控制性超排卵中过早黄素化对体外受精影响妊娠结局及分子机制的初步研究
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摘要
控制性超排卵(controlled ovarian hyperstimulation,COH)是目前临床体外受精-胚胎移植(in vitro fertilization and embryo transfer,IVF-ET)治疗程序中常规进行的程序。随着辅助生殖技术的快速发展,促排药物的不断改进以及COH方案和监测手段的不断完善,胚胎移植后的着床率及临床妊娠率都得以不断提高,然而仍有超过半数的治疗周期未能妊娠,其影响妊娠成功的因素和机制纷繁而复杂。其中在控制性超排卵中,注射人绒毛膜促性腺激素(human chorionicgonadotropin,HCG)日常常发生过早的孕酮水平(progesterone,P)升高,同时在黄体生成素(luteinizing hormone,LH)的作用下伴随卵巢颗粒细胞过早向黄体细胞分化的过程,常称为过早黄素化(premature luteinization,PL)。关于过早黄素化产生原因,在GnRH激动剂(GnRH-agonist)或拮抗剂(GnRH-antagonist)的运用以前,一直认为是黄体生成素所致,但是GnRH-a在临床的运用已经能有效的抑制LH,但过早黄素化的发生率仍然高达13%至61%。研究表明过早黄素化对IVF-ET治疗的影响主要是损害卵子和胚胎质量,诱导卵母细胞过早恢复减数分裂,使子宫内膜过早向分泌期转化,影响子宫内膜容受性,从而降低临床妊娠率,但是也有研究认为过早黄素化对临床结局无影响。关于过早黄素化的分子机理国外有少量研究认为可能与生长分化因子9(growth differentiation factor-9,GDF9)以及神经生长因子(nerve growth factor,NGF)表达异常有关,鉴于目前国内外对过早黄素化与IVF-ET临床结局的关系的研究仍然存在争议以及我们对控制性超排卵中发生过早黄素化的分子机制远未了解,本研究采用回顾性统计学方法分析了HCG注射日过早黄素化与IVF结局的关系,并利用抑制消减杂交技术、macroarray分离和鉴定了过早黄素化颗粒细胞差异表达基因,并用real-time PCR、Western blot、流式细胞仪等技术检测了过早黄素化颗粒细胞特异基因mRNA和蛋白水平的表达差异,并分析了过早黄素化与颗粒细胞凋亡发生之间的关系,以期对研究过早黄素化的发生机制、预防、治疗对策以及远期指导临床超排卵合理用药提供科学依据。
第一章控制性超排卵中过早黄素化对IVF结局的影响
【目的】鉴于目前国内外对过早黄素化与IVF-ET临床结局的关系的研究仍然存在争议探讨长方案体外受精-胚胎移植(IVF-ET)控制性超排卵中注射HCG日过早黄素化现象与IVF-ET妊娠率的关系,分析过早黄素化病因。
【方法】回顾性分析2278个长方案进行IVF-ET的治疗周期,采用ROC曲线筛选过早黄素化诊断阈值并根据该阈值进行分组,从各组随机抽取316个周期比较临床参数。线性回归分析hCG日孕激素与其他临床变量之间的关系。
【结果】随着过早黄素化程度加深(注射hCG日孕激素值升高),临床妊娠率呈明显的下降趋势;P＜1.1 ng/mL是过早黄素化的最佳诊断阈值,具有94.6%的敏感度,45.6%的特异度;有19.6%(446)的治疗周期发现过早黄素化,过早黄素化组的FSH总用量(1949.0±595.8vs.1742.9±616.9),注射HCG日血清E_2(3065.9±1319.8 vs.2435.3±1063.5)和LH(3.1±2.8 vs.2.4±2.9)水平以及回收卵数(13.3±5.7 vs.11.3±5.6)明显高于非过早黄素化组周期,但是受精率(58.3±0.36 vs 69.2±0.24),IVF优质胚胎数(2.3±3.8 vs 3.5±2.6)及IVF-ET妊娠率(35.8%vs 48.2%)显著低于非过早黄素化组。线性回归分析仅鉴定出孕激素升高与E_2水平(r=0.135,P=0.016)和回收卵数(r=0.239,P＜0.01)相关。过早黄素化组的总临床妊娠率明显低于非过早黄素化组(38.6%vs 48.1%),两组间移植胚胎数,ICSI优质胚胎数和ICSI妊娠率无明显差异。
【结论】首次采ROC曲线筛选诊断过早黄素化诊断阈值。中国女性诊断过早黄素化的最好的诊断标准应该是P＞1.1ng/ml,过早黄素化的出现可能与HCG日雌激素和回收卵子数有关,IVF-ET周期中过早黄素化可能导致卵子质量下降,最终导致临床妊娠率显著下降;然而在ICSI周期中过早黄素化对优质胚胎数和妊娠率似乎并无显著影响,在临床中患者如若出现过早黄素化迹象,可适时建议进行ICSI治疗,以避开IVF-ET周期中PL对卵子的负面影响。
第二章控制性超排卵中过早黄素化颗粒细胞差异表达基因的分离和鉴定
【目的】在COH中常常发生过早的孕激素升高,同时伴发过早卵巢颗粒细胞向黄体细胞分化的过程,称为过早黄素化。其分子机理尚不清楚,为探索其分子基础,应用抑制消减杂交技术(Suppression subtractive hybridization,SSH)构建过早黄素化cDNA消减文库,并采用macroarray(膜阵列)和RT-PCR鉴定相关的差异表达基因,了解这些差异基因与过早黄素化发生的关系。
【方法】分离入选的过早黄素化病人(PL组30例)和对照组病人(非PL组30例)的卵泡液颗粒细胞。抽提颗粒细胞总RNA,逆转录合成cDNA,cDNA经RsaI酶切后,将PL组cDNA分成两组,分别与两种不同的接头街接,再与对照组cDNA进行两次消减杂交及两次抑制巢式PCR反应,将产物与pMD18-T载体连接,构建cDNA消减文序,并转染大肠杆菌进行文库扩增,随机挑选阳性克隆经PCR扩增后进行macroarray(膜阵列)杂交验证并RT-PCR半定量分析。经验证的克隆送测序并进行生物信息学同源性分析。
【结果】179个阳性克隆被随机挑选出来,86个克隆送测序并进行生物信息学分析。其中84个克隆代表了47个已知基因。这些基因参与类固醇合成,蛋白翻译,细胞黏附,细胞代谢,脂质代谢以及细胞凋亡。
【结论】首次成功构建了COH中过早黄素化颗粒细胞的差异基因的cDNA消减文库。这些基因功能涉及类固醇合成,蛋白翻译,细胞黏附,细胞代谢,脂质代谢以及凋亡。过早黄素化的发生可能与颗粒细胞内过度活跃的类固醇合成,脂质合成,凋亡活动以及细胞因子表达异常有关,研究这些差异基因与过早黄素化发生之间的关系,将有助于我们进一步了解过早黄素化发生的分子机制。
第三章过早黄素化差异基因mRNA及蛋白分析
【目的】进一步研究这些差异基因及编码蛋白在过早黄素化发生进程中的差异表达情况以及作用机制,我们根据第二章的研究结果、差异基因与过早黄素化发生的相关性以及我们所能获得的研究材料,挑选出部分基因采用real-time PCR和Western blot进行mRNA水平和蛋白水平的研究。
【方法】分离入院行辅助生殖技术治疗时发生过早黄素化病人和未发生过早黄素化病人的卵泡液颗粒细胞,一部分颗粒细胞提取RNA和细胞总蛋白,RNA逆转录合成cDNA,采用real-time PCR分析两组间类固醇急性合成调节蛋白(steroidogenic acute regulator,StAR)、乙酰辅酶A羧化酶(Acetyl-CoA carboxylase,ACC)、GDF9、bcl-2(B-cell lymphomaleukema 2)、P450aro(P450 aromatase)、P450侧链裂解酶(P450side-chain cleavage,P450ssc)、PHLDA1(pleckstrin homology-likedomain,family A,member 1)以及ubiquitin protein ligase E3的mRNA表达差异,细胞总蛋白采用Western blot方法分析两组间StAR、GDF9、bcl-2、PHLDA1蛋白表达差异。另一部分颗粒细胞分离后培养一部分添加GDF9(200ng/ml)干预,继续48小时培养观察GDF9对StAR蛋白的表达的影响。
【结果】在过早黄素化颗粒细胞中StAR、ACC、P450scc、PHLDA1及ubiquitin protein ligase E3的mRNA表达水平显著升高,而bcl-2和GDF9的mRNA表达下降(P＜0.05)。蛋白水平上发现StAR(30kDa)、PHLDA1(40kDa)、bcl-2(26kDa)、GDF9(51kDa)蛋白均能在颗粒细胞中表达,过早黄素化颗粒细胞中StAR(30kD)和PHLDA1(40kD)蛋白表达明显上调。然而bcl-2(26kDa)和GDF9(51kD)蛋白表达水平明显下调。培养的颗粒细胞添加GDF9(200ng/ml)干预后,颗粒细胞StAR蛋白表达明显下调,但基础StAR活性并未受到影响。
【结论】GDF9能明显抑制颗粒细胞内过度活跃的类固醇合成活性,但并不影响基础类固醇合成活性。过早黄素化的发生可能与GDF9过低表达以及凋亡基因PHLDA1表达升高和抗凋亡基因bcl-2表达过低导致的颗粒细胞凋亡活动增加有关。
第四章IVF-ET中颗粒细胞凋亡与过早黄素化关系
【目的】细胞凋亡(apoptosis)是指在特定信号诱导下,一系列基因按程序时空顺序表达,细胞内死亡级联反应导致程序性细胞死亡。生殖系统内组织细胞的凋亡变化在妊娠过程中有重要意义,任何一个环节失调,都可能影响妊娠的顺利进行。卵泡凋亡最初是从颗粒细胞开始发生的。在前面研究中我们在过早黄素化颗粒细胞中筛选出两个与凋亡相关的基因PHLDA1和bcl-2并发现PHLDA1表达水平上调,而抗凋亡基因bcl-2表达下降,同时观察到GDF9表达下降,因此我们推测细胞内凋亡活动上调也是过早黄素化发生的原因之一,而GDF9可能具有拮抗颗粒细胞凋亡的作用,本章的目的即为验证此假设。
【方法】根据细胞在凋亡启动时发生细胞皱缩,细胞膜发泡等形态异常,以及细胞膜发生磷脂酰丝氨酸(phosphatidylserine,PS)外翻这一特点,采用流式细胞仪和AnnexinV/FITC和PI双标法检测了过早黄素化颗粒细胞凋亡情况。此外,我们观察了添加200ng/mlGDF9干预对颗粒细胞凋亡的影响。
【结果】与非过早黄素化颗粒细胞(P＜1.1ng/ml)相比,过早黄素化颗粒细胞形态异常率升高(16.28%vs 5.38%,P＜0.05);过早黄素化组颗粒细胞的平均凋亡率明显增加(25.43%vs 10.05%,P＜0.05);过早黄素化组(P=1.4ng/ml、1.7ng/ml、2.0ng/ml)添加200ng/mlGDF9干预后颗粒细胞凋亡率显著下降
【结论】过早黄素化颗粒细胞凋亡活动增加,而GDF9能抑制过度活跃的凋亡活动,过早黄素化颗粒细胞GDF9低表达和颗粒细胞的凋亡可能是造成过早黄素化患者卵母细胞质量下降的原因之一。
Objective: To evaluate the effect of premature luteinization (PL)on the clinical outcomes and analyse the cause of PL in long GnRH-a cycles. Methods: 2278 patients with GnRH-a down regulation long protocol in our institution from May 2003 to May 2006 were assessed retrospectively. The patients were grouped (PL group and non-PL group) according to serum P cut-off threshold value on the day of hCG administration (P>1.1 ng/mL or P<1.1 ng/mL) which was determined by receiver operating characteristic (ROC) curve. Of them, 316 patients were sampling randomly from both groups respectively to compare clinical variable. Ovarian down-regulation was achieved using GnRH agonist downregulation long protocol with injection of GnRH-a in the midluteal phase of the previous cycle. Ovarian stimulation was started with daily injections of r-FSH (Gonal F, 75 IU, Serono Switzerland) or human menopausal gonadotrophin (hMG) until the day of hCG administration. The cut-off progesterone threshold was determined by ROC curve. The main outcome measures included fertilization rates and clinical pregnancy rates. Groups were compared by using the unpaired Student t, chi-squared test. The relationships between P level on hCG day and other variables were analyzed by multiple linear regression analysis. P<0.05 was considered statistically significant.
Results: The ROC curve showed a progesterone value (P>1.1 ng/mL ) as the most efficient cut-off threshold to discriminated between the pregnant and no pregnant cycles with a 94.6% sensitivity,45.6% specificity. Four hundred forty six (19.6%) of the 2278 patients enrolling in this study demonstrated premature luteinization. The total FSH dose(1949.0±595.8 vs. 1742.9±616.9), E_2(3065.95±1319.8 vs. 2435.3±1063.5), LH (3.13±2.8 vs. 2.36±2.99) level on hCG day, number of mature oocytes retrieved (13.3±5.7 vs. 11.3±5.6)were significantly higher in PL group as compared to the non-PL group. However, the fertilization rate (58.3±0.36% vs69.2±0.24%)and the number of good quality embryo(2.3±3.8vs3.5±2.6)were significantly lower in the PL group. The multiple linear regression analysis did not show a positive and significant association between the total FSH dose, LH, PRL and the serum P levels, but show a positive and significant association between E_2 (r=0.135, P=0.016), number of oocytes retrieved (r=0.239, P<0.01) and the serum P level. The fertilization rate and number of high quality embryos were similar between the two groups. The clinical pregnancy rate (38.6% vs. 48.1%) was significantly lower in the PL group.
Conclusions: The best P cut-off value to define premature luteinization may be P>1.1 ng/ml. Premature luteinization could adversely affect the pregnancy rate of IVF-ET in long GnRH-a cycles and it seems to have negative impact on oocytes quality. Premature luteinization could not be related to low ovarian reserve. Premature progesterone elevation of PL is related to E_2 on hCG day and number of mature oocytes retrieved.
Objective: A premature serum progesterone (P) elevation untimely before HCG administration during controlled ovarian hyperstimulation (COH) and the concomitant process of granulosa cells differentiate into luteal cells is usually called premature luteinization (PL), which could adversely affect clinical outcomes in IVF-ET. However, the molecular mechanisms of PL are not completely understood. The aim of this stuy is to explore the molecular mechanisms of premature luteinization.
Methods: Suppression subtractive cDNA hybridization was performed to identify genes differentially expressed in granulosa cell of premature luteinization. Differentially expressed genes were confirmed by macroarray dot blot analysis and real- time PCR. The differential cDNA fragments was sequenced and further analyzed by bioinformatics.
Results: 179 putative positive clones were randomly picked,and 86 clones were sequenced and searched in the GenBank. Among them, 84 clones represented 47 identified genes. These genes were involved in steroidogenesis, translation,cell adhesion,cellular metabolism, lipid metablism and apoptosis.
Conclusions: The differentially cDNA subtractive library of premature luteinization was first successfully constructed. The differentially expressed genes may have an important role in process of PL. Further studies of these genes should shed new light on understanding the molecular mechanism of premature luteinization.
Objective: To explore the relationship between the differentially expressed genes and the process of premature luteinization.
Methods: In the previous chapter we have constructed the differentially cDNA subtractive library of premature luteinization successfully and suggested these differentially expressed genes may have an important role in process of premature luteinization. According to their potential roles in the premature luteinization ,several genes and their encoding proteins were selected from the SSH cDNA library for further studies at mRNA or protein level by real-time PCR and Western blot. And we also examined the effect of growth differentiation facor-9 treatment on the expression of steroidogenic acute regulatory protein (StAR) by Western blot.
Results: As the results,we observed a remarkable mRNA up-regulation of steroidogenic acute regulatory protein (StAR), Acetyl-CoA carboxylase (ACC), P450 side chain cleavage enzyme (P450scc), pleckstrin homology- like domain, family A, member l(PHLDAl) and ubiquitin protein ligase E3 in PL granulosa cell and concurrent mRNA down-regulation of growth differentiation factor-9 (GDF9) and bcl-2. Significant up-regulations were also observed in the StAR (30kD), PHLDA1(40kD) protein levels. However, the GDF9(51kD) and bcl-2 (26kDa) protein level significantly reduced in the PL granulosa cells. GDF-9 treatment inhibited premature luteinization granulosa StAR expression but did not affect basal StAR expression.
Conclusions: So we concluded the increased expression of StAR, attenuated GDF9 protein and apoptosis induced by increased PHLDA1 and decreased bcl-2 protein may be responsible for the premature luteinization.
Objective: To investigate the relationship between premature luteinizaton and granulosa cell apoptosis in controlled ovarian hyperstimulation and to investigate the anti-apoptotic effect of growth differentiation factor-9 (GDF9) in the premature luteinizaton granulosa cells.
Methods: Granulosa cell of premature luteinization and non-premature luteinizaton patients were isolated and determined by Annexin-V/ propidium iodide (PI) Double- Staining by flow cytometry or were exposed to 200ng/ml GDF9 and then determined by the same method.
Results: The percentage of morphological abnormal and apoptotic granulosa cell was higher in the premature luteinization group(P>1.1ng/ ml) than that of non premature luteinization group(P<1.1 ng/ml).The apoptosis percentage was significantly decreased after treatment by 200ng/ml GDF9.
Conclusions: The increased apoptosis activity of premature luteinization granulosa cell may be related to decreased GDF9 level.
第一章控制性超排卵中过早黄素化对IVF结局的影响
【目的】鉴于目前国内外对过早黄素化与IVF-ET临床结局的关系的研究仍然存在争议探讨长方案体外受精-胚胎移植(IVF-ET)控制性超排卵中注射HCG日过早黄素化现象与IVF-ET妊娠率的关系,分析过早黄素化病因。
【方法】回顾性分析2278个长方案进行IVF-ET的治疗周期,采用ROC曲线筛选过早黄素化诊断阈值并根据该阈值进行分组,从各组随机抽取316个周期比较临床参数。线性回归分析hCG日孕激素与其他临床变量之间的关系。
【结果】随着过早黄素化程度加深(注射hCG日孕激素值升高),临床妊娠率呈明显的下降趋势;P＜1.1 ng/mL是过早黄素化的最佳诊断阈值,具有94.6%的敏感度,45.6%的特异度;有19.6%(446)的治疗周期发现过早黄素化,过早黄素化组的FSH总用量(1949.0±595.8vs.1742.9±616.9),注射HCG日血清E_2(3065.9±1319.8 vs.2435.3±1063.5)和LH(3.1±2.8 vs.2.4±2.9)水平以及回收卵数(13.3±5.7 vs.11.3±5.6)明显高于非过早黄素化组周期,但是受精率(58.3±0.36 vs 69.2±0.24),IVF优质胚胎数(2.3±3.8 vs 3.5±2.6)及IVF-ET妊娠率(35.8%vs 48.2%)显著低于非过早黄素化组。线性回归分析仅鉴定出孕激素升高与E_2水平(r=0.135,P=0.016)和回收卵数(r=0.239,P＜0.01)相关。过早黄素化组的总临床妊娠率明显低于非过早黄素化组(38.6%vs 48.1%),两组间移植胚胎数,ICSI优质胚胎数和ICSI妊娠率无明显差异。
【结论】首次采ROC曲线筛选诊断过早黄素化诊断阈值。中国女性诊断过早黄素化的最好的诊断标准应该是P＞1.1ng/ml,过早黄素化的出现可能与HCG日雌激素和回收卵子数有关,IVF-ET周期中过早黄素化可能导致卵子质量下降,最终导致临床妊娠率显著下降;然而在ICSI周期中过早黄素化对优质胚胎数和妊娠率似乎并无显著影响,在临床中患者如若出现过早黄素化迹象,可适时建议进行ICSI治疗,以避开IVF-ET周期中PL对卵子的负面影响。
第二章控制性超排卵中过早黄素化颗粒细胞差异表达基因的分离和鉴定
【目的】在COH中常常发生过早的孕激素升高,同时伴发过早卵巢颗粒细胞向黄体细胞分化的过程,称为过早黄素化。其分子机理尚不清楚,为探索其分子基础,应用抑制消减杂交技术(Suppression subtractive hybridization,SSH)构建过早黄素化cDNA消减文库,并采用macroarray(膜阵列)和RT-PCR鉴定相关的差异表达基因,了解这些差异基因与过早黄素化发生的关系。
【方法】分离入选的过早黄素化病人(PL组30例)和对照组病人(非PL组30例)的卵泡液颗粒细胞。抽提颗粒细胞总RNA,逆转录合成cDNA,cDNA经RsaI酶切后,将PL组cDNA分成两组,分别与两种不同的接头街接,再与对照组cDNA进行两次消减杂交及两次抑制巢式PCR反应,将产物与pMD18-T载体连接,构建cDNA消减文序,并转染大肠杆菌进行文库扩增,随机挑选阳性克隆经PCR扩增后进行macroarray(膜阵列)杂交验证并RT-PCR半定量分析。经验证的克隆送测序并进行生物信息学同源性分析。
【结果】179个阳性克隆被随机挑选出来,86个克隆送测序并进行生物信息学分析。其中84个克隆代表了47个已知基因。这些基因参与类固醇合成,蛋白翻译,细胞黏附,细胞代谢,脂质代谢以及细胞凋亡。
【结论】首次成功构建了COH中过早黄素化颗粒细胞的差异基因的cDNA消减文库。这些基因功能涉及类固醇合成,蛋白翻译,细胞黏附,细胞代谢,脂质代谢以及凋亡。过早黄素化的发生可能与颗粒细胞内过度活跃的类固醇合成,脂质合成,凋亡活动以及细胞因子表达异常有关,研究这些差异基因与过早黄素化发生之间的关系,将有助于我们进一步了解过早黄素化发生的分子机制。
第三章过早黄素化差异基因mRNA及蛋白分析
【目的】进一步研究这些差异基因及编码蛋白在过早黄素化发生进程中的差异表达情况以及作用机制,我们根据第二章的研究结果、差异基因与过早黄素化发生的相关性以及我们所能获得的研究材料,挑选出部分基因采用real-time PCR和Western blot进行mRNA水平和蛋白水平的研究。
【方法】分离入院行辅助生殖技术治疗时发生过早黄素化病人和未发生过早黄素化病人的卵泡液颗粒细胞,一部分颗粒细胞提取RNA和细胞总蛋白,RNA逆转录合成cDNA,采用real-time PCR分析两组间类固醇急性合成调节蛋白(steroidogenic acute regulator,StAR)、乙酰辅酶A羧化酶(Acetyl-CoA carboxylase,ACC)、GDF9、bcl-2(B-cell lymphomaleukema 2)、P450aro(P450 aromatase)、P450侧链裂解酶(P450side-chain cleavage,P450ssc)、PHLDA1(pleckstrin homology-likedomain,family A,member 1)以及ubiquitin protein ligase E3的mRNA表达差异,细胞总蛋白采用Western blot方法分析两组间StAR、GDF9、bcl-2、PHLDA1蛋白表达差异。另一部分颗粒细胞分离后培养一部分添加GDF9(200ng/ml)干预,继续48小时培养观察GDF9对StAR蛋白的表达的影响。
【结果】在过早黄素化颗粒细胞中StAR、ACC、P450scc、PHLDA1及ubiquitin protein ligase E3的mRNA表达水平显著升高,而bcl-2和GDF9的mRNA表达下降(P＜0.05)。蛋白水平上发现StAR(30kDa)、PHLDA1(40kDa)、bcl-2(26kDa)、GDF9(51kDa)蛋白均能在颗粒细胞中表达,过早黄素化颗粒细胞中StAR(30kD)和PHLDA1(40kD)蛋白表达明显上调。然而bcl-2(26kDa)和GDF9(51kD)蛋白表达水平明显下调。培养的颗粒细胞添加GDF9(200ng/ml)干预后,颗粒细胞StAR蛋白表达明显下调,但基础StAR活性并未受到影响。
【结论】GDF9能明显抑制颗粒细胞内过度活跃的类固醇合成活性,但并不影响基础类固醇合成活性。过早黄素化的发生可能与GDF9过低表达以及凋亡基因PHLDA1表达升高和抗凋亡基因bcl-2表达过低导致的颗粒细胞凋亡活动增加有关。
第四章IVF-ET中颗粒细胞凋亡与过早黄素化关系
【目的】细胞凋亡(apoptosis)是指在特定信号诱导下,一系列基因按程序时空顺序表达,细胞内死亡级联反应导致程序性细胞死亡。生殖系统内组织细胞的凋亡变化在妊娠过程中有重要意义,任何一个环节失调,都可能影响妊娠的顺利进行。卵泡凋亡最初是从颗粒细胞开始发生的。在前面研究中我们在过早黄素化颗粒细胞中筛选出两个与凋亡相关的基因PHLDA1和bcl-2并发现PHLDA1表达水平上调,而抗凋亡基因bcl-2表达下降,同时观察到GDF9表达下降,因此我们推测细胞内凋亡活动上调也是过早黄素化发生的原因之一,而GDF9可能具有拮抗颗粒细胞凋亡的作用,本章的目的即为验证此假设。
【方法】根据细胞在凋亡启动时发生细胞皱缩,细胞膜发泡等形态异常,以及细胞膜发生磷脂酰丝氨酸(phosphatidylserine,PS)外翻这一特点,采用流式细胞仪和AnnexinV/FITC和PI双标法检测了过早黄素化颗粒细胞凋亡情况。此外,我们观察了添加200ng/mlGDF9干预对颗粒细胞凋亡的影响。
【结果】与非过早黄素化颗粒细胞(P＜1.1ng/ml)相比,过早黄素化颗粒细胞形态异常率升高(16.28%vs 5.38%,P＜0.05);过早黄素化组颗粒细胞的平均凋亡率明显增加(25.43%vs 10.05%,P＜0.05);过早黄素化组(P=1.4ng/ml、1.7ng/ml、2.0ng/ml)添加200ng/mlGDF9干预后颗粒细胞凋亡率显著下降
【结论】过早黄素化颗粒细胞凋亡活动增加,而GDF9能抑制过度活跃的凋亡活动,过早黄素化颗粒细胞GDF9低表达和颗粒细胞的凋亡可能是造成过早黄素化患者卵母细胞质量下降的原因之一。
Objective: To evaluate the effect of premature luteinization (PL)on the clinical outcomes and analyse the cause of PL in long GnRH-a cycles. Methods: 2278 patients with GnRH-a down regulation long protocol in our institution from May 2003 to May 2006 were assessed retrospectively. The patients were grouped (PL group and non-PL group) according to serum P cut-off threshold value on the day of hCG administration (P>1.1 ng/mL or P<1.1 ng/mL) which was determined by receiver operating characteristic (ROC) curve. Of them, 316 patients were sampling randomly from both groups respectively to compare clinical variable. Ovarian down-regulation was achieved using GnRH agonist downregulation long protocol with injection of GnRH-a in the midluteal phase of the previous cycle. Ovarian stimulation was started with daily injections of r-FSH (Gonal F, 75 IU, Serono Switzerland) or human menopausal gonadotrophin (hMG) until the day of hCG administration. The cut-off progesterone threshold was determined by ROC curve. The main outcome measures included fertilization rates and clinical pregnancy rates. Groups were compared by using the unpaired Student t, chi-squared test. The relationships between P level on hCG day and other variables were analyzed by multiple linear regression analysis. P<0.05 was considered statistically significant.
Results: The ROC curve showed a progesterone value (P>1.1 ng/mL ) as the most efficient cut-off threshold to discriminated between the pregnant and no pregnant cycles with a 94.6% sensitivity,45.6% specificity. Four hundred forty six (19.6%) of the 2278 patients enrolling in this study demonstrated premature luteinization. The total FSH dose(1949.0±595.8 vs. 1742.9±616.9), E_2(3065.95±1319.8 vs. 2435.3±1063.5), LH (3.13±2.8 vs. 2.36±2.99) level on hCG day, number of mature oocytes retrieved (13.3±5.7 vs. 11.3±5.6)were significantly higher in PL group as compared to the non-PL group. However, the fertilization rate (58.3±0.36% vs69.2±0.24%)and the number of good quality embryo(2.3±3.8vs3.5±2.6)were significantly lower in the PL group. The multiple linear regression analysis did not show a positive and significant association between the total FSH dose, LH, PRL and the serum P levels, but show a positive and significant association between E_2 (r=0.135, P=0.016), number of oocytes retrieved (r=0.239, P<0.01) and the serum P level. The fertilization rate and number of high quality embryos were similar between the two groups. The clinical pregnancy rate (38.6% vs. 48.1%) was significantly lower in the PL group.
Conclusions: The best P cut-off value to define premature luteinization may be P>1.1 ng/ml. Premature luteinization could adversely affect the pregnancy rate of IVF-ET in long GnRH-a cycles and it seems to have negative impact on oocytes quality. Premature luteinization could not be related to low ovarian reserve. Premature progesterone elevation of PL is related to E_2 on hCG day and number of mature oocytes retrieved.
Objective: A premature serum progesterone (P) elevation untimely before HCG administration during controlled ovarian hyperstimulation (COH) and the concomitant process of granulosa cells differentiate into luteal cells is usually called premature luteinization (PL), which could adversely affect clinical outcomes in IVF-ET. However, the molecular mechanisms of PL are not completely understood. The aim of this stuy is to explore the molecular mechanisms of premature luteinization.
Methods: Suppression subtractive cDNA hybridization was performed to identify genes differentially expressed in granulosa cell of premature luteinization. Differentially expressed genes were confirmed by macroarray dot blot analysis and real- time PCR. The differential cDNA fragments was sequenced and further analyzed by bioinformatics.
Results: 179 putative positive clones were randomly picked,and 86 clones were sequenced and searched in the GenBank. Among them, 84 clones represented 47 identified genes. These genes were involved in steroidogenesis, translation,cell adhesion,cellular metabolism, lipid metablism and apoptosis.
Conclusions: The differentially cDNA subtractive library of premature luteinization was first successfully constructed. The differentially expressed genes may have an important role in process of PL. Further studies of these genes should shed new light on understanding the molecular mechanism of premature luteinization.
Objective: To explore the relationship between the differentially expressed genes and the process of premature luteinization.
Methods: In the previous chapter we have constructed the differentially cDNA subtractive library of premature luteinization successfully and suggested these differentially expressed genes may have an important role in process of premature luteinization. According to their potential roles in the premature luteinization ,several genes and their encoding proteins were selected from the SSH cDNA library for further studies at mRNA or protein level by real-time PCR and Western blot. And we also examined the effect of growth differentiation facor-9 treatment on the expression of steroidogenic acute regulatory protein (StAR) by Western blot.
Results: As the results,we observed a remarkable mRNA up-regulation of steroidogenic acute regulatory protein (StAR), Acetyl-CoA carboxylase (ACC), P450 side chain cleavage enzyme (P450scc), pleckstrin homology- like domain, family A, member l(PHLDAl) and ubiquitin protein ligase E3 in PL granulosa cell and concurrent mRNA down-regulation of growth differentiation factor-9 (GDF9) and bcl-2. Significant up-regulations were also observed in the StAR (30kD), PHLDA1(40kD) protein levels. However, the GDF9(51kD) and bcl-2 (26kDa) protein level significantly reduced in the PL granulosa cells. GDF-9 treatment inhibited premature luteinization granulosa StAR expression but did not affect basal StAR expression.
Conclusions: So we concluded the increased expression of StAR, attenuated GDF9 protein and apoptosis induced by increased PHLDA1 and decreased bcl-2 protein may be responsible for the premature luteinization.
Objective: To investigate the relationship between premature luteinizaton and granulosa cell apoptosis in controlled ovarian hyperstimulation and to investigate the anti-apoptotic effect of growth differentiation factor-9 (GDF9) in the premature luteinizaton granulosa cells.
Methods: Granulosa cell of premature luteinization and non-premature luteinizaton patients were isolated and determined by Annexin-V/ propidium iodide (PI) Double- Staining by flow cytometry or were exposed to 200ng/ml GDF9 and then determined by the same method.
Results: The percentage of morphological abnormal and apoptotic granulosa cell was higher in the premature luteinization group(P>1.1ng/ ml) than that of non premature luteinization group(P<1.1 ng/ml).The apoptosis percentage was significantly decreased after treatment by 200ng/ml GDF9.
Conclusions: The increased apoptosis activity of premature luteinization granulosa cell may be related to decreased GDF9 level.
引文
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