Monoamine oxidases activity maintains endometrial monoamine homeostasis and participates in embryo implantation and development.

BACKGROUND: Monoamine oxidases (MAOs) is an enzyme that catalyzes the deamination of monoamines. The current research on this enzyme is focused on its role in neuropsychiatric, neurodevelopmental, and neurodegenerative diseases. Indeed, MAOs with two isoforms, namely, A and B, are located on the outer mitochondrial membrane and are widely distributed in the central nervous system and peripheral tissues. Several reports have described periodic changes in the levels of this enzyme in the human endometrial tissue. RESULTS: The novel role of MAOs in endometrial receptivity establishment and embryonic development by maintaining monoamine homeostasis was investigated in this study. MAOs activity was observed to be enhanced during the first trimester in both humans and mice under normal conditions. However, under pathological conditions, MAOs activity was reduced and was linked to early pregnancy failure. During the secretory phase, the endometrial stromal cells differentiated into decidual cells with a stronger metabolism of monoamines by MAOs. Excessive monoamine levels cause monoamine imbalance in decidual cells, which results in the activation of the AKT signal, decreased FOXO1 expression, and decidual dysfunction. CONCLUSIONS: The findings suggest that endometrial receptivity depends on the maintenance of monoamine homeostasis via MAOs activity and that this enzyme participates in embryo implantation and development.

High progesterone levels on the day after HCG injection has no effect on clinical pregnancy outcomes in in vitro fertilization-embryo transfer.

Background: This study investigates the potential impact of high progesterone (P) level on the day following human chorionic gonadotropin (HCG) injection on the clinical pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET). Methods: Retrospective analysis was conducted on 6418 cycles of IVF-ET performed at Liuzhou Maternal and Child Health Hospital between August 2020 to December 2021. Excluding cycles with progesterone levels ≥1.5ng/ml on HCG injection, a total of 781 cycles were identified according to the standard, and they were divided into five groups according to the progesterone level on the day after HCG: Group A: progesterone level < 2.5 ng/ml (n = 128); Group B: 2.5 ng/ml ≤ progesterone level < 3.5 ng/ml (n = 174); Group C: 3.5 ng/ml ≤ progesterone level < 4.5 ng/ml (n = 153); Group D: 4.5 ng/ml ≤ progesterone level < 5.5 ng/ml (n = 132); Group E progesterone level ≥5.5 ng/ml(n=194). Comparative analyses of clinical data, including general clinical data, and clinical pregnancy outcomes such as clinical pregnancy rate, miscarriage rate, and live birth rate were performed among these groups. Results: There were significant differences in estradiol levels on HCG injection, but there were no differences in available embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Binary logistic regression analysis showed that there was no significant correlation between P level on the day after HCG injection and the live birth rate. Conclusion: Under the condition of low P level on HCG injection, high progesterone levels on the day after HCG injection does not affect the clinical pregnancy outcomes of IVF-ET.

Peri-implantation estradiol level has no effect on pregnancy outcome in vitro fertilization- embryo transfer.

Background: The necessity of monitoring luteal endocrine functions in in vitro fertilization- embryo transfer (IVF-ET) remains uncertain. Specifically, the significance of luteal phase estradiol (E2) levels is a matter of debate in current literature. Objective: To assess the impact of luteal phase (day 11 after HCG trigger) estradiol levels on IVF-ET outcomes. Design: Twelve thousand five hundred and thirty-five (n = 12,535) IVF-ET cycles performed in our center between 2015 and 2021 were divided into 5 groups based on the middle and late luteal phase serum E2 (MllPSE2) level percentiles as follows: Group A < 50 pg/mL (N=500), group B 50 pg/mL≤E2<150 pg/mL (N=2545), group C 150 pg/mL≤E2<250 pg/mL (N=1327), group D 250 pg/mL≤E2<500 pg/mL (N=925), group E E2≥500 pg/mL (n=668). The clinical pregnancy rates, abortion rates, and live birth rates of each group were compared. Binary logistic regression analysis was carried out to assess the potential impact of MllPSE2 on the live birth rate (LBR). Results: No significant differences were found in various parameters when comparing the five groups. The level of MllPSE2 showed no significant difference between the pregnant group and the non-pregnant group. The binary logistic regression analysis model demonstrated that MllPSE2 was not significantly related to LBR. Conclusion: The influence of E2 during the peri-implantation period (day 11) on clinical outcome in IVF-ET is not affected, even if E2<50 pg/mL. It is speculated that ovarian-derived E2 in MllPSE2 is not deemed necessary for endometrial receptivity. Although caution is warranted due to the retrospective nature of the analysis and the potential for unmeasured confounding, it is argued that the need for luteal E2 monitoring in IVF-ET may be of questionable value.

A systematic review and meta-analysis: clinical outcomes of recurrent pregnancy failure resulting from preimplantation genetic testing for aneuploidy.

Background: Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic chromosomal abnormalities. However, the clinical benefits of PGT-A in recurrent pregnancy failure (RPF) patients, particularly in young RPF patients, remains uncertain. Objective and rationale: This meta-analysis aimed to determine whether RPF patients undergoing PGT-A had better clinical outcomes compared to those not undergoing PGT-A, thus assessing the value of PGT-A in clinical practice. Search methods: We systematically searched PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database for Chinese Technical Periodicals (VIP) from 2002 to 2022. Thirteen published studies involving 930 RPF patients screened using PGT-A and over 1,434 RPF patients screened without PGT-A were included in this meta-analysis. Clinical outcomes were evaluated based on embryo transfers after PGT-A (n=1,015) and without PGT-A (n=1,799). Clinical outcomes: The PGT-A group demonstrated superior clinical outcomes compared to the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) group. The PGT-A group had a significantly higher implantation rate (IR) (RR=2.01, 95% CI: [1.73; 2.34]), clinical pregnancy rate (CPR) (RR=1.53, 95% CI: [1.36; 1.71]), ongoing pregnancy rate (OPR) (RR=1.76, 95% CI: [1.35; 2.29]), live birth rate (LBR) (RR=1.75, 95% CI: [1.51; 2.03]), and significantly lower clinical miscarriage rate (CMR) (RR=0.74, 95% CI: [0.54; 0.99]). Subgroup analysis based on patient age (under 35 years and 35 years or older) showed that both PGT-A subgroups had significantly better CPR (P<0.01) and LBR (P<0.05) values compared to the IVF/ICSI groups. Summary: This meta-analysis demonstrates that PGT-A in RPF patients, is associated with improved clinical outcomes, including higher IR, CPR, OPR, and LBR values, and lower CMR compared to the IVF/ICSI group. These findings support the positive clinical application of PGT-A in RPF patients. Systematic Review Registration: http://INPLASY.com, identifier INPLASY 202320118.

Maternal anxiety affects embryo implantation via impairing adrenergic receptor signaling in decidual cells.

Recurrent implantation failure (RIF) is defined as the failed pregnancy after good embryo transfer over 3 cycles during in vitro fertilization (IVF).The human endometrium plays a vital role in providing the site for embryo implantation, with several factors implicated in unsatisfactory endometrial receptivity in RIF. Our present results revealed that women with pregnancy loss or infertility have a higher serum epinephrine level, indicating a potential correlation between psychological stress and pregnancy failure. RNA-sequencing of the tissues collected at the endometrial receptive phase in normal and RIF women showed that stress hormones could affect the functional status of endometrial receptivity. Subsequent analysis revealed that the epinephrine signaling acts as an important regulator of endometrial receptivity through the PI3K-AKT and FOXO1 signaling pathways. We also found that patients with RIF show attenuated expression of the alpha-2C-adrenergic receptor (ADRA2C) and that its down regulation induced by high level epinephrine could inhibit the decidualization. Early pregnant mice treated with stress showed high serum epinephrine levels, defective uterine adrenergic receptor expression, and low pregnancy rates. Altogether, our findings indicate that mental stress during early pregnancy can alter the functional status of endometrial receptivity.

SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization.

The establishment of pregnancy in human necessitates appropriate decidualization of stromal cells, which involves steroids regulated periodic transformation of endometrial stromal cells during the menstrual cycle. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of decidualization in humans is yet to be fully elucidated. In this investigation, we document that SOX4 is a key regulator of human endometrial stromal cells decidualization by directly regulating FOXO1 expression as revealed by whole genomic binding of SOX4 assay and RNA sequencing. Besides, our immunoprecipitation and mass spectrometry results unravel that SOX4 modulates progesterone receptor (PGR) stability through repressing E3 ubiquitin ligase HERC4-mediated degradation. More importantly, we provide evidence that dysregulated SOX4-HERC4-PGR axis is a potential cause of defective decidualization and recurrent implantation failure in in-vitro fertilization (IVF) patients. In summary, this study evidences that SOX4 is a new and critical regulator for human endometrial decidualization, and provides insightful information for the pathology of decidualization-related infertility and will pave the way for pregnancy improvement.

The intrauterine perfusion of granulocyte-colony stimulating factor (G-CSF) before frozen-thawed embryo transfer in patients with two or more implantation failures.

The objective of this study was to investigate the clinical benefits of intrauterine perfusion with G-CSF in patients undergoing a frozen-thawed embryo transfer (FET) after at least two previous implantation failures. This was a prospective, randomized, single-blind study. The intervention group received an intrauterine infusion of G-CSF whereas the placebo group was given an intrauterine infusion of physiological saline before embryo transfer. A third (control) group did not receive an intrauterine infusion prior to embryo transfer. The clinical pregnancy rates of both the intervention and placebo group were significantly higher than that in the control group (p < 0.05). But the miscarriage rates of the G-CSF were significantly lower than those of the other two groups (p < 0.05). The intrauterine infusion of G-CSF before frozen-thawed embryo transfer significantly reduced miscarriage rates and improve the live birth rates. While intrauterine perfusion with physiological saline did not reduce miscarriage rates.

Talin1 regulates the endometrial epithelial cell adhesive capacity by interacting with LASP1 and Vitronectin.

The endometrium is a highly complex tissue that is vulnerable to subtle gene expression changes and is the first point of contact for an implanting blastocyst. Talin1 has previously been identified to regulate cytoskeleton and cell motility, however it has not been investigated in association with infertility. Herein, we presented that Talin1 dysregulation in the missed abortion endometrium would negatively influence endometrial adhesive capacity. Mechanistically, intracellular Talin1 inhibited the nuclear transportation of LIM and SH3 protein 1 (LASP1) and restored the expression of adhesion-associated protein. Moreover, extracellular Talin1 enforces endometrial epithelial cell adhesive capacity by interacting with Vitronectin (VTN) and activating the FAK/Src/ERK signalling pathway. This finding provides a novel insight into the potential use of Talin1 for managing endometrial epithelia cell adhesion. This study represents the first demonstration of Talin1 function in endometrial epithelial cell adhesion and endometrial receptivity. Our findings indicate that re-expression of Talin1 might represent a useful strategy for preventing and treating early pregnancy failure and infertility.

Progestin-primed ovarian stimulation is a feasible method for poor ovarian responders undergoing in IVF/ICSI compared to a GnRH antagonist protocol: A retrospective study.

BACKGROUND: Poor ovarian response (POR) to ovarian hyperstimulation is one of the biggest challenges in assisted reproduction technology. The objective of this study was to compare the efficacy of progestin-primed ovarian stimulation (PPOS) with a GnRH antagonist (GnRH-ant) in poor ovarian response (POR) patients. MATERIALS AND METHODS: This retrospective analysis included a total of 186 cycles of POR patients between 2014 and 2016. The patients were divided into two groups according to the method of stimulation protocol, as follows: 63 cycles were PPOS, and 123 cycles were GnRH-ant. Reproduction-related clinical outcomes in the two groups were compared. RESULTS: There were no significant differences in patients' age, dose and duration of gonadotropin (Gn) treatment, serum luteinizing hormone (LH) and E2 levels on the day of hCG injection, or the number of oocytes retrieved between the two groups. The MII oocyte rates, fertilization rates, good-quality embryo rates were significantly higher in the PPOS group than they were in the antagonist group (p<0.05). In the subsequent frozen-thawed embryo transfer (FET), clinical pregnancy and live birth rates were significantly higher in the PPOS group than they were in the antagonist group (p<0.05). CONCLUSIONS: Compared with the GnRH-ant protocol, the PPOS protocol may be a better regime for POR that can effectively improve clinical pregnancy and live birth rates.

Modified hMG stimulated: an effective option in endometrial preparation for frozen-thawed embryo transfer in patients with normal menstrual cycles.

To evaluate the clinical efficacy of modified human menopausal gonadotropin (hMG) stimulated, hormone replacement therapy (HRT), natural cycling and letrozole ovulation induction during endometrial preparation for frozen-thawed embryo transfer (FET) in patients with normal menstrual cycles. This retrospective analysis included a total of 5070 cycles of patients with normal menstrual patterns who underwent FET between October 2009 and September 2015. The patients were divided into four groups according to the method of endometrial preparation for FET: 1838 cycles were natural, 1666 underwent HRT, 340 underwent letrozole ovulation induction and 1226 underwent modified hMG stimulated. Reproduction-related clinical outcomes in the four groups were compared. The clinical pregnancy rates and live birth rates of patients in the modified hMG stimulated group were significantly higher than that in the other groups p < .05. While abortion rates were not significantly different among all four groups (all p >.05). Modified hMG stimulated resulted in a higher pregnancy rate compared to the other treatment groups. Therefore, modified hMG stimulated may be an effective option in endometrial preparation for FET in patients with normal menstrual cycles.

Effects of intrauterine perfusion of human chorionic gonadotropin in women with different implantation failure numbers.

PROBLEM: The aim of this research was to investigate the effects of the intrauterine perfusion of hCG before a frozen-thawed embryo transfer (FET) in women with different implantation failure numbers. METHOD OF STUDY: This was a retrospective analysis of patients undergoing FET who received an intrauterine injection hCG 1000 IU before embryo transfer. The groups included women with their first implantation failure (A group, n = 26), second implantation failure (B group, n = 122), and three or more failures (C group, n = 77). Corresponding control groups (no infusion) were also included. The pregnancy rates were compared among these groups. RESULTS: After intrauterine injection hCG, the biochemical pregnancy rates were 92.30%, 63.11%, 49.02%, and the clinical pregnancy rates were 76.92%, 54.91%, 48.05%, in the A, B, and C groups, respectively. The biochemical and clinical pregnancy rates were significantly higher in the A group than in the other groups (P < .05). The clinical pregnancy rates of the A and C groups were significantly higher than in the corresponding (no infusion) control groups (76.92% vs 56.81% and 48.05% vs 33.33%, P < .05). CONCLUSION: Pregnancy rates decreased with the number of transplant failures. The intrauterine administration of hCG before FET significantly improved the pregnancy rates, especially after one and three or more implantation failures.

A study of intrauterine infusion of human chorionic gonadotropin (hCG) before frozen-thawed embryo transfer after two or more implantation failures.

OBJECTIVE: To investigate the effect of intrauterine infusion of human chorionic gonadotropin (hCG) before frozen-thawed embryo transfer (FET) after two or more implantation failures (TIFs). METHODS: The study was a prospective randomized single-blind study of 161 cycles in patients undergoing FET who had TIFs. The intervention group received an intrauterine injection of 1000 IU of hCG before embryo transfer (ET) (n = 62). A placebo group (n = 49) received an intrauterine injection of physiological saline before ET. A control group (n = 50) did not receive an intrauterine injection. Clinical pregnancy rates, abortion rates, and ongoing pregnancy rates were compared between the three groups. RESULTS: The clinical pregnancy rates were 59.68%, 53.06%, and 32.00% in the hCG group, placebo group, and control group, respectively. The clinical pregnancy rates were significantly higher in the hCG and placebo groups than in the control group. There were no significant differences in the abortion rates among the three groups. CONCLUSION: An intrauterine administration of hCG before FET significantly improved the pregnancy rates after TIFs. But local injury caused by the operation of intrauterine perfusion may play an important role in improving clinical pregnancy rates.

Gonadotropin-releasing hormone agonist for oocyte triggering in endometrial preparation of letrozole stimulation protocols does not affect clinical outcome of frozen-thawed embryo transfer.

OBJECTIVE: This study aims to evaluate the effectiveness of GnRH agonist in comparison with hCG for triggering final oocyte maturation in endometrial preparation of letrozole stimulation protocols for frozen-thawed embryo transfer. METHODS: The frozen-thawed embryo transfer cycles (FET) that use the letrozole stimulation protocols for endometrial preparation were divided into two groups according the different method of triggering final oocyte maturation. The serum LH and E2 levels, and the endometrial thickness on the day of triggering, the clinical pregnancy rates, the miscarriage rates and live birth rates were compared. RESULTS: There were no significant differences in the age, the endometrial thickness, the number of embryos transferred between the two groups. The clinical pregnancy rate, abortion rate and live birth rates of the group A were similar compared with the group B, P<0.05. CONCLUSION: Using GnRH agonist for oocyte triggering in endometrial preparation of letrozole stimulation protocols for frozen-thawed embryo transfer does not affect the clinical outcome compared with hCG under the same luteal phase support.