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Endometriosis (EMs), one of the most common gynecological diseases, seriously affects the health and wellness of women; however, the underlying pathogenesis remains unclear. This study focused on dysregulated genes and their predicted transcription factors (TFs) and miRNAs, which may provide ideas for further mechanistic research. The microarray expression dataset GSE58178, which included six ovarian endometriosis (OE) samples and six control samples, was downloaded from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs). Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to study the cellular and organism-level functions of DEGs. The protein-protein interaction (PPI) network was built and visualized using Cytoscape, and modules and hub genes were explored using various algorithms. Furthermore, we predicted miRNAs and TFs of hub genes using online databases, and constructed the TF-miRNA-hub gene network. There were 124 upregulated genes and 66 downregulated genes in EMs tissues. GO enrichment analysis showed that DEGs were concentrated in reproductive structure development and collagen-containing extracellular matrix, while KEGG pathway analysis showed that glycolysis/gluconeogenesis and central carbon metabolism in cancer require further exploration. Subsequently, HIF1A, LDHA, PGK1, TFRC, and CD9 were identified as hub genes, 22 miRNAs and 34 TFs were predicted to be upstream regulators of hub genes, and these molecules were pooled together. In addition, we found three key feedback loops in the network, MYC-miR-34a-5p-LDHA, YY1-miR-155-5p-HIF1A, and RELA-miR-93-5p-HIF1A, which may be closely related to OE development. Taken together, our study structured a TF-miRNA-hub gene network to decipher the molecular mechanism of OE, which may provide novel insights for clinical diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Sun and Sun.)

Introduction: Women with diminished ovarian reserve (DOR) have a lower pregnancy rate and higher cancellation rate compared to those without DOR when seeking assisted reproductive technology. However, which factors are associated with reproductive outcomes and whether AMH is a predictor of clinical pregnancy remain unclear., Objective: This retrospective study was designed to find factors associated with reproductive outcomes in DOR patients and then discuss the role of AMH in predicting cycle results among this population., Method: A total of 900 women were included in the study. They were diagnosed with DOR with the following criteria: (i) FSH > 10 IU/L; (ii)AMH < 1.1 ng/ml; and (iii) AFC <7. They were divided into different groups: firstly, based on whether they were clinically pregnant or not, pregnant group vs. non-pregnant group (comparison 1); secondly, if patients had transferrable embryos (TE) or not, TE vs. no TE group (comparison 2); thirdly, patients undergoing embryo transfer (ET) cycles were divided into pregnant I and non-pregnant I group (comparison 3). The baseline and ovarian stimulation characteristics of these women in their first IVF/ICSI cycles were analyzed. Logistic regression was performed to find factors associated with clinical pregnancy., Results: Of the 900 DOR patients, 138 women got pregnant in their first IVF/ICSI cycles while the rest did not. AMH was an independent predictor of TE after adjusting for confounding factors (adjusted OR:11.848, 95% CI: 6.21-22.62, P< 0.001). Further ROC (receiver operating characteristic) analysis was performed and the corresponding AUC (the area under the curve) was 0.679 (95% CI: 0.639-0.72, P< 0.001). Notably, an AMH level of 0.355 had a sensitivity of 62.6% and specificity of 65.6%. However, there was no statistical difference in AMH level in comparison 3, and multivariate logistic regression showed female age was associated with clinical pregnancy in ET cycles and women who were under 35 years old were more likely to be pregnant compared to those older than 40 years old (adjusted OR:4.755, 95% CI: 2.81-8.04, P< 0.001)., Conclusion: AMH is highly related to oocyte collection rate and TE rate,and 0.355 ng/ml was a cutoff value for the prediction of TE. For DOR patients who had an embryo transferred, AMH is not associated with clinical pregnancy while female age is an independent risk factor for it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Sun, Wang, Zhang and Sun.)

Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disease in reproductive women associated with poor pregnancy outcomes. In modern society, people pay more attention to the female factor, but it is uncertain whether sperm quality is another factor affecting pregnancy outcomes of patients with PCOS., Method: The effect of sperm DNA fragmentation (SDF) on oocyte fertilization, embryonic development, and pregnancy outcomes for patients with PCOS who underwent in vitro fertilization (IVF) treatment was studied. A total of 141 PCOS patients and 332 control patients undergoing IVF treatment were recruited from January 2017 to December 2019. All female patients were designated into two groups according to the Rotterdam criteria. Each group was divided into two sets, DNA fragmentation index (DFI) ≤15% and DFI > 15%, on the basis of sperm DFI., Result: There were no differences in basic clinical characteristics between couples with a sperm DFI ≤ 15% or DFI > 15%. For control patients, no differences were observed in IVF outcomes. However, for PCOS patients, although there were no differences in the fertilization (60.4% vs. 59.9%, p = 0.831), high-quality embryo (68.5% vs. 67.9% p = 0.832), clinical pregnancy (78.4% vs. 66.7%, p = 0.148), and abortion (12.5% vs. 11.5%, p = 1.000) rates, a significantly lower high-quality blastocyst formation rate (26.3% vs. 16.3%, p = 0.023) was observed for couples with a sperm DFI > 15% compared with a sperm DFI ≤ 15%., Conclusion: For PCOS patients undergoing IVF, oocytes fertilized using sperm with higher DFI led to a lower high-quality blastocyst formation rate but had no influence on fertilization, high-quality embryo, clinical pregnancy, and miscarriage rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Li, Zhu, Xu, Jiang, Chen, Sun and Yang.)

Background: A number of publications have examined the relation between blood group and female infertility including ovarian reserve, recurrent miscarriage, and live birth. However, there is a lack of literature investigating joint mother/father ABO blood type in a large cohort. This study aimed to investigate the association between couple combinations for ABO blood groups and assisted reproductive technology (ART) outcomes in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)., Methods: This retrospective cohort study included 30,717 couples who underwent IVF cycles between 2010 and 2019. The clinical outcomes of IVF treatment were the primary outcome. History of spontaneous miscarriage, embryo quality, and birth sex, weights, defects rate were also studied., Results: There was no difference in the baseline demographics between the blood type groups. There was a statistically significant positive association between the combination of female blood type AB and male blood type AB with biochemical pregnancy, clinical pregnancy, and live birth rate (OR 1.36; 95% CI, 1.05-1.78; P = 0.02 and OR 1.31; 95% CI, 1.0-1.68; P = 0.031 and OR 1.28; 95% CI, 1.01-1.63; P = 0.041 respectively). No statistically significant difference was observed between joint mother/father ABO blood types and high-quality embryo rate, early abortion rate, birth sex, birth weights, and birth defect rate., Conclusions: Our findings suggest that the success rate of IVF/ICSI cycles in parent mating AB blood type is higher than that in other blood type combination groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bao, Zhao, Shi, Bu, Liang and Sun.)

Ovarian aging refers to the gradual decline of ovarian function with increasing physiological age, manifested as decreased ovarian reserve, elevated aging-related markers, and reduced oocyte quality. With a declining female fertility and a growing aging population, it is urgent to delay ovarian aging to maintain fertility and improve the life quality of women. Theaflavin 3, 3'-digallate (TF3) is a naturally bioactive polyphenol compound extracted from black tea, and its antioxidant properties play an important role in maintaining human health and delaying aging; however, the effects of TF3 on female reproduction and ovarian function are not yet clear. Here, we show that TF3 can preserve primordial follicle pool, partially restore the estrous cycle, and increase the offspring number of aged mice. Meanwhile, TF3 gavage increased the number of oocytes retrieved, decreased the level of reactive oxygen species, increased the level of glutathione, and decreased the abnormal rate of oocyte spindle after ovulation induction. Moreover, TF3 inhibited human granulosa cell apoptosis and improved their antioxidative stress ability. High-throughput sequencing and small-molecule-targeted pharmacological prediction show that TF3 affects multiple pathways and gene expression levels, mainly involved in reproductive and developmental processes. It may also affect cellular function by targeting mTOR to regulate the autophagic pathway, thereby delaying the process of ovarian aging. This study shows that TF3 can be used as a potential dietary supplement to protect ovary function from aging and thereby improving the life quality of advanced-age women., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Jiahuan He et al.)

Background: Whether female BMI impacts the DNA repair ability in the oocytes after fertilization has not been investigated. The aim of this study is to assess the early embryo quality and reproductive outcomes of oocytes from overweight women when fertilized with sperm with varying degrees of DNA fragmentation., Methods: A total number of 1,612 patients undergoing fresh autologous in vitro fertilization (IVF) cycles was included. These patients were divided into two groups according to maternal body mass index (BMI): normal weight group (18.5-24.9 kg/m 2 ; n=1187; 73.64%) and overweight group (≥25 kg/m 2 ; n=425; 26.36%). Each group was then subdivided into two groups by sperm DNA fragmentation index (DFI): low fragmentation group (<20% DFI, LF) and high fragmentation group (≥20% DFI, HF). Laboratory and clinical outcomes were compared between subgroups., Results: For the normal-weight group, there was no statistical significance in embryo quality and reproductive outcomes between the LF and HF groups. But in the overweight group, significantly lower fertilization rate (LF: 64%; HF: 59%; p=0.011), blastocyst development rate (LF: 57%; HF: 44%; p=0.001), as well as high-quality blastocyst rate (LF: 32%; HF: 22%; p=0.034) were found in the HF group, despite the similar pregnancy rates (LF: 56%; HF: 60%; p=0.630)., Conclusions: Decreased DNA repair activity in oocytes may be a possible mechanism for the low early development potential of embryos from overweight patients in in vitro fertilization cycles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wang, Zhu, Xu, Jiang, Chen, Sun and Yang.)

Background: Currently, in China, only women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles can donate oocytes to others, but at least 15 oocytes must be kept for their own treatment. Thus, the aim of this study was to determine whether oocyte donation compromises the cumulative live birth rate (CLBR) of donors and whether it is possible to expand oocyte donors' crowd., Methods: This was a retrospective cohort study from August 2015 to July 2017 including a total of 2,144 patients, in which 830 IVF-embryo transfer (IVF-ET) patients were eligible for oocyte donation and 1,314 patients met all other oocyte donation criteria but had fewer oocytes retrieved (10-17 oocytes). All 830 patients were advised to donate approximately three to five oocytes to others and were eventually divided into two groups: the oocyte donation group (those who donated) and the control group (those who declined). The basic patient parameters and CLBR, as well as the number of supernumerary embryos after achieving live birth, were compared. These two factors were also compared in all patients (2,144) with oocyte ≥10., Results: In 830 IVF-ET patients who were eligible for oocyte donation, only the oocyte number was significantly different between two groups, and the donation group had more than the control group (25.49 ± 5.76 vs. 22.88 ± 5.11, respectively; p = 0.09). No significant differences were found between the two groups in other factors. The results indicate that the live birth rate in the donation group was higher than that in the control group (81.31% vs. 82.95%, p = 0.371), without significance. In addition, CLBR can still reach as high as 73% when the oocyte number for own use was 10. Supernumerary embryos also increased as the oocyte number increased in all patients (oocyte ≥10)., Conclusions: Currently, oocyte donation did not compromise CLBR, and oocyte donation can decrease the waste of embryos. In addition, in patients with 10 oocytes retrieved, the CLBR was still good (73%). Thus, it is possible to expand oocyte donors if the number of oocyte kept for own use was decreased from 15 to 10 after enough communication with patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bu, Zhang, Zhang and Sun.)

Uniparental embryos derived from only the mother (gynogenetic [GG]) or the father (androgenetic [AG]) are unique models for studying genomic imprinting and parental contributions to embryonic development. Human parthenogenetic embryos can be obtained following artificial activation of unfertilized oocytes, but the production of AG embryos by injection of two sperm into one denucleated oocyte leads to an extra centriole, resulting in multipolar spindles, abnormal cell division, and developmental defects. Here, we improved androgenote production by transferring the male pronucleus from one zygote into another haploid androgenote to prevent extra centrioles and successfully generated human diploid AG embryos capable of developing into blastocysts with an identifiable inner cell mass (ICM) and trophectoderm (TE). The GG embryos were also generated. The zygotic genome was successfully activated in both the AG and GG embryos. DNA methylome analysis showed that the GG blastocysts partially retain the oocyte transcription-dependent methylation pattern, whereas the AG blastocyst methylome showed more extensive demethylation. The methylation states of most known imprinted differentially methylated regions (DMRs) were recapitulated in the AG and GG blastocysts. Novel candidate imprinted DMRs were also identified. The production of uniparental human embryos followed by transcriptome and methylome analysis is valuable for identifying parental contributions and epigenome memory transitions during early human development., (© 2021 Xu et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Some studies have demonstrated that adenomyosis patients can achieve a comparable pregnancy outcome with women with normal uteruses, while there is no unanimous conclusion at present., Method: We recruited 65 adenomyosis patients and 260 frequency-matched control women with endometriosis at a ratio of 1:4 according to age. Clinical pregnancy rate, spontaneous abortion rate, and live birth rate were compared between these two groups after controlling other factors., Results: Compared with endometriosis patients, adenomyosis patients had a higher antral follicle count (AFC) (12.71 vs 11.65, P =0.027). Though the two groups had the same number of embryos transferred, adenomyosis patients had an obviously declined implantation rate (31.91% vs 46.74%, P =0.005), clinical pregnancy rate (47.06% vs 64.42%, P=0.028), live birth rate (31.37% vs 54.81%, P=0.004), and significantly increased spontaneous abortion rate (33.33% vs 13.43%, P=0.034). Multivariate logistic regression analysis showed that adenomyosis had adverse influences on pregnancy outcome when age and the number of embryo transfers were controlled (adjusted OR=0.361, P=0.003)., Conclusion: Even after being matched with age, adenomyosis still had adverse influences on the pregnancy outcome of IVF in patients undergoing the long protocol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Hu, Bu and Sun.)

Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous endocrine disorder characterized by ovulation dysfunction, androgen excess, ovarian polycystic changes, insulin resistance, and infertility. Although underlying mechanisms for PCOS are still unknown, inflammation and mitochondrial dysfunction in granulosa cells (GCs) of PCOS patients have been reported. Here, we found that Nicotinamide Adenine Dinucleotide (NAD+) levels in GCs of PCOS patients was significantly decreased when compared with controls. Also, we found that higher expression of inflammation factors, increased reactive oxygen species (ROS) accumulation, lower adenosine triphosphate (ATP) generation, and decreased mitochondrial membrane potential, as well as abnormal mitochondrial dynamics in GCs of PCOS patients. In addition, the NAD+ levels were decreased after activation of inflammation in human granulosa-like tumor cell line (KGN) treated by Lipopolysaccharide (LPS). However, supplementation of nicotinamide riboside (NR), a NAD+ precursor, could largely restore the NAD+ content, reduce ROS levels and improve mitochondrial function demonstrated by increased mitochondrial membrane potential and ATP generation in LPS-treated KGN cells. Our data suggested that inflammation decreased NAD+ levels in GCs of PCOS patients, while supplementation of NR could restore NAD+ levels and alleviated mitochondrial dysfunction in GCs of PCOS patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients., (© 2021 Federation of American Societies for Experimental Biology.)

Calcium is a crucial factor in regulating the biological behavior of cells. The imbalance of calcium homeostasis in cytoplasm will cause abnormal behavior of cells and the occurrence of diseases. In intracytoplasmic sperm injection (ICSI) cycle, the dysfunction of oocyte activation caused by insufficient release of Ca 2+ from endoplasmic reticulum is one of the main reasons for repeated fertilization failure. Calcium ionophore (A23187) is a highly selective calcium ionophore, which can form stable complex with Ca 2+ and pass through the cell membrane at will, effectively increasing intracellular Ca 2+ levels. It has been reported that calcium ionophore (A23187) can activate oocytes and obtain normal embryos. However, there are few studies on unfertilized oocytes after calcium ionophore (A23187) rescue activation in ICSI cycle. The purpose of this study was to analyze the effects of calcium ionophore (A23187) rescue activation on the activation of unfertilized oocytes, embryonic development potential, embryonic development timing and chromosomal aneuploidy, and to compare and analyze the clinical data of patients with calcium ionophore (A23187) activation in clinical application. The results showed that a certain proportion of high-quality blastocysts with normal karyotype could be obtained after calcium ionophore (A23187) rescue activation of unfertilized oocytes, and it did not have a significant effect on the timing of embryo development. In clinical practice, direct activation with calcium ionophore (A23187) after ICSI was better than rescue activation the next day. In conclusions, the studies on the effectiveness and safety of calcium ionophore (A23187) rescue activation for oocytes with ICSI fertilization failure can enable some patients to obtain usable, high-quality embryos during the first ICSI cycle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xu, Yao, Niu, Fan, Ma, Shi, Jin, Song and Sun.)

Objective: To explore the genetic etiology for a fetus with congenital orofacial cleft., Methods: Single nucleotide polymorphism microarray (SNP array) was carried out on skin tissues sampled from the fetus following induced abortion for the detection of copy number variation (CNVs). Pathogenicity of the candidate gene was validated through experiment., Results: SNP array revealed that the fetus has carried a hemizygous 9.23Mb deletion at Xq21.31-q22.1(91 063 807-100 293 555), which was inherited from its mother. The region contained 13 OMIM genes and 1 ncRNA coding gene(MIR548M). Inhibiting of the expression of the MIR548M gene in oral epithelial celllines has resulted in up-regulation of the expression of SUMO1 gene which was known to involve in the pathogenesis of orofacial cleft., Conclusion: Dosage insufficiency of the MIR548M gene may underlie the etiology of orofacial cleft in this fetus.

Background: Ovarian hyperstimulation syndrome (OHSS) is a common disease during controlled ovarian hyperstimulation treatment. However, the obstetric and neonatal outcomes of this group of patients are unknown. The aim of this study was to explore the effects of late moderate-to-critical OHSS on obstetric and neonatal outcomes., Methods: This prospective observational study included 17,537 patients who underwent IVF/ICSI-fresh embryo transfer (ET) between June 2012 and July 2016 and met the inclusion criteria, including 7,064 eligible patients diagnosed with clinical pregnancy. Ultimately, 6,356 patients were allocated to the control group, and 385 patients who were hospitalized and treated at the center for late moderate-to-critical OHSS were allocated to the OHSS group. Then, propensity score matching analysis was performed, matching nine maternal baseline covariates and the number of multiple gestations; 385 patients with late moderate-to-critical OHSS were compared with a matched control group of 1,540 patients. The primary outcomes were the live birth rate, preterm delivery rate, miscarriage rate, gestational age at birth (weeks), obstetric complications and neonatal complications., Results: The duration of gestation in the matched control group was significantly higher than that in the OHSS group. The live birth delivery rate did not significantly differ between the OHSS and matched control groups. The incidence rates of the obstetric complications venous thrombosis (VT) and gestational diabetes mellitus (GDM), neonatal complications and the number of neonates admitted to the NICU were significantly higher in the OHSS group than in the matched control group., Conclusions: Pregnant women undergoing IVF with fresh ET whose course is complicated by late moderate-to-critical OHSS appear to experience shortened gestation and increased obstetrical and neonatal complications compared with matched controls whose course is not complicated by OHSS. However, the live birth rate, average neonatal weight, and incidence rates of premature delivery, miscarriage, early abortion, hypertensive disorder of pregnancy (HDP), placenta previa (PP), intrahepatic cholestasis of pregnancy (ICP), and low neonatal birth weight (LBW) did not differ significantly between the two groups.

In this Letter, the 'Open chromatin' label in Fig. 4a should have been centred above the first three columns, and the black horizontal line underneath the label should have been removed. In addition, there should have been a vertical black line between the last two sets of panels for consistency. Minor changes have also been made to Fig. 1 and to the legend of Fig. 3. These errrors have been corrected online, and see Supplementary Information to the accompanying Amendment for the original Fig. 4.

Upon fertilization, drastic chromatin reorganization occurs during preimplantation development 1 . However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) 2 . We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing 3-5 . Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization.

Reciprocal translocations (RecT) and Robertsonian translocations (RobT) are among the most common chromosomal abnormalities that cause infertility and birth defects. Preimplantation genetic testing for aneuploidy using comprehensive chromosome screening for in vitro fertilization enables embryo selection with balanced chromosomal ploidy; however, it is normally unable to determine whether an embryo is a translocation carrier. Here we report a method named "Mapping Allele with Resolved Carrier Status" (MaReCs), which enables chromosomal ploidy screening and resolution of the translocation carrier status of the same embryo. We performed MaReCs on 108 embryos, of which 96 were from 13 RecT carriers and 12 were from three RobT carriers. Thirteen of the sixteen patients had at least one diploid embryo. We have confirmed the accuracy of our carrier status determination in amniotic fluid karyotyping of seven cases as well as in the live birth we have thus far. Therefore, MaReCs accurately enables the selection of translocation-free embryos from patients carrying chromosomal translocations. We expect MaReCs will help reduce the propagation of RecT/RobT in the human population., Competing Interests: Conflict of interest statement: S.L. and X.S.X. are cofounders and shareholders of Yikon Genomics Company, Ltd. Z.Z., Y. Gao, W.L., S.B., M.H., and J.R. receive research funding from Yikon Genomics Company, Ltd.

Polycystic ovary syndrome (PCOS) is one of the most frequently encountered endocrine malfunctions. The etiology of PCOS is complex and unclear. We aimed to investigate the role of three common SNPs (rs1800896, rs1800871 and rs1800872) of IL-10 in the development of PCOS in a Chinese population. We recruited 360 patients with PCOS and 360 healthy controls in this study. SNP genotyping of IL-10 rs1800896, rs1800871 and rs1800872 was implemented in a 384-well plate format on the Sequenom MassARRAY ® System (Sequenom, San Diego, USA). Individuals carrying the GG genotype of rs1800872 were associated with an increased risk of PCOS when compared with the AA genotype (OR = 3.04, 95% CI = 1.62-5.69). No linkage disequilibrium was observed among IL-10 rs1800896, rs1800871 and rs1800872. The C-T-A (OR = 1.53, 95% CI = 1.05-2.35) haplotype indicated an increased risk of PCOS, while the A-C-G (OR = 0.72, 95% CI = 0.53-0.98) showed a reduced risk of PCOS. In summary, this study firstly estimates the association between IL-10 polymorphisms and haplotype and PCOS risk in the Chinese population., Competing Interests: None., (IJCEP Copyright © 2017.)

Primordial germ cells (PGCs) derived from human embryonic stem cells (hESCs) represent as a desirable experimental model as well as a potential strategy for treating male infertility. Here, we developed a simple and feasible method for differentiation of PGCs from hESCs by using CHIR99021 (an inhibitor of glycogen synthase kinase 3) and retinoic acid (RA). We firstly found that the deleted in azoospermia-like (DAZL) protein can be detected in 3 d CHIR99021 plus 9 d retinoic acid treated cultures and 12 d CHIR99021 plus retinoic acid co-treated cultures, but not expressed in single CHIR99021 treated cultures, single retinoic acid treated cultures, as well as 3 d retinoic acid plus 9 d CHIR99021 treated cultures. Next, we showed that several PGCs' markers were expressed in the 12 d CHIR99021 and retinoic acid co-treated cultures or 3 d CHIR99021 plus 9 d retinoic acid treated cultures. Moreover, meiosis was initiated in CHIR99021 and retinoic acid co-treated cultures as evidenced by a significant expression of the punctate synaptonemal complex protein 3 (SCP3). Fluorescent in situ hybridization (FISH) analysis indicated that a small percentage of putative 1N populations were formed. Mechanically, we found that β-catenin relocated into nucleus after the treatment of 3 d CHIR99021 suggesting that Wnt signaling pathway was activated. Furthermore, blockade of Wnt signaling pathway by IWR-1 can reverse CHIR99021 and retinoic acid mediated-effects. Taken together, our results indicate that CHIR99021 combined with retinoic acid can effectively differentiate hESCs into PGCs via activating Wnt signaling pathway.

Purpose: The purpose of the present study is to explore the influence of body mass index (BMI) on outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) techniques in Chinese women with polycystic ovary syndrome (PCOS)., Methods: This was a multicenter, prospective, observational study that enrolled 800 subjects with PCOS from nine hospitals in China. Patients were categorized according to BMI categories: underweight, <18.5 kg/m 2 ; normal, 19-23.9 kg/m 2 ; overweight, 24-27.9 kg/m 2 ; and obese, ≥28 kg/m 2 . Total recombinant follicle-stimulating hormone (rFSH) dose used, estradiol, and progesterone levels on human chorionic gonadotropin (hCG) day; implantation rate; and biochemical, clinical, and ongoing pregnancy rates were compared among BMI categories. Hormone levels (estradiol, follicle-stimulating hormone (FSH), LH, testosterone, and progesterone) were measured using electrochemiluminescence assays., Results: Among the 774 subjects, 27.3 % were overweight and 8.1 % were obese. The rFSH dose used differed significantly among BMI categories (P < 0.001). The implantation rate was lower in obese subjects than that in normal-weight subjects (25.3 vs 45.7 %). Clinical pregnancy rate per transfer differed among BMI categories (P = 0.033), but there was no difference for biochemical (P = 0.327) and ongoing (P = 0.084) pregnancy rates. The miscarriage rate was similar among BMI categories., Conclusions: More than one third of Chinese women with PCOS undergoing IVF/ICSI are overweight or obese. Elevated BMI is associated with reduced clinical pregnancy rate but similar ongoing pregnancy rates, suggesting that BMI has little impact on IVF outcomes.

Study Question: What is the relationship between telomere length in sperm and early embryonic development in in vitro fertilization (IVF)?, Summary Answer: Sperm telomere length (STL) is positively associated with embryo quality in IVF., What Is Known Already: Previous studies have shown that STL differs among human males., Study Design, Size, Duration: In order to determine the associations between STL, fertilization laboratory parameters and clinical pregnancy in IVF, 418 couples were recruited from August 2013 to August 2014., Materials, Setting, Methods: We collected semen samples and used quantitative PCR technique to detect the mean STL for each patient. These data were compared with the IVF outcomes., Main Results and the Role of Chance: The mean STL was positively correlated with the age of patient (rP = 0.100; P = 0.041) and total sperm count/ejaculate (rp = 0.28; P < 0.001). Analysis of the age-adjusted mean STL in relation to the male patient's paternal and maternal ages at the time of his conception showed significant positive relationships between STL and both paternal (r = 0.16; P = 0.003) and maternal (r = 0.19; P < 0.001) ages at the time of conception. In addition, significant correlations were found between STL and good quality embryo (regression coefficient: 1.63; P < 0.001) and transplantable embryo rates (regression coefficient: 1.57; P < 0.001), but clinical pregnancy rates were not affected (odds ratio = 1.00 [95% CI: 0.93-1.07]; P = 0.90)., Limitations, Reasons for Caution: This study showed that STL was positively associated with embryo quality in IVF. Additional studies are needed to confirm these observations., Wider Implication of the Findings: STL has the potential to be used as a marker for the prediction of embryonic quality., Study Funding/competing Interests: This work was supported by the National Natural Science Foundation of China (Grants 31271605 and 31471404), and the National Science Foundation for Young Scientists of China (Grant 31401274), and Science Foundation of First Affiliated Hospital of Zhengzhou University for Yong Scientists. The authors have declared that no competing interests exist., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In order to evaluate whether the ratio of serum estrogen level on the day of human chorionic gonadotrophin (hCG) administration to number of oocyte retrieved has any impact on live birth rate in women undergoing in vitro fertilization (IVF), we retrospectively analyzed the clinical data from 7,112 women treated with GnRH-a long protocol in our center. Cycles were firstly divided into 6 groups according to the E2/oocyte ratio (< 150 pg/ml; 150~300 pg/ml; 300~450 pg/ml; 450-600 pg/ml; 600-750 pg/ml; ≥ 750 pg/ml). Live birth rate (39.4%) in women with E2/oocyte ratio ≥ 750 pg/ml was the lowest compared with that in other groups. We further divided the top 10% of patients into high estrogen group (E2/oocyte ≥ 740 pg/ml; n = 713). Compared with controls, those with high E2/oocyte ratio had significantly higher peak E2 level (6711.85 pg/ml versus 4670.89 pg/ml; P = 0.000) on the day of hCG administration; however, the live birth rate (39.27% versus 45.67%; P = 0.001) was significantly lower for women with high estrogen level. Thus, we conclude that high E2/oocyte ratio adversely affects live birth rate in women undergoing IVF treated with GnRH-a long protocol.

In vitro differentiation of human embryonic stem cells (hESCs) into endometrium-like cells may provide a useful tool for clinical treatment. The aim of the present study was to investigate the differentiation potential of hESCs into endometrium-like cells using three methods, which included induction by feeder cells, co-culture with endometrial stromal cells and induction with embryoid bodies. Following differentiation, the majority of cells positively expressed cytokeratin and epithelial cell adhesion molecule (EPCAM). Factors associated with endometrium cell function, namely the estrogen and progesterone receptors (ER and PR), were also detected. At day 21 following the induction of differentiation, the expression levels of cytokeratin, EPCAM, ER and PR were significantly increased in the co-culture method group, as compared with the other two methods. Furthermore, these cells became decidualized in response to progesterone and prolactin. In addition, the number of cytokeratin-positive or EPCAM-positive cells significantly increased following the induction of differentiation using the co-culture method, as compared with the other two methods. The mRNA expression levels of Wnt members that are associated with endometrial development were subsequently examined, and Wnt5a was found to be significantly upregulated in the differentiated cells induced by feeder cells and co-culture with endometrial stromal cells; however, Wnt4 and Wnt7a expression levels were unaffected. Additionally, the mRNA expression levels of Wnt5a in the differentiated cells co-cultured with endometrial stromal cells were higher when compared with those induced by feeder cells. In conclusion, the present findings indicated that the co-culture system is the optimal protocol for the induction of hESC differentiation into endometrium-like cells, and Wnt5a signaling may be involved in this process.

This study explored the value of detection of human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125) from serum in diagnosis of early endometrial cancer of different pathological subtypes and discussed the mechanism of HE4 and CA125 in diagnosis. In this study, enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect HE4 and CA125 from serum in endometrial cancer and control groups. Besides, the concentration of HE4 and CA125 was compared in these two groups, and the expression of CA125 and HE4 and clinicopathological characteristics in patients with endometrial cancer were also analyzed. Compared with the control group, the expression of HE4 was much higher in serum of patients with endometrial cancer, while there was no obvious change in the expression of CA125. The threshold detection value was acquired by receiver operating characteristic analysis method, that is, 141.5 pmol/L and 54.5 U/L, respectively. When comparing the concentration of HE4 in patients with endometrial cancer at the early stage (stage I) with healthy people, the difference therein had statistical significance, but there was no obvious difference in CA125. HE4 and CA125 in diagnosis of endometrial cancer in the stages I and II were found with no statistically significant difference. The difference of HE4 in the stages II and III had statistical significance while the difference of CA125 had no statistical significance. The specificity of both HE4 and CA125 was 95%, and the sensitivity of HE4 to uterine papillary serous carcinomas was higher than that to endometrioid adenocarcinoma. Thus, the serum HE4 is much better than CA125 in detecting the endometrial cancer at an early stage.

It is common to see HBV infected couple seeking fertility treatment in reproductive medical centers. However, it is still unclear whether HBV infection has any relationship with IVF outcome. To assess the impact of male HVB infection on the outcomes of IVF, we retrospectively analyzed data from two hundred and seventy-seven subfertile couples undergoing oocyte donation cycles in our center. Twenty men (7.2%) were HBV seropositive in 277 couples. 20 couples with seropositive husbands had similar semen parameters and fertilization rate when compared with their controls. Among the 215 couples undergoing their first oocyte donation cycles, 19 couples with seropositive husbands/seronegative wives had lower implantation rate (26.7% vs. 40.6%; P > 0.05), and lower clinical pregnancy rate (42.1% vs. 63.8%; P > 0.05), but the difference was not statistically significant. In binary regression model, male HBV infection had no association with clinical pregnancy. Our study shows that male HBV infection has little impact on IVF outcomes.

Many protocols have been proposed to improve IVF outcomes for poor ovarian responders. The aim of this study was to explore the relationship between age, ovarian hyperstimulation protocol and IVF/ICSI outcomes in poor ovarian responder (POR) according to the Bologna criteria, and to compare the efficacy of different protocols used in PORs undergoing IVF/ICSI. We retrospectively analyzed clinical data of 4875 IVF/ICSI cycles, including 592 cycles of women diagnosed with POR according to Bologna criteria. We explored the association of age, different types of ovarian hyperstimulation protocols and prevalence of POR, IVF/ICSI outcomes. Age, basic FSH, AFC, and as well as ovarian hyperstimulation protocols, were all associated with POR. Irrespective of age, PORs in different ovarian hyperstimulation protocol groups had similar AFC, basic sex hormones, number of retrieved oocyte, implantation rate and clinical pregnancy rate as well. However, PORs treated with mild stimulation protocol used least doses of gonadotropins and shortest days of stimulation compared with those treated with other protocols (P<.05). The current study has shown that age, basic FSH, AFC and ovarian stimulation protocols patients used are all significantly associated with POR according to the Bologna criteria. It seems that there is no difference in clinical outcomes such as clinical pregnancy rate, implantation rate and spontaneous abortion rate between different protocols.

Overweight and obesity may have negative impact on IVF/ICSI treatment outcomes. However, it is not clear whether overweight and obesity have impact on IVF/ICSI outcomes in PCOS patients. The aim of this study was to examine the effect of overweight and obesity on IVF/ICSI treatment outcomes in PCOS patients treated with GnRH agonist long protocol. This retrospective study was conducted in a reproductive medicine center from January 2009 to June 2013. IVF/ICSI characteristics and outcomes were analyzed in 688 PCOS patients according to their BMI. A total of 409 normal weight patients (group A, 18.5 kg/m(2) ≤ BMI <24 kg/m(2)) and 279 overweight and obese patients (group B, BMI ≥24 kg/m(2)) were included into this study. Patient age, basal FSH, basal LH and peak E2 concentration were comparable in the two groups. Compared with patients in group A, patients in group B had similar number of retrieved oocytes, 2PN, and high quality embryos. However, overweight and obese women needed more ampoules of gonadotrophin and longer days of stimulation. In addition, the implantation rate (38.3% vs. 35.6%; P=0.000) was also higher in normal weight patients. Overweight and obese women seemed to have lower clinical pregnancy rate (56.9% vs. 53.4%; P>0.05), but the difference was not statistically significant. In conclusion, overweight and obesity is associated with unfavorable IVF/ICSI outcomes in PCOS patients treated with GnRH agonist long protocol.

Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P-value by meta-analysis P(meta) = 7.55 × 10⁻²¹, odds ratio (OR) 0.71); 2p21 (rs13429458, P(meta) = 1.73 × 10⁻²³, OR 0.67); and 9q33.3 (rs2479106, P(meta) = 8.12 × 10⁻¹⁹, OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended.

Objective: To review the experience with and clinical outcomes for recipients of embryos from oocytes donated under different regulatory standards in China. Initially, the oocytes were provided by one of the patient's consanguineous sisters. Then, the oocytes were obtained from another patient treated with assisted reproduction techniques (ART). Presently, oocytes thus produced are cryopreserved for at least 6months before transfer., Methods: The records from all women treated with ART at First Affiliated Hospital of Zhengzhou University since 2001 were reviewed and the pregnancy rates and clinical outcomes were determined for each of the 3 periods., Results: In the second period, the mean implantation and clinical pregnancy rates were significantly higher for the 22 oocyte recipients than for their donors. In the third period, the rates for the 56 recipients were compared with the 78 other regular ART patients fertilized with their own oocytes. There were 40 live births for 32 of the recipients over 28 cycles, and the rates of implantation and clinical pregnancy were much higher for the recipients than for the other ART patients (P<0.001)., Conclusion: Using freshly donated eggs yields a higher pregnancy rate but there is a risk of infectious disease. Using frozen oocytes can significantly decrease this risk but implantation rates are lower., (Copyright (c) 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine the best site for embryo placement in uterine cavities of varying shapes., Method: In this prospective investigation, 638 embryo transfers were allocated to two groups: for group 1 (n=558) embryos were transferred into uterine cavities of normal shape; for group 2 (n=80) embryos were transferred into uterine cavities of abnormal shape. The uterine cavity was divided into 3 equal regions: upper, middle, and lower. Pregnancy outcomes for placements in each region were compared within and between the 2 groups., Results: No significant differences were found in rates of pregnancy or implantation among the 3 regions in group 1. In contrast, the implantation rate in group 2 was highest when embryos were placed in the middle region of the uterine cavity: 28.8% compared with 6.8% and 8.3% for the upper and lower regions, respectively (P<0.05)., Conclusion: For the normal uterine cavity, pregnancy outcomes do not depend on embryo placement. However, for uterine anomalies, embryo placement in the middle region of the uterine cavity gave the best outcome.