多囊卵巢综合征(polycystic ovary syndrome,PCOS)是一种生殖功能障碍与糖脂代谢异常并存的内分泌紊乱综合征.PCOS以月经稀发或闭经、不孕、高雄激素血症、卵巢多囊样改变等为主要临床表现,在无排卵性不孕中占30％～60％,常伴有代谢异常如肥胖、胰岛素抵抗、血脂异常等,可增加2型糖尿病、心脑血管疾病和子宫内膜癌的发病几率,危害女性健康.在全球范围内,PCOS患病率5％～15％,我国是全球PCOS患病率增长最决的国家之一[1].我国育龄人群PCOS的患病率从2010年的5.61％上升到2020年的8.6％[2].PCOS的病因迄今未明,治疗以生活方式调整为主,应用药物治疗代谢并发症,合并不孕症者可诱导排卵或行人类辅助生殖技术(ART)助孕治疗.

Objective:To compare cumulative live birth rate (LBR) between progestin-primed ovarian stimulation (PPOS) and GnRH antagonist protocols of preimplantation genetic testing (PGT) cycles in different populations.Methods:This was a retrospective cohort study. A total of 865 patients were enrolled and separate analyses were performed for three populations: 498 patients with predicted normal ovarian response (NOR), 285 patients with PCOS, and 82 patients with predicted poor ovarian response (POR). The primary outcome was cumulative LBR for one oocyte retrieval cycle. The results of response to ovarian stimulation were also investigated, including numbers of oocytes retrieved, MII oocytes, 2PN, blastocysts, good-quality blastocysts, and usable blastocysts after biopsy, as well as rates of oocyte yield, blastocyst formation, good-quality blastocysts, and moderate or severe OHSS. Univariable and multivariable logistic regression analyses were used to identify potential confounders that may be independently associated with cumulative live birth.Results:In NOR, the cumulative LBR of PPOS protocol was significantly lower than that of GnRH antagonists (28.4% vs. 40.7%; P=0.004). In multivariable analysis, the PPOS protocol was negatively associated with cumulative LBR (adjusted OR=0.556; 95% CI, 0.377-0.822) compared to GnRH antagonists after adjusting for potential confounders. The number and ratio of good-quality blastocysts were significantly reduced in PPOS protocol compared to GnRH antagonists (2.82 ± 2.83 vs. 3.20 ± 2.79; P=0.032 and 63.9% vs. 68.5%; P=0.021), while numbers of oocytes, MII oocytes and 2PN did not show any significant difference between GnRH antagonist and PPOS protocols. PCOS patients had similar outcomes as NOR. The cumulative LBR of PPOS group appeared to be lower than that of GnRH antagonists (37.4% vs. 46.1%; P=0.151), but not significantly. Meanwhile, the proportion of good-quality blastocysts in PPOS protocol was also lower compared to GnRH antagonists (63.5% vs. 68.9%; P=0.014). In patients with POR, the cumulative LBR of PPOS protocol was comparable to that of GnRH antagonists (19.2% vs. 16.7%; P=0.772). There was no statistical difference in the number and rate of good-quality blastocysts between the two protocols in POR, while the proportion of good-quality blastocysts appeared to be higher in PPOS group compared to GnRH antagonists (66.7% vs. 56.3%; P=0.182). In addition, the number of usable blastocysts after biopsy was comparable between the two protocols in three populations.Conclusion:The cumulative LBR of PPOS protocol in PGT cycles is lower than that of GnRH antagonists in NOR. In patients with PCOS, the cumulative LBR of PPOS protocol appears to be lower than that of GnRH antagonists, albeit lacking statistical difference, whereas in patients with diminished ovarian reserve, the two protocols were comparable. Our findings suggest the need for caution when choosing PPOS protocol to achieve live births, especially for normal and high ovarian responders.

Abstract Background Reduced trophoblast migration and invasion contributes markedly to recurrent spontaneous abortion (RSA). Aquaporin 3 (AQP3) is a key protein necessary for trophoblast migration and invasion in the fetal–maternal crosstalk during early pregnancy. However, the involvement of AQP3 in RSA remains unknown. Here, the molecular mechanisms acting upstream and downstream of AQP3 and modulatory effects on trophoblast migration and invasion were examined. Methods AQP3 expression was detected in the villi of patients with RSA. The molecular mechanisms whereby AQP3 regulates the migration and invasion of human extravillous trophoblasts (HTR-8/SVneo cells), including the role of the PI3K/AKT signaling pathway and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), were investigated. Results AQP3 expression was lower in the villi of patients with RSA than in the controls. Key PI3K/AKT signaling pathway kinase expression levels were elevated after AQP3 overexpression (OE); the opposite effects occurred after AQP3 knockdown. PI3K/AKT signaling inhibition by LY294002 partially reversed trophoblast migration and invasion and AQP3 OE-mediated PI3K/AKT activation. IGF2BP1 knockdown reduced AQP3 mRNA stability and impaired trophoblast migration and invasion; IGF2BP1 OE exerted the opposite effects. AQP3 mRNA bound to the IGF2BP1 protein, and the m6A-modified AQP3 was significantly enriched in HTR-8/SVneo cells. Conclusions IGF2BP1 detects and binds to AQP3 mRNA, enhancing its stability and activating the PI3K/AKT pathway, thereby affecting the migration and invasion of HTR-8/SVneo cells. These findings indicate a new fundamental mechanism for treating RSA.

Endometriosis (EMs) is a life-long endocrine disorder and a common cause for female infertility and pelvic pain. The key characteristics of eutopic endometrium of EMs patients are high proliferative and migratory potentials. Cuproptosis is a recently identified copper- and-mitochondrial-dependent regulated cell death. Regretfully, its role in EMs remains unclear. In this study, Kyoto Encyclopedia of Genes and Genomes analyses of differentially expressed genes (DEGs) indicated strong activation of the PI3K-Akt-mTOR pathway and biological process analysis reported positive regulation of kinase activity. Next, we screened 11 cuproptosis-related DEGs and found all of them were downregulated in the EMs group, which indicated the suppression of cuproptosis in EMs. One key cuproptosis-related gene, PDHA1, was selected via support vector machine, random forest algorithm and lasso regularization to build a risk-scoring model, which was tested in both internal and external validations. In conclusion, the downregulation and kinase activity of PDHA1 may function with the PI3K-Akt-mTOR pathway in some way, which could suppress the cuproptosis level and account for the cancer-like pathology in EMs.