林 孝典

BACKGROUND: When using assisted reproductive technology, there are cases where, despite the transfer of a good embryo, sometimes pregnancy may not be the case. Thus, during hormone replacement cycle implantation, it is important to synchronize the number of days of progesterone administration with the degree of embryo maturity. This study aimed to compare the outcomes of the administration of oral dydrogesterone for the duration of progestin use during the hormone replacement cycle for frozen-thawed blastocyst transfer. MATERIAL AND METHODS: The primary outcome of this study was the clinical pregnancy rate. We performed a retrospective cohort study of patients who underwent frozen-thawed blastocyst transfers between January 2017 and December 2024. According to our standard protocol, a vitrified-warmed blastocyst transfer was performed using dydrogesterone, which was administered orally at our center. A total of 554 cases were included in the study. Using the Gardner classification to evaluate the quality of blastocysts, grade AA was classified as the best quality, the AB/BA group as good quality, and the BB group as fair quality. We classified the 554 cases into 317 AA, 163 AB/BA, and 74 BB cases using the Gardner classification. Based on the duration of progestin administration, patients were divided into four groups: 120 hours (120 h), 132 hours (132 h), 144 hours (144 h), and 156 hours (156 h). We used the Shapiro-Wilk method and the Steel-Dwass test to determine whether there were differences in patients' background age and BMI among the four groups (120 h, 132 h, 144 h, and 156 h). We used Fisher's exact test and the Bonferroni method to determine whether there were differences in the final outcome of pregnancy rate between the four groups of 120 h, 132 h, 144 h, and 156 h. RESULTS: In the analysis of all embryos, the pregnancy rate at each timepoint of the primary evaluation was significantly higher in the 144-h group than in the 132-h group. Next, on analyzing the results by embryo grade, there was no difference in the pregnancy rate at each timepoint in the AA group. In the AB/BA group, the pregnancy rate was higher in the 144-h group than in the 132-h group. In the BB group, the pregnancy rate was higher in the 144-h group than in the 132-h group. CONCLUSION: This study clarified two aspects. First, the pregnancy rate in the 144-h group was significantly higher than that in the 132-h group in the analysis of all embryos. Second, the window of implantation may be more important for poor-quality embryos. This study showed that the oral administration of dydrogesterone requires a window of implantation of at least 144 hours.

Estrogen is synthesized throughout various tissues in the body, and its production is regulated by the rate-limiting enzyme aromatase (encoded by the Cyp19a1 gene). Notably, aromatase is also expressed in central nervous system cells, allowing for localized estrogen synthesis in regions such as the hypothalamus. Estrogens produced within these neurons are referred to as neuroestrogens. In this study, we investigated the role of neuroestrogens in the regulation of appetite through modulation of hypothalamic pathways in OVX, ArKO, and aromatase-restored mice. Estrogen suppresses appetite by influencing the expression of appetite-regulating peptides, including POMC and NPY, via MC4R. We explored the direct effects of neuroestrogens, independent from ovarian estrogen, on appetite suppression and the underlying molecular mechanisms. We monitored body weight and food intake and evaluated the expression of Cyp19a1, Mc4r, and other appetite-related genes. Our findings indicate that OVX and ArKO mice exhibited increased body weight and food consumption, which correlated with altered expression of Mc4r and Cyp19a1. Conversely, restoration of Cyp19a1 expression in a neuron specific manner significantly decreased food intake and increased Mc4r expression in the hypothalamus. Furthermore, neuroestrogens enhanced leptin responsiveness. Our results imply that neuroestrogens likely contribute to appetite regulation and may be relevant for body weight reduction.

Adipocyte-cancer cell interactions promote tumor development and progression. Previously, we identified adipsin (CFD) and its downstream effector, hepatocyte growth factor (HGF), as adipokines that enhance adipocyte-breast cancer stem cell interactions. Here, we show that adipsin-dependent adipocyte maturation and the subsequent upregulation of HGF promote tumor invasion in breast cancers. Mature adipocytes, but not their precursors, significantly induced breast tumor cell migration and invasion in an adipsin expression-dependent manner. Promoters of tumor invasion, galectin 7 and matrix metalloproteinases, were significantly upregulated in cancer cells cocultured with mature adipocytes; meanwhile, their expression levels in cancer cells cocultured with adipocytes were reduced by adipsin knockout (Cfd KO) or a competitive inhibitor of CFD. Tumor growth and distant metastasis of mammary cancer cells were significantly suppressed when syngeneic mammary cancer cells were transplanted into Cfd KO mice. Histological analyses revealed reductions in capsular formation and tumor invasion at the cancer-adipocyte interface in the mammary tumors formed in Cfd KO mice. These findings indicate that adipsin-dependent adipocyte maturation may play an important role in adipocyte-cancer cell interaction and breast cancer progression.

Epithelial-mesenchymal transition (EMT) plays a pivotal role in cancer metastasis and treatment resistance, which worsens prognosis. In phase III trials, eribulin improved overall survival in metastatic breast cancer (MBC) patients. In preclinical studies, eribulin suppressed EMT. However, clinical data on the use of eribulin for MBC patients are limited. In this exploratory, prospective study, we examined the effect of eribulin on EMT in MBC patients. Twenty-two patients aged 44-82 years with recurrent breast cancer or MBC were treated with eribulin. Breast cancer tissue samples were obtained before treatment and on day 15 ± 5 of the first cycle of eribulin treatment. EMT markers (E-cadherin, claudin-3, vimentin, N-cadherin) were analysed using western blotting. EMT changes were evaluated based on the ratio of epithelial to mesenchymal markers before and after treatment in individual tumours. E-cadherin/vimentin, claudin-3/vimentin, E-cadherin/N-cadherin, and claudin-3/N-cadherin ratios were significantly higher after treatment (P = 0.007, P = 0.005, P = 0.006, and P = 0.011, respectively). Based on E-cadherin/vimentin, 65.0% of tumours shifted to an epithelial phenotype, as compared to 66.7% based on claudin-3/vimentin, 84.6% based on E-cadherin/N-cadherin, and 71.4% based on claudin-3/N-cadherin ratios. Thus, our results showed that eribulin suppressed EMT in breast cancer tissues.