Human Reproductive Failure Research Articles

Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression.

Aneuploidy in preimplantation embryos is a major cause of human reproductive failure. Unlike uniformly aneuploid embryos, embryos diagnosed as diploid-aneuploid mosaics after preimplantation genetic testing for aneuploidy (PGT-A) can develop into healthy infants. However, the reason why these embryos achieve full reproductive competence needs further research. Current RNA sequencing techniques allow for the investigation of the human preimplantation transcriptome, providing new insights into the molecular mechanisms of embryo development. In this prospective study, using euploid embryo gene expression as a control, we compared the transcriptome profiles of inner cell mass and trophectoderm samples from blastocysts with different levels of chromosomal mosaicism. A total of 25 samples were analyzed from 14 blastocysts with previous PGT-A diagnosis, including five low-level mosaic embryos and four high-level mosaic embryos. Global gene expression profiles visualized in cluster heatmaps were correlated with the original PGT-A diagnosis. In addition, gene expression distance based on the number of differentially expressed genes increased with the mosaic level, compared to euploid controls. Pathways involving apoptosis, mitosis, protein degradation, metabolism, and mitochondrial energy production were among the most deregulated within mosaic embryos. Retrospective analysis of the duration of blastomere cell cycles in mosaic embryos revealed several mitotic delays compared to euploid controls, providing additional evidence of the mosaic status. Overall, these findings suggest that embryos with mosaic results are not simply a misdiagnosis by-product, but may also have a genuine molecular identity that is compatible with their reproductive potential.

Japanese encephalitis virus restricts HMGB1 expression to maintain MAPK pathway activation for viral replication

Japanese encephalitis virus (JEV) is a typical insect-borne flavivirus and an important zoonotic pathogen that causes human viral encephalitis and reproductive failure in pigs. Various strategies were utilized by JEV to facilitate its replication. It is important to identify key molecules that mediate JEV infection, as well as to investigate their underlying mechanism. In this study, the critical role of high-mobility group box 1 (HMGB1), a non-histone, DNA-binding protein, was assessed in JEV propagation. Upon JEV infection, the HMGB1 mRNA and protein levels were down-regulated at late infection in Huh7 cells. JEV replication was significantly enhanced with HMGB1 knock-down by siRNA and knock-out by the CRISPR/Cas9 system, whereas JEV growth was restricted in HMGB1-over-expressed Huh7 cells. Further investigation showed that HMGB1 suppressed MAPK pathway, and demonstrated that the weakening of MAPK pathway negatively regulated JEV infection. Together, these results suggested that JEV restricted HMGB1 expression to maintain MAPK pathway activation for viral replication. Our data showed that HMGB1 played a key role in JEV infection, providing the potential for the development of a novel drug to combat JEV infection.

The effects of hepatitis B virus infection on natural and IVF pregnancy: A meta-analysis study.

Hepatitis B virus (HBV) has been considered a significant cause of human reproductive failure in different studies; however, there is a considerable disagreement on the true impacts of HBV on female reproduction. This study has evaluated the impact of HBV infection on pregnancy complications in natural pregnancy and also on pregnancy outcomes in women undergoing in vitro fertilization(IVF) treatment. We searched Embase, Web of Science, PubMed and Google Scholar databases to identify the potentially relevant studies. Summary odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis and publication bias testing were also performed. A total of 42studies concerning the effect of HBV infection on the natural and IVF pregnancy were included in this study. Our meta-analysis results revealed that HBV infection had a positive correlation to gestational diabetes mellitus (GDM) [OR=1.32 (1.17-1.48) (p<0.01)] and preterm birth [OR=1.26 (1.14-1.40) (p<0.01)] in natural pregnancy; however, HBV infection was not significantly associated with decreased fertility rates among the patients who underwent IVF. This study revealed a strong association of GDM and preterm birth with higher rates of HBV infection in pregnant women. Also, our results suggested that HBV infection in patients undergoing IVF may not negatively influence the pregnancy outcome. It may be rational to conclude that IVF might be rather a safe and effective method for HBV+ females who desire to have children.

Maternal Effect Mutations: A Novel Cause for Human Reproductive Failure.

Genetic alterations significantly contribute to the aetiology of reproductive failure and comprise monogenic, chromosomal and epigenetic disturbances. The implementation of next-generation sequencing (NGS) based approaches in research and diagnostics allows the comprehensive analysis of these genetic causes, and the increasing detection rates of genetic mutations causing reproductive complications confirm the potential of the new techniques. Whereas mutations affecting the fetal genome are well known to affect pregnancies and their outcome, the contribution of alterations of the maternal genome was widely unclear. With the recent mainly NGS-based identification of maternal effect variants, a new cause of human reproductive failure has been identified. Maternal effect mutations affect the expression of subcortical maternal complex (SCMC) proteins from the maternal genome, and thereby disturb oocyte maturation and progression of the early embryo. They cause a broad range of reproductive failures and pregnancy complications, including infertility, miscarriages, hydatidiform moles, aneuploidies and imprinting disturbances in the fetus. The identification of women carrying these molecular alterations in SCMC encoding genes is therefore essential for a personalised reproductive and genetic counselling. The diagnostic application of new NGS-based assays allows the comprehensive analysis of these factors, and helps to further decipher these functional links between the factors and their disturbances. A close interdisciplinary collaboration between different disciplines is definitely required to further decipher the complex regulation of early embryo development, and to translate the basic research results into clinical practice.

Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences.

Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes. This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine. Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms 'multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction' were used in various combinations. A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders. Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.

Novel immunotherapeutic approaches for treatment of infertility.

One of the most important reasons of infertility and human reproductive failure is related to uncontrolled immunological response of maternal immune system to early embryo or fetus, that cause rejection of this semi-allograft. Therefore, a tolerance in the immune system is essential to modulate the reactions against the fetus to avoid rejection. The immune system imbalance during implantation or pregnancy may lead to implantation failure or miscarriage. So, use of immunosuppressive or immunomodulator agents can be helpful to prevent immunological attack. Initially, there was a focus on steroids like prednisolone or intralipids in treatment of miscarriage that suppressed the activity of most immune cells, Intravenous Immunoglobulin (IVIG) was then introduced with various mechanisms. Nowadays, novel and specific strategies are established such as monoclonal antibodies and cytokines. More recently, Tacrolimus and Cyclosporine, which were utilized in prevention of transplantation reject, are used as immunosuppressive factors in modulation of immune responses against the fetus. This review is focused on the main immunotherapeutic methods of infertility treatment.

Endometrial stem cells and human reproductive failure

Endometrial stem cells and human reproductive failure

Trichomonas vaginalis: pathogenicity and potential role in human reproductive failure.

Trichomonas vaginalis, which colonizes the genitourinary tract of men and women, is a sexually transmitted parasite causing symptomatic or asymptomatic trichomoniasis. The host-parasite relationship is very complex, and clinical symptoms cannot likely be attributed to a single pathogenic effect. Among the many factors responsible for interactions between T. vaginalis and host tissues, contact-dependent and contact-independent mechanisms are important in pathogenicity, as is the immune response. This review focuses on the potential virulence properties of T. vaginalis and its role in female and male infertility. It highlights the association between T. vaginalis infection and serious adverse health consequences experienced by women, including infertility, preterm birth and low-birth-weight infants. Long-term clinical observations and results of in vitro experimental studies indicate that in men, trichomoniasis has been also associated with infertility through inflammatory damage to the genitourinary tract or interference with sperm function. These results contribute significantly to improving our knowledge of the role of parasitic virulence factors in the development of infection and its role in human infertility.

Role of Seminal Plasma in Human Female Reproductive Failure: Immunomodulation, Inflammation, and Infections.

Human seminal plasma contains factors that can regulate the female immune system and potentially promote reproductive fitness. Adverse effects on fertility and pregnancy may occur when seminal plasma provides insufficient, excessive, or altered signals or when the female partner is incapable of receiving these signals.

Endocrine disruptors and human reproductive failure: the in vitro effect of phthalates on human luteal cells

To evaluate the influence of phthalates on human luteal cell function. Laboratory study. University hospital. Twenty-three normally menstruating patients in the midluteal phase. Human luteal cells isolated from corpora lutea for primary cultures. Progesterone (P4) and prostaglandin release assayed by enzyme immunoassay, vascular endothelial growth factor (VEGF) secretion by enzyme-linked immunosorbent assay (ELISA), and VEGF mRNA expression by real-time polymerase chain reaction. We investigated the effect of di(2-ethylhexyl)phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) on basal and hCG-induced progesterone (P4) release, as well as DEHP effect on the balance between prostaglandin (PG) E2, vascular endothelial growth factor (VEGF)-luteotrophic factors, and the luteolitic PGF2α in isolated human steroidogenc cells. Phthalates influence on VEGF expression has been also evaluated. DEHP, DBP, and BBP were able to reduce both basal and hCG-stimulated P4 as well as PGE2 release. PGF2α release was reduced after DEHP incubation. VEGF protein release was decreased by the incubation with the tested phthalates. VEGF mRNA expression was not affected by DEHP, DBP, and BBP. As expected, both hCG and cobalt chloride were able to induce P4 release and VEGF release and mRNA expression in human luteal cells respectively. The results show the ability of phthalates to affect luteal steroidogenesis as well as the balance between luteotrophic and luteolytic factors suggesting an interference of phthalates in human luteal function. These data may contribute to clarify the classically known impaired reproductive health observed after phthalates exposure.

Phenolphthalein induces centrosome amplification and tubulin depolymerization in vitro

Aneuploidy is a major cause of human reproductive failure and plays a large role in cancer. Phenolphthalein (PHT) induces tumors in rodents but its primary mechanism does not seem to be DNA damage. In heterozygous TSG-p53(®) mice, PHT induces lymphomas and also micronuclei (MN), many containing kinetochores (K), implying chromosome loss (aneuploidy). The induction of aneuploidy would be compatible with the loss of the normal p53 gene seen in the lymphomas. In this study, we confirm PHT's aneugenicity and determine the aneugenic mechanism of PHT by combining traditional genetic toxicology assays with image and flow cytometry methods. The data revealed that PHT induces tubulin polymerization abnormalities and deregulates the centrosome duplication cycle causing centrosome amplification. We also show that one of the consequences of these events is apoptosis.

The genomics of the human endometrium

The endometrium is a complex tissue that lines the inside of the endometrial cavity. The gene expression of the different endometrial cell types is regulated by ovarian steroids and paracrine-secreted molecules from neighbouring cells. Due to this regulation, the endometrium goes through cyclic modifications which can be divided simply into the proliferative phase, the secretory phase and the menstrual phase. Successful embryo implantation depends on three factors: embryo quality, the endometrium's state of receptivity, and a synchronised dialogue between the maternal tissue and the blastocyst. There is a need to characterise the endometrium's state of receptivity in order to prevent reproductive failure. No single molecular or histological marker for this status has yet been found. Here, we review the global transcriptomic analyses performed in the last decade on a normal human endometrium. These studies provide us with a clue about what global gene expression can be expected for a non-pathological endometrium. These studies have shown endometrial phase-specific transcriptomic profiles and common temporal gene expression patterns. We summarise the biological processes and genes regulated in the different phases of natural cycles and present other works on different conditions as well as a receptivity diagnostic tool based on a specific gene set profile. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.

Recent advances in understanding immunology of reproductive failure

Aspects of the immunological relationship between mother and conceptus still remain a mystery, although the recent advances in molecular biology have enlightened some of the parameters that participate in fetomaternal cross-talk during implantation. The atypical expression of major histocompatibility complex (MHC), the specific role of some hormones and cytokines, as well as the temporal and spatial distributions of uterine natural killer cells, represent substantive parameters of fetomaternal immunotolerance during implantation. Although human maternal and fetal immunology is difficult to investigate, aberrant immune responses and an imbalanced cytokine network may be related to infertility, implantation failures after IVF and recurrent pregnancy losses. In this review, immunological and interacting factors involved in human reproductive failure are summarized and critically evaluated.

Autoantibodies targeting phosphatidylserine, cardiolipin, β2-glycoprotein I, annexin V and prothrombin in patients with recurrent spontaneous miscarriage (148.18)

Abstract An association between human reproductive failure and the presence of anti-phospholipid autoantibodies (APA) was suggested; both traditional and nontraditional APAs were associated with increased risk of recurrent spontaneous miscarriage (RSM). We measured levels of antibodies to phosphatidylserine (anti-PS), cardiolipin (ACA), β2-glycoprotein-I (anti-β2GPI), annexin V (anti-Anx V) and prothrombin (anti-PT) in 277 women with idiopathic RSM, and 288 control women by ELISA. Anti-PS IgG, ACA IgM/IgG, anti-Anx V IgM/IgG, and anti-PT IgM positivity were significantly associated with higher RSM risk, after controlling for age, BMI, menarche, and gravida. RSM was independently associated with high levels of ACA IgM (OR, 6.5; 95% CI, 2.5-17.1) and IgG (OR, 12.1; 95% CI, 6.6-22.2), anti-PS IgG (OR, 13.3; 95% CI, 6.4-27.4), anti-AnxV IgM (OR, 31.1; 95% CI, 15.7-56.6) and IgG (OR, 23.3; 95% CI, 8.8-51.7), and anti-PT IgM (OR, 2.8; 95% CI, 1.3-5.9). Levels of autoantibodies were categorized into 5 strata (percentiles 1-75, 76-99, 91-95, 96-99, &amp;gt;99 among control patients) and analyzed in logistic regression models. The adjusted OR increased as the percentile value of ACA IgM/IgG ,anti-PS IgG and anti-Anx V IgM/IgG, and anti-PT IgM, increased. In conclusion, the presence of ACA IgM/IgG, anti-Anx IgM/IgG, anti-PS IgG, and anti-PT IgM antibodies are risk factors for RSM. The strongest association was seen for anti-Anx V IgM and IgG, followed by ACA IgG, and anti-PS IgG antibodies.

Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2

Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2

Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2.

Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells--specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells--influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success.

Progesterone Function in Human Endometrium: Clinical Perspectives

Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.

Mammalian oocyte proteome relative to mid reproductive age

OBJECTIVE: A combination of factors contribute to oocyte quality including, aneuploidy and gene products essential for fertilization and embryonic development. Oocyte quality is a primary contributor to human reproductive failure and has been strongly associated with advanced reproductive age. However, oocyte quality may also play a role in cases of women who present with unexplained infertility and are not considered of advanced reproductive age. This study investigated the protein profiles of MII oocytes from young and mid reproductive age female mice.

Impact of aneuploidy following unexplained recurrent miscarriage

OBJECTIVE: Recurrent miscarriage (ReMAB) is a significant contributor to human reproductive failure. The aim of this study was to examine the impact of aneuploidy in embryos derived from women presenting for infertility treatment following unexplained ReMAB (≥3 miscarriages).

Stress and reproductive failure: past notions, present insights and future directions.

Maternal stress perception is frequently alleged as a cause of infertility, miscarriages, late pregnancy complications or impaired fetal development. The purpose of the present review is to critically assess the biological and epidemiological evidence that considers the plausibility of a stress link to human reproductive failure. All epidemiological studies published between 1980 and 2007 that tested the link between stress exposure and impaired reproductive success in humans were identified. Study outcomes were evaluated on the basis of how associations were predicted, tested and integrated with theories of etiology arising from recent scientific developments in the basic sciences. Further, published evidence arising from basic science research has been assessed in order to provide a mechanistic concept and biological evidence for the link between stress perception and reproductive success. Biological evidence points to an immune-endocrine disequilibrium in response to stress and describes a hierarchy of biological mediators involved in a stress trigger to reproductive failure. Epidemiological evidence presents positive correlations between various pregnancy failure outcomes with pre-conception negative life events and elevated daily urinary cortisol. Strikingly, a relatively new conceptual approach integrating the two strands of evidence suggests the programming of stress susceptibility in mother and fetus via a so-called pregnancy stress syndrome. An increasing specificity of knowledge is available about the types and impact of biological and social pathways involved in maternal stress responses. The present evidence is sufficient to warrant a reconsideration of conventional views on the etiology of reproductive failure. Physicians and patients will benefit from the adaptation of this integrated evidence to daily clinical practice.