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Background Follicular fluid is an important external environment for the growth and development of oocytes. A thorough identification of specific components in follicular fluid can better the existing understand of intracellular signal transduction and reveal potential biomarkers of oocyte health in women undergoing assisted reproductive therapy. To study on follicular fluid metabolomics components at different ages based on lipid metabolism, we have adopted a new method of SWATH to MRM(the sequential window acquisition of all theoretical fragment-ion spectra to multiple reaction monitor)metabolomics to provide extensive coverage and excellent quantitative data. This was done to investigate the differences in follicular fluid of patients undergoing in vitro fertilization (IVF) and embryo transfer in different age groups and to further explore the relationship between follicular fluid, age and reproductive function. Method A combination of Ultra-high-performance liquid chromatography and high resolution mass spectrometry techniques were used to analyze the follicular fluid of 230 patients enrolled for the IVF cycle. The patients were of different ages grouped into two groups:the younger and older patients.The obtained multidimensional chromatographic data were processed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). The charge ratios and mass numbers enabled for the identification of different fragments in the samples. Matching information obtained through database search and the fragment information obtained by fragment ion scan structurally identified substances in the samples. This was used to determine the differential compounds. Results The quality of oocytes decline with age,and the lipid composition in follicular fluid also changes,The lipid metabolism that changes with age may be related to the quality of oocytes.The main differences were in lipid metabolites. Some were up-regulated: Arachidonate, LysoPC(16:1), LysoPC(20:4) and LysoPC(20:3) while others were down-regulated: LysoPC(18:3) and LysoPC(18:1). Conclusions Metabolomic analysis of follicular fluid revealed that with the increase in age, several differential metabolites are at play. Among these metabolites, lipid metabolism undergoes significant changes that affect the development of oocytes thus causing reduced fertility in older women. These differential metabolites related to follicular development may provide possible detection and treatment targets for promoting oocyte health, and provide scientific basis for understanding the environment of oocyte development.

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.

Mitochondrial function and its regulation within the placenta are critical for maintaining a healthy pregnancy. This study investigated the role of G-protein signaling 12 (RGS12) in placental mitochondrial function and pregnancy outcomes. RGS12 was found to be localized within the mitochondria of placental trophoblast cells. RGS12 knockdown in human placental cells resulted in decreased mitochondrial abundance, impaired oxidative phosphorylation, and reduced antioxidant capacity. Mechanistically, RGS12 enhanced the function of ATP5B, a key mitochondrial enzyme, by promoting its tyrosine phosphorylation. In a mouse model, placental RGS12 deficiency led to reduced tolerance to preterm birth (PTB) challenge, decreased fetal weight, and trophoblast cell death. These adverse effects were associated with diminished ATP synthase activity and activation of the p38MAPK signaling pathway, while restoring RGS12 expression improved the phenotype of mitochondrial dysfunction in placental trophoblast cells. Furthermore, reduced RGS12 expression and impaired mitochondrial function were observed in placentas from cases experiencing PTB. Collectively, these findings provide hitherto undocumented evidence of a specific molecular mechanism by which placental mitochondrial dysfunction contributes to adverse pregnancy outcomes. Our study suggests that RGS12 may represent a novel therapeutic target for improving pregnancy outcomes through its role in regulating placental mitochondrial function.

Background Polycystic ovary syndrome (PCOS) is a complex disorder associated with multiple metabolic disturbance, including defective glucose metabolism and insulin resistance. The altered metabolites caused by the related metabolic disturbance may affect ovarian follicles, which can be reflected in follicular fluid composition. The aim of this study is to investigate follicular fluid metabolic profiles in women with PCOS using an advanced sequential window acquisition of all theoretical fragment-ion spectra (SWATH) mass spectrometry. Materials and methods Nineteen women with PCOS and twenty-one healthy controls undergoing IVF/ET were recruited, and their follicular fluid samples were collected for metabolomic study. Follicular fluid metabolic profiles, including steroid hormones, free fatty acids, bioactive lipids, and amino acids were analyzed using the principal component analysis (PCA) and partial least squares to latent structure-discriminant analysis (PLS-DA) model. Results Levels of free fatty acids, 3-hydroxynonanoyl carnitine and eicosapentaenoic acid were significantly increased ( P  < 0.05), whereas those of bioactive lipids, lysophosphatidylcholines (LysoPC) (16:0), phytosphingosine, LysoPC (14:0) and LysoPC (18:0) were significantly decreased in women with PCOS ( P  < 0.05). Additionally, levels of steroid hormone deoxycorticosterone and two amino acids, phenylalanine and leucine were higher in the PCOS patients ( P  < 0.05). Conclusion Women with PCOS display unique metabolic profiles in their follicular fluid, and this data may provide us with important biochemical information and metabolic signatures that enable a better understanding of the pathogenesis of PCOS.

ObjectiveEarly monitoring of plasma human chorionic gonadotropin (β-hCG) level is vital in predicting pregnancy outcome. This study investigated the predictive value of serum β-hCG level on the seventh day after frozen–thawed embryo transfer (FET) for ongoing pregnancy (OP) and adverse pregnancy (AP).DesignRetrospective study.SettingThe Reproductive and Genetic Center of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, China.Participants1061 pregnant women who underwent FET between January 2014 and January 2017.Primary and secondary outcome measuresPregnancy outcome.ResultsSerum β-hCG levels on the seventh day after FET were higher in the single OP group compared with the biochemical pregnancy group (p<0.001). Besides, the serum β-hCG cut-off level at 4.34 mIU/mL on the seventh day showed high predictive value (area under the curve (AUC)=0.852). Serum β-hCG levels on the seventh day after FET were higher in the twin OP group compared with the single OP group (p<0.001). Also, the serum β-hCG cut-off level at 17.95 mIU/mL on the seventh day showed high predictive value (AUC=0.903). Serum β-hCG levels on the seventh day after FET were lower in the ectopic pregnancy group compared with the single OP group (p<0.001) whereas, serum β-hCG cut-off level at 4.53 mIU/mL on the seventh day exhibited a high predictive value (AUC=0.860). Further, the serum β-hCG levels on the seventh day after FET were lower in the single early spontaneous abortion group compared with the single OP group (p<0.001) while the serum β-hCG cut-off level at 5.34 mIU/mL on the seventh day exhibited high predictive value (AUC=0.738).ConclusionSerum β-hCG on the seventh day after FET has good clinical significance for the prediction of OP and AP.

To evaluate the clinical efficacy of Xiaonang Yusi decoction (XNYSD, ) in patients with phlegm-dampness type polycystic ovary syndrome (PCOS) undergoing fertilization and embryo transfer (IVF-ET), and to investigate its underlying mechanism by examining the arachidonic acid (AA) metabolic pathway. Women undergoing IVF-ET were divided into a treatment group (TCM treatment), a phlegm-dampness PCOS group, and a tubal factor control group (  32 each); all received a GnRH antagonist protocol. The study evaluated IVF-ET laboratory and clinical outcomes, alongside changes in TCM syndrome scores. To elucidate the therapeutic mechanism, follicular fluid AA metabolites were quantified by targeted metabolomics. These data were integrated with a network pharmacology analysis to link the active ingredients of Xiaonang Yusi decoction, PCOS targets, and differential metabolites. A protein-protein interaction (PPI) network was then constructed (STRING) and analyzed for GO/KEGG enrichment (DAVID) to systematically clarify the treatment's mode of action. Clinical findings demonstrate that Traditional Chinese Medicine (TCM) intervention significantly ameliorates phlegm-dampness symptoms in PCOS patients, with marked improvements in embryo implantation rate (52.0% vs. 28.0%), clinical pregnancy rate (67.9% vs. 29.0%), and ongoing pregnancy rate (60.7% vs. 29.0%) (all  0.05), while showing no significant intergroup differences in early miscarriage rates (  0.05). Metabolomic profiling revealed significantly elevated levels of four arachidonic acid metabolites, including 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), in follicular fluid of PCOS patients compared to controls (  0.05), with TCM treatment effectively reducing 15(S)-HETE concentrations (  0.05). Network pharmacological analysis suggests that Xiaonang Yusi Decoction may modulate PCOS pathophysiology through targeting 15(S)-HETE-mediated pathways, acting on core targets including ESR1 and SIRT1, and influencing critical signaling pathways such as cancer-related pathways, lipid metabolism, and PI3K-Akt signaling. Molecular docking results show favourable interactions, indicating the active compound can spontaneously bind and modulate multiple key targets. Xiaonang Yusi Decoction significantly improves TCM syndrome manifestations and IVF-ET outcomes in phlegm-dampness PCOS patients, enhancing embryo quality and pregnancy rates. The therapeutic effects appear mediated through regulation of arachidonic acid metabolites, particularly 15(S)-HETE, in follicular fluid. Network pharmacology analysis has preliminarily elucidated the underlying mechanisms, providing novel evidence for TCM-based PCOS treatment strategies.

Introduction In recent years, the prevalence of infertility has significantly increased and has become a global reproductive health problem. The female ovarian reserves have been shown to decrease progressively with an increase in age. Besides, the rate of embryo implantation and clinical pregnancy also decreases. Traditional Chinese medicine has been widely applied in assisted reproductive technology. It is reported to have a significant influence on improving the quality of oocytes, improving endometrial receptivity, increasing clinical pregnancy rate, reducing pregnancy-related complications, etc. Therefore, this study will investigate the effect of Guilu Xian, a traditional Chinese medicine formula on IVF-ET outcome in older women with low prognosis. Methods and analysis This trial is a prospective, multicenter, randomized double-blind clinical trial. A total of 120 infertile patients with low prognosis and receiving IVF or ICSI in 3 public hospitals in China will be randomly divided into two parallel groups: Guilu Xian group ( n = 60) and placebo group ( n = 60). Patients in both groups will be treated with antagonist regimens to promote ovulation, and all the patients will be required to take the medication from the 2nd to 4th day of the menstrual cycle to the day of egg retrieval. A comparison of the total number of oocytes obtained, the fertilization rate, clinical pregnancy rate, embryo quality, embryo implantation rate, and early spontaneous abortion rate between the experimental group and the placebo group will be performed. Trial registration Chinese Clinical Trials Registry ChiCTR1900028255 . Registered on 16 December 2019.

Background Approximately 15% of couples in the reproductive age are affected by infertility. Women with diminished ovarian reserves (DOR) or with a poor ovarian response (POR) are required to undergo in vitro fertilization and embryo transfer (IVF-ET) to achieve pregnancy. However, studies indicate that poor response to gonadotropin stimulation has been reported in women undergoing IVF-ET. Results from two recent clinical studies in China suggest that traditional Chinese medicine (TCM) formula Dingkun pill (DKP) showed a curative effect by improving the clinical pregnancy rate in women with DOR and POR. However, the heterogeneity of the studies does not allow one to draw a definitive conclusion on the therapeutic effect of DKP. Therefore, the purpose of this study was to investigate the effect of DKP on improving the clinical outcome of pregnancy of IVF-ET in women with low prognosis. Methods A multicenter, double-blinded, randomized placebo-controlled trial was conducted. A total of 460 infertile patients undergoing IVF or intracytoplasmic sperm injection (ICSI) were recruited from 12 public hospitals in China. Participants were randomly divided into the experimental group (DKP formula) or the placebo group (control) at a ratio of 1:1. All patients were treated with GnRH antagonist protocol and ovarian stimulation performed for 5 weeks (from the 5th day of the previous menstrual cycle to the day of oocyte retrieval). The patients were followed up for 6 months to record their conception outcome. The primary outcome is to compare the pregnancy outcome to those under placebo treatment. Secondary outcomes included the total count of the retrieved oocyte, embryo quality, endometrial thickness on ET day, implantation rate, and early miscarriage rate. Discussion Currently, no multicenter, double-blind, randomized, placebo-controlled trials have been performed on the use of the DKP formula to improve on the clinical outcome of the conception of IVF-ET in women with low prognosis. DKP might provide a good clinical solution for females with low prognosis and undergoing IVF. There is no contemporary Western medicine to improve on the clinical outcome of conception in IVF-ET in women with low prognosis. Therefore, it is important to undertake a well-designed randomized trial to determine the effect of DKP in improving the clinical outcome of the conception of IVF-ET in women with low prognosis. Trial registration Chinese Clinical Trial Registry (ChiCTR). Trial registration number: ChiCTR1900026614 . Registered on 16 October 2019.

Many undergoing in vitro fertilization-embryo transfer (IVF-ET) procedures treatments have been tried for older infertile patients, but still can not reverse the aging effect on oocyte, and infertility treatment is expensive, even for people in developed countries. The study aimed to compare outcomes following the application of luteal phase ovulation induction (LPOI) and ultra-short gonadotropin-releasing hormone agonist (GnRH-a) protocols in patients aged more than 40 years undergoing IVF-ET and to examine the effectiveness and feasibility of LPOI. A total of 266 IVF-ET cycles in 155 patients aged 40 years and over were retrospectively analyzed. Of these patients, 105 underwent the ultra-short GnRH-a protocol (GnRH-a group) and 50 underwent LPOI (LPOI group). Various clinical outcomes were compared between these two groups using either t-tests or the chi-square test. The study showed patients in the LPOI group required a higher dosage of human menopausal gonadotropin and a lower dosage of recombinant follicle stimulating hormone than those in the GnRH-a group. Furthermore, though the total dosage of gonadotropin was higher in the LPOI, its cost was lower. Finally, fertilization rates were higher and high-quality embryo rates were lower in the LPOI group, and the live birth rate of LPOI group is higher than (GnRH-a group) . These between-group differences were all significant (P < 0.05). Compared with the ultra-short GnRH-a protocol, LPOI may enable higher 2-pronuclear embryo fertilization rates and lower gonadotropin costs to be achieved, indicating that LPOI might be an ideal choice for older patients undergoing IVF-ET.

Objective. To explore the clinical effect of acupoint application on the outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with polycystic ovary syndrome (PCOS) of the phlegm-dampness type and elucidate its possible mechanism of action from the perspective of follicular fluid metabolomics. Methods. A total of 90 patients undergoing IVF-ET due to infertility were selected and divided into three groups: the treatment group (PCOS with acupoint application, n = 30), the control group (PCOS without acupoint application, n = 30), and the normal group (non-PCOS, n = 30). All patients received a gonadotropin-releasing hormone agonist (GnRH-a) long protocol for controlled ovarian hyperstimulation (COH). Among them, the treatment group was also given the acupoint application from the day of pituitary downregulation to the day of the human chorionic gonadotrophin (hCG) trigger. Ultrahigh-performance liquid chromatography connected with quadrupole time-of-flight mass spectrometry (UHPLC-MS) was adopted for untargeted metabolomic analysis of follicular fluid collected from the three groups of patients on the day of oocyte pick-up (OPU). The significantly differential metabolites were screened using univariate and multivariate statistical analysis, and the related metabolic pathways were identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results. Metabolomic analysis showed that the treatment group’s follicular fluid samples were aggregated with the normal group and separated from the control group. A total of 34 significantly differential metabolites were found in the follicular fluid of patients with phlegm-dampness PCOS and normal people. With the intervention of acupoint application, seven metabolites (pseudouridine, phenol, 2-oxoadipic acid, 9R,10S-EpOME, DL-lactate, nicotinamide, and DL-indole-3-lactic acid) were all downregulated, mainly involving the pathways of pyruvate metabolism, nicotinate and nicotinamide metabolism, protein digestion and absorption, biosynthesis of amino acids, and pyrimidine metabolism. Conclusions. Acupoint application can effectively improve the clinical symptoms and the outcome of IVF-ET treatment in patients with PCOS of the phlegm-dampness type, and its mechanism of action may be related to the regulation of the pathways of pyruvate metabolism, nicotinate and nicotinamide metabolism, protein digestion and absorption, biosynthesis of amino acids, and pyrimidine metabolism.