Immediate versus delayed frozen embryo transfer in women following a failed IVF-ET attempt: a multicenter randomized controlled trial.

BACKGROUND: The optimal time at which to perform a frozen-thawed embryo transfer (FET) following a failed in-vitro fertilization-embryo transfer (IVF-ET) attempt remains elusive to most reproductive experts. Physicians often delay the introduction of FET due to concerns related to potential residual effects of ovarian hyperstimulation which may interfere with the regular menstrual cycle. Moreover, given that most of the published studies on the topic are retrospective and have inconsistent findings, it is crucial to develop evidence-based randomized control guides for clinical practice. Therefore, this well-designed randomized controlled trial (RCT) was conducted to determine whether it is necessary to delay FET for at least one menstrual cycle after the failure of fresh embryo transfer. METHODS: Infertile women eligible for IVF-ET were invited to participate in this multicenter, randomized, non-inferiority, parallel-group, unblinded, controlled trial at the academic fertility centers of four public hospitals in Chinese Mainland. Infertile women scheduled to receive their first FET cycle after a failed IVF-ET attempt were randomly assigned to either (a) the immediate FET group in which FET was performed in the first menstrual cycle following the failed IVF-ET cycle (n = 366) or (b) the delayed FET group in which FET was performed in the second or subsequent menstrual cycle following the failed IVF-ET cycle (n = 366). All FET cycles were performed during hormone replacement cycles for endometrial preparation. The primary outcome was the ongoing pregnancy, defined as a detectable fetal heart beat beyond twelve weeks of gestation. Secondary outcomes were other pregnancy-related outcomes, maternal and neonatal complications. Analysis was performed by both intention-to-treat and per-protocol principles. RESULTS: A total of 646 FETs were completed. The frequency of moderate to severe depression and high stress level prior to FET in delayed FET group were significantly higher than that in immediate FET group (10.6% vs 6.1%, p = 0.039; 30.3% vs 22.4%, p = 0.022, respectively). Immediate FET resulted in a higher frequency of clinical pregnancy than did delayed FET (41.7% vs 34.1%), for a relative risk (RR) of 1.23 (95% confidence interval [CI], 1.00-1.50; p = 0.045). Women who underwent immediate FET also had a lower frequency of biochemical pregnancy loss (11.7% vs. 30.6%), with a RR of 0.28 (95% CI 0.23-0.63, p < 0.001), and a higher frequency of embryo implantation (25.2% vs. 20.2%), with a RR of 1.25 (95% CI 1.01-1.53; p = 0.038). Although the ongoing pregnancy and live birth rates did not differ significantly between the immediate FET and delayed FET groups (37.1% vs 30.3%, RR 1.22, 95% CI 0.99-1.52, p = 0.067; 36.5% vs 30.0%, RR 1.22, 95% CI 0.98-1.52, p = 0.079, respectively), a multivariate logistic regression analysis adjusted for potential confounders such as depression and stress levels revealed that the immediate FET group had a significantly higher ongoing pregnancy and live birth rates than the delayed FET group (odds ratio 0.68, 95% CI 0.47-0.99, p = 0.041; odds ratio 0.67, 95% CI 0.46-0.96, p = 0.031). The risks of maternal and neonatal complications were comparable between the two groups. CONCLUSIONS: In women with a previous failed IVF-ET attempt, immediate FET resulted in higher ongoing pregnancy and live birth rates than delayed FET. These findings warrant caution in the indiscriminate application of a delayed FET strategy when apparent risk of high stress level is perceived. TRIAL REGISTRATION: ChiCTR2000033313 .

Metabolomic Analysis Of Human Follicular Fluid: Potential Follicular Fluid Markers Of Reproductive Aging.

OBJECTIVE: To assess the difference in the metabolomics profiles of follicular fluid between older and younger reproductive-aged women. METHODS: The retrospective study was conducted at the Centre of Reproduction and Genetics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China and comprised patient data related to the period between July and October 2015. Follicular fluid was obtained from male-factor infertility women aged 28-35 years as the younger group A, and those aged 35-42 years as the older group B. The subjects were undergoing in vitro fertilization / intracytoplasmic sperm injection and were retrospectively analysed by ultra-performance liquid chromatography-high-resolution mass spectrometry. The fragments were structurally identified using debris' information obtained from fragmented ion scans to identify the different compounds. RESULTS: Of the 55 cases studied, 28(51%) were in group A with a mean age of 29.57 ± 2.92 years, and 27(49%) were in group B with a mean age of 39.19±2.95 years. Compared with the group A, four types of compounds, hormones, licithin, lysophospholipids, and protein degradation fragments, were expressed significantly differentially in group B (p<0.05 each). Nicotine glucuronide and phosphatidylcholine were found only in Group B follicular fluid. CONCLUSIONS: The components of follicular fluid and relative contents were found changed with ageing.

Efficacy and safety of Shen Que (RN8) moxibustion on reproductive outcomes in unexpected poor ovarian responders: a randomized controlled trial.

BACKGROUND: Managing infertility patients with poor ovarian response (POR) to ovarian stimulation remains unmet clinically. Besides economic burdens, patients with POR have a poor prognosis during in vitro fertilization and embryo transfer (IVF-ET). In this study, we assessed the efficacy and safety of Shen Que (RN8) moxibustion on reproductive outcomes in POSEIDON patients (Group 2a). METHODS: Women eligible for IVF were invited to participate in this randomized, open-label, superiority trial at an academic fertility center from January 2022 to December 2023. One hundred patients ≤ 44 years old equally divided between Shen Que moxibustion (SQM) and control groups were randomized. These patients must meet the POSEIDON criteria, Group 2a, which requires antral follicle count (AFC) ≥ 5 or anti-müllerian hormone (AMH) ≥ 1.2ng/ml, and a previous unexpected POR (< 4 oocytes). Twelve moxibustion sessions were conducted in the SQM group prior to oocyte retrieval, while only IVF treatment was performed in the control group. The primary outcome was the number of oocytes retrieved. RESULTS: As compared with the IVF treatment alone, the SQM + IVF treatment significantly increased the number of retrieved oocytes (4.7 vs. 5.8, p = 0.012), mature oocytes (3.0 vs. 5.0, p = 0.008), and available embryos (2.0 vs. 4.0, p = 0.014) in unexpected poor ovarian responders aged more than 35 years. In the SQM group, the cumulative live birth rate was 27.3% (9/33) in comparison to 13.3% (4/30) in the control group, whereas no statistical significance was detected (p = 0.172). During the study, no significant adverse effects were observed. CONCLUSIONS: Women with unexpected POR who meet POSEIDON Group 2a can benefit from Shen Que (RN8) moxibustion treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05653557.

Effect of rapid rehabilitation nursing on improving clinical outcomes in postoperative patients with colorectal cancer.

BACKGROUND: Surgical resection is the cornerstone treatment for colorectal cancer. Rapid rehabilitation care predicated on evidence-based medical theory aims to improve postoperative nursing care, subsequently reducing the physical and mental traumatic stress response and helping patients who undergo surgery recover rapidly. AIM: To assess the effect of rapid rehabilitation care on clinical outcomes, including overall postoperative complications, anastomotic leaks, wound infections, and intestinal obstruction in patients with colorectal cancer. METHODS: We searched the PubMed, Web of Science, Embase, Elsevier Science Direct, and Springer Link databases from January 1, 2010, to January 1, 2024, to screen eligible studies on rapid rehabilitation care among patients who underwent colorectal cancer surgery. Patients were screened based on the inclusion and exclusion criteria. RevMan 5.4 software was used for statistical analysis of the data. RESULTS: Twelve studies were enrolled, which included 2420 patients. The results showed that rapid rehabilitation care decreased the incidence of overall postoperative complications (OR: 0.44, 95%CI: 0.26-0.74, P = 0.002), anastomotic leaks (OR: 0.68, 95%CI: 0.41-1.12, P = 0.13), wound infections (OR: 0.45, 95%CI: 0.29-0.72, P = 0.0007), and intestinal obstruction (OR: 0.54, 95%CI: 0.34-0.86, P = 0.01) compared to conventional care. Further trials and studies are needed to confirm these results. CONCLUSION: Rapid rehabilitation care decreased the occurrence of postoperative complications, anastomotic leaks, wound infections, and intestinal obstruction compared to conventional care in patients who underwent colorectal surgery. Therefore, promoting the application of rapid rehabilitation care in clinical practice cannot be overemphasized.

Optimal timing of GnRH antagonist initiation in IVF-ET: a retrospective cohort study on advanced maternal age women.

Background: Several studies have compared the effects of fixed and flexible gonadotropin releasing hormone antagonist (GnRH-ant) protocols during in vitro fertilization and embryo transfer (IVF-ET). However, which GnRH-ant initiation strategy is better remains controversial. Moreover, no studies have assessed the optimal timing of GnRH-ant initiation in women of advanced maternal age (AMA). Methods: In this retrospective cohort study, a total of 472 infertile women aged ≥ 35 years old undergoing their first IVF cycle from August 2015 to September 2021 at a tertiary academic medical center were recruited, of whom 136 followed fixed GnRH-ant protocol and 336 followed flexible GnRH-ant protocol. The primary outcomes measured were the cumulative live birth rate (CLBR) per IVF cycle and the time to live birth (TTLB) from the date of oocyte retrieval. Cox proportional models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of CLBR regarding GnRH-ant timing. Results: No significant difference in CLBR was found between the fixed and flexible GnRH-ant groups (27.9% vs 20.5%, p=0.105). The TTLB was also comparable between groups (10.56 vs 10.30 months, p=0.782). The Kaplan-Meier analysis for CLBR also showed comparable results between groups (P=0.351, HR=0.83; 95%CI: 0.56-1.23). After establishing a multiple Cox proportional hazard model, the fixed GnRH-ant group still had comparable CLBR with the flexible GnRH-ant group (HR=0.85; 95%CI: 0.53-1.38; P=0.518). Subgroup and sensitivity analyses also demonstrated similar results. Conclusion: GnRH-ant protocols can be tailored to the needs of AMA women, and timing of GnRH-ant initiation can be adjusted flexibly.

Premature timing of progesterone luteal phase support initiation did not negatively impact live birth rates in modified natural frozen thawed embryo transfer cycles.

Study question: In a modified natural cycle frozen-thawed embryo transfer (mNC-FET), does the premature timing of progesterone luteal phase support (LPS) initiation 24 h following human chorionic gonadotropin (hCG) trigger impact live birth? Summary answer: Premature LPS initiation did not negatively affect the live birth rate (LBR) in mNC-FET cycles compared with conventional LPS initiation 48 h after hCG triggering. What is known already: During natural cycle FET, human chorionic gonadotropin is routinely used to mimic endogenous luteinizing hormone (LH) surge to induce ovulation, which allows more flexibility in embryo transfer scheduling, thus relieving the burden of multiple visits by patients and laboratory workloads, which is also known as mNC-FET. Moreover, recent data demonstrates that ovulatory women undergoing natural cycle FETs have a lower risk of maternal and fetal complications due to the essential role of the corpus luteum in implantation, placentation and pregnancy maintenance. While several studies have confirmed the positive effects of LPS in mNC-FETs, the timing of progesterone LPS initiation is still unclear, as compared with fresh cycles where robust research has been conducted. To the best of our knowledge, no clinical studies comparing different beginning days in mNC-FET cycles have been published. Study design size duration: This retrospective cohort study involved 756 mNC-FET cycles performed at a university-affiliated reproductive center between January 2019 and August 2021. The primary outcome measured was the LBR. Participants/materials setting methods: Ovulatory women ≤42 years of age who were referred for their autologous mNC-FET cycles were included in the study. According to the timing of progesterone LPS initiation following the hCG trigger, patients were assigned into two categories: premature LPS group (progesterone initiation 24 h after hCG trigger, n = 182) versus conventional LPS group (progesterone initiation 48 h after hCG trigger, n = 574). Multivariate logistic regression analysis was used to control for confounding variables. Main results and the role of chance: There were no differences in background characteristics between the two study groups, except for the proportion of assisted hatching (53.8% in premature LPS group versus 42.3% in conventional LPS group, p = 0.007). In the premature LPS group, 56 of 182 patients (30.8%) had a live birth, compared to 179 of 574 patients (31.2%) in the conventional LPS group, with no significant difference observed between groups (adjusted odds ratio [aOR] 0.98, 95% confidence interval [CI] 0.67-1.43, p = 0.913). In addition, there was no significant difference between the two groups in other secondary outcomes. A sensitivity analysis for LBR according to the serum LH and progesterone levels on hCG trigger day also confirmed the aforementioned findings. Limitations reasons for caution: In this study, retrospective analysis was conducted in a single center and was therefore prone to bias. Additionally, we did not anticipate monitoring the patient's follicle rupture and ovulation after hCG triggering. Future prospective clinical trials remain necessary to confirm our results. Wider implications of the findings: While exogenous progesterone LPS was added 24 h after hCG triggering, embryo-endometrium synchrony would not be adversely affected so long as sufficient time was allowed for endometrial exposure to exogenous progesterone. Our data support promising clinical outcomes following this event. As a result of our findings, clinicians and patients will be able to make better informed decisions. Study funding/competing interests: No specific funding was available for this study. The authors have no personal conflicting interests to declare. Trial registration number: N/A.

Dual trigger for final oocyte maturation in expected normal responders with a high immature oocyte rate: a randomized controlled trial.

Objective: To evaluate whether dual trigger could improve reproductive outcomes in women with low oocyte maturation rates compare to human chorionic gonadotropin (hCG) trigger. Methods: This study included expected normal ovarian responders younger than 40 years old whose immature oocyte rate in the previous cycle was more than 50% at the reproductive center from July 2021 to November 2022. A total of 73 patients were enrolled at trigger, including 34 in the hCG trigger group and 39 in the dual trigger group (co-administration of gonadotrophin releasing hormone (GnRH) agonist and hCG, 40 and 34 h prior to oocyte retrieval, respectively). The primary outcome was oocyte maturation rate. Results: There was no significant difference in the number of oocytes retrieved between the two study groups, but the oocyte maturation rate was higher in dual trigger group (84.0% [14.0%] vs. 55.5% [19.8%], p < 0.001). Moreover, there were also higher cumulative pregnancy rate (69.4% vs. 40.0%, p = 0.035) and cumulative live birth rate (66.7% vs. 36.0%, p = 0.022) in dual trigger group. Conclusion: For normal responders with low oocyte maturation rates, the dual trigger may be more effective than the conventional hCG trigger. Clinical trial registration: ClinicalTrials.gov, identifier ChiCTR2100049292.

Does endometrial compaction before embryo transfer affect pregnancy outcomes? a systematic review and meta-analysis.

Objective: There is no clear evidence of clinical significance of endometrial compaction, which can be measured by a reduction in endometrial thickness (EMT) during the follicular-luteal transition before the day of embryo transfer. In this study, we aim to determine whether endometrial compaction has an effect on in vitro fertilization (IVF) success. Methods: We searched PubMed, Cochrane, Embase, and Web of Science electronic databases for studies published in English up to March 2023. Heterogeneity between studies was assessed using the I2 statistic. The random effects model and fixed effects model was used to pool the risk ratio (RR) with a corresponding 95% confidence interval (CI). A subgroup analysis was performed based on different methods of ultrasonic measurement and different endometrial compaction rates (ECR). Stata 17.0 software was used for meta-analysis. Pregnancy outcomes, which included clinical pregnancy rate, ongoing pregnancy rate, live birth rate, and spontaneous abortion rate, were evaluated. Results: In this study, 18 cohort studies were included, involving 16,164 embryo transfer cycles. Pooled results indicated that there was no significant difference between the endometrial compaction group and the non-compaction group in terms of clinical pregnancy rate (RR [95% CI]=0.98 [0.90,1.08]; I2 = 69.76%), ongoing pregnancy rate (RR [95% CI]=1.18 [0.95,1.47]; I2 = 78.77%), live birth rate (RR [95% CI]= 0.97 [0.92,1.02]; I2 = 0.00%) or spontaneous abortion rate (RR [95% CI]= 1.07[0.97,1.26]; I2 = 0.00%). According to the subgroup analysis of ultrasonic measurement methods, in the transvaginal ultrasound (TVUS) combined with abdominal ultrasonography (AUS) cycles of the endometrial compaction group, the rate of ongoing pregnancy (RR [95% CI] = 1.69 [1.26, 2.26]; I2 = 29.27%) and live birth (RR [95% CI] = 1.27 [1.00,1.61]; I2 = 62.28%) was significantly higher than that of the non-compaction group. Additionally, subgroup analysis based on ECR revealed a significantly higher rate of ongoing pregnancy when ECR ≥ 15% (RR [95% CI] = 1.99 [1.61, 2.47]; I2 = 0.00%). Conclusion: Endometrial compaction has no adverse effect on clinical pregnancy rate, ongoing pregnancy rate, live birth rate, or spontaneous abortion rate. A possible explanation for the contradictory findings of previous studies lies in the method by which the EMT is measured. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023430511, identifier CRD42023430511.

Effect of Flexible Half-Dose Gonadotropin-Releasing Hormone Antagonist Protocol on in vitro Fertilization Outcome in Predicted Normal Responder: A Study Protocol for a Multicentered, Randomized, Non-Inferiority, Parallel Controlled Trial.

Background: Gonadotropin-releasing hormone antagonists (GnRH-ant) are widely used in current in vitro fertilization-embryo transfer (IVF-ET), however, whether the lowest daily dose of GnRH-ant is individualized remains unknown. Due to the negative effect of GnRH-ant on endometrial receptivity, lessening the amount of GnRH-antagonists used during controlled ovarian stimulation may be helpful for embryo implantation. As such, a randomized controlled study is essential to validate the feasibility and efficacy of daily GnRH-ant dose reduction to 0.125 mg geared towards providing scientific evidence for guidance in clinical practice. Methods: In total, 620 infertile women undergoing in vitro fertilization will be enrolled in the multicentered, randomized, parallel controlled trial. Based on a computer-generated random list, they will be randomly and equally subdivided into half-dose GnRH-ant group or conventional-dose GnRH-ant group. The primary outcome is ongoing pregnancy ie, intrauterine pregnancy diagnosed by pelvic ultrasonography at more than 12 weeks of gestation accompanied by normal fetal heartbeats. Secondary outcomes include cycle cancellation, premature luteinizing hormone surge, positive pregnancy, embryo implantation rate, clinical pregnancy, early spontaneous abortion, and live birth. The intention-to-treat and per protocol analyses will be used to initially analyze the difference in ongoing pregnancy rate between the two groups, while the multiple imputation method was used to handle missing values in the data. Discussion: At present, no randomized controlled trials (RCTs) have been performed on the use of the half-dose GnRH-ant protocol (0.125mg/d) to improve reproductive outcomes of IVF-ET in predicted normal responder, compared to conventional-dose GnRH-ant protocol (0.25mg/d). Half-dose GnRH-ant protocol might provide a suitable clinical solution for predicted normal responder undergoing IVF treatment. Thus, it is critical to conduct a well-designed RCT to evaluate the impact of a half-dose GnRH-ant protocol on the reproductive outcomes of IVF-ET in predicted normal responder. Trial Registration: This study was registered in the Chinese Clinical Trials Registry Platform on August 29, 2020. (chictr.org.cn; identifier: ChiCTR2000037629). This trial is version 1.3.

Application of Human Menopausal Gonadotropins in the Treatment of Idiopathic Hypogonadotropic Hypogonadism (IHH)-Based Infertility in Females: A Case Report.

Rationale: Idiopathic hypogonadotropic hypogonadism (IHH) is a prevalent congenital genetic disorder with multiple inheritance patterns. IHH can manifest as normal hypogonadotrophic sexual hypofunction (nIHH) or with an abnormal sense of smell, known as Kallmann. It primarily affects the production and effectiveness of gonadotropin-releasing-hormone (GnRh), leading to reduced follicle-stimulating hormone and luteinizing hormone levels. This results in infertility and underdeveloped secondary sexual characteristics. Patient Concerns: A 29-year-old female presented with infertility. Diagnosis: IHH diagnosis was confirmed through magnetic resonance (MR) scan, endocrine tests, physical examination, and B ultrasonic inspection. Additionally, genetic studies, including chromosome analysis, were conducted for the patient. The results confirmed no genetic abnormalities or concerns. Interventions: The patient underwent multiple ovulation induction programs. Outcome: After several ovulation induction cycles, the patient conceived and delivered a live baby. Lessons: For IHH patients, a tailored human menopausal gonadotropin (HMG) dose is recommended. High-dose HMG can benefit those with poor follicular response. The addition of letrozole (5-7.5mg) may enhance follicular response during stimulation. Our approach, which emphasizes the combined use of high-dose HMG, letrozole, and the adjustment of FSH and LH ratios, offers a unique perspective compared to traditional treatments. If HMG treatment is ineffective, alternative ovulation induction methods, such as r-fsh combined with r-lh or HMG combined with rLH, can be considered. Adjusting the FSH and LH ratio and varying rFSH and rLH additions might help achieve dominant follicles and live birth in resistant cases. This case report underscores the potential benefits of our regimen, suggesting its consideration for future research and clinical applications.

The role of Erzhi Tiangui formula in expected poor ovarian responders undergoing in vitro fertilization-embryo transfer: A multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Advanced age is one of the primary risk factors for infertility. Poor ovarian response (POR) to exogenous gonadotropin is a prominent characteristic of advanced-age women undergoing in vitro fertilization and embryo transfer (IVF-ET), which results in fewer retrieved oocytes and poor pregnancy outcomes. Traditional Chinese medicine (TCM) has been shown to improve female fertility. Erzhi Tiangui (EZTG) formula, in the form of granules with 10 herbal ingredients, demonstrated potential benefits in improving oocyte and embryo quality and ovarian reserve. Thus, this study aims to evaluate the efficacy and safety of EZTG formula. METHOD: The study is a multicenter, double-blind, placebo-controlled, randomized controlled trial (RCT), which will be conducted at 10 reproductive centers of tertiary hospitals. This study will enroll 480 women with expected POR of advanced age (≥35 years old) who fulfill the 2011 Bologna criteria. Participants will be assigned to either the EZTG group or the placebo group at random in an equal ratio. Each individual will receive conventional IVF-ET with EZTG granules or placebo as a complementary treatment. The primary outcome is the number of oocytes retrieved. Adverse events and safety assessments will be also conducted. DISCUSSION: This study aims to provide robust evidence of the efficacy and safety of EZTG formula as a complementary treatment for advanced-age women with expected POR undergoing IVF-ET.

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).

Effectiveness of oestrogen pretreatment in patients with expected poor ovarian response (POSEIDON groups 3 and 4) undergoing GnRH antagonist protocol: study protocol for a randomised controlled trial.

INTRODUCTION: Women characterised by diminished ovarian reserve are considered to have poor ovarian response (POR) according to Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. Patients in this population often have a poor prognosis for treatment with assisted reproductive technology. In previous studies, oestrogen pretreatment before ovarian stimulation has been shown to have a beneficial effect. However, recent studies presented conflicting conclusions. This study aims to evaluate the effectiveness of oestrogen pretreatment in patients with expected POR (POSEIDON groups 3 and 4) undergoing gonadotrophin releasing hormone antagonist (GnRH-ant) protocol. METHODS AND ANALYSIS: A prospective superiority randomised parallel controlled trial will be conducted at a tertiary university-affiliated hospital. A total of 316 patients will be randomly divided into two groups at a ratio of 1:1. In the intervention group, oral oestrogen pretreatment will be administered from day 7 after ovulation until day 2 of the next menstrual cycle. Afterwards, a flexible GnRH-ant protocol will be initiated. The control group will receive no additional intervention beyond routine ovarian stimulation. The primary outcome is the number of oocytes retrieved. Secondary outcomes include the total number of retrieved metaphase II oocytes, average daily dose of gonadotropin, total gonadotropin dose and duration of ovarian stimulation, cycle cancellation rate, top quality embryos rate, blastocyst formation rate, embryo implantation rate, clinical pregnancy rate, early miscarriage rate and endometrial thickness on trigger day. All data will be analysed according to the intention-to-treat and per-protocol principles. ETHICS AND DISSEMINATION: The ethical approval has been confirmed by the reproductive ethics committee of the affiliated hospital of Shandong University of Traditional Chinese Medicine (SDUTCM/2022.9.20). In addition, written informed consent will be obtained from all the participants before the study. The results will be disseminated via publications. TRIAL REGISTRATION NUMBER: ChiCTR2200064812.

Comprehensive analysis of the role of a four-gene signature based on EMT in the prognosis, immunity, and treatment of lung squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT), a biological process through which epithelial cells transform into mesenchymal cells, contributes to tumor progression and metastasis. However, a comprehensive analysis of the role of EMT-related genes in Lung squamous cell carcinoma (LUSC) is still lacking. In this study, data were downloaded from available databases, including The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The association between differentially expressed EMT-related genes (EMT-RDGs) and LUSC prognosis, drug sensitivity, mutation, and immunity was analyzed using bioinformatics methods. In the results, Lasso and univariate Cox regression analyses identified four EMT-RDGs that were differentially expressed, and used to establish a prognostic model capable of distinguishing between high- and low-risk groups. Then, prognostic factors were identified by multivariate Cox regression analysis and used to construct a nomogram. The high-risk group had a significantly poorer prognosis than the low-risk group. The tumor immune environment was significantly different between the two groups, with the low-risk group exhibiting a better response to immunotherapy. In addition, the half-maximal inhibitory concentration prediction indicating that the constructed model could effectively predict sensitivity to chemotherapy. This study provides new reference for further exploration of new clinical therapeutic strategies for LUSC.

Comparison of pregnancy outcomes of letrozole-induced frozen-thawed embryo transfer cycles in PCOS women with two different abnormal ovulation patterns: A retrospective cohort study.

No studies have been conducted on the impact of different types of ovulatory dysfunction on the outcomes of frozen-thawed embryo transfers (FETs) in a letrozole-stimulated cycle in women with polycystic ovarian syndrome (PCOS). This study aimed to compare whether pregnancy outcomes of the letrozole-induced protocol in FET cycles differed between oligo-ovulatory and anovulatory women with PCOS. In a retrospective cohort study, women with PCOS who had undergone letrozole-induced FET at a university-affiliated fertility clinic from February 2014 to October 2020 were identified. The primary end point was live birth rate (LBR) per embryo transfer. Propensity score matching and multivariate logistic regression analyses were performed to control for the relevant confounders. A total of 652 women with PCOS undergoing letrozole-induced FET were included in the final analysis. Three hundred sixty-three of these women had oligo-ovulatory periods, while 289 had anovulatory periods. Propensity score matching analysis showed that LBR did not differ between groups (36.8% in oligo-ovulatory group vs 32.8% in anovulatory group, P = .431). Nevertheless, after controlling for potential confounding factors, LBR was significantly lower in anovulatory than oligo-ovulatory women (adjusted odds ratio 1.57, 95% confidence interval 1.08-2.29, P = .018). Furthermore, the pregnancy loss rate among the oligo-ovulatory group remained lower than those among the anovulatory group (adjusted odds ratio 0.23, 95% confidence interval 0.12-0.44, P < .001). Despite adjustment for confounding factors, those with oligo-ovulatory PCOS had a higher LBR and lower pregnancy loss rate compared with those with anovulatory PCOS. This may indicate that when oligo-ovulation is detected, PCOS patients should be intervened in time to conceive as soon as possible. Prospective studies must be conducted in the future to verify our findings.

Impact of progesterone-free luteal phase support following natural cycle frozen embryo transfer: Study protocol for a multicenter, non-inferiority, randomized controlled trial.

Introduction: Nowadays, frozen-thawed embryo transfer (FET) has become one of the standard treatments for infertility in the field of assisted reproductive technology (ART). Natural cycle FET (NC-FET) has many advantages, such as simplicity and economics, no effect on patients' menstrual cycles, estrogen and progesterone levels, as well as no interference in endometrial growth and transformation, which is aligned with the natural physiological state of embryo implantation. Nonetheless, there is a controversy regarding the need for luteal phase support (LPS) during NC-FET cycles. The purpose of this study is to assess whether LPS was not inferior to non-LPS in terms of OPR in NC-FET cycles. Methods and analysis: This study including 1,010 ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles with an elective freeze-all strategy followed by NC-FET will be performed at four university-affiliated reproductive centers. Participants will be randomly assigned in a 1:1 ratio to receive LPS treatment or not. This study is designed as an open-label, non-inferiority, randomized controlled trial (RCT), and the primary statistical strategies were intention-to-treat (ITT) and per-protocol (PP) analysis. Discussion: There may not have been any significant difference in the chance of a live birth after FET if no progesterone was supplemental during the luteal phase. However, due to the limited number of previous studies, which are mainly retrospective, evidence is still limited. Thus, by conducting this multicenter RCT, we intend to evaluate whether LPS is necessary in NC-FET. Ethics and dissemination: A Reproductive Ethics Committee of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine (SDUTCM) has approved this study. This study will handle the data as required by general data protection regulations. Participants will sign a written informed consent regarding participation in the study and storage of blood samples in a biobank for future research. This study will be monitored by study personnel trained in Good Clinical Practice who are not involved in the study. The results of this study will be disseminated through publication in international peer-reviewed scientific journals. Clinical trial registration: [https://www.chictr.org.cn/], identifier [ChiCTR2200057498].

Short (seven days) versus standard (fourteen days) oestrogen administration in a programmed frozen embryo transfer cycle: a retrospective cohort study.

RESEARCH QUESTION: What influence does seven days of oestrogen administration versus fourteen days have on the reproductive outcomes of frozen-thawed embryo transfer (FET) in programmed endometrial preparation cycles? DESIGN: In a retrospective study, conducted at a university-affiliated tertiary hospital, a total of 2628 infertile patients (4142 FET cycles) were divided into one of two groups between January 2014 and December 2020: group A (n = 1406, seven days of oestrogen before progesterone (P4) supplementation) and group B (n = 2716, fourteen days of oestrogen before P4 supplementation). The primary outcome was cumulative live birth rate (CLBR). Secondary outcomes were other pregnancy-related outcomes, maternal and neonatal complications. RESULTS: No significant difference in CLBR was observed when comparing seven versus fourteen days of oestrogen administration before starting P4 supplementation (47.6% vs. 48.8%, P = 0.537). Furthermore, multivariable logistic regression analysis revealed that oestrogen administration in programmed FET cycles (7 days vs. 14 days) was not significantly associated with CLBR (OR 1.04, 95% CI 0.89-1.23). The risks of maternal and neonatal complications were comparable between the two groups. CONCLUSIONS: Variation in the duration of oestradiol supplementation before P4 initiation does not impact FET reproductive outcomes. For infertile women who desire to conceive as soon as feasible, short (seven days) oestrogen administration in a programmed FET cycle may be a suitable alternative.

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.

Efficacy of Qizi Yusi Pill on Pregnancy Outcomes in Women of Advanced Reproductive Age: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To evalvate efficacy of Qizi Yusi Pills (QYP), a Chinese medicine compound preparation, on in vitro fertilization-embryo transfer (IVF-ET) in women of advanced reproductive age. METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was conducted from June 2018 to October 2019. A total of 124 patients were randomly allocated to either the QYP group or the placebo group using a stratified block randomization design, with 62 patients in each group. All patients completed controlled ovarian stimulation using a standard gonadotropin-releasing hormone agonist (GnRH-a) long protocol. As the QYP group, QYP was administered while the control group received placebo. QYP and placebo were administered for a total of 24 to 30 days from the day of GnRH-a pituitary downregulation to transvaginal oocyte retrieval. Both medications were taken orally at doses of 10 g three times each day. The primary outcome was cumulative pregnancy rate, and the secondary outcomes were periodic medication, follicular status, serum hormone and endometrial receptivity. Follow-up continued until 4 weeks after delivery. Maternal and neonatal complications, such as gestational diabetes, were also observed. RESULTS: Overall, 119 patients completed the study, 60 in the QYP group and 59 in the placebo group. Per protocol (PP) analysis revealed that 6-month cumulative pregnancy rate in the QYP group was significantly higher than that in the placebo group [43.33% (26/60) vs. 25.42% (15/59), P=0.040). Additionally, more oocytes were retrieved from the QYP group than those from the placebo group (8.95 ± 3.12 vs. 7.85 ± 1.91, P=0.022). Moreover, the endometrial thickness of HCG day in the QYP group was significantly higher than that in the placebo group (11.78 ± 2.27 mm vs. 10.68 ± 2.07 mm, P=0.012). Maternal and neonatal complications between the two groups were not significantly different (P>0.05). Intention-to-treat analysis was in line with PP results. CONCLUSIONS: QYP can enhance ovarian reserve capacity and ovarian response, and possibly promote endometrial receptivity. QYP effectively improves cumulative pregnancy rates in older patients (⩾35 years) undergoing IVF-ET. (Registration No. ChiCTR1800014427).

Anxiety and depression among pregnant women undergoing IVF-ET and WeChat group peer support during the COVID-19 pandemic: Study protocol for a randomized controlled trial.

INTRODUCTION: The psychological well-being of pregnant women following assisted reproductive has increasingly gained attention in recent years. Anxiety and depression may be associated to pregnancy outcomes. This study aims to determine whether peer support and the WeChat group platform will reduce anxiety and depression among in vitro fertilization and embryo transfer (IVF-ET) women. METHODS AND ANALYSIS: In the present randomized controlled study, 296 patients with confirmed clinical pregnancy following IVF-ET will be randomly assigned to receive standard intervention support or WeChat peer support on a 1:1 basis. The levels of anxiety and depression are the primary endpoints. Assessments will be performed at baseline measurements, first trimester, second trimester, and third trimester, and data will be collected. ETHICS AND DISSEMINATION: This study has been approved as ethical by the affiliated hospital of Shandong University of Traditional Chinese Medicine's Reproductive Ethics Committee. Each patient will sign a written statement of informed permission. All information and biological samples will be legally protected. A peer-reviewed academic journal will publish the findings of this investigation. DISCUSSION: Given the inconvenience of visits due to the current pandemic of COVID-19, this study addresses the patient's visit needs by combining WeChat, the most widely used social software in China, with peer support, while helping improve maternal anxiety, depression, and pregnancy outcomes following IVF-ET.