The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra-physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n = 357), frozen ET (n = 212), and natural conception (NC) (n = 380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. ChicCTR-OCC-14004682 (22-05-2014)

Ruan H, et al. Yonsei Med J. 2023 Feb;64:e17. https://doi.org/10.3349/ymj.2022.0239

Background: Endometriosis is associated with systemic metabolic indicators, including body mass index (BMI), glucose metabolism and lipid metabolism, while the association between metabolic indexes and the occurrence and assisted reproductive technology (ART) outcome of endometriosis is unclear. We aimed to evaluate the characteristics of systemic metabolic indexes of endometriosis patients with infertility and their effects on pregnancy outcome after ART treatment. Methods: A retrospective cohort study involve 412 endometriosis patients and 1551 controls was conducted. Primary outcome was metabolic indexes, and secondary measures consisted of the influence of metabolic indexes on the number of retrieved oocytes and ART outcomes. Results: Endometriosis patients had higher insulin (INS) [6.90(5.10–9.50) vs 6.50(4.80–8.90) μU/mL, P = 0.005]. A prediction model for endometriosis combining the number of previous pregnancies, CA125, fasting blood glucose (Glu) and INS, had a sensitivity of 73.9%, specificity of 67.8% and area under curve (AUC) of 0.77. There were no significant differences in ART outcomes and complications during pregnancy. The serum levels of Glu before pregnancy were associated with GDM both in endometriosis group (aOR 12.95, 95% CI 1.69–99.42, P = 0.014) and in control group (aOR 4.15, 95% CI 1.50–11.53, P = 0.006). Conclusions: We found serum Glu is related to the number of retrieved oocytes in control group, serum INS is related to the number of retrieved oocytes in endometriosis group, while serum Glu and INS before pregnancy are related to the occurrence of GDM in two groups. A prediction model based on metabolic indexes was established, representing a promising non-invasive method to predict endometriosis patients with known pregnancy history.

Basonuclin (BNC1) is expressed primarily in proliferative keratinocytes and gametogenic cells. However, its roles in spermatogenesis and testicular aging were not clear. Previously we discovered a heterozygous BNC1 truncation mutation in a premature ovarian insufficiency pedigree. In this study, we found that male mice carrying the truncation mutation exhibited progressively fertility loss and testicular premature aging. Genome-wide expression profiling and direct binding studies (by chromatin immunoprecipitation sequencing) with BNC1 in mouse testis identified several spermatogenesis-specific gene promoters targeted by BNC1 including kelch-like family member 10 (Klhl10), testis expressed 14 (Tex14), and spermatogenesis and centriole associated 1 (Spatc1). Moreover, biochemical analysis showed that BNC1 was associated with TATA-box binding protein-associated factor 7 like (TAF7L), a germ cell-specific paralogue of the transcription factor IID subunit TAF7, both in vitro and in testis, suggesting that BNC1 might directly cooperate with TAF7L to regulate spermatogenesis. The truncation mutation disabled nuclear translocation of the BNC1/TAF7L complex, thus, disturbing expression of related genes and leading to testicular premature aging. Similarly, expressions of BNC1, TAF7L, Y-box-binding protein 2 (YBX2), outer dense fiber of sperm tails 1 (ODF1), and glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) were significantly decreased in the testis of men with non-obstructive azoospermia. The present study adds to the understanding of the physiology of male reproductive aging and the mechanism of spermatogenic failure in infertile men.

Polycystic ovary syndrome (PCOS) is increasingly recognized as a metabolic disorder, with dysregulated lipid metabolism emerging as a key factor in its pathogenesis. However, the precise mechanisms underlying this relationship remain unclear. We employed a summary data-based Mendelian randomization (SMR) approach to investigate the potential causal relationships between lipid metabolism-related genes and PCOS. First, we integrated PCOS genome-wide association study (GWAS) data from the Finngen_R11_E4_PCOS cohort with three layers of blood-based molecular quantitative trait loci (QTLs): methylation QTLs (mQTLs), expression QTLs (eQTLs), and protein QTLs (pQTLs). To ensure the robustness of the SMR signals, we performed the heterogeneity in dependent instruments (HEIDI) test to detect potential horizontal pleiotropy and conducted colocalization analysis to identify shared potential causal genetic variants. Findings were validated in two independent cohorts: Phenocode_265.4 and Felix. We then integrated mQTL and eQTL data to further dissect methylation-mediated gene expression regulation. Finally, we examined the expression profiles of key candidate genes using publicly available transcriptomic datasets from the Gene Expression Omnibus (GEO) database. SMR analysis in the discovery cohort identified 132 mQTLs (corresponding to 70 genes), 16 eQTLs, and 7 pQTLs associated with PCOS. Among these, 71 mQTLs (corresponding to 39 genes), 11 eQTLs, and 4 pQTLs were supported by strong colocalization evidence. Further validation in the Phenocode_265.4 and Felix cohorts confirmed the association of 13 mQTLs (corresponding to 7 genes) and 2 eQTLs with PCOS. Specifically, the associations of ACOX2 (cg22012981), GLIPR1 (cg01554451), and PIK3R3 (cg27584146) with PCOS were further supported by subsequent analyses. mQTL‑eQTL SMR analysis confirmed the negative regulatory effects of these methylation sites on the expression of their corresponding genes. Finally, transcriptomic data revealed upregulation of GLIPR1 and PIK3R3 in tissues from patients with PCOS. This study shows the association of lipid metabolism-related genes, particularly ACOX2, PIK3R3, and GLIPR1, with PCOS pathogenesis. These findings highlight them as candidates for further functional studies and potential future therapeutic development. The online version contains supplementary material available at 10.1186/s13048-026-02014-z.

Background: Preoperative differentiation between uterine mesenchymal tumors and benign uterine fibroids remains challenging in postmenopausal women. This study aimed to develop an exploratory risk-stratification model for uterine mesenchymal tumors and to characterize complementary molecular features of uterine leiomyosarcoma using a public transcriptomic dataset. Methods: A retrospective case–control study was conducted in postmenopausal patients with uterine masses who underwent surgery between 2011 and 2021. A total of 23 uterine mesenchymal tumor cases and 92 frequency-matched fibroid controls were included. Clinical variables were analyzed using univariable and multivariable logistic regression to develop an exploratory risk-stratification model. Model performance was evaluated using ROC analysis, calibration analysis, decision curve analysis, and confusion matrix assessment. Exploratory transcriptomic analysis was performed using the GEO dataset GSE64763 to characterize molecular differences between uterine leiomyosarcoma and fibroid tissues. Results: Pelvic pressure, abnormal uterine bleeding, and tumor diameter were independently associated with uterine mesenchymal tumors. The model achieved an apparent AUC of 0.859 and an optimism-corrected AUC of 0.846 after 1000 bootstrap resamples. Exploratory transcriptomic analysis revealed distinct expression patterns and upregulation of proliferation-associated genes, including CCNB1, BUB1B, PRC1, TOP2A, and FOXM1, with enrichment of cell cycle–related pathways. Conclusions: An exploratory model based on routinely available preoperative variables demonstrated preliminary discriminatory ability within the development cohort. Independent external validation in representative prospective cohorts is required before any assessment of clinical utility.