Primary Unexplained Infertility Research Articles

Asymptomatic endometrial cancer with Lynch syndrome; in a woman with primary infertility-A case report and literature review.

Lynch syndrome, also called hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder characterized by germline pathogenic mutations in DNA mismatch repair genes-resulting in increased susceptibility to colorectal, endometrial, and other tumors. This case report presents an incidental finding of endometrial cancer with Lynch syndrome during investigation for primary infertility. A 34-year-old woman presented to the fertility clinic with unexplained primary infertility. Investigations showed possible endometrial polyp, 13 × 11 mm in size. Hysteroscopic polypectomy and endometrial biopsy revealed complex endometrial hyperplasia amounting to endometroid adenocarcinoma. The case was discussed at the West of Scotland Gynecology-Oncology MDT meeting-management options including fertility-sparing treatment or radical surgery were presented to the patient and she opted for the latter. A total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed with pathology results consistent with well-differentiated endometroid adenocarcinoma Stage 1A. Peritoneal washings showed no malignant cells. Genetic testing confirmed a diagnosis of Lynch syndrome. On further questioning, it was revealed that the patient had a strong family history of colon cancer but had not previously met the criteria for genetic testing. She was referred to colorectal surgeons and underwent colonoscopy. This showed no abnormality; she was therefore scheduled for 2-yearly colonoscopic surveillance.

Hysteroscopic hysteroplasty for the treatment of T-shaped uteri in women with reproductive failure.

To evaluate the efficacy of hysteroscopic hysteroplasty in the treatment of uterine malformation complicated by primary reproductive disorders. Women with unexplained primary infertility, repeated in vitro fertilization (IVF) failure or repeated spontaneous abortion, and uterine malformations unrelated to diethylstilbestrol who visited the obstetrics and gynecology department of our hospital from January 2019 to December 2022 were included in the prospective cohort study. Uterine malformation in the patients was confirmed by three-dimensional ultrasound and diagnostic hysteroscopy. Hysteroscopic hysteroplasty was performed using a 5-mm diameter hysteroscope and 5-FR surgical scissors, and after 3 months, palliative care was proposed for patients with unexplained infertility or repeated spontaneous abortion, and after 6 months, IVF treatment was recommended for patients with repeated in vitro fertilization (IVF) failures, with a planned minimum follow-up time of 1 year. A total of 83 women enrolled in the study, including 33 cases of primary infertility, 29 cases of repeated spontaneous abortion, and 21 cases of repeated IVF failure. No complications occurred during the hysteroscopic surgery. During the follow-up period, the clinical pregnancy rate of the women enrolled in the study increased to 77.1%, the live birth rate went up to 79.7%, the fetus delivered at full term accounted for 64.1%, and the cesarean section rate was 27.5%. The miscarriage rate was 9.4%. Hysteroscopic hysteroplasty can improve the reproductive outcomes in women with primary reproductive disorders and uterine malformations.

Oxidative stress markers cannot be used as endometriosis biomarkers in infertile patients

Objectives Endometriosis is a common benign gynaecological disease that significantly compromises the quality of life of patients. To date, invasive surgery is the method of choice to visually and histologically confirm endometriosis. Thus, there is a major interest to develop noninvasive diagnostic tools. Oxidative stress is one of the proposed mechanisms of pathogenesis and may be involved in pelvic pain, dysmenorrhea, dyspareunia, and infertility in endometriosis patients. Thus, markers of oxidative stress may serve as diagnostic biomarkers for endometriosis. Design This prospective case–control study assessed erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPX), serum hexanoyl lysine (HEL) and peritoneal fluid HEL. Participants/Materials, Setting, and Methods We enrolled 86 women with primary infertility; the case group included 57 women with endometriosis, and the control group included 29 women with unexplained primary infertility. All the patients underwent laparoscopy, and the diagnosis was confirmed histologically. RANDOX and RANSEL reagents were used to determine the levels of SOD and GPX, respectively, and ELISA was used to determine the levels of HEL. Results We found no statistically significant differences in the erythrocyte levels of GPX (p value 0.623) or SOD (p value 0.122) or the serum or peritoneal fluid levels of HEL (p value 0.562 and 0.329 accordingly). Conclusions SOD, GPX, and HEL levels most likely do not differ between patients with unexplained infertility and patients with endometriosis.

Cervical fluid pH, electrolytes and osmolarity changes and expression of ion transporters (ENaC, CFTR and AQP) in cervix of women with primary unexplained infertility.

Unexplained infertility could arise from a defect in the cervix. However, the contribution of abnormal cervical fluid microenvironment to this problem still needs to be identified. Therefore, this study identifies the changes in the cervical fluid microenvironment, i.e., pH, electrolytes and osmolarity as well as expression of ion transporters in the cervix including ENaC, CFTR and AQP in fertile women and in women suffering from primary unexplained infertility. Fertile women and women with unexplained infertility but having regular 28-day menstrual cycles were chosen in this study, Day-22 serum progesterone levels were determined. In the meantime, serum FSH and LH levels were determined on day 2 while, cervical flushing was performed at day 14 to analyse changes in the cervical fluid pH, osmolarity, Na+ and Cl- levels. Meanwhile, cells retrieved from cervical fluid were subjected to mRNA expression and protein distribution analysis for CFTR, AQP and ENaC by qPCR and immunofluorescence, respectively. No significant changes in serum progesterone, FSH and LH levels were observed between the two groups. However, cervical fluid pH, osmolarity, Na+ and Cl- levels were significantly lower in primary unexplained infertile group when compared to fertile group. Expression of CFTR and AQP (AQP 1, AQP 2, AQP 5 and AQP 7) in endocervical cells was lower and expression of β-ENaC was higher in primary unexplained infertile women (p < 0.05 when compared to fertile group). Alterations in the cervical fluid microenvironment linked to the defective ion transporter expression in the cervix might contribute towards the unfavourable condition that accounts for unexplained infertility in women.

Expression of concern: “Determinants of fertility and reproductive success after hysteroscopic septoplasty for women with unexplained primary infertility: a prospective analysis of 88 cases” [Eur J Obstet Gynecol Reprod Biol. 2011 Mar;155(1):54-7. doi: 10.1016/j.ejogrb.2010.11.015. Epub 2010 Dec 23. PMID: 21185112

This is a note of a temporary expression of concern related to the above-mentioned publication. Following recent issues with the reliability of the data in articles published by some of the authors of this article (See Bordewijk E.M., Wang R., Askie L.M., Gurrin L.C., Thornton J.G., van Wely M., et al. Data integrity of 35 randomised controlled trials in women’ health. Eur J Obstet Gynecol Reprod Biol. 2020; 249: 72-83), the editors decided to open an investigation for this article in the journal. The editors have written to both authors who could not supply original data. The authors have confirmed that they no longer have the raw data as the paper in question was published in 2010. The concern and this note will remain appended to the above-mentioned article, unless the parties provide the editors of European Journal of Obstetrics & Gynecology and Reproductive Biology with the raw data or other data that validates the results of the paper. Determinants of fertility and reproductive success after hysteroscopic septoplasty for women with unexplained primary infertility: a prospective analysis of 88 casesEuropean Journal of Obstetrics and Gynecology and Reproductive BiologyVol. 155Issue 1PreviewTo evaluate prospectively the effect of hysteroscopic septoplasty as therapy for unexplained primary infertility in women with uterine septum as a sole cause for reproductive failure and to define the factors influencing reproductive success. Full-Text PDF

Correlation between hysteroscopy finding and chronic Endometritis in Unexplained Primary Infertility

Correlation between hysteroscopy finding and chronic Endometritis in Unexplained Primary Infertility

Is There a Relevant Clinical Impact in Differentiating Idiopathic versus Unexplained Male Infertility?

Overall, male factor infertility (MFI) accounts for up to 50% of etiologies of couple's infertility, with almost 30% of MFI cases being idiopathic in nature. Idiopathic MFI does not support a tailored treatment work-up in clinical practice. To investigate rates of and characteristics of men presenting for idiopathic versus unexplained primary infertility as compared with same-ethnicity, age-comparable fertile men. Demographic, clinical and laboratory data from 3,098 primary infertile men consecutively evaluated were analyzed and compared with those of 103 fertile controls. Idiopathic male infertility (IMI) was defined for abnormality at semen analysis with no previous history of diseases affecting fertility and normal findings on physical examination and genetic and laboratory testing. Unexplained male infertility (UMI) was defined as infertility of unknown origin with completely normal findings at semen analysis. Descriptive statistics and logistic regression models tested the association between clinical variables and idiopathic infertility status. Overall, 570 (18.5%) and 154 (5.0%) patients depicted criteria suggestive for either IMI or UMI, respectively. Groups were similar in terms of age, BMI, CCI, recreational habits, hormonal milieu, and sperm DNA fragmentation indexes. Conversely, testicular volume was lower in IMI (p<0.001). Vitamin D3 levels were lower in IMI vs. UMI vs. fertile controls (p=0.01). At multivariable logistic regression analysis only vitamin D3 deficiency (OR, 9.67; p=0.03) was associated with IMI. Characteristics suggestive for IMI versus UMI were observed in almost 20% and 5% of men, respectively. Overall, clinical differences between groups were slightly significant and certainly not supportive of a tailored management work-up. Current findings further support the urgent need of a more detailed and comprehensive assessment of infertile men to better tailoring their management work-up in the everyday clinical setting.

The effect of cytokine leukemia-inhibitory factor (LIF) and interleukin-11 (IL-11) gene expression on the primary infertility related to polycystic ovary syndrome, Tubal factor, and Unexplained infertility in Turkish women

BackgroundSuccessful implantation of blastocysts is indeed an important path in mammalian reproduction that is governed by a complicated web of cytokines interactions. Leukemia inhibitory factor (LIF) and interleukin-11 (IL-11) part of the interleukin (IL)-6 groups are cytokines that are needed for effective implantation and prevent infertility symptoms. This study aimed to determine the expression level (LIF, IL-11) genes in patients with primary infertility related to polycystic ovary syndrome (PCOS), tubal factor infertility (TFI), and unexplained infertility (UI).ResultsIn this study, 75 infertility women and 40 controls were involved. The expressions of LIF and IL-11 genes were evaluated by quantitative real-time polymerase chain reaction qRT–PCR Light Cycler in patients and healthy controls. PCOS, TFI, and UI groups showed promising results regarding LIF gene, which appeared at very small levels compared to the control (p < 0.0001). Regarding IL-11, the two groups TFI and UI were significantly linked to the lower level of gene expression, while the PCOS group has no significant difference when it is compared to the control group (p < 0.0001, < 0.05, 0.19), respectively.ConclusionThe current findings show that low levels of LIF and IL-11 gene expression are linked to various primary infertility conditions, including PCOS, tubal factor, and unexplained infertility since they play a fundamental role in embryo implantation.

Proteomic analysis of peritoneal fluid identified COMP and TGFBI as new candidate biomarkers for endometriosis

Endometriosis is a common non-malignant gynecological disease that significantly compromises fertility and quality of life of the majority of patients. The gold standard for diagnosis is visual inspection of the pelvic organs by surgical laparoscopy and there are no biomarkers that would allow non-invasive diagnosis. The pathogenesis of endometriosis is not completely understood, thus analysis of peritoneal fluid might contribute in this respect. Our prospective case–control study included 58 patients undergoing laparoscopy due to infertility, 32 patients with peritoneal endometriosis (cases) and 26 patients with unexplained primary infertility (controls). Discovery proteomics using antibody microarrays that covered 1360 proteins identified 16 proteins with different levels in cases versus the control patients. The validation using an ELISA approach confirmed significant differences in the levels of cartilage oligomeric matrix protein (COMP) and transforming growth factor-β-induced protein ig-h3 (TGFBI) and nonsignificant differences in angiotensinogen (AGT). A classification model based on a linear support vector machine revealed AUC of > 0.83, sensitivity of 0.81 and specificity of 1.00. Differentially expressed proteins represent candidates for diagnostic and prognostic biomarkers or drug targets. Our findings have brought new knowledge that will be helpful in the understanding of the pathophysiology of endometriosis and warrant further studies in blood samples.

Changes in the Expression of Endometrial Receptivity Genes after Hysteroscopic Metroplasty in Infertile Women with Uterine Malformation

Study Objective To determine the effect of hysteroscopic metroplasty on the expression of endometrial receptivity genes, such as HOX family and LIF gene, in infertile women with congenital uterine malformations. Design a prospective observational study conducted between June 2016 and March 2020. Setting Tertiary care University hospital in Italy. Patients or Participants Forty-four patients with a diagnosis of dysmorphic uterus or uterine septum (according to the ESHRE/ESGE classification), with history of primary unexplained infertility, repeated (>2) early miscarriages, or severe preterm labor (<25w) were enrolled in the study. Interventions All patients underwent hysteroscopic metroplasty either in office or OR settings, in the proliferative phase. Endometrial hysteroscopic biopsy was performed immediately before the metroplasty and at the two-month follow up. The endometrial samples were immediately stored at -80°C and RT-PCR was used to evaluate the expression of each gene. Measurements and Main Results The metroplasty was completed in all cases, resulting in a significant optimization of uterine morphology (44/44). After hysteroscopic metroplasty, overall, 1.05-fold increase in endometrial HOX-10 expression and overall 1.09-fold increase in endometrial HOX-11 expression were detected in comparison with baseline values. The mRNA expression level of LIF gene resulted under expressed, with a -1.12-fold decrease. Conclusion Our data demonstrate that hysteroscopic metroplasty provides favorable effect on endometrial HOXA-10 and 11 mRNA expression. These preliminary data suggest that hysteroscopic metroplasty could induce an important uterine remodeling involving not only macroscopic but also microscopic changes. To determine the effect of hysteroscopic metroplasty on the expression of endometrial receptivity genes, such as HOX family and LIF gene, in infertile women with congenital uterine malformations. a prospective observational study conducted between June 2016 and March 2020. Tertiary care University hospital in Italy. Forty-four patients with a diagnosis of dysmorphic uterus or uterine septum (according to the ESHRE/ESGE classification), with history of primary unexplained infertility, repeated (>2) early miscarriages, or severe preterm labor (<25w) were enrolled in the study. All patients underwent hysteroscopic metroplasty either in office or OR settings, in the proliferative phase. Endometrial hysteroscopic biopsy was performed immediately before the metroplasty and at the two-month follow up. The endometrial samples were immediately stored at -80°C and RT-PCR was used to evaluate the expression of each gene. The metroplasty was completed in all cases, resulting in a significant optimization of uterine morphology (44/44). After hysteroscopic metroplasty, overall, 1.05-fold increase in endometrial HOX-10 expression and overall 1.09-fold increase in endometrial HOX-11 expression were detected in comparison with baseline values. The mRNA expression level of LIF gene resulted under expressed, with a -1.12-fold decrease. Our data demonstrate that hysteroscopic metroplasty provides favorable effect on endometrial HOXA-10 and 11 mRNA expression. These preliminary data suggest that hysteroscopic metroplasty could induce an important uterine remodeling involving not only macroscopic but also microscopic changes.

O-151 Detailed characterization of infertile men with idiopathic versus unexplained infertility: a single-center experience

Abstract Study question We aimed to investigate the rate of and the clinical characteristics of men with idiopathic versus unexplained infertility from a cohort of white-European men. Summary answer Approximately 20% and 5% of men evaluated for primary couple’s infertility depicted characteristics suggestive for idiopathic and unexplained infertility, respectively. What is known already Male factor infertility (MFI) can be associated with clinical, hormonal and genetic diseases, but MFI is idiopathic in almost 30% of cases. Study design, size, duration Data from 3098 infertile men (according to WHO definition) consecutively evaluated between 2003-2020 at a single academic centre were analysed and compared with those of 103 fertile controls. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Idiopathic infertility was defined for pathological semen analysis but normal physical examination and endocrine, genetic and biochemical laboratory testing. Unexplained infertility is defined as infertility of unknown origin with normal sperm parameters. Participants/materials, setting, methods Testicular volume (TV) was assessed with a Prader’s orchidometer. Serum hormones and sperm DNA fragmentation index (SDF) were measured in every patient. Vitamin D3 (VitD) deficiency was considered for vitD levels &amp;lt;20 ng/mL. Semen analyses were based on the 2010 WHO reference criteria. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Main results and the role of chance Overall, 570 (18.5%) and 154 (5.0%) patients depicted criteria suggestive for either idiopathic or unexplained primary infertility, respectively. Groups were similar in terms of age, BMI, CCI, recreational habits, circulating serum hormones and SDF. Testicular volume was lower in men with idiopathic vs. unexplained infertility [median (IQR) 20 (15-25) vs. 20 (17-25); p &amp;lt; 0.001]; more idiopathic than unexplained infertile men depicted TV &amp;lt; 15ml (23.4% vs. 12%; p &amp;lt; 0.01). Similarly, vitD levels were lower [22 (17-28) vs. 27 (21-42) ng/mL; p &amp;lt; 0.001] in idiopathic vs. unexplained infertile men, with a higher rate of pathologic VitD levels in the same group (42.1% vs. 10%; p = 0.04). When compared to fertile controls, groups were similar in terms of age, BMI, CCI and serum hormones values. TV was larger in fertile controls than idiopathic and unexplained infertile men (all p &amp;lt; 0.01). At multivariable logistic regression analysis only vitD deficiency (OR 8.1, p = 0.03) was found to be associated with idiopathic infertility after accounting for age, BMI, testosterone values and TV. Limitations, reasons for caution The small number of fertile controls may raise the possibility of biases. Wider implications of the findings Idiopathic and unexplained infertility were identified in approximately 20% and 5% of men evaluated, respectively. Idiopathic infertile men showed lower TV and lower vitD values compared to men with unexplained infertility. Future studies are needed to develop a more tailored management to these difficult MFI cases. Trial registration number .

P–534 A novel heterozygous mutation in the luteinizing hormone/choriogonadotropin receptor (LHCGR) gene in a patient with ‘genuine’ empty follicle syndrome

Abstract Study question Whether empty follicle syndrome (EFS) in a patient has a genetic basis. Summary answer Our findings would expand the mutational spectrum of LHCGR, in patients with GEFS What is known already The LHCGR gene (OMIM #52790) is located on chromosome 2p21 has 11 exons The LHCGRs present in gonadal cells; granulosa, theca and luteal cells in women and Leydig cells in menandplays a critical role in male sexual differentiation, female ovarian development and fertility (folliculogenesis, ovulation, corpus luteum formation and progesterone secretion) Inactivating mutations in males can lead to Leydig cell hypoplasia, which causes disorders in sexual development (MIM #238 320). Phenotype of women is less severe and variable and has no effect on the secondary sex characteristics, but it could cause amenorrhoea and infertility Study design, size, duration: In the context of clinical genetics, Next Generation Sequencing libraries were prepared in line with the manufacturer’s orders using QIASeq™ Targeted DNA Custom Panel (Qiagen) targeting exons and 20 bp exon-intron boundaries of selected genes (AR, BMP15, CATSPER1, CFTR, CYP21A2, FSHB, FSHR, HESX1, LHB, LHCGR, NR5A1, POU1F1, SRY, ZP1). The variant detected in NGS analysis was further confirmed using Sanger sequencing (MiSeq, Illumina, San Diego, CA). Participants/materials, setting, methods A 27 years old Turkish women with 6 year history of primary unexplained infertility underwent controlled ovarian hyperstimulation and IVF with an antagonist protocole in Ankara City Hospital. Although normal follicular development, E2 levels, and bioavailable β-hCG plasma levels, no oocytes or cumulus-corona complexes were retrieved by follicular aspiration. Main results and the role of chance A novel heterozygous mutation on Exon 5 of LHCGR (NM_000233.4):c.453C&amp;gt;G (p.Phe151Leu). This variant has not been reported in GnomAD database and is a novel variant as per controlled from ClinVar and HGMD mutation databases Also coagulation tests were done Patient was heterozygote for the prothrombin mutation (FXIII) and homozygote for MTHFR C677T mutation. The patient has normal pubertal development and female karyotype (46,XX). Gonadotropin and E2 levels were normal, nor any history of anosmia, primary amenorrhoea, polycystic ovaries, hyperandrogenism, systemic disorder, or neurologic defect. According to ACMG 2015 and HGMD detected variant was classified as unknown clinical significance (VUS) variant In 22nd World Congress COGI in 2015 we have presented another recurrent GEFS case with compound heterozygous frameshift mutations in exon 5 and 11 of LHCGRgene(c.1764_1765insT) and (c.430G&amp;gt;T, p.V144F) who developed premature ovarian failure at the end The different types of LHCGR mutations would lead to the different functional effects and clinical phenotypes in different ages; primary amenorrhea with high levels of LH, poor ovarian response (Poesidon group1), GEFS and secondary amenorrhea (premature ovarian failure) GEFS may be a gradual biological occurrence related to ovarian ageing. Long term follow up is important, since some clinical manifestations appear later in life. Limitations, reasons for caution LH resistance in females were always found due to their effected brothers and only 10 GEFS cases of 46, XX females with LHCGR gene defect reported in literature. Patient was heterozygous for indicated mutation; therefore segregation study should be done in family members and in vitro studies should be performed. Wider implications of the findings: Screening for mutations in the LHCGR gene in Poseidon group 1 and in patients GEFS especially the recurrent ones will provide valuable information and time for clinical management, corresponding treatment and give the opportunity of wise and cost effective counseling of patients about their future reproductive choices. Trial registration number it is a case report

Novel nomogram-based integrated gonadotropin therapy individualization in in vitro fertilization/intracytoplasmic sperm injection: A modeling approach.

ObjectiveThis study aimed to characterize a validated model for predicting oocyte retrieval in controlled ovarian stimulation (COS) and to construct model-based nomograms for assistance in clinical decision-making regarding the gonadotropin protocol and dose.MethodsThis observational, retrospective, cohort study included 636 women with primary unexplained infertility and a normal menstrual cycle who were attempting assisted reproductive therapy for the first time. The enrolled women were split into an index group (n=497) for model building and a validation group (n=139). The primary outcome was absolute oocyte count. The dose-response relationship was tested using modified Poisson, negative binomial, hybrid Poisson-Emax, and linear models. The validation group was similarly analyzed, and its results were compared to that of the index group.ResultsThe Poisson model with the log-link function demonstrated superior predictive performance and precision (Akaike information criterion, 2,704; λ=8.27; relative standard error (λ)=2.02%). The covariate analysis included women’s age (p<0.001), antral follicle count (p<0.001), basal follicle-stimulating hormone level (p<0.001), gonadotropin dose (p=0.042), and protocol type (p=0.002 and p<0.001 for short and antagonist protocols, respectively). The estimates from 500 bootstrap samples were close to those of the original model. The validation group showed model assessment metrics comparable to the index model. Based on the fitted model, a static nomogram was built to improve visualization. In addition, a dynamic electronic tool was created for convenience of use.ConclusionBased on our validated model, nomograms were constructed to help clinicians individualize the stimulation protocol and gonadotropin doses in COS cycles.

Correlation between Serum Anti-Müllerian Hormone Levels and Antral follicle count in prediction of clinical pregnancy in women with unexplained infertility undergoing ICSI cycles

Background: It is obvious that after years of publications worldwide. The question of whether the serum level of AMH predicts pregnancy after ICSI still unresolved. In the present study the correlation between serum AMH levels and pregnancy rate in a population of women undergoing their first ICSI cycle is investigated.Objective: We assess accuracy of serum anti-mullerian hormone levels and anti follicle count in prediction of clinical pregnancy in women with unexplained infertility and undergoing ICSI cycles. Patients and Methods: This is a retrospectively study in assisted reproductive technology unit at Maternity Hospital – Ain Shams University from August 2018 to June 2019. This study included 71 women with unexplained primary infertility in ART unit undergoing ICSI cycles. Simple random sampling. Results: we included (patients with unexplained primary infertility who underwent their first ICSI cycle aged 20-35 years with BMI ≤ 30 without associated medical problems as diabetes mellitus, hypertension and polycystic ovary. Serum AMH was measured within 3 months before the beginning of the ICSI cycle, ovarian stimulation was carried out, and all embryos transfer were carried out on a fresh cycle. Conclusion: In this study it was found that as the AMH level increases, the number of oocytes increases as well, but it is not a predictor of oocyte quality or pregnancy rate.

Human Herpesviruses 6A and 6B in Reproductive Diseases.

Human herpesviruses 6A (HHV-6A) and human herpesvirus 6B (HHV-6B)—collectively, HHV-6A/B—are recently-discovered but ancient human viruses. The vast majority of people acquire one or both viruses, typically very early in life, producing an ineradicable lifelong infection. The viruses have been linked to several neurological, pulmonary and hematological diseases. In early human history, the viruses on multiple occasions infected a germ cell, and integrated their DNA into a human chromosome. As a result, about 1% of humans are born with the full viral genome present in every cell, with uncertain consequences for health. HHV-6A may play a role in 43% of cases of primary unexplained infertility. Both the inherited and acquired viruses may occasionally trigger several of the factors that are important in the pathogenesis of preeclampsia. Transplacental infection occurs in 1-2% of pregnancies, with some evidence suggesting adverse health consequences for the child. While emerging knowledge about these viruses in reproductive diseases is not sufficient to suggest any changes in current practice, we write this review to indicate the need for further research that could prove practice-changing.

Patients with unexplained primary infertility have similar uterine and ovarian blood flow parameters compared with fertile cases: A prospective cross-sectional study Running title: unexplained primary infertility and uterine-ovarian blood flow

Patients with unexplained primary infertility have similar uterine and ovarian blood flow parameters compared with fertile cases: A prospective cross-sectional study Running title: unexplained primary infertility and uterine-ovarian blood flow

Is there a role of antisperm antibodies in women with unexplained infertility - a Turkish pilot cross sectional case control study

Aim: Although some studies indicate that the presence of antisperm antibody (ASA) is important in the etiology of female infertility, this remains a controversial issue. The aim of this study was to determine whether the presence of ASA was important or not in primary and secondary unexplained infertility patients.Materials and Methods: Female patients (n = 90) were divided into three groups as follows: the primary infertility group (n = 30), the secondary infertility group (n = 28) and a control group (n = 32). In addition to laparoscopic evaluations, the presence of ASA in the study groups was also examined in serum and peritoneal washing liquid. The ASA - immunoglobulin G was measured using the Enzyme-Linked ImmunoSorbent Assay (ELISA) method with a qualitative measurement kit.Results: When the demographic data were analyzed, it was observed that the study groups were homogeneous in terms of age and period of infertility. The results of the study demonstrated that, when compared to the secondary infertility and control groups, the ASA positivity in the serum in the primary infertility group was significant (p 0.05).Conclusion: This study showed that the presence of ASA in serum may be an impact on the etiology of unexplained primary infertility.

Tripeptidyl peptidase I promotes human endometrial epithelial cell adhesive capacity implying a role in receptivity

The endometrium undergoes cyclic remodelling throughout the menstrual cycle in preparation for embryo implantation which occurs in a short window during the mid-secretory phase. It is during this short ‘receptive window’ that the endometrial luminal epithelium acquires adhesive capacity permitting blastocysts firm adhesion to the endometrium to establish pregnancy. Dysregulation in any of these steps can compromise embryo implantation resulting in implantation failure and infertility. Many factors contribute to these processes including TGF-β, LIF, IL-11 and proteases. Tripeptidyl peptidase 1 (TPP1) is a is a lysosomal serine-type protease however the contribution of the TPP1 to receptivity is unknown. We aimed to investigate the role of TPP1 in receptivity in humans.In the current study, TPP1 was expressed in both epithelial and stromal compartments of the endometrium across the menstrual cycle. Expression was confined to the cytoplasm of luminal and glandular epithelial cells and stromal cells. Staining of mid-secretory endometrial tissues of women with normal fertility and primary unexplained infertility showed reduced immunostaining intensity of TPP1 in luminal epithelial cells of infertile tissues compared to fertile tissues. By contrast, TPP1 levels in glandular epithelial and stromal cells were comparable in both groups in the mid-secretory phase. Inhibition of TPP1 using siRNA compromised HTR8/SVneo (trophoblast cell line) spheroid adhesion on siRNA-transfected Ishikawa cells (endometrial epithelial cell line) in vitro. This impairment was associated with decreased sirtuin 1 (SIRT1), BCL2 and p53 mRNA and unaltered, CD44, CDH1, CDH2, ITGB3, VEGF A, OSTEOPONTIN, MDM2, CASP4, MCL1, MMP2, ARF6, SGK1, HOXA-10, LIF, and LIF receptor gene expression between treatment groups. siRNA knockdown of TPP1 in primary human endometrial stromal cells did not affect decidualization nor the expression of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Taken together, our data strongly suggests a role for TPP1 in endometrial receptivity via its effects on epithelial cell adhesion and suggests reduced levels associated with unexplained infertility may contribute to implantation failure.

Novel compound heterozygous mutation in WEE2 is associated with fertilization failure: case report of an infertile woman and literature review

BackgroundFertilization failure after intracytoplasmic sperm injection continues to affect couples and the etiology is not well-understood.Case presentationWe characterized a couple with 2-year history of primary unexplained infertility. Three different assisted reproduction attempts (IVF + rescue ICSI, ICSI and ICSI-AOA) showed repeated fertilization failure for MII oocyte retrieval after controlled ovarian hyperstimulation. After whole-exome sequencing and sanger sequencing of the couple and their family members, variant pathogenicity was assessed using SIFT, PolyPhen2, Mutation Taster, and Human Splicing Finder software. We identified novel compound heterozygous mutations, c.1535 + 3A > G and c.946C > T (p. Leu316Phe), in WEE2 in the female proband. Trios analysis of the variations revealed an autosomal recessive pattern. c.1535 + 3A > G in WEE2 was predicted to break the wild-type donor site and affect splicing, and the missense mutation c.946C > T (p. Leu316Phe) of WEE2 was predicted to be pathogenic.ConclusionA novel compound heterozygous mutation in WEE2 was identified in an infertile female who experienced repeated fertilization failure even after ICSI-AOA. These novel mutations in WEE2 provided genetic evidence for fertilization failure.

Chloride intracellular channel 4 is dysregulated in endometrium of women with infertility and alters receptivity

The endometrium remodels in each menstrual cycle to become receptive in preparation for embryo implantation which occurs in the mid-secretory phase of the cycle. Failure of blastocyst adhesion and implantation cause infertility. We compared chloride intracellular channel 4 (CLIC4) expression in human endometrium from women with normal fertility and primary unexplained infertility in the mid-secretory/receptive phase of the menstrual cycle. CLIC4 localised to both the epithelial and stromal regions of the endometrium of fertile tissues across the cycle. CLIC4 expression was significantly reduced in the luminal and glandular epithelium and remained unchanged in the stromal region of mid-secretory infertile endometrium compared to fertile endometrium. siRNA knockdown of CLIC4 significantly compromised adhesive capacity of Ishikawa cells (endometrial epithelial cell line). This reduced adhesion and CLIC4 expression was associated with elevated SGK1, p53, SIRT1, BCL2 and MCL1 gene expression in the Ishikawa cells. CLIC4 expression was increased in primary human endometrial stromal cells during decidualization, however, siRNA knockdown of CLIC4 did not affect decidualization. Our data provide evidence that CLIC4 may regulate receptivity and facilitate blastocyst attachment initiating implantation. Reduced CLIC4 levels may be causative of implantation failure in women.