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.

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.

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.

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.