Impact of sexual intercourse on frozen-thawed embryo transfer outcomes: a randomized controlled trial.

BACKGROUND: Exposure of the female reproductive tract to either seminal plasma or fluid component of the ejaculate is beneficial to achieving successful embryo implantation and normal embryo development. But whether the "physical" component of sexual intercourse during the peri-transfer period have any influence on frozen-thawed embryo transfer (FET) pregnancy outcomes is not clear. METHODS: We conducted a randomized trial that included 223 patients undergoing in vitro fertilization (IVF) treatment at a university-affiliated reproductive center from 19 July 2018 to 24 February 2019. Enrolled patients undergoing IVF treatment were randomized either to engage sexual intercourse using the barrier contraception (Group A, n = 116) or to abstain (Group B, n = 107) one night before FET. The primary outcome was clinical pregnancy rate. RESULTS: Patients having intercourse had higher clinical pregnancy rate (51.72% vs. 37.07%, P = 0.045) and implantation rate (38.31% vs. 24.77%, P = 0.005) compared to those did not engage intercourse. However, there was no significant difference of the spontaneous abortion rate between two groups (11.67% 33 vs. 14.63%, P = 0.662). CONCLUSIONS: Sexual intercourse before embryo transfer may improve the clinical pregnancy and implantation rates during FET cycles. However, it should be noted that patients choose only one time for sexual intercourse, that is, the night before embryo transfer. TRIAL REGISTRATION: The present study was registered at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ , ChiCTR1800017209).

Association of urinary bisphenol A concentrations with in vitro fertilisation outcomes: a systematic review and meta-analysis protocol.

INTRODUCTION: Bisphenol A (BPA) is a common environmental endocrine disruptor. BPA has been reported to be associated with female infertility, which may not only affect natural pregnancy and natural fertility but also affect the outcomes of in vitro fertilisation (IVF). BPA exposure may help to partly explain the unsatisfactory IVF outcomes, but the relationship between the concentrations of BPA in urine and IVF outcomes remains controversial. Therefore, we will perform a meta-analysis to identify and review the relationship between urinary BPA concentrations and IVF outcomes. METHODS AND ANALYSIS: A comprehensive literature search will be performed in PubMed, Web of Science and the Cochrane central register of controlled trials for relevant articles using MeSH terms and related entry terms (up to 20 April 2022). The language will be restricted to English. Articles will be screened for inclusion in or exclusion from the study independently by two reviewers after removing the duplicates. The titles and abstracts followed by full-text screening will also be conducted independently by two reviewers. In addition, the references of the included literature will also be traced to supplement our search results and to obtain all relevant literature. The Newcastle-Ottawa Scale will be used to assess the methodological quality of the included studies using a star rating system ranging from 0 to 9 stars. Heterogeneity in estimates from different articles will be quantified, and publication bias will be investigated using funnel plots. Finally, a sensitivity analysis will also be conducted to estimate whether our results could have been markedly affected by a single included study. ETHICS AND DISSEMINATION: Ethical approval is not required for this protocol, as participants are not included. Findings will be disseminated through peer-reviewed publications and conference presentations.

Association of IL-4 and IL-10 Polymorphisms With Preterm Birth Susceptibility: A Systematic Review and Meta-Analysis.

Objective: Preterm birth (PTB) is a typical inflammatory disease with unclear pathogenesis. The studies investigating the relationship between anti-inflammatory factors IL-4 and IL-10 gene polymorphisms and PTB produced conflicting results. This systematic review and meta-analysis aimed to summarize the effects of IL-4 and IL-10 gene polymorphisms and clarify their possible association with PTB. Methods: A systematic literature review was conducted using PubMed, Web of Science, and Cochrane library (up to 02 April 2022). The MeSH terms, related entry terms, and other names in "Gene" database were used to find relevant articles. A fixed- or random-effects model was used to calculate the significance of IL-4 and IL-10 gene polymorphisms, depending on study heterogeneity. The odds ratios (OR) and 95% confidence intervals (CIs) were calculated in the allele, recessive, dominant, co-dominant, and over-dominant models. The Eggers publication bias plot was used to graphically represent the publication bias. Results: Polymorphisms in two interleukins (IL-4-590C/T (rs2243250) = 5 and IL-10-592A/C (rs1800872), -819T/C (rs1800871) and -1082A/G (rs1800896) = 16) were found in 21 articles. Overall, only the over-dominant gene model AA + GG vs. AG revealed significant association between IL-10-1082A/G (rs1800896) and PTB (OR [95% CI] = 0.87 [0.76, 0.99], p = 0.04). However, in the allele model, recessive model, dominant model, co-dominant model, and over-dominant model, the polymorphisms for IL-4-590C/T (rs2243250), IL-10-592A/C (rs1800872), and IL-10-819T/C (rs1800871) were not found to be associated with the risk of PTB. In gene models, no statistically significant association was found between IL-4-590C/T (rs2243250), IL-10-592A/C (rs1800872), IL-10-819T/C (rs1800871), and IL-10-1082A/G (rs1800896) polymorphisms and PTB in subgroup analyses by racial or control group Hardy-Weinberg Equilibrium (HWE) p-value. Eggers's publication bias plot and heterogeneity test (I2<50%, p = 0.05) of IL-10-1082A/G (rs1800896) suggested that the funnel asymmetry could be due to publication bias rather than heterogeneity. Conclusion: The current study suggests that the over-dominant gene model AA + GG vs. AG of IL-10-1082A/G (rs1800896) polymorphism may be associated with genetic susceptibility to PTB and may have a protective function against PTB risk. There was unclear association found between IL-4-590C/T (rs2243250), IL-10-592A/C (rs1800872) and IL-10-819T/C (rs1800871) polymorphisms and PTB. Due to the limitations of included studies and the risk of publication bias, additional research is required to confirm our findings. Systematic Review Registration: https://inplasy.com/inplasy-2022-4-0044, identifier INPLASY202240044.

Quantitative label-free proteomic analysis of human follicle fluid to identify novel candidate protein biomarker for endometriosis-associated infertility.

BACKGROUND: Endometriosis (EM) leads to a decline in fertility, which is characterized by a decrease in the number and quality of follicles, and thus has a negative impact on in vitro fertilization (IVF) outcomes. However, the mechanism of how EM affects oocytes and leads to infertility remains unclear. As a potentially available sample directly related to oocyte growth, follicular fluid (FF) has important research value. Evaluating the association of FF content and EM-associated infertility through proteomics may helpful to explore the possible pathogenesis of EM-associated infertility. METHODS: In the present experimental study, from August 2019 to June 2020, FF samples were obtained as control group (CON-G; n = 10) from women with no one female factor of infertility and were undergoing IVF due to other reasons, 20 women with EM-associated infertility undergoing IVF with no other female factors were distributed into the EM group according to the time for IVF: (i) EM-group 1 (EM-G1, Stage I to Stage III, n = 10); (ii) EM-group 2 (EM-G2, Stage I to Stage III, n = 10). label-free quantitative proteomics (LFQP) technology and parallel reaction monitoring (PRM) approach were combined to aid in identifying and validating FF protein biomarkers for EM-associated infertility. In PRM analysis, another 20 subjects were enrolled as EM-associated infertility group (EM,Stage I to Stage III, n = 10) and controls (CON, n = 10) within the same time and inclusion criteria are the same as previously described. Finally, a potential protein biomarker panel of FF differential expressed proteins to EM-associated infertility was also evaluated by t-test and receiver operating characteristic (ROC) curve and binary Logistic regression models. RESULTS: 7 significant differential expressed proteins which closely related to EM-associated infertility were found by LFQP technology, among which immunoglobulin lambda variable 7-46 (IGLV7-46), Immunoglobulin heavy constant gamma 2 (IGHG2), glia-derived nexin (GDN) and Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) were significantly up-regulated (p < 0.05), while corticosteroid-binding globulin (CBG), angiotensinogen (AGT) and Fetuin-B (FETUB) were significantly down regulated (p < 0.05). Additionally, GDN and AGT was identified as a potential protein biomarker by further PRM analysis for EM-associated infertility according to ROC curve analysis and t-test (p < 0.05), the area under the curve (AUC) for GDN and AGT was 0.78 and 0.69 with optimum sensitivity of 50%, 70% and specificity of 100%, 90%, respectively. According to binary logistic regression and evaluated ROC analysis, the AUC for the combination of GDN and AGT was 0.80. CONCLUSIONS: To the best of our knowledge, this is the first time that elevated GDN protein levels have been found in the FF of patients with EM-associated infertility. Combining LFQP technology and PRM method we found the abnormal of GDN and AGT in FF may be the potential cause of EM-associated infertility which may help to better understand the physiological and pathological mechanism of EM-associated infertility. Further experimental studies are required to confirm their mechanism in EM-associated infertility. The results of this study are also consistent with the previous conclusion that EM is a chronic inflammatory disease. SIGNIFICANCE: To the best of our knowledge, this is the first time that elevated GDN protein levels have been found in the follicular fluid of patients with EM-associated infertility. Combining LFQP technology and PRM methods we found the abnormal of GDN and AGT protein in FF may be the potential cause of EM-associated infertility which may help to better understand the physiological and pathological mechanism of EM-associated infertility. Clinically, it has been recognized that EM is related to infertility, but the mechanism remains unclear. Our study combines label-free quantitative proteomics technology and parallel reaction monitoring methods to identify and verify the FF protein biomarkers of EM-associated infertility, which provides a good research method for follow-up research.

Study protocol: a multi-center, double-blind, randomized, 6-month, placebo-controlled trial to investigate the effect of supplementing hormone therapy FET cycles with Gushen'antai pills on the outcomes of in vitro fertilization.

BACKGROUND: Infertility is a widespread global challenge. Currently, the most effective treatment strategy for infertility is in vitro fertilization (IVF), which is an assisted reproductive technique (ART). The use of IVF for assisted pregnancy dates back to the last 41 years when the first IVF baby was born. During IVF, many oocytes are obtained in an IVF cycle, and more than one embryo is formed. Subsequently, frozen-thawed embryo transfer (FET) is increasingly being used in IVF cycles for women in whom a fresh embryo transfer fails to result in a pregnancy, or in those who return for a second baby. However, the pregnancy success rates following FET treatment cycles are reportedly lower than in fresh embryo transfers. Therefore, recent related studies are increasing determining mechanisms of improving the sustained pregnancy rate of FET and reducing the rate of early abortion. The Gushen'antai pill (GSATP), which contains a mixture of 10 herbs, has been widely used in traditional Chinese medicine (TCM) as a pharmacological option to prevent miscarriage. However, randomized controlled trials (RCT) have never been conducted to provide high-level clinical evidence on the clinical efficacy of GSATP. The objective of this study is to investigate the effect of GSATP of hormone therapy (HT) FET cycles on pregnancy rate. METHODS: A total of 300 subjects aged between 18 and 40 years which prepared for HT cycle FET will be enrolled in the study. The patients were from five different hospitals, with 60 patients from each hospital. Patients were randomly divided into two groups, and medication was started on the day of endometrial transformation. After FET 28 days, B-ultrasound was done to determine whether to continue the medication. Baseline assessments were carried out before the trial and outcomes were collected 4, 6, 8, 10, and 12 weeks of each gestational cycle. DISCUSSION: Differences in ongoing pregnancy rate, clinical pregnancy rate, implantation rate, and threatened abortion rate between the two groups will be statistically analyzed. We can finally have an objective evaluation of the efficacy of the traditional Chinese medicine Gushen'antai pills. TRIAL REGISTRATION: ChiCTR1900026737 . Registered October 20, 2019.

The Role of Traditional Chinese Formula Ding-Kun Pill (DKP) in Expected Poor Ovarian Response Women (POSEIDON Group 4) Undergoing In Vitro Fertilization-Embryo Transfer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: The primary objective of the study was to assess traditional Chinese formula DKP supplementation in terms of efficacy and safety on reproductive outcomes of expected poor ovarian responder (POR, POSEIDON Group 4) undergoing in vitro fertilization-embryo transfer (IVF-ET). Design Setting and Participants: Women eligible for IVF-ET were invited to participate in this randomized, double-blind, placebo-controlled, superiority trial at academic fertility centers of ten public hospitals in Chinese Mainland. A total of 462 patients (35-44 years) equally divided between DKP and placebo groups with antral follicle count (AFC) <5 or anti-müllerian hormone (AMH) <1.2 ng/ml were randomized. Interventions: All participants were given DKP or 7 g placebo twice daily on the previous menstrual cycle day 5 until oocyte retrieval, which took approximately 5 to 6 weeks. Main Outcome Measure: The primary outcome was the ongoing pregnancy defined as more than 20 gestational weeks of an intrauterine living fetus confirmed by pelvic ultrasonography. Results: Demographic characteristics were equally distributed between the study populations. Intention-to-treat (ITT) analysis revealed that ongoing pregnancy rate (OPR) was not significantly different between DKP and placebo groups [26.4% (61/231) versus 24.2% (56/231); relative risk (RR) 1.09, 95% confidence interval (CI) 0.80 to 1.49, P = 0.593]. No significant differences between groups were observed for the secondary outcomes. The additional per protocol (PP) analysis was in line with ITT results: OPR in DKP group was 27.2% (61/224) versus 24.1% (55/228) in placebo group [RR 1.13, 95%CI (0.82 to 1.55), P = 0.449]. After subgroup analysis the findings concluded that POR population of 35-37 years had a significantly higher OPR after 5-6 weeks of oral DKP (41.8%, 33/79) versus placebo (25.4%, 18/71) [RR 1.65, 95% CI (1.02 to 2.65), P = 0.034, P for interaction = 0.028]. Conclusion: This well-designed randomized controlled trial (RCT) offers new high-quality evidence to supplement existing retrospective literature concerning DKP performance in expected PORs. DKP could be recommended as a safe and natural remedy for expected PORs (aged 35-37 years) who fulfill the POSEIDON group 4 criteria. However, additional interventional clinical studies are undoubtedly required to be conducted in the future to validate this hypothesis. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR1900026614.

Association of Interleukin-6-174G/C Polymorphism With Ischemic Stroke: An Updated Meta-Analysis.

Background: Although numerous epidemiological studies have investigated the association between -174G/C(rs1800795) polymorphism in the interleukin-6 (IL-6) gene-stimulatory region and the risk of ischemic stroke (IS), they failed to reach a unified conclusion. The true relationship between -174G/C(rs1800795) polymorphism and IS remains controversial and unclear. Therefore, in this meta-analysis, we aimed to analyze more precisely the association between -174G/C(rs1800795) single-nucleotide polymorphism (SNP) of IL-6 gene and IS in a larger pooled population. Methods: A comprehensive literature search was performed in PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials until June 30, 2021. A fixed or random-effects model was utilized based on heterogeneity between studies. The odds ratios (ORs) and 95% confidence intervals (Cis) were calculated in the models of allele comparison (G vs. C), homozygote comparison (GG vs. CC) and (GC vs. CC), dominant (GG vs. GC + CC), hyper dominant (GG + CC vs. GC), and recessive (GG + GC vs. CC) to determine the strength of associations. Results: This meta-analysis included 13 case-control studies in 35 articles with 5,548 individuals. Overall, no significant associations between IL-6 -174G/C(rs1800795) and IS were identified (G vs. C:OR [95% CI] = 0.99 [0.81, 1.21], P = 0.91; GG + CC vs. GC:0.97 [0.85, 1.11], P = 0.66; GG vs. GC + CC: 1.01 [0.81, 1.25], P = 0.94; GC vs. CC: OR [95% CI] = 1.01 [0.68, 1.5], P = 0.96; GG vs. CC:0.93 [0.57, 1.51], P = 0.76; GG + GC vs. CC:0.97 [0.64, 1.47], P = 0.89). In the subgroup analyses by ethnicity or HWE P-value, there was a statistically significant association between IL-6 -174G/C(rs1800795) polymorphisms and IS in the alleles model; (G vs. C: LogOR [95% CI] = 0.14 [-0.16,.45], P = 0.00), homozygote model (GG vs. CC: LogOR [95% CI] = 0.18 [-0.58,.95], P = 0.00) and (GC vs. CC: LogOR [95% CI] = 0.2 [-0.46,.85], P = 0.00), dominant model (GG vs. GC + CC: OR [95% CI] = 0.02 [-0.72, 0.77], P = 0.00), and recessive model (GG + GC vs. CC: OR [95% CI]= -0.17 [-0.86,.52], P = 0.00) of the European population and in the dominant model (GG vs. GC + CC: OR [95% CI] = -0.13 [-0.51, 0.24]) of the Asian population. No statistical significance was identified in both six models of HWE p ≥ 0.2 group (both P ≥ 0.05). Conclusion: This meta-analysis revealed no correlation between IL-6 -174G/C(rs1800795) polymorphism and IS, whereas the subgroup analysis indicated that the relationship between IL-6 -174G/C(rs1800795) polymorphism and IS susceptibility varied significantly according to ethnicity and geography.

Effects of a Chinese Patent Medicine Gushen'antai Pills on Ongoing Pregnancy Rate of Hormone Therapy FET Cycles: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

In the past decade, the number of frozen-thawed embryo transfer (FET) has increased dramatically with the expansion of surgical indications and the improvement of freezing related technologies. How to improve the success rate and reduce the adverse effects of FET is our research priorities. This study aimed to investigate the safety and effectiveness of Gushen'antai pills (GSATP) by measuring the ongoing pregnancy rate (OPR) in patients from FET and hormone therapy (HT) cycle. From November 2019 to May 2020, 5 Chinese hospitals conducted a multi-center, randomized, double-blind, placebo-controlled study. In total, 271 HT FET cycles in patients were randomly divided (1:1 ratio) to receive GSATP (6 g, tid) or placebo (6g, tid) for 12 weeks of pregnancy. Patients, clinicians, and researchers were blinded to treatment allocation. The primary endpoint was the OPR at week 12 of pregnancy. The secondary endpoints were vaginal bleeding or brown discharge rate, implantation rate (IR), clinical pregnancy rate (CPR) and abortion rate (AR). Adverse events were recorded during the treatment period. The results showed that the OPR remained higher in the GSATP group when compared to placebo group (56.62% vs. 44.44%, p = 0.045). Vaginal bleeding or brown discharge rate was lower in the GSATP group than the placebo group (10% vs. 23.08%, p = 0.032), while the IR (35.16% vs. 27.64%, p = 0.070), CPR (58.82% vs. 48.15%, p = 0.078), incidence of total adverse events (8.09% vs. 3.22%, p = 0.051) and AR (3.75% vs. 7.69%, p = 0.504) were similar between GSATP and placebo groups. Subgroup analysis showed that there were significant differences in CPR (74.19% vs. 54.17%, p = 0.004) and OPR (72.04% vs. 51.04%, p = 0.003) between GSATP group and Placebo group when the patient was younger than 35 years old. This multi-center, randomized, double-blinded, placebo-controlled clinical study showed for the first evidence that GSATP may have potential to improve the OPR and decrease vaginal bleeding or brown discharge rate in HT FET cycle patients.

Association of TNF-α gene T-1031C polymorphism with endometriosis: A meta-analysis.

The single nucleotide polymorphism T-1031C has shown to have an important role in the regulation and transcription efficiency of TNF-α gene. Yet, the relationship between TNF-α T-1031C gene polymorphism and the development of endometriosis (EM) still remains unclear. The aim of this meta-analysis was to summarize the effects of TNF-α T-1031C gene polymorphism and clarify their possible association with EM. A comprehensive literature search was performed using PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials (up to August 10, 2019). A fixed- or random-effects model was employed according to the heterogeneity among studies. The log odds ratios and 95% confidence intervals (CIs) were estimated in the models of allele comparison (T vs C), homozygote comparison (TT vs CC) and (TC vs CC), dominant (TT vs TC + CC), hyperdominant (TT + CC vs TC), and recessive (TT + TC vs CC) to estimate the strength of the associations. A total of 7 case-control studies were included in this meta-analysis. Overall, significant associations between TNF-α T-1031C and EM were identified from (T vs C: log OR [95% CI] = 0.31 [-0.09, 0.71]; TT + CC vs TC: 0.27 [0.04, 0.50]; TC + CC vs TT: -0.83 [-1.19, -0.47]). On the other hand, no significant correlation was found in other gene models (TT vs TC: log OR [95% CI] = 0.89 [0.64, 1.13]; TT vs CC: 0.3 [-0.74, 1.36]; TT + TC vs CC: 0.17 [-0.81, 1.15]). In subgroup analyses by ethnicity or HWE P-value, there was a statistically significant association between TNF-α T-1031C polymorphisms and EM in the dominant model (TT vs TC + CC: log OR [95%] = -0.84 [-1.60, -0.09]) for the European population, and in hyperdominant model (TT + CC vs TC: log OR [95%] = 0.24 [0.001, 0.49]) for Asian population. To sum up, this meta-analysis showed that TNF-α T-1031C polymorphism was associated with EM susceptibility and has a protective effect in Asian and European populations.

Borderline form of empty follicle syndrome treated with a novel dual trigger method combined with delayed oocyte retrieval: A case report.

BACKGROUND: Borderline form of empty follicle syndrome is a condition in which only a few mature or immature oocytes are recovered after meticulous follicular aspiration, despite adequate ovarian response to stimulation. It is a rare phenomenon with an unclear cause. Currently, the condition still lacks effective treatment. CASE SUMMARY: A patient with secondary infertility who had undergone three cycles of assisted reproductive technique (ART) is described. With regard to good follicular response, two oocytes were obtained in the first two ART cycles, but no embryo was formed. In the third ART cycle, which is the subject of this study, ovulation was induced by dual trigger of a supernormal dose of human chorionic gonadotropin (HCG) combined with a delayed oocyte retrieval approach. The method involved administration of gonadotropin-releasing hormone agonist, recombinant HCG, and urinary HCG 39 h before ovum pick-up. Ten oocytes were recovered, two out of three mature eggs were fertilized after intracytoplasmic sperm injection, resulting in two embryos that were subsequently cryopreserved. The case report guidelines have been used herein to present the first case of this novel dual trigger method. CONCLUSION: This approach provides a new treatment option for patients with a similar condition in the future. This study can also inspire further investigation on the effects of various ß-HCG serum levels 36 h after intramuscular HCG administration.