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STUDY QUESTION: Can an extended letrozole (LE) regimen result in a higher ovulatory rate than a conventional regimen in patients with polycystic ovary syndrome (PCOS) undergoing their first ovulation induction cycle? SUMMARY ANSWER: There was no statistical difference in ovulation rate between patients with PCOS using the extended LE regimen and those using the conventional LE regimen. WHAT IS KNOWN ALREADY: LE has become the first-line agent for ovulation induction. However, there is still a proportion of non-responsive cycles in patients with PCOS undergoing ovulation induction therapy with LE alone, and the extended LE regimen has been demonstrated to be a feasible method for inducing ovulation in these non-responders. Nevertheless, whether the extended regimen could be applied to all patients with PCOS as a first choice for the induction of ovulation remains to be explored. STUDY DESIGN SIZE DURATION: This was a prospective randomized controlled trial that included 148 female patients with PCOS who underwent their first ovulation induction cycle with LE from January 2021 to October 2022. PARTICIPANTS/MATERIALS SETTING METHODS: Participants were randomly assigned to receive an extended (5 mg LE daily for 7 days) or conventional regimen (5 mg LE daily for 5 days) for one treatment cycle. The ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, and the rate of multiple pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE: The ovulation rate among patients receiving an extended LE regimen was slightly higher than the rate with a conventional LE regimen, but the difference did not reach statistical significance in either the intention-to-treat analysis (90.54% [67/74] vs 79.73% [59/74], P = 0.065; relative risk [95% CI]: 0.881 [0.768-1.009]) or the per-protocol analysis (90.54% [67/74] vs 84.29% [59/70], P = 0.257; relative risk [95% CI]: 0.931 [0.821-1.055]). The number of preovulatory follicles was nearly identical in the two groups (1.39 ± 0.62 vs 1.37 ± 0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. With regards to the endometrial parameters, the mean endometrium thickness was slightly thicker with the conventional LE regimen compared to that with the extended LE regimen, though with no statistical difference (9.27 ± 1.72 mm vs 9.57 ± 2.28 mm, P = 0.792). In the per-protocol analysis, the rates of clinical pregnancy (20.27% [15/74] vs 14.29% [10/70], P = 0.343; relative risk [95% CI]: 0.705 [0.34-1.463]) and live birth (13.51% [10/74] vs 11.43% [8/70], P = 0.705; relative risk [95% CI]: 0.846 [0.354-2.019]) did not differ significantly between treatment groups. Moreover, all conceptions were singletons without neonatal defects. LIMITATIONS REASONS FOR CAUTION: The major concerns regarding this study are its single-center and open-label nature. Additionally, the limited number of lean patients with PCOS with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restricted the generalizability of our findings. WIDER IMPLICATION OF THE FINDINGS: A change from the standard strategy of ovulation induction in patients with PCOS is not advisable, because a statistically superior effect of the extended LE regimen over a conventional regimen was not detected. The extended LE regimen could be applied with caution in a specific population who failed to respond to a conventional regimen rather than all the patients with PCOS during ovulation induction. Additional prospective trials with larger sample sizes and different PCOS subgroups are needed to assess the ovulatory effects of various LE treatment durations. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Shanghai First Maternity and Infant Hospital, affiliated with Tongji University School of Medicine (grant numbers: 2023B03 to Y.F., 2023B18 to X.Z., and 2020RC02 to Y.F.). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2100042082). TRIAL REGISTRATION DATE: 13 January 2021. DATE OF FIRST PATIENT'S ENROLMENT: 21 January 2021.

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RESEARCH QUESTION: Are maternal depression and/or anxiety disorders (MDAD) before and during pregnancy associated with IVF outcomes? DESIGN: A total of 5661 women starting their first IVF cycle between 15 August 2014 and 31 December 2015 were pooled from a prospective cohort of IVF-conceived children. The self-rating depression scale (SDS) and self-rating anxiety scale (SAS) were used to determine MDAD. IVF outcomes were compared between MDAD+ and MDAD- groups. RESULTS: A total of 10.3% (572/5556) of women had MDAD before IVF (bMDAD). The fertilization rate was lower in the bMDAD+ group (59.41 ± 22.11% versus 61.72 ± 22.18%, Padjust < 0.05). No difference was found in the other IVF outcomes. Pregnancy and neonatal outcomes in women with singleton live births were similar between the two groups. A total of 17.4% (347) women with singleton live births had MDAD during the first trimester (pMDAD). Birthweight (3383 ± 556 g versus 3447 ± 518 g, Padjust < 0.05) was lower and incidence of low birthweight (LBW) (6.9% versus 3.3%, Padjust < 0.01) was higher in the pMDAD group. After adjustment for potential confounders (gestational age, maternal age, maternal pre-pregnancy body mass index, threatened abortion, hypertensive disorder complicating pregnancy and gestational diabetes mellitus), pMDAD remained significantly associated with LBW (odds ratio [OR] 2.50, 95% confidence interval [CI] 1.16-5.42, Padjust < 0.05). The preconception psychological state in the pMDAD group did not demonstrate any additional impact on neonatal outcomes. CONCLUSIONS: MDAD during the first trimester is associated with increased risk of LBW in offspring, whether preconception MDAD exists or not.

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Mammalian oocytes carry specific nongenetic information, including DNA methylation to the next generation, which is important for development and disease. However, evaluation and manipulation of specific methylation for both functional analysis and therapeutic purposes remains challenging. Here, we demonstrate evaluation of specific methylation in single oocytes from its sibling first polar body (PB1) and manipulation of specific methylation in single oocytes by microinjection-mediated dCas9-based targeted methylation editing. We optimized a single-cell bisulfite sequencing approach with high efficiency and demonstrate that the PB1 carries similar methylation profiles at specific regions to its sibling oocyte. By bisulfite sequencing of a single PB1, the methylation information regarding agouti viable yellow (Avy )-related coat color, as well as imprinting linked parthenogenetic development competency, in a single oocyte can be efficiently evaluated. Microinjection-based dCas9-Tet/Dnmt-mediated methylation editing allows targeted manipulation of specific methylation in single oocytes. By targeted methylation editing, we were able to reverse Avy -related coat color, generate full-term development of bimaternal mice, and correct familial Angelman syndrome in a mouse model. Our work will facilitate the investigation of specific methylation events in oocytes and provides a strategy for prevention and correction of maternally transmitted nongenetic disease or disorders.

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