Comparison of pregnancy outcomes in women with normal ovarian response to the gonadotropin-releasing hormone agonist protocol using different trigger methods: a single-center retrospective cohort study based on propensity score matching.

PURPOSE: To investigate whether gonadotropin-releasing hormone agonist (GnRH-a) combined with human chorionic gonadotropin (HCG) can improve pregnancy outcomes in patients with normal ovarian response (NOR). METHODS: In this retrospective cohort study, data of 404 NOR patients undergoing fresh embryo transfer (ET) from 2018 to 2022 were studied. Patients were divided into HCG group and HCG plus GnRH-a group according to trigger methods. After confounding factors were controlled by propensity score matching, 67 cases were included in HCG group and HCG plus GnRH-a group, respectively, and pregnancy outcomes were assessed. Basal data, ovarian stimulation, embryological data and pregnancy outcomes were compared. The effect of trigger methods on pregnancy outcomes was analyzed by binary logistic regression. RESULTS: There was no statistically significant differences in embryological data, embryo implantation rate, clinical pregnancy rate, live birth rate of ET, number of fresh embryos transferred and total number of embryos transferred after one cycle of oocyte retrieval. While, cumulative live birth rate (CLBR) was better in the dual-trigger group than in the HCG group. The binary logistic regression analysis indicated that the trigger methods had an independent influence on embryo implantation and cumulative live birth. CONCLUSIONS: During IVF/ICSI, dual-trigger could potentially play a role in improving oocyte quality, ensuring embryo implantation rate, clinical pregnancy rate, live birth rate of ET and cumulative live birth rate at the end of one ovum pick-up (OPU) cycle, and reducing the physical, temporal and financial negative consequences due to repeated OPU cycle.

Causal association between rheumatoid arthritis and pregnancy loss and intrauterine growth retardation: A bidirectional two-sample Mendelian randomization study.

OBJECTIVE: To investigate the causal relationship between rheumatoid arthritis (RA) and pregnancy loss and intrauterine growth retardation (IUGR) using Mendelian randomization (MR). METHODS: Genetic variants associated with RA (12,555 cases and 240,862 controls), miscarriage (1475 cases and 149,622 controls), and IUGR (3558 cases and 207,312 controls) were obtained from the FinnGen consortium, and supplementary data on RA (5201 cases and 457,732 controls) and miscarriage (7069 cases and 250,492 controls) were obtained from the Medical Research Council Integrated Epidemiology Unit (MRC-IEU). 47 Single nucleotide polymorphisms (SNPs) associated with RA were screened as instrumental variables (IV). The causal relationship between RA and pregnancy loss and IUGR were assessed by 5 MR methods, mainly inverse variance weighting (IVW). Sensitivity analyses were also performed to test the stability of the results. RESULTS: Bidirectional MR showed that genetically predicted RA was causally associated with pregnancy loss and IUGR in forward MR analyses, and that RA significantly increased pregnancy loss [odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.00-1.33, P = .03] and IUGR (OR = 1.08, 95% CI: 1.01-1.15, P = .019). In the reverse MR, there was no causal association between pregnancy loss (P = .15) and IUGR (P = .87) and RA. CONCLUSION: This study found a significant genetic association between RA and pregnancy loss and IUGR. RA is considered to be a high-risk factor for adverse maternal outcomes. Pre-pregnancy prophylaxis and intra-pregnancy control of patients should be emphasized to reduce the incidence of adverse pregnancy outcomes such as pregnancy loss and IUGR.

LH level on the antagonist administration day as a predictor of the reproductive outcomes in women with normal ovarian function.

Introduction: The addition of antagonists is mainly based on estrogen level and follicle size, while LH level has not received sufficient attention.In this study, LH Level on the antagonist administration day was used as the main research objective to explore its relationship with laboratory indicators and pregnancy outcomes. Methods and Analysis: We enrolled 854 patients with normal ovarian function undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) between May 2021 to May 2022 at the Reproductive Center of Shandong University of Traditional Chinese Medicine.We used the quartile method to group LH levels on the antagonist administration day. There were four groups: Q1 (0.53IU/L≤LH ≤ 1.89IU/L); Q2 (1.89IU/L

Effect of the ratios of estradiol increase on the outcome of in vitro fertilization-embryo transfer with antagonist regimens: a single center retrospective cohort study.

BACKGROUND: The outcome of in vitro fertilization-embryo transfer (IVF) is often determined according to follicle and estradiol levels following gonadotropin stimulation. In previous studies, although most of them analyzed the estrogen level from ovaries or the average estrogen level of a single follicle, there was no study on the ratio of estrogen increase, which was also correlated with pregnancy outcomes in the clinic. This study aimed to make timely adjustments to follow-up medication to improve clinical outcomes based on the potential value of estradiol growth rate. METHODS: We comprehensively analyzed estrogen growth during the entire ovarian stimulation period. Serum estradiol levels were measured on the day of gonadotropin treatment (Gn1), five days later (Gn5), eight days later (Gn8), and on the trigger day (HCG). This ratio was used to determine the increase in estradiol levels. According to the ratio of estradiol increase, the patients were divided into four groups: A1 (Gn5/Gn1 ≤ 6.44), A2 (6.44 < Gn5/Gn1 ≤ 10.62), A3 (10.62 < Gn5/Gn1 ≤ 21.33), and A4 (Gn5/Gn1 > 21.33); B1 (Gn8/Gn5 ≤ 2.39), B2 (2.39 < Gn8/Gn5 ≤ 3.03), B3 (3.03 < Gn8/Gn5 ≤ 3.84), and B4 (Gn8/Gn5 > 3.84). We analyzed and compared the relationship between data in each group and pregnancy outcomes. RESULTS: In the statistical analysis, the estradiol levels of Gn5 (P = 0.029, P = 0.042), Gn8 (P < 0.001, P = 0.001), and HCG (P < 0.001, P = 0.002), as well as Gn5/Gn1 (P = 0.004, P = 0.006), Gn8/Gn5 (P = 0.001, P = 0.002), and HCG/Gn1 (P < 0.001, P < 0.001) both had clinical guiding significance, and lower one significantly reduced the pregnancy rate. The outcomes were positively linked to groups A (P = 0.036, P = 0.043) and B (P = 0.014, P = 0.013), respectively. The logistical regression analysis revealed that group A1 (OR = 0.376 [0.182-0.779]; P = 0.008*, OR = 0.401 [0.188-0.857]; P = 0.018*) and B1 (OR = 0.363 [0.179-0.735]; P = 0.005*, OR = 0.389 [0.187-0.808]; P = 0.011*) had opposite influence on outcomes. CONCLUSION: Maintaining a serum estradiol increase ratio of at least 6.44 on Gn5/Gn1 and 2.39 on Gn8/Gn5 may result in a higher pregnancy rate, especially in young people.

The effect of large follicle puncture and aspiration on the outcomes of IVF-ET in patients with asynchronized follicles under the long GnRH-a protocol: a retrospective cohort study.

OBJECTIVE: This retrospective study aimed to explore whether puncturing and aspirating asynchronized large follicles during long GnRH-a protocol COH impacted IVF-ET outcomes. METHODS: A total of 180 patients with asynchronized follicles during long GnRH-a protocol COH were retrospectively analyzed. They were divided into a puncture group, Group 1 (n = 81), and a non-puncture group, Group 2 (n = 99), according to whether puncture and aspiration were performed on the prematurely developing large follicles. The data of the selected patients were statistically analyzed to assess the effect of large follicle puncture and aspiration during ovulation induction on the final pregnancy results. In addition, we tentatively divided these 180 patients into either Group A (DF ≤ 14 mm) or Group B (DF > 14 mm) according to whether the diameter of the dominant large follicles (DF) exceeded 14 mm at the time of appearance. These two groups were then further divided into four subgroups: Subgroup A1 (DF ≤ 14 mm, patients underwent large follicle puncture), Subgroup A2 (DF ≤ 14 mm, patients did not undergo large follicle puncture), Subgroup B1 (DF > 14 mm, patients underwent large follicle puncture), and Subgroup B2 (DF > 14 mm, patients did not undergo large follicle puncture) based on whether large follicle puncture and aspiration were performed or not, aiming to compare the effects of large follicle puncture and aspiration on the clinical outcomes of patients with dominant large follicles at different time points. RESULTS: Group 1 exhibited significantly higher oocyte maturation rate (92.3% vs. 88.9%, P = 0.009) and high-quality embryo rate (75.2% vs. 65.7%, P = 0.007) compared with Group 2. No differences were observed in the number of oocytes retrieved, 2PN fertilization rate, clinical pregnancy rate, abortion rate, and live birth rate between the two groups (P > 0.05). When the dominant large follicles' diameter was ≤ 14 mm, the final oocyte maturation rate (92.7% vs. 88.1%, P = 0.023), high-quality embryo rate (72.9% vs. 61.8%, P = 0.047) and live birth rate (54.5% vs. 31.9%, P = 0.043) of Subgroup A1 were significantly higher than those of Subgroup A2. In contrast, when the dominant large follicles' diameter was > 14 mm, no statistical difference was observed in all data. CONCLUSIONS: Large follicle puncture and aspiration in long GnRH-a protocol COH could improve the oocyte maturation rate and high-quality embryo rate in patients with asynchronized follicles. However, clinical pregnancy and live birth rates were not significantly improved. In addition, when the dominant follicles' diameter did not exceed 14 mm, large follicles puncture and aspiration significantly improved the patient's oocyte maturation rate, high-quality embryo rate and live birth rate.

Intracavitary physiotherapy combined with acupuncture mediated AMPK/mTOR signalling to improve endometrial receptivity in patients with thin endometrium.

OBJECTIVE: To explore the mechanism of intracavitary physiotherapy combined with acupuncture to improve the receptivity of thin endometrium. METHODS: From October 2020 to April 2021, 40 patients diagnosed with thin endometrium and preparing for hormone replacement cycle freeze-thaw embryo transfer in our centre for Reproduction were included, 40 patients were randomized to treatment group and control group. 20 patients with normal endometrium during the same period were selected as the normal group.All patients underwent freeze-thaw embryo transfer using hormone replacement cycles.The treatment group added endovascular physiotherapy combined with acupuncture. RESULTS: The endometrial receptivity of the patients with thin endometrium was significantly lower than that of the normal group(P < 0.01). Endovascular therapy combined with acupuncture can significantly increase endometrial thickness in patients with thin endometrium and the proportion of patients with type A endometrium, reduce bilateral Uterine arterial pulsatilityindex (PI), Uterine arterial resistance index (RI), and peaksystolicvelocity/diastolicvelocity (S/D), upregulate the expression of HOXA10 protein and mRNA in endometrium tissue, and improve the rate of embryo implantation and clinical pregnancy(P < 0.01).there was no significant difference between the treatment group and the normal group (P > 0.05). This may be related to the regulation of the AMPK/mTOR signalling pathway by intracavitary physiotherapy combined with acupuncture, downregulation of the expression of the AMPK gene and protein and upregulation of the expression of the mTOR gene and protein. CONCLUSIONS: 1. Abnormal energy metabolism is present in the endometrium of patients with thin endometrium, which affects the autophagy process and leads to a decrease in the receptivity of thin endometrium. 2. Intracavitary physiotherapy combined with acupuncture mediated the AMPK/mTOR pathway to improve energy metabolism, promote the autophagy process, improve endometrial morphology and ultrasonic indicators of patients, upregulate the expression of endometrial receptivity-related HOXA10 genes and proteins, and improve the embryo implantation rate and clinical pregnancy rate.

The effect of mildly stimulated cycle versus artificial cycle on pregnancy outcomes in overweight/obese women with PCOS prior to frozen embryo transfer: a retrospective cohort study.

BACKGROUND: Previous studies have shown that frozen embryo transfer (FET) resulted in increased live birth rates (LBR) and reduced the risk of ovarian hyperstimulation syndrome (OHSS) than did fresh embryo transfer in women with polycystic ovary syndrome (PCOS). In addition, overweight/obese women with PCOS are at increased risk of subfertility and complications of pregnancy, compared with normal-weight women. The ovarian stimulation and artificial hormone regimes are the two more commonly used endometrial preparation protocols in PCOS patients.This retrospective study aims to compare the pregnancy outcomes of mildly stimulated cycles (mSTC) and artificial cycles (AC) prior to FET in overweight/obese women with PCOS. METHODS: A retrospective analysis was conducted in overweight/obese women with PCOS who underwent their first FET cycles from January 2018 to December 2020. Two endometrial preparation protocols were used: the mildly stimulated cycles (N = 173) and the artificial cycles (N = 507). All pregnancy outcomes were analyzed by Student's t-test, Chi-square (χ2) statistics and multivariable logistic regression analyses. RESULTS: This study enrolled 680 cases of FET cycles. The mSTC group exhibited significantly higher LBR compared with the AC group (49.7% vs. 41.0%; P = 0.046), while the rate of miscarriage was significantly lower (6.4% vs. 23.0%; P < 0.001). No statistically significant differences were observed in positive pregnancy rate (57.8% vs. 60.0%, P = 0.618), clinical pregnancy rate (54.3% vs. 55.6%, P = 0.769), and ectopic pregnancy rate (2.1% vs. 3.2%, P = 0.860) between two groups. After adjusting for possible confounding factors, multivariate logistic regression analysis also yielded similar results. CONCLUSIONS: For overweight/obese women with PCOS, mSTC-FET demonstrated a higher LBR and a lower pregnancy loss rate than that in the AC-FET. When considering the most cost-effective treatment with the least adverse effects on patients, the mSTC for FET endometrial preparation may be considered. To corroborate our findings, additional prospective randomized clinical trials with larger sample sizes are required.

Effects of half-dose and full-dose GnRH antagonists on IVF-ET outcomes: a retrospective study.

BACKGROUND: Gonadotropin-releasing hormone antagonist(GnRH-ant) has been shown to have a negative effect on endometrial receptivity. Therefore, the use of lower doses of GnRH-ant during controlled ovarian stimulation (COS) may improve endometrial receptivity and clinical pregnancy rate. However, the GnRH-ant dose is relatively flexible and there is no fixed requirement for guidance. In this retrospective study, we determined the effects of half-dose and full-dose GnRH-ant on IVF-ET outcomes. METHODS: Of the 316 cycles in the 314 patients analyzed in this study, 149 received GnRH-ant half-dose (Group1), while 167 received GnRH-ant full-dose (Group2). The groups were further classified based on age and BMI. Age subgroups, were divided as age ≤ 35(subgroup A) and age > 35(subgroup B): 180 cycles in subgroup A (107 cycles in subgroup A1,73 cycles in subgroup A2), 136 cycles in subgroup B (42 cycles in subgroup B1,94 cycles in subgroupB2). The subgroups based on BMI were divided as BMI < 25 (subgroup C)and BMI ≥ 25 (subgroup D):208 cycles in subgroup C (94 cycles in subgroup C1,114 cycles in subgroup C2), 108 cycles in subgroup D (55 cycles in subgroup D1,53 cycles in subgroup D2). RESULTS: The number of fertilized oocytes, superior-quality embryos, clinical pregnancy rate, and live birth rate differed significantly between the two groups. However, the number of retrieved oocytes and available embryos were significantly higher in Group 1 than Group 2 (8.17 ± 4.10 vs. 7.07 ± 4.05, 2.96 ± 2.03 vs. 2.52 ± 1.62, respectively,p<0.05). Differences between the age subgroups were not statistically significant. However, in the subgroups based on BMI, the fertilized oocytes, available embryos, the number of superior-quality embryos, and the live birth rate differed significantly between the four subgroups. The number of retrieved oocytes was higher in subgroup C1 than in subgroup C2 (8.24 ± 4.04 vs. 6.83 ± 3.92,p < 0.05), In addition, the clinical pregnancy rate was slightly higher in subgroup D1 than in subgroup D2(45.45 vs. 24.53%, P < 0.05). CONCLUSIONS: The results showed that half-dose GnRH-ant was as effective as full-dose GnRH-ant for most patients. Moreover, half-dose GnRH-ant may be more suitable in patients with BMI greater than or equal to 25. The findings of this study need to be validated in a large sample RCT. TRIAL REGISTRATION: Retrospectively registered.

Paeonol alleviates migration and invasion of endometrial stromal cells by reducing HIF-1α-regulated autophagy in endometriosis.

Background: Dysregulated migration and invasion of endometrial stromal cells is implicated in the pathogenesis of endometriosis. Hypoxia functions as critical microenvironmental factor that results in promotion of endometrial stromal cells migration and invasion through up-regulation of autophagy. Paeonol functioned as a tumor suppressor in human ovarian cancer and promoted cytoprotective autophagy. However, the role of paeonol in hypoxia-induced autophagy in endometriosis remains unknown. Methods: Stromal cells were isolated from endometriotic patients by enzymatic digestion of ectopic endometrial tissues, and then characterized by immunohistochemical analysis of cytoskeleton 19 (CK19) and vimentin. Cellular morphology was evaluated under microscope. Cell viability, proliferation and apoptosis of stromal cells were assessed by Cell Counting Kit-8, EdU labeling and flow cytometry, respectively. Wound healing and transwell assays were performed to detect metastasis of the stromal cells. Hypoxia-induced autophagy was evaluated through immunohistochemistry and western blot. Results: Paeonol treatment dosage dependently decreased cell proliferation and metastasis of the ectopic endometrial stromal cells (ecESCs), while promoted the cell apoptosis. Hypoxia-induced autophagy in the ecESCs was repressed by paeonol through down-regulation of LC3-II/LC3-I and Beclin-1, while up-regulation of p62. Hypoxia-inducible factor-1α (HIF-1α) was reduced post paeonol treatment, and paeonol-induced increase of p62 and decrease of LC3-II/LC3-I and Beclin-1 were reversed by over-expression of HIF-1α. Over-expression of HIF-1α also attenuated the suppressive effect of paeonol on cell growth of ecESCs. Conclusions: Paeonol attenuated HIF-1α-induced promotion of ecESCs migration and invasion through reducing autophagy, and reduced HIF-1α-induced endometriotic lesion in rats, providing potential therapeutic strategy for the treatment of endometriosis.

A comparison of pregnancy rate between natural cycle and hormone replacement cycle in patients who underwent frozen embryo transfer using 2 consecutive hormone replacement regiments: A STROBE-compliant retrospective study.

For frozen embryo transplantation patients who failed to use hormone replacement cycle (HRC) transplantation for 2 consecutive times, the third time of transplantation was divided into 2 groups: HRC and natural cycle (NC), and the pregnancy rate of the 2 groups, especially the clinical pregnancy rate, was compared.Retrospective study of 174 patients in the reproductive medicine center of an affiliated hospital of Shandong University of Traditional Chinese Medicine between January 2015 and September 2018.The 174 patients were all infertile with regular menstruation. They had undergone 2 consecutive failed cycles of endometrial preparation with hormone replacement therapy and prepare for the third frozen embryo transplantation.A third cycle of treatment was planned using either NC or HRC for endometrial preparation. All the embryos were obtained during the same oocyte retrieval cycle. Patients were divided into groups based on the method of endometrial preparation: 98 were classified as NC and 76 as HRC.The pregnancy outcomes for the 2 groups were compared. Confounding factors that may affect clinical pregnancy rates were analyzed.We found that on the day of endometrial transformation, estrogen levels and endometrial thickness in the NC group were significantly higher than those in the HRC group. There were no significant differences in the rates of biochemical pregnancy, clinical pregnancy, cumulative pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy, or live birth between the 2 groups. It is concluded by binary regression analysis that the different endometrial preparation protocol have no significant effect on the CPR.NC is as effective as HRC after 2 previous cycles of HRC. Because this was a retrospective study design, selection bias is possible, although the baseline characteristics of the 2 groups of patients were matched.

Metabolomic alternations of follicular fluid of obese women undergoing in-vitro fertilization treatment.

Obesity exerts negative effects on the metabolic homeostasis of cells in various tissues, but how it influences ovum metabolism is not fully understood. Previous studies demonstrate that oocyte genes that regulate oxidative stress, lipid metabolism, and inflammation are highly expressed in obese women. However, the metabolic effects of these genetic variations are not clear. To address this gap, we conducted an exploratory evaluation of follicular fluid (FF) metabolites in underweight, normal-weight, overweight, and obese women undergoing in vitro fertilization (IVF) treatment. The FF samples from the underweight (Group A, n = 40), normal-weight (Group B, n = 40), overweight (Group C, n = 40), and obese women (Group D, n = 40) were analyzed using ultra-performance liquid chromatography high-resolution mass spectrometry. A novel, high-coverage, semi-targeted metabolomics method (SWATH to MRM) and a targeted metabolomics method were employed to identify and verify the differential metabolites between the four groups. Sixteen differentially expressed FF metabolites were identified. Increase of BMI was associated with upregulation of 5 metabolites, ganoderiol H, LPI (18:3), sedoheptulose 1,7-bisphosphate, austalide L and 2 - {[hydroxyl (3-hydroxy-4-methoxyphenylmethylidene] amino} acetic acid, and downregulation of 5 metabolites, 1-phenyl-1,3-elcosanedione, retinol acetate, p-Cresol sulfate, setariol and arachidonyl carnitine. These metabolites were enriched in different metabolic pathways of retinol metabolism and fatty acid metabolism. These obesity-related differential metabolites provide a pathogenesis mechanism that explains the decline of oocyte development during obesity. These results suggest that obesity affects follicular environment prior to pregnancy, a time-window that may be important for lifestyle interventions to decrease obesity levels.