羅穗豫 王瑜

妊娠期血漿CRH、E2及 P與早產(chǎn)關(guān)系的研究

羅穗豫 王瑜

目的 探討促腎上腺激素釋放激素(corticotropin releasing hormone, CRH)、雌二醇(estradiol, E2)及孕激素(progesterone, P)在妊娠期間的濃度變化及其在早產(chǎn)中的預(yù)測作用。方法 選取正常妊娠組孕婦54例, 先兆早產(chǎn)組孕婦54例, 采集外周靜脈血分離血漿, 用免疫化學(xué)發(fā)光法測定E2、P, 放射免疫法測定CRH水平。結(jié)果 ①正常妊娠血CRH均值28～33周組與＞37周組比, 明顯低于＞37周組, 經(jīng)t檢驗P＜0.05；血E2各組間均值經(jīng)t檢驗P＞0.05, 差異無統(tǒng)計學(xué)意義；血P各組均值, 28～33周組明顯高于＞37周組, 經(jīng)t檢驗P＜0.05, 差異有統(tǒng)計學(xué)意義, 其余各組差異無統(tǒng)計學(xué)意義。②正常妊娠組和先兆早產(chǎn)組在妊娠28～33周血CRH分別為 (68.23±13.34)ng/L和(298.42±162.78 )ng/L；在34～36周分別為 (132.75±126.3) ng/L和(354.42±50.46) ng/L, 經(jīng)t檢驗, P值均＜0.05, 差異有統(tǒng)計學(xué)意義。正常妊娠組和先兆早產(chǎn)組血E2在28～33周分別為(128.72±50.83)μg /L和(152.94±31.7)μg/L；在34～36周分別為(136.24±62.41)μg /L和(173.58±92.3)μg/L, 兩組均值經(jīng)t檢驗, P值均＜0.05, 差異無統(tǒng)計學(xué)意義。正常妊娠組和先兆早產(chǎn)組血P在28～33周分別為(523.52±105.43)μg/L和(353.21±52.21)μg/L, 34～36周(483.24±113.52)μg/L和(310.25±83.02)μg/L, 差異有統(tǒng)計學(xué)意義。結(jié)論 血P在妊娠晚期各孕周組間變化較為明顯, 妊娠＞37周之后明顯下降。妊娠晚期正常妊娠組中的血漿CRH值隨著孕周增加而逐漸升高,而血E2值無明顯變化。

促腎上腺皮質(zhì)激素釋放激素；雌二醇；孕酮；早產(chǎn)

早產(chǎn)占整個妊娠的7% ～10%, 早產(chǎn)兒死亡率為15%, 是圍生期新生兒死亡的首要原因。探討促腎上腺激素釋放激素(corticotropin releasing hormone, CRH)、雌二醇(estradiol, E2)及孕激素(progesterone, P)在妊娠期間的濃度變化及其在早產(chǎn)中的預(yù)測作用。

1 資料與方法

1.1 一般資料 研究對象選自2012年1月～2012年12月,在河南省人民醫(yī)院進行產(chǎn)前檢查的108例孕婦。排除心臟病、高血壓、糖尿病等妊娠合并癥及并發(fā)癥。

1.1.1 實驗分組 正常妊娠組54例：根據(jù)孕周分為28～33周、34～36周組、大于37周組, 每組各18例, 平均年齡28.2歲。先兆早產(chǎn)組54例：根據(jù)孕周分為小于33周組和34～36周組,每組各27例, 平均年齡28.5歲。

1.1.2 診斷標準 早產(chǎn)、先兆早產(chǎn)的診斷標準參照樂杰主編的《婦產(chǎn)科學(xué)》［1］。

1.2 實驗方法 收集孕婦肘靜脈血2 ml, 正常妊娠組于上午10時在門診采血, 先兆早產(chǎn)組于入院時采血, 采血后, EDTA抗凝, 3500 r/min離心10 min, 分離血漿, -20℃保存?zhèn)溆谩?/p>

主要試劑:CRH放射免疫分析試劑盒(上海銳聰科技公司)。E2免疫化學(xué)發(fā)光試劑盒, P免疫化學(xué)發(fā)光試劑盒( 上海江萊生物科技有限公司)。

1.3 統(tǒng)計學(xué)方法 用SPSS19.0統(tǒng)計軟件處理。所得數(shù)據(jù)均數(shù)用( x-±s)示。均數(shù)比較采用獨立樣本t檢驗。P＜0.05為差異有統(tǒng)計學(xué)意義。

2 結(jié)果

2.1 正常妊娠組血CRH、E2、P變化

2.1.1 CRH 妊娠28～33周孕婦血CRH(68.23±13.34)ng/L, 34～36周(132.75±126.30) ng/L, ＞37周(352.12±166.05) ng/L。妊娠晚期正常妊娠組血CRH濃度隨著孕周增加而逐漸升高。妊娠28～33周組與34～36周組血CRH均值比較P=0.0383,差異有統(tǒng)計學(xué)意義；28～33周組與＞37周組均值經(jīng)t檢驗P= 0.0001, 差異有統(tǒng)計學(xué)意義。

2.1.2 E2、P: 妊娠28～33周正常孕婦血E2(128.72±50.83)μg /L, 34～36周 (136.24±62.41) ug /L, ＞37周(125.37±52.25)μg /L。各孕周組間血E2均值經(jīng)t檢驗, P＞0.05, 各組間差異無統(tǒng)計學(xué)意義。妊娠28～33周正常孕婦血P (523.52±105.43)μg /L, 34～36周(483.24±113.52)μg /L, ＞37周(423.23±121.62)μg /L。血P在28～33周為(523.52±105.43) μg /L, 34～36周(483.24±113.52)μg /L, ＞37周(423.23±121.62)μg /L, 均值經(jīng)t檢驗, 28～33周組與＞37周組P=0.0123, 差異有統(tǒng)計學(xué)意義, 其余各組差異無統(tǒng)計學(xué)意義。見表1。

2.2 先兆早產(chǎn)組血CRH、E2、P變化 妊娠晚期先兆早產(chǎn)組血CRH、E2濃度隨妊娠周數(shù)緩慢升高, 血P＞37周顯著下降。28～33周血CRH (298.42±162.78) ng/L, 34～36周血CRH (354.42±50.46)ng/L, P＞0.05, 兩組差異無統(tǒng)計學(xué)意義。28～33周血E2(152.94±31.7) μg /L, 34～36周血E2(173.58±92.3) μg /L, P＞0.05, 兩組差異無統(tǒng)計學(xué)意義。28～33周組血P (353.21±52.21) μg/L, 34～36周血P (310.25±83.02)μg/L, P＜0.05, 兩組差異有統(tǒng)計學(xué)意義。見表2。

2.3 正常妊娠組與先兆早產(chǎn)組血CRH、E2、P的比較 正常妊娠組與先兆早產(chǎn)組在28～33周、34～36周血CRH均值經(jīng)t檢驗, P＜0.05, 差異有統(tǒng)計學(xué)意義。見表3。

在28～33周和34-36周兩組血E2均值經(jīng)t檢驗, P值分別為0.0551、0.1409差異無統(tǒng)計學(xué)意義。見表4。

在28～33周和34～36周, 兩組血P均值經(jīng)t檢驗, P值均＜0.05, 差異有統(tǒng)計學(xué)意義。見表5。

表1 正常妊娠組不同孕期血CRH、E2和P的均值（x-±s）

表2 先兆早產(chǎn)組血CRH和E2、P的變化（x-±s）

表3 正常妊娠組與先兆早產(chǎn)組血CRH的比較（-x±s）

表4 正常妊娠組與先兆早產(chǎn)組血E2的比較( x-±s)

表5 正常妊娠組與先兆早產(chǎn)組血P的比較( x-±s)

3 討論

3.1 CRH、E2和P在妊娠過程的作用 促腎上腺激素釋放激素(CRH)是一種41個氨基酸的下丘腦多肽, 近年來發(fā)現(xiàn)胎盤CRH的分泌量遠遠超過下丘腦的分泌量, 成為妊娠期母體外周血CRH的主要來源［2］。

胎盤CRH作用在胎兒垂體-腎上腺軸, 刺激腎上腺產(chǎn)生雄激素、皮質(zhì)醇并且同時直接通過受體作用在子宮平滑肌細胞上。CRH在孕16～20周開始升高, 它像定時器一樣控制著妊娠的時限, 調(diào)控著胎盤的功能, 而且, 分娩并不是分娩的那一刻的結(jié)果, 而是在孕早期就注定的一個過程［3］。本文正常分娩組血CRH隨妊娠周數(shù)增加逐漸上升, 與報道一致。

妊娠期血漿中CRH水平呈指數(shù)性升高, 然而, 相比足月分娩的婦女, 在先兆早產(chǎn)的婦女中升高的幅度大, 過期分娩的婦女中幅度小。本研究中先兆早產(chǎn)組CRH在各孕周組的濃度都顯著高于正常妊娠組, 可以認為CRH可能在早產(chǎn)的發(fā)病中起重要作用, CRH的異常升高可能決定了分娩時間的提前。因此, 在臨床上監(jiān)測孕婦CRH的變化有望成為預(yù)測早產(chǎn)的可靠指標。

本研究中血E2在正常妊娠組與早產(chǎn)組各妊娠階段值波動不大, 而血P變化明顯, 與譚春英［4］的研究結(jié)果一致, 認為E2、P在正常妊娠的發(fā)動中是以P為主, 在分娩晚期質(zhì)量濃度明顯下降,不能維持子宮的相對靜止狀態(tài),使得子宮平滑肌敏感性加強,最終導(dǎo)致分娩發(fā)動。P還作為免疫調(diào)節(jié)劑控制著許多孕期的免疫反應(yīng), 它的撤退會抑制免疫反應(yīng)。有效的孕激素撤退發(fā)生在分娩的開始, 機體通過孕激素的分解代謝、受體結(jié)合和抵抗孕激素的分子結(jié)構(gòu)變化等方法使游離孕激素濃度減少［5］。子宮平滑肌也由靜息狀態(tài)向敏感狀態(tài)轉(zhuǎn)化。本文血P在33周后逐漸下降, 與報道一致。

3.2 CRH、E2和P的相互作用 在分娩時胎盤 CRH在血漿中呈指數(shù)升高, 刺激胎盤產(chǎn)生雌激素, 抑制胎盤合成孕激素。胎盤CRH也釋放到胎兒循環(huán), 刺激胎兒腎上腺產(chǎn)生脫氫表雄酮。脫氫表雄酮是胎盤雌激素合成的前體［6］。孕激素對于妊娠的維持是非常重要的, 產(chǎn)生于腎上腺、黃體、腦和胎盤,在懷孕期間使子宮處于靜止期, 它的撤退會導(dǎo)致分娩期子宮平滑肌的收縮［7］。孕激素對胎盤CRH的分泌有抑制作用,其通過與滋養(yǎng)細胞內(nèi)糖皮質(zhì)激素受體結(jié)合而發(fā)揮作用［8］。臨床試驗顯示預(yù)防性使用孕激素可以減少早產(chǎn)的發(fā)生［9］。然而, 因CRH像定時器一樣控制著妊娠的時限, 所以孕激素治療不會減少自發(fā)性早產(chǎn)的發(fā)生［10］, 而CRH拮抗劑可以通過PKC-依賴途徑介導(dǎo)使孕激素升高, 減低早產(chǎn)的風(fēng)險［11］, 聯(lián)合治療比單藥治療也許能更好的改善早產(chǎn)［12］。

將來, 以P 、CRH以及炎性免疫應(yīng)答為基礎(chǔ)的臨床應(yīng)用可能會對預(yù)防早產(chǎn)有益, 這是目前導(dǎo)致新生兒致病和致死的重要原因。

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Study on the relationships between the plasma CRH, E2and P during pregnancy and premature delivery

LUO Sui-yu, WANG Yu.Department of obstetrics and Gynetology,People’s Hospital of Zhengzhou University (Henan People’s Hospital), Zhengzhou 450003, China

Objective To discuss the concentration changes of Corticotropin Releas ing Hormone(CRH), Estradiol (E2), and Progesterone (P) during the third trimester and analyze its predictive role in preterm.Methods 54 pregnant women of threatened prematurity were enrolled as the threatened prematurity group, 54 normal pregnant women were selected as normal pregnant group.Three milliliters of venous blood were taken from all of the women.The levels of E2, P were detected by chemiluminescence immunoassay (CLIA), CRH by radioimmunoassay (RIA).Results The mean plasma CRH of 28～33 weeks group was significantly lower than ＞ 37 weeks group in the normal pregnant group (P＜0.05).There was no significant deference in each groups about the E2(P＞0.05). The mean plasma P of 28～33 weeks group was significantly higher than ＞ 37 weeks group (P＜0.05).In 28～33 weeks the plasma CRH were respectively (68.23±13.34)ng/L and (298.42±162.78 ) ng/ L in the group of normal pregnant and the group of threatened prematurity.The same as (132.75±126.3) ng/ L and (354.42±50.46) ng/L in 34～36 weeks.There was a significant difference in the plas ma CRH in the two groups (P＜0.05).In 28～33 weeks the plasma CRH were res pectively (68.23±13.34)ng/L and (298.42±162.78 ) ngl/L in the group of normal pregnant and the group of threatened prematurity.The same as (132.75±126.3) ng/L and (354.42±50.46) ng/L in 34-36 weeks.There was a significant difference in the plasma CRH in the two groups (P＜0.05).In 28～33 weeks the plasma E2were respectively (128.72±50.83)μg/L and (152.94±31.7) μg/L in the group of normal pregnant and the group of threatened prematurity.The same as (136.24±62.41)μg/L and (173.58±92.3)μg/L in 34～36 weeks.There was no significant difference in the plasma E2in the two groups(P＞0.05).In 28-33 weeks the plasma P were respectively (523.52±105.43)μg/L and (353.21±52.21)μg/L in the group of norm al pregnant and the group of threatened prem aturity.The same as (483.24±113.52)μg/L and (310.25±83.02)μg/L in 34～36 weeks.There was a significant difference in the plasma E2in the two groups (P＜0.05).Conclusion The plasma P changed obviously in the third trimester.It was declined significantly after the 37th weeks.In the trimester the plasma CRH gradually increased with the increasing gestational age.But there was no significant changes in E2. CRH may be an important factor in onset of delivery.

Corticotropin releasing hormone (CRH)；Estradiol (E2)；Progesterone (P)；Premature delivery

450003 鄭州大學(xué)人民醫(yī)院暨河南省人民醫(yī)院婦產(chǎn)科

王瑜