周玲玲，劉 華

(湖北省宜城市人民醫(yī)院，湖北 宜城 441400)

胰島素樣生長(zhǎng)因子-1與多囊卵巢綜合征的相關(guān)研究

周玲玲，劉 華

(湖北省宜城市人民醫(yī)院，湖北 宜城 441400)

胰島素樣生長(zhǎng)因子-1；多囊卵巢綜合征

多囊卵巢綜合征(polycystic ovarian syndrome，PCOS)是育齡期婦女常見的內(nèi)分泌疾病，患病率在5%～10%[1]。該病以雄激素過(guò)多、高胰島素血癥、胰島素抵抗和持續(xù)無(wú)排卵為主要臨床特征，臨床表現(xiàn)為月經(jīng)失調(diào)、不孕、肥胖、多毛、痤瘡和B超卵巢增大、卵泡增多以及伴隨生化改變。PCOS可影響婦女從青春期至絕經(jīng)后整個(gè)過(guò)程的身心健康，遠(yuǎn)期糖尿病并發(fā)癥和血脂紊亂的發(fā)生風(fēng)險(xiǎn)增加[2-3]。該病發(fā)病機(jī)制尚不清楚，新的觀點(diǎn)不斷出現(xiàn)，是婦科內(nèi)分泌學(xué)研究的熱點(diǎn)和難點(diǎn)[4-6]。目前認(rèn)為PCOS的中心環(huán)節(jié)是胰島素抵抗。除了FSH、黃體生成素(LH)等經(jīng)典的調(diào)節(jié)因子外，胰島素樣生長(zhǎng)因子(insulin growth-like factor，IGF)亦參與胰島素和雄激素的調(diào)節(jié)。目前研究表明IGF中IGF-1在PCOS中起主要作用?，F(xiàn)將IGF-1與PCOS的相關(guān)研究做一綜述。

1 IGF-1相關(guān)知識(shí)

IGF是一類多功能細(xì)胞增殖因子，通過(guò)與靶細(xì)胞膜上特異性IGF受體結(jié)合而發(fā)揮效應(yīng)。IGF與胰島素原有很高的同源性，體內(nèi)外研究均表明它有促有絲分裂及合成代謝的作用，主要包括IGF-1和IGF-2。IGF-1是下丘腦-垂體-卵巢軸的調(diào)節(jié)因子，其由70個(gè)氨基酸組成，其編碼基因位于12號(hào)染色體短背上，是一種能促進(jìn)生長(zhǎng)發(fā)育、促進(jìn)物質(zhì)代謝的多肽[7]。正常人卵巢內(nèi)含有內(nèi)源性IGF等系統(tǒng)，對(duì)雄激素產(chǎn)生旁分泌及自分泌作用。在卵巢組織中,IGF-I起主要作用。

2 IGF-1與高胰島素和高雄激素的關(guān)系

有研究表明,IGF-1可協(xié)同胰島素和LH促進(jìn)雄激素的生成,高胰島素抑制胰島素樣生長(zhǎng)因子結(jié)合蛋白-1(IGFBP-1)基因轉(zhuǎn)錄，血清和卵泡液IGFBP-1的濃度在PCOS患者中減少，從而導(dǎo)致游離IGF-1水平的升高；而高胰島素血癥介導(dǎo)的IGF-1活性改變又與高雄激素血癥和無(wú)排卵有關(guān)[8]，高胰島素通過(guò)IGF-1的作用,使原始卵泡不斷啟動(dòng),加強(qiáng)初級(jí)卵泡發(fā)育及間質(zhì)細(xì)胞增生,從而促成多囊卵巢的形成[9]。

IGF-I 能使大鼠卵巢合成雄激素的酶P450c17α、3β-羥類固醇脫氫酶和5α-還原酶增加,擴(kuò)大LH的生物活性,增加正常卵泡膜間質(zhì)細(xì)胞LH受體的表達(dá),從而促進(jìn)雄激素的合成[10];另外,IGF-I能提高卵巢顆粒細(xì)胞對(duì)FSH的敏感性,提高芳香化酶的活性,促進(jìn)雌、孕激素和抑制素的合成，從而導(dǎo)致高雄激素及雌孕激素的升高[11]。Silfen等[12]體外研究證實(shí),胰島素和IGF-I能增加卵泡膜細(xì)胞和腎上腺皮質(zhì)細(xì)胞雄激素的產(chǎn)生。

3 IGF-1在卵巢作用機(jī)制

IGF-1除主要由生長(zhǎng)激素刺激下的肝臟產(chǎn)生外，卵巢局部也以自分泌或旁分泌方式產(chǎn)生。6mm直徑的小卵泡粒膜細(xì)胞可檢測(cè)出豐富的IGF-1信使核糖核酸表達(dá)，而顆粒細(xì)胞上未能檢測(cè)出，這種表達(dá)方式與閉鎖中的卵泡相似，優(yōu)勢(shì)卵泡的顆粒細(xì)胞和粒膜細(xì)胞均不能檢測(cè)出IGF-1信使核糖核酸表達(dá)[13]。與IGF-1信使核糖核酸表達(dá)相反，優(yōu)勢(shì)卵泡組成細(xì)胞有豐富的胰島素樣生長(zhǎng)因子結(jié)合蛋白表達(dá)，而閉鎖卵泡和小卵泡組成細(xì)胞胰島素樣生長(zhǎng)因子結(jié)合蛋白表達(dá)量極低，其結(jié)果是導(dǎo)致小卵泡局部的游離IGF-1水平高，而優(yōu)勢(shì)卵泡局部的游離IGF-1水平低。

Zhang等[14]體外細(xì)胞培養(yǎng)發(fā)現(xiàn)：IGF-1可通過(guò)對(duì)AKT和MPK酶的磷酸化使細(xì)胞通過(guò)G1/S期轉(zhuǎn)換,進(jìn)入S期,并可依賴雌激素受體α使細(xì)胞周期素D1(cyclinD1)和細(xì)胞周期素E2(cyclinE2)表達(dá)增強(qiáng),促進(jìn)細(xì)胞增殖。另外,臨床上也觀察到子宮內(nèi)膜增殖癥患者的子宮內(nèi)膜上,胰島素樣生長(zhǎng)因子受體(insulin growth- like factor receptor，IGFR)表達(dá)增加同時(shí)，AKT途徑也被激活[15]。IGF對(duì)體內(nèi)外細(xì)胞都有激活與細(xì)胞凋亡增殖有關(guān)的關(guān)鍵酶AKT作用, 從而促進(jìn)細(xì)胞增生。這可能與PCOS患者卵巢血流增加、體積增大、皮質(zhì)包膜增厚有關(guān)。

4 IGF-1與PCOS的關(guān)系

Klinger等[16]報(bào)道用重組IGF-I長(zhǎng)期治療6例女性拉倫侏儒患者,其中4例發(fā)展為具有與PCOS相似的臨床特征，包括肥胖、多毛、閉經(jīng)、痤瘡、雄激素增高、LH上升。當(dāng)停用或減少IGF-I用量后，PCOS的臨床表現(xiàn)消失，這證實(shí)了血中高IGF-I與PCOS密切相關(guān)，自此對(duì)PCOS與IGF-1的相關(guān)性開始了更多的探索。

Diaa等[17]報(bào)道，血漿IGF-1水平PCOS組顯著高于正常對(duì)照組(P<0.01)。Dessel等[18]和Deleo等[19]報(bào)道IGF-1對(duì)正常卵泡生成和排卵有負(fù)面影響，暗示PCOS的發(fā)病機(jī)制與IGF-1和卵巢類固醇系統(tǒng)的異常相關(guān)。Homburg等[20]研究發(fā)現(xiàn)PCOS組血漿IGF-1濃度與非PCOS組比較差異無(wú)統(tǒng)計(jì)學(xué)意義，但PCOS組IGFBP-1水平降低，PCOS組游離IGF-1水平高于非PCOS組，PCOS組高水平的血漿IGF-1與通過(guò)多普勒測(cè)量的構(gòu)成血流增強(qiáng)的增加的血管分布相關(guān)。Bergh等[21]報(bào)道PCOS患者中經(jīng)常發(fā)現(xiàn)LH升高，膜細(xì)胞產(chǎn)生IGF-1增加，從而增加雄激素的產(chǎn)生，與之相關(guān)的IGF-1受體在膜細(xì)胞已經(jīng)被檢測(cè)出；而且IGF-1可以刺激粒層細(xì)胞雌激素的產(chǎn)生，刺激人類卵巢芳香化酶的活性[22]。梁曉燕等[8]和Premoli等[23]研究表明IGF-1與非肥胖型PCOS的高雄激素相關(guān)。以上研究都證明了PCOS患者中IGF-1水平升高，可能的機(jī)制與高LH和高雄激素密切相關(guān)。

IGF-1與PCOS卵泡發(fā)展紊亂相關(guān)。Hahn等[24]發(fā)現(xiàn)PCOS患者有更高的IGF-1、LH/FSH水平和痤瘡、多毛評(píng)分，PCOS患者卵巢卵泡液中IGF-1含量顯著高于正常對(duì)照組。這些證據(jù)表明IGF-1影響PCOS的生殖功能，與PCOS的無(wú)排卵型不孕有關(guān)。Amin等[25]研究發(fā)現(xiàn)對(duì)克羅米芬抵抗的PCOS患者行腹腔鏡打孔術(shù)后其雄激素、LH、IGF-1和卵巢血流水平均下降，從反面論證了IGF-1與PCOS的相關(guān)性。

總之，PCOS患者血漿中游離IGF-1的升高與高LH、高胰島素、高雄激素相互作用，互為因果，共同促進(jìn)了PCOS病理生理的發(fā)展，至于誰(shuí)因誰(shuí)果尚有待于進(jìn)一步探討。

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10.3969/j.issn.1008-8849.2015.14.042

R711.75

A

1008-8849(2015)14-1588-03

2014-05-30