Targeting Estrogen Receptor Beta Ameliorates Diminished Ovarian Reserve via Suppression of the FOXO3a/Autophagy Pathway.

Diminished ovarian reserve (DOR) refers to a decrease in the number and/or quality of oocytes, leading to infertility, poor ovarian response and adverse pregnancy outcomes. Currently, the pathogenesis of DOR is largely unknown, and the efficacy of existing therapeutic methods is limited. Therefore, in-depth exploration of the mechanism underlying DOR is highly important for identifying molecular therapeutic targets for DOR. Our study showed that estrogen receptor beta (ERß) mRNA and protein expression was upregulated in granulosa cells (GCs) from patients with DOR and in the ovaries of DOR model mice. Mechanistically, elevated ERß promotes forkhead transcription factor family 3a (FOXO3a) expression, which contributes to autophagic activation in GCs. Activation of FOXO3a/autophagy signalling leads to decreased cell proliferation and increased cell apoptosis and ultimately leads to DOR. In a cyclophosphamide (Cy)-induced DOR mouse model, treatment with PHTPP, a selective ERß antagonist, rescued fertility by restoring normal sex hormone secretion, estrus cycle duration, follicle development, oocyte quality and litter size. Taken together, these findings reveal a pathological mechanism of DOR based on ERß overexpression and identify PHTPP as a potential therapeutic agent for DOR.

Effect of frozen-thawed embryo transfer with a poor-quality embryo and a good-quality embryo on pregnancy and neonatal outcomes.

BACKGROUND: To evaluate the impact of embryo quality and quantity, specifically a poor quality embryo (PQE) in combination with a good quality embryo (GQE), by double embryo transfer (DET) on the live birth rate (LBR) and neonatal outcomes in patients undergoing frozen-thawed embryo transfer (FET) cycles. METHODS: A study on a cohort of women who underwent a total of 1462 frozen-thawed cleavage or blastocyst embryo transfer cycles with autologous oocytes was conducted between January 2018 and December 2021. To compare the outcomes between single embryo transfer (SET) with a GQE and DET with a GQE and a PQE, propensity score matching (PSM) was applied to control for potential confounders, and a generalized estimating equation (GEE) model was used to determine the association between the effect of an additional PQE and the outcomes. Subgroup analysis was also performed for patients stratified by female age. RESULTS: After PS matching, DET-GQE + PQE did not significantly alter the LBR (adjusted odds ratio [OR] 1.421, 95% CI 0.907-2.228) compared with SET-GQE in cleavage-stage embryo transfer but did increase the multiple birth rate (MBR, [OR] 3.917, 95% CI 1.189-12.911). However, in patients who underwent blastocyst-stage embryo transfer, adding a second PQE increased the live birth rate by 7.8% ([OR] 1.477, 95% CI 1.046-2.086) and the multiple birth rate by 19.6% ([OR] 28.355, 95% CI 3.926-204.790), and resulted in adverse neonatal outcomes. For patients who underwent cleavage-stage embryo transfer, transferring a PQE with a GQE led to a significant increase in the MBR ([OR] 4.724, 95% CI 1.121-19.913) in women under 35 years old but not in the LBR ([OR] 1.227, 95% CI 0.719-2.092). The increases in LBR and MBR for DET-GQE + PQE compared with SET-GQE in women older than 35 years were nonsignificant toward. For patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE had a greater LBR ([OR] 1.803, 95% CI 1.165-2.789), MBR ([OR] 24.185, 95% CI 3.285-178.062) and preterm birth rate (PBR, [OR] 4.092, 95% CI 1.153-14.518) than did SET-GQE in women under 35 years old, while no significant impact on the LBR ([OR] 1.053, 95% CI 0.589-1.884) or MBR (0% vs. 8.3%) was observed in women older than 35 years. CONCLUSIONS: The addition of a PQE has no significant benefit on the LBR but significantly increases the MBR in patients who underwent frozen-thawed cleavage-stage embryo transfer. However, for patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE resulted in an increase in both the LBR and MBR, which may lead to adverse neonatal outcomes. Thus, the benefits and risks of double blastocyst-stage embryo transfer should be balanced. In patients younger than 35 years, SET-GQE achieved satisfactory LBR either in cleavage-stage embryo transfer or blastocyst-stage embryo transfer, while DET-GQE + PQE resulted in a dramatically increased MBR. Considering the low LBR in women older than 35 years who underwent single cleavage-stage embryo transfer, selective single blastocyst-stage embryo transfer appears to be a more promising approach for reducing the risk of multiple live births and adverse neonatal outcomes.

ERß-activated LINC01018 promotes endometriosis development by regulating the CDC25C/CDK1/CyclinB1 pathway.

Endometriosis refers to as an estrogen-dependent disease. Estrogen receptor ß (ERß), the main estrogen receptor subtype which is encoded by the estrogen receptor 2 (ESR2) gene, can mediate the action of estrogen in endometriosis. Although selective estrogen receptor modulators can target the ERß, they are not specific due to the wide distribution of ERß. Recently, long noncoding RNAs have been implicated in endometriosis. Therefore, we aim to explore and validate the downstream regulatory mechanism of ERß, and to investigate the potential role of long intergenic noncoding RNA 1018 (LINC01018) as a nonhormonal treatment for endometriosis. Our study demonstrates that the expression levels of ESR2 and LINC01018 are increased in ectopic endometrial tissues and reveals a significant positive correlation between the ESR2 and LINC01018 expression. Mechanistically, ERß directly binds to an estrogen response element located in the LINC01018 promoter region and activates LINC01018 transcription. Functionally, ERß can regulate the CDC25C/CDK1/CyclinB1 pathway and promote ectopic endometrial stromal cell proliferation via LINC01018 in vitro. Consistent with these findings, the knockdown of LINC01018 inhibits endometriotic lesion proliferation in vivo. In summary, our study demonstrates that the ERß/LINC01018/CDC25C/CDK1/CyclinB1 signaling axis regulates endometriosis progression.

[Research Progress on Epigenetics in Endometriosis].

Epigenetics refers to heritable changes in gene expression and function without alterations in gene sequences,including DNA methylation,histone modification,and non-coding RNAs.Endometriosis is a benign gynecological disease that affects the fertility and health of reproductive-age women,the etiology of which remains unclear.The recent studies have demonstrated that epigenetics plays a key role in the occurrence and development of endometriosis.This article reviews the research progress in the regulatory mechanism and application of epigenetics in endometriosis.

The presence of ovarian endometrioma adversely affect ovarian reserve and response to stimulation but not oocyte quality or IVF/ICSI outcomes: a retrospective cohort study.

BACKGROUND: The possible impact of ovarian endometriomas (OMAs) on in vitro fertilization (IVF) outcomes remains controversial. Therefore, this study aimed to assess the impact of OMAs on IVF cycle parameters, including ovarian reserve and response to stimulation, embryo quality and pregnancy outcomes. METHODS: This retrospective cohort study included 2067 patients undergoing their first IVF/ICSI cycles between January 2018 and December 2020. The study group included 154 infertile women who had OMAs. The control group consisted of 1913 women without endometriosis, and finally 305 women were matched according to maternal age, body mass index (BMI), and infertility duration by propensity score matching (PSM). Cumulative live birth rate (CLBR) was set as the primary outcome measure. Logistic regression analysis was conducted on the basis of clinical covariates assessed for their association with CLBRs. Subgroup analyses were performed to evaluate the effect of ovarian surgery, cyst size and laterality on CLBRs. RESULTS: Women with OMAs had significantly lower ovarian reserve markers (AMH and AFC), number of follicles, oocytes, embryos, and top-quality embryos than women in the control group (p < 0.05). However, the CLBRs were comparable between the two groups (55.64% versus 54.34%, p = 0.806), regardless of previous history of ovarian surgery. Multivariate analysis revealed association between age (OR = 0.861; 95% CI [0.806-0.921]; p = 0.000), top-quality embryos (OR = 1.829; 95% CI [1.526-2.193]; p = 0.000) and the CLBRs. A negative correlation between OMA size and AFC levels in patients with unoperated OMAs was detected (r = -0.264, p = 0.007). Meanwhile, significant decrease in ovarian reserve with lower AFC, fewer oocytes, embryos and top-quality embryos were observed in patients with OMAs size ≥ 6 cm (p < 0.05). Moreover, ovaries with OMAs had a significantly lower AFC (P = 0.006) but similar number of oocytes when compared with contralateral ovaries without OMAs. CONCLUSION: Infertile women with OMAs were implicated in considerable decreases in ovarian reserve and response to stimulation, but no apparent adverse effects on oocyte quality or clinical outcomes. OMAs surgery and OMAs size may adversely affect ovarian reserve, but not CLBR.

Role of Abdominal Aortic Balloon Placement in Planned Conservative Management of Placenta Previa With Placenta Increta or Percreta.

Background: We investigated the role of balloon placement in the abdominal aorta (BPAA) in planned conservative management of placenta previa with placenta increta or percreta and the effects of BPAA on perinatal adverse maternal events. Methods: This retrospective case-control study included women with placenta previa (increta or percreta), who underwent pregnancy termination at the Qilu Hospital of Shandong University between January 2016 and June 2019. Patients were categorized into the BPAA and non-BPAA groups based on the BPAA placement before delivery. The Chi-square and non-parametric rank-sum tests were used for the intergroup comparison of patient characteristics. The propensity score matching algorithm was used to minimize the intergroup differences in clinical characteristics. Logistic regression analysis was used to identify the factors associated with a high risk of adverse pregnancy outcomes. The area under the receiver operating characteristic curve [area under the curve (AUC)] was used to evaluate the classification of the selected high-risk factors. Results: The study included 260 patients, and 104 patients were identified after propensity score matching. In the post-matched cohort, intraoperative blood loss was significantly lower in the BPAA than in the non-BPAA group (median 1,000 vs. 2,250 ml, P < 0.001). Intraoperative B-Lynch suture was performed in fewer patients in the BPAA (15.4 vs. 34.6%, P = 0.024) than in the non-BPAA group. The packed red blood cell (PRBC) transfusion rate was lower in the BPAA group (median 4 vs. 8 units, P < 0.001). Overall, 46 (45.1%) patients developed adverse maternal events; however, the rate of adverse maternal events was lower in the BPAA group (19.6 vs. 80.4%, P < 0.001). No ligation of the ascending branch of the uterine artery (P = 0.034), no BPAA (P < 0.001), intraplacental vascular lacunae (P = 0.046), and cervical hypervascularity (P = 0.001) were associated with a high risk of adverse perinatal maternal events. The AUC of the high-risk factors was 0.89 in the post-matched and 0.76 in the pre-matched cohorts. Conclusion: Planned conservative management using BPAA significantly minimized the intraoperative blood loss, the need for a B-Lynch suture, and PRBC transfusion in patients with severe placenta accreta spectrum and placenta previa.

Development and Validation of a Clinical Pregnancy Failure Prediction Model for Poor Ovarian Responders During IVF/ICSI.

Backgrounds: Despite the great advances in assisted reproductive technology (ART), poor ovarian response (POR) is still one of the most challenging tasks in reproductive medicine. This predictive model we developed aims to predict the individual probability of clinical pregnancy failure for poor ovarian responders (PORs) under in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods: The nomogram was developed in 281 patients with POR according to the Bologna criteria from January 2016 to December 2019, with 179 in the training group and 102 in the validation group. Univariate and multivariate logistic regression analyses were used to identify characteristics that were associated with clinical pregnancy failure. The nomogram was constructed based on regression coefficients. Performance was evaluated using both calibration and discrimination. Results: Age >35 years, body mass index (BMI) >24 kg/m2, basic follicle-stimulating hormone (FSH) >10 mIU/ml, basic E2 >60 pg/ml, type B or C of endometrium on human chorionic gonadotropin (hCG) day, and the number of high-quality embryos <2 were associated with pregnancy failure of POR patients. The area under the receiver operating characteristic curve (AUC) of the training set is 0.786 (95% confidence interval (CI): 0.710-0.861), and AUC in the validation set is 0.748 (95% CI: 0.668-0.827), showing a satisfactory goodness of fit and discrimination ability in this nomogram. Conclusion: Our nomogram can predict the probability of clinical pregnancy failure in PORs before embryo transfer in IVF/ICSI procedure, to help practitioners make appropriate clinical decisions and to help infertile couples manage their expectations.

Development and validation of nomograms for predicting blood loss in placenta previa with placenta increta or percreta.

BACKGROUND: To develop the risk prediction model of intraoperative massive blood loss in placenta previa with placenta increta or percreta. METHODS: This study included 260 patients, of whom 179 were allocated to the development group and 81 to the validation group. Univariate and multivariate logistic regression analyses were used to identify characteristics that were associated with massive blood loss (≥2,500 mL) during cesarean section. A nomogram was constructed based on regression coefficients. Receiver-operating characteristic curve, calibration curve, and decision curve analyses were applied to assess the discrimination, calibration, and performance of the model. RESULTS: Two models were constructed. The preoperative feature model (model A) consisted of vascular lacunae within the placenta and hypervascularity of the uterine-placental margin, uterine serosa-bladder wall interface, and cervix. The preoperative and surgical feature model (model B) consisted of an emergency cesarean section, no preoperative balloon placement of the abdominal aorta, and the previously mentioned four ultrasound signs. Model B had better discrimination than model A (area under the curve: development group: 0.839 vs. 0.732; validation group: 0.829 vs. 0.736). Model B showed a higher area under the decision curve than model A in both the training and validation groups. CONCLUSIONS: The preoperative and surgical feature model for placenta previa with placenta increta or percreta can improve the early identification and management of patients who are at high risk of intraoperative massive blood loss.

Severe hyponatremia in preeclampsia: a case report and review of the literature.

PURPOSE: To summarize the clinical characteristics and treatments of preeclampsia complicated with hyponatremia. METHODS: We reported a new case of preeclampsia complicated with severe hyponatremia; searched for relevant articles from the PubMed, Scopus and Cochrane databases; and reviewed all reported cases. RESULTS: Twenty-one reported cases were found. Our case is 22nd, and the serum sodium level in this case was the lowest reported. After treatment comprising fluid restriction, hypertonic saline and caesarean section, a relatively good outcome was achieved. In all reported cases, SIADH, preeclampsia or the combined effect of preeclampsia and induced nephrotic syndrome were the speculated pathogeny. Termination was performed due to adverse manifestations; six cases underwent transvaginal deliveries, and sixteen cases underwent caesarean section. Fifteen patients recovered from hyponatremia within 72 h after delivery. CONCLUSION: The pathogenesis of hyponatremia occurring in patients with preeclampsia is still unclear. Termination of the pregnancy led to a stabilization of the sodium level, ICU monitoring was necessary, and fluid restriction and hypertonic saline intake were applied; however, there was no evidence of the effectiveness of the treatments.