卵巢早衰的遗传学研究进展

卵巢早衰(POF)是一种临床高度异质且病因复杂的疾病,遗传因素是其重要的发病原因。遗传因素主要包括X染色体、常染色体异常、微小RNA表达异常等。全基因组关联研究(GWAS)、高通量测序(NGS)技术等迅猛发展,可对基因标志物或核苷酸多态性进行统计分析,发现其间的内部联系,揭示新的致病基因,为POF的遗传学基础研究提供崭新的平台。     

卵巢早衰相关基因突变的最新研究进展

目前,对卵巢早衰(premature ovarian failure,POF)的病因和发病机制的认识还很不清楚。但无论是基因单核苷酸多态性的分析、家系的研究还是进一步功能性的研究,都显示X染色体上的BMP15、FMR1、FMR2和常染色体上的GDF-9、FSHR、INH、FOXL2、FOXO3a等可能与卵巢早衰的发生有关。但对于各基因进一步的功能研究相对较少,在不同人群中对各基因的研究结果尚缺乏一致性,研究中采纳的POF患者病例数还相对偏少。故需进一步对POF进行分子机制进行研究。     

自噬机制与卵巢早衰的关系

细胞自噬是哺乳动物细胞物质代谢的一种重要机制,细胞自噬异常将导致细胞功能异常甚至死亡。细胞自噬异常在卵巢早衰(POF)的发病中扮演着重要的角色,细胞自噬与细胞凋亡之间存在着许多分子联系,凋亡相关蛋白Bcl-2、Caspase与自噬相关蛋白Beclin-1互相作用,可以引起卵巢发育异常;凋亡蛋白Bim、Fas与自噬相关信号通路PTEN-PI3K及下游转录因子Fox O蛋白互相作用,可以导致卵巢卵泡激活异常;激素异常通过TGF-β/Smad3通路介导凋亡和自噬相关蛋白异常,导致卵泡闭锁,从而可以导致POF的发病。细胞自噬极有可能与细胞凋亡一起,是POF的主要发病机制。     

卵巢早衰危险因素的Meta分析

目的:探讨卵巢早衰(premature ovarian failure,POF)的危险因素,为该病的防治提供依据。方法:运用Meta分析对国内、外发表的11篇关于POF的病例对照研究资料进行定量综合分析;采用Stata11.0软件对所选的因素进行异质性检验、合并OR值及95%CI。结果:与POF有关的因素主要包括遗传因素(家族史);医源性因素(盆腔手术史、腹部及盆腔X线照射);感染因素(腮腺炎病史);饮食生活习惯(吸烟、饮酒、经常食用蔬菜、经常食用豆制品、染发);心理因素(心情);月经、婚育史(月经初潮早、离异或丧偶、口服避孕药、人工流产次数)。各因素合并OR值及95%CI分别为吸烟1.97(1.56,2.48)、盆腔手术史3.88(2.77,5.42)、腮腺炎病史8.77(1.62,47.40)、离异或丧偶2.15(1.07,4.32)、经常食用蔬菜0.54(0.42,0.70)、饮酒2.19(1.36,3.55)、人工流产次数1.52(1.23,1.89)、经常食用豆制品0.65(0.25,1.66)、心情0.16(0.11,0.24)、口服避孕药2.47(0.97,6.27)、月经初潮早1.38(0.59,3.21)、家族史4.46(1.89,10.53)、腹部及盆腔X线照射2.92(1.88,4.54)、染发3.56(2.01,6.31)。结论:经常食用蔬菜和心情好是卵巢早衰的保护因素;经常食用豆制品、口服避孕药及月经初潮早与POF的关联无统计学意义;其余均为危险因素。     

顺铂腹腔化疗与静脉化疗的药物分布比较

顺铂腹腔化疗与静脉化疗的药物分布比较滕雪玲蔡桂凤宋磊王莲凤顺铂用于卵巢癌化疗，静脉用药因毒副作用严重使用药剂量受到限制，而腹腔用药可减低毒性反应且可加大用药剂量。本研究通过比较腹腔化疗与静脉化疗顺铂在人体组织的分布，以及小鼠腹水瘤细胞ＤＮＡ中的含量变...     

卵巢早衰的研究现状与进展

卵巢早衰(POF)是生殖医学的一大难题,卵子形成与发育的任一环节受损都有可能导致POF。POF的病因复杂多样,其中遗传因素目前认为是最主要的原因,而环境因素近几年越来越受到重视。能被病因诊断的POF患者极少,大量研究专注于寻找POF形成的相关基因。改善低雌激素引起的症状,尽可能恢复患者生育功能是POF的主要治疗原则。     

紫杉醇、顺铂联合化疗在晚期卵巢上皮性癌的应用

目的评价对晚期卵巢上皮性癌患者术后行紫杉醇静脉和顺铂腹腔灌注联合化疗的疗效及副反应。方法晚期卵巢上皮性癌30例行肿瘤细胞减灭术后,采用PT方案化疗,紫杉醇135mg/m2静脉滴注,顺铂60～80mg/m2腹腔灌注,21～28天1疗程,平均6～8个疗程数。结果Ⅲ期总有效率为76.92%,Ⅳ期为50.00%。结论PT方案联合化疗效果好,毒副反应轻,有助于提高患者5年生存率和生存质量。     

含奈达铂与含顺铂联合化疗方案治疗晚期卵巢癌的临床对比研究

目的:比较含奈达铂与含顺铂联合化疗方案治疗晚期卵巢癌的疗效和不良反应。方法:2003年1月至2005年6月收治晚期卵巢癌患者37例,分别进入奈达铂+环磷酰胺或顺铂+环磷酰胺组,分析两组的近期疗效及毒副作用。结果:奈达铂组与顺铂组的近期有效率分别为41.18%和56.25%,两组无统计学差异(0.5>P>0.25);奈达铂组血液学毒性的发生率高于顺铂组,III度+IV度粒细胞减少、血小板减少尤为明显(发生率分别为65.0%vs 52.9%,15.0%vs 5.9%),但无统计学意义(P>0.25);奈达铂组与顺铂组胃肠道反应总体发生率近似,但III度+IV度胃肠道反应发生率前者低于后者,分别为20.0%和41.2%(0.25>P>0.1);奈达铂组2例患者(10%)出现肝功能损害,顺铂组未发现肝功能损害。两组均未出现肾功能损害病例。血β2-MG异常两组间也相似,但顺铂组尿β2-MG异常显著高于奈达铂组,并有统计学意义(P<0.025)。结论:奈达铂+环磷酰胺为晚期卵巢癌的有效化疗方案,近期疗效接近顺铂+环磷酰胺;奈达铂组的毒副作用以骨髓抑制为主,少数患者出现肝功能损害;顺铂组的毒副作用以胃肠道反应及早期肾功能异常为主。     

卵巢上皮性癌顺铂持续冲洗腹腔化疗14例近期疗效观察

目的：探讨持续腹腔冲洗化疗（washing intraperitoneal chemotherapy,WIP)是否较常规腹腔化疗（conventional intraperitoneal chemothrapy,CIP）更有效。方法：将29例Ⅱ期以上卵巢上皮癌患者随机分为WIP组（14例）和CIP组（15例）进行以顺铂（70mg/m^2)腹腔化疗为主的全身化疗（PAC方案）,WIP组给予DDP（70mg/m^2）常规腹腔化疗后开发以（DDP17．5mg.m^2 NS500mL)的浓度进行持续冲洗化疗;500mL/2h,治疗总时间为12h;CIP组为一次性灌注DDP70mg/m^2 NS2000mL。以治疗后前后CA125、腹水细胞周期及细胞凋亡率,尿β2m来评价近期临床疗效。结果：WIP组（CR＋PR）率为56％,CIP组20％,P＜0．05;S期在WIP组呈下降趋势;凋亡率在WIP组的差值（7．64％）显著高于CIP组（1．82％）,P＜0．05;尿β2m在两组的变化也具有统计学意义（P＜0．05）。结论：持续冲洗腹腔化疗的近期疗效优于常规腹腔化疗方法,可适用于临床。     

中药补肾调冲方对卵巢早衰大鼠激素水平和卵巢Bcl-2/Bax表达的影响

目的:探讨补肾调冲方对雷公藤多苷片(GTW)致卵巢早衰(POF)的治疗作用。方法:雌性SD大鼠42只,随机分为正常组、模型组、结合雌激素片(雌激素组)和补肾调冲方治疗高、中、低剂量组。运用酶联免疫吸附试验(ELISA)法检测血清中雌二醇(E_2)、卵泡刺激素(FSH)、抑制素B(INHB)水平。Western blotting法和RT-PCR法检测卵巢组织中Bcl-2、Bax蛋白及mRNA的表达水平。结果:正常组和各给药组E_2的含量均高于模型组(P0.01)。正常组和各给药组FSH含量均低于模型组(P0.01);正常组和各给药组INHB含量均高于模型组(P0.01)。低剂量组INHB的含量与雌激素组比较,差异有统计学意义(P0.05)。模型组大鼠卵巢中Bcl-2蛋白和mRNA水平的表达显著低于正常组(P0.05);各给药组Bcl-2蛋白和mRNA水平的表达显著高于模型组(P0.01)。模型组大鼠卵巢中Bax蛋白和m RNA水平的表达显著高于正常组(P0.05);各给药组Bax蛋白和mRNA水平的表达显著低于模型组(P0.01)。低剂量组Bax蛋白的表达与雌激素组比较,差异有统计学意义(P0.05)。结论:中药补肾调冲方对卵巢性激素水平具有调节作用,能提高卵巢对性激素的敏感性,促进卵巢排卵;通过上调Bcl-2和下调Bax的表达,抑制卵巢中颗粒细胞的过度凋亡,减少卵泡闭锁,促进卵巢功能的恢复。     

Effect of chemotherapy on primordial follicular reserve of rat: an animal model of premature ovarian failure and infertility

AIM: To determine the effect of paclitaxel and cisplatin in the reduction of primordial follicular reserve in rat. MATERIAL AND METHODS: Thirty young female rats were divided randomly into three groups of 10 rats each. Paclitaxel 7.5 mg/kg and cisplatin 5 mg/kg were administered intraperitoneally in a single dose sterile technique to paclitaxel (n=10), and cisplatin (n=10) groups, and sterile saline solution was given to a control group (n=10). To assess the effects of chemotherapeutic agents on the primordial follicles, the rats were oophorectomised 7 days after the administration of chemotherapeutic agents. Haematoxylin and eosin staining was used to determine the number of primordial follicles. Primordial follicles were identified by the presence of an oocyte encapsulated partially or completely by a single layer of flattened follicular cells without a theca layer at the ovarian cortex. RESULTS: The number of primordial follicles in the control group was 23.1 +/- 16.1 follicles. The number of primordial follicles were decreased significantly in both paclitaxel and cisplatin groups compared to control group (10.3 +/- 13.0 and 13.9 +/- 15.2 follicles, respectively) (P=0.001 and P=0.01, respectively). The difference in the number of primordial follicles between the paclitaxel and cisplatin groups was insignificant (P=0.465). CONCLUSION: The administration of high dose paclitaxel and cisplatin to young rats causes the depletion of primordial follicles. However, no significant difference was observed between the two agents.     

Profiling of differentially expressed microRNAs in premature ovarian failure in an animal model

Premature ovarian failure (POF) contributes to amenorrhoea, infertility, early onset of menostasia and osteoporosis. This study profiled differentially expressed miRNAs for association with POF development. Ovarian tissue samples from 4-vinylcyclohexene diepoxide (VCD)-induced rat POF and normal rats were profiled for differentially expressed miRNAs using miRNA microarrays. A total of 63 miRNAs were up-regulated and 20 miRNAs were down-regulated in rat POF tissues versus the control tissues. qRT-PCR verified some of these altered miRNAs, i.e. miR-29a and miR-144 were down-regulated in POF tissues, which may target expression of PLA2G4A that is involved in prostaglandin biosynthesis, whereas miR-27b and miR-190 were up-regulated in POF tissues by negative control of PAPPA and CCL2 expression, respectively, both of which have been shown to relate to response to hormone stimulus. Moreover, the up-regulated miR-151 and miR-672 can also target expression of TNFSF10 and FNDC1, which have been shown to positively regulate cell apoptosis. Profiling of differentially expressed miRNAs in POF provided a novel insight into the molecular events involving the role of miRNAs in POF development with specific emphasis upon miR-27b, miR-190, miR-151, miR-672, miR-29a and miR-144.     

顺铂腹腔注射对小鼠卵巢功能损伤机制的研究

目的 探讨顺铂（CDDP）对卵巢功能损伤的机制。方法 小鼠腹腔注射CDDP后,检测血清生殖激素水平、卵巢排卵计数、卵巢组织中丙二醛（MDA）的含量及总抗氧化能力（T-AOC）,观察卵巢形态。结果 CDDP给药后小鼠血清FSH和LH均升高,而E2和P均降低。卵巢组织MDA增高,T-AOC降低,卵泡计数减少,卵泡闭锁增加,细胞间质增生明显,卵巢呈现“纤维化”改变。结论 CDDP可通过氧化损伤作用,使细胞外基质的形成与降解的失衡,从而抑制卵泡和颗粒细胞功能状态,使卵巢功能早衰。     

Effectiveness of microlaparoscopy in the diagnosis of premature ovarian failure

AIM: Premature ovarian failure (POF) cases contain a mixture of cases possessing follicles (type A) and those depleted of follicles (type B). Differentiation between the two types is important because the treatment policy and pregnancy prognosis vary greatly. The objective of this study was to examine the usefulness of microlaparoscopy in the differentiation of types A and B. METHODS: Among 66 patient with POF diagnosed at our department between May 1996 and April 2004, 47 patients who gave informed consent and underwent microlaparoscopy were studied. The cases were divided into four groups based on the laparoscopic ovarian morphology. These groups were analyzed with respect to patient background, blood hormone levels, antinuclear antibody positive rate, visualization of the ovary on transvaginal ultrasonography, presence or absence of follicles in biopsy specimen, and number of follicles. RESULT: No significant differences in patient background and serum hormone levels were observed between groups. There was a tendency of increase in antinuclear antibody positive rate, increase in proportion of cases with follicles, and increase in number of follicles as the ovarian morphology approached normal. Transvaginal ultrasonography failed to identify the ovary in all the patients. CONCLUSION: Microlaparoscopy is useful in the differentiation between type A and B POF, and is further expected to become an indicator of response to treatment.     

Case report: Pregnancies established by gamete intrafallopian transfer and pronuclear-stage transfer in patients with premature ovarian failure using donated oocytes and low-dose oral micronized estradiol and progesterone

This report describes both gamete intrafallopian transfer (GIFT) and pronuclear-stage transfer (PROST) of donated oocytes to patients with premature ovarian failure (POF), using micronized oral progesterone (P₄) and lowdose micronized estradiol (E₂) for endometrial preparation and maintenance. Patient A, with POF of 15 years' duration, received four donated oocytes for GIFT and subsequently delivered a normal, term, female infant. Patient B was diagnosed as POF 3 years ago. She received four donated oocytes, which were subsequently fertilized in vitro with husband's sperm. The following day, four pronuclear-stage embryos were transferred to her fallopian tubes. She recently delivered twin, healthy female infants. These procedures, along with exogenous hormonal development of the endometrium, provide a simplified means to establish and maintain pregnancy in POF patients. Both patients were maintained on lowdose micronized E₂ prior to their procedure, Patient A on 3 mg E₂ per day cyclically and Patient B on 0.5 mg E₂ continuously. Micronized oral P₄ was used to maintain pregnancy.