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Abstract Background Isolated congenital bilateral absence of vas deferens (iCBAVD) in men results in obstructive azoospermia and is mainly caused by pathogenic variants in cystic fibrosis transmembrane conductance regulator (CFTR) or adhesion G protein‐coupled receptor G2 (ADGRG2). Methods The next‐generation sequencing (NGS) was used to screen the mutations in the proband, and Sanger sequencings were performed to validate the compound heterozygous variant of CFTR in his family members. Protein structure simulation was performed to discover the potential pathological mechanism. Results This study reported novel compound heterozygous CFTR mutations (NM:000492.4, Intron: 5T; c.3965_3969dupTTGGG: p.R1325Gfs*5) in two brothers with obstructive azoospermia. The compound heterozygous CFTR mutations were first screened out by NGS in an infertile male patient who exhibited iCBAVD from a nonconsanguineous Chinese family. Histological analysis of the testicular biopsy from this patient revealed normal spermatogenesis and mature spermatozoa were observed in the seminiferous tubules. Surprisingly, the same compound heterozygous CFTR mutations were also observed in his brothers who also exhibited iCBAVD, with their parents being a heterozygous carrier for the mutations, as verified by Sanger sequencing. Protein structure simulation revealed that these mutations potentially led to impaired ATP‐binding ability of CFTR. Conclusion We identified novel compound heterozygous CFTR mutations in two brothers and summarized the literature regarding CFTR mutation and male infertility. Our study may contribute to the genetic diagnosis of iCBAVD and future genetic counseling.

Background: Up to now, a number of studies have explored the influence of blastocyst biopsy on maternal and neonatal outcomes, and the results have been somewhat inconsistent. Therefore, the aim of this study was to investigate whether blastocyst biopsy is associated with an elevated risk of hypertensive disorders of pregnancy (HDP) and other adverse perinatal outcomes during frozen embryo transfer (FET) cycles in singleton live births resulting from intracytoplasmic sperm injection (ICSI) in women aged ≤ 35 years. Methods: A total of 1,008 women were involved in this study from January 2020 to June 2022, who underwent ICSI cycles and received single FET, leading to the birth of a live singleton newborn. The study population were categorized into two groups: the preimplantation genetic testing (PGT) group, comprising 269 women whose blastocysts underwent trophectoderm biopsy, and the control group, consisting of 739 women whose blastocysts did not undergo biopsy. The primary outcome assessed in this study was HDP. Additionally, various relevant perinatal outcomes related to both maternal and neonatal health were also evaluated. Results: In comparison to the control group, notable disparities were observed between the groups in relation to infertility duration, EMT, infertility type, infertility cause and endometrial preparation protocol (P < 0.05, for all). The percentage of female gender significantly increased in the PGT group in comparison with the control group (P < 0.05). However, the risk of HDP, other maternal and neonatal outcomes exhibited comparable results between the two groups (P > 0.05, for all). Moreover, univariate regression analyses further revealed that PGT had no influence on maternal and neonatal outcomes, except for gender (aOR 1.44; 95% CI, 1.03–2.01; P = 0.031). Conclusions: In the short-term perspective, it could be inferred that blastocyst biopsy may not increase the risks associated with HDP or other unfavorable maternal and neonatal outcomes. However, despite the limited sample size, our findings may not be applicable to those aged 35 or over; therefore, larger cohort studies are imperative for the validation of our results. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency (POI) has recently been reported to be linked with epigenetic changes. Previous studies have focused on the regulation of individual genes associated with ovarian function through single‐gene epigenetic variations; however, there is a deficiency in the comprehensive comprehension of the epigenetic profile for POI. Therefore, we conducted a multi‐omics study integrating methylation, hydroxymethylation and transcriptome sequencing analyses in cumulus cells from women with POI and their matched controls. Our data revealed significant global increases in methylation and hydroxymethylation levels in POI patients. We observed a predominance of hypermethylated and hyperhydroxymethylated regions across the genome, with methylation in gene bodies negatively correlating with gene expression, especially in promoter regions. Subsequent experimental validation was performed to confirm the involvement of candidate genes (EGR1, EGR2 and DLX5) in ovarian steroid hormone synthesis. Interestingly, our findings indicate that these epigenetic modifications are associated with genes implicated in POI, ovarian function and the epigenetic age clock. This comprehensive epigenetic profile underscores the potential for identifying novel biomarkers and therapeutic targets for POI by unravelling the complex interplay between DNA epigenetics and ovarian function. [ABSTRACT FROM AUTHOR]

Introduction: Obesity has been associated with an increased risk of reproductive failure, especially preterm birth. As preimplantation genetic testing for aneuploidies (PGT-A) is increasingly used worldwide, however, it is still unclear whether body mass index (BMI) has an effect on the preterm birth rate in patients undergoing in vitro fertilization (IVF) with PGT-A when transferring a single euploid blastocyst. Materials and methods: This retrospective, single-center cohort study included 851 women who underwent the first cycle of frozen-thawed single euploid blastocyst transfer with PGT-A between 2015 and 2020. The primary outcome was the preterm birth rate. Secondary outcomes were clinical pregnancy, miscarriage, ectopic pregnancy, pregnancy complications, and live birth. Results: Patients were grouped by World Health Organization (WHO) BMI class: underweight (<18.5, n = 81), normal weight (18.5–24.9, n = 637), overweight (25–30, n = 108), and obese (≥30, n = 25). There was no difference in the clinical pregnancy, miscarriage, ectopic pregnancy, pregnancy complication, and live birth by BMI category. In multivariate logistic regression analysis, preterm birth rates were significantly higher in women with overweight (adjusted odds ratio [aOR] 3.18; 95% confidence interval [CI], 1.29–7.80, p =.012) and obese (aOR 1.49; 95% CI, 1.03–12.78, p =.027) compared with the normal weight reference group. Conclusion: Women with obesity experience a higher rate of preterm birth after euploid embryo transfer than women with a normal weight, suggesting that the negative impact of obesity on IVF and clinical outcomes may be related to other mechanisms than aneuploidy. [ABSTRACT FROM AUTHOR]

Background/Objectives To examine the effect of pre-pregnancy maternal body mass index (BMI) on neonatal weight outcomes of twin infants who were conceived by assisted reproductive technology (ART). Subjects/Methods A 10-year (2006-2015) Chinese sample of 3431 mothers and their twin infants conceived by ART from a retrospective cohort were included. The effects of pre-pregnancy maternal BMI on gestational age and birth weight were assessed by generalized linear model and generalized estimating equation model. Results Compared with a normal weight group, pre-pregnancy maternal underweight was associated with lower birth weight and increased risk of small for gestational age (SGA) in twins conceived by ART (birth weight: difference -59.22 g, 95% CI -93.16 to -25.27 g; SGA: RR 1.25, 95% CI 1.09 to 1.43). Pre-pregnancy maternal obesity was associated with higher birth weight and increased risk of preterm birth (birth weight: difference 65.82 g, 95% CI 10.66 to 120.99 g; preterm birth: RR 1.19, 95% CI 1.03-1.37). A nonlinear relationship between pre-pregnancy maternal BMI and SGA was observed. The risk of SGA decreased with the pre-pregnancy maternal BMI up to the turning point (BMI = 21) (RR 0.90, 95% CI 0.86-0.95). Conclusions Among mothers undergoing ART, pre-pregnancy maternal obesity is associated with higher birth weight and higher risk of preterm birth for twin pregnancy, and pre-pregnancy maternal underweight is associated with lower birth weight and higher risk of SGA. Women preparing for ART should maintain a normal BMI to lower the chances of adverse neonatal outcomes., Author(s): Pengfei Qu [sup.1] [sup.2] [sup.3] , Doudou Zhao [sup.1] [sup.2] , Yang Mi [sup.4] , Shaonong Dang [sup.5] , Juanzi Shi [sup.1] [sup.2] , Wenhao Shi [sup.1] [sup.2] Author [...]

Objective: This study aimed to evaluate the impact of adding 4 mg estradiol valerate to progesterone for luteal support on pregnancy rates in IVF cycles following a long protocol with reduced luteal serum estradiol levels post-hCG triggering. Design, setting, and participants: The prospective randomized controlled trial was conducted at a public tertiary hospital reproductive center with 241 patients who experienced a significant decrease in serum estrogen levels post-oocyte retrieval. Interventions: Participants received either a daily 4 mg dose of estradiol valerate in addition to standard progesterone or standard progesterone alone for luteal support. Results: The ongoing pregnancy rate did not show a significant difference between the E2 group and the control group (56.6% vs. 52.2%, with an absolute rate difference (RD) of 4.4%, 95% CI -0.087 to 0.179, P = 0.262). Similarly, the live birth rate, implantation rate, clinical pregnancy rate, early abortion rate, and severe OHSS rate were comparable between the two groups. Notably, the E2 group had no biochemical miscarriages, contrasting significantly with the control group (0.0% vs. 10.7%, RD -10.7%, 95% CI -0.178 to -0.041, P = 0.000). In the blastocyst stage category, the clinical pregnancy rate was notably higher in the E2 group compared to the control group (75.6% vs. 60.8%, RD 14.9%, 95% CI 0.012 to 0.294, P = 0.016). Conclusion: Adding 4 mg estradiol valerate to progesterone for luteal support does not affect the ongoing pregnancy rate in embryo transfer cycles using a long protocol with a significant decrease in serum estradiol levels after hCG triggering. However, it may reduce biochemical miscarriages and positively impact clinical pregnancy rates in blastocyst embryo transfer cycles. Trial registration: ChiCTR1800020342. [ABSTRACT FROM AUTHOR]

N-linked glycoproteins are rich in seminal plasma, playing essential roles in supporting sperm function and fertilization process. The alteration of seminal plasma glycans and its correspond glycoproteins may lead to sperm dysfunction and even infertility. In present study, an integrative analysis of glycoproteomic and proteomic was performed to investigate the changes of site-specific glycans and glycoptoteins in seminal plasma of asthenozoospermia. By large scale profiling and quantifying 5,018 intact N- glycopeptides in seminal plasma, we identified 92 intact N- glycopeptides from 34 glycoproteins changed in asthenozoospermia. Especially, fucosylated glycans containing lewis x, lewis y and core fucosylation were significantly up-regulated in asthenozoospermia compared to healthy donors. The up-regulation of fucosylated glycans in seminal plasma may interfere sperm surface compositions and regulation of immune response, which subsequently disrupts sperm function. Three differentiated expression of seminal vesicle-specific glycoproteins (fibronectin, seminogelin-2, and glycodelin) were also detected with fucosylation alteration in seminal plasma of asthenozoospermia. The interpretation of the altered site-specific glycan structures provides data for the diagnosis and etiology analysis of male infertility, as well as providing new insights into the potential therapeutic targets for male infertility. [ABSTRACT FROM AUTHOR]

Preimplantation embryo arrest (PREMBA) is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, the genetic basis of PREMBA is largely unrevealed. Here, using whole-exome sequencing data from 606 women experiencing PREMBA compared with 2,813 controls, we performed a population and gene-based burden test and identified a candidate gene, karyopherin subunit [alpha]7 (KPNA7). In vitro studies showed that identified sequence variants reduced KPNA7 protein levels, impaired KPNA7 capacity for binding to its substrate ribosomal L1 domain-containing protein 1 (RSL1D1), and affected KPNA7 nuclear transport activity. Comparison between humans and mice suggested that mouse KPNA2, rather than mouse KPNA7, acts as an essential karyopherin in embryonic development. [Kpna2.sup.-/-] female mice showed embryo arrest due to zygotic genome activation defects, recapitulating the phenotype of human PREMBA. In addition, female mice with an oocyte-specific knockout of Rsl1d1 recapitulated the phenotype of [Kpna2.sup.-/-] mice, demonstrating the vital role of substrate RSL1D1. Finally, complementary RNA (cRNA) microinjection of human KPNA7, but not mouse Kpna7, was able to rescue the embryo arrest phenotype in [Kpna2.sup.-/-] mice, suggesting mouse KPNA2 might be a homologue of human KPNA7. Our findings uncovered a mechanistic understanding for the pathogenesis of PREMBA, which acts by impairing nuclear protein transport, and provide a diagnostic marker for PREMBA patients., Introduction Successful human reproduction requires normal embryonic development. Preimplantation embryo arrest (PREMBA) is a common reason for recurrent failure of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and [...]

Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).