SARS-CoV-2 infection, vaccination and in vitro fertilization treatment: A prospective cohort study.

BACKGROUND: The impact of COVID-19 on reproductive health is controversial. The association between female SARS-CoV-2 infection and laboratory and pregnancy outcomes following subsequent in vitro fertilization (IVF) treatment remains unclear. This study aimed to investigate the relationship between IVF treatment at different time intervals after SARS-CoV-2 infection and reproductive outcomes. METHODS: A prospective cohort study of 920 IVF cycles post-SARS-CoV-2 infection was conducted. Modified Poisson regression and logistic regression models were utilized to evaluate oocyte- and embryo-related outcomes as well as clinical outcomes. Stratified analyses were also performed based on the vaccination status of the female participants. RESULTS: SARS-CoV-2 infection within three months was associated with reduced available [Adjusted RR (aRR): 0.96, 95 %CI: 0.91-1.00] and top-quality embryos (aRR: 0.90, 95 %CI: 0.83-0.98) in subsequent IVF treatment. Among patients failing to finish the three-dose vaccination, the interval between SARS-CoV-2 infection and cycle initiation of less than 90 days was associated with a lower number of oocytes retrieval (aRR: 8.81, 95 %CI: 8.24-9.41 vs aRR: 9.64, 95 %CI: 9.06-10.25), available embryos (aRR: 0.93, 95 %CI: 0.88-0.99), and top-quality embryos (aRR: 0.81, 95 %CI: 0.72-0.91) rather than among fully vaccinated women. Moreover, COVID-19 infection was not associated with biochemical pregnancy, clinical pregnancy, embryo implantation, and early abortion either in fresh embryo transfer (ET) or frozen ET. CONCLUSIONS: This study indicated that initiating IVF treatment within 90 days of SARS-CoV-2 infection might reduce the likelihood of obtaining available and top-quality embryos, especially among those who had not completed the three-dose vaccination. Nevertheless, female COVID-19 infection did not affect pregnancy or early abortion. Further rigorously designed studies are required to support these findings.

Fertility history and intentions of married women, China.

Objective: To estimate the proportion of married women in China who intend to become pregnant given the country's pronatalist population policy and to investigate fecundity, with an emphasis on the influence of socioeconomic factors. Methods: A nationally representative survey of 12 815 married women aged 20 to 49 years (mean: 36.8 years) was conducted during 2019 and 2020. All completed questionnaires, 10 115 gave blood samples and 11 710 underwent pelvic ultrasound examination. Fertility intention was the desire or intent to become pregnant combined with engagement in unprotected sexual intercourse. We defined infertility as the failure to achieve pregnancy after 12 months or more of unprotected intercourse. We considered an anti-Müllerian hormone level < 1.1 ng/mL and an antral follicular count < 7 as indicating an abnormal ovarian reserve. Findings: Fertility intentions were reported by 11.9% of women overall but by only 6.1% of current mothers (weighted percentages). Fertility intention was significantly less likely among women in metropolises (odds ratio, OR: 0.38; 95% confidence interval, CI: 0.31-0.45) and those with a higher educational level (OR: 0.74; 95% CI: 0.62-0.88). Overall, 18.0% had experienced infertility at any time and almost 30% had an abnormal ovarian reserve on assessment. An abnormal ovarian reserve and infertility were less likely in women in metropolises (P < 0.05) but more likely in obese women (P < 0.05). Conclusion: The willingness of Chinese married women to give birth remained low, even with relaxation of the one-child policy.

The impact of COVID-19 on the mental and sexual health of patients with infertility: a prospective before-and-after study.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has seriously impacted the mental and sexual health of the general population. Patients dealing with infertility constitute a unique subset within society, susceptible to heightened sensitivity amid pressures and crises. However, to the best of our knowledge, the impact of the different stages of the COVID-19 pandemic on the mental and sexual health of patients with infertility has not been investigated. Therefore, this study aimed to investigate the mental and sexual health of patients with infertility during different stages of the COVID-19 pandemic (during the lockdown, when controls were fully liberalized, and during the post-pandemic era). METHODS: This prospective before-and-after study was conducted between April and May 2022 (during the lockdown), December and January 2023 (when controls were fully liberalized), and May and August 2023 (during the post-pandemic era). This study explored the sexual and mental health of women with infertility during the three stages of the COVID-19 pandemic using standardized mental health and sexual function questionnaires. The Chi-square test was used to compare categorical data, and the ANOVA test was used to compare numerical data. RESULTS: Patients had the highest 7-item Generalized Anxiety Disorder Scale (GAD-7) and 9-item Patient Health Questionnaire (PHQ-9) scores and the highest rates of anxiety and depression during the immediate full-release phase. During the complete liberalization phase, patients had the lowest Female Sexual Function Index (FSFI) scores and the highest incidence of sexual dysfunction. CONCLUSION: This study is the first one to report the repercussions of COVID-19 on the mental and sexual well-being of individuals experiencing infertility across various phases of the pandemic. Upon the complete lifting of control measures, close to 99% of participants exhibited varying degrees of anxiety and depression. Our research underscores that individuals with infertility faced elevated levels of anxiety, depression, and sexual dysfunction during the phase of full liberalization of COVID-19 control measures, in stark contrast to the periods of lockdown and the post-pandemic era.

S100A8/A9 promotes endometrial fibrosis via regulating RAGE/JAK2/STAT3 signaling pathway.

Intrauterine adhesion (IUA) is characterized by endometrial fibrosis. S100A8/A9 plays an important role in inflammation and fibroblast activation. However, the role of S100A8/A9 in IUA remains unclear. In this study, we collect normal and IUA endometrium to verify the expression of S100A8/A9. Human endometrial stromal cells (hEnSCs) are isolated to evaluate fibrosis progression after S100A8/A9 treatment. A porcine IUA model is established by electrocautery injury to confirm the therapeutic effect of menstrual blood-derived stromal cells (MenSCs) on IUA. Our study reveals increased S100A8/A9 expression in IUA endometrium. S100A8/A9 significantly enhances hEnSCs proliferation and upregulates fibrosis-related and inflammation-associated markers. Furthermore, S100A8/A9 induces hEnSCs fibrosis through the RAGE-JAK2-STAT3 pathway. Transplantation of MenSCs in a porcine IUA model notably enhances angiogenesis, mitigates endometrial fibrosis and downregulates S100A8/A9 expression. In summary, S100A8/A9 induces hEnSCs fibrosis via the RAGE-JAK2-STAT3 pathway, and MenSCs exhibit marked effects on endometrial restoration in the porcine IUA model.

Effect of Paternal Body Mass Index on In Vitro Fertilization and Neonatal Outcomes among Oligozoospermia and Asthenospermia Patients.

PURPOSE: Male overweight and obesity could affect sperm quality and reproductive health. However, the impact of body mass index (BMI) on assisted reproductive technology (ART) outcomes in oligospermia and/or asthenospermia patients is yet lacking. This study aims to assess the impact of paternal BMI on ART and neonatal outcomes among oligozoospermia and/or asthenospermia patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: In this study, 2,075 couples undergoing their first fresh embryo transfer between January 2015 and June 2022 were recruited. Following the World Health Organization's (WHO's) categories, couples were stratified into three cohorts based on paternal BMI: normal weight (18.5-24.9 kg/m²), overweight (25.0-29.9 kg/m²), and obese (≥30.0 kg/m²). Modified Poisson regression models were used to assess the associations of paternal BMI with fertilization, in vitro embryonic development, and pregnancy outcomes. Logistic regression models were performed to investigate the associations of paternal BMI with pregnancy loss and neonatal outcomes. Furthermore, stratified analyses were performed based on fertilization methods, male infertility cause, and maternal BMI. RESULTS: Higher paternal BMI is associated with a lower likelihood of achieving normal fertilized (p-trend=0.002), Day 3 transferable (p-trend=0.007), and high-quality embryos (p-trend=0.046) in IVF cycles, rather than in ICSI cycles. Paternal BMI of oligospermia or asthenospermia was negatively correlated with day 3 transferable (p-trend=0.013 and 0.030) and high-quality embryos (p-trend=0.024 and 0.027). Moreover, for neonatal outcomes, paternal BMI was positively associated with macrosomia (p-trend=0.019), large for gestational age (LGA) (p-trend=0.031), and very LGA (p-trend=0.045). CONCLUSIONS: Our data suggested that higher paternal BMI was associated with fetal overgrowth, reduced fertilization, and embryonic development potential. Among males with oligospermia and/or asthenospermia, the impact of overweight and obesity on the choice of fertilization method and the long-term effects on their offspring need to be further investigated.

Exosomes derived from menstrual blood stromal cells ameliorated premature ovarian insufficiency and granulosa cell apoptosis by regulating SMAD3/AKT/MDM2/P53 pathway via delivery of thrombospondin-1.

Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells (MenSCs)-derived exosomes (EXOs) effectively improved ovarian functions in the POI rat model. In this study, we investigated whether TSP1 is the key component in EXOs to ameliorate ovarian functions and further explored the molecular mechanism of EXOs in improving granulosa cell (GCs) activities. Our results demonstrated that knockdown TSP1 significantly debilitated the therapeutic effect of EXOs on estrous cyclicity, ovarian morphology, follicle numbers and pregnancy outcomes in 4-vinylcyclohexene diepoxide (VCD) induced POI rat model. In addition, EXOs treatment significantly promoted the activities and inhibited the apoptosis of VCD induced granulosa cells in vitro. Moreover, EXOs stimulation markedly activated the phosphorylation of SMAD3(Ser425) and AKT(Ser473), up-regulated the expressions of BCL2 and MDM2 as well as down-regulated the expressions of CASPASE3, CASPASE8, P53 and BAX. All these effects were supressed by SIS3, a inhibitor of TGF1/SMAD3. Our study revealed the key role of TSP1 in EXOs in improving POI pathology, restoring ovarian functions and GCs activities, andprovided a promising basis for EXOs in the treatment of ovarian dysfunction.

P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination.

BACKGROUND: Intrauterine adhesion (IUA) is a recurrent and refractory reproductive dysfunction disorder for which menstrual blood-derived stromal cells (MenSCs) might be a promising intervention. We reported that administration of MenSCs-derived exosomes (MenSCs-EXO) could achieve similar therapeutic effects to MenSCs transplantation, including alleviating endometrial fibrosis and improving fertility in IUA rats. The mass spectrometry sequencing result suggested that UBR4, a member of the proteasome family, was abundantly enriched in MenSCs-EXO. This study aimed to investigate the key role of UBR4 in MenSCs-EXO for the treatment of IUA and the specific molecular mechanism. RESULTS: UBR4 was lowly expressed in the endometrial stromal cells (EndoSCs) of IUA patients. MenSCs-EXO treatment could restore the morphology of IUA endometrium, reduce the extent of fibrosis, and promote endometrial and vascular proliferation. Knockdown of UBR4 in MenSCs did not affect the characteristics of exosomes but attenuated the therapeutic effect of exosomes. UBR4 in MenSCs-EXO could alleviate endometrial fibrosis by boosting YAP ubiquitination degradation and promoting YAP nuclear-cytoplasmic translocation. Moreover, P65 could bind to the UBR4 promoter region to transcriptionally promote the expression level of UBR4 in MenSCs. CONCLUSION: Our study clarified that MenSCs-EXO ameliorated endometrial fibrosis in IUA primarily by affecting YAP activity mediated through UBR4, while inflammatory signaling P65 may affect UBR4 expression in MenSCs to enhance MenSCs-EXO therapeutic effects. This revealed a novel mechanism for the treatment of IUA with MenSCs-EXO, proposing a potential option for the clinical treatment of endometrial injury.

Therapeutic effect of menstrual blood stem cells in rats with thin endometrium. / æœˆç»è¡€å¹²ç»†èƒžå¯¹è–„åž‹å­å®«å† è†œå¤§é¼ çš„æ²»ç–—ä¿®å¤ä½œç”¨.

OBJECTIVES: To explore the therapeutic effect of transplantation of menstrual blood stem cells (MenSCs) in rats with thin endometrium. METHODS: Thirty SPF grade female SD rats aged 8-10 weeks were randomly divided into model control group and MenSC group, with 15 rats in each group. The thin endometrium injury model was prepared by chemical method in one side of the uterus of both groups. On the 7th day of modeling, normal saline or the third generation of MenSCs were injected into the model uterus at multiple points, and the other side of the uterus was used as an internal control without treatment. HE staining was used to observe the histological structure of endometrium; immunohistochemical staining was used to observe the expression of cyto-keratin (CK) 18 and vimentin in endometrial tissue; 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay was used to evaluate the cell proliferation in endometrial tissue; immunofluorescence staining was used to detect the expression of vascular endothelial marker CD34 and vascular endothelial growth factor (VEGF) in endometrial tissue; the expression of leukemia inhibitory factor (LIF), integrin ß3 (ITGß3) and homeobox A10 (HOXA10) in endometrial tissue was determined by realtime RT-PCR. After treatments, the female and male rats were caged in a ratio of 2∶1 to observe the effect of MenSC on the reproductive function of thin endometrium model rats. RESULTS: Compared with the surgical control group, the endometrium in the model control group was thinner, and the numbers of glands and blood vessels were less (all P<0.01). After MenSC transplantation, the thickness of endometrium, the numbers of blood vessels and glands were significantly increased (all P<0.01). The proliferative cells in the basal layer of endometrium in MenSC group were more than those in the model control group (P<0.05), and the expression of vimentin, CK18, CD34 and VEGF in the uterus of rats in MenSC group were significantly higher than those in the model control group (P<0.05). LIF, ITGß3 and HOXA10 gene expression levels were also significantly higher than those in the model control group (all P<0.05). The results of pregnancy experiment showed that the number of embryo implantation in MenSC group was higher than that in model control group (P<0.05). CONCLUSIONS: MenSC transplantation can promote the proliferation of endometrial cells, upregulate vimentin, CK18, CD34 and VEGF levels, and promote the recovery of endometrial morphology and function, thus improving the endometrial receptivity and fertility of the rats with thin endometrium.

Interaction of air pollution and meteorological factors on IVF outcomes: A multicenter study in China.

BACKGROUND: Previous studies revealed associations between air-pollutant exposure and in vitro fertilization (IVF) outcomes. However, modification effects of air pollution on IVF outcomes by meteorological conditions remain elusive. METHODS: This multicenter retrospective cohort study included 15,217 women from five northern Chinese cities during 2015-2020. Daily average concentrations of air pollutants (PM2.5, PM10, O3, NO2, SO2, and CO) and meteorological factors (temperature, relative humidity, wind speed, and sunshine duration) during different exposure windows were calculated as individual approximate exposure. Generalized estimating equations models and stratified analyses were conducted to assess the associations of air pollution and meteorological conditions with IVF outcomes and estimate potential interactions. RESULTS: Positive associations of wind speed and sunshine duration with pregnancy outcomes were detected. In addition, we observed that embryo transfer in spring and summer had a higher likelihood to achieve a live birth compared with winter. Exposure to PM2.5, SO2, and O3 was adversely correlated with pregnancy outcomes in fresh IVF cycles, and the associations were modified by air temperature, relative humidity, and wind speed. The inverse associations of PM2.5 and SO2 exposure with biochemical pregnancy were stronger at lower temperatures and humidity. Negative associations of PM2.5 with clinical pregnancy were only significant at lower temperatures and wind speeds. Moreover, the effects of O3 on live birth were enhanced by higher wind speed. CONCLUSIONS: Our results suggested that the associations between air-pollutant exposure and IVF outcomes were modified by meteorological conditions, especially temperature and wind speed. Women undergoing IVF treatment should be advised to reduce outdoor time when the air quality was poor, particularly at lower temperatures.

Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization: A Randomized Clinical Trial.

Importance: Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of implantation and pregnancy, although the evidence for efficacy is inadequate. Objective: To determine the efficacy of 10 mg of prednisone compared with placebo on live birth among women with recurrent implantation failure. Design, Setting, and Participants: A double-blind, placebo-controlled, randomized clinical trial conducted at 8 fertility centers in China. Eligible women who had a history of 2 or more unsuccessful embryo transfer cycles, were younger than 38 years when oocytes were retrieved, and were planning to undergo frozen-thawed embryo transfer with the availability of good-quality embryos were enrolled from November 2018 to August 2020 (final follow-up August 2021). Interventions: Participants were randomized (1:1) to receive oral pills containing either 10 mg of prednisone (n = 357) or matching placebo (n = 358) once daily, from the day at which they started endometrial preparation for frozen-thawed embryo transfer through early pregnancy. Main Outcomes and Measures: The primary outcome was live birth, defined as the delivery of any number of neonates born at 28 or more weeks' gestation with signs of life. Results: Among 715 women randomized (mean age, 32 years), 714 (99.9%) had data available on live birth outcomes and were included in the primary analysis. Live birth occurred among 37.8% of women (135 of 357) in the prednisone group vs 38.8% of women (139 of 358) in the placebo group (absolute difference, -1.0% [95% CI, -8.1% to 6.1%]; relative ratio [RR], 0.97 [95% CI, 0.81 to 1.17]; P = .78). The rates of biochemical pregnancy loss were 17.3% in the prednisone group and 9.9% in the placebo group (absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04). Of those in the prednisone group, preterm delivery occurred among 11.8% and of those in the placebo group, 5.5% of pregnancies (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). There were no statistically significant between-group differences in the rates of biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, other adverse events, or mean birthweights. Conclusions and Relevance: Among patients with recurrent implantation failure, treatment with prednisone did not improve live birth rate compared with placebo. Data suggested that the use of prednisone may increase the risk of preterm delivery and biochemical pregnancy loss. Our results challenge the value of prednisone use in clinical practice for the treatment of recurrent implantation failure. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800018783.

PDGFBB improved the biological function of menstrual blood-derived stromal cells and the anti-fibrotic properties of exosomes.

BACKGROUND: Intrauterine adhesion (IUA) is a reproductive dysfunction disease characterized by endometrial fibrosis, with limited therapeutic options and poor prognosis. Our previous studies confirmed that menstrual blood-derived stromal cells (MenSCs) effectively attenuated endometrial fibrosis in an animal model of IUA mainly through exosomes. This therapeutic effect can be enhanced by platelet-rich plasma (PRP), in which PDGFBB is an abundant growth factor. Therefore, we aimed to compare the effects of PRP and PDGFBB on the biological activities of MenSCs in vitro, and to further investigate the molecular mechanism of MenSCs-derived exosomes in alleviating endometrial fibrosis. METHODS: MenSCs were isolated for in vitro functional assays to examine the viability, migration, and stemness of MenSCs. Endometrial stromal cells (EndoSCs) were treated with 50 ug/ml of MenSCs-derived exosomes, obtained by differential ultracentrifugation extraction. The molecular mechanisms by which PDGFBB improves MenSCs and exosomes alleviate EndoSCs fibrosis were then explored using immunofluorescence, western blot, and co-immunoprecipitation. RESULTS: Both 100 ng/ml PDGFBB and 10% activated PRP promoted the proliferation, increased the S phase of cell cycle, and inhibited apoptosis of MenSCs in vitro. Compared with PRP, PDGFBB significantly promoted MenSCs migration. All of these effects were inhibited by sorafenib, a PDGFR-ß inhibitor. PRP and PDGFBB activated AKT/NF-κB signaling pathway in MenSCs and increased the expression of P65 and OCT4. Moreover, pretreatment of PDGFBB did not increase the secretion of MenSCs but significantly increased the anti-fibrosis effects of MenSCs-derived exosomes on IUA-EndoSCs. MenSCs-derived exosomes attenuated SMAD3 phosphorylation and increased YAP ubiquitination, which reduced the binding of YAP/SMAD3. Pretreatment with PDGFBB amplified this effect. CONCLUSIONS: In summary, PDGFBB could improve the biological functions of MenSCs via AKT/NF-κB signaling pathway, including viability, migration, and stemness. Our results indicated that PDGFBB amplified MenSCs-derived exosomes to attenuate endometrial fibrosis by inhibiting YAP activity, revealing a novel mechanism by which PRP enhanced the ability of MenSCs to repair tissue injury and providing a potential option for improving stem cell efficacy in IUA.

A Novel Three-Dimensional Follicle Culture System Decreases Oxidative Stress and Promotes the Prolonged Culture of Human Granulosa Cells.

Tissue engineering advancements have made it possible to modify biomaterials to reconstruct a similar three-dimensional structure of the extracellular matrix (ECM) for follicle development and to supply the required biological signals. We postulated that an artificial polysaccharide hydrogel modified with an ECM mimetic peptide may produce efficient irritation signals by binding to specific integrins providing a suitable environment for follicular development and influencing the behavior of human granulosa cells (hGCs). Laminin, an important component of the extracellular matrix, can modulate hGCs and oocyte growth. Specifically, follicles of mice were randomly divided into two-dimensional (2D) and three-dimensional (3D) culture systems established by a hydrogel modified with RGD or laminin mimetic peptides (IKVAV and YIGSR) and RGD (IYR). Our results showed that 3D cultured systems significantly improved follicle survival, growth, and viability. IYR peptides enhanced the oocyte meiosis competence. Additionally, we explored the effect of 3D culture on hGCs, which improved hGCs viability, increased the proportion of S- and G2/M-phase cells, and inhibited cell apoptosis of hGCs. On days 1 and 2, the secretion of progesterone was reduced in 3D-cultured hGCs. Notably, 3D-cultured hGCs exhibited delayed senescence, decreased oxidative stress, and elevated mitochondrial membrane potential. Moreover, the expression levels of cumulus expansion-related genes (COX2, HAS2, and PTX3) and integrin α6ß1 were upregulated in 3D-cultured hGCs. In conclusion, a 3D culture utilizing hydrogels modified with Laminin-mimetic peptides can provide a durable physical environment suitable for follicular development. The laminin-mimetic peptides may regulate the biological activity of hGCs by attaching to the integrin α6ß1.

Amniotic membrane extract-enriched hydrogel augments the therapeutic effect of menstrual blood-derived stromal cells in a rat model of intrauterine adhesion.

We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) is a safe and effective therapy for treating intrauterine adhesions (IUA). However, improving the colonization and therapeutic efficiency of MenSCs is still needed before full clinical application. Here, we established an amniotic membrane extract (AME)-enriched RGD hydrogel, and evaluated the therapeutic effect of this adjuvant combined with MenSCs transplantation in an IUA rat model. Our results indicated that AME promoted the proliferation and secretion of MenSCs in vitro, up-regulated the expression of apoptosis-suppressing gene BCL2 and down-regulated the expression of apoptosis-related genes Caspase-3 and Caspase-8. The AME-enriched hydrogel was biocompatible, and improved the survival of MenSCs in vitro and in vivo. It also promoted the retention of MenSCs in IUA uterus and augmented the effects of MenSCs on improving uterus morphology, endometrial proliferation, endometrial receptivity and fibrosis suppression. In addition, co-transplantation of MenSCs with AME-enriched hydrogel markedly down-regulated the expressions of inflammation-related genes IL10 and TGFß while up-regulated the IL4/IFN-γ ratio in the IUA endometrium, and improved the expressions of cell proliferation-related antigen, gland-regeneration-related marker leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), angiogenesis-related marker platelet and endothelial cell adhesion molecule 1 (PECAM1), endometrial receptivity related genes ITGα5 and ITGß3. Our study suggested that AME and MenSCs had a synergistic effect. Co-transplantation of MenSCs with AME-enriched hydrogel provided a promising approach for stem cell-based IUA treatment.

Estimates of global research productivity in primary ovarian insufficiency from 2000 to 2021: Bibliometric analysis.

Background: Primary ovarian insufficiency (POI) is a heterogeneous disease with diverse clinical phenotypes and etiologies, which is defined as ovarian dysfunction under the age of 40 years. The global prevalence of POI is approximately about 1.1%, and it severely affects female fertility. Nevertheless, bibliometric analysis in this field is extremely limited. We aimed to visualize the research hotspots and trends of POI using bibliometric analysis and tried to predict the future development of this field. Methods: The original articles regarding POI were culled from the Web of Science Core Collection. Countries, institutions, journals, authors, and keywords in this field were visually analyzed by employing CiteSpace software and Microsoft Excel 2021 software. Results: A total of 2,999 publications were included for further bibliometric analysis after screening the titles and abstracts stringently. The number of literature regarding POI significantly increased yearly. These publications come from 78 countries. The USA was dominant in the field of POI in terms of the number of publications (865), average citations per item (57.36), and h-index (112). The Institut National De La Sante Et De La Recherche Medicale Inserm is the most high-yield institution in this field with 351 publications. Fertility and Sterility ranked first with the highest number of publications (152), followed by Human Reproduction (138). According to the keyword cluster analysis from 2000 to 2021, the eight keyword clusters encountered frequently were apoptosis, osteoporosis, fertility preservation, mutation, fragile x syndrome, adrenal insufficiency, DNA repair, ovarian reserve. Keyword citation burst analysis revealed that whole-exome sequencing, ovarian tissue cryopreservation, and DNA repair had a citation burst until 2021. Conclusions: Great progress has been made in POI research over the past 20 years, which is widely researched but unevenly developed in the world. In terms of influence, the United States may be in the lead. The research hotspots in POI are mainly pathogenesis and treatment, including genetic mutation, hormone therapy, fertility preservation, and stem cell transplantation.

Comparative clinical outcome following individualized follitropin delta dosing in Chinese women undergoing ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection.

BACKGROUND: To compare the efficacy and safety of follitropin delta in its individualized fixed-dose regimen with follitropin alfa in a conventional adjustable dosing regimen in Chinese women.  METHODS: This was a subgroup analysis of the randomized, multi-center, assessor-blind, non-inferiority trial (GRAPE) including 759 Chinese women (aged 20-40 years) recruited in 16 reproductive medicine clinics in China. Women were randomized in a 1:1 ratio to be treated with either follitropin delta dose based on anti-Müllerian hormone (AMH) and body weight or conventional dosing with follitropin alfa following a gonadotropin-releasing hormone (GnRH) antagonist protocol. The primary outcome was ongoing pregnancy rate assessed 10-11 weeks after embryo transfer in the fresh cycle (non-inferiority margin -10.0%). RESULTS: 378 in the follitropin delta group and 381 in the follitropin alfa group were randomized and exposed. Non-inferiority was confirmed with respect to ongoing pregnancy with rates of 31.0% vs. 25.7% for follitropin delta compared to follitropin alfa, estimated mean difference of 5.1% (95% confidence interval (CI) -1.3% to 11.5%). The clinical pregnancy rate (35.4% vs. 31.5%, P = 0.239) and live birth rate (31.0% vs. 25.5%, P = 0.101) were comparable between the follitropin delta group and the follitropin alfa group. Overall, the individualized follitropin delta treatment resulted in fewer oocytes retrieved compared to follitropin alfa treatment (10.3 ± 6.2 vs. 12.5 ± 7.5, P < 0.001), which was mainly due to fewer oocytes (10.5 ± 6.4 vs. 13.9 ± 7.8) in women with AMH ≥ 15 pmol/L. Accordingly there was a lower incidence of early ovarian hyper-stimulation syndrome (OHSS) and/or preventive interventions (6.1% vs. 11.0%, P = 0.013). A daily follitropin delta dose of 10.2 µg (95% CI: 9.3-11.2 µg) was estimated to provide the same number of oocytes retrieved as a starting dose of 150 IU/d of follitropin alfa. CONCLUSION: Follitropin delta in its individualized fixed-dose regimen showed similar efficacy and improved safety compared with follitropin alfa in a conventional adjustable dosing regimen in Chinese women. CLINICAL TRIAL REGISTRATION NUMBER: NCT03296527.

A bibliometric analysis of global research on vitamin D and reproductive health between 2012 and 2021: Learning from the past, planning for the future.

Background: Vitamin D plays an invaluable role in reproductive health, but vitamin D insufficiency and deficiency are generally common among couples of childbearing age and pregnant women. This study aimed to evaluate the evolution, development trend, and research hotspot of publications on vitamin D and reproductive health. Methods: The literature on vitamin D and reproductive health between 2012 and 2021 was retrieved from the Web of Science Core Collection (WoSCC). We used VOSviewer and CiteSpace to analyze publication years, countries, institutions, journals, highly cited authors and publications, and co-occurrence and citation bursts of keywords. Results: A total of 1,828 articles and reviews on vitamin D and reproductive health published between 2012 and 2021 were identified. The annual publication outputs showed steady growth, with the most publications (272) and citations (7,097) in 2021. The United States contributed the most publications (458) and had the highest h-index (58). In terms of the number of publications and h-index, the journal named Nutrients ranked first. Nutrition dietetics, obstetrics gynecology, and endocrinology metabolism were three well-represented disciplines in research on vitamin D and reproductive health. Hollis BW, Wagner CL, and Litonjua AA were the top three most productive authors in this field during the last decade. Apart from vitamin D, the five keywords with the most frequent occurrence were vitamin D deficiency, pregnancy, risk, vitamin D supplementation, and 25-hydroxyvitamin D. Keyword citation burst analysis revealed that low birth weight, adipose tissue, marker, and embryo had a citation burst lasting until 2021. Conclusion: In conclusion, vitamin D has received continuous attention in the field of reproductive health, and there appears to have a higher level of research in North America. Multidisciplinary intersection contributed to the in-depth exploration in this field. And the effect of maternal vitamin D levels on fetal lipid metabolism and the prediction of fertility by vitamin D-related markers might be hotspots for the research.

Automatic evaluation of endometrial receptivity in three-dimensional transvaginal ultrasound images based on 3D U-Net segmentation.

Background: Endometrial thickness is an essential factor affecting female fertility. Clinically, ultrasound imaging is the first choice for the examination of uterine and endometrial-related diseases. However, the boundary of some endometrial is challenging to distinguish due to the effects of image resolution and noise. In addition, the irregular shape of the endometrium makes it more difficult for doctors to measure its thickness. Through the automatic segmentation and extraction of the endometrium, the maximum thickness of the endometrium can be measured automatically and accurately. This provides a quantitative index for doctors to use diagnostically. Methods: In this study, 85 cases of three-dimensional transvaginal ultrasound (3D TVUS) images were collected retrospectively, including 75 cases of endometrial adhesion and 10 cases of non-adhesion. Firstly, the ultrasound images were filtered by block-matching and 3D filtering and speckle reducing anisotropic diffusion (SRAD). These two kinds of filtered images were combined with the original image to construct a three-channel image. Then, the augmented images were sent to 3D U-Net to realize endometrium segmentation. The performance of the segmentation models was evaluated using the Dice similarity coefficient (DSC), Jaccard, sensitivity, and 95th percentile Hausdorff distance (HD95). Finally, the medial axis transform was used to extract the endometrial centerline, based on which the endometrial thickness could be automatically measured. Results: The endometrium segmentation method proposed in this paper achieved 90.83% in Dice, 83.35% in Jaccard, 90.85% in sensitivity, and 12.75 mm in HD95 in the testing set. Taking the doctor's manual measurement as the gold standard, 94.20% of the automatic endometrial thickness measurements based on the segmentation results were within the allowable error range of clinical diagnosis. Conclusions: This paper presents an automatic endometrium segmentation and thickness measurement method for 3D TVUS images. The experimental results show that this method has high segmentation accuracy to recognize endometrial adhesion images. Furthermore, the thickness measurement based on the segmentation results has high reliability and repeatability, and the accuracy can meet clinical diagnosis needs.

Age-specific random day serum antimüllerian hormone reference values for women of reproductive age in the general population: a large Chinese nationwide population-based survey.

BACKGROUND: Antimüllerian hormone, the most reliable biomarker of ovarian reserve, is widely used in various clinical situations. Antimüllerian hormone levels consistently decrease with age. However, there is no standard, age-specific reference values for antimüllerian hormone in women of reproductive age, which limits its application. OBJECTIVE: This study aimed to establish age-specific antimüllerian hormone percentile reference values for women of reproductive age. STUDY DESIGN: A nationwide, population-based cross-sectional survey was conducted between May 2019 and April 2021 in 15 provinces and municipalities in mainland China. A total of 10,053 eligible women aged 20 to 49 years were selected using a multistage stratified sampling procedure. Women who were pregnant, had undergone ovarian surgery, took hormone drugs in the past 3 months, or had an antimüllerian hormone outlier value were excluded from establishing antimüllerian hormone percentile reference values. Serum antimüllerian hormone concentrations were measured using ultrasensitive, 2-site enzyme-linked immunosorbent assays (Ansh Lab, Webster, TX) in the Reproductive Endocrinology Laboratory of Peking University Third Hospital. Generalized additive models for location scale and shape with the Box-Cox t original distribution were used to estimate the fitted antimüllerian hormone percentile reference values. RESULTS: A total of 9112 eligible women aged 21 to 49 years were included in the fitting model. The fitted 50th (2.5th-97.5th) percentiles of antimüllerian hormone values for women aged 21, 25, 30, 35, 40, 45, and 49 years were 4.83 (0.79-18.41), 4.47 (0.72-16.58), 3.67 (0.50-13.82), 2.59 (0.24-10.35), 1.35 (0.05-6.68), 0.33 (<0.01 to 3.40), and 0.04 (<0.01 to 1.77) ng/mL, respectively. The population-based decline rate of antimüllerian hormone accelerated with increasing age, especially age >35 years. The magnitude of the decline of the 25th antimüllerian hormone percentile curve was greater than that of the 75th percentile curve. CONCLUSION: This study established age-specific antimüllerian hormone percentile reference values for women of reproductive age based on a large representative sample of the general population and described antimüllerian hormone changes. These findings may facilitate antimüllerian hormone application in clinical practices.

Association Between the Ratio of Ovarian Stimulation Duration to Original Follicular Phase Length and In Vitro Fertilization Outcomes: A Novel Index to Optimise Clinical Trigger Time.

The duration of ovarian stimulation which is largely dependent on the ovarian response to hormonal stimulation may influence in vitro fertilization (IVF) outcomes. Menstrual cycle length is potentially a good indicator of ovarian reserve and can predict ovarian response. Ovarian stimulation and the follicular phase of the menstrual cycle are both processes of follicular development. There is no published research to predict the duration of ovarian stimulation based on the length of the menstrual cycle. Our retrospective cohort study included 6110 women with regular menstrual cycles who underwent their first IVF treatment between January 2015 and October 2020. Cycles were classified according to quartiles of the ratio of ovarian stimulation duration to original follicular phase length (OS/FP). Multivariate generalized linear models were applied to assess the association between OS/FP and IVF outcomes. The odds ratio (OR) or relative risk (RR) was estimated for each quartile with the lowest quartile as the comparison group. OS/FP of 0.67 to 0.77 had more retrieved and mature oocytes (adjusted RR 1.11, 95% confidence interval [CI] 1.07-1.15, p for trend = 0.001; adjusted RR 1.14, 95% CI 1.09-1.19, p for trend = 0.001). OS/FP of 0.67 to 0.77 showed the highest rate of fertilization (adjusted OR 1.11, 95% CI 1.05-1.17, p for trend = 0.001). OS/FP > 0.77 had the lowest rate of high-quality blastocyst formation (adjusted OR 0.81, 95% CI 0.71-0.93, p for trend = 0.01). No apparent association was noted between OS/FP and clinical pregnancy, live birth, or early miscarriage rate. In conclusion, OS/FP has a significant effect on the number of oocytes, fertilization rate, and high-quality blastocyst formation rate. MCL could be used to predict the duration of ovarian stimulation with an OS/FP of 0.67 to 0.77, which provides a new indicator for the individualized clinical optimization of the trigger time.