대한임상건강증진학회지제 9 권제 1 호 2009 Korean J Health Promot Dis Prev Vol. 9, No. 1, 2009 [ 원저 ] 한국폐경여성에서생물학적스트레스지표와대사증후군의요소 최영근, 오한진, 주일우 관동대학교의과대학제일병원가정의학과 Biologic Stress Markers and Components of Metabolic Syndrome in Postmenopausal Korean Women Younggun Choi, Hanjin Oh, Ilwoo Joo College of Medicine, Kwandong University Dept. of Family Medicine, Cheil General Hospital Background Methods Results Conclusions Key words The key pathophysiology of metabolic syndrome (MS) is insulin resistance. Chronic stress may induce increased insulin resistance, high blood glucose, visceral obesity, and high blood pressure via increased cortisol levels from chronic activation of the hypothalamus-pituitary-adrenal axis (HPA axis). However, the relationships between cortisol, dehydroepiandrosterone sulfate (DHEA-S), and cortisol)/dhea-s and each of the components of MS have not yet been thoroughly investigated. In our study, we evaluated the relationships between cortisol, DHEA-S, and cortisol/dhea-s as biologic stress markers and components of MS in postmenopausal Korean women. This study was a cross-sectional analysis of 223 postmenopausal women who visited our climacteric clinic at a university hospital in Seoul with stressful events. These women were seen between January 2001 and March 2008. Metabolic syndrome was diagnosed according to the NCEP-ATP III criteria using body mass index (BMI) instead of waist circumference. We evaluated the relationships between each biological stress marker and the components of MS. Independent t-tests were conducted on each cut-off point of the MS components. The study population was classified as normal subjects (no MS components) or MS subjects (>3 MS components). Mean differences in biologic stress markers between normal and MS subjects were evaluated by independent t-tests. Cortisol levels were positively associated with FPG (p=0.01), and DHEA-S levels were negatively associated with TG (p=0.019), but not with the other components of MS. DHEA-S levels showed statistically significant mean differences from BMI, FPG, TG, and HDL-C (p=0.022; p=0.004; p=0.012; p=0.010) by independent t-tests. Significant mean differences in DHEA-S and cortisol/dhea-s between normal subjects and MS subjects were also observed (p=0.0002, p=0.039), but the mean difference in cortisol was not significant. It has been hypothesized that persistent chronic psychosocial stress may be a causative factor of MS. Unfortunately, we were unable to look into this hypothesis because of the limitations of the cross-sectional design. However, this study suggests that DHEA-S levels and MS might be meaningfully correlated. (Korean J Health Promot Dis Prev 2009 ; 9(1):50-55) metabolic syndrome, stress, cortisol, DHEA-S 교신저자 : 주일우 주소 : 중구묵정동 1-19 제일병원가정의학과 전화 : 02-2000-7159 E-mail : yeora@unitel.co.kr 접수일 : 2008년 10월 1일 채택일 : 2008년 12월 5일 1) 서론대사증후군은심혈관질환의발생과밀접한관련성을가지고있다. 1,2) 대사증후군은 1988년 Reaven GM에의해처음기술된이후로많은관심과임상적의의를가지게되었다. 3) 50
[Biologic Stress Markers and Components of Metabolic Syndrome in Postmenopausal Korean Women] 대사증후군의유병률은사용되는진단기준에따라같은연구집단에서도차이를보이지만진단의핵심요소는대체로복부비만, 고중성지방혈증, 낮은 HDL 콜레스테롤, 고혈압, 고혈당이다. 실제로많은환자들에서질환이한가지만존재하기보다는비만, 고혈압, 당뇨병, 고지혈증과같은여러질환이공존하고있는경우가많다. 또한여러대사이상을보이는대사증후군의핵심병리기전은인슐린저항성으로생각되어지고있으며 4), 유전적인자와더불어여러환경인자및생활습관이대사증후군을유발하는것으로추정되어진다. 5,6) 스트레스에대한우리몸의반응은자율신경계와시상하부- 뇌하수체-부신축에의한내분비계에의해나타난다. 코르티솔 (cortisol), DHEA-S, 또는코르티솔 (cortisol)/dhea-s 는여러급, 만성스트레스에대한연구지표로활용되어왔다. 7-9) 특히 DHEA 는 ACTH-regulated steoid 로서스트레스에따른 anti-glucocorticoid property를나타내므로최근스트레스에대한민감도가우수한것으로입증된바있다. 8-9) Brunner 등은대조군연구를통해대사증후군에서코르티솔 (cortisol) 레벨의상승과카테콜라민분비증가, 심장의교감신경계우세성을입증하였다. 5) 스트레스에의한교감신경계이상은심장과큰혈관에영향을주어혈압의상승과근육에서포도당을흡수하는데장애를일으켜인슐린감수성을저하시킨다. 10,11) 또한근골격계의교감신경계항진은근육으로가는영양혈류의흐름을저해하여지단백분해효소의접근성이떨어져이상지혈증이나타나는데기여를한다. 급, 만성스트레스에대한반응으로코르티솔 (cortisol) 레벨이상승하여 hypercortisolemia 가초래되면조직에지나친코르티솔 (cortisol) 노출로비만을일으킬수있다. 12) 이처럼스트레스로인해나타나는우리몸의반응은스트레스가대사증후군을유발하는원인또는악화인자가될수있다는가설을가능하게한다. 13,14) 이에본연구는대사증후군과스트레스와의연관성을밝히기위해대사증후군의요소와생물학적스트레스지표인코르티솔 (cortisol), DHEA-S, 코르티솔 (cortisol)/dhea-s와의연관성을살펴보고나아가정상군과대사증후군간의차이가있는지확인해보고자하였다. 1. 연구대상 방법 2001년 1월부터 2008년 3월까지서울시내일개종합병원에스트레스를주소로내원하여코르티솔 (cortisol) 과 DHEA-S 검사가시행된폐경후여성 293명을대상으로하였다. 폐경은마지막 생리후 1년이경과하고여포자극호르몬 (follicular stimulation hormone) 이 40 miu/ml 이상인경우로정의하였다. 스트레스의정의는매우모호하다. 본연구에서사용되는스트레스라는용어는 Chrosus, Gold 그리고 McEwen 이제시한 항상성을위협받는상태 를의미하며, 만성스트레스는 항상성에대해장기적으로반복되는붕괴 를뜻한다. 15,16) 특히본연구는육체적스트레스가아닌정신사회적스트레스에한정하고있다. 환자들은대부분남편과의갈등, 이혼, 경제적어려움, 자녀와의갈등등장기적인생활스트레스를주소로내원하였다. 대상환자중정신분열증이나조울증과같은심각한정신과적질환, 갑갑상선질환이있는경우, AST(aspartate aminotransferase) 또는 ALT(Alanine aminotransferase) 수치가 100 이상인경우, Creatinine이 1.5이상인경우를제외하였고, 나이가 45세미만이거나 60세이상인환자는제외하였다. 따라서선정된 293명중 70명이배제되고총 223명이연구대상군으로확정되었다. 2. 연구방법 대상환자들로부터연령과체질량지수 (kg/m 2 ), 공복혈당, 총콜레스테롤, 중성지방, HDL 콜레스테롤, LDL 콜레스테롤, 혈압을측정하였고생물학적스트레스지표로코르티솔 (cortisol), DHEA-S 및코르티솔 (cortisol)/dhea-s 를확인하였다. 신장및체중은가벼운옷을입은상태에서신체계측기와전자체중계를사용하였으며체중을신장의제곱으로나누어체질량지수를계산하였다. 혈압은환자가충분히안정을취한후심장과같은높이에서동일검사자에의하여측정되었으며초진과이후 2회내원시측정된혈압의평균값으로하였다. 혈액검사는대상자가 8시간이상금식후시행되었으며, 공복혈당은 glucose oxidase법을이용하여측정하였고, 지질농도는자동분석기 (Hitachi 7150, Tokyo, Japan) 로분석하였다. HDL, LDL 콜레스테롤의분류는침전기법으로고밀도지단백콜레스테롤을먼저효소법으로측정후 choelstest-ldl 을실시하였다. 혈청코르티솔 (cortisol) 과 DHEA-S 는아침 9시에서 10시사이에채취되어방사면역측정법 (N-tactosteo SP, INCSTAR Corp., Stillwater, MN) 을사용하여측정되었다. 대사증후군은NCEP-ATP III 진단기준 17) 을사용하되허리둘레대신체질량지수를적용하여다음다섯가지중세가지이상인경우로하였다. 1) 비만, 체질량지수 25.0 kg/m 2 인경우로정의하였다 ; 2) 높은혈압, 수축기혈압이 130 mmhg 이상이거나혹은이완기혈압이 85mmHg 이상인경우 ; 3) 고중성지방혈증, 공복혈청중성지방레벨이 150 mg/dl 이상인경우 ; 4) 낮은 HDL 콜레스테롤, 혈청 HDL 콜레스테롤이 51
[ 한국폐경여성에서생물학적스트레스지표와대사증후군의요소 ] 50 mg/dl 미만인경우 ; 5) 고혈당상태, 공복혈장포도당레벨이 110 mg/dl 이상인경우. 3. 통계분석 HDL 콜레스테롤은 57.5±10.8[S.D.]mg/dL, 혈압은 129.2/82.0±10.7/ 8.1[S.D.]mmHg 이었다. 혈청코르티솔 (cortisol) 은 8.94±3.44, DHEA-S 는 68.08±35.96이었으며, 코르티솔 (cortisol)/dhea-s는 0.174±0.127이었다 (Table 1). 생물학적스트레스지표와각대사증후군의요소와의상관성을밝히기위해 Pearson 상관계수가사용되었다. 각각의대사증후군의요소에서경계점을기준으로생물학적지표의평균간차이가있는지알아보기위해독립표본 T-test 가사용되었다. 마지막으로대상환자들을대사증후군의요소수가 3개이상인경우와그미만인경우로각각대사증후군환자와정상군으로나누었을때생물학적스트레스지표들의각군간평균이유의한차이가있는지알아보기위해독립표본 T-test 가사용되었다. 모든통계분석은 SPSS version 12.0 (for windows) 을이용하였으며 P value 0.05 미만을통계학적으로유의하다고간주하였다. 결과 1. 연구대상자들의일반적특징대상군의평균연령은 53.5±4.4[S.D.]( 범위 47~59) 세이며평균체질량지수는 23.5±3.0[S.D.]kg/m 2 이었다. 공복혈당의평균은 99.0±21.3[S.D.]mg/dL 이었고중성지방은 132.7±67.0[S.D.]mg/dL, 2. 생물학적스트레스지표와대사증후군요소와의상관성 코르티솔 (cortisol), DHEA-S 그리고코르티솔 (cortisol)/dhea-s 와대사증후군의요소간의상관성에대해살펴보면코르티솔 (cortisol) 은공복혈당과유의한양의상관관계 (r=0.170, p=0.010) 가있었고, DHEA-S는중성지방과유의한음의상관관계 (r=-0.155, p=0.019) 를보였다 (Table 2). Table 2. Relationships between biologic stress markers and components of metabolic syndrome cortisol DHEA-S cortisol/dhea-s r values (s) BMI (kg/m 2 ) 0.025 (0.702) -0.068 (0.303) 0.039 (0.557) FPG (mg/dl) 0.170 (0.010)* 0.010 (0.878) 0.032 (0.635) TG (mg/dl) 0.093 (0.161) -0.155 (0.019)* 0.110 (0.096) HDL-C (mg/dl) 0.041 (0.538) 0.111 (0.095) 0.024 (0.715) SBP (mmhg) 0.047 (0.481) -0.050 (0.450) 0.061 (0.359) DBP (mmhg) 0.057 (0.389) -0.078 (0.240) 0.071 (0.284) * p < 0.05 Table 3. Independent t-test comparing biologic stress markers and components of metabolic syndrome Table 1. Characteristics of the study population (mean ± S.D.) Total (n=223) Range Age (yrs) 53.54 ± 4.37 47-59 BMI (kg/m 2 ) 23.52 ± 2.97 16.7-35.2 FPG (mg/dl) 99.00 ± 21.30 65-320 TC (mg/dl) 209.69 ± 37.02 105-346 TG (mg/dl) 132.68 ± 66.99 39-496 HDL-C (mg/dl) 57.50 ± 10.79 28-100 LDL-C (mg/dl) 125.71 ± 33.34 34.6-267.2 SBP (mmhg) 127.18 ± 11.76 90-170 DBP (mmhg) 81.90 ± 7.08 50-110 cortisol (μg/dl) 8.94 ± 3.44 2-24 DHEA-S (μg/dl) 68.08 ± 35.96 4-188 cortisol/dhea-s 0.174 ± 0.127 0.03-0.82 BMI = body mass index, FPG = fasting plasma glucose, TC = total cholesterol, TG = triglyceride, HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol, SBP = systolic blood pressure, DBP = diastolic blood pressure, DHEA-S = dehydroepiandrosterone sulfate. BMI 25 <25 FPG 110 <110 TG 150 <150 HDL-C <50 50 SBP 130 <130 DBP 85 <85 * p<0.05 cortisol DHEA-S cortisol/dhea-s Mean ± S.D. 9.09 ± 3.20 8.89 ± 3.52 0.707 10.08 ± 4.07 8.72 ± 3.28 0.065 9.30 ± 4.33 8.79 ± 2.30 0.381 8.92 ± 3.41 8.98 ± 3.56 0.912 9.14 ± 3.43 8.70 ± 3.46 0.341 9.52 ± 3.55 8.72 ± 3.38 0.113 59.61 ± 29.19 70.84 ± 37.57 0.022* 56.25 ± 23.45 70.30 ± 37.48 0.004* 58.84 ± 32.79 71.93 ± 36.61 0.012* 71.26 ± 37.35 58.54 ± 29.73 0.010* 65.30 ± 34.44 71.45 ± 37.62 0.200 66.68 ± 36.11 68.61 ± 35.70 0.718 0.20 ± 0.12 0.17 ± 0.13 0.130 0.20 ± 0.10 0.17 ± 0.13 0.141 0.20 ± 0.11 0.16 ± 0.13 0.097 0.17 ± 0.13 0.19 ± 0.12 0.227 0.18 ± 0.12 0.16 ± 0.13 0.251 0.18 ± 0.10 0.17 ± 0.14 0.681 52
[Biologic Stress Markers and Components of Metabolic Syndrome in Postmenopausal Korean Women] Table 4. Independent t-test comparing normal subjects and those with metabolic syndrome cortisol DHEA-S cortisol/dhea- S Mean ±S.D. Normal 8.80 ± 3.38 71.24 ± 37.44 0.17 ± 0.13 MS 9.56 ±3.69 53.66 ± 23.67 0.21 ± 0.11 0.202 <0.001* 0.039* Normal: number of metabolic components < 3 MS: metabolic syndrome, number of metabolic components 3 * p<0.05 3. 분리점을사용한평균비교 다섯개의대사증후군요소각각에대해정의에따른분리점을사용하여두군으로나누어코르티솔 (cortisol), DHEA-S, 그리고코르티솔 (cortisol)/dhea-s 의두집단간평균의차이가있는지독립표본 T-test 를통해알아보았다. 코르티솔 (cortisol) 과코르티솔 (cortisol)/dhea-s는어떤요소에서도유의한평균차이를보이지않았다. 그러나 DHEA-S 는다섯요소중혈압을제외한네가지요소에서유의한평균차이 ( 체질량지수, p=0.022; 공복혈당, p=0.004; 중성지방, p=0.012; HDL-C, p=0.010) 를보였다 (Table 3). 독립표본 T-test 를이용하여대상군을요소수가 3개이상인대사증후군과 2개이하인정상군으로분류하여평균비교를하였다. 코르티솔 (cortisol) 은정상군과대사증후군간에유의한차이가없었으나 DHEA-S 와코르티솔 (cortisol)/dhea-s에서는두군간에유의한차이 (p<0.001, p=0.039) 가있었다 (Table 4). 고찰 스트레스에대한자율신경계의반응은맥박과혈압상승식욕감소및장운동의저하로나타나고, 내분비반응인시상하부- 뇌하수체-부신축은부신피질의글루코코르티코이드를분비하여우리몸의항상성과스트레스반응을조절한다. 급성스트레스에대한이러한우리몸의반응은좋은측면으로는한개체의생존을도모하고감정적, 지적성장과발전을향상시키는긍정적기능을가지고있다. 18) 그러나, 개체가감당할수없는조절불가능한위협적상황에노출되거나만성적인스트레스상황에놓이는경우시상하부- 뇌하수체- 부신축의만성적인활성화를초래하여감정적, 신체적질환을초래할수도있다. 19-21) 스트레스에대한반응중내분비반응인시상하부-뇌하수체-부신축의활성화는비만, 우울증, 대사증후군과같은질환과유사한병태생리를공유하고있다. 22) 여러역학자료들은코르티솔 (cortisol) 수 치와대사증후군의핵심요소들간의양의상관관계에대해밝히고있으며, 코르티솔 (cortisol), DHEA 또는 DHEA-S 는스트레스를연구한많은논문들에서생물학적지표로사용되어왔다. 특히 DHEA 는 ACTH-regulated steoid로서스트레스에따른 anti-glucocorticoid property를나타내므로최근스트레스에대한민감도가우수한것으로입증된바있다. 8-9) 본연구는만성적인스트레스와대사증후군사이의연관성을생물학적스트레스지표인코르티솔 (cortisol), DHEA-S 및코르티솔 (cortisol)/dhea-s로알아보고자하였다. 본연구의결과에서코르티솔 (cortisol) 은공복혈당과양의상관관계를보였으나그외의대사증후군요소와는통계학적유의성이없었고독립표본 T-test 에서도유의한평균차이를보이는요소는없었다. DHEA-S는중성지방과음의상관관계를보였으며, 독립표본 T-test 에서체질량지수, 공복혈당, 중성지방, HDL 콜레스테롤의분리점에서유의한평균차이를볼수있었다. 급성스트레스로유발된 Hyper 코르티솔 (cortisol)ism은고혈당, 비만, 고중성지질혈증, 낮은 HDL 콜레스테롤과상관성을보인다. 23-24) 또한만성적인스트레스노출로반복되는부신피질자극호르몬의분비는부신의민감성을증가시켜분비되는코르티솔 (cortisol) 의양을증가시킬수있다. 25) 본연구에서는대사증후군과연관된비만관련인자나이상지혈증이코르티솔 (cortisol) 과는연관성이없는것으로나타났으나향후코르티솔 (cortisol) 의일주기에따른측정방법을통해그관련성을확인해야할것으로생각된다. 반면코르티솔 (cortisol) 과공복혈당간의양의상관관계결과는만성적인스트레스노출에의해증가된새벽의코르티솔 (cortisol) 레벨이오전공복시에측정되는혈당치에영향을주어나타난결과로생각되어진다. DHEA 역시부신피질자극호르몬에의해분비되는부신피질의스테로이드호르몬이다. 26) 혈청 DHEA 와 DHEA-S 의나이와연관된현저한감소는노화와관련된질환들과원인적연관성이있을수있다는것을시사한다. 27) 체질량지수와 DHEA 간에는음의상관관계를보이는것으로여겨지지만 28-30), DHEA-S의경우그결과가일치하지않는다. Barrett-Connor 와 Ferrara 는 659명의폐경후여성을대상으로한연구에서체질량지수와 DHEA-S 간에음의상관관계 (r=-0.06) 를보인다고하였다. 29) 본연구에서체질량지수와 DHEA-S 간에 Pearson 상관계수는 -0.068이었으나통계학적유의성은없었다 (p=0.303). 이는폐경후특정연령의여성만을대상으로한연구자료의한계성으로생각된다. 본연구에서는복부비만의진단지표로사용되었어야할허리둘레대신체질량지수를사용하였다. 체질량지수역시여러 53
[ 한국폐경여성에서생물학적스트레스지표와대사증후군의요소 ] 연구에서당뇨의발생과대사이상등을예측하는데좋은결과를보였다. 31-34) 그러나대사증후군의요소인허리둘레를체질량지수로대체한것이본연구의한계성의하나임을인정할수밖에없다. 이상에서살펴본본연구의제한점은다음과같다. 1) 단면연구이기때문에만성스트레스와대사증후군간의인과관계에대한설득력이부족하며선택편견의오류가능성을배제할수없다. 2) 코르티솔 (cortisol) 의측정방법이일중변동을반영하지못하였다. 3) DHEA-S 의결과해석에노화에따른연령의영향이있을수있다. 4) 체질량지수를허리둘레의대체지표로사용한것에이의를제기할수있다. 그러나본연구가만성스트레스와대사증후군간의선후관계를명확히입증할수는없으나대사증후군의요소와연관된 DHEA-S 의유의한차이는만성스트레스와대사증후군간의연관가능성을시사한다고볼수있다. 이는대사증후군등의유발에정신적인스트레스가영향을미친다는것을간과해서는안됨을주지시키고있으며이를위한향후코르티솔 (cortisol) 및 DHEA 의일중변동을고려한대규모의전향적연구가필요할것이다. 보이고중성지방과 DHEA-S 간에는음의상관관계 (p=0.019) 를보였다. 대사증후군의요소각각에대해정의에따른분리점을사용하여두군으로나누어생물학적지표의두집단간평균비교를했을때 DHEA-S 만이혈압을제외한네가지요소에서유의한평균차이 ( 체질량지수, p=0.022; 공복혈당, p=0.004; 중성지방, p=0.012; HDL-C, p=0.010) 를보였다. 대상환자를정상과대사증후군으로구분하여비교하였을때 DHEA-S 와코르티솔 (cortisol)/dhea-s의집단간평균이유의 (p<0.001, p=0.039) 한차이가있었다. 결론본연구결과가만성스트레스와대사증후군간의인과관계를명확히밝힐수는없으나 DHEA-S 의대사증후군의요소증가에따른유의한차이와각요소와의관련성은만성스트레스와대사증후군간의밀접한연관성을시사한다고볼수있다. 향후대규모의구체화된실험적연구가필요할것이다. 중심단어 연구배경 요약 대사증후군, 스트레스, 코르티솔, DHEA-S, 코르티솔 (cortisol)/ DHEA-S 대사증후군의핵심병리기전은인슐린저항성이다. 만성스트레스는뇌하수체-시상하부-부신축의활성화로코르티솔 (cortisol) 수치의증가를유발하여혈당상승, 인슐린저항성의증가및혈압의상승을초래할수있다. 이에우리는폐경이란특수상황을공통적으로겪은폐경후여성을대상으로대사증후군의요소와생물학적스트레스지표인코르티솔 (cortisol), dehydroepiandrosterone(dhea-s), 그리고코르티솔 (cortisol)/dhea-s와의연관성에대해알아보고자하였다. 방법 2001년 1월부터 2008년 3월까지서울시내일개종합병원에스트레스를주소로내원한폐경후여성 223명을대상으로하였다. 대사증후군은 NCEP-ATP III 진단기준을적용하되허리둘레대신체질량지수를사용하였다. 생물학적스트레스지표들과대사증후군의요소과의상관성에대해확인하였다. 결과공복혈당은코르티솔 (cortisol) 과양의상관관계 (p=0.01) 를 참고문헌 1. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-16. 2. Laaksonen DE, Lakka HM, Niskanen KL, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes: application and validation of recently suggested definitions of the metabolic syndrome in a prospective Cohort study. Am J Epidemiol. 2002;156:1070-7. 3. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-607. 4. Hanley AJ, Wagenknecht LE, D Agostino RB Jr, et al. Identification of subjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome. Diabetes. 2003;52:2740-7. 5. Brunner EJ, Hemingway H, Walker BR, et al. Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study. Circulation. 2002;106:2659-65. 6. Rosmond R. Role of stress in the pathogenesis of the metabolic syndrome. Psychoneuroendocrinology. 2005;30:1-10. 54
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