OBJECTIVE: To evaluate the effect of berberine as adjuvant therapy for the treatment of reduced fertility potential in women with polycystic ovary syndrome (PCOS) through a meta-analysis.
METHODS: We comprehensively searched CNKI, SinoMed, Wanfang, Cochrane Library, PubMed, Embase databases to identify randomized controlled trials (RCTs) evaluating the effect of berberine as adjuvant therapy for treating reduced fertility potential in women with PCOS.
RESULTS: A total of 10 RCTs involving 713 patients were included. Berberine in combination with Western medicine significantly improved endometrial thickness (weight mean difference [WMD] 1.62 mm; 95 % confidence interval [CI] 1.39-1.85), ovulation rate (risk ratio [RR] 1.41; 95 % CI 1.26-1.60), and clinical pregnancy rate (RR 1.96; 95 % CI 1.59-2.41) compared to Western medicine alone. Moreover, berberine as adjuvant therapy also significantly reduced the blood levels of luteinizing hormone (WMD -2.07 U/L; 95 % CI -2.62 to -1.51) and total testosterone (standard mean difference -0.70; 95 % CI -1.02 to -0.39) but not the level of follicle-stimulating hormone level (WMD -0.23 IU/L; 95 % CI -0.52 to 0.06).
CONCLUSIONS: Berberine may serve as an adjuvant therapy to enhance ovulation and increase clinical pregnancy rates in women with PCOS. The potential advantages of berberine may be linked to improvements in endometrial thickness, total testosterone, and luteinizing hormone level. However, further clinical trials are needed to confirm these findings and establish definitive conclusions.

Oocyte aging is a key constraint on oocyte quality, leading to fertilization failure and abnormal embryonic development. In addition, it is likely to generate unfavorable assisted reproductive technology (ART) outcomes. SCM-198, a synthetic form of leonurine, was found to rescue the rate of oocyte fragmentation caused by postovulatory aging. Therefore, the aim of this study was to conduct a more in-depth investigation of SCM-198 by exploring its relationship with aged oocytes after ovulation or maternal aging and clarifying whether it affects cell quality. The results indicate that, compared to the postovulatory aged group, the 50 µM SCM-198 group significantly improved sperm-egg binding and increased fertilization of aged oocytes, restoring the spindle apparatus/chromosome structure, cortical granule distribution, and ovastacin and Juno protein distribution. The 50 µM SCM-198 group showed significantly normal mitochondrial distribution, low levels of reactive oxygen species (ROS), and a small quantity of early oocyte apoptosis compared to the postovulatory aged group. Above all, in vivo supplementation with SCM-198 effectively eliminated excess ROS and reduced the spindle/chromosome structural defects in aged mouse oocytes. In summary, these findings indicate that SCM-198 inhibits excessive oxidative stress in oocytes and alters oocyte quality both in vitro and in vivo.

Chronic stress has become a major problem that endangers people\'s physical and mental health. Studies have shown that chronic stress impairs female reproduction. However, the related mechanism is not fully understood. P2X7 receptor (P2X7R) is involved in a variety of pathological changes induced by chronic stress. Whether P2X7R is involved in the effect of chronic stress on female reproduction has not been studied. In this study, we established a chronic restraint stress mouse model and chronic cold stress mouse model. We found that the number of corpora lutea was significantly reduced in the two chronic stress models. The number of corpora lutea indirectly reflects the ovulation, suggesting that chronic stress influences ovulation. P2X7R expression was significantly increased in ovaries of the two chronic stress models. A superovulation experiment showed that P2X7R inhibitor A-438079 HCL partially rescued the ovulation rate of the two chronic stress models. Further studies showed that activation of P2X7R signaling inhibited the cumulus expansion and promoted the expression of NPPC in granulosa cells, one key negative factor of cumulus expansion. Moreover, sirius red staining showed that the ovarian fibrosis was increased in the two chronic stress models. For the fibrosis-related factors, TGF-β1 was increased and MMP2 was decreased. In vitro studies also showed that activation of P2X7R signaling upregulated the expression of TGF-β1 and downregulated the expression of MMP2 in granulosa cells. In conclusion, P2X7R expression was increased in the ovaries of the chronic restraint-stress and chronic cold-stress mouse models. Activation of P2X7R signaling promoted NPPC expression and cumulus expansion disorder, which contributed to the abnormal ovulation of the chronic stress model. Activation of P2X7R signaling is also associated with the ovarian fibrosis changes in the chronic stress model.

BACKGROUND: Study objectives included the development of a practical nomogram for predicting live birth following frozen-thawed embryo transfers in ovulatory women.
METHODS: Totally, 2884 patients with regular menstrual cycles in our center were retrospectively enrolled. In an 8:2 ratio, we randomly assigned patients to training and validation cohorts. Then we identified risk factors by multivariate logistic regression and constructed nomogram. Finally, receiver operating characteristic curve analysis, calibration curve and decision curve analysis were performed to assess the calibration and discriminative ability of the nomogram.
RESULTS: We identified five variables which were related to live birth, including age, anti-Müllerian hormone (AMH), protocol of frozen-thawed embryo transfer (FET), stage of embryos and amount of high-quality embryos. We then constructed nomograms that predict the probabilities of live birth by using those five parameters. Receiver operating characteristic curve analysis (ROC) showed that the area under the curve (AUC) for live birth was 0.666 (95% CI: 0.644-0.688) in the training cohort. The AUC in the subsequent validation cohorts was 0.669 (95% CI, 0.625-0.713). The clinical practicability of this nomogram was demonstrated through calibration curve analysis and decision curve analysis.
CONCLUSIONS: Our nomogram provides a visual and simple tool in predicting live birth in ovulatory women who received FET. It could also provide advice and guidance for physicians and patients on decision-making during the FET procedure.

BACKGROUND: Accurately predicting ovulation timing is critical for women undergoing natural cycle-frozen embryo transfer. However, the precise predicting of the ovulation timing remains challenging due to the lack of consensus among different clinics regarding the definition of this significant event.
OBJECTIVE: To compare the effectiveness of preovulatory serum progesterone levels (P4) versus luteinizing hormone levels (LH) in predicting ovulation time using two machine learning models.
METHODS: 771 patients who underwent autologous natural cycle-frozen embryo transfer between January 2015 and February 2022 were recruited. Utilizing variables including follicle diameters, preovulatory serum levels of LH, E2, and P4, two machine learning models were constructed to predict the ovulation time, the importance of the variables in predicting ovulation timing was further ranked.
RESULTS: Two machine learning models have the capability to accurately predict the timing of ovulation, specifically within 72, 48, or 24 h. The overall accuracy rates of the validation dataset, as determined by the classification trees and random forest models, were found to be 78.83% and 85.28% respectively. Notably, when predicting ovulation within 24 h, the accuracy rate of P4 ≥ 0.65ng/ml exceeded 92%. Furthermore, it was important to consider LH or E2 levels in conjunction with P4 when assessing ovulation timing in cases where P4<0.65ng/ml.
CONCLUSIONS: Preovulatory serum P4 levels are better predictors of ovulation timing than LH levels and could be used as an alternative in clinical settings, and the model we developed can be used to pinpoint the day of ovulation. Ongoing research and advancements in technology are anticipated to enhance and refine the ovulation method.

UNASSIGNED: Endometriosis is a chronic inflammatory disease of women during their reproductive years. The relationship between the severity and location of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery remains unclear.
UNASSIGNED: We explored the association between the various phenotypes of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery, using two-sample Mendelian randomization (MR) and summary data on endometriosis stages and locations from the FinnGen consortium and women\'s menstruation, ovulation, reproductive function, and mode of delivery from OpenGWAS and ReproGen. Inverse-variance weighting was used for the primary MR analysis. In addition, a series of sensitivity analyses, confounding analyses, co-localization analyses, and multivariate MR analyses were performed.
UNASSIGNED: MR analysis showed a negative effect of moderate to severe endometriosis on age at last live birth (OR = 0.973, 95% CI: 0.960-0.986) and normal delivery (OR = 0.999, 95% CI: 0.998-1.000; values for endpoint were excluded), ovarian endometriosis on age at last live birth (OR = 0.976, 95% CI: 0.965-0.988) and normal delivery (OR = 0.999, 95% CI: 0.998-1.000; values for endpoint were excluded), and fallopian tubal endometriosis on excessive irregular menstruation (OR = 0.966, 95% CI: 0.942-0.990). Bidirectional MR analysis showed that age at menarche had a negative causal effect on intestinal endometriosis (OR = 0.417, 95% CI: 0.216-0.804). All MR analyses were confirmed by sensitivity analyses, and only the genetic effects of moderate to severe endometriosis on normal delivery and age at last live birth were supported by co-localization evidence.
UNASSIGNED: Our findings deepen the understanding of the relationship between various types of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery and clarify the important role of moderate to severe endometriosis.

The mechanisms behind the selection and initial recruitment of primordial follicles (PmFs) from the non-growing PmF pool during each estrous cycle in females remain largely unknown. This study demonstrates that PmFs closest to the ovulatory follicle are preferentially activated in mouse ovaries under physiological conditions. PmFs located within 40 μm of the ovulatory follicles were more likely to be activated compared to those situated further away during the peri-ovulation period. Repeated superovulation treatments accelerated the depletion of the PmF reserve, whereas continuous suppression of ovulation delayed PmF reserve consumption. Spatial transcriptome sequencing of peri-ovulatory follicles revealed that ovulation primarily induces the degradation and remodeling of the extracellular matrix (ECM). This ECM degradation reduces mechanical stress around PmFs, thereby triggering their activation. Specifically, Cathepsin L (CTSL), a cysteine proteinase and lysosomal enzyme involved in ECM degradation, initiates the activation of PmFs adjacent to ovulatory follicles in a distance-dependent manner. These findings highlight the link between ovulation and selective PmF activation, and underscore the role of CTSL in this process under physiological conditions.

BACKGROUND: At present, a number of clinical trials have been carried out on GLP-1 receptor agonist liraglutide in the treatment of polycystic ovary syndrome (PCOS). However, the effect of liraglutide on follicle development and its specific mechanism are still unclear.
METHODS: RNA sequencing was used to explore the molecular characteristics of granulosa cells from patients with PCOS treated with liraglutide. The levels of C-X-C motif chemokine ligand 10 (CXCL10) in follicular fluid were detected by ELISA, the expression levels of ovulation related genes and inflammatory factor genes in follicles and granulosa cells were detected by qPCR and the protein levels of connexin 43 (Cx43), Janus Kinase 2 (JAK2) and phosphorylated JAK2 were detected by Western blot. The mouse ovarian follicles culture system in vitro was used to detect the status of follicle development and ovulation.
RESULTS: In the present study, we found that liraglutide inhibited the secretion of inflammatory factors in PCOS granulosa cells, among which CXCL10 was the most significant. In addition, CXCL10 was significantly higher in granulosa cells and follicular fluid in PCOS patients than in non-PCOS patients. We applied in vitro follicle culture and other techniques to carry out the mechanism exploration which revealed that CXCL10 disrupted the homeostasis of gap junction protein alpha 1 (GJA1) between oocyte and granulosa cells before physiological ovulation, thus inhibiting follicular development and ovulation. Liraglutide inhibited CXCL10 secretion in PCOS granulosa cells by inhibiting the JAK signaling pathway and can improved dehydroepiandrosterone (DHEA)-induced follicle development disorders, which is reversed by CXCL10 supplementation.
CONCLUSIONS: The present study suggests that liraglutide inhibits CXCL10 secretion in granulosa cells through JAK signaling pathway, thereby improving the homeostasis of GJA1 between oocyte and granulosa cells before physiological ovulation and ultimately improving the follicular development and ovulation of PCOS, which provides more supportive evidence for the clinical application of liraglutide in the treatment of ovulatory disorders in PCOS.
BACKGROUND: Not applicable.

OBJECTIVE: To observe the protective effect of acupuncture at \"Zhibian\" (BL 54) through \"Shuidao (ST 28)\" based on the PI3K/AKT/FOXO3a pathway in mice with poor ovarian response (POR), and to explore the possible mechanism of acupuncture in inhibiting ovarian granulosa cells apoptosis in POR.
METHODS: A total of 45 mice with regular estrous cycles were randomly divided into a blank group, a model group and an acupuncture group, with 15 mice in each group. Mice in the model group and the acupuncture group were given triptolide suspension (50 mg•kg-1•d-1) by gavage for 2 weeks to establish POR model. After successful modeling, mice in the acupuncture group were given acupuncture at \"Zhibian\" (BL 54) through \"Shuidao\" (ST 28) for 2 weeks, once a day, 20 min each time. Ovulation induction was started the day after the intervention ended, and samples were taken from each group after ovulation induction. Vaginal smears were used to observe changes in the estrous cycle of mice. The number of oocytes retrieved, ovarian wet weight, final body weight, and ovarian index were measured. The levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), estradiol (E2), and luteinizing hormone (LH) in serum were detected by ELISA. The morphology of ovarian tissue was observed by HE staining. The apoptosis of ovarian granulosa cells was detected by TUNEL staining. The mRNA expression of PI3K, AKT, and FOXO3a in ovarian tissue was detected by real-time fluorescence quantitative PCR. The protein expression of Bcl-2 associated X protein (BAX), caspase-3, phosphorylated phosphatidylinositol 3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) in ovarian tissue was detected by Western blot.
RESULTS: Compared with the blank group, the rate of estrous cycle disorder in the model group was increased (P<0.01); compared with the model group, the rate of estrous cycle disorder in the acupuncture group was decreased (P<0.01). Compared with the blank group, the number of oocytes retrieved, ovarian wet weight, ovarian index, and final body weight in the model group were decreased (P<0.01); compared with the model group, the number of oocytes retrieved, ovarian index, and ovarian wet weight were increased (P<0.01, P<0.05), and there was no significant difference in final body weight (P>0.05) in the acupuncture group. Compared with the blank group, the serum levels of FSH and LH were increased (P<0.01), and the serum levels of AMH and E2 were decreased (P<0.01) in the model group; compared with the model group, the serum levels of FSH and LH were decreased (P<0.01, P<0.05), and the serum levels of AMH and E2 were increased (P<0.01, P<0.05) in the acupuncture group. Compared with the blank group, the number of normal developing follicles in ovarian tissue in the model group was decreased and the morphology was poor, while the number of atretic follicles increased; compared with the model group, the number, morphology, and granulosa cell structure of follicles in the acupuncture group improved to varying degrees, and the number of atretic follicles decreased. Compared with the blank group, the apoptosis rate of ovarian granulosa cells in the model group was increased (P<0.01); compared with the model group, the apoptosis rate of ovarian granulosa cells in the acupuncture group was decreased (P<0.01). Compared with the blank group, the FOXO3a mRNA expression and caspase-3 and BAX protein expression in ovarian tissue in the model group were increased (P<0.01), and the mRNA expression of PI3K and AKT and the protein expression of p-PI3K, p-AKT, and p-FOXO3a in ovarian tissue were decreased (P<0.01); compared with the model group, the mRNA expression of FOXO3a and protein expression of caspase-3 and BAX in ovarian tissue in the acupuncture group were decreased (P<0.05, P<0.01), and the mRNA expression of PI3K and AKT and the protein expression of p-PI3K, p-AKT, and p-FOXO3a in ovarian tissue were increased (P<0.01, P<0.05).
CONCLUSIONS: Acupuncture at \"Zhibian\" (BL 54) through \"Shuidao\" (ST 28) could inhibit ovarian cell apoptosis, and improve ovarian function in POR mice, and its mechanism may be related to the regulation of key factors in the PI3K/AKT/FOXO3a pathway.
目的：基于磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）/叉头蛋白O3a（FOXO3a）通路观察“秩边透水道”针刺对卵巢低反应（POR）小鼠卵巢功能的保护作用，探析针刺抑制POR卵巢颗粒细胞凋亡的可能机制。方法：将动情周期规律的45只小鼠随机分成空白组、模型组和针刺组，每组15只。模型组和针刺组小鼠予雷公藤多苷混悬液（50 mg•kg-1•d-1）灌胃2周制备POR模型。造模成功后针刺组小鼠予“秩边透水道”针刺干预连续2周，每日1次，每次20 min。干预结束次日开始促排卵，各组促排卵后完成取材。采用阴道脱落细胞涂片观察小鼠动情周期变化，记录小鼠取卵数、卵巢湿重、末次体质量与卵巢指数；ELISA法检测小鼠血清抗缪勒管激素（AMH）、卵泡刺激素（FSH）、雌二醇（E2）、黄体生成素（LH）含量；HE染色法观察小鼠卵巢组织形态；TUNEL染色法观察小鼠卵巢颗粒细胞凋亡情况；实时荧光定量PCR法检测小鼠卵巢组织PI3K、AKT、FOXO3a mRNA表达；Western blot法检测卵巢组织B淋巴细胞瘤-2（Bcl-2）关联X的蛋白（BAX），半胱氨酸天冬氨酸蛋白酶-3（Caspase-3）、磷酸化磷脂酰肌醇3-激酶（p-PI3K）和磷酸化蛋白激酶B（p-AKT）蛋白表达。结果：与空白组比较，模型组小鼠动情周期紊乱率升高（P<0.01）；与模型组比较，针刺组小鼠动情周期紊乱率降低（P<0.01）。与空白组比较，模型组小鼠取卵数、卵巢湿重、卵巢指数和末次体质量降低（P<0.01）；与模型组比较，针刺组小鼠取卵数、卵巢指数和卵巢湿重升高（P<0.01，P<0.05），末次体质量比较差异无统计学意义（P>0.05）。与空白组比较，模型组小鼠血清FSH、LH含量升高（P<0.01），血清AMH、E2含量降低（P<0.01）；与模型组比较，针刺组小鼠血清FSH、LH含量降低（P<0.01，P<0.05），血清AMH、E2含量升高（P<0.01，P<0.05）。与空白组比较，模型组小鼠卵巢组织各级正常发育卵泡数量减少且形态较差，各级闭锁卵泡增多；与模型组比较，针刺组小鼠卵泡数量、形态和颗粒细胞结构有不同程度改善，各级闭锁卵泡减少。与空白组比较，模型组小鼠卵巢颗粒细胞凋亡率升高（P<0.01）；与模型组比较，针刺组小鼠卵巢颗粒细胞凋亡率降低（P<0.01）。与空白组比较，模型组小鼠卵巢组织FOXO3a mRNA及Caspase-3、BAX蛋白表达升高（P<0.01），卵巢组织PI3K、AKT mRNA及p-PI3K、p-AKT和p-FOXO3a蛋白表达降低（P<0.01）；与模型组比较，针刺组小鼠卵巢组织FOXO3a mRNA及Caspase-3、BAX蛋白表达降低（P<0.05，P<0.01），卵巢组织PI3K、AKT mRNA及p-PI3K、p-AKT、p-FOXO3a蛋白表达升高（P<0.01，P<0.05）。结论：“秩边透水道”针刺可以抑制POR小鼠卵巢颗粒细胞凋亡，改善卵巢功能，其机制可能与调节PI3K/AKT/FOXO3a通路中的关键因子有关。.

Ovulation is vital for successful reproduction. Following ovulation, cumulus cells and oocyte are released, while mural granulosa cells (mGCs) remain sequestered within the post-ovulatory follicle to form the corpus luteum. However, the mechanism underlying the confinement of mGCs has been a longstanding mystery. Here, in vitro and in vivo evidence is provided demonstrating that the stiffening of mGC-layer serves as an evolutionarily conserved mechanism that prevents mGCs from escaping the post-ovulatory follicles. The results from spatial transcriptome analysis and experiments reveal that focal adhesion assembly, triggered by the LH (hCG)-cAMP-PKA-CREB signaling cascade, is necessary for mGC-layer stiffening. Disrupting focal adhesion assembly through RNA interference results in stiffening failure, mGC escape, and the subsequent development of an abnormal corpus luteum characterized by decreased cell density or cavities. These findings introduce a novel concept of \"mGC-layer stiffening\", shedding light on the mechanism that prevents mGC escape from the post-ovulatory follicle.