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Background: Evidence from observational studies and clinical trials has associated gut microbiota with infectious diseases. However, the causal relationship between gut microbiota and infectious diseases remains unclear., Methods: We identified gut microbiota based on phylum, class, order, family, and genus classifications, and obtained infectious disease datasets from the IEU OpenGWAS database. The two-sample Mendelian Randomization (MR) analysis was then performed to determine whether the gut microbiota were causally associated with different infectious diseases. In addition, we performed reverse MR analysis to test for causality., Results: Herein, we characterized causal relationships between genetic predispositions in the gut microbiota and nine infectious diseases. Eight strong associations were found between genetic predisposition in the gut microbiota and infectious diseases. Specifically, the abundance of class Coriobacteriia , order Coriobacteriales , and family Coriobacteriaceae was found to be positively associated with the risk of lower respiratory tract infections (LRTIs). On the other hand, family Acidaminococcaceae , genus Clostridiumsensustricto1 , and class Bacilli were positively associated with the risk of endocarditis, cellulitis, and osteomyelitis, respectively. We also discovered that the abundance of class Lentisphaeria and order Victivallales lowered the risk of sepsis., Conclusion: Through MR analysis, we found that gut microbiota were causally associated with infectious diseases. This finding offers new insights into the microbe-mediated infection mechanisms for further clinical research., 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 © 2024 Wang, Yin, Sun, Li, Guo, Wang, Zhang, Sun and Sun.)

Introduction: Despite the global prevalence of coronavirus disease 2019 (COVID-19), limited research has been conducted on the effects of SARS-CoV-2 infection on human reproduction. The aims of this study were to investigate the impact of SARS-CoV-2 infection during controlled ovarian stimulation (COS) on the outcomes of assisted reproductive treatment (ART) and the cytokine status of patients., Methods: This retrospective cohort study included 202 couples who received ART treatment, 101 couples infected with SARS-CoV-2 during COS and 101 matched uninfected couples. The parameters of ovarian stimulation and pregnancy outcomes were compared between the two groups. The All-Human Inflammation Array Q3 kit was utilized to measure cytokine levels in both blood and follicular fluid., Results: No difference was found in the number of good-quality embryos (3.3 ± 3.1 vs. 3.0 ± 2.2, P = 0.553) between the infected and uninfected groups. Among couples who received fresh embryo transfers, no difference was observed in clinical pregnancy rate (53.3% vs. 51.5%, P = 0.907). The rates of fertilization, implantation, miscarriage, ectopic pregnancy and live birth were also comparable between the two groups. After adjustments were made for confounders, regression models indicated that the quality of embryos (B = 0.16, P = 0.605) and clinical pregnancy rate ( P = 0.206) remained unaffected by SARS-CoV-2 infection. The serum levels of MCP-1, TIMP-1, I-309, TNF-RI and TNF-RII were increased, while that of eotaxin-2 was decreased in COVID-19 patients. No significant difference was found in the levels of cytokines in follicular fluid between the two groups., Conclusion: Asymptomatic or mild COVID-19 during COS had no adverse effects on ART outcomes. Although mild inflammation was present in the serum, it was not detected in the follicular fluid of these patients. The subsequent immune response needs further investigation., 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 © 2024 Hu, Feng, Chen, Sang, Chen, Wang, Liu, Bai and Zhu.)

Background: Autoimmune thyroid disease (AITD) ranks among the most prevalent thyroid diseases, with inflammatory cytokines playing a decisive role in its pathophysiological process. However, the causal relationship between the inflammatory cytokines and AITD remains elusive., Methods: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal connection between AITD and 41 inflammatory cytokines. Genetic variations associated with inflammatory cytokines were sourced from the FinnGen biobank, whereas a comprehensive meta-analysis of genome-wide association studies (GWASs) yielded data on Graves' disease (GD) and Hashimoto thyroiditis. Regarding the MR analysis, the inverse variance-weighted, MR-Egger, and weighted median methods were utilized. Additionally, sensitivity analysis was conducted using MR-Egger regression, MR-pleiotropy residual sum, and outliers., Results: Seven causal associations were identified between inflammatory cytokines and AITD. High levels of tumor necrosis factor-β and low levels of stem cell growth factor-β were indicative of a higher risk of GD. In contrast, high levels of interleukin-12p70 (IL-12p70), IL-13, and interferon-γ and low levels of monocyte chemotactic protein-1 (MCP-1) and TNF-α suggested a higher risk of HD. Moreover, 14 causal associations were detected between AITD and inflammatory cytokines. GD increases the levels of macrophage inflammatory protein-1β, MCP-1, monokine induced by interferon-γ (MIG), interferon γ-induced protein 10 (IP-10), stromal cell-derived factor-1α, platelet-derived growth factor BB, β-nerve growth factor, IL-2ra, IL-4, and IL-17 in blood, whereas HD increases the levels of MIG, IL-2ra, IP-10, and IL-16 levels., Conclusion: Our bidirectional MR analysis revealed a causal relationship between inflammatory cytokines and AITD. These findings offer valuable insights into the pathophysiological mechanisms underlying AITD., 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 © 2024 Yao, Guo, Tan, Zhang, Geng, Yang and Wang.)

Background: Polycystic ovarian syndrome (PCOS) is a common reproductive disorder that affects a considerable number of women worldwide. It is accompanied by irregular menstruation, hyperandrogenism, metabolic abnormalities, reproductive disorders and other clinical symptoms, which seriously endangers women's physical and mental health. The etiology and pathogenesis of PCOS are not completely clear, but it is hypothesized that immune system may play a key role in it. However, previous studies investigating the connection between immune cells and PCOS have produced conflicting results., Methods: Mendelian randomization (MR) is a powerful study design that uses genetic variants as instrumental variables to enable examination of the causal effect of an exposure on an outcome in observational data. In this study, we utilized a comprehensive two-sample MR analysis to examine the causal link between 731 immune cells and PCOS. We employed complementary MR methods, such as the inverse-variance weighted (IVW) method, and conducted sensitivity analyses to evaluate the reliability of the outcomes., Results: Four immunophenotypes were identified to be significantly associated with PCOS risk: Memory B cell AC (IVW: OR [95%]: 1.123[1.040 to 1.213], p = 0.003), CD39+ CD4+ %CD4+ (IVW: OR [95%]: 0.869[0.784 to 0.963], p = 0.008), CD20 on CD20- CD38-(IVW: OR [95%]:1.297[1.088 to 1.546], p = 0.004), and HLA DR on CD14- CD16+ monocyte (IVW: OR [95%]:1.225[1.074 to 1.397], p = 0.003). The results of the sensitivity analyses were consistent with the main findings., Conclusions: Our MR analysis provides strong evidence supporting a causal association between immune cells and the susceptibility of PCOS. This discovery can assist in clinical decision-making regarding disease prognosis and treatment options, and also provides a new direction for drug development., 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 © 2023 Aru, Yang, Chen and Liu.)

Introduction: Thin endometrium leads to an impaired implantation rate. The aim of the study is to compare the clinical outcomes of tamoxifen (TAM) and hormone replacement therapy (HRT) used in patients with thin endometrium (<7mm) in frozen-thawed embryo transfer (FET)cycles., Methods: A total of 176 FET cycles with thin endometrium were retrospectively analyzed in our center from Jan 2020 to May 2022. According to patients' own will, 112 patients were allocated to the HRT group and 64 patients chose the TAM protocol. Clinical outcomes were compared between two groups., Result: The duration of treatment was shorter in the TAM group(12.03±2.34d) than the HRT group (16.07±2.52 d), which was statistically different (p<0.05). The endometrial thickness on the transfer day of the TAM group (7.32±1.28 mm) was significantly thicker than that of the HRT group (6.85±0.89mm, p<0.05). The clinical pregnancy rate of the TAM group (50.0%) was higher than that of the HRT group (36.6%), but there was no significant difference (p >0.05). The early miscarriage rate was significantly lower in the TAM group compared with the HRT group (5.9% Vs 26.8%, adjusted OR 0.10, p<0.05), while the live birth rate was higher in the TAM group (46.9% Vs 26.8%, adjusted OR 2.24, p<0.05) compared with the HRT group., Conclusion: For patients with thin endometrium, TAM effectively improved the endometrial thickness and increased the live birth rate. TAM can be used as an alternative protocol for patients with thin endometrium., 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 © 2023 Ji, Fu, Huang, Wu, Jiang and Huang.)

Background: Term birth (TB) and preterm birth (PTB) are characterized by uterine contractions, rupture of the chorioamniotic membrane, decidual activation, and other physiological and pathological changes. In this study, we hypothesize that inflammation can cause changes in mRNA expression and metabolic stability in the placenta, decidua, chorioamniotic membrane, uterus and peripheral blood, ultimately leading to PTB., Methods: To comprehensively assess the effects of inflammation on mRNA expression and metabolite production in different tissues of pregnancy, we used a mouse PTB model by intraperitoneally injecting lipopolysaccharide (LPS) and integrated transcriptomics and metabolomics studies., Results: Our analysis identified 152 common differentially expressed genes (DEGs) and 8 common differentially expressed metabolites (DEMs) in the placenta, decidua, chorioamniotic membrane, uterus, and peripheral blood, or placenta and uterus after LPS injection, respectively. Our bioinformatics analysis revealed significant enrichment of the NOD-like receptor signaling pathway (mmu04621), TNF signaling pathway (mmu04668), IL-17 signaling pathway (mmu04657), and NF-kappa B signaling pathway in the transcriptomics of different tissues, and Hormone synthesis, Lysosome, NOD-like receptor signaling pathway, and Protein digest and absorption pathway in metabolomics. Moreover, we found that several upstream regulators and master regulators, including STAT1, STAT3, and NFKB1, were altered after exposure to inflammation in the different tissues. Interaction network analysis of transcriptomics and metabolomics DEGs and DEMs also revealed functional changes in mice intraperitoneally injected with LPS., Conclusions: Overall, our study identified significant and biologically relevant alterations in the placenta, decidua, chorioamniotic membrane, uterus, peripheral blood transcriptome and the placenta and uterus metabolome in mice exposed to LPS. Thus, a comprehensive analysis of different pregnancy tissues in mice intraperitoneally injected with LPS by combining transcriptomics and metabolomics may help to systematically understand the local and systemic changes associated with PTB caused by inflammation., 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 © 2023 Cao, Zhou, Chen and Xu.)

Kawasaki disease (KD), an acute febrile systemic vasculitis in children, has become the leading cause of acquired heart disease in developed countries. Recently, the altered gut microbiota was found in KD patients during the acute phase. However, little is known about its characteristics and role in the pathogenesis of KD. In our study, an altered gut microbiota composition featured by the reduction in SCFAs-producing bacteria was demonstrated in the KD mouse model. Next, probiotic Clostridium butyricum ( C. butyricum ) and antibiotic cocktails were respectively employed to modulate gut microbiota. The use of C. butyricum significantly increased the abundance of SCFAs-producing bacteria and attenuated the coronary lesions with reduced inflammatory markers IL-1β and IL-6, but antibiotics depleting gut bacteria oppositely deteriorated the inflammation response. The gut leakage induced by dysbiosis to deteriorate the host's inflammation was confirmed by the decreased intestinal barrier proteins Claudin-1, Jam-1, Occludin, and ZO-1, and increased plasma D-lactate level in KD mice. Mechanistically, SCFAs, the major beneficial metabolites of gut microbes to maintain the intestinal barrier integrity and inhibit inflammation, was also found decreased, especially butyrate, acetate and propionate, in KD mice by gas chromatography-mass spectrometry (GC-MS). Moreover, the reduced expression of SCFAs transporters, monocarboxylate transporter 1 (MCT-1) and sodium-dependent monocarboxylate transporter 1 (SMCT-1), was also shown in KD mice by western blot and RT-qPCR analyses. As expected, the decrease of fecal SCFAs production and barrier dysfunction were improved by oral C. butyricum treatment but was deteriorated by antibiotics. In vitro , butyrate, not acetate or propionate, increased the expression of phosphatase MKP-1 to dephosphorylate activated JNK, ERK1/2 and p38 MAPK against excessive inflammation in RAW264.7 macrophages. It suggests a new insight into probiotics and their metabolites supplements to treat KD., 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 © 2023 Wang, Qian, Zhang, Zhao, Cen, Zhang, Zhou, Luo, Jia, Rong and Chu.)

Primary ovarian insufficiency (POI) is among the foremost causes of women infertility due to premature partial or total loss of ovarian function. Resistant ovary syndrome (ROS) is a subtype of POI manifested as normal ovarian reserve but insensitive to gonadotropin stimulation. Inactivating variants of follicle-stimulating hormone receptor (FSHR), a class A G-protein coupled receptor, have been associated with POI and are inherited via an autosomal recessive pattern. In this study, we investigated the genetic causes of a primary infertility patient manifested as POI with ROS, and elucidated the structural and functional impact of variants of uncertain significance. Next-generation sequencing (NGS) combined with Sanger sequencing revealed novel compound heterozygous FSHR variants: c.1384G>C/p.Ala462Pro and c.1862C>T/p.Ala621Val, inherited from her father and mother, respectively. The two altered amino acid sequences, localized in the third and seventh transmembrane helix of FSHR, were predicted as deleterious by in silico prediction. In vitro experiments revealed that the p.Ala462Pro variant resulted in barely detectable levels of intracellular signaling both in cAMP-dependent CRE-reporter activity and ERK activation and displayed a severely reduced plasma membrane receptor expression. In contrast, the p.Ala621Val variant resulted in partial loss of receptor activation without disruption of cell surface expression. In conclusion, two unreported inactivating FSHR variants potentially responsible for POI with ROS were first identified. This study expands the current phenotypic and genotypic spectrum of POI., 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 © 2023 Chen, Chen, Wang, Shu, Zhou, Wu, Jin, Yang, Sun, Qi and Shu.)

Trophoblast immune cell interactions are central events in the immune microenvironment at the maternal-fetal interface. Their abnormalities are potential causes of various pregnancy complications, including pre-eclampsia and recurrent spontaneous abortion. Matrix metalloproteinase (MMP) is highly homologous, zinc(II)-containing metalloproteinase involved in altered uterine hemodynamics, closely associated with uterine vascular remodeling. However, the interactions between MMP and the immune microenvironment remain unclear. Here we discuss the key roles and potential interplay of MMP with the immune microenvironment in the embryo implantation process and pregnancy-related diseases, which may contribute to understanding the establishment and maintenance of normal pregnancy and providing new therapeutic strategies. Recent studies have shown that several tissue inhibitors of metalloproteinases (TIMPs) effectively prevent invasive vascular disease by modulating the activity of MMP. We summarize the main findings of these studies and suggest the possibility of TIMPs as emerging biomarkers and potential therapeutic targets for a range of complications induced by abnormalities in the immune microenvironment at the maternal-fetal interface. MMP and TIMPs are promising targets for developing new immunotherapies to treat pregnancy-related diseases caused by immune imbalance., 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 © 2023 Jing, Chen, Qiu, He, Zhou, Li, Wang, Jiao and Liu.)

A dysregulated immune microenvironment at the maternal-fetal interface in early pregnancy may lead to early pregnancy loss, fetal growth restriction, and preeclampsia. However, major questions about how epigenetic modifications regulate the immune microenvironment during the decidualization process and embryo implantation remain unanswered. DNA methylation, the main epigenetic mechanism involved in the endometrial cycle, is crucial for specific transcriptional networks associated with endometrial stromal cell (ESC) proliferation, hormone response, decidualization, and embryo implantation. Ten-eleven translocation (TET) enzymes, responsible for catalyzing the conversion of 5-methylcytosine to 5-hydroxymethylcyosine, 5-formylytosine, and 5-carboxylcyosine to achieve the DNA demethylation process, appear to play a critical role in decidualization and embryo implantation. Here, we provide a comprehensive view of their structural similarities and the common mechanism of regulation in the microenvironment at the maternal-fetal interface during decidualization and early pregnancy. We also discuss their physiological role in the decidual immune microenvironment. Finally, we propose a key hypothesis regarding TET enzymes at the maternal-fetal interface between decidual immune cells and ESCs. Future work is needed to elucidate their functional role and examine therapeutic strategies targeting these enzymes in pregnancy-related disease preclinical models, which would be of great value for future implications in disease diagnosis or 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 © 2023 Jin, Ji, Chen, Zhou, Wang and Liu.)

Purpose: To study whether physical exercise can effectively ameliorate obesity-induced abnormalities in male fertility and provide a new perspective on the role of small noncoding RNAs in spermatogenesis in obese male mice., Methods: In this study, four-week-old C57/Bl6 male mice were randomly allocated to receive a control diet, a high-fat diet or physical exercise intervention for 40 weeks. Purified round spermatids and spermatozoa were obtained after intervention. Sperm motility, concentration, the ability of the sperm to undergo capacitation and acrosome reaction were assessed. Small RNA sequencing was conducted on round spermatids and spermatozoa. The small noncoding RNAs expression pattern was systematically analyzed., Results: The spermatozoa concentration and percentage of motile spermatozoa, the capacitation and acrosome reaction, and the reproductive success rate, including mating success and pregnancy success, were decreased or delayed in the obesity group compared with controls. Physical exercise was able to restore the parameters to normal levels. Three microRNAs were consistently upregulated and 5 were downregulated in round spermatids and epididymal spermatozoa between the obesity and control groups., Conclusions: This report provides evidence that the adverse effects of obesity could be offset after physical exercise. small noncoding RNAs, especially microRNAs in germ cells, may play an important role in the effects of obesity and physical exercise on spermatozoa., 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 Lin, Zhang, Zhou, Wu, Liu and Huang.)

This study was to explore whether postponing frozen embryo transfers (FET) after oocyte pickup (OPU) improves clinical and neonatal outcomes. From May 2018 to Dec 2020, a total of 1109 patients underwent their first OPU cycles adopting a non-selective freeze-all policy were included in this retrospective cohort study. In the immediate group (n=219), patients underwent FET in the first menstrual cycle after OPU, and patients in the postponed group (n=890) waited for more than 1 menstrual cycle after OPU to perform FET. A propensity score matching (PSM) model was used to evaluate the clinical outcomes and neonatal outcomes between the two groups. There were 209 patients in the immediate group and 499 patients in the postponed one after PSM. Patients waited for a significantly shorter period for FET in the immediate group (30.74 ± 3.85 days) compared with the postponed group (80.39 ± 26.25 days, P<0.01). The clinical pregnancy rate (CPR) and live birth rate (LBR) in the immediate group were 58.4% and 48.3%, respectively, which were comparable to those of the postponed one (58.1%, 49.7%, P > 0.05). No statistical significance was found in the average birth weight (3088.82 ± 565.35 g vs 3038.64 ± 625.78 g, P > 0.05) and height (49.08 ± 1.87 cm vs 49.30 ± 2.52 cm) of neonates between the two groups. The gender ratio, the incidence of macrosomia and low birth weight did not differ significantly between the two groups. In conclusion, postponing FET does not improve clinical and neonatal outcomes. If patients have no contraindications, FETs should be carried out immediately after OPU., 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 Ji, Jin, Guo, Wu, Jiang, Zhang and Shu.)

Many patients with congenital adrenal hyperplasia (CAH) refrain from seeking pregnancy, suffer from infertility or worry about pregnancy complications, mainly due to genitalia abnormalities, anovulation, unreceptive endometrium and metabolic disturbances. Despite those challenges, many live births have been reported. In this systematic review, we focused on the key to successful assisted reproduction strategies and the potential pregnancy complications. We did a systematic literature search of Pubmed, Medline and Scopus for articles reporting successful pregnancies in CAH other than 21-hydroxylase deficiency, and found 25 studies reporting 39 pregnancies covering deficiency in steroidogenic acute regulatory protein, 17α-hydroxylase/17,20-lyase, 11β-hydroxylase, P450 oxidoreductase, cytochrome b5 and 3β-hydroxysteroid dehydrogenase. We summarized various clinical manifestations and tailored reproduction strategy for each subtype. Furthermore, a meta-analysis was performed to evaluate the pregnancy complications of CAH patients. A total of 19 cross-sectional or cohort studies involving 1311 pregnancies of classic and non-classic CAH patients were included. Surprisingly, as high as 5.5% (95% CI 2.3%-9.7%) of pregnancies were electively aborted, and the risk was significantly higher in those studies with a larger proportion of classic CAH than those with only non-classical patients (8.43% (4.1%-13.81%) VS 3.75%(1.2%-7.49%)), which called for better family planning. Pooled incidence of miscarriage was 18.2% (13.4%-23.4%) with a relative risk (RR) of 1.86 (1.27-2.72) compared to control. Glucocorticoid treatment in non-classical CAH patients significantly lowered the miscarriage rate when compared to the untreated group (RR 0.25 (0.13-0.47)). CAH patients were also more susceptible to gestational diabetes mellitus, with a prevalence of 7.3% (2.4%-14.1%) and a RR 2.57 (1.29-5.12). However, risks of preeclampsia, preterm birth and small for gestational age were not significantly different. 67.8% (50.8%-86.9%) CAH patients underwent Cesarean delivery, 3.86 (1.66-8.97) times the risk of the control group. These results showed that fertility is possible for CAH patients but special care was necessary when planning, seeking and during pregnancy., Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=342642, CRD42022342642., 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 Guo, Zhang, Yu, Zhang, Ullah, Ji, Jin and Shu.)

Background: A large registry-based study found the increasing disorders of cardiovascular and metabolism in IVF children but underlying mechanism is still unknown. Few studies have investigated any association between OHSS and cardiovascular or metabolic function in subsequent children., Objective: To evaluate the effect of ovarian hyperstimulation syndrome (OHSS) on blood pressure of singletons after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI)., Study Design: The singlet-center corhort study included 1780 singletons born with IVF/ICSI and 83 spontaneously conceived children from 2003 to 2014. Follow-up has lasted more than 10 years, and is still ongoing. This study analyzed data from follow-up surveys at 3 to 6 years of age., Participants Setting and Methods: We recruited 83 children (Group E) spontaneously conceived (SC) as control group and 1780 children born with IVF/ICSI including 126 children born to OHSS-fresh embryo transfer (ET) women (Group A), 1069 children born to non OHSS-ET women (Group B), 98 children conceived by women who developed into moderate or severe OHSS after oocyte retrieval and selected the frozen-thawed embryo transfer (FET) (Group C), 487 children conceived with non OHSS-FET (Group D). We evaluated cardiometabolic function, assessed BP in mmHg, heart rate, anthropometrics, and metabolic index including glucose, serum lipid (triglyceride, total cholesterol, low density lipoprotein, high density lipoprotein), thyroid function, of those children. The BP and heart rate were measured twice on the same day. We applied several multiple regression analyses to investigate the effect of OHSS in the early pregnancy., Main Findings: By the single factor analysis, the SBP and DBP in the SC group (SBP: 99.84 ± 8.9; DBP: 55.27 ± 8.8) were significantly lower than OHSS-ET group's, while the blood pressure was similar between the SC group and other three ART groups. Children had higher BP in the OHSS-ET group (SBP: 101.93 ± 8.17; DBP: 58.75 ± 8.48) than in the non OHSS-ET (SBP: 99.49 ± 8.91; DBP: 56.55 ± 8.02) or OHSS-FET group (SBP: 99.38 ± 8.17; DBP: 55.72 ± 7.94). After using multiple regression analysis to adjust current, early life, parental and ART characteristics, the differences in the SBP and DBP (B (95% confidence interval)) between OHSS-ET and non OHSS-ET remained significant (SBP: 3.193 (0.549 to 2.301); DBP: 3.440 (0.611 to 2.333)). And the BP showed no significant difference complementarily when compared non OHSS-FET group with non OHSS-ET group. In addition, the anthropometrics, fast glucose, serum lipid, and thyroid index did not differ among the ART groups., Principal Conclusions: OHSS might play an independent key role on offspring's BP even cardiovascular function. Electing frozen-thawed embryo transfer for high risk of OHSS population may reduce the risk of the high BP trend., Wider Implications of the Findings: It is a large sample study to investigate the effect of OHSS on offspring's health. These findings provide a clinic evidence of the impact of early environment (embryo even oocyte stage) on the offspring's cardiovascular health. Our study emphasis the importance of the accuracy of IVF clinic strategy and preventing the OHSS after fresh embryo transfer., 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 Zhu, Fu, Tang, Yan, Zhang, Hu, Feng, Sun and Xing.)

A randomized sibling-embryo pilot trial investigated whether two ways of laser-assisted hatching result in different blastulation and clinical outcomes after extended in vitro culture process of highly fragmented day-3 cleavage embryos. From 92 couples, a total of 315 highly fragmented day-3 embryos (the fragmentation >25%) were recruited and randomized into laser-assisted zona thinning (LAT, n=157) and opening (LAO, n=158) groups, and then underwent a blastocyst culture in vitro . The main endpoint measurements including blastocyst formation and grading as well as the clinical pregnancy after blastocyst transfer were obtained during the treatment procedure of in vitro fertilization and embryo transfer, and then analyzed with generalized estimating equation (GEE) and/or time-to blastocyst analysis models. A total of 166 day-3 embryos developed into blastocyst stage (52.70%), of which 97 were viable blastocysts (30.79%), and 42 top-quality ones (13.33%). LAT did not have any inferior or superior to LAO in the endpoints of either total, viable, top-quality or hatched blastocyst formation, with the ORs (95%CI) from GEE model as 0.89 (0.55-1.45), 0.71 (0.42-1.21), 1.12 (0.56-2.25) and 0.68 (0.42-1.12) respectively for LAT treatment. And the time-to-blastocyst analysis showed a similar result. Additionally, no difference in clinical outcomes after blastocyst transfer was found between the two groups. The author concluded that when applying the LAHs during the extended culture of highly fragmented embryos, both LAT and LAO can generate a promising clinical outcome, and the LAT operation be equivalent to the LAO. Future well-designed, multiple-center, larger-sample investigations are required to ascertain above conclusion., 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 Zhang, Zhou, Wu, Wu, Li, Zhang, Jin, Shu, Xu and Shu.)

Objective: To investigate the effectiveness and limitations of multifetal pregnancy reduction (MFPR) on the improvement of pregnancy outcomes of triplet or twin pregnancies conceived by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)., Methods: We performed a cohort study of women undergoing IVF or ICSI from 2002-2016 in reproductive center, women's hospital, Zhejiang University School of Medicine. The cohort included 502 women who underwent MFPR and 9641 non-reduced women. Pregnancy outcomes were gestational age (GA) at delivery, pregnancy loss, preterm delivery, low birth weight (LBW), very low birth weight (VLBW), and small for gestational age (SGA). Multiple linear regression and logistic regression models were used to compare pregnancy outcomes between groups., Results: Triplets reduced to singletons had a longer median GA (39.07 vs 37.00, P<0.001), and lower rates of LBW (8.9% vs 53.2%, P<0.001) and SGA (17.8% vs 44.7%, P=0.001) than triplets reduced to twins, with a similar pregnancy loss rate (6.7% vs 6.6%, P=0.701). Twins reduced to singletons had a comparable pregnancy loss rate (4.8% vs. 6.5%, P=0.40), a longer median GA (38.79 vs. 37.00, P<0.001), and lower rates of LBW (13.5% vs. 47.0%, P<0.001) and SGA (13.5% vs. 39.6%, P<0.001) than primary twins. Triplets reduced to twins had higher rates of LBW (53.2% vs. 47.0%, P=0.028) and SGA (44.7% vs. 39.6%, P=0.040) than primary twins, with a similar pregnancy loss rate (6.6% vs. 6.5%, P=0.877). Singletons reduced from triplets/twins had higher rates of preterm delivery (15.8% vs. 7.3%, P<0.001), LBW (12.3% vs. 4.32%, P<0.001), VLBW (2.3% vs. 0.4%, P=0.002), and SGA (14.6% vs.6.6%, P<0.001) than primary singletons, with a comparable pregnancy loss rate (5.3% vs. 5.4%, P=0.671)., Conclusions: This study suggests that the pregnancy loss rate is similar between reduction and non-reduction groups. MFPR improves pregnancy outcomes, including the risk of preterm delivery, LBW, and SGA, but still could not completely reverse the adverse pregnancy outcomes of multiple pregnancies., 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 Yimin, Minyue, Yanling, Huanmiao, Saijun, Qingfang, Xiaoling and Lanfeng.)

Background: As the survival rates of patients with renal cell carcinoma (RCC) continue to increase, noncancer causes of death cannot be ignored. The cause-specific mortality in patients with RCC is not well understood., Objective: Our study aimed to explore the mortality patterns of contemporary RCC survivors., Methods: We performed a retrospective cohort study involving patients with RCC from the Surveillance, Epidemiology, and End Results (SEER) database. We used standardized mortality ratios (SMRs) to compare the death rates in patients with RCC with those in the general population., Results: A total of 106,118 patients with RCC, including 39,630 who died (27%), were included in our study. Overall, compared with the general US population, noncancer SMRs were increased 1.25-fold (95% confidence intervals [CI], 1.22 to 1.27; observed, 11,235), 1.19-fold (95% CI, 1.14 to 1.24; observed, 2,014), and 2.24-fold (95% CI, 2.11 to 2.38; observed, 1,110) for stage I/II, III, and IV RCC, respectively. The proportion of noncancer causes of death increased with the extension of survival time. A total of 4,273 men with stage I/II disease (23.13%) died of RCC; however, patients who died from other causes were 3.2 times more likely to die from RCC ( n = 14,203 [76.87%]). Heart disease was the most common noncancer cause of death ( n = 3,718 [20.12%]; SMR, 1.23; 95% CI, 1.19-1.27). In patients with stage III disease, 3,912 (25.98%) died from RCC, and 2,014 (13.37%) died from noncancer causes. Most patients (94.99%) with stage IV RCC died within 5 years of initial diagnosis. Although RCC was the leading cause of death ( n = 12,310 [84.65%]), patients with stage IV RCC also had a higher risk of noncancer death than the general population (2.24; 95% CI, 2.11-2.38)., Conclusions: Non-RCC death causes account for more than 3/4 of RCC survivors among patients with stage I/II disease. Patients with stage IV are most likely to die of RCC; however, there is an increased risk of dying from septicemia, and suicide cannot be ignored. These data provide the latest and most comprehensive assessment of the causes of death in patients with RCC., 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 Yu, Chen, Wu, Wu, Xin, Jiang, Li and Zhang.)

Background: The opportunity for fertility preservation in adolescent and young adult (AYA) transmen is growing. Many AYA transmen desire future biologic children and are interested in ways to preserve fertility through oocyte cryopreservation prior to full gender affirmation, yet utilization of oocyte cryopreservation remains low. Additionally, standard practice guidelines currently do not exist for the provision of oocyte cryopreservation to AYA transmen. Our objective was to review our experience with oocyte cryopreservation in adolescent and young adult transmen in order to synthesize lessons regarding referral patterns, utilization, and oocyte cryopreservation outcomes as well as best practices to establish treatment guidance., Methods: This is a case series of all AYA transmen (aged 10 to 25 years) who contacted, consulted or underwent oocyte cryopreservation at a single high volume New York City based academic fertility center between 2009 and 2021., Results: Forty-four adolescent and young adult transmen made contact to the fertility center over the study period. Eighty percent (35/44) had a consultation with a Reproductive and Endocrinology specialist, with a median age of 16 years (range 10 to 24 years) at consultation. The majority were testosterone-naive (71%, 25/35), and had not pursued gender affirming surgery (86%, 30/35). Expedited initiation of testosterone remained the most commonly cited goal (86%, 30/35). Fifty-seven percent (20/35) pursued oocyte cryopreservation. Ninety-five percent (19/20) underwent successful transvaginal oocyte aspiration, with a median of 22 oocytes retrieved and 15 mature oocytes cryopreserved. There were no significant adverse events. At time of review, no patient has returned to utilize their cryopreserved oocytes., Conclusions: Oocyte cryopreservation is a safe fertility preservation option in AYA transmen and is an important aspect of providing comprehensive transgender care. Insights from referral patterns, utilization, and oocyte cryopreservation outcomes from a single center's experience with adolescent and young adult transmen can be integrated to identify lessons learned with the goal of providing transparency surrounding the oocyte cryopreservation process, improving the education and comfort of patients and providers with fertility preservation, and easing the decision to pursue an oocyte cryopreservation cycle in parallel to gender-affirmatory care., 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 Barrett, Shaw, Blakemore and Fino.)

Follicle arrest is one of the main characteristics of polycystic ovary syndrome (PCOS), the most common endocrinological disorder in reproductive-aged women. Increasing evidence proves that high anti-Mullerian hormone (AMH) levels may play an important role in follicular development. Long noncoding RNA (lncRNA) with a length of more than 200 nt is widely involved in the directional differentiation, growth, and development of cells, whereas whether lncRNA is involved in AMH's role in follicular development is unknown. In this study, we analyzed lncRNA expression in ovarian granulosa cells (GCs) collected from women with and without PCOS via high-throughput sequencing. The results showed that a total of 79 noncoding transcripts were differently expressed in GCs of PCOS patients, including upregulated lncRNA MALAT1. The upregulation of MALAT1 was further confirmed by RT-qPCR in GCs from a larger cohort of PCOS patients. Furthermore, knockdown MALAT1 can promote the proliferation of KGN cell in vitro . These data suggested a role for MALAT1 in the development of PCOS. Meanwhile, MALAT1 and phosphorylated SMAD 1/5 (Ser463/465) protein were upregulated in KGN cells after exogenous AMH stimulation, which identified AMH perhaps as a regulator for the expression of MALAT1. We also found that MALAT1 can predict clinical pregnancy outcome to a certain extent by ROC curve analysis (area: 0.771, p  = 0.007, 95% CI: 0.617-0.925, sensitivity: 57.1%, specificity: 91.7%). Thus, our findings revealed a role of lncRNA MALAT1 in inhibiting granulosa cell proliferation and may be correlated with pregnancy outcome in PCOS., 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 Tu, Wu, Wang, Huang, Qian, Li, Lv, Ying, Liu, Liu, Zhang, Zhao and Zhang.)

Female fertility declines with age, and this natural variation culminates in reproductive senescence. Human follicular fluids are rich in low-molecular weight metabolites which are responsible for the maturation of oocytes. The metabolomic approaches are powerful tools to study biochemical markers of oocyte quality in the follicular fluids. It is necessary to identify and quantify the reliable metabolites in follicular fluids reflecting oocyte developmental potential. The goal of this study is to conduct a metabolomic analysis of the follicular fluids in women of different ages and study the metabolomic profile of the follicular fluids in relationship with oocyte quality in assisted reproductive technology (ART) treatment. A total of 30 women seeking for ART treatment at the Women's Hospital, Zhejiang University School of Medicine from October 2014 to April 2015 were recruited for the present study. Fifteen women aged from 39 to 47 were grouped as advanced maternal age, and the other 15 women aged from 27 to 34, as young controls. Ovarian stimulation and oocyte retrieval were conducted using a regular protocol involving mid-luteal pituitary down-regulation and controlled ovarian stimulation. Follicular fluids from mature follicles were collected and centrifuged for analyses. Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography-Mass Spectroscopy (GC-MS) were used to perform the quantitative metabolomic analysis. The follicular fluid levels of 311 metabolites and the metabolic significance were assessed. 70 metabolites showed significant differences between women with young and advanced ages. Follicular fluids from women with advanced age showed significantly higher levels of creatine, histidine, methionine, trans-4-hydroxyproline, choline, mevalonate, N2,N2-dimethylguanosine and gamma-glutamylvaline, as compared to those from the young age group. 8 metabolites were found significantly correlated with maternal age positively. Moreover, 3 metabolites were correlated with the number of oocytes retrieved, and 5 metabolites were correlated with cleaved embryo numbers, both negatively. The follicular fluids from women undergoing ART treatment exhibited age-dependent metabolomic profile. Metabolites associated with oocyte quality were identified, suggesting them as potential biomarkers for oocyte maturation and ART outcomes., 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 Huang, Tu, Qian, Ma, Chen, Liu, Wu, Chen, Liu, Ying, Chen, Ye, Xing, Zhang, Hu, Zhang, Ruan and Zhang.)

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. The characteristics of early human chorionic gonadotropin (hCG) levels and the rise pattern in patients with GDM after in vitro fertilization (IVF) are unclear. The present investigation was a retrospective cohort analysis of eligible viable pregnancies achieved through IVF in the authors' hospital between October 2015 and June 2020. The characteristics of initial hCG concentration and the rise pattern in patients with GDM after IVF, and the difference between those of normoglycemic pregnant women, were explored. Using random-effects models, the preferred pattern to describe the increase in log hCG was a quadratic. When gestational age was within 39 days, the linear model adequately characterized the profile, and the average slope was 0.173, yielding a predicted increase of 1.55 (55%) in 1 day and 3.11 (211%) in 2 days. Absolute hCG values-but not the rate of rise-were significantly higher in double embryo transfers and twin pregnancies. Curves reflecting hCG rise from the GDM and non-GDM groups did not differ substantially. The proportion of patients with low initial hCG values (16 days post-oocyte retrieval <100 mIU/ml) was higher in the GDM group (5% vs. 2.09%), although the difference was not statistically significant. Early hCG rise in pregnant women after IVF-whether GDM or non-GDM-could be characterized by quadratic and linear models. However, hCG values on days 14 and 16 post-oocyte retrieval in the GDM group were lower than those in the non-GDM group, with the exception of twin pregnancies. Low hCG values in early pregnancy may be a clue to help predict GDM in the subsequent gestation period., 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 Wu, Zhang, Li, Hu, Chen and Tian.)

We first reported that the Hippo-YAP signaling pathway plays a critical role in the pathogenesis of endometriosis (EMS). Autophagy is also related to the invasion ability of endometrial cells and is involved in the pathogenesis of EMS through multi-levels. However, the precise regulatory mechanism of YAP on autophagy in the eutopic endometrial stromal cells (ESCs) is still unclear. Primary eutopic ESCs of EMS patients ( n = 12) and control patients without EMS ( n = 9) were isolated and cultured to investigate the expressions of YAP and mTOR, the role of YAP in autophagy, and the effect of the YAP-autophagy signal on the decidualization of the eutopic ESCs. Endometriosis-related sequencing data (GSE51981) in the GEO database were used to find the genes significantly correlated with YAP. We found 155 genes with significant differences in the interaction with YAP in EMS from the dataset, and the autophagy pathway was significantly enriched. Following on from our previous studies of YAP knockdown, overexpression of YAP resulted in an increased expression of mTOR and decreased ratio of LC3-II/LC3-I and autophagy markers, in the eutopic ESCs; transmission electron microscope observation also showed fewer autophagosomes compared with the control cells. Furthermore, ESCs of the Rapamycin-treated group showed significant decidual-like changes with significantly increased decidual prolactin level at 72 h after in vitro decidualization. These results demonstrate that the increased YAP inhibited the level of autophagy by upregulating the mTOR signal in the eutopic ESCs of endometriosis. The YAP-autophagy signal plays an important role in the pathogenesis of endometriosis-associated infertility., 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 Pei, Luo, Huang, Liu, Li, Xiao, Huang, Ouyang and Zhu.)

Objective: To assess and compare the feasibility of progestin-primed ovarian stimulation (PPOS) protocol with mild stimulation protocol for advanced age women with diminished ovarian reserve (DOR) undergoing their first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle., Methods: Patients aged ≥35 years and DOR undergoing their first IVF/ICSI cycle were enrolled in this retrospective cohort study: 139 and 600 patients underwent the PPOS and mild stimulation protocols, respectively. The primary outcomes were cumulative clinical pregnancy rate (CCPR) and cumulative live birth rate (CLBR). The secondary outcomes were the number of oocytes retrieved and top-quality embryos., Results: There was nearly no significant difference of baseline characteristics between the two groups. Although a greater amount of total gonadotropin (1906.61 ± 631.04 IU vs. 997.72 ± 705.73 IU, P <0.001) and longer duration of stimulation (9 (10-7) vs. 6 (8-4), P <0.001) were observed in the PPOS group, the number of retrieved oocytes (3 (6-2) vs. 2 (4-1), P <0.001) and top-quality embryos (1 (2-0) vs. 1 (2-0), P =0.038) was greater in the PPOS group than the mild stimulation group. Meanwhile, the incidence of premature luteinizing hormone (LH) surge rate was significantly lower in the PPOS group (0.7% vs.8.3%, P =0.001) than the mild stimulation group. However, there was no significant difference in conservative CCPR, conservative CLBR, optimistic CCPR, and optimistic CLBR between the two groups (all P >0.05). A multivariate logistic regression model showed significant positive effects of the number of retrieved oocytes and number of top-quality embryos on conservative CCPR (OR=1.236, 95%CI: 1.048-1.456, P =0.012, OR=2.313, 95%CI: 1.676-3.194, P <0.001) and conservative CLBR (OR=1.250, 95%CI: 1.036-1.508, P =0.020, OR=2.634, 95%CI: 1.799-3.857, P <0.001) respectively, while significant negative effects of age were identified for conservative CCPR (OR=0.805, 95%CI: 0.739-0.877, P <0.001) and conservative CLBR (OR=0.797, 95%CI: 0.723-0.879, P <0.001)., Conclusion: The PPOS protocol is an effective alternative to the mild stimulation protocol for advanced age patients with DOR, as it provides comparable reproductive outcomes and better control of premature LH surge. Further, more oocytes and top-quality embryos were obtained in the PPOS group, which had a positive association with conservative CCPR and CLBR., 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 Tu, You, Jing, Lin and Zhang.)

Background: Primary breast signet ring cell carcinoma (SRCC) is a rare type of breast cancer with typical morphological characteristics, high aggressiveness, and poor prognosis. SRCC is different from mucinous breast adenocarcinoma (MBC). However, only a few studies have explored the clinicopathological features and prognosis of SRCC and MBC., Methods: Data retrieved from the Surveillance, Epidemiology, and End-Results (SEER) database (2004-2015) were used to explore the prognostic effect of clinicopathological features and treatment modalities on survival outcomes of SRCC and MBC patients. Kaplan-Meier plot analysis, multivariate Cox proportional risk model, propensity score matching (PSM), and subgroup analysis were performed., Results: A total of 167 patients with SRCC and 11,648 patients with MBC were included in the study. SRCC patients exhibited higher histological grade ( p < 0.001), larger tumor volume ( p < 0.001), higher rate of lymph node metastasis ( p < 0.001), and higher frequency of distal metastasis ( p < 0.001) compared with MBC patients. Cox proportional hazards regression analysis showed that SRCC patients had lower overall survival (OS) and breast cancer-specific survival (BCSS) compared with MBC patients. Subgroup survival analysis showed that the SRCC patients had lower OS and BCSS in subgroups including younger than 60 years old, white race, married, without chemotherapy, and received radiotherapy compared with the MBC patients in these subgroups. In addition, the SRCC patients had lower BCSS in subgroups including other races (including Asian or Pacific Islander and American Indian/Alaska Native), without surgery, and lymph node metastasis., Conclusion: The findings showed that primary breast SRCC patients have unique clinical characteristics and worse prognosis compared with MBC patients. Notably, different treatment methods resulted in different prognosis for SRCC and MBC types; therefore, SRCC patients should be distinguished from MBC patients to improve efficacy of 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 © 2021 Wang, Zhang, Yin, Zhang, Yang and Wang.)

Background: Invasive micropapillary breast carcinoma (IMPC) is a relatively rare pathological type of invasive breast cancer. Little is currently known on the efficacy and safety of breast-conserving treatment (BCT, lumpectomy plus postsurgical radiation) compared with mastectomy in women diagnosed with early-stage IMPC. Accordingly, we sought to investigate the long-term prognostic differences between BCT and mastectomy in patients with T1-3N0-3M0 invasive micropapillary breast carcinoma using data from the Surveillance, Epidemiology, and End Results (SEER) database., Materials and Methods: We retrospectively analyzed 1,203 female patients diagnosed with early-stage IMPC between 2004 and 2015 from the SEER database. The impact of different surgical approaches on patient prognosis was assessed by the Kaplan-Meier method and Cox proportional risk models., Results: A total of 609 and 594 patients underwent mastectomy and BCT, respectively. Compared with patients who underwent a mastectomy, patients in the BCT group were older and had lower tumor diameters, lower rates of lymph nodes metastasis, and higher rates of ER receptor positivity and PR receptor positivity ( p  < 0.05). Kaplan-Meier plots showed that the overall survival (OS) and breast cancer-specific survival (BCSS) were higher in the BCT group than in the mastectomy group. In subgroup analysis, patients with T2 stage in the BCT group had better OS than the mastectomy group. Multivariate analysis showed no statistical difference in OS and BCSS for patients in the mastectomy group compared with the BCT group (hazard ratio (HR) = 0.727; 95% confidence interval (95% CI) 0.369-1.432, p  = 0.357; HR = 0.762; 95% CI 0.302-1.923, p  = 0.565; respectively). During the multivariate analysis and stratifying for the T stage, a better OS was found for patients with T2 stage in the BCT group than the mastectomy group (HR = 0.333, 95% CI: 0.149-0.741, p  = 0.007). There was no significant difference in OS for patients with T1 and T3 stages between the BCT and mastectomy groups ( p  > 0.05)., Conclusion: In women with early-stage IMPC, BCT was at least equivalent to mastectomy in terms of survival outcomes. When both procedures are feasible, BCT should be recommended as the standard surgical treatment, especially for patients with T2 disease., 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 Wang, Zhang, Yin, Wang and Yang.)

Objective: To determine whether serum anti-Müllerian hormone (AMH) level is a predictor of clinical pregnancy in women trying to achieve a natural conception., Methods: The PubMed, Embase, and Cochrane Library databases were searched for articles published until August 2020. Studies that met the inclusion and exclusion criteria were included in the meta-analysis; no language limitations were imposed. Quality was appraised using the Quality Assessment of Diagnostic Accuracy Studies-2 checklist. Heterogeneity due to the threshold effect was identified; thus, we plotted a summary receiver operating characteristic curve and calculated its area under the summary receiver operating characteristic curve (AUC) and Cochran's Q index to assess whether AMH level is a predictor of spontaneous pregnancy. Publication bias and sensitivity were also assessed., Results: Eleven studies (4,388 women) were ultimately included in this meta-analysis. The AUC and Cochran's Q indices were 0.5932 and 0.5702, respectively. For women younger than 35 years, the AUC was 0.6355 and the Q index was 0.6025. For those older than 35 years, the AUC was 0.5536 and the Q index was 0.5403. Subgroup analyses by study type and population characteristics showed results similar to the overall outcome. No publication bias was identified, and the sensitivity analysis confirmed the robustness of the final result., Conclusions: Serum AMH levels have poor predictive value for natural pregnancy. The predictive value of AMH was poor in the younger and older subgroups. Our findings suggest that low serum AMH levels are not associated with reduced fertility., Introduction: This study investigated the predictive value of anti-Müllerian hormone (AMH) level for natural pregnancy. Other than age, few factors can predict the chances of natural fertility. AMH is an established biomarker of ovarian reserve that is widely used to predict oocyte yield in cases of in vitro fertilization (IVF) and menopause. In clinical practice, the applications of AMH are increasing. However, its predictive value for natural conception remains controversial. In this study, since AMH is closely related with ovarian reserve, we evaluated whether it has predictive value for natural pregnancy. Our findings will fine-tune the clinical application of AMH in pre-pregnancy counseling. The topic should be of wide interest to investigators in the reproductive endocrinology and gynecology fields., Systematic Review Registration: PROSPERO 2020 CRD42020216265, Available from: https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42020216265., 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 Lin, Jing, Zhu, Tu, Chen, Wang, Zheng and Zhang.)

Controlled ovarian hyperstimulation (COH) is the most common therapeutic protocol to obtain a considerable number of oocytes in IVF-ET cycles. To date, the risk factors affecting COH outcomes remain elusive. Growth differentiation factor 8 (GDF-8), a member of transforming growth factor β (TGF-β) superfamily, has been long discerned as a crucial growth factor in folliculogenesis, and the aberrant expression of GDF-8 is closely correlated with the reproductive diseases. However, less is known about the level of GDF-8 in IVF-ET patients with different ovarian response. In the present study, the potential risk factors correlated with ovarian response were explored using logistic regression analysis methods. Meanwhile, the expression changes of GDF-8 and its responsible cellular receptors in various ovarian response patients were determined. Our results showed that several factors were intensely related to poor ovarian response (POR), including aging, obesity, endometriosis, surgery history, and IVF treatment, while irregular menstrual cycles and PCOS contribute to hyperovarian response (HOR). Furthermore, POR patients exhibited a decrease in numbers of MII oocytes and available embryos, thereby manifesting a lower clinical pregnancy rate. The levels of GDF-8, ALK5, and ACVR2B in POR patients were higher compared with those in control groups, whereas the expression level of ACVR2A decreased in poor ovarian response patients. In addition, clinical correlation analysis results showed that the concentration of GDF-8 was negatively correlated with LH and estradiol concentration and antral follicle count. Collectively, our observations provide a novel insight of ovarian response-associated risk factors, highlighting the potential role of GDF-8 levels in ovarian response during COH process., 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 Bai, Pan, Zhao, Chen, Xiang, Yang and Zhu.)

Objective: To evaluate the association between neck circumference (NC) and hyperuricemia in women with polycystic ovary syndrome (PCOS)., Methods: This is a cross-sectional study that recruited 601 women with PCOS from January 2018 to January 2021. PCOS was diagnosed according to the Rotterdam definition. Hyperuricemia was defined as serum uric acid level of at least 357 μmol/L., Results: PCOS females with hyperuricemia had significantly greater values of NC, body mass index (BMI), waist circumference (WC) and hip circumference (HC). NC was positively associated with serum uric acid levels, with a standardized regression coefficient of 0.34 after adjusting for confounding factors. Furthermore, logistic regression analysis showed that NC was significantly associated with an increased risk of hyperuricemia, with an adjusted odds ratio of 1.36. The associations between NC and serum uric acid levels were more considerable in those with medium/high BMI (BMI ≥ 21.63 kg/m 2 ), all ranges of WC or medium/high HC (HC ≥ 90 cm). The optimal cut-off point of NC in predicting hyperuricemia was 32.0 cm (Youden index = 0.48), with the sensitivity and negative predictive value of 84.81% and 92.08%, respectively., Conclusions: NC was positively correlated with serum uric acid levels and the prevalence of hyperuricemia in women with PCOS. Therefore, we suggest NC as a simple, novel, and reliable anthropometric measure to be used in the routine clinical assessment of women with PCOS to screen those at high risk of hyperuricemia., 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 Yang, Liu, Jin, Yu, Ding and Mu.)

Capsule: Oligo/amenorrhea is an independent risk factor of low ovarian response but not high ovarian response, particularly in women with low AMH levels., Objective: To investigate the association of menstrual cycle length (MCL) with anti-Müllerian hormone (AMH) and ovarian response., Methods: This was a retrospective cohort study. A total of 7471 women who underwent ovarian stimulation and oocyte retrieval were enrolled. The main outcome was the number of oocytes retrieved., Main Results: A total of 5734 patients were eligible for analysis. In women without polycystic ovary syndrome (PCOS), serum AMH levels and antral follicle count were significantly lower in women with short cycles and higher in women with oligo/amenorrhea than those with a normal menstrual cycle. In women with PCOS, compared to women with a normal menstrual cycle, women with short cycles and women with oligo/amenorrhea showed higher antral follicle count and higher serum AMH levels. Compared with the 0-25th range group of AMH levels, 75-100th percentile groups showed a significantly increased rate of oligo/amenorrhea in women with and without PCOS [adjusted odds ratio (OR) =1.9 (1.04, 3.46), 2.4 (1.70, 3.35)]. In women without PCOS, the low ovarian response was more common in women with short cycles and less common in women with oligo/amenorrhea compared to women with normal cycles [OR=3.0 (2.38, 3.78), 0.7 (0.55, 0.96), respectively]. When adjusted for AMH levels, both short cycles and oligo/amenorrhea were associated with an increased risk of low response [adjusted OR=1.3 (1.02, 1.75), 1.3 (0.93, 1.86), respectively]. In women without PCOS and with low AMH levels, the low ovarian response was more common in women with short cycles as well as in women with oligo/amenorrhea [OR=1.5 (1.08, 1.98), 1.7 (1.08, 2.69), adjusted OR=1.2 (0.86, 1.74), 2.2 (1.31, 3.82), respectively]., Conclusion: AMH levels are significantly associated with increased risk of oligo/amenorrhea in women with and without PCOS. AMH is an indispensable confounder in the association between MCL and ovarian response in women without PCOS. Oligo/amenorrhea is an independent risk factor associated with a low ovarian response in women without PCOS, particularly those with low AMH levels., 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 Hu, Gan, Ying, Zheng, Chen, Xue, Wu, Liu, Zhu, Xing and Zhang.)

Toll-like receptor 4 (TLR4) may play a critical role in regulating follicular development. Data are scarce on the role of TLR4 in the follicle. This study investigated the effects of TLR4 on steroidogenesis in human granulosa cells. Immunohistochemical analysis revealed stage-specific expression of TLR4 in the mouse ovarian cycle, and immunofluorescence showed TLR4 expression in the human granulosa-like tumor cell line (KGN). TLR4 agonist lipopolysaccharides (LPS) significantly inhibited follicular development and synthesis of estradiol (E2) in mice. In KGN cells, TLR4 activation significantly inhibited CYP19A1, FSHR and StAR, and TLR4 inhibition reversed these effects. TLR4 activation also inhibited forskolin-induced secretion of E2 by inhibiting CYP19A1, with no effect on progesterone. Further studies showed activation of p38, JNK and NF-κB signaling after TLR4 activation. Subsequent analyses showed that an NF-κB antagonist reversed the inhibitory effects on CYP19A1 expression and E2 secretion. Together, our results suggest that TLR4 activation may suppress CYP19A1 expression and E2 secretion via NF-κB signaling in human granulosa cells, with important implications for the regulation of ovarian pathophysiology., 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 Guan, Xia, Chen, Wang, Tang and Zhang.)

Context: The widespread distribution of the Vitamin D (VitD) receptor in reproductive tissues suggests an important role for VitD in human reproduction. The assessment of patient´s VitD is based on the 25-hydroxyvitamin D (25(OH)D) metabolite measurement. However, most of the circulating 25(OH)D is bound to either VitD-binding protein (VDBP) (88%) or albumin (12%) and less than 1% circulates free., Objective: To determine a possible correlation between VitD levels in serum (S) and follicular fluid (FF) and blastocyst ploidy status in patients undergoing infertility treatment., Methods: A prospective observational study was performed including couples planned for preimplantation genetic testing for aneuploidies (PGT-A) from ART Fertility Clinics. Patients were classified according to their 25(OH)D-Serum levels: VitD deficient group <20 ng/ml and insufficient/replete ≥20 ng/ml defined as VitD non-deficient group., Results: Serum samples and 226 FF from individual follicles were collected for 25(OH)D, bioavailable 25(OH)D, free 25(OH)D, and % free 25(OH)D measurement. 25(OH)D-Serum in VitD deficient and non-deficient were 13.2±4.0 ng/ml vs 32.3±9.2 ng/ml; p<0.001. FF from 40 and 74 biopsied blastocysts was analysed of which 52.5 and 60.8% were euploid (p = 0.428), respectively. In VitD deficient patients, mean 25(OH)D-FF, bioavailable 25(OH)D-FF, and free 25(OH)D-FF were higher in euploid vs aneuploid blastocysts (18.3±6.3 ng/ml vs 13.9±4.8 ng/ml; p = 0.040; 1.5±0.5 ng/ml vs 1.1±0.4 ng/ml; p = 0.015; 0.005±0.002 ng/ml vs 0.003±0.001 ng/ml; p = 0.023, respectively), whilst no differences were found in VitD non-deficient patients (37.9±12.3 ng/ml vs 40.6±13.7 ng/ml; p = 0.380; 3.1±1.1 ng/ml vs 3.3±1.2 ng/ml; p = 0.323; 0.01±0.003 ng/ml vs 0.01±0.004 ng/ml; p = 0.319, respectively)., Conclusion: VitD non-deficient patients have a significantly higher probability of obtaining a euploid blastocyst compared to VitD deficient patients (OR:33.36, p = 0.002)., 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 Arnanz, De Munck, El Khatib, Bayram, Abdala, Melado, Lawrenz, Coughlan, Pacheco, Garcia-Velasco and Fatemi.)

Purpose: This study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) in CRPC patients treated with novel hormonal therapy (NHT) (Abiraterone and Enzalutamide) or taxane-based chemotherapy (Docetaxel and Cabazitaxel)., Methods: A comprehensive literature search was conducted on PubMed, Embase, and the Web of Science from inception to February 2020. Studies focusing on the prognostic values of AR-V7 in CRPC patients treated with NHT or chemotherapy were included in our meta-analysis. The OS and PFS were analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for the AR-V7 conversion after treatment and the PSA response., Results: The AR-V7 positive proportion increased significantly after NHT treatment (OR 2.56, 95% CI 1.51-4.32, P<0.001), however, it declined after chemotherapy (OR 0.51, 95% CI 0.28-0.93, P=0.003). AR-V7-positive patients showed a significantly decreased PSA response rate after NHT (OR 0.13, 95% CI 0.09-0.19, P<0.001) but not statistically significant for chemotherapy (OR 0.63, 95% CI 0.40-1.01, P=0.06). Notably, PFS (HR 3.56, 95% CI 2.53-5.01, P<0.001) and OS (HR 4.47, 95% CI 3.03-6.59, P<0.001) were worse in AR-V7-positive ttreated with NHT. Similarly, AR-V7 positivity correlated with poor prognosis after chemotherapy as evidenced by shorter OS (HR 1.98, 95% CI 1.48-2.66, P<0.001) and a significantly shorter PFS (HR 1.35, 95% CI 0.97-1.87, P=0.07)., Conclusion: NHT treatment increased AR-V7 positive proportion whereas chemotherapy decreased it. Moreover, AR-V7 positivity correlated with lower PSA response, poorer PFS, and OS in CRPC treated with NHT, and shorter OS in patients receiving chemotherapy., (Copyright © 2020 Wang, Shen, Ma, Li, Mao, Wang and Xie.)

Objective: This study aimed to investigate the associations between previous TORCH infection (cytomegalovirus, toxoplasmosis, herpes simplex virus, and rubella) with pregnancy and neonatal outcomes in couples undergoing IVF/ICSI-ET. Materials and Methods: A total of 18,074 couples underwent fresh IVF/ICSI-ET ( in vitro fertilization/intracytoplasmic sperm injection-embryo transfer) cycles were included in our analyses. TORCH infection status was determined by serological confirmation of cytomegalovirus, toxoplasmosis, herpes simplex virus, and rubella IgG in the absence of IgM antibodies. Clinical pregnancy, ectopic pregnancy, miscarriage, live birth, preterm birth, congenital malformation, and perinatal death were evaluated in both infection and non-infection group. Multivariate logistic regression was applied to calculate odds ratio. Results: Previous toxoplasmosis infection is associated with a significantly decreased preterm birth rate [ P = 0.045, OR = 0.755 (95% CI, 0.571-0.997), Adjusted OR = 0.749 (95%CI, 0.566-0.991)]. No differences in clinical pregnancy, ectopic pregnancy, miscarriage, and perinatal death were observed between the corresponding TORCH infection group [IgM (-) IgG(+)] and the non-infection group [IgM (-) IgG (-)]. Conclusions: Previous TORCH infections were not associated with adverse pregnancy and neonatal outcomes in IVF/ICSI-ET overall, and toxoplasmosis infection might be associated with a lower preterm birth rate in patients underwent IVF/ICSI-ET. The necessity of TORCH IgG screening in IVF procedure might need re-evaluation, and further cost-effective analysis might be helpful for the clinical management strategy., (Copyright © 2020 Liu, Wu, Wang, Wang, Zhao, Chen, Tu, Qian, Liao, Huang, Zhang, Xu and Zhang.)

Objective: To study whether melatonin treatment can increase clinical pregnancy rate and live birth rate in assisted reproductive technology (ART) cycles. Methods: Literature searches were conducted to retrieve randomized trials that reported the effect of melatonin treatment on ART outcomes. Databases searched included PubMed, EMBASE, Cochrane Library, Web of Science, and Google Scholar. Results: Ten studies matched the inclusion criteria. Clinical pregnancy was reported in all of the included studies and live birth was reported in three studies. Melatonin treatment significantly increased the clinical pregnancy rate [OR = 1.43 (1.11, 1.86), power = 0.98, 10 RCTs, low-quality evidence] but not the live birth rate [OR = 1.38 (0.78, 2.46), power = 0.34, 3 RCTs, low-quality evidence]. Melatonin treatment increased the number of oocyte collected [SMD = 0.34 (0.01, 0.67), 7 RCTs, low-quality evidence], the number of maturated oocyte [SMD = 0.56 (0.27, 0.85), 7 RCTs, low-quality evidence], and the number of good quality embryo [MD = 0.36 (0.18, 0.55), 3 RCTs, low-quality evidence]. Melatonin treatment significantly increased the biochemical pregnancy rate [OR = 1.65 (1.14, 2.38), 6 RCTs, low-quality evidence] and had no significant effect on the miscarriage rate [OR = 1.28 (0.65, 2.51), 5 RCTs, low-quality evidence]. Conclusion: Melatonin treatment significantly increases the clinical pregnancy rate but not live birth rate in ART cycles. Melatonin treatment also increases the number of oocyte collected, maturated oocyte, and good quality embryo. No clear evidence suggested that melatonin treatment increased the adverse events in ART cycles. The actual findings may be compromised due to the wide heterogeneity of the included IVF patients, from PCOS to low ovarian reserve., (Copyright © 2020 Hu, Ye, Wang and Zhang.)

Cryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3).