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.

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.

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.

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.

Transcriptomic profiling of human granulosa cells between women with advanced maternal age with different ovarian reserve.

BACKGROUND: Age-related diminished ovarian reserve (DOR) is not absolute. Some advanced maternal age (AMA) still have normal ovarian reserve (NOR) and often show better pregnancy outcomes. Exploring the transcriptomic profile of granulosa cells (GCs) in AMA could lead to new ideas for mitigating age-related diminished ovarian reserve. AIM: This study aimed to analyze the transcriptomic profile of GCs in AMA with different ovarian reserve. RESULTS: In total, 6273 statistically significant differential expression genes (DEGs) (|log2fc|> 1, q < 0.05) were screened from the two groups, among which 3436 genes were upregulated, and 2837 genes were downregulated in the DOR group. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, the potential functions of dysregulated genes in AMA with DOR or NOR were predicted. The GO enrichment analysis revealed that the DEGs were mainly enriched in obsolete oxidation-reduction process, mitochondrion, metal ion binding, ATP binding, etc. The KEGG pathway enrichment analysis revealed that the above-mentioned DEGs were mainly enriched in ferroptosis, regulation of actin cytoskeleton, oxidative phosphorylation, etc. Meanwhile, verification of the mRNA expression levels of DEGs revealed the possible involvement of "ferroptosis" in age-related diminished ovarian reserve. CONCLUSIONS: From a new clinical perspective, we presented the first data showing the transcriptomic profile in GCs between AMA with different ovarian reserve. At the same time, we identified the role of ferroptosis in the GCs of AMA, providing a new biological basis for studying ovarian aging and improving pregnancy outcomes of AMA.

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.

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.

Research progress on the impact of anxiety and depression on embryo transfer outcomes of in vitro fertilization. / 焦虑和抑郁状态对体外受精-èƒšèƒŽç§»æ¤ç»“å±€å½±å“çš„ç ”ç©¶è¿›å±•.

Infertile women who receive in vitro fertilization-embryo transfer (IVF-ET) often present psychological distress such as anxiety, depression and perceived stress. This adverse psychological state can affect the immune homeostasis at the mother-fetus interface, the incubation of blastula and the receptivity of the maternal endometrium through the psycho-neuro-immuno-endocrine network, which in turns affect the proliferation, invasion and vascular remodeling of the embryo trophoblast, and reduces the success rate of embryo transfer. This adverse outcome of embryo transfer will further aggravate the psychological pain of patients, forming a vicious circle. The positive partner effect between husband and wife or the use of cognitive behavioral therapy, acupuncture, yoga and other measures for psychological intervention before and after IVF-ET, may break the vicious cycle and improve clinical pregnancy rate, continuous pregnancy rate and live birth rate after IVF-ET by alleviating anxiety and depression. This article reviews the research progress on anxiety and depression states in women receiving IVF-ET and the impact on outcome of IVF-ET and related mechanisms, as well as the application of psychological intervention for alleviating anxiety and depression, so as to provide insights in improving the outcome of IVF-ET.

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.

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).

Comparison of two different starting dose of rhFSH in GnRH antagonist protocol for patients with normal ovarian reserve.

Objective: To evaluate different starting doses of recombinant human follicle-stimulating hormone (rhFSH) on pregnancy outcomes for patients with normal ovarian reserve during gonadotropin- releasing hormone antagonist (GnRH-ant) protocol-controlled ovarian stimulation of in vitro fertilization (IVF) cycles. Methods: In this retrospective study, a total of 1138 patients undergoing IVF cycles following the GnRH-ant protocol were enrolled. Patients were divided into two groups according to the starting dose of rhFSH. 617 patients received a starting dose of rhFSH of 150 IU, and 521 patients received a starting dose of rhFSH of 225 IU. We compared demographic characteristics, ovarian stimulation and embryological characteristics, and pregnancy and birth outcomes between the two groups. Multivariate logistic regression analysis was performed to examine the possible effects of the known potential confounding factors on pregnancy outcomes. Results: The number of oocytes retrieved in the 150 IU rhFSH group was significantly lower than those in the 225 IU rhFSH group. There was no significant difference between the two groups referring to embryological characteristics. The proportion of fresh embryo transfer in the 150 IU rhFSH group was significantly higher than that in the 225 IU rhFSH group (48.30% vs. 40.90%), and there was no difference in the risk of ovarian hyperstimulation syndrome and pregnancy outcomes between the two groups. Conclusions: In conclusion, the starting dose of rhFSH of 150 IU for ovarian stimulation has a similar pregnancy outcome as starting dose of rhFSH of 225 IU in GnRH-ant protocol for patients with normal ovarian reserve. Considering the potential cost-effectiveness and shorter time to live birth, the starting dose of rhFSH of 150 IU may be more suitable than 225 IU.

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.

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.

The optimal timing of frozen-thawed embryo transfer: delayed or not delayed? A systematic review and meta-analysis.

Background: The use of frozen embryo transfer (FET) has grown exponentially over the past few years. However, in clinical practice, there are no specific criteria as to whether a delay of at least one menstrual cycle is required for an FET after a failed fresh ET or a freeze-all cycle. Objective: Through the effects on live birth rate (LBR), clinical pregnancy rate (CPR) and pregnancy loss rate (PLR), to determine whether FET requires a delay of at least one menstrual cycle after fresh ET failure or a freeze-all cycle. Methods: The search was conducted through PubMed, Web of Science, CNKI, and Wanfang databases for terms related to FET timing as of April 2023. There are no restrictions on the year of publication or follow-up time. Women aged 20 to 46 with any indication for in vitro fertilization and embryo transfer (IVF-ET) treatment are eligible for inclusion. Oocyte donation studies are excluded. Except for the case report, study protocol, and abstract, all original studies are included. Results: In 4,124 search results, 19 studies were included in the review. The meta-analysis includes studies on the adjusted odds ratio (OR) and 95% confidence interval (CI) of reported live birth rate (LBR), clinical pregnancy rate (CPR), and pregnancy loss rate (PLR), 17 studies were retrospective cohort study, and 2 studies were randomized controlled trial, a total of 6,917 immediate FET cycles and 16,105 delayed FET cycles were involved. In this meta-analysis, the combined OR of LBR was [OR = 1.09, 95% CI (0.93­1.28)], the combined OR of CPR was [OR = 1.05, 95% CI (0.92­1.20)], and the combined OR of PLR was (OR = 0.96, 95% CI 0.75­1.22). There was no statistical significance between the two groups. Conclusion: Overall, delaying FET by at least one menstrual cycle has no advantage in LBR, CPR, or PLR. So, flexible scheduling of FETs is available to both doctors and patients. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020161648.

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].

Impact of intracytoplasmic sperm injection in women with non-male factor infertility: A systematic review and meta-analysis.

Objective: The purpose of this study is to determine whether intracytoplasmic sperm injection (ICSI) is beneficial in patients with non-male factor infertility. Methods: This systematic review and meta-analysis included articles from inception to May 2022. Published studies of non-male factor infertile women undergoing ICSI or in vitro fertilization (IVF) included in PubMed, Embase, web of science, Wanfang Database, and CNKI were searched by computer, without language restrictions. A random-effect model was applied to calculate the risk ratios (RRs) and their 95% confidence intervals (CIs). Letters, case reports, and review articles including meta-analyses and expert opinions were excluded. The primary endpoints were laboratory outcomes and pregnancy outcomes. The Secondary endpoints were neonatal outcomes. Results: Six randomized controlled studies and 20 retrospective cohort studies met the inclusion criteria. In meta-analytic forest plots, compared with IVF, those who received ICSI treatment were not different in fertilization rate (RR = 0.99, 95% CI [0.90-1.09], P = 0.88), total fertilization failure rate (RR = 1.30, 95% CI [1.17-1.45], P < 0.00001), and good quality embryo rate (RR = 0.94, 95% CI [ 0.86-1.02], P = 0.15), clinical pregnancy rate (RR = 0.84, 95% CI [0.70-1.01], P = 0.06), live birth rate (RR = 0.89, 95% CI [0.77-1.03], P = 0.13), miscarriage rate (RR = 1.06, 95% CI [0.78-1.43], P = 0.71), preterm neonatal delivery rate (RR = 0.92, 95% CI [0.67-1.26], P = 0.61), and low neonatal weight rate (RR = 1.13, 95% CI [0.80-1.61], P = 0.48). However, the implantation rate of IVF was better than ICSI (RR = 0.77, 95% CI [0.64-0.93], P = 0.005). In the subgroup analysis of the live birth rate of fresh embryo transfer, IVF performed in those ≥35 years had a higher live birth rate (RR = 0.82, 95% CI [0.78-0.83], P < 0.001). Conclusion: The findings of this study indicate that ICSI is not superior to IVF in the treatment of infertility related to non-male factors. In order to confirm this result, more high-quality clinical studies are needed.

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).

GnRH Agonist and hCG (Dual Trigger) Versus hCG Trigger for Final Oocyte Maturation in Expected Normal Responders With a High Immature Oocyte Rate: Study Protocol for a Randomized, Superiority, Parallel Group, Controlled Trial.

Introduction: The choice of trigger drug for the controlled ovarian hyperstimulation (COH) protocol correlates with the outcome of in vitro fertilization/intracytoplasmic sperm injection embryo transfer (IVF/ICSI-ET). The co-administration of gonadotropin releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG), i.e., dual trigger, for final oocyte maturation, has received much attention in recent years. This trial was designed to determine whether a dual trigger approach by lengthening the time between trigger and ovum pick-up (OPU) improves the quantity and quality of mature oocytes/top-quality embryos and pregnancy outcomes in expected normal responders with a high immature oocyte rate. Methods and Analysis: We propose a study at the Affiliated Hospital of Shandong University of Chinese Medicine. A total of 90 individuals undergoing COH use a fixed GnRH antagonist protocol. They will be assigned randomly into two groups according to the trigger method and timing: recombinant hCG (6500 IU) will be injected only 36 hours before OPU for final oocyte maturation (hCG-only trigger); co-administration of GnRH-a and hCG for final oocyte maturation, 40 and 34 hours prior to OPU, respectively (Dual trigger). The primary outcome is metaphase-II (MII) oocytes rate. Secondary outcomes are number of oocytes retrieved, fertilization rate, top-quality embryos rate, blastula formation rate, embryo implantation rate, clinical pregnancy rate, miscarriage rate, live birth rate, cumulative pregnancy/live birth rates, and ovarian hyperstimulation syndrome (OHSS) rate. Ethics and Dissemination: The reproductive ethics committee of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine certified this study (Identifier: SDUTCM/2021.7.26) as ethical. All individuals will sign written informed consent. All data and biological samples will be protected according to law. The results of this study will be disseminated in a peer-reviewed scientific journal. Clinical Trial Registration: [chictr.gov.cn], identifier [ChiCTR2100049292].