Role of Molecular Biomarkers in Endometriosis-Related Infertility: A Narrative Review of the Literature.

Endometriosis is a chronic benign inflammatory disease that affects women of reproductive age. The clinical presentations of endometriosis include dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. There is a well-established association between endometriosis and infertility. Therefore, there is a need for an early diagnosis of endometriosis-related infertility. In this study, we aim to identify the role of biomarkers as predictive factors of the presence of the disease and its severity and their correlation with the pregnancy outcome. We performed an electronic database search of all published studies in PubMed and EMBASE from January 2018 to May 2023. Numerous innovative biomarkers identified in cases of endometriosis and infertility have been studied over the past years, including micro-RNAs, BCL6 endometrial expression, cytotoxic T-lymphocyte antigen 4, human leukocyte antigen G, programmed cell death protein 1, programmed cell death ligand 1 immune checkpoint molecules, plasma fibronectin-fibrin complexes, homeobox A10 gene, systemic inflammatory response markers, uterine natural killer cells, and the eutopic endometrium proteome. Considerable research has been done to identify diagnostic biomarkers for the early detection and prevention of endometriosis-associated infertility. However, none of these biomarkers displayed enough diagnostic accuracy to be used in daily clinical practice. Future research is valuable to establish them as reliable diagnostic tools.

Prenatal Identification of a Missense Mutation of the L1CAM Gene Associated With Hydrocephalus Using Next-Generation Sequencing.

We present the case of a 35-year-old pregnant woman who visited our department for a routine ultrasonography screening scan for fetus anatomy during the 22nd week of gestation. Our report revealed a male fetus with marked hydrocephalus and severe intrauterine growth retardation. After extensive counseling, the couple decided to proceed with an invasive diagnosis via amniocentesis. The cytogenetic analysis showed findings related to clinical history and ultrasound findings related to the presence of a nucleotide change in c.578T>C with an amino acid change in p.Leu198Pro of the L1CAM gene. The result was reported as a hemizygote missense L1CAM gene variant of unknown significance. After extensive parental counseling, the couple decided on pregnancy termination. We report the present case of L1CAM mutation in p.Leu198Pro to add to the limited knowledge regarding the clinical presentation of mutations of the L1CAM gene with emphasis on prenatal diagnosis.

The Contribution of Proteomics in Understanding Endometrial Protein Expression in Women with Recurrent Implantation Failure.

Recurrent implantation failure (RIF) poses a significant challenge in assisted reproductive technology (ART) outcomes. The endometrium plays a crucial role in embryo implantation, and its protein expression profile is integral in determining receptivity. Proteomics has emerged as a valuable tool in unraveling the molecular intricacies underlying endometrial receptivity and RIF. The aim of the present review is to analyze the contribution of proteomics to the understanding of endometrial protein expression in women with RIF, based on the results of significant proteomic studies. Medline/Pubmed databases were searched using keywords pertaining to proteomics combined with terms related to RIF. 15 studies were included in the present review. Several proteins have been found to exbibit differential expression in endometrial biopsies and fluid samples between fertile women and women with RIF during the receptive endometrial phase. The profile of endometrial proteins varied significantly among the studies. Nevertheless, similar changes in the expression levels of annexin-6, progesterone receptor, MMP-2, and MMP-9 in the endometrium of women with RIF, were found in more than one study indicating that certain proteins could potentially be effective biomarkers of endometrial receptivity. Proteomics contributes significantly to the understanding of protein expression in the endometrium of women with RIF and the analysis of proteins in endometrial fluid are promising for improving the clinical management of RIF.

Endometriosis Predictive Models Based on Self-Assessment Questionnaire, Evidence from Clinical Examination or Imaging Findings: A Narrative Review.

OBJECTIVE: The aim of this narrative review is to evaluate existing questionnaires on predictive models for endometriosis. These symptom-based models have the potential to serve as screening tools for adult women to detect endometriosis. DATA SOURCES: A comprehensive search of PubMed and Embase databases was conducted to identify studies on endometriosis screening. SELECTION OF STUDIES: The search targeted predictive models for endometriosis localisation, bowel involvement, need for bowel surgery and fertility. Due to the heterogeneity identified, a systematic review was not possible. A total of 23 studies were identified. DATA EXTRACTION AND SYNTHESIS: Among these studies, twelve included measures for general endometriosis, two targeted specific sites, four focused on deep infiltrating endometriosis (DIE), and three addressed the need for endometriosis-related bowel surgery. Many measures combined clinical, imaging and laboratory tests with patient questionnaires. Validation of these models as screening tools was lacking in all studies, as the focus was on diagnosis rather than screening. CONCLUSION: This review did not identify any fully validated, symptom-based questionnaires for endometriosis screening in adult women. Substantial validation work remains to establish the efficacy of such tools.

Advanced Paternal Age in Focus: Unraveling Its Influence on Assisted Reproductive Technology Outcomes.

As global demographics shift toward increasing paternal age, the realm of assisted reproductive technologies (ARTs), particularly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), faces new challenges and opportunities. This study provides a comprehensive exploration of the implications of advanced paternal age on ART outcomes. Background research highlights the social, cultural, and economic factors driving men toward later fatherhood, with a focus on the impact of delayed paternity on reproductive outcomes. Methods involve a thorough review of existing literature, centering on changes in testicular function, semen quality, and genetic and epigenetic shifts associated with advancing age. Study results point to intricate associations between the father's age and ART outcomes, with older age being linked to diminished semen quality, potential genetic risks, and varied impacts on embryo quality, implantation rates, and birth outcomes. The conclusions drawn from the current study suggest that while advanced paternal age presents certain risks and challenges, understanding and mitigating these through strategies such as sperm cryopreservation, lifestyle modifications, and preimplantation genetic testing can optimize ART outcomes. Future research directions are identified to further comprehend the epigenetic mechanisms and long-term effects of the older father on offspring health. This study underscores the need for a comprehensive approach in navigating the intricacies of delayed fatherhood within the context of ART, aiming for the best possible outcomes for couples and their children.

The Expression of microRNAs and Their Involvement in Recurrent Pregnancy Loss.

Background: Recurrent pregnancy loss refers to the spontaneous demise of two or more pregnancies before the 24 weeks of gestation. In almost half of the cases of recurrent miscarriages, the causes remain unknown since there is no reliable way of prognosis, early diagnosis, or treatment. Recent research has detected differential expression of certain miRNAs in reproductive system pathologies. Methods: The aim of the present review is to focus on microRNAs and their relationship with idiopathic recurrent miscarriages and to correlate miRNA expression with recurrent miscarriage and examine their potential role as biomarkers. Pubmed/Medline and Scopus databases were searched up to 31st January 2024 with terms related to recurrent pregnancy loss and miRNAs. Results: In total, 21 studies were selected for the review. A total of 75 different miRNAs were identified, showing a statistically significant differential expression. Around 40 miRNAs had increased expression, such as miR-520, miR-184 and miR-100-5p, 21 decreased, such as let-7c, and 14 had either increased or decreased expression depending on the study, such as miR-21. Conclusions: The dysregulation of miRNA expression is strongly associated with recurrent miscarriages. The circulating in the peripheral blood miRNAs, miR-100-5p and let-7c, might be utilized as biomarkers and establish a valuable non-invasive prognostic and diagnostic tool in the future.

Oocyte Maturation and miRNAs: Studying a Complicate Interaction to Reveal Possible Biomarkers for Female Infertility.

Cellular metabolism, apoptosis, fertilization, and proliferation of granulosa cells belong to a battery of processes where microRNAs can be detected and associated with infertility. The aim of the present review is to focus on mammalian oocyte maturation events and the association between oocyte growth and miRNA expression. PubMed/Medline, Google Scholar and Scopus databases were searched, and 33 studies were included. Regarding the correlation among miRNA expression and the regulation of granulosa cells and cumulus cells, the most important miRNAs were let-7b, let-7c and miR-21. Additionally, the loss of Dicer, an enzyme involved in miRNA biogenesis, is probably a crucial factor in oogenesis, oocyte maturation and embryogenesis. Furthermore, miRNAs interfere with different cellular mechanisms like apoptosis, steroidogenesis, genome integrity, angiogenesis, antioxidative response and, consequently, oocyte maturation. Hence, it is of major importance to clarify the role and mechanism of each miRNA as understanding its action may develop new tools and establish new diagnostic and treatment approaches for infertility and ovarian disorders.

Supervised Pelvic Floor Muscle Training Improves Sexual Function and Diminishes Sexual Distress in Women with Relapsing-Remitting Multiple Sclerosis: A Randomised Controlled Study.

This study investigates the impact of pelvic floor muscle training (PFMT) on sexual function and distress in women with multiple sclerosis (MS), a prevalent chronic nervous system disorder associated with sexual dysfunction. This study's primary aim was to assess the effectiveness of PFMT at improving sexual function and alleviating sexual distress in this population. In a randomised controlled trial, 82 women with MS were divided into two groups: Group A (41 women) underwent 12 weeks of PFMT, while Group B (41 women) served as a control group with no intervention. Both groups were assessed at the beginning and end of this study using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised (FSDS-R). Statistical analysis, including Chi-square tests, was employed to compare the outcomes between the two groups, with a p-value of less than 0.05 considered significant. The results revealed no significant differences in baseline sexual function and distress between the groups. However, at the conclusion of the 12-week period, Group A exhibited statistically significant improvements in nearly all domains of FSFI and FSDS-R compared to Group B, except in the pain domain. This study concludes that PFMT can effectively enhance sexual function and reduce sexual distress in women suffering from MS. These findings underscore the potential of PFMT as a therapeutic intervention in managing sexual dysfunction associated with MS.

Diagnosis and Treatment of Adenomyosis with Office Hysteroscopy-A Narrative Review of Literature.

INTRODUCTION: Adenomyosis is a common chronic disease in women of reproductive age, characterised by the presence of ectopic endometrial tissue within myometrium. Even though adenomyosis presents with chronic pelvic pain, menorrhagia or abnormal uterine bleeding, dysmenorrhoea, and dyspareunia and is often recognised after hysterectomies. However, the development of ultrasonography and magnetic resonance imaging has improved the pre-operative diagnosis of the disease. Hysteroscopy provides information in real time from the uterine cavity and the offers the possibility of obtaining direct biopsies. MATERIAL AND METHODS: The literature was searched via Pubmed and Embase with the following headings: diagnosis of adenomyosis or adenomyoma and office hysteroscopy, hysteroscopy findings of adenomyosis or adenomyoma, treatment of adenomyosis or adenomyoma with office hysteroscopy. RESULTS: The literature showed that hysteroscopy can identify superficial adenomyosis. There are a variety of hysteroscopic images that can be connected with the disease. New equipment like the spirotome has been used to access deeper layers of myometrium and obtain biopsies under direct vision from the adenomyotic areas. Different methods of treatment have been also described, like enucleation of focal superficial adenomyoma, coagulation, evacuation of cystic adenomyosis when the lesion is smaller than 1.5 cm, and resection of adenomyotic nodules in case of bigger lesions (>1.5 cm). Diffuse superficial adenomyosis is also managed by resection. CONCLUSIONS: Hysteroscopy has revolutionised the approach to adenomyosis. It is a useful tool in assessing mainly superficial adenomyosis. The role of hysteroscopy in surgical management of adenomyosis need to be confirmed with further studies.

Ovarian Masses in Children and Adolescents: A Review of the Literature with Emphasis on the Diagnostic Approach.

Most abdominal masses in the pediatric population derive from the ovaries. Ovarian masses can occur in all ages, although their incidence, clinical presentation and histological distribution vary among different age groups. Children and adolescents may develop non-neoplastic ovarian lesions, such as functional cysts, endometrioma, torsion, abscess and lymphangioma as well as neoplasms, which are divided into germ cell, epithelial, sex-cord stromal and miscellaneous tumors. Germ cell tumors account for the majority of ovarian neoplasms in the pediatric population, while adults most frequently present with epithelial tumors. Mature teratoma is the most common ovarian neoplasm in children and adolescents, whereas dysgerminoma constitutes the most frequent ovarian malignancy. Clinical manifestations generally include abdominal pain, palpable mass, nausea/vomiting and endocrine alterations, such as menstrual abnormalities, precocious puberty and virilization. During the investigation of pediatric ovarian masses, the most important objective is to evaluate the likelihood of malignancy since the management of benign and malignant lesions is fundamentally different. The presence of solid components, large size and heterogenous appearance on transabdominal ultrasonography, magnetic resonance imaging and computed tomography indicate an increased risk of malignancy. Useful tumor markers that raise concern for ovarian cancer in children and adolescents include alpha-fetoprotein, lactate dehydrogenase, beta subunit of human chorionic gonadotropin, cancer antigen 125 and inhibin. However, their serum levels can neither confirm nor exclude malignancy. Management of pediatric ovarian masses needs to be curative and, when feasible, function-preserving and minimally invasive. Children and adolescents with an ovarian mass should be treated in specialized centers to avoid unnecessary oophorectomies and ensure the best possible outcome.

A Large Exophytic Tumor of the Cervix Causing Vaginal Bleeding in Pregnancy: A Case Report.

Vaginal bleeding in the second and third trimesters of pregnancy is usually due to placental causes, namely placental abruption and placenta previa. Other causes include uterine rupture, vasa previa, and hematologic disorders. However, benign or malignant lesions of the vagina and the cervix may also cause vaginal bleeding or spotting. Although cervical cancer in pregnancy is rare, about 8% of pregnant women have an abnormal Pap smear and 3% of the total cervical cancers are diagnosed during pregnancy. We report a case of a 20-week pregnant woman who presented with vaginal bleeding; a visual inspection revealed a large exophytic lesion of the cervix. The Pap smear demonstrated a low-grade squamous intraepithelial lesion (LSIL) related to human papillomavirus (HPV) infection. The differential diagnosis based on the findings of the colposcopy included invasive cervical carcinoma, warty lesions, and perishable lesion. A cesarean section and the removal of the cervical tumor were scheduled and carried out as planned at 37 weeks of gestation. The histologic examination showed extensive lesions of low-grade squamous intraepithelial cervical neoplasia (LSIL/CIN1). Despite the fact that exophytic tumors of the cervix are extremely rare, in women presenting with vaginal bleeding or spotting during the second or third trimester of pregnancy, the ultrasound scan must be followed by a visual inspection of the vagina and the cervix.

Leydig cell hyperplasia as a cause of virilization in a postmenopausal woman: A case report.

Virilization is a rare condition in postmenopausal women, usually attributed to androgen excess of ovarian or adrenal origin. A 62-year-old woman presented with excessive hair loss of 3 months' duration and was investigated for an endocrine cause of alopecia. The hormonal evaluation revealed increased testosterone but normal levels of androstenedione and dehydroepiandrosterone sulfate, while the results of transvaginal ultrasonography and abdominal computed tomography were unremarkable. Based on these findings, the possibility of an adrenal androgen-secreting tumor was ruled out and suspicion of Leydig cell hyperplasia was raised. A bilateral laparoscopic salpingo-oophorectomy was performed due to the age of the patient and the diagnosis of Leydig cell hyperplasia was confirmed by histopathological examination. The postoperative course of the patient was uneventful and a repeat hormonal evaluation after the operation showed a normalization of androgen levels. In conclusion, Leydig cell hyperplasia should be considered as a likely cause of hyperandrogenism of ovarian origin in women who develop virilization. In postmenopausal women, bilateral oophorectomy will treat the disorder and provide a conclusive diagnosis via histopathological examination.

Genetic Disorders Underlying Polyhydramnios and Congenital Hypotonia: Three Case Reports and a Review of the Literature.

An abnormal rise in the amount of amniotic fluid is a frequent prenatal observation called polyhydramnios, which can indicate a number of underlying problems. Even while it frequently goes undiagnosed during pregnancy, it may be linked to dangerous fetal illnesses. In three cases of newborns with congenital hypotonia, polyhydramnios was the sole prenatal symptom reported in this study. This fact highlights the significance of understanding the possible connection between genetic abnormalities or neurological problems and polyhydramnios, underscoring the responsibility obstetricians have in educating expectant mothers who are at potential risk for these uncommon but serious illnesses. Whole-genome sequencing (WES), an advanced kind of prenatal testing, is essential for determining genetic reasons and assisting families in making decisions. Working together with specialists in fetal medicine is crucial in guaranteeing the best possible treatment and results for the mother and child.

Pregnancy physical activity questionnaire: Translation and cross-cultural adaptation of a Greek version.

OBJECTIVE: The aim of this study was to translate and adapt the Pregnancy Physical Activity Questionnaire (PPAQ) into Greek culture. STUDY DESIGN: The procedure followed to translate the PPAQ included the stages: forward translation, synthesis, backward translation and an expert committee review. Members of the research team discussed ambiguities, discordances and equivalence at each stage. Then, the pre-final Greek version of the PPAQ was pre-tested on 46 pregnant women; a quantitative and qualitative analysis was conducted. RESULTS: Few modifications were done to the original PPAQ, in order to ensure cultural adaptation and clinical implementation. Appropriate changes to the international metric units were done. In addition, two items have been modified to achieve relevance with Greek culture. Two items were merged into one and three items were splitted, which maintained their initial meaning. Those changes were made to match the energy expenditure compendium update for physical activities. Participants at the pre-test had a mean age of 34,23 years, response time to the questionnaire varied between 5 and 10 min and there were no missing data. No difficulties or misunderstandings were reported by the participants during pre-testing. Thus, the research team agreed on the pre-final PPAQ Greek version. CONCLUSION: The final PPAQ Greek version indicated transcultural equivalence to the original PPAQ in English. It is also a unique questionnaire for assessing physical activity in Greek pregnant women and will be a useful tool in clinical routine.

ANRIL rs4977574 Gene Polymorphism in Women with Recurrent Pregnancy Loss.

BACKGROUND: ANRIL rs4977574 gene polymorphism has been associated with arterial thrombosis and cardiovascular disease development. ANRIL rs4977574 gene polymorphism could also be associated with recurrent pregnancy loss (RPL) since there is increasing evidence in favor of a potential shared pathophysiological mechanism with cardiovascular disease, potentially through arterial thrombosis. This study's goal is to investigate the differences in ANRIL rs4977574 gene polymorphism between women with and without RPL, if any, as well as a potential association with the number of pregnancy losses. METHODS: DNA was isolated from peripheral blood samples, and the sequence containing the polymorphism of interest was amplified with PCR. Results were visualized under UV light following electrophoresis in 3% agarose gel with ethidium bromide. ANRIL rs4977574 (A>G) prevalence was compared between 56 women with and 69 without RPL. Results were adjusted for women's age and BMI, while a stratified analysis was performed according to number of pregnancy losses. RESULTS: Allele A was significantly more prevalent in the control group compared to RPL women [31 (44.9%) vs. 14 (25%), p = 0.021]. Although not reaching statistical significance, a gradually decreasing prevalence of allele A with an increasing number of pregnancy losses was observed [31 (44.9%) in control, eight (30.7%) with two, six (23.1%) with three, and 0 (0.0%) with four pregnancy losses, p = 0.078]. Results were also similar following adjustment. CONCLUSIONS: This is the first study that demonstrates an association between RPL presence and ANRIL rs4977574 gene polymorphism (lower prevalence of allele A), while a difference according to the number of pregnancy losses cannot be excluded.

Placental Ultrasonographical Findings during SARS-CoV-2 Infection.

Infection with SARS-CoV-2 virus (COVID-19) during pregnancy has been associated with several complications. Increasing evidence suggests that COVID-19 infection leaves tell-tale signs of placental injury. During ultrasound examination and placental evaluation of COVID-19 infected pregnancies, we recorded signs of placental involvement, with findings indicating malperfusion, chorangiosis, deciduitis, and subchorionitis. Early detection of placental damage through the use of specific ultrasound findings could indicate which pregnancies are at increased risk for complications.

Effects of leptin on the expression of fatty acid-binding proteins in human placental cell cultures.

The present study aimed to evaluate the protein expression of the transmembrane translocase FAT/CD36 and cytoplasmic H-FABP and L-FABP in human trophoblast tissue and evaluate the effects of exogenous leptin upon differential expression of each biomolecule; consequently, it aimed to derive information regarding the effects of leptin upon the expression of proteins implicated in fatty acid metabolism. Protein and total RNA were isolated from 72 samples of trophoblast tissue obtained from chorionic villous sampling. Of these, 36 samples were evaluated for protein (supernatant and pellet fraction separated) and the other 36 for total RNA expression. For each subgroup of samples, 12 were treated immediately and 24 were cultured. Half of the cultured samples were treated with 10 ng/-ml exogenously added leptin and the other half were untreated. Western blotting and PCR techniques were used for the evaluation of biomolecule expression. Our results were obtained from samples at a mean gestational week of 12+5 (n=72; min, 11+0; max, 14+1 gw; SD,0.89). In promptly treated samples we observed the presence of FAT/|CD36 protein and absence of cytoplasmic FABPs. In the latter, only mRNA transcription of H-FABP was noted. A cytoplasmic pool of FAT/CD36 was also noted in the supernatant fraction of proteins. For cultured samples, when leptin was added, a statistically significant increase in FAT/CD36 protein expression was observed (n=24, p<0.001; mean difference, 0.219; SD, 0.0315; CI, -0.284 to -0.154). In our study we demonstrated the protein and mRNA expression of biomolecules implicated in fatty acid metabolism in human placenta. A cytoplasmic pool of the transmembrane protein FAT/CD36 was noted. Leptin caused the increase in FAT/CD36 protein expression in the cultured samples. Therefore, we conclude that leptin has an immediate effect and plays a role in lipid metabolism in human placenta.