大韓不妊學會誌 : 第 32 卷第 4 號 2005 Kor. J. Fertil. Steril., Vol. 32, No. 4, 2005, 12 과체중및비만다낭성난소증후군환자에서의 Metformin 과 Rosiglitazone 의효용성 서울대학교의과대학산부인과학교실 배광범 Effects of Metformin and Rosiglitazone in Overweight or Obese Women with Polycystic Ovarian Syndrome Kwang Bum Bai Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, Korea Objective: The purpose of this study was to evaluate and compare the effects of metformin and rosiglitazone in overweight or obese women with polycystic ovarian syndrome. Methods: Twenty Six overweight or obese patients with polycystic ovarian syndrome were randomly treated with either metformin (500 mg three times daily, n=13) or rosiglitazone (4 mg once daily, n=13) for 6 months. Hormonal studies were performed before and after treatment. Insulin resistances were calculated by computerized HOMA 2 Calculator v2.2. Results: Testosterone decreased while SHBG increased after 6 months treatment in both metformin and rosiglitazone treatment groups. Fasting glucose decreased after metformin or rosiglitazone treatment. HOMA insulin resistance improved after treatment with either drug. There was no differences in hormonal changes and insulin resistance between 2 treatment groups. Conclusions: This study shows that metformin and rosiglitazone are effective in improving insulin sensitivity and ameliorating hyperandrogenism in overweight/obese polycystic ovarian syndrome women. Key Words: Polycystic ovarian syndrome, Metformin, Rosiglitazone, Obese, Insulin resistance 다낭성난소증후군 (polycystic ovarian syndrome) 은무배란및희소월경다모증남성화현상을동반하는가임기여성에서흔히볼수있는질환이며많은다낭성난소증후군환자들에서인슐린저항성및비만을동반하는것이관찰되었다. 1~3 다낭성난소증후군에서인슐린저항성은고인슐린혈증을유도하며비만여성에서는그정도가심한것으로알려져있다. 4 고인슐린혈증은안드로젠분비를촉진시켜다낭성난소증후군에서불임을야기하는한원인으로도작용하게된다. 5,6 인슐린저항성의증가에의한고인슐린혈증은난소에서의 cytochrome p450c 17α 를자극하고혈중 SHBG 농도의감소및유리안드로젠의증가를유발하여남성화현상을심화시킨다. 7,8 인슐린저항성이증가되어있는다낭성난소증후군환자들은내당성이저하되어제2형당뇨병, 주관책임자 : 배광범, 우 ) 156-707 서울특별시동작구신대방동 425, 서울대보라매병원산부인과 Tel: (02) 840-2397, Fax: (02) 831-2826, e-mail: kbbai@snu.ac.kr * 본연구는서울대보라매병원단독연구과제연구비지원에의해수행되었음. - 347 -
이상지혈증, 고혈압및심혈관질환위험성이높은것으로알려져있다. 9,10 다낭성난소증후군이인슐린저항성과밀접한관계가있다는사실이밝혀짐에따라서인슐린감수성을증가시키는제제를사용하여인슐린및당대사를교정하려는방법이시도되고있다. 11 Biguanide 제제인 metformin은제2형당뇨병치료제로알려져있는데간에서포도당생성을감소시키며췌장에자극은주지않으므로저혈당을유발하지않는비교적안전한약제로알려져있다. 12.13 인슐린감작제로새로이개발된 thiazolidinedione 제제는간, 근육, 지방조직등에주로분포하는 peroxisome proliferator-activated receptor γ를통하여인슐린의분비를증가시키지않고인슐린감수성을향상시킨다. 14 Thiazolidinedione 제제중가장처음개발된 troglitazone이간독성이문제가되어사용이금지된이래현재는 pioglitazone과 rosiglitazone이사용중에있다. 과거에다낭성난소증후군환자들에서 metformin과같은약제들은배란율을향상시켜임신율을높이려는목적으로단기간에걸쳐사용되곤하였다. 인슐린저항성이있는다낭성난소증후군환자들이대사증후군의범주에속하는확률이일반인에비해현저하고이들은차후에제2형당뇨병을비롯한성인병으로발전하여심혈관질환으로귀결된다는연구들이보고되고있다. 이에저자는대사증후군으로발전할가능성이많은과체중및비만의다낭성난소증후군여성에서 metformin과 rosiglitazone의치료효과를개별적및상호비교하여이들약제가불임증이외의대사장애및내분비장애의예방및치료목적으로유용한지를알아보고자본연구를시행하였다. 연구대상및방법 1. 연구대상 2003년 11월부터 2005년 3월까지보라매병원산부인과에내원하여다낭성난소증후군으로진단을받고지속적인관리하에있던여성들중체질량지수 23 이상의과체중및비만환자들만선택하였으며임신을원하는경우는연구대상에서제외시켰 다. 다낭성난소증후군의진단기준은희소월경 / 무월경, 고안드로젠혈증이나기타남성화현상, 초음파검사에의한다낭성난소의존재의확인의 3 가지요소증 2개이상을만족시킬경우로하였다. 15 대상들중내과적만성질환환자나기타내분비에영향을줄약물을복용하고있는경우제외시켰으며, 공복혈당치 110 mg/ml 이상일경우에는연구에포함시키지않았다. 대상환자들은무작위추출에의해 metformin 투여군과 rosiglitazone 투여군으로나누었고 6개월간의치료를계속한 26명을평가하였다. 2. 연구방법 Metformin 군은 500 mg 1일 3회를, rosiglitazone 군은매일 4 mg을각각 6개월간복용시켰다. 대상환자들은치료개시전과 6개월치료종료시계획된검사를시행하였다. 비만도를알기위하여신장체중복부둘레체질량지수를측정하였고기본적인채혈검사외에 LH, FSH, 테스토스테론, SHBG, DHEA-S를치료전및치료종료시 2회조사하였다. 인슐린저항성에관해서는공복혈당량과공복인슐린치를측정하였다. 인슐린저항성및췌장베타세포기능의평가는 2004년에새롭게개선된 HOMA 2 Calculator (version 2.2) 에의해자동으로계산하였다. 각군간의비교는 Mann-Whitney test를군내에서의변화의비교는 paired student's t test를 SPSS 패캐지를사용하여계산하였다. 결과 1. 임상적특성및내분비변화다낭성난소증후군환자들이흔히병원에내원하게되는불임이주소가아닌여성들을대상으로하여서양쪽대상자들은 30대중반의연령분포를보이고있으며, 체질량지수 23 이상의과체중및비만환자들이였다. LH와 FSH의경우 6개월의치료후 metformin 및 rosiglitazon 군모두에서 LH 농도의감소를관찰하였으나 FSH는큰변화를보이지않았다. 치료군간에치료전및치료후의 LH 및 FSH의차이는관찰할수가없었다. - 348 -
Table 1. Clinical and hormonal characteristics of the patients Metformin Rosilgitazone Baseline 6 Months Baseline 6 Months Age (years) 32.5±4.6 32.9±5.1 BMI (kg/m 2 ) 26.7±2.2 26.2±2.4 26.8±1.9 27.0±2.0 Abdominal circumference (cm) 82.5±6.5 81.4±6.1 82.8±7.5 82.9±7.1 LH (miu/ml) 7.4±1.5 5.9±1.2 a 7.7±1.7 5.8±1.4 a FSH (miu/ml) 5.3±1.2 5.1±1.1 5.5±1.4 5.6±1.3 Testosterone (ng/ml) 0.55±0.15 0.43±0.13 a 0.57±0.16 0.40±1.15 a SHBG (nmol/l) 31.5±5.6 41.2±7.7 a 30.5±7.7 43.3±8.5 a DHEA-S (ng/ml) 2107±350 2035±370 2076±290 2015±420 Values are means ± SEM, a p<0.05 compared with baseline value Table 2. Metabolic parameters about insulin resistance Metformin Rosilgitazone Baseline 6 Months Baseline 6 Months Fasting glucose (mg/dl) 90.3±9.4 89.3±9.0 90.9±8.6 89.5±9.4 Fating insulin (µu/ml) 17.2±7.3 10.5±3.3 a 16.5±6.5 10.1±2.5 a HOMA beta cell function (%B) 163.4±16.1 119.4±10.5 a 156.8±15.0 115.8±7.5 a HOMA IR 2.2±0.9 1.4±0.2 a 2.1±0.8 1.3±0.3 a Values are means ± SEM, a p<0.05 compared with baseline value 두군모두에서치료후에테스토스테론은감소하였고, SHBG는증가하였으나 metformin과 rosiglitazone 군간에차이는없었다. DHEA-S의경우치료전후및약제에따른변화는관찰되지않았다 (Table 1). 2. 인슐린저항성및베타세포기능공복혈당의경우 metformin이나 rosiglitazone 군에서약간씩감소하였으나유의한차이는없었고치료군간에차이점도관찰할수가없었다. 공복인슐린농도는 metformin 군에서 17.2±7.3 µu/ml에서 10.5±3.3 µu/ml로 rosiglitazone 군에서는 16.5±6.5 µu/ml에서 10.1±2.5 µu/ml로개선되었으며두치료군간에농도의차이는관찰되지않았다. HOMA 2 calculator (version 2.2) 에의하여자동적으로산출되는 HOMA 베타세포기능성은 metformin은 163.4±16.1% 에서 119.4±10.5% 로 rosiglita- zone은 156.8±15.0% 에서 115.8±7.5% 로유의하게감소하여이들약제에의해서췌장의베타세포의과부하가상당히개선됨을알수있었으나두치료군간에차이는발견할수없었다. HOMA IR은과거에는공복인슐린 (µu/ml) 공복혈당 (mmol/l)/22.5 공식을이용하여산출하였으나개선된 HOMA 2 calculator (version 2.2) 를이용하여자동계산이가능한데 metformin 군에서는 2.2± 0.9에서 1.4±0.2로 rosiglitazone 군에서는 2.1±0.8에서 1.3±0.3으로인슐린저항성이완화됨을알수있었다. 양군간의완화의정도에유의한차이는나타나지않았다 (Table 2). 고찰다낭성난소증후군에서고인슐린혈증이중요한역할을하는데인슐린은난소를자극하여안드로젠 - 349 -
을증가시킨다. 15 인슐린에의해자극된난포막세포는테스토스테론생성에관여하고외부에서인위적으로인슐린을투여하면안드로젠농도가상승하는것이관찰되고, 인슐린은간에서의 SHBG 생성을억제하여유리테스토스테론이증가한다고알려져왔다. 16,17 당뇨병환자에주로사용되던인슐린감작제제들은인슐린저항성을개선하고고인슐린혈증을완화하기때문에다낭성난소증후군여성에서배란유도용으로도사용되고있다. 18,19 Metformin은다낭성난소증후군환자들에최초로사용된인슐린감작제인데체중감소의효과가있는반면위장장애와같은부작용을초래하기도하며비만도가높은여성에서는효능이떨어진다고보고되었다. 20,21 Thiazolidinedione 제제중최초로개발된 troglitazone은당뇨병치료이외에다낭성난소증후군환자에사용시배란율이증가하였고내분비이상에효과가있다고알려져있고배란율, 다모증, 고안드로젠혈증, 인슐린저항성이약용량에비례하여개선되는연구가보고되었다. 22 본연구에서는 metformin 군과 rosiglitazone 군에서공복인슐린농도가감소되어인슐린감수성개선의결과가나타났고 LH, 테스토스테론, SHBG 농도가유의하게변화하였으나양치료군간의차이는관찰되지않았고이는 troglitazone 14,22 혹은 metfromin을연구약제로사용한다른연구들과일치하는소견을보였다. 23~25 한편 pioglitazone과 metformin의효과를비교분석하여 pioglitazone이 metformin에비해서공복인슐린농도및 area under curve(auc)-insulin을유의하게감소시켜인슐린감수성효능이뛰어나다는보고가있었는데, 26 본연구에서는두약물간에차이가관찰되지않았다. 이는선택된약의종류, 용량및용법의차이와각각의연구에서대상자들의비만도및인슐린저항성정도등이근본적으로다른것에기인한다고생각된다. 본연구대상자들은평균 26.7 및 26.8의체질량지수를가진여성들인반면타연구들에서는보통 35이상의체질량지수의고도비만을대상으로선택하여 metformin 효과가 rosiglitazone이나 pioglitazone에비해미약하게나타난것으로추정된다. 20,21 Metformin은초기치료시체중감소가나타나는반면 thiazolidinedion 제제는미약한체중증가가나타나는데인슐린저항성의개선이나안드로젠농도의감소효과는유사하거나 thiazolidinedion 제제가약간우수하다고알려져있다. Thiazolidinedione 제제의경우복부지방을기타피하조직으로이동시켜결과적으로인슐린저항성이감소하기때문이다. 27~29 본연구에서는 metformin 군에서유의하지는않지만체중이약간감소하였고 rosiglitazone 군은별변화가없었는데이역시연구대상자들이고도비만이아니어서그효과가미약하였거나 metformin 제제의체중감소효과가그다지크지않기때문인것으로추정된다. HOMA (Homeostasis Model Assessment) 지수는공복혈당과공복인슐린을이용하여인슐린저항성을평가하는방법으로비교적간단한공식인 HOMA 지수 = 공복인슐린 (µu/ml) 공복혈당 (mmol/l)/ 22.5에의하여측정하였으나최근에는 HOMA 2 calculator (v2.2) 버전을무료로다운받아사용할수있게되었다. 30 HOMA 2 calculator를이용하면과거공식에의한 HOMA 지수의문제점을상당히극복하고실제에가까운췌장베타세포기능및인슐린저항성을측정할수있는장점이있다. 본연구에서는인슐린저항성이양치료군에서치료전에 2.2 및 2.1로증가되어있었는데 ( 표준치 1.0) 이는표준체중이상인다낭성난소증후군환자들의경우공복혈당치가 90 mg/dl 정도의정상치를유지함에도불구하고인슐린저항성은증가되어있음을의미하고이경우약물치료를실시하면인슐린저항성이 1.4 및 1.3으로정상가까이감소하는것을관찰하였다. 결론적으로과체중및비만의다낭성난소증후군여성들에서인슐린감작제인 metformin이나 rosiglitazone은인슐린감수성을증가시키고고안드로젠증을완화시키는유용한제제로서건강및삶의질향상에큰도움이된다고사료된다. 참고문헌 1. Franks S. Polycystic ovary syndrome. N Engl J Med - 350 -
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