多囊卵巢綜合征患者血清游離脂肪酸水平測定及其相關因素分析

宋 穎,李啟富,田 波,鐘 立,楊淑敏,夏 偉,畢小云

(重慶醫科大學附屬第一醫院1.內分泌科;2.檢驗科 400016)

多囊卵巢綜合征患者血清游離脂肪酸水平測定及其相關因素分析

宋 穎1,李啟富1,田 波1,鐘 立1,楊淑敏1,夏 偉1,畢小云2△

(重慶醫科大學附屬第一醫院1.內分泌科;2.檢驗科 400016)

目的分析多囊卵巢綜合征(PCOS)患者血清游離脂肪酸(FFAs)水平的變化,并探討其相關因素?方法 納入133例PCOS患者及116例年齡匹配的健康女性,測量身高?體質量?腰圍;行75g無水葡萄糖耐量試驗,并測空腹血清血脂?空腹胰島素(FINS)?血清FFAs?總睪酮,計算胰島素抵抗指數(HOMA-IR);對101例PCOS患者及20例正常人行高胰島素-正葡萄糖鉗夾術?結果PCOS患者血清FFAs水平明顯高于對照組(P0.01);亞組分析顯示,與兩個體質量匹配的對照組相比,PCOS患者的FFAs水平也明顯增高(P0.01)?相關分析顯示,FFAs水平與體質量指數(BMI)?腰圍?總膽固醇(TC)?低密度脂蛋白膽固醇(LDL-c)?總睪酮(r分別為0.20?0.18?0.19?0.18?0.18,P0.05)呈正相關;與高密度脂蛋白膽固醇(HDL-c)?穩態期120～180min葡萄糖代謝率(M120-180)(r分別為-0.17?-0.22,P0.05)呈負相關?結論與年齡匹配的健康婦女相比,PCOS患者血清FFAs水平顯著升高,且與BMI?腰圍?TC?LDL-c?總睪酮水平呈正相關,與 HDL-c?M120-180呈負相關?

多囊卵巢綜合征;游離脂肪酸;胰島素抵抗

多囊卵巢綜合征(polycystic ovary syndrome,PCOS)是一種育齡期婦女常見的生殖內分泌紊亂疾病,PCOS患者肥胖?糖脂代謝異常的發生率均較正常人顯著增高?目前,已證實2型糖尿病和肥胖患者體內常有血清游離脂肪酸(free fatty acids,FFAs)水平的增高,并且FFAs與胰島素抵抗(insulin resistance,IR)呈正相關[1]?雖然已有研究表明,PCOS患者也存在血清FFAs水平的增高及IR[2-3],但目前對此類人群的研究不多,且缺乏大樣本量及年齡匹配的對照組的研究?本研究旨在進一步分析PCOS患者空腹血清FFAs水平的變化,并探討其相關因素,從而為進一步探討PCOS發生?發展的機制提供重要的理論依據?

1 資料與方法

1.1 一般資料 納入重慶地區2007年11月至2010年1月就診于本院婦科及內分泌科的133例PCOS患者及116例年齡匹配的健康婦女作為對照?受試者均無糖尿病史,未懷孕,絕經前或最近至少3個月未服用過降糖藥和激素類藥物?PCOS的診斷標準參照歐洲人類生殖與胚胎學會和美國生殖醫學學會在鹿特丹會議上推薦的標準[4],并排除其他引起高雄激素?排卵障礙的內分泌疾病,如先天性腎上腺增生?庫欣綜合征?分泌雄激素的腫瘤?高催乳素血癥?甲狀腺疾病等?本研究得到重慶醫科大學倫理委員會的認可,所有調查均取得受試對象的知情同意?

1.2 研究方法

1.2.1 病史采集及人體學測量 采用統一制定的健康信息調查表,由專人對受試者進行病史詢問及體格檢查,身體測量包括:身高?體質量?腰圍;按照體質量/身高(kg/m2)計算體質量指數(body mass index,BMI)?

1.2.2 實驗室檢查 (1)所有受試者于月經第5～8天(閉經者不限時間)禁食8～12h,次日清晨空腹抽肘靜脈血后行口服75g無水葡萄糖耐量試驗(oral glucose tolerance test,OG-TT),并測定空腹胰島素(fasting insulin,FINS)?血清FFAs?總睪酮?總膽固醇(total cholesterol,TC)?三酰甘油(triacylglycerol,TG)?高密度脂蛋白膽固醇(high density lipoprotein cholestorol,HDL-c)?低密度脂蛋白膽固醇(low density lipoprotein cholestorol,LDL-c);另擇日對其中101例PCOS患者及20例正常人行高胰島素-正葡萄糖鉗夾術[5],以穩態期120～180 min葡萄糖代謝率(M120-180)評估胰島素敏感性?(2)血漿葡萄糖測定采用己糖激酶法(邁瑞BS-200全自動生化分析儀),試劑盒由中生北控生物科技股份有限公司提供;空腹胰島素和總睪酮測定采用電化學發光法,試劑盒由德國羅氏診斷有限公司提供;血脂測定采用OLYMPUS AU5400型全自動生化檢測儀,試劑由日本和光純藥工業株式會社提供;血清FFAs測定采用酶法測定,試劑由日本積水藥療株式會社提供?

1.2.3 評價標準 (1)超重?肥胖的診斷參照《中國成人超重和肥胖癥預防控制指南》[6],24.0kg/m2≤BMI28.0kg/m2為超重,BMI≥28.0kg/m2為肥胖;中心性肥胖:女性腰圍不低于80cm?(2)IR的診斷參照1999年 WHO的標準[7]以正常對照組鉗夾術中M120-180下四分位數為切點將PCOS組分為IR組(M120-18010.76mg?min-1?kg-1,n=80)和非IR組(M120-180≥10.76mg?min-1?kg-1,n=21)?(3)采用穩態模型計算胰島素抵抗指數(homeostasis model assessment-IR,HOMA-IR)評價胰島素抵抗:HOMA-IR=FINS×空腹血糖(fasting plasma glucose,FPG)/22.5[8-9]?

1.3 統計學處理 使用SPSS13.0統計軟件進行分析?計量資料以±s表示,偏態分布的變量[TG?FPG?餐后2小時血糖(2-hour postprandial blood glucose,2hPG)?FINS?HOMAIR]經對數轉換后呈正態分布再進行分析?兩組間均數比較采用t檢驗;多組均數之間的兩兩比較采用方差分析?以PCOS組的FFAs為應變量,以其他因素為自變量行Pearson相關分析?P0.05為差異有統計學意義?

2 結 果

2.1 一般情況 兩組研究對象年齡差異無統計學意義(P0.05),與對照組相比,PCOS組有更高的 BMI?腰圍?FPG?2hPG?FINS?HOMA-IR?總睪酮?FFAs?TG和更低的 HDL-c?M120-180(P0.05或P0.01),而TC?LDL-c在兩組間的差異無統計學意義(P0.05),見表1?

表1 PCOS組與對照組一般情況及生化指標的比較(±s)

表1 PCOS組與對照組一般情況及生化指標的比較(±s)

#:經對數轉換后進行統計分析;*:P0.05,**:P 0.01,與對照組比較?

項目 PCOS組25.61±4.36 25.92±2.67 BMI(kg/m2) 23.65±4.44** 20.96±2.16腰圍(cm) 78.66±11.11** 70.32±6.10 FPG(mmol/L)# 5.19±0.60** 4.95±0.37 2hPG(mmol/L)# 7.12±1.88** 5.53±1.08 TC(mmol/L) 4.24±0.87 4.38±0.63 TG(mmol/L)# 1.36±1.39** 0.76±0.37 HDL-c(mmol/L) 1.09±0.24** 1.37±0.28 LDL-c(mmol/L) 2.08±0.68 2.09±0.44 FINS(mIU/L)# 10.97±11.01* 7.29±6.68 HOMA-IR# 2.61±2.86* 1.60±1.35 M120-180(mg/min×kg-1) 8.32±2.90** 12.08±1.78總睪酮(ng/dL) 58.35±29.40** 41.77±19.85 FFAs(μmol/L) 893.57±319.60**對照組年齡(歲)657.55±290.31

2.2 亞組間血清FFAs水平比較 按BMI是否超過了24.0kg/m2重新分組?PCOS組分為正常體質量的PCOS組(n=76)和超重/肥胖的PCOS組(n=57);對照組分為正常體質量的對照組(n=108)和超重/肥胖的對照組(n=8)?四個亞組中血清FFAs水平的比較見表2?

表2 四個亞組間血清FFAs水平的比較

2.3 PCOS的兩個亞組血清FFAs水平的比較 兩組均高于體質量匹配的對照組(P0.01),但FFAs在PCOS的兩個亞組間比較,P0.05?以正常對照組鉗夾術中 M120-180下四分位數為切點將PCOS組分為IR組(M120-18010.76mg?min-1?kg-1,n=80,79.2%)和非IR 組(M120-180≥10.76 mg?min-1?kg-1,n=21,20.8%)?PCOS兩個亞組間血清FFAs水平的比較見表3?PCOS患者的IR組較非IR組有更高的BMI和FFAs濃度?

表3 PCOS患者的兩個亞組間血清FFAs水平的比較

2.4 血清FFAs水平相關因素分析 以PCOS患者的FFAs水平為應變量,Pearson相關分析顯示,FFAs水平與BMI?腰圍?TC?LDL-c?總睪酮(r分別為0.20?0.18?0.19?0.18?0.18?0.05)呈 正 相 關;與 HDL-c?M120-180(r分 別 為 -0.17?-0.22,P0.05)呈負相關;與年齡?FPG?2hPG?FINS?TG?HOMA-IR(r分別 為 0.01?0.09?0.16?0.14?0.13?0.12,P0.05)無相關性?

3 討 論

本研究顯示,PCOS患者血清FFAs水平明顯高于對照組(P0.01),與體質量匹配的對照組相比,超重/肥胖的PCOS患者FFAs水平明顯增高(P0.01),PCOS患者的IR組較非IR組也有更高的FFAs濃度;相關分析提示PCOS患者的FFAs水平分別與BMI?腰圍?TC?LDL-c?總睪酮呈正相關,與HDL-c?M120-180呈負相關?

Holte等[10]研究發現,PCOS患者較之體質量匹配的正常婦女有更高的血清FFAs水平,本研究結果與之一致?而肥胖的PCOS患者減輕體質量后血清FFAs水平和胰島素敏感性都有一定程度的改善,部分可恢復排卵[11],具體機制尚不清楚?另外,肥胖與PCOS患者的IR及糖尿病的發生相關,且獨立于糖尿病家族史[12]?本研究中,超重/肥胖的PCOS組患者血清FFAs水平高于體質量正常的PCOS組,且PCOS患者血清FFAs水平與BMI?腰圍呈正相關,提示肥胖,特別是中心性肥胖的PCOS患者,其腹部脂肪堆積程度與血清FFAs濃度之間存在一定的相關性?

報道顯示,中國南部的PCOS患者中大約46.9%發生IR[13]?高水平的血清FFAs分別與PCOS患者的IR[2]及2型糖尿病的發生有關[14],且胰島素增敏劑對PCOS患者IR的治療有效[15-16]?本研究PCOS患者中IR的發生概率為79.2%,明顯高于之前報道;且IR組與非IR組相比,前者血清FFAs水平明顯高于后者,雖然差異無統計學意義,但相關分析得出血清FFAs水平與M120-180呈負相關?目前對于PCOS患者血清FFAs水平的升高與IR的發生機制尚不明確?有研究認為[17-20]激素敏感性脂肪酶和脂蛋白脂酶之間的失調及抗脂解作用減弱,是IR時FFAs升高的重要原因,但對于PCOS患者來說,僅FFAs單一因素并不能解釋IR的發生[21-22]?

另外,研究發現[23],存在IR的PCOS患者,因白細胞與內皮細胞的相互作用,損害內皮及線粒體氧化功能?而FFAs同時也是導致氧化應激的物質之一,受高水平的FFAs刺激,活性氧簇生成增多,氧耗降低?因此,存在高FFAs水平的PCOS患者,炎癥反應更明顯,心血管疾病的發生風險將會更高?

進一步研究發現,短期高水平的FFAs可通過增強肝臟硫酸轉移酶的活性致正常體內高雄激素血癥[24-25]?而且,胰島素增敏劑可改善PCOS患者高雄激素的臨床特征[26]?Reed等[27]研究發現,居住在倫敦西北部的亞洲婦女其血清FFAs水平與睪酮水平呈正相關?另外,年輕的PCOS患者中,隨著雄激素水平的增高,其患代謝綜合征的風險增加,且這種作用獨立于肥胖及IR[28]?本研究也得到了類似的結果,提示血清FFAs水平增高可能是PCOS發病的重要機制之一[22]?此外,對高加索人[29]?印度人[30]的研究表明,血清高FFAs水平均為糖調節受損,向糖尿病進展的一個獨立危險因素?本研究尚未得到FFAs與血糖的相關性,可能與研究對象的年齡及PCOS的病程有關?另外,本研究僅為橫斷面研究,關于FFAs與糖尿病發生的關系,還需要進行長期隨訪觀察?

綜上所述,與年齡匹配的健康婦女相比,PCOS患者血清FFAs水平顯著升高,并且與肥胖?血脂異常?高雄激素?IR等因素相關?因此,降低PCOS患者空腹血清FFAs的水平,可能會有助于PCOS相關疾病的改善及遠期并發癥的預防,成為治療PCOS的一個新思路[31]?

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Concentration of serum free fatty acids and its correlation analyses in patients with polycystic ovarian syndrome

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ObjectiveTo measure the concentration of free fatty acids(FFAs)and to analyze its associations with correlative factors in the patients with polycystic ovarian syndrome(PCOS).Methods133PCOS women and 116healthy,age-matched controls were recruited.Physical examination and laboratory analysis were performed.All subjects underwent a standard 75-g oral glucose tolerance test.101PCOS women and 20controls underwent hyperinsulinemic euglycemic clamp to assess their insulin sensitivity.IR was also estimated by homeostasis model assessment of insulin resistance(HOMA-IR).ResultsThe levels of serum FFAs in PCOS women were significantly higher as compared with controls(P0.01).Subgroup analysis showed that the levels of serum FFAs in two PCOS subgroups were significantly higher as compared with the two weight-matched control subgroups(P0.01).Correlation analyses showed that in all subjects,FFAs positively correlated with BMI,waist circumference,total cholesterol(TC),LDL-c and total testosterone(r=0.20,r=0.18,r=0.19,r=0.18,r=0.18,P0.05)and negatively correlated with HDL-c and M120-180value(r=-0.17,r=-0.22,P0.05).ConclusionComparing with age-matched healthy women,the levels of serum FFAs in PCOS women are elevated evidently and positively correlated with BMI,waist circumference,TC,LDL-c and total testosterone,negatively correlated with HDL-c and M120-180value.

polycystic ovary syndrome;free fatty acids;insulin resistance

10.3969/j.issn.1671-8348.2012.16.009

A

1671-8348(2012)16-1585-04

△通訊作者,E-mail:bxy20061963@163.com?

2011-10-19

2011-11-22)

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