Evaluation of an Updated Gene Panel as a Diagnostic Tool for Both Male and Female Infertility.

In recent years, an increasing number of genes associated with male and female infertility have been identified. The genetics of infertility is no longer limited to the analysis of karyotypes or specific genes, and it is now possible to analyse several dozen infertility genes simultaneously. Here, we present the diagnostic activity over the past two years including 140 patients (63 women and 77 men). Targeted sequencing revealed causative variants in 17 patients, representing an overall diagnostic rate of 12.1%, with prevalence rates in females and males of 11% and 13%, respectively. The gene-disease relationship (GDR) was re-evaluated for genes due to the addition of new patients and/or variants in the actual study. Five genes changed categories: two female genes (MEIOB and TBPL2) moved from limited to moderate; two male genes (SOHLH1 and GALNTL5) moved from no evidence to strong and from limited to moderate; and SEPTIN12, which was unable to classify male infertility, was reclassified as limited. Many infertility genes have yet to be identified. With the increasing integration of genetics in reproductive medicine, the scope of intervention extends to include other family members, in addition to individual patients or couples. Genetic counselling consultations and appropriate staffing will need to be established in fertility centres. Trial registration number: Not applicable.

Pseudoxanthomatous Salpingitis: A Rare Granulomatous Pathology of the Fallopian Tube.

Uncommon presentations of granulomatous salpingitis are pseudoxanthoma salpingitis (PSX) and xanthogranulomatous salpingitis (XGS). The clinical features and image modalities can mimic ovarian malignancy. Thus, a proper pre-operative evaluation of this entity is vital to avoid radical treatment. Here, we report a case of a 31-year-old woman with primary infertility diagnosed with pseudoxanthoma salpinx. This patient was a known case of endometriosis and presented with gross ascites.

A pathway study of factors influencing quality of fertility life.

BACKGROUD: To investigate the factors influencing fertility quality of life in infertile men, constructing a structural equation model of the factors influencing fertility quality of life in infertile men, and to provide suggested measures for improving fertility quality of life in infertile men. METHODS: It is a Observational study. Infertile men (n = 250) attending a fertility centre in a hospital in Xinjiang, matched 1:2 men with no obvious male factor in the control group (n = 500).The Quality of Fertility Life Scale, the Social Support Scale, the Fertility Stress Scale and the Positive Attention Awareness Scale were used to conduct the survey. The model was constructed by applying the maximum likelihood estimation method in Mplus 8.3 software, to explore the factors influencing the quality of reproductive life of infertile men through path analyses. Differences between the case and control groups were statistically significant (P < 0.05) in terms of total fertility quality of life scores, core entry dimensions, affective responses, physical and mental relationships, selective treatment dimensions, and treatment tolerance. RESULTS: Past medical history, history of exposure to hazardous environments, health insurance reimbursement, social support, fertility stress, and mindfulness are important factors affecting the quality of fertility life of infertile men. CONCLUSION: The quality of fertility life of infertile men is not optimistic. By improving the level of mindfulness, fertility stress, and social support, we propose appropriate measures to improve the quality of fertility life of infertile men. These measures can improve their confidence in clinical diagnosis and infertility treatment, enabling them to cope positively with these challenges.

Distribution and Positive Predictive Value of Follicle Stimulating Hormone Levels Among Nonazoospermic Men.

PURPOSE: Our goal was to characterize the distribution of follicle stimulating hormone (FSH) in fertile and subfertile nonazoospermic men, and to determine the ability of various FSH thresholds to predict fertility status. MATERIALS AND METHODS: We performed a retrospective cohort study of 1389 nonazoospermic men who presented for fertility evaluation. Men with at least 2 semen analyses and 1 FSH level were included. Men were dichotomized into fertile and subfertile groups based on total motile sperm count. FSH was evaluated within a multivariable model, and positive predictive values (PPVs) for subfertility were used to assess the clinical utility of various FSH thresholds. RESULTS: One thousand fifteen (80%) men were classified as fertile and 274 (20%) as subfertile. Age, presence of varicocele, and testosterone levels were not statistically different between the groups. Median FSH was 4.0 vs 6.0 (P < .001) among fertile vs subfertile men. Multiple FSH thresholds ranging from 2.9 to 9.3 performed similarly in predicting fertility status (PPV 0.49-0.59). Only FSH thresholds above the 95th percentile (12.1) had PPVs greater than 0.7. The highest PPV (0.84) was seen at an FSH of 20.8 (99th percentile). CONCLUSIONS: While there were significant differences in FSH levels among fertile and subfertile nonazoospermic men, multiple FSH cutoffs between 2.2 and 9.3 performed poorly for prediction of fertility status as determined by total motile sperm count. It was not until the 95th percentile FSH value that a clinically useful level of predictability for subfertility was reached, indicating that FSH should not be used as a standalone test of fertility status. Nonetheless, FSH testing remains clinically useful and may be most informative in the setting of extreme values or discordant FSH and semen analysis results.

Undiagnosed RASopathies in infertile men.

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 in 1,000. Patients are typically identified in childhood based on diverse characteristic features, including cryptorchidism (CR) in >50% of affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0-39 million), we hypothesized that men seeking infertility management include cases with undiagnosed RASopathies. Likely pathogenic or pathogenic (LP/P) variants in 22 RASopathy-linked genes were screened in 521 idiopathic SPGF patients (including 155 CR cases) and 323 normozoospermic controls using exome sequencing. All 844 men were recruited to the ESTonian ANDrology (ESTAND) cohort and underwent identical andrological phenotyping. RASopathy-specific variant interpretation guidelines were used for pathogenicity assessment. LP/P variants were identified in PTPN11 (two), SOS1 (three), SOS2 (one), LZTR1 (one), SPRED1 (one), NF1 (one), and MAP2K1 (one). The findings affected six of 155 cases with CR and SPGF, three of 366 men with SPGF only, and one (of 323) normozoospermic subfertile man. The subgroup "CR and SPGF" had over 13-fold enrichment of findings compared to controls (3.9% vs. 0.3%; Fisher's exact test, p = 5.5 × 10-3). All ESTAND subjects with LP/P variants in the Ras/MAPK pathway genes presented congenital genitourinary anomalies, skeletal and joint conditions, and other RASopathy-linked health concerns. Rare forms of malignancies (schwannomatosis and pancreatic and testicular cancer) were reported on four occasions. The Genetics of Male Infertility Initiative (GEMINI) cohort (1,416 SPGF cases and 317 fertile men) was used to validate the outcome. LP/P variants in PTPN11 (three), LZTR1 (three), and MRAS (one) were identified in six SPGF cases (including 4/31 GEMINI cases with CR) and one normozoospermic man. Undiagnosed RASopathies were detected in total for 17 ESTAND and GEMINI subjects, 15 SPGF patients (10 with CR), and two fertile men. Affected RASopathy genes showed high expression in spermatogenic and testicular somatic cells. In conclusion, congenital defects in the Ras/MAPK pathway genes represent a new congenital etiology of syndromic male infertility. Undiagnosed RASopathies were especially enriched among patients with a history of cryptorchidism. Given the relationship between RASopathies and other conditions, infertile men found to have this molecular diagnosis should be evaluated for known RASopathy-linked health concerns, including specific rare malignancies.

Therapeutic roles of platelet-rich plasma to restore female reproductive and endocrine dysfunction.

Millions of women worldwide are infertile due to gynecological disorders, including premature ovarian insufficiency, polycystic ovary syndrome, Asherman syndrome, endometrial atrophy, and fallopian tube obstruction. These conditions frequently lead to infertility and have a substantial impact on the quality of life of the affected couples, primarily because of their psychological implications and high financial costs. Recently, using platelets to stimulate cell proliferation and tissue differentiation has emerged as a promising approach in regenerative medicine. Platelet-rich plasma (PRP) shows considerable potential for promoting endometrial hypertrophy and follicle development, making it a promising therapeutic option for tissue repair or replacement. This review provides an overview of the recent advancements and underlying mechanisms of PRP therapy for various female reproductive diseases and presents new therapeutic options for addressing female infertility.

Comparison of Baseline Characteristics, Sociodemographics, and Gynecological Risk Factors Associated with Secondary Infertility of Females in Pakistan.

Introduction: Secondary infertility is characterized by the inability to conceive for a period of 1 year, after having previously conceived at least once. Objectives: To explore the risk factors of secondary infertility and compare sociodemographics and anthropometric variables of each studied group. Methods: Study was conducted at University Institute of Public Health, Faculty of Allied Health Sciences, The University of Lahore, collecting data from Gilani Ultrasound Center in 18 months after approval of synopsis. Total 690 females (345 cases and 345 controls) were enrolled. Participants were included in case group if they were 20-45 years of age, having any parity, and confirmed diagnosis of secondary infertility. Results: The mean age of cases and controls was 33.08 ± 4.17 years and 31.37 ± 4.36 years, respectively. The mean body mass index (BMI) in cases was 27.61 ± 4.27 kg/m2, and in controls the mean BMI was 25.52 ± 4.30 kg/m2. There was not a significant difference among religion that shows no association (p = 0.73) with secondary infertility as profession has association with it (p = 0.01). History of polycystic ovary syndrome, pelvic inflammatory disease, endometriosis, uterine fibroids, menorrhagia, intermenstrual bleeding, and history of abortion are associated with secondary infertility. Conclusions: While several sociodemographic features and medical disorders have been associated to secondary infertility, it is vital to stress that not all of these factors are controllable by medical therapy. Factors like age and certain medical issues may be unaffected by intervention. However, for controllable variables like BMI and certain medical diseases, focused therapies and lifestyle changes may reduce the chance of subsequent infertility.

Analysis of weighted gene co-expression networks and clinical validation identify hub genes and immune cell infiltration in the endometrial cells of patients with recurrent implantation failure.

Background: About 10% of individuals undergoing in vitro fertilization encounter recurrent implantation failure (RIF), which represents a worldwide social and economic concern. Nevertheless, the critical genes and genetic mechanisms underlying RIF are largely unknown. Methods: We first obtained three comprehensive microarray datasets "GSE58144, GSE103465 and GSE111974". The differentially expressed genes (DEGs) evaluation, enrichment analysis, as well as efficient weighted gene co-expression network analysis (WGCNA), were employed for distinguishing RIF-linked hub genes, which were tested by RT-qPCR in our 30 independent samples. Next, we studied the topography of infiltration of 22 immune cell subpopulations and the association between hub genes and immune cells in RIF using the CIBERSORT algorithm. Finally, a novel ridge plot was utilized to exhibit the potential function of core genes. Results: The enrichment of GO/KEGG pathways reveals that Herpes simplex virus 1 infection and Salmonella infection may have an important role in RIF. After WGCNA, the intersected genes with the previous DEGs were obtained using both variance and association. Notably, the subsequent nine hub genes were finally selected: ACTL6A, BECN1, SNRPD1, POLR1B, GSK3B, PPP2CA, RBBP7, PLK4, and RFC4, based on the PPI network and three different algorithms, whose expression patterns were also verified by RT-qPCR. With in-depth analysis, we speculated that key genes mentioned above might be involved in the RIF through disturbing endometrial microflora homeostasis, impairing autophagy, and inhibiting the proliferation of endometrium. Furthermore, the current study revealed the aberrant immune infiltration patterns and emphasized that uterine NK cells (uNK) and CD4+ T cells were substantially altered in RIF endometrium. Finally, the ridge plot displayed a clear and crucial association between hub genes and other genes and key pathways. Conclusion: We first utilized WGCNA to identify the most potential nine hub genes which might be associated with RIF. Meanwhile, this study offers insights into the landscape of immune infiltration status to reveal the underlying immune pathogenesis of RIF. This may be a direction for the next study of RIF etiology. Further studies would be required to investigate the involved mechanisms.

Genetic Analysis of a Mosaic Fra(16)(q22)/Del(16)(q22) Karyotype in a Primary Infertile Woman.

Purpose: Fragile sites are specific chromosomal regions showing gaps, poor staining, contractions, or even breaks in the chromosomes. These spontaneous and heritable fragile sites are prone to structural variations which can lead to adverse reproductive outcomes. This paper aims to present a specific case study of a female patient, with a mosaic karyotype involving chromosome 16q22 fragile site which is very rare in clinic and her experience of infertility. Case Presentation: A 37-year-old woman is diagnosed with ten-year primary infertility. She worked in a factory, and she was occasionally exposed to paint. She underwent two cycles of follicular monitoring with intrauterine insemination (IUI) using her husband's sperm six years ago but failed. Most of her prepregnancy tests were normal, except a not smooth right fallopian tube. Her G-band karyotype of peripheral blood lymphocytes was mos 46, XX, del(16)(q22)[40]/46, XX, fra(16)(q22)[29]/46, XX, fra(16)tr(16)(q22)[3]/46, XX[28] which inherited from her mother. The SCE assay detected a significantly higher frequency of SCEs in the 16q region of the patient's chromosomes compared to her mother and a healthy control. However, the average SCEs per chromosome were quite close. Moreover, copy number variation (CNV) sequencing showed no deletion nor duplication at 16q22. Conclusion: Infertility cannot be completely attributed to the fragile site on chromosome 16q22. Assisted reproductive technology combined with preimplantation genetic testing may help in achieving a healthy live birth.

Effects of Tcte1 knockout on energy chain transportation and spermatogenesis: implications for male infertility.

STUDY QUESTION: Is the Tcte1 mutation causative for male infertility? SUMMARY ANSWER: Our collected data underline the complex and devastating effect of the single-gene mutation on the testicular molecular network, leading to male reproductive failure. WHAT IS KNOWN ALREADY: Recent data have revealed mutations in genes related to axonemal dynein arms as causative for morphology and motility abnormalities in spermatozoa of infertile males, including dysplasia of fibrous sheath (DFS) and multiple morphological abnormalities in the sperm flagella (MMAF). The nexin-dynein regulatory complex (N-DRC) coordinates the dynein arm activity and is built from the DRC1-DRC7 proteins. DRC5 (TCTE1), one of the N-DRC elements, has already been reported as a candidate for abnormal sperm flagella beating; however, only in a restricted manner with no clear explanation of respective observations. STUDY DESIGN SIZE DURATION: Using the CRISPR/Cas9 genome editing technique, a mouse Tcte1 gene knockout line was created on the basis of the C57Bl/6J strain. The mouse reproductive potential, semen characteristics, testicular gene expression levels, sperm ATP, and testis apoptosis level measurements were then assessed, followed by visualization of N-DRC proteins in sperm, and protein modeling in silico. Also, a pilot genomic sequencing study of samples from human infertile males (n = 248) was applied for screening of TCTE1 variants. PARTICIPANTS/MATERIALS SETTING METHODS: To check the reproductive potential of KO mice, adult animals were crossed for delivery of three litters per caged pair, but for no longer than for 6 months, in various combinations of zygosity. All experiments were performed for wild-type (WT, control group), heterozygous Tcte1+/- and homozygous Tcte1-/- male mice. Gross anatomy was performed on testis and epididymis samples, followed by semen analysis. Sequencing of RNA (RNAseq; Illumina) was done for mice testis tissues. STRING interactions were checked for protein-protein interactions, based on changed expression levels of corresponding genes identified in the mouse testis RNAseq experiments. Immunofluorescence in situ staining was performed to detect the N-DRC complex proteins: Tcte1 (Drc5), Drc7, Fbxl13 (Drc6), and Eps8l1 (Drc3) in mouse spermatozoa. To determine the amount of ATP in spermatozoa, the luminescence level was measured. In addition, immunofluorescence in situ staining was performed to check the level of apoptosis via caspase 3 visualization on mouse testis samples. DNA from whole blood samples of infertile males (n = 137 with non-obstructive azoospermia or cryptozoospermia, n = 111 samples with a spectrum of oligoasthenoteratozoospermia, including n = 47 with asthenozoospermia) was extracted to perform genomic sequencing (WGS, WES, or Sanger). Protein prediction modeling of human-identified variants and the exon 3 structure deleted in the mouse knockout was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: No progeny at all was found for the homozygous males which were revealed to have oligoasthenoteratozoospermia, while heterozygous animals were fertile but manifested oligozoospermia, suggesting haploinsufficiency. RNA-sequencing of the testicular tissue showed the influence of Tcte1 mutations on the expression pattern of 21 genes responsible for mitochondrial ATP processing or linked with apoptosis or spermatogenesis. In Tcte1-/- males, the protein was revealed in only residual amounts in the sperm head nucleus and was not transported to the sperm flagella, as were other N-DRC components. Decreased ATP levels (2.4-fold lower) were found in the spermatozoa of homozygous mice, together with disturbed tail:midpiece ratios, leading to abnormal sperm tail beating. Casp3-positive signals (indicating apoptosis) were observed in spermatogonia only, at a similar level in all three mouse genotypes. Mutation screening of human infertile males revealed one novel and five ultra-rare heterogeneous variants (predicted as disease-causing) in 6.05% of the patients studied. Protein prediction modeling of identified variants revealed changes in the protein surface charge potential, leading to disruption in helix flexibility or its dynamics, thus suggesting disrupted interactions of TCTE1 with its binding partners located within the axoneme. LARGE SCALE DATA: All data generated or analyzed during this study are included in this published article and its supplementary information files. RNAseq data are available in the GEO database (https://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE207805. The results described in the publication are based on whole-genome or exome sequencing data which includes sensitive information in the form of patient-specific germline variants. Information regarding such variants must not be shared publicly following European Union legislation, therefore access to raw data that support the findings of this study are available from the corresponding author upon reasonable request. LIMITATIONS REASONS FOR CAUTION: In the study, the in vitro fertilization performance of sperm from homozygous male mice was not checked. WIDER IMPLICATIONS OF THE FINDINGS: This study contains novel and comprehensive data concerning the role of TCTE1 in male infertility. The TCTE1 gene is the next one that should be added to the 'male infertility list' because of its crucial role in spermatogenesis and proper sperm functioning. STUDY FUNDING/COMPETING INTERESTS: This work was supported by National Science Centre in Poland, grants no.: 2015/17/B/NZ2/01157 and 2020/37/B/NZ5/00549 (to M.K.), 2017/26/D/NZ5/00789 (to A.M.), and HD096723, GM127569-03, NIH SAP #4100085736 PA DoH (to A.N.Y.). The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Impaired Spermatogenesis in Infertile Patients with Orchitis and Experimental Autoimmune Orchitis in Rats.

Experimental autoimmune orchitis (EAO) is a well-established rodent model of organ-specific autoimmunity associated with infertility in which the testis immunohistopathology has been extensively studied. In contrast, analysis of testis biopsies from infertile patients associated with inflammation has been more limited. In this work, testicular biopsies from patients with idiopathic non-obstructive azoospermia diagnosed with hypospermatogenesis (HypoSp) [mild: n = 9, and severe: n = 11], with obstructive azoospermia and complete Sp (spermatogenesis) (control group, C, n = 9), and from Sertoli cell-only syndrome (SCOS, n = 9) were analyzed for the presence of immune cells, spermatogonia and Sertoli cell (SCs) alterations, and reproductive hormones levels. These parameters were compared with those obtained in rats with EAO. The presence of increased CD45+ cells in the seminiferous tubules (STs) wall and lumen in severe HypoSp is associated with increased numbers of apoptotic meiotic germ cells and decreased populations of undifferentiated and differentiated spermatogonia. The SCs showed an immature profile with the highest expression of AMH in patients with SCOS and severe HypoSp. In SCOS patients, the amount of SCs/ST and Ki67+ SCs/ST increased and correlated with high serum FSH levels and CD45+ cells. In the severe phase of EAO, immune cell infiltration and apoptosis of meiotic germ cells increased and the number of undifferentiated and differentiated spermatogonia was lowest, as previously reported. Here, we found that orchitis leads to reduced sperm number, viability, and motility. SCs were mature (AMH-) but increased in number, with Ki67+ observed in severely damaged STs and associated with the highest levels of FSH and inflammatory cells. Our findings demonstrate that in a scenario where a chronic inflammatory process is underway, FSH levels, immune cell infiltration, and immature phenotypes of SCs are associated with severe changes in spermatogenesis, leading to azoospermia. Furthermore, AMH and Ki67 expression in SCs is a distinctive marker of severe alterations of STs in human orchitis.

Vitamin D3 among neonates born after in vitro fertilization compared with neonates from the general population.

INTRODUCTION: Sufficient levels of vitamin D have been associated with higher chances for both clinical pregnancy and live birth among women undergoing assisted reproductive techniques, whereas low levels of maternal vitamin D have been associated with preeclampsia and late miscarriage. In Denmark, subgroups at risk for low vitamin D levels, including neonates and toddlers, are recommended to use supplementation. The aim was to study the level of vitamin D3 among neonates born after in vitro fertilization compared with neonates from the general population. MATERIAL AND METHODS: In this cohort study a random sample of 1326 neonates representing the general population and 1200 neonates conceived by in vitro fertilization born in Denmark from 1995 to 2002 were identified from registries covering the whole Danish population. Information on use of assisted reproduction was collected from the Danish In Vitro Fertilization register, ICD-10 code: DZ358F. 25-Hydroxyvitamin D was measured from dried blood spots routinely collected by heel prick 48-72 h after birth and corrected according to the hematocrit fraction for capillary blood of neonates. Linear regression analysis was performed, both crude and adjusted, for predefined putative confounders, identified through directed acyclic graphs. RESULTS: Vitamin D3 analysis could be performed from a total of 1105 neonates from the general population and 1072 neonates conceived by in vitro fertilization that were subsequently included in the study. The median vitamin D3 was 24.0 nmol/L (interquartile range [IQR] 14.1-39.3) and 33.0 nmol/L (IQR 21.3-48.8) among neonates from the general population and neonates conceived by in vitro fertilization, respectively. The adjusted mean difference between neonates from the general population and those conceived by in vitro fertilization was 6.1 nmol/L (95% confidence interval 4.1-8.1). CONCLUSIONS: In this study, children born after in vitro fertilization have a higher vitamin D3 than a random sample of neonates in Denmark.

Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal preimplantation embryogenesis.

Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.

Utilization of sperm cryopreservation in patients with testicular cancer.

PURPOSE: We assessed factors that affect the utilization of sperm cryopreservation before 2021, when patients covered expenses, and the influence on quality of life. METHODS: Between 2011 and 2021, testicular cancer survivors (TCS) at our clinic completed a questionnaire, including EORTC QLQ-TC26, covering sperm cryopreservation, sociodemographic details, post-treatment births, and artificial insemination. RESULTS: After 5.7 ± 3.0 years, 279 participants (64%) responded to the questionnaire. Among them, 33% (91/279) of testicular cancer survivors chose sperm cryopreservation prior to treatment, with 11% (10/91) using it for insemination. Conversely, 2% (3/188) without cryopreservation reported unfulfilled desire to have children. Univariate analysis showed TCS with cryopreservation were younger (30.6 ± 7.1 (35 (21-59)) vs. 42.4 ± 10.9 (48 (22-81)) years; p = 0.001), had a lower BMI (24.2 ± 3.3 vs. 26.6 ± 4.6 kg/m2; p = 0.009) and a lower Charlson Score (> 3: 36% vs. 60%; p < 0.001). Multivariate analysis revealed older age (≥ 37 years: OR 13.1 (5.5-31.2), p < 0.001) and lower education (middle school or less: OR 3.3 (1.6-6.9), p = 0.001) as independent factors associated with not undergoing cryopreservation. Regarding quality of life, multivariate analysis identified a lower infertility anxiety score (OR 4.3 (2.0-9.0), p < 0.001) and higher age (≥ 44 years: OR 5.4 (2.6-11.3); p < 0.001) as predictors for the absence of prior cryopreservation. CONCLUSIONS: Age and education seem to impact the choice of undergoing paid sperm cryopreservation. Urologists should inform testicular cancer patients about costs and coverage. Importantly, the occurrence of unmet desires for parenthood is minimal among those who forego cryopreservation.

Uterine fluid microRNAs in repeated implantation failure.

Recurrent implantation failure (RIF) is a significant obstacle in assisted reproductive procedures, primarily because of compromised receptivity. As such, there is a need for a dependable and accurate clinical test to evaluate endometrial receptiveness, particularly during embryo transfer. MicroRNAs (miRNAs) have diverse functions in the processes of implantation and pregnancy. Dysregulation of miRNAs results in reproductive diseases such as recurrent implantation failure (RIF). The endometrium secretes several microRNAs (miRNAs) during the implantation period, which could potentially indicate whether the endometrium is suitable for in vitro fertilization (IVF). The goal of this review is to examine endometrial miRNAs as noninvasive biomarkers that successfully predict endometrium receptivity in RIF.

How phytochemicals influence reproductive outcomes in women receiving assisted reproductive techniques: a systematic review.

CONTEXT: Over the past few years, there has been an increasing amount of scholarly literature suggesting a connection between the nutritional status of pregnant mothers and early fetal development, as well as the long-term health consequences of their offspring. Multiple studies have documented that alterations in dietary patterns prior to conception have the potential to affect the initial stages of embryonic development. OBJECTIVES: The aim of this study was to perform a comprehensive review of the research pertaining to the correlation between phytochemicals ( specifically, polyphenols, carotenoids and phytoestrogens) and assisted reproductive technology (ART). DATA SOURCES: PubMed, Scopus, Web of Science, and Clinical Trials databases were searched from January 1978 to March 2023. STUDY SELECTION: This study comprised observational, randomized controlled, and cohort studies that examined the effects of phytochemicals on ART results. The study's outcomes encompass live birth rate, clinical pregnancy, and ongoing pregnancy. DATA EXTRACTION: The assessment of study quality was conducted by 2 researchers, independently, using the Quality Criteria Checklist for Primary Research. RESULTS: A total of 13 studies were included, of which there were 5 randomized controlled studies, 1 nonrandomized controlled study, 6 prospective cohort studies, and 1 retrospective cohort study. CONCLUSION: This research focused on investigating the impact of phytochemicals on ART and has highlighted a dearth of articles addressing that topic. Collaboration among patients, physicians, and nutritionists is crucial for doing novel research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023426332.

Alpha-lipoic Acid: An Antioxidant with Anti-Aging Properties for Disease Therapy.

The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.

Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis.

RATIONALE: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and primary immunodeficiency disorders), but most cases remain idiopathic. OBJECTIVES: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. METHODS: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived, cells, cell cultures and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. MEASUREMENTS AND MAIN RESULTS: We identified bi-allelic pathogenic variants in WFDC2 in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and thus secretion of mature WFDC2. CONCLUSIONS: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Effect of calorie restriction and intermittent fasting on glucose homeostasis, lipid profile, inflammatory, and hormonal markers in patients with polycystic ovary syndrome: a systematic review.

Background and objective: Polycystic ovary syndrome (PCOS) is a complex hormonal disorder that leads to ovarian cysts, irregular ovulation, and hormonal swings in women. It is a complex and heterogeneous condition that affects 4 to 20% of women of reproductive age worldwide and relates to reproductive, metabolic, and psychosocial dysfunction. Dietary and lifestyle modifications have been proposed to play a central role in the management of PCOS. This study aimed to provide a comprehensive systemic overview of the existing literature on the effects of intermittent fasting (IF) and calorie restriction (CR) regimens on disease markers of PCOS. Designs and methods: Several databases, such as CINAHL, Cochrane, EBSCOhost, EMBASE, Google Scholar, ProQuest Medical, PubMed/MEDLINE, ScienceDirect, Scopus, and Web of Science databases were searched for clinical trials and observational studies examined the effects of IF regimens such as time-restricted eating and Ramadan model of IF (RIF) on glucose homeostasis, lipid profile, inflammatory and hormonal markers in patients with PCOS. Results: This systematic review solicited three articles, comprising a collective sample size of 75 females diagnosed with PCOS. The studies were published between 2015 to 2023 and were undertaken in three countries: China, Turkey, and Iran. The research articles examined the effects of intervention with IF and CR on PCOS-related parameters such as anthropometric measures and biochemical tests which included enzymes, glycemic control, lipid profile, hormonal, and oxidative stress, and inflammatory markers. The articles yielded mixed results, with two of them showing significant changes across all tested parameters. One of the three studies did not exhibit any significant changes. Conclusion: Very limited studies examined the relationship between IR and CR with markers of PCOS. Further well-controlled studies need to be undertaken the combined results from the limited studies illustrate the intricate and diverse nature of IF, including the RIF, and its influence on measurements of body composition and biochemical markers related to PCOS.

Metformin ameliorates endometrial thickness in a rat model of thin endometrium.

Metformin, a well-established anti-diabetic drug, is also used in managing various other metabolic disorders including polycystic ovarian syndrome (PCOS). There are evidences to show that metformin improves endometrial functions in PCOS women. However, fewer studies have explored the direct effects of metformin on endometrium. Previous in vitro studies have shown that therapeutic serum concentrations of metformin enhance endometrial epithelial cell proliferation. The present study was undertaken to investigate in vivo effects of metformin on endometrial proliferation in a rat model of thin endometrium. Toward this, a rat model of thin endometrium was developed. Metformin (0.1% or 1% w/v) was administrated orally for 15 days in rats with thin endometrium. Oral metformin administration for three consecutive estrous cycles (15 days) in the thin endometrium rat model led to an increase in endometrial thickness compared to sham endometrium. Histological analysis showed a significant increase in the number of endometrial glands (P < 0.05), stromal cells (P < 0.01) and blood vessels (P < 0.01) in metformin-treated (n = 10 in each group) uterine horns compared to sham (saline-treated) uterine horns in rats. The expression of proliferating cell nuclear antigen and vascular epithelial growth factor was found to be upregulated on treatment with 1% metformin-treated group (n = 7). However, pregnancy outcomes in the rats treated with metformin remained unaltered despite the restoration of endometrial thickness. In conclusion, the study demonstrated that metformin ameliorates endometrial thickness in a rat model of thin endometrium by increasing endometrial proliferation and angiogenesis, without restoration of embryo implantation.