perrone L: Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity. Int J Obes Relat Metab Disord 28: , Ukkola O, Kesaniemi YA: Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus. J Intern Med 254: , Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Novel modulator for endothelial adhesion molecules: adipocyte derived plasma protein adiponectin. Circulation. 100: , Matsubara M, Maruoka S, Katayose S: Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 87: , Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79-83, Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsazawa Y, Chao CL, Chen CL, Tai TY, Chuang LM: Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86: , Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA: Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86: , Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K, Okazaki Y, Ishii T, Nishikai K, Saruta T: Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high density lipoprotein-cholesterol, independent of

8 - 이혜진외 6인 : 한국인다낭성난소증후군환자의아디포넥틴과그렐린유전자다형성 - body mass index, in the Japanese population. Clin Sci (Lond) 103: , Orio F Jr, Palomba S, Cascella T, Milan G, Mioni R, Pagano C, Zullo F, Colao A, Lombardi G, Vettor R: Adiponectin levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88: , Panidis D, Kourtis A, Farmakiotis D, Mouslech T, Rousso D, Koliakos G: Serum adiponectin levels in women with polycystic ovary syndrome. Hum Reprod 18: , Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270: , Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Haring H: Association of the T-G polymorphism in adiponectin (exon2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes 51:37-41, Yang WS, Tsou PL, Lee WJ, Tseng DL, Chen CL, Peng CC, Lee KC, Chen MJ, Huang CJ, Tai TY, Chung LM: Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity. J Mol Med 81: , Yang WS, Hsiung CA, Ho LT, Chen YT, He CT, Curb JD, Grove J, Quertermous T, Chen YD, Kuo SS, Chuang LM: Sapphire Study Group. Genetic epistasis of adiponectin and PPARgamma2 genotypes in modulation of insulin sensitivity: a family-based association study. Diabeologia 46: , Haap M, Machicao F, Stefan N, Thamer C, Tschritter O, Schnuck F, Wallwiener D, Stumvoll M, Haring HU, Fritsche A: Genetic determinants of insulin action in polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 113: ,

3차_JKDA 16권3호 05_( ) 성연아_저자-간행 교정.indd

3차_JKDA 16권3호 05_( ) 성연아_저자-간행 교정.indd J Korean Diabetes 2015;16:189-193 Vol.16, No.3, 2015 ISSN 2233-7431, 이화여자대학교의과대학내과학교실 Epidemiology and Diagnostic Criteria of Polycystic Ovary Syndrome Hyejin Lee, Yeon-Ah Sung Department of Internal Medicine,