一、芳香化酶基因多态性和十一酸睾酮药物避孕差异相关性的研究 二、利用米非司酮药物建立小鼠子宫出血模型的研究
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摘要
目前世界上仍没有一个临床上正式推广使用的男性避孕药,研制安全、有效、可逆和能广为接受的男性避孕药已经是当务之急。睾酮作为男性激素避孕药物进行系统研究,迄今已有三十余年,在已经完成的多项男性激素避孕的临床实验研究中,睾酮(或其衍生物)作为一种甾体药物应用于男性激素避孕,单独或配伍使用雌激素(和/或孕激素)类药物,取得了很好的避孕效果,是一个非常有前景的男性避孕药物。
在研究过程中,发现人体对这类药物的反应具有多样性(药物反应存在着群体间和个体间的差异),可以观察到这类甾体药物对精子的抑制情况(如抑制精子发生的程度和显效时间的快慢等)在不同的人种间和个体间以及个体内都存在一定的差异,其发生的机制尚不清楚。
在临床实验中观察到雌激素对下丘脑和垂体具有负反馈调控作用,睾酮对下丘脑和垂体的负反馈作用较雌二醇弱得多,外源性睾酮主要通过芳香化酶作用转化为雌激素从而在垂体中发挥作用。此外,临床中发现的芳香化酶功能缺陷患者激素水平的表现也支持这种调控方式,这些患者共有的基本表型就是体内检测不到雌激素,但睾酮和促性腺激素的水平高于正常。因此,有理由认为睾酮在中枢神经系统芳香化酶的催化作用下转化为雌二醇,对下丘脑和垂体起负反馈抑制作用导致FSH和LH分泌减少,LH的减少影响Leydig细胞合成睾酮,并最终引起精原细胞发育和精子排放障碍,是男性使用外源性睾酮激素避孕中抑制精子发生的根本原因。由于睾酮抑制精子发生的作用是男性生殖内分泌调控的结果,越来越多的证据表明雌激素在男性生殖内分泌的负反馈调控中具有重要作用。因此,芳香化酶,一个催化雄激素转化为雌激素的关键酶,是本研究的兴趣所在。
同一药物在不同个体产生的效果不是完全相同的。环境因素和遗传因素都有可能产生和影响人体对药物反应的多样性,而这种差异首先是具有遗传差异基础的,是由于药物本身在不同个体体内活化、代谢、清除方面的差异所决定的。通过研究遗传多态性与个体对药物敏感性或耐受性之间的相关性,可以阐明遗传因素对药物效用的影响,从而为医生针对性的用药和药物的开发提供指导和依据。因此认识和阐明甾体药物反应群体和个体间差异产生和影响的机制,不仅对于提高药物作用的效果及未来个体化用药,同时对于揭示和完善甾体激素在人类生殖、发育和代谢中的作用机理以及男性生殖内分泌调控的具体机制具有极其重要的意义。
为此本研究目的在于从基因组水平探索芳香化酶基因多态性和睾酮药物避孕中药物反应多样性的相关性,并进一步研究这种相关性产生的机制。
方法:利用参加十一酸睾酮酯(TU)避孕有效性的多中心Ⅲ期临床研究的150名有生育史的正常中国河北两个地区汉族成年男性志愿者,对其中一组50名男子利用DHPLC和测序方法检测了CYP19基因的单核苷酸多态性,包括CYP19基因的9个编码外显子和PI.f及其各自上下游100～200bp范围序列共约7kb范围。对检测到的SNP位点进行相关表型的关联分析,并在另一组人群中进行了关联关系验证。对CYP19基囚检测到的多态性位点使用生物信息学工具对其进行了单体型界定和单体域分析,并进行表型的关联分析。对于发现的显著关联位点和区域通过核酸蛋白质结合反应对具体机制做了初步探讨。结果:在中国河北地区50名汉族男性中,检测出14个CYP19基因的多态性位点,其中有3个是首次检出,并与可检索到的人群相关数据进行了比较分析,认为CYP19多态性位点在编码区出现频率较少,在非编码区则出现的频率较多,其多态性在人群中的分布不均一,具有明显的人群差异性和种族差异性,并具有地区差异,提示芳香化酶的进化与环境因素相关。通过关联分析,人群的身高在位于intron 2和exon3的两个多态性位点的不同基因型间存在显著性差异(身高在GG和AA基因型间差距达4～5cm,P＜0.05)。利用检测出的SNP位点,使用生物信息学工具,界定了15种单体型,其中4种常见单体型的频率在人群中占81.8%,并且发现其中1种单体型与外源性睾酮抑制精子发生程度密切相关,在有精子组和无精子组中存在显著差异(P＜0.05)。在进一步单体域分析中,发现位于脑组织特异性启动子区域内的两个位点组成的单体型AC与外源性睾酮抑制精子发生程度密切相关,在有精子组和无精子组中存在显著性差异(P＜0.05),单体型AC个体更容易完全抑制精子的发生;通过蛋白质核酸的特异性结合反应,发现其中一个位点附近区域序列可以和脑组织细胞核核蛋白提取物发生特异性结合反应。结论:芳香化酶基冈的多态性在人群中存在种族和地域的明显差异。该基因的两个多态性位点5845A/G和5998A/G与身高密切相关,分别位于intron2和exon3中。芳香化酶基因脑组织特异性启动子区域中的两个多态性位点组成的单体型AC与外源性睾酮抑制精子发生程度差异有关,认为芳香化酶基因多态性与外源性睾酮抑制精子程度差异有关;并且其中一个位点附近区域存在与脑组织细胞核提取物中的蛋白特异性结合位点,表明该区域含有与脑组织特异性转录相关的顺式作用元件。
子宫内膜周期性的脱落、出血和再生是灵长类和其他月经动物特有的现象。人的子宫内膜是一个动态的组织,在宫内优势的内分泌和旁分泌环境的影响下,在适当时期未能受孕时,子宫内膜为准备下一次胚胎植入而经历一个极典型的大面积脱落、出血、修复、增殖和分化的循环,即存在一个反复的生理学损伤和修复重建过程。月经的状况直接关系着妇女的生殖健康。月经机制的研究受限于动物模型。可检索文献中仅有两个小鼠月经模型的报告,采用停止孕酮的注射或取出孕酮皮下埋植物模仿了灵长类分泌期黄体崩解所导致的情况。临床研究发现在黄体中晚期服用米非司酮常(Mifepristone,RU486)能促使子宫内膜脱落、出血,诱导月经提前出现。
因此本研究目的在于利用米非司酮建立小鼠子宫出血模型。方法:成年雌性去势NIH小鼠在花生油诱导蜕膜化后,给予米非司酮灌胃,间隔8小时检测形态学和血清激素水平至给药后48小时,并利用阴道细胞学检查监测出血状况。同时,利用免疫组织化学和原位杂交方法检测了VEGF在出血不同时程中子宫内膜中的表达。结果:蜕膜化子宫内膜在给药后16小时崩解严重,24小时脱落,伴阴道出血。子宫内膜在24小时出现再生,至48小时基本恢复。此过程中血清孕酮浓度保持不变,而雌激素浓度升高。VEGF主要表达在子宫内膜的腺体上皮细胞和间质细胞,在模型中子宫内膜出血的初期(8h)、高峰时期(16h和24h)以及修复期(32h)表达量较高。结论:人工诱导蜕膜化后的小鼠,利用米非司酮模拟孕酮的药理撤退,能够成功诱导发生月经样的改变。VEGF检测结果提示VEGF在子宫发生出血和修复中具有重要作用。
From a public health perspective,the need for contraception has been greater. For man,although there existed few male-specific methods(withdrawal,condoms, and vasectomy),the shortcomings of the existing methods not being negligible,and so some new male contraceptive methods were in researching such as hormonal contraceptive,contraceptive vaccine and so on.
Recent studying have demonstrated that the hormonal contraception is the new choice for male contraceptive methods,which is the most prospective in clinical application.Investigators have sought to develop a male hormonal contraceptive based on the observation that spermatogenesis depends on stimulation by gonadotropins,follicle-stimulating hormone(FSH) and luteinising hormone(LH). Most clinical trials demonstrated that exogenous high-dosage testosterone combined with or without progestin is a safe,effective and fully reversible method of male contraception.Compared with withdrawal and condoms,the participants' satisfaction with testosterone contraception was good.
In those completed clinical trails,however,a consistent finding in these studies is that azoospermia is achieved in only 40- 70%of Caucasian men and 97%of Chinese, and the remainder show exhibited various degrees of oligozoospermia.This diverse polymorphism of response to TU were observed inter- and intra-races.The explanation for the nonuniform induction of azoospermia by testosterone remains unknown.
Therefore,understanding the basis of the heterogeneity in response would not only provide important insights into the physiology of the male reproductive system but could,as a second step of development,also lead to a male contraceptive tailored to individual requirements
In this study,based on extensive reviewing research of male hormone contraception,it is indicated that estrogen is important for spermatogenesis and is a major regulator of the gonadal-pituitary feedback for the gonadotropin axis in male hormone contraception with exogenous high-dosage testosterone.In other words, androgen contraceptives may inhibit spermatogenesis by negative feeback effect on hypothalamus-pituitary-testis axis of estrogen transformed from testosterone.
Aromatase is the key enzyme responsible for the formation of estrogens from androgens.The aromatase gene encoding aromatase P450(estrogen synthetase) is expressed in several extragonadal sites and regulated in a tissue-specific fashion. Activation of each promoters give rise splicing of these untranslated alternative exons to form the mature transcript occurs at a common 3'-splice junction that is upstream of the translational start site.This means that although transcripts in different tissues have different 5'-termini,the coding region and thus the protein expressed in these various tissue sites are always the same.However,the promoter regions upstream of each of the several untranslated first exons have different cohorts of response elements,and so regulation of aromatase expression in each tissue that synthesizes estrogens is different.In human males,a number of tissues have the capacity to express aromatase and hence synthesize estrogens including testes and numerous sites in the brain such as several areas of the hypothalamus,limbic system,and cerebral cortex.
So,we set out association studies between complex phenotype in response to male TU contraception and polymorphism of aromatase gene aiming at providing clues to explain the diversity of contraceptive action among the subjects using present TU contraceptive regimen.
Methods:In this research,to identify and characterize of cyp19 gene polymorphism was performed by denaturing high-performance liquid chromatograph and sequencing in the population of which used TU contraception from China Hebei. The sequence of special promotor PI.f with 5' flanking region and all the cyp19 coding exons with some up and downstream sequences respectively were analysed. Then,we study the association within those found variation allele and phenotype in the population from hormone contraception by using ANOVA and some bioinformatic tools such as haplotyping etc.Finally,to determine whether we found the sequences strong related with nonuniform induction of azoospermia by testosterone in PI.f 5'flanking region can binding a certain transfactor,the electrophoretic mobility shift assay(EMSA) was used in analysis of DNA-protein interactions.
Results:In our study,fourteen variable sites were identified within a span of 7kb and deep divergence in the distribution of some SNPs was noted.We have performed an association study using these 14 biallelic polymorphism of cyp19 and determined there are two loci are associated with variation in height in 142 adult males from Han Chinese(p＜0.05).In association analysis within pheonotype and polymorphism of cyp19 gene used with haplotyping and haplotype blocking,we identified 15 haplotypes and 4 common haplotyps represent 81.8%of the study population with 8 variate allelels.Moreover,a haplotype block with two loci was found strong association with diverse induction of azzospermia by testosterone,which located that PI.f 5'flanking region.EMSA conformed that this special region in PI.f 5' flanking region can binding a certain protein.
Conclusion:These observations indicate that in men,genetic variation in cyp19 are involved in determining normal adult height,and contribute to the diverse induction of azoospermia by testosterone.In PI.f promoter region,there exits a transcript regulation region which have two found viriate site.Moreover,the analyses of haplotype and haplotype block defined by the grouping and interaction of several variants rather than any individual SNP correlated with complex phonotypes is more effective.
Humans and old-world primates differ from most other animals in that their endometrium undergoes bleeding,shedding,remodelling and subsequent regeneration if pregnancy is not established at the opportune time.Human endometrium is thus a dynamic tissue that,to prepare for implantation,undergoes well-defined cycles of proliferation,differentiation,and shedding(menstruation) in response to the prevailing endocrine and paracrine environment.The endometrium is consequently a site of recurrent physiological injury and repair。Research into menstrual mechanisms is hindered by the lack of availability of rodent models to assess the role of various factors in regulating menstrual function.Up to now,there are two reports about mouse menstrual-like model by physical progesterone withdrawl.In some clinical researching,RU 486,given to normally cycling women at midluteal and lateluteal phase,provokes uterine bleeding,shedding and menstruating in advanced.
So,we set out study on model of uterus bleeding-like changes in mice by using mifepristone.Methods:Ovarectomized NIH female mice were administered with mifepristone following oil-induced decidualization.Morphology,hormone levels were evaluated at an interval of 8 hours in 48 hours after treatment and bleedings were monitored by using vaginal smears examination.Expression ofVEGF mRNA and protein were evaluated by in situ hybridization and immunohistochemistry during menstrual-like progressing in mice model.Results:Decidual endometrium was breakdown drastically by 16 h,and shed by 24h accompanying the bleeding.The endometrium regenerated from 24 h and restored completely by 48 h.Progesterone levels in serum remained invariable,estradiol levels in serum increased during the process.VEGF mRNA and protein were localized in both the stroma and glandular epithelium.Expression is increased in the decidual endometrium zone during early bleeding and in remnant stroma zone and regenerated epitheliums fllowing that.The high levels of VEGF were correlated with the increase of serum estradiol levels in control uterus com.Conclusions:Menstrual-like changes in artificial decidualization mice were provoked by using mifepristone which mimic withdrawal of progesterone on pharmacologicl level.The expression of the vascular endothelial growth factor suggested that VEGF plays an important role in bleeding and regeneration in the endometrium in mice menstrual-like model using mifepristione.
在研究过程中,发现人体对这类药物的反应具有多样性(药物反应存在着群体间和个体间的差异),可以观察到这类甾体药物对精子的抑制情况(如抑制精子发生的程度和显效时间的快慢等)在不同的人种间和个体间以及个体内都存在一定的差异,其发生的机制尚不清楚。
在临床实验中观察到雌激素对下丘脑和垂体具有负反馈调控作用,睾酮对下丘脑和垂体的负反馈作用较雌二醇弱得多,外源性睾酮主要通过芳香化酶作用转化为雌激素从而在垂体中发挥作用。此外,临床中发现的芳香化酶功能缺陷患者激素水平的表现也支持这种调控方式,这些患者共有的基本表型就是体内检测不到雌激素,但睾酮和促性腺激素的水平高于正常。因此,有理由认为睾酮在中枢神经系统芳香化酶的催化作用下转化为雌二醇,对下丘脑和垂体起负反馈抑制作用导致FSH和LH分泌减少,LH的减少影响Leydig细胞合成睾酮,并最终引起精原细胞发育和精子排放障碍,是男性使用外源性睾酮激素避孕中抑制精子发生的根本原因。由于睾酮抑制精子发生的作用是男性生殖内分泌调控的结果,越来越多的证据表明雌激素在男性生殖内分泌的负反馈调控中具有重要作用。因此,芳香化酶,一个催化雄激素转化为雌激素的关键酶,是本研究的兴趣所在。
同一药物在不同个体产生的效果不是完全相同的。环境因素和遗传因素都有可能产生和影响人体对药物反应的多样性,而这种差异首先是具有遗传差异基础的,是由于药物本身在不同个体体内活化、代谢、清除方面的差异所决定的。通过研究遗传多态性与个体对药物敏感性或耐受性之间的相关性,可以阐明遗传因素对药物效用的影响,从而为医生针对性的用药和药物的开发提供指导和依据。因此认识和阐明甾体药物反应群体和个体间差异产生和影响的机制,不仅对于提高药物作用的效果及未来个体化用药,同时对于揭示和完善甾体激素在人类生殖、发育和代谢中的作用机理以及男性生殖内分泌调控的具体机制具有极其重要的意义。
为此本研究目的在于从基因组水平探索芳香化酶基因多态性和睾酮药物避孕中药物反应多样性的相关性,并进一步研究这种相关性产生的机制。
方法:利用参加十一酸睾酮酯(TU)避孕有效性的多中心Ⅲ期临床研究的150名有生育史的正常中国河北两个地区汉族成年男性志愿者,对其中一组50名男子利用DHPLC和测序方法检测了CYP19基因的单核苷酸多态性,包括CYP19基因的9个编码外显子和PI.f及其各自上下游100～200bp范围序列共约7kb范围。对检测到的SNP位点进行相关表型的关联分析,并在另一组人群中进行了关联关系验证。对CYP19基囚检测到的多态性位点使用生物信息学工具对其进行了单体型界定和单体域分析,并进行表型的关联分析。对于发现的显著关联位点和区域通过核酸蛋白质结合反应对具体机制做了初步探讨。结果:在中国河北地区50名汉族男性中,检测出14个CYP19基因的多态性位点,其中有3个是首次检出,并与可检索到的人群相关数据进行了比较分析,认为CYP19多态性位点在编码区出现频率较少,在非编码区则出现的频率较多,其多态性在人群中的分布不均一,具有明显的人群差异性和种族差异性,并具有地区差异,提示芳香化酶的进化与环境因素相关。通过关联分析,人群的身高在位于intron 2和exon3的两个多态性位点的不同基因型间存在显著性差异(身高在GG和AA基因型间差距达4～5cm,P＜0.05)。利用检测出的SNP位点,使用生物信息学工具,界定了15种单体型,其中4种常见单体型的频率在人群中占81.8%,并且发现其中1种单体型与外源性睾酮抑制精子发生程度密切相关,在有精子组和无精子组中存在显著差异(P＜0.05)。在进一步单体域分析中,发现位于脑组织特异性启动子区域内的两个位点组成的单体型AC与外源性睾酮抑制精子发生程度密切相关,在有精子组和无精子组中存在显著性差异(P＜0.05),单体型AC个体更容易完全抑制精子的发生;通过蛋白质核酸的特异性结合反应,发现其中一个位点附近区域序列可以和脑组织细胞核核蛋白提取物发生特异性结合反应。结论:芳香化酶基冈的多态性在人群中存在种族和地域的明显差异。该基因的两个多态性位点5845A/G和5998A/G与身高密切相关,分别位于intron2和exon3中。芳香化酶基因脑组织特异性启动子区域中的两个多态性位点组成的单体型AC与外源性睾酮抑制精子发生程度差异有关,认为芳香化酶基因多态性与外源性睾酮抑制精子程度差异有关;并且其中一个位点附近区域存在与脑组织细胞核提取物中的蛋白特异性结合位点,表明该区域含有与脑组织特异性转录相关的顺式作用元件。
子宫内膜周期性的脱落、出血和再生是灵长类和其他月经动物特有的现象。人的子宫内膜是一个动态的组织,在宫内优势的内分泌和旁分泌环境的影响下,在适当时期未能受孕时,子宫内膜为准备下一次胚胎植入而经历一个极典型的大面积脱落、出血、修复、增殖和分化的循环,即存在一个反复的生理学损伤和修复重建过程。月经的状况直接关系着妇女的生殖健康。月经机制的研究受限于动物模型。可检索文献中仅有两个小鼠月经模型的报告,采用停止孕酮的注射或取出孕酮皮下埋植物模仿了灵长类分泌期黄体崩解所导致的情况。临床研究发现在黄体中晚期服用米非司酮常(Mifepristone,RU486)能促使子宫内膜脱落、出血,诱导月经提前出现。
因此本研究目的在于利用米非司酮建立小鼠子宫出血模型。方法:成年雌性去势NIH小鼠在花生油诱导蜕膜化后,给予米非司酮灌胃,间隔8小时检测形态学和血清激素水平至给药后48小时,并利用阴道细胞学检查监测出血状况。同时,利用免疫组织化学和原位杂交方法检测了VEGF在出血不同时程中子宫内膜中的表达。结果:蜕膜化子宫内膜在给药后16小时崩解严重,24小时脱落,伴阴道出血。子宫内膜在24小时出现再生,至48小时基本恢复。此过程中血清孕酮浓度保持不变,而雌激素浓度升高。VEGF主要表达在子宫内膜的腺体上皮细胞和间质细胞,在模型中子宫内膜出血的初期(8h)、高峰时期(16h和24h)以及修复期(32h)表达量较高。结论:人工诱导蜕膜化后的小鼠,利用米非司酮模拟孕酮的药理撤退,能够成功诱导发生月经样的改变。VEGF检测结果提示VEGF在子宫发生出血和修复中具有重要作用。
From a public health perspective,the need for contraception has been greater. For man,although there existed few male-specific methods(withdrawal,condoms, and vasectomy),the shortcomings of the existing methods not being negligible,and so some new male contraceptive methods were in researching such as hormonal contraceptive,contraceptive vaccine and so on.
Recent studying have demonstrated that the hormonal contraception is the new choice for male contraceptive methods,which is the most prospective in clinical application.Investigators have sought to develop a male hormonal contraceptive based on the observation that spermatogenesis depends on stimulation by gonadotropins,follicle-stimulating hormone(FSH) and luteinising hormone(LH). Most clinical trials demonstrated that exogenous high-dosage testosterone combined with or without progestin is a safe,effective and fully reversible method of male contraception.Compared with withdrawal and condoms,the participants' satisfaction with testosterone contraception was good.
In those completed clinical trails,however,a consistent finding in these studies is that azoospermia is achieved in only 40- 70%of Caucasian men and 97%of Chinese, and the remainder show exhibited various degrees of oligozoospermia.This diverse polymorphism of response to TU were observed inter- and intra-races.The explanation for the nonuniform induction of azoospermia by testosterone remains unknown.
Therefore,understanding the basis of the heterogeneity in response would not only provide important insights into the physiology of the male reproductive system but could,as a second step of development,also lead to a male contraceptive tailored to individual requirements
In this study,based on extensive reviewing research of male hormone contraception,it is indicated that estrogen is important for spermatogenesis and is a major regulator of the gonadal-pituitary feedback for the gonadotropin axis in male hormone contraception with exogenous high-dosage testosterone.In other words, androgen contraceptives may inhibit spermatogenesis by negative feeback effect on hypothalamus-pituitary-testis axis of estrogen transformed from testosterone.
Aromatase is the key enzyme responsible for the formation of estrogens from androgens.The aromatase gene encoding aromatase P450(estrogen synthetase) is expressed in several extragonadal sites and regulated in a tissue-specific fashion. Activation of each promoters give rise splicing of these untranslated alternative exons to form the mature transcript occurs at a common 3'-splice junction that is upstream of the translational start site.This means that although transcripts in different tissues have different 5'-termini,the coding region and thus the protein expressed in these various tissue sites are always the same.However,the promoter regions upstream of each of the several untranslated first exons have different cohorts of response elements,and so regulation of aromatase expression in each tissue that synthesizes estrogens is different.In human males,a number of tissues have the capacity to express aromatase and hence synthesize estrogens including testes and numerous sites in the brain such as several areas of the hypothalamus,limbic system,and cerebral cortex.
So,we set out association studies between complex phenotype in response to male TU contraception and polymorphism of aromatase gene aiming at providing clues to explain the diversity of contraceptive action among the subjects using present TU contraceptive regimen.
Methods:In this research,to identify and characterize of cyp19 gene polymorphism was performed by denaturing high-performance liquid chromatograph and sequencing in the population of which used TU contraception from China Hebei. The sequence of special promotor PI.f with 5' flanking region and all the cyp19 coding exons with some up and downstream sequences respectively were analysed. Then,we study the association within those found variation allele and phenotype in the population from hormone contraception by using ANOVA and some bioinformatic tools such as haplotyping etc.Finally,to determine whether we found the sequences strong related with nonuniform induction of azoospermia by testosterone in PI.f 5'flanking region can binding a certain transfactor,the electrophoretic mobility shift assay(EMSA) was used in analysis of DNA-protein interactions.
Results:In our study,fourteen variable sites were identified within a span of 7kb and deep divergence in the distribution of some SNPs was noted.We have performed an association study using these 14 biallelic polymorphism of cyp19 and determined there are two loci are associated with variation in height in 142 adult males from Han Chinese(p＜0.05).In association analysis within pheonotype and polymorphism of cyp19 gene used with haplotyping and haplotype blocking,we identified 15 haplotypes and 4 common haplotyps represent 81.8%of the study population with 8 variate allelels.Moreover,a haplotype block with two loci was found strong association with diverse induction of azzospermia by testosterone,which located that PI.f 5'flanking region.EMSA conformed that this special region in PI.f 5' flanking region can binding a certain protein.
Conclusion:These observations indicate that in men,genetic variation in cyp19 are involved in determining normal adult height,and contribute to the diverse induction of azoospermia by testosterone.In PI.f promoter region,there exits a transcript regulation region which have two found viriate site.Moreover,the analyses of haplotype and haplotype block defined by the grouping and interaction of several variants rather than any individual SNP correlated with complex phonotypes is more effective.
Humans and old-world primates differ from most other animals in that their endometrium undergoes bleeding,shedding,remodelling and subsequent regeneration if pregnancy is not established at the opportune time.Human endometrium is thus a dynamic tissue that,to prepare for implantation,undergoes well-defined cycles of proliferation,differentiation,and shedding(menstruation) in response to the prevailing endocrine and paracrine environment.The endometrium is consequently a site of recurrent physiological injury and repair。Research into menstrual mechanisms is hindered by the lack of availability of rodent models to assess the role of various factors in regulating menstrual function.Up to now,there are two reports about mouse menstrual-like model by physical progesterone withdrawl.In some clinical researching,RU 486,given to normally cycling women at midluteal and lateluteal phase,provokes uterine bleeding,shedding and menstruating in advanced.
So,we set out study on model of uterus bleeding-like changes in mice by using mifepristone.Methods:Ovarectomized NIH female mice were administered with mifepristone following oil-induced decidualization.Morphology,hormone levels were evaluated at an interval of 8 hours in 48 hours after treatment and bleedings were monitored by using vaginal smears examination.Expression ofVEGF mRNA and protein were evaluated by in situ hybridization and immunohistochemistry during menstrual-like progressing in mice model.Results:Decidual endometrium was breakdown drastically by 16 h,and shed by 24h accompanying the bleeding.The endometrium regenerated from 24 h and restored completely by 48 h.Progesterone levels in serum remained invariable,estradiol levels in serum increased during the process.VEGF mRNA and protein were localized in both the stroma and glandular epithelium.Expression is increased in the decidual endometrium zone during early bleeding and in remnant stroma zone and regenerated epitheliums fllowing that.The high levels of VEGF were correlated with the increase of serum estradiol levels in control uterus com.Conclusions:Menstrual-like changes in artificial decidualization mice were provoked by using mifepristone which mimic withdrawal of progesterone on pharmacologicl level.The expression of the vascular endothelial growth factor suggested that VEGF plays an important role in bleeding and regeneration in the endometrium in mice menstrual-like model using mifepristione.
引文
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