邻苯二甲酸酯类化合物与睾丸源性生殖障碍综合征

流行病学研究显示妇女在怀孕期间接触邻苯二甲酸酯类化合物后,所产男婴易患隐睾、尿道下裂、成年期睾丸肿瘤及精液质量低下等症状。这类症状可统称为睾丸源性生殖障碍综合征(testicular dysgenesis syndrome,TDS)。TDS可能是由男性胎儿睾丸的发育在子宫内受到影响不能发育出具有正常功能的睾丸间质(Leydig)细胞和支持(Sertoli)细胞引起的。例如,睾丸间质细胞接触邻苯二甲酸酯类化合物后,睾丸间质细胞的两种产物———睾酮和胰岛素样生长因子3(INSL3)———受到了抑制,两者对于睾丸下降起关键作用。成年期睾丸的胎儿型间质细胞和支持细胞错位可能是精子生成减少的原因。     

唯支持细胞综合征发病机制研究进展

唯支持细胞综合征(sertoli cell only syndrome,SCOS)是一种少见的的男性不育症,目前确诊主要根据睾丸组织活检见睾丸曲细精管内生精上皮细胞缺如,仅剩下支持细胞.SCOS发病机制复杂,目前对Y染色体长臂无精子症因子(azoospemia fator,AZF)的微缺失方面较深入,而错配修复蛋白缺陷、SPA-TA12、热休克转化因子、NuPR1、转化生长因子β也可能参与SCOS的发生,本文旨在对SCOS发病机制作一综述.     

睾丸生殖细胞瘤基因组学研究进展

睾丸生殖细胞瘤(TGCT)是最常见的睾丸恶性肿瘤,发病率逐年升高。然而,睾丸肿瘤的发病原因及机制尚未明确,新兴的第2代测序技术(NGS)已成为TGCT发病机制研究的主流手段。本文将对多年来TGCT基因组学研究进行总结,以便从基因层面上揭示该肿瘤的发病机制。总结发现基因表达差异、基因突变、易感基因主导的信号通路及性染色体上相关基因的改变在TGCT发生、发展过程中起到重要作用。睾丸肿瘤的基因组学研究意义重大,找出关键致病基因,为从基因水平上早期诊断筛查及后续的靶向治疗提供理论基础。     

细胞因子在精索静脉曲张导致男性不育中所起的作用

精索静脉曲张(varicocele,VC)是男性泌尿生殖系统中常见的疾病之一.其对男性生育的影响越来越受到重视.目前普遍认为可能的机制有:睾丸温度升高机制、睾丸缺血缺氧机制、毒素反流机制、附睾损害机制、生殖激素机制、生物学机制以及一氧化氮(N0)与细胞凋亡等.近来人们发现,细胞因子在男性不育的发病机制中起着十分重要的作用,是影响睾丸功能、精子发生的重要因素.本文从细胞因子角度,结合近年的相关文献进行综述.     

Desert Hedgehog调控Leydig细胞增殖分化的研究进展

Hedgehog信号通路是内分泌腺体发育的一个重要调控因子通路。近年来,Desert Hedgehog(Dhh)在睾丸性腺发育中的调控作用备受关注,尤其是对Leydig细胞的调节作用。在睾丸中,Dhh由Sertoli细胞旁分泌产生而作用于Leydig细胞,对其增殖、分化过程及其分泌睾酮的功能起调控作用。睾酮的分泌对睾丸发育、精子发生及雄性表型的维持至关重要,因而对Dhh因子的正确调控是生精功能的前提条件。对睾丸中Hedgehog信号通路的研究,也将对雄激素不足及生精障碍等疾病的病理生理机制研究和临床治疗具有一定的潜在意义。     

异位骨化发病机制的研究进展

目的总结异位骨化(heterotopic ossification,HO)发病机制的研究进展。方法查阅近年有关HO危险因素及发病机制的文献,并综合分析。结果 HO发病机制尚未明确,但对HO相关的细胞外因子、信号通路、转录因子等有了更深入了解,如BMP、Smad信号通路、核心结合因子α1/成骨特异性转录因子2等可能参与了HO的形成,而一些相关的微小RNA也有可能参与HO形成。结论通过对HO发病机制进一步研究,为有效防治HO奠定基础。     

纤溶酶原激活因子及其抑制因子与睾丸支持细胞

纤溶酶原激活因子 (PA)及其抑制因子 (PAI)参与机体的多种生理、病理活动。支持细胞是睾丸精曲小管的重要组成部分 ,其正常功能的发挥对精子发生等生物学行为的正常进行具有非常重要的意义。睾丸支持细胞在激素及其他因子的作用下 ,分泌PA及PAI,发挥生物学作用 ,维持正常的精子发生、精子活力及受精过程 ,两者之间的关系正日益受到人们的重视     

影响睾丸引带发育的内分泌因素研究进展

睾丸引带与睾丸下降关系密切,它的分化发育和多种因素有关,特别是雄激素、降钙素基因相关肽、胰岛素样因子3、苗勒管抑制物质、表皮生长因子以及环境雌激素(EEs)等,其中降钙素基因相关肽、胰岛素样因子3和EEs对生殖系统的影响是目前研究的热点。从影响睾丸引带发育的角度探讨EEs对睾丸及生殖发育的影响很有意义。     

诱蛋白基因敲除对雄性小鼠细胞因子水平的影响

细胞因子是一系列参与造血、免疫细胞发育、炎症反应和免疫应答等的调节蛋白.有的细胞因子可直接影响睾丸细胞的功能.有研究显示,细胞因子在睾丸的发育和发挥正常功能方面有着重要的作用[1].致炎细胞因子包括白细胞介素(IL)-1和IL-6对于生精细胞的分化和睾丸甾体激素的合成有着直接的作用.干细胞因子、白血病抑制因子和参与造血作用的细胞因子对于精子发生也有一定的作用.本课题组研究发现,attractin(Atrn)基因敲除后小鼠的生育能力有不同程度的下降.本实验旨在了解Atrn基因敲除后小鼠的细胞因子水平变化,为进一步研究Atrn基因对雄性生殖的影响机制提供依据.     

睾丸中生殖细胞凋亡通路的调节机制研究进展

细胞凋亡是生物体细胞的主动消亡过程,是多细胞有机体调控机体生长发育、控制细胞衰老,并维持机体内外环境稳定的重要机制,也是当今生命科学领域的热点。而细胞凋亡作为一种维持体内平衡的基本生物学过程,在睾丸中细胞的分化、精子的成熟及存活中也发挥着重要作用。在精子发生的过程中,任何环节的改变都有可能影响凋亡过程的进行,从而破坏生殖细胞存活与死亡之间的平衡。目前研究表明,线粒体通路、细胞死亡受体通路以及内质网通路是睾丸中生殖细胞凋亡的重要途径,且上述3条通路中各因子之间互相影响,从而形成了复杂的生殖细胞凋亡调控网络。本文对近年来国内外关于睾丸生殖细胞凋亡通路研究的相关文献进行回顾与总结,具体阐述3条通路的相关调节机制。     

Testicular dysgenesis syndrome and the origin of carcinoma in situ testis

Recent increases in male reproductive disorders have been linked to exposure to environmental factors leading to the testicular dysgenesis syndrome (TDS). Testicular cancer is the most severe condition in TDS and studies have shown a clear correlation between risk of testicular cancer and other components of TDS and that the geographical location of the mother during pregnancy can be a risk factor. This suggests that the dysgenesis has its origin in utero and that TDS is initiated by environmental factors, including possibly hormone-disrupting compounds that act on the mother and the developing foetus, but the genetic background may also play a role. The morphological similarity of carcinoma in situ (CIS) cells (the precursor of the majority of invasive testicular cancers) with primordial germ cells and gonocytes, and overlap in expression of protein markers suggests an origin of CIS from primordial germ cells or gonocytes. CIS cells and germ cell-derived cancers of the human type have so far not been described in any animal model of TDS, which could be caused by species differences in the development of the male gonad. Regardless of this, it is plausible that the dysgenesis, and hence the development of CIS cells, is a result of disturbed signalling between nurse cells and germ cells that allow embryonic germ cells to survive in the pre-pubertal and adult testis. The post-pubertal proliferation of CIS cells combined with aberrant signalling then leads to an accumulation of genetic changes in the CIS cells, which eventually results in the development of invasive testicular cancer in the adult.     

A rare diagnosis： testicular dysgenesis with carcinoma in situ detected in a patient with ultrasonic microlithiasis

A rare case is presented where a dysgenetic testis with microinvasive carcinoma in situ （CIS, also known as intratubular germ cell neoplasm of unclassified type [IGCNU] and testicular intraepithelial neoplasia [TIN]） with microinvasion to rete testis and the interstitial tissue was found in a 32-year-old man presenting with mild scrotal pain and ultrasonic testicular microlithiasis. Knowledge of the association of ultrasound and CIS is important to diagnose patients at the stage prior to development of an overt germ cell tumor. The patient had three of four disorders considered symptoms of the testicular dysgenesis syndrome （TDS）： a dysgenetic left testicle with CIS, a mild left-sided cryptorchidism （high positioned scrotal hypotrophic testis） and a slightly reduced semen quality. Therefore, it should be kept in mind that a patient with one TDS symptom may harbour the other, even CIS or testicular cancer. Accordingly, patients with one TDS symptom ought to be examined for the presence of the others, and if more that one is present, extra concern is warranted.     

Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations

Recently a worldwide rise in the incidence of testicular germ cell cancer (TGCC) has been repeatedly reported. The changing disease pattern may signal that other testicular problems may also be increasing. We have reviewed recent research progress, in particular evidence gathered in the Nordic countries, which shows strong associations between testicular cancer, undescended testis, hypospadias, poor testicular development and function, and male infertility. These studies have led us to suggest the existence of a testicular dysgenesis syndrome (TDS), of which TGCC, undescended testis, hypospadias/disorders of sex differentiation and male fertility problems may be symptoms with varying penetration. In spite of their fetal origin, most of the TDS symptoms, including TGCC and poor semen quality, can only be diagnosed in adulthood. Data from a Danish-Finnish research collaboration strongly suggest that trends in TGCC rates of a population may be 'whistle blowers' of other reproductive health problems. As cancer registries are often of excellent quality - in contrast to registries for congenital abnormalities - health authorities should consider an increase in TGCC as a warning that other reproductive health problems may also be rising.     

Reproductive dysgenesis in wildlife: a comparative view

Abnormal reproductive development in males has been linked to environmental contaminant exposure in a wide variety of vertebrates. These include humans, rodent models, and a large number of comparative wildlife species. In human males, abnormal reproductive development can manifest as a suite of symptoms, described collectively as testicular dysgenesis syndrome (TDS). TDS is also described as demasculinization or feminization of the male phenotype. The suite includes cryptorchidism, in situ germ cell carcinoma of the testis and overt testicular cancer, reduced semen quality, and hypospadias. In this paper, we review examples of TDS among comparative species. Wildlife exposed to environmental contaminants are susceptible to some of the same developmental abnormalities and subsequent symptoms as those seen in human males with TDS. There are additional end points, which are also discussed. In some cases, the symptoms are more severe than those normally seen in humans with TDS (i.e. oocytes developing within the testis) because some non-mammalian species exhibit greater innate reproductive plasticity, and are thus more easily feminized. Based on our review, we present an approach regarding the ontogeny of TDS. Namely, we suggest that male susceptibility to the androgynizing influences of environmental contaminants originates in the sexually undifferentiated embryo, which, in almost all species, including humans, consists of bipotential reproductive tissues. These tissues can develop as either male or female and their ultimate direction depends on the environment in which they develop.     

Risk factors for hypospadias in Norwegian boys - association with testicular dysgenesis syndrome?

It has been proposed that hypospadias, cryptorchidism and testicular cancer, as well as decreasing sperm quality are symptoms of an underlying entity called testicular dysgenesis syndrome (TDS). We wanted to study the risk factors for hypospadias and compare them with those of the other conditions belonging to TDS. A large case-control study was undertaken on data on all live-born boys registered in the Medical Birth Registry of Norway during the period 1967-1998 (n = 961 396; hypospadias cases = 2382). Logistic regression analysis was used to study the association between potential risk factors and hypospadias, estimated by odds ratio (OR). The risk factors for hypospadias were divided into four categories: (i) maternal characteristics, e.g. low parity [p(trend) < 0.001], hypertension (OR = 1.49) and bleeding (OR = 1.39) during index pregnancy, and (pre)eclampsia (OR = 1.84); (ii) complications during delivery, e.g. retained placenta (OR = 1.67) or Caesarean section (OR = 1.36); (iii) characteristics of the newborn, e.g. low birth weight [p(trend) < 0.001], small for gestational age (OR = 2.16), and presence of congenital malformations other than hypospadias (OR = 2.72), e.g. inguinal hernia (OR = 5.65); (iv) prevalence among relatives of hypospadias cases, e.g. brother with hypospadias (OR = 20.81). The novel finding of retained placenta as a risk factor indicates that early malfunction of placenta could be a causative factor for hypospadias. When comparing with previously published risk factors for hypospadias, cryptorchidism and testicular cancer, we found that the following risk factors were common to all three conditions: low parity, low birth weight, low gestational age, inguinal hernia, bleeding during pregnancy and Caesarean section. In conclusion, our results support the notion that the conditions of TDS share risk factors.     

睾丸微结石的临床意义及处理

睾丸微结石(TM)是生精小管内的钙盐沉积。随着阴囊B超的广泛应用,临床诊断的TM病例增多。TM可并发于多种疾病,包括隐睾、男性不育、精索静脉曲张、睾丸扭转、克氏综合征、生精小管生殖细胞内瘤(IGCN)和睾丸生殖细胞瘤(TGCT)等。泌尿外科及男科医师关注的问题是TM常并发IGCN、TGCT及男性不育。TM的病因不明,其生物学性能及临床意义未能确定。目前对TM与IGCN、TGCT及男性不育之间的相互关系尚有争议。本文介绍TM的定义、发病率、病因学及组织病理学,并简要概述TM并发IGCN及TGCT,TM并发男性不育及TM的处理。     

慢性睾丸痛的诊断治疗进展附光盘简

慢性睾丸痛定义为间断或持续性单侧或双侧睾丸疼痛不适、病程超过3个月的慢性疼痛综合征。慢性睾丸痛是个棘手的临床难题，因缺乏有效的诊断和治疗手段，给泌尿外科和男科医生带来了强有力的挑战。慢性睾丸痛的治疗选择多依据病因，但其病因繁多，而且很多无法找到确切病因。精索显微去神经术是治疗慢性睾丸痛的有效方法，术前精索封闭呈阳性反应对预测手术成功率有帮助。本文对慢性睾丸痛的发病率、发病机制、病因、诊断和治疗的最新进展进行了复习。     

Evaluation of HLA Expression on Gametogenic Cells Isolated from Human Testis/Auswertung der HLA-Expression von Keimzellen aus dem menschlichen Hoden

Human germinal cells were isolated using a combined mechanical method and enzymatic digestion of testicular tissue. The attempt to fractionate the testicular cells by centrifugation in the continuous and discontinuous Percoll gradient was undertaken. The homogeneous (100%) fraction of late spermatids and enriched fractions of spermatocytes (up to 60%) and round spermatids (approx. 66%) were obtained. Cell-binding radioimmunoassay (CB-RIA) was used to evaluate the HLA expression both on heterogeneous suspensions and enriched fractions of testicular, germ cells using mouse monoclonal antibodies directed to Class I (HLA, -A, -B, -C) and Class II (HLA, -DR) determinants of MHC (main histocompatibility complex). Consistently negative results were obtained as well for heterogenous populations of germinal cells as their fractions in respect to both Class I and Class II antigenic determinants of HLA system.