Growth factors controlling ovarian functions

The present review demonstrates an important role of different growth factors (of insulin-like growth factors, epidermal growth factors, vascular endothelial growth factor, thrombopoietin, erytropoietin, hepatocyte growth factor, and growth factors of Hedgehog, Wnt and Notch families) in control of different ovarian functions--ovarian cell proliferation, apoptosis, folliculogenesis, luteogenesis, oogenesis, release of hormones, response to upstream hormonal regulators, fertility and, in some cases, in development of ovarian disorders. The possibility of practical application of these growth factors for characterization, prediction, and regulation the ovarian state is demonstrated.     

Production, reproductive, and metabolic factors associated with chlamydial seropositivity and reproductive tract antigens in dairy herds with fertility disorders

While chlamydial infections cause abortions in cattle, its role in other reproductive disorders is uncertain. This study identified the risk factors for chlamydial infection in herds with history of subfertility. We investigated the possible effects of coinfections, different metabolic parameters, abortion, ovarian cysts, pathological vaginal discharge, length of the open period, milk yield, housing conditions and age. In cows from 34 farms with elevated reproductive disorders, 41.5% had antibodies against chlamydia, while chlamydia antigen was detected in the vagina and uterus of 46.7%. A statistical relationship between seropositivity and antigen positivity was not found. Abortion (OR = 6.6) and loose housing (OR = 2.3) were risk factors for the presence of chlamydia antibodies. Furthermore, there were significant relationships between metabolic disorders and chlamydial infections. Increased levels of beta-hydroxybutaric acid (OR = 6.8) and hypocalcaemia (OR = 6.0) often accompanied chlamydia antigen in the vagina. Increased age (OR = 1.2) and pathological vaginal discharge (OR = 2.4) were identified as risk factors for chlamydia antigen in the vagina. The largest risk factor was for the association of ovarian cysts (OR = 21.5) with uterine antigen. In conclusion, chlamydial infection in dairy herd cows is best understood as a multifactorial disease.     

Raised serum chondroitin sulfate epitope level in ovarian epithelial cancer

OBJECTIVE: To determine the value of serum chondroitin sulfate epitope WF6 and hyaluronan (HA) levels as a biomarker for early detection of ovarian epithelial cancer and other gynecological disorders. METHOD: Serum WF6 CS epitope and HA were measured in 91 patients with ovarian epithelial cancer, 39 patients with non-cancer gynecological disorders and 30 healthy women. Serum chondroitin sulfate (CS) WF6 epitope was determined by a competitive immunoassay with the monoclonal antibodies WF6, which specifically recognizes an epitope in native CS chains. In addition, serum HA concentration was measured by an ELISA-based assay with a biotinylated affinity HA-binding proteins. RESULTS: The serum concentration of CS (WF6) epitope was highly increased in epithelial types of ovarian cancer and at all stages of development (p < 0.005). Serum HA in ovarian cancer patients was significantly higher than normal controls (p < 0.05). CONCLUSION: These results reflect changes in ECM metabolism in progressive ovarian cancer, which cause an increase in serum CS epitopes and HA. Therefore, serum CS epitopes may provide useful biomarkers for cancers and other disorders of the ovary. Measurement of serum HA provided complementary information, which may be useful as a discriminator between benign ovarian disorders and malignant ovarian diseases.     

The role of molecular genetic alterations in genes involved in folate and homocysteine metabolism in multifactorial diseases pathogenesis

The molecular genetic modifications in multiple genes involved in folate and homocysteine metabolism play the pivotal role in the development of hyperhomocysteinemia. Hyperhomocysteinemia is observed in 5% of patients worldwide and accompanies various multifactorial diseases, including neurodegenerative, autoimmune and vascular disorders and tumors. It should be noted that increased homocysteine level itself may point to some imbalance in the organism and represent a diagnostic marker of the development of some pathology. The present review describes the role of molecular-genetic modifications in one carbon metabolism accompanying different multifactorial diseases, including congenital birth defects, vascular disorders, diabetes, and hormone-dependent cancers such as breast and ovarian cancer. Data of the association between the SNPs in functionally significant genes involved in the one carbon metabolism and pathologies mentioned above were demonstrated. In addition, we firstly represent the data of the involvement of epigenetic factors (hypermethylation and miRNA) in regulation of these genes in multifactorial diseases. The section devoted to the role of molecular-genetic impairments in the genes involved in homocysteine metabolism associated with breast and ovarian cancer includes worldwide findings and our own results.     

An update on primary ovarian insufficiency

Primary ovarian insufficiency (POI) occurs in about 1% of female population under the age of 40, leading to reproductive problems, an earlier encounter with menopausal symptoms, and complicated diseases. There are three presumable mechanisms involved in the development of POI, namely apoptosis acceleration, follicular maturation blocking and premature follicle activation, through the following studied causes: (i) chromosomal abnormalities or gene mutations: mostly involve X chromosome, such as FMR1 premutation; more and more potentially causal genes have been screened recently; (ii) metabolic disorders such as classic galactosaemia and 17-OH deficiency; (iii) autoimmune mediated ovarian damage: observed alone or with some certain autoimmune disorders and syndromes; but the specificity and sensitivity of antibodies towards ovary are still questionable; (iv) iatrogenic: radiotherapy or chemotherapy used in cancer treatment, as well as pelvic surgery with potential threat to ovaries?? blood supply can directly damage ovarian function; (v) virus infection such as HIV and mumps; (vi) toxins and other environmental/lifestyle factors: cigarette smoking, toxins (e.g., 4-vinylcyclohexene diepoxide), and other environmental factors are associated with the development of POI. The etiology of a majority of POI cases is not identified, and is believed to be multifactorial. Strategies to POI include hormone replacement and infertility treatment. Assisted conception with donated oocytes has been proven to achieve pregnancy in POI women. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation have been used to preserve ovarian reserve in women undergoing cancer treatments.     

Genomewide discovery and classification of candidate ovarian fertility genes in the mouse

Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility.     

CCR9和CCL25蛋白在上皮性卵巢癌中表达及临床意义

目的:探讨CCR9和CCL25蛋白在不同卵巢组织中的表达及其与上皮性卵巢癌患者临床病理因素之间的关系。方法:通过组织芯片结合免疫组织化学法检测78例上皮性卵巢癌组织和30例正常卵巢组织中CCR9和CCL25表达水平,结合上皮性卵巢癌病人的临床病理资料,进行统计分析。结果:CCR9和CCL25在上皮性卵巢癌中高表达,在正常卵巢组织中低表达,二者的表达与上皮性卵巢癌的组织类型、患者年龄无显著相关(P0.05),而与淋巴结转移、组织学分级和临床分期有显著相关(P0.05);上皮性卵巢癌组织中CCR9与CCL25表达相关(P0.05)。结论:CCR9和CCL25在上皮性卵巢癌的发生发展中可能起重要作用,二者可能是上皮性卵巢癌治疗的一个潜在的分子靶点。     

TROP2在卵巢浆液性囊腺癌中的表达及其与预后的关系

目的:探讨TROP2在不同卵巢组织中的表达及其与卵巢浆液性囊腺癌患者临床病理因素之间的关系,明确TROP2表达是否与卵巢浆液性囊腺癌患者预后有关。方法:应用免疫组化法检测TROP2在98例卵巢浆液性囊腺癌组织及50例正常卵巢组织中的表达情况,分析TROP2表达与卵巢浆液性囊腺癌患者临床病理特征的关系,采用COX比例风险回归模型分析影响卵巢浆液性囊腺癌患者预后的因素。结果:TROP2在卵巢浆液性囊腺癌、正常卵巢组织中的表达阳性率分别为55.1%及24.0%,差异有统计学意义(P0.05)。TROP2表达与卵巢浆液性囊腺癌患者年龄无显著相关(P0.05),而与患者有无淋巴结转移,组织学分级和临床分期有显著相关(P0.05);临床分期、病理组织学分级、术后残余灶大小、TROP2基因表达均为影响卵巢浆液性囊腺癌患者预后的危险因素(P0.05)。结论:TROP2可能成为卵巢浆液性囊腺癌患者治疗的新靶点。     

Clinical analysis of reproductive failure among female buffaloes (Bubalus bubalis) under village management in Andhra Pradesh

Analysis of the clinical data of 20, 439 infertile graded Murrah female buffaloes (Bubalus bubalis ) of small and marginal farmers in Andhra Pradesh, examined over a period of two years, revealed that 2.50, 73.77 and 23.73 percent of the animals had reproductive disorders which were of anatomical, functional and non-specific infectious nature, respectively. Highest frequencies were of infantile tracts, ovarian quiescence and endometritis in each group, which together constituted 79.13 percent. The average gross incidence of various conditions encountered in order of frequency was: ovarian quiescence (56.36%), endometritis (20.68%), silent ovulations (5.3%), anovular heats (4.35%), sub-oestrus (3.48%), luteal persistency (3.37%), genital infantilism (2.09%), vaginitis (o.99%), salpingitis (0.98%), cystic ovarian degeneration (0.91%), bursal adhesions (0.75%), cervicitis (0.3%), hypoplasia of the ovaries and tracts (0.24%), paraovarian cysts (0.15%) and hydrosalpinx (0.03%). The incidence of quiescent ovaries followed seasonal trend with significant differences between seasons of the year both in heifers and cows. Between herds and between years, no marked difference in the incidence of different reproductive disorders was observed. It was estimated that 2.93 percent of the animals had disorders which rendered them unfit for breeding and, hence, sterile. Freemartinism was recorded in four cases. The comparative clinical features of freemartinism and cystic ovarian dgeneration in buffalo cows were described. The factors predisposing for higher incidence of endometritis in the species were also discussed.     

Clinico-roentgenologic diagnosis of chronic venous insufficiency of the ovaries

The paper is devoted to clinico-roentgenological correlations of venous reno-gonadal hemodynamics in 168 women of reproductive age (151 women with infertility, habitual abortion, disordered menstrual function and 17 patients without disorders of the reproductive tract). Clinico-laboratory investigation was followed by visceral and parietal phlebography for the detection of a pathological venous reflux into the ovarian pampiniform plexus. A retrograde blood flow along the internal ovarian vein with the development of venostasis and secondary pelvic varicocele was diagnosed in 67 women with disturbed reproductive function. In 17 women without disorders of reproductive function a reno-gonadal venous reflux was undetectable. Clinico-roentgenological semiotics of chronic venous ovarian insufficiency was analyzed. Infertility was shown to be the main clinical manifestation of ovarian varicocele.     

Protein kinases and ovarian functions

The present focus survey represents a short review of current knowledge concerning involvement of protein kinases in control of basic ovarian functions. Ovarian cells produce a number of protein kinases, whose expression depends on type of cells, their state and action of hormones and other protein kinases. A number of protein kinases are involved in control of ovarian cell proliferation, apoptosis, oocyte maturation, hormone release, reception and response to hormones, as well as in mediating action of hormones on these ovarian functions. Complexity of interrelationships between different protein kinase‐dependent signaling pathways occurs. Protein kinases and their regulators could be used for characterization, prediction and control of ovarian folliculogenesis and atresia, Corpus luteum functions, oocyte maturation, fertility, release of hormones, response of ovarian structures to hormonal regulators, as well as for treatment of some reproductive disorders. The present data demonstrate importance of protein kinases in control of basic ovarian function and potential usage of protein kinases for characterization, prediction and control of these functions. J. Cell. Physiol. 226: 37–45, 2010. © 2010 Wiley‐Liss, Inc.     

The ovarian insulin-like growth factors, a local amplification mechanism for steroidogenesis and hormone action

The importance of the ovarian insulin-like growth factors (IGFs) has been suggested by data from numerous laboratories and several approaches in the last several years. In the aggregate, these data indicate that this system could function as an important local amplification mechanism for steroidogenesis and gonadotropin action. Studies supporting this hypothesis have described several interacting components of this autocrine/paracrine system. First, the several types of ovarian cells possess an IGF-response system, which includes receptors for IGFs and an effective intracellular transduction system. The IGFs can promote growth and/or differentiation of ovarian cells, and their predominant actions depend on the nature of the cells and the presence of additional modulating factors. The biochemical events leading to enhanced steroidogenesis are now understood in considerable detail and include induction of several steps in the cAMP-dependent steroidogenic cascade. The second component of the ovarian IGF system comprises hormone-responsive local production of IGFs. Both IGF-I and IGF-II may be secreted; gonadotropins, gonadal steroids and locally produced growth factors can regulate the IGF system at this level. Finally, ovarian cells secrete a heterogeneous and complex family of IGF-binding proteins (IGFBPs). These proteins can impact on multiple ovarian functions in a manner which is generally opposite to that of the IGFs themselves. As is the case for the IGFs, the secretion of these proteins by ovarian cells is regulated by gonadotropins and locally produced ovarian factors. Collectively, these several components provide an integrated, synergistically cooperative local network to promote gonadotropin-dependent growth and differentiation in the ovary.     

膜联蛋白A4表达与卵巢浆液性囊腺癌化疗耐药性相关

目的:了解膜联蛋白A4(Annexin A4)在不同卵巢组织中的表达及其与卵巢浆液性囊腺癌患者临床病理因素之间的关系,明确Annexin A4表达与卵巢浆液性囊腺癌患者化疗敏感性是否有关。方法:通过免疫组化SP法检测58例卵巢浆液性囊腺癌组织和30例良性卵巢肿瘤中Annexin A4表达水平,对卵巢浆液性囊腺癌病人进行随访,了解其化疗敏感性,进行统计分析。结果:Annexin A4在卵巢浆液性囊腺癌组织中(74.1%)表达明显高于良性卵巢肿瘤(26.7%)(P0.05),且其表达在有无淋巴结转移及有无绝经的卵巢浆液性囊腺癌患者中无显著性差异(P0.05),而与患者组织分化程度、手术病理分期有关(P0.05)。Annexin A4蛋白在化疗耐药组(92.0%)的表达明显高于化疗敏感组(60.6%)(P0.05)。结论:Annexin A4在卵巢浆液性乳头状囊腺癌的发生发展中可能起重要作用,且与患者化疗耐药性有关,有望成为预测化疗敏感性的生物学指标。     

Regulation of the ovarian reserve by members of the transforming growth factor beta family

Genetic or environmental factors that affect the endowment of oocytes, their assembly into primordial follicles, or their subsequent entry into the growing follicle pool can disrupt reproductive function and may underlie disorders such as primary ovarian insufficiency. Mouse models have been instrumental in identifying genes important in ovarian development, and a number of genes now associated with ovarian dysfunction in women were first identified as causing reproductive defects in knockout mice. The transforming growth factor beta (TGFB) family consists of developmentally important growth factors that include the TGFBs, anti‐Müllerian hormone (AMH), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factor 9 (GDF9). The ovarian primordial follicle pool is the source of oocytes in adults. Development of this pool can be grossly divided into three key processes: (1) establishment of oocytes during embryogenesis followed by (2) assembly and (3) activation of the primordial follicle. Disruptions in any of these processes may cause reproductive dysfunction. Most members of the TGFB family show pivotal roles in each of these areas. Understanding the phenotypes of various mouse models for this protein family will be directly relevant to understanding how disruptions in TGFB family signaling result in reproductive diseases in women and will present new areas for development of tailored diagnostics and interventions for infertility. Mol. Reprod. Dev. 79: 666–679, 2012. © 2012 Wiley Periodicals, Inc.     

RNA interference and ovarian functions

RNA interference, a recently discovered new mechanism controlling gene expression via small RNAs, was shown to be involved in characterization and control of basic ovarian cell functions. The main classes of small RNAs, as well as their expression in ovaries have been described. Furthermore, the successful application of RNA interference for study and control of basic ovarian functions (proliferation, apoptosis, secretory activity, luteogenesis, oocyte maturation, and related ovarian cell malignant transformation) and production of recombinant proteins have been demonstrated. Application of RNA interference in reproductive biology and medicine can be successful in two main areas: (1) characterization and prediction of physiological and pathological state (association between particular small RNA and physiological or pathological processes), (2) application of small RNAs for regulation of reproductive processes and treatment of reproductive disorders or their particular indexes. Problems of improvement of small RNA delivery to target ovarian cells and potent RNA interference‐related approaches for treatment of ovarian disorders (especially of ovarian cancer) have been discussed. J. Cell. Physiol. 225: 354–363, 2010. © 2010 Wiley‐Liss, Inc.     

生物钟在卵巢生理和病理中的作用

哺乳动物的昼夜节律是基因编码的分子钟在体内产生的一种以大约24 h为周期的生理现象,使机体的生理过程与外界环境的变化相协调,是对环境适应的一种表现.在哺乳动物中,繁殖生理功能受生物钟系统的调节.在下丘脑-垂体-卵巢(hypothalamic-pituitary-ovarian,HPO)轴的各组织中均已观察到生物钟基因的...     

Genetic analysis of reproductive disorders in Israeli Holstein dairy cows

The heritability of common reproductive disorders was asessed in Israeli Holstein cows. Data were collected from 76,000 calvings on 102 collective farms (kibbuts) over a 36-mo period. The disorders considered were those of retained placenta, abnormal lochia, endometritis, anestrus, ovarian cysts with anestrus and ovarian cysts with nymphomania. The statistical model included fixed effects of herd-year, month of calving, duration of previous pregnancy, interaction between calving difficulty and sex of offspring, and the random effect of the sire. Herd-year effects consituted 0.68 of the explained variance of the incidence of retained placenta and approximately 0.89 of all the other disorders. Sire and calving-month effects were significant (P<0.05) for all the disorders. Heritability estimates of the disorders were 0.01 for retained placenta, abnormal lochia, and endometritis; 0.02 for anestrus; and 0.03 for all disorders. Correlations between any two disorders did not exceed 0.20. High genetic correlations were found between retained placenta and either abnormal lochia (0.90) or endometritis (0.70), while moderate genetic correlations were found among each of these and anestrus (0.30). Reproductive disorders occur as part of a complex which may be efficiently controlled by management measures. Nevertheless, breeding for resistance to reproductive disorders may also be feasible by using appropriate sires evaluated on a large number of daughters.