Reproductive capacity in women starts to decline beyond their mid-30s and pregnancies in older women result in higher rates of miscarriage with aneuploidy. Age-related decline in fertility is strongly attributed to ovarian aging, diminished ovarian reserves, and decreased developmental competence of oocytes. In this review, we discuss the underlying mechanisms of age-related decline in oocyte quality, focusing on oxidative stress (OS) in oocytes. The primary cause is the accumulation of spontaneous damage to the mitochondria arising from increased reactive oxygen species (ROS) in oocytes, generated by the mitochondria themselves during daily biological metabolism. Mitochondrial dysfunction reduces ATP synthesis and influences the meiotic spindle assembly responsible for chromosomal segregation. Moreover, reproductively aged oocytes produce a decline in the fidelity of the protective mechanisms against ROS, namely the ROS-scavenging metabolism, repair of ROS-damaged DNA, and the proteasome and autophagy system for ROS-damaged proteins. Accordingly, increased ROS and increased vulnerability of oocytes to ROS lead to spindle instability, chromosomal abnormalities, telomere shortening, and reduced developmental competence of aged oocytes.

Purpose To create a gonadotropin starting dose calculator for controlled ovarian stimulation, which can adjust the target number of oocytes and stimulation duration for each facility to achieve individualized controlled ovarian stimulation among the Japanese patients. Methods The patients received controlled ovarian stimulation using the gonadotropin‐releasing hormone antagonist protocol, and oocytes were retrieved. Using single regression analysis, we selected age, anti‐Müllerian hormone (AMH), and initial serum follicle‐stimulating hormone as variables to predict the number of oocytes retrieved per gonadotropin dose (oocyte sensitivity index). Each variable was then analyzed using backward stepwise multiple regression. Results Age and AMH were selected as predictive variables from the backward stepwise multiple regression, and we developed a multiple regression equation. We decomposed the equation as the number of oocytes retrieved/(gonadotropin starting dose × stimulation duration days) and created a calculation formula to predict the gonadotropin starting dose from the target number of oocytes and stimulation duration days. Conclusions This is the first study to develop an individualized dosing algorithm for gonadotropins among Japanese patients. Our calculator will improve controlled ovarian stimulation performance and enable national standardization by allowing all physicians, regardless of their years of experience, to determine the appropriate starting dose of gonadotropins equally.

Purpose The aneuploidy and sex concordance between cell‐free DNA in spent culture media (SCM) and DNA from whole embryo with respect to different morphological grading were examined to evaluate the feasibility of non‐invasive preimplantation genetic testing for aneuploidy (niPGT‐A). Methods A total of 46 pairs of embryos and corresponding SCM were divided into two groups based on the morphological grade. DNA was extracted from 22 and 24 pairs of low‐ and high‐grade embryos, respectively, and respective SCM followed by chromosomal analysis using next‐generation sequencing. Aneuploidy study and sex determination were conducted for both groups, and concordance rates were calculated. Results For low‐grade embryos, 63.6% (14/22) were determined as aneuploidy by whole embryo analysis, and concordance rates were 54.5% (12/22) using niPGT‐A. On the contrary, for high‐grade embryos 41.7% (10/24) were determined as aneuploidy by whole embryo analysis, and concordance rates were 62.5% (15/24) using niPGT‐A. The concordance rates were not statistically different between the low‐grade and high‐grade embryo groups ( p = 0.804). For sex determination, concordance rates between whole embryo and SCM were 81.8% (18/22) and 87.5% (21/24) in low‐ and high‐grade groups, respectively. Conclusion Aneuploidy and sex evaluation by niPGT‐A may be feasible for both morphologically low‐ and high‐grade embryos.

Purpose We focused on the metabolism of oocytes in pre‐culture and insemination and compared these results between our existing fertilization medium, GEMS Fertilisation Medium (GEMS group) (Merck BioPharma) and Continuous Single Culture Medium—NX Complete (CSCM‐NXC group) (FUJIFILM Irvine Scientific). Methods Patients under 42 years of age were received controlled ovarian stimulation and oocytes were retrieved. Those were pre‐cultured and fertilized with either GEMS fertilization medium or CSCM‐NXC. After fertilization was confirmed, embryos were cultured using CSCM‐NXC in both groups. The embryos were cryopreserved at blastocyst stage (3BB or more, Gardner classification) and then transferred in HRT cycles. Results The fertilization rate of both groups was the same, but the 3PN rate was significantly lower in the CSCM‐NXC group. In terms of embryo culture results, the CSCM‐NXC group had a significantly higher rate of good quality blastocysts, high‐grade embryos, and embryos with a high degree of expansion. Conclusions The use of CSCM‐NXC, a low lactate embryo culture medium, from pre‐culture and for insemination, increases the energy metabolic efficiency of oocytes and cumulus cells, making it possible to supply sufficient energy ATP for fertilization and early division, which is thought to promote good embryonic development.

Background: We compared the performance of follitropin delta and follitropin alfa in the gonadotropin-releasing hormone (GnRH) antagonist protocol for controlled ovarian stimulation (COS) and discussed the distinctive features of follitropin delta in COS. Methods: Patients underwent COS using the GnRH antagonist protocol with either recombinant follicle-stimulating hormone (FSH) and oocytes were retrieved. We compared the results of COS, oocyte pick up, fertilization, embryo culture, and clinical pregnancy between the follitropin alfa group and the follitropin delta group. Results: The serum estrogen level at trigger was significantly lower in the delta than in the alfa group (3,576.69 ± 1,775.60 vs. 2,833.19 ± 1,567.88) as was serum P4 level (2.14 ± 1.26 vs. 1.19 ± 0.85). The stimulation duration (in days) were longer (12.97 ± 2.38 vs. 13.96 ± 2.26) and total gonadotropin dose significantly lower (199.69 ± 54.47 vs. 114.27 ± 39.92), respectively, in the delta group than in the alfa group. The ovarian hyperstimulation syndrome (OHSS) rate was significantly lower in the delta than in the alfa group (48.1% vs. 58.6%). Fertilization, good blastocyst, and clinical pregnancy rates were not significantly different. COS using follitropin delta is characterized by significantly slower follicle development than COS using follitropin alfa. A comparison of developing follicles showed that the minimum follicle was significantly smaller in the delta group on days 6–8 of COS. The maximum follicle was significantly smaller in the delta group on days 6–8 and 11–13 of COS. The number of follicles larger than 14 mm was significantly lower in the delta group on days 6–8 of COS. Conclusions: Using follitropin delta is associated with slow follicular development, slow serum E2 elevation, and longer stimulation duration; however, excessive elevation of serum estrogen levels during COS is reduced and so is the incidence of mild OHSS.