Journal of Assisted Reproduction and Genetics最新文献

Purpose: Since 2021, elective egg freezing (EEF) without medical indication has been authorized and fully reimbursed in France for women aged 29 to 37. While this regulatory change represents a significant advancement in reproductive rights, it also raises new ethical and organizational challenges. This study aimed to explore the ethical issues experienced by infertility specialists involved in the clinical implementation of EEF in France.

Methods: This prospective, qualitative, monocentric study was conducted in a university-based ART center. All physicians involved in EEF at the center were invited to participate in semi-structured interviews. Data were analyzed inductively using Grounded Theory methodology.

Results: Eight practitioners participated. Four main themes emerged: (1) challenges in accessing EEF due to resource constraints and growing demand; (2) a new relationship between caregiver and patient in a context where care is no longer strictly medical; (3) a need to redefine the role of EEF in society, including the terminology used and funding mechanisms; and (4) questions about the future of EEF, including prioritization criteria, equitable access, and sustainability of the current model.

Conclusions: While EEF is widely supported by healthcare professionals, its integration into routine practice reveals tensions between autonomy, justice, beneficence, and public resource management. National guidelines, improved access to information, and further research-particularly incorporating women's perspectives-are essential to ensure ethically sound implementation.

Background and objective: Artificial intelligence (AI) has emerged as a promising tool for clinical decision support in reproductive medicine, yet the performance of general-purpose large language models (LLMs) in predicting in vitro fertilization (IVF) outcomes remains insufficiently characterized. This exploratory proof-of-concept study aimed to evaluate and compare the out-of-the-box performance of three widely accessible LLM-based systems (ChatGPT, DeepSeek, and Gemini) in forecasting key clinical and laboratory outcomes of IVF treatments.

Methods: This retrospective single-center study used data from 1473 autologous IVF/ICSI cycles, each representing a unique patient. For each cycle, relevant clinical and laboratory variables were incorporated into a standardized anonymized patient-level vignette and submitted via the publicly available web interfaces of three LLMs (ChatGPT, DeepSeek, Gemini) without any fine-tuning or internal customization. The models were asked to predict stimulation protocol, ovulation trigger type, total and mature oocyte counts, usable embryo counts, and clinical pregnancy. Predictive performance was evaluated using accuracy and tolerance-based accuracy for categorical and count-based outcomes, mean absolute error for numerical predictions, and the area under the receiver operating characteristic (ROC) curve for clinical pregnancy.

Results: Gemini achieved the highest accuracy in predicting stimulation protocols (51.26%) and embryo counts (68.22%), while DeepSeek demonstrated the lowest numerical error for oocyte count predictions. Clinical pregnancy prediction was the most challenging task; all models showed only moderate discrimination, with Gemini achieving the highest AUC (0.711), followed by ChatGPT (0.690) and DeepSeek (0.676). Overall, model performance varied considerably across tasks and remained below thresholds that would be considered sufficient for reliable stand-alone clinical use.

Conclusions: In this exploratory proof-of-concept setting, general-purpose AI systems showed variable and overall suboptimal performance in predicting IVF outcomes from standardized clinical vignettes. Although certain models demonstrated relative strengths in specific tasks, none reached the reliability, consistency, or interpretability required for safe clinical implementation. These findings indicate that, in their current form, such models should not be used as clinical decision-support tools for IVF decision-making and that their use should remain restricted to carefully controlled research settings until they have been prospectively validated in multicenter cohorts and systematically compared with rigorously developed, task-specific prediction models. This study provides comparative insight into how these AI systems behave in IVF-related prediction tasks and underscores the need for cautious interpretation of AI-generated outputs.

Purpose: To systematically investigate the genetic architecture of severe male infertility in Indian men, with a specific focus on chromosomal abnormalities and the contribution of de novo variants.

Method: We recruited 247 infertile males between 2021 and 2024 presenting with severe quantitative and qualitative sperm defects. All patients underwent karyotyping and Y chromosome microdeletion STS-PCR. A single molecule molecular inversion probe-based targeted sequencing assay covering 39 male infertility genes was performed in 120 patients, while whole exome sequencing (WES) was conducted in 48 patients using a duo/trio-based approach to enable segregation and de novo variant detection.

Result: Gonosomal aneuploidies were observed in 3/247 patients (1.2%, 95% CI 0.3-3.5%) and causal AZF microdeletions in 8/247 (3.2%, 95% CI 1.4-6.3%). Targeted sequencing identified pathogenic/likely pathogenic (P/LP) variants in 4/120 patients (3.3%, 95% CI 0.9-8.3%), with additional CFTR variants in 3 patients where parental DNA was unavailable for phasing. WES yielded P/LP variants in 4/48 patients (8.3%, 95% CI 2.3-19.9%) affecting PMFBP1, DNAH1, and AR genes, confirmed via segregation analysis. No de novo or copy number variants were confirmed as causative, though several candidate genes were prioritised. Sequencing-based approaches provided an additional ~ 6-8% diagnostic yield, with the overall diagnostic rate reaching 7.7% (19/247; 95% CI 4.7-11.8%).

Conclusion: Sequencing-based strategies, particularly family-based trio WES, significantly enhance diagnostic yield beyond current guideline-recommended tests, with data supporting their adoption as first-tier investigations for severe male infertility. This represents India's largest cohort-based genomic study on male infertility to date. Larger family-based cohorts will be essential to delineate the contribution of de novo variants to male infertility genetics.

Purpose: To assess the associations between vanishing twin (VT) and fetal reduction (FR) with obstetric and perinatal outcomes following in vitro fertilization (IVF)-frozen embryo transfer (FET).

Methods: This was a retrospective cohort study involving women who had undergone FR or experienced VT during the period from 2012 to 2022. Cohorts were stratified by timing into early (< 15 weeks) and late (≥ 15 weeks) VT/FR. Controls comprised primary singletons and non-reduced twins. The primary outcome measurements were maternal and birth complications.

Results: Among 33,238 ongoing pregnancies, there were 24,316 primary singletons, 7452 non-reduced twins, 1354 VTs, and 116 FRs. Multivariable analyses showed birth outcomes in the study groups were similar to or better than non-reduced twin deliveries. Compared to primary singletons, both early and late FRs were associated with increased risk of preterm birth (PTB); late FR also increased the risk of low birthweight (LBW). Early and late VTs similarly had higher risks of PTB and LBW versus primary singletons. Obstetric complications were generally comparable or lower in the study groups versus twin deliveries; however, late FR was linked to a higher risk of hypertensive disorders of pregnancy compared with primary singletons, and late VT was associated with increased abnormal placentation versus primary singletons and twins.

Conclusions: In this large IVF-FET cohort, most birth and maternal outcomes were comparable or better than in non-reduced twins, but certain complications remained more common in both VT and FR groups. Both exposures were linked to adverse perinatal outcomes versus primary singletons. Moreover, VT and FR appear to be more problematic when these occur later in pregnancy.

Purpose: To compare the time to initiation of first therapeutic treatment and the outcomes of controlled ovarian stimulation (COS) in breast cancer patients undergoing fertility preservation (FP) in the neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) treatment settings.

Methods: A retrospective cohort study involving patients with stage 1-3 breast cancer treated with NAC/AC, who underwent FP with random-start COS, between 2015-2023. Baseline, oncologic and COS characteristics and outcomes were collected. Time points related to cancer diagnosis, FP, and first oncologic intervention (surgery or chemotherapy) were calculated.

Results: 70 NAC-treated patients were compared to 42 AC-treated patients. Groups were similar in terms of age, marital status, parity and BMI. NAC-treated patients had more advanced disease, more often with lymph node involvement. Median time from diagnosis to FP consult (17 vs 30 days) and to stimulation start (22 vs 59 days) was significantly shorter for NAC-treated patients. Median time from diagnosis to first therapeutic intervention was slightly longer for NAC-treated patients (45 vs 41 days, p < 0.05). Stimulation characteristics were comparable apart from a less frequent use of hCG trigger among NAC-treated patients (4% vs 16%, p < 0.05). First stimulation cycle outcomes such as peak E2 levels, number of retrieved oocytes and fertilization rate were similar, though median number of M2 oocytes was higher in NAC- treated patients (11 vs 8, p < 0.05).

Conclusion: Expedited patient care at the neoadjuvant setting led to a statistically significant, yet clinically minimal, delay of cancer therapy. Neither oncologic treatment timelines nor FP outcomes were compromised in the NAC setting.

Purpose: Sperm DNA damage is linked to male infertility and poor reproductive outcome. Single-stranded DNA (ssDNA) damage in sperm is the most common type of damage yet is not specifically targeted by the commonly used DNA damage assays. This study aimed to quantitatively detect sperm ssDNA damage using a novel, direct method.

Methods: The sperm repair-assisted damage detection (SRADD) assay is a single-molecule technique that uses specific repair enzymes to excise damaged segments and incorporates fluorescently labeled nucleotides, enabling visualization and quantification of the damage. We assessed ssDNA damage in sperm donors following induced damage using varying concentrations of H₂O₂. The assay was evaluated for sensitivity, repeatability, and reproducibility. SRADD results were compared with the direct TUNEL assay and the indirect sperm chromatin dispersion (SCD) assay.

Results: SRADD demonstrated high inter-slide reproducibility (ICC = 0.95). Sensitivity was confirmed by quantifying induced damage in a dose-dependent manner (0.5, 1, 1.5 mM of H₂O₂), demonstrating mean damage ratios of 1.06, 2.16, and 4.83 relative to control, respectively. Baseline damage levels exhibited strong positive correlation with increased induced damage (r = 0.91, p < 0.001). Analysis of healthy sperm donors (n = 59) revealed that 8.5% of men with normal sperm parameters presented with high ssDNA damage levels. SRADD had a moderate correlation with SCD assay and no correlation with conventional semen parameters and TUNEL assay.

Conclusion: The SRADD assay quantifies sperm ssDNA with high sensitivity and can process dozens of samples simultaneously, making it valuable for andrology and toxicology research and potentially useful in clinical settings such as sperm banks and male-infertility assessment.

Trial registration: (6573-19-SMV).

Purpose: Recurrent implantation failure (RIF) constitutes a significant challenge in reproductive medicine, with compromised endometrial receptivity identified as a principal etiological factor. Cellular senescence, characterized by irreversible cell cycle arrest and senescence-associated secretory phenotype (SASP), has been implicated in endometrial dysfunction. This investigation aims to elucidate the molecular mechanisms by which SETD7, a lysine-specific methyltransferase, regulates endometrial stromal cell senescence and decidualization processes.

Methods: Transcriptomic analyses from endometrial tissues on RIF patients were to evaluate SETD7 expression and its association with senescence-related and decidualization markers. In vitro experiments using human endometrial stromal cells (hESCs) assessed the effects of SETD7 upregulation on cellular senescence, decidualization capacity, and the expression of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Molecular pathway analyses were conducted to investigate SETD7-mediated regulation of the AKT-FOXO1 signaling axis. Pharmacological inhibition of FOXO1 phosphorylation was applied to determine its impact on restoring decidualization in RIF-derived hESCs. Clinical correlation analyses validated the relationship between SETD7 and FOXO1 expression in endometrial samples.

Results: SETD7 expression was significantly upregulated in RIF endometria compared with fertile controls; this correlated positively with senescence-associated genes and inversely with decidualization markers. In vitro, SETD7 overexpression in hESCs induced senescence in a dose-dependent manner, increased expression of senescence markers, and severely suppressed PRL and IGFBP1 induction during decidualization. Mechanistically, SETD7 enhanced AKT-dependent phosphorylation of FOXO1 at T24, promoting FOXO1 protein accumulation. Pharmacological inhibition of FOXO1 phosphorylation attenuated senescence effects and partially restored decidualization capacity in RIF-derived hESCs. Clinical tissue analyses confirmed a strong positive correlation between SETD7 and FOXO1 expression.

Conclusion: These findings collectively establish SETD7 as a crucial molecular regulator of decidual senescence and identify it as a potential therapeutic target for enhancing endometrial receptivity in patients with recurrent implantation failure.

Purpose: To explore men's assisted reproductive technology (ART) experiences, awareness and concerns about fertility-associated health outcomes, and perceptions of using administrative health records in the United Kingdom (UK) without consent to investigate these outcomes.

Methods: Over a 2-year period, all adult men were eligible to complete an anonymous online survey distributed via a UK-based fertility charity's social media. Free-text responses underwent thematic analysis, and categorical responses were analysed with descriptive statistics and Fisher's exact test.

Results: Among 80 participants, most were aged ≥ 40 (66.7%), completed university (70.2%), White (77.2%), and UK residents (83.0%). Older (p = 0.004) and White (p = 0.001) men more likely underwent ART. Most ART users received treatment privately (60%) within the past three years (71.4%). Only one-fifth of the 15 men with identified fertility problems received discussion on fertility-associated health outcomes in clinic. Regarding perceptions, most were unaware of but concerned about these outcomes across biopsychosocial aspects, with participant quotes reflecting uncertainty and vulnerability. Recency of ART was associated with awareness (p = 0.015) and concerns (p = 0.001). Overall, 90.3% supported using administrative health records to investigate long-term health of fertility-challenged men, and 84.2% had no concerns about doing so without individual consent under established legal frameworks. Others raised concerns about the reliability of data anonymisation. Quotes suggested participants' desire to understand the wider health implications of male fertility amidst a perceived gender imbalance in fertility research.

Conclusions: Gaps in participant knowledge, clinician communication, and research in male fertility-associated outcomes support the need for universal education and further investigations in these outcomes.

Purpose: This study aimed to determine whether the mitochondrial DNA to genomic DNA (mtDNA/gDNA) ratio in spent culture medium (SCM) can reliably predict embryo quality and clinical pregnancy outcomes in in vitro fertilization (IVF). Current embryo selection methods rely primarily on morphological assessment, which has limitations in predicting implantation success and cannot distinguish aneuploid embryos.

Methods: A prospective clinical trial was conducted from July 2022 to July 2023 involving 174 women with unexplained infertility undergoing IVF-ICSI at CHA University, Korea. Day 5 blastocyst culture media were analyzed for mtDNA/gDNA ratio using quantitative real-time PCR. Embryos were evaluated using a blastocyst scoring system (BS) categorizing them as good (BS 3-5), fair (BS 6-9), or poor (BS 10-14). Statistical analyses included correlation analysis and ROC curve analysis to assess the predictive value for clinical pregnancy rates.

Results: Higher mtDNA/gDNA ratios correlated significantly with lower embryo quality grades (good: 1.12, fair: 1.15, poor: 2.14; p < 0.001). ROC analysis confirmed the mtDNA/gDNA ratio as a reliable predictor of clinical pregnancy rates with AUC > 0.8 (p < 0.001) across all age groups. No significant differences in clinical pregnancy rates were observed across different age groups (p = 0.392).

Conclusion: The mtDNA/gDNA ratio in SCM shows promising potential as a non-invasive indicator of embryo quality and clinical pregnancy outcomes. However, given the exploratory nature of this study and current methodological limitations, further validation with larger, independent cohorts and standardized analytical protocols is required before clinical application.

Purpose: Touch print smear (TPS) of testicular specimens provides immediate diagnostic results comparable to histopathology and in vitro fertilization laboratory findings. This study aimed to validate TPS as a rapid complement to histopathology for detecting post-meiotic germ cells in azoospermic patients.

Materials and methods: We retrospectively analyzed 495 azoospermic patients (274 with obstructive azoospermia [OA]) who underwent testis needle biopsy (2015-2022). Specimens were immediately smeared onto sterile slides, then transferred into Bouin's solution for pathological diagnosis. Slides were stained with thionine and examined under light microscopy. Spermatogenesis development was compared between TPS findings and histopathology.

Results: TPS and histopathology were concordant in 98.2% (269/274) of OA and 75.6% (167/221) of non-obstructive azoospermia (NOA) cases. Among discordant NOA patients, 74.1% (40/54) showed more advanced spermatogenesis with TPS. Of 20 patients in whom post-meiotic germ cells were identified by TPS but not by histopathology, 95% (19/20) achieved successful sperm retrieval during subsequent microdissection testicular sperm extraction (mTESE). Conversely, in NOA patients where TPS suggested less advanced spermatogenesis and failed to identify post-meiotic germ cells, the sperm retrieval rate was 57.1% (4/7).

Conclusion: TPS allows rapid identification of post-meiotic germ cells with excellent concordance in OA and provides clinically relevant information in NOA. Patients in whom TPS demonstrates post-meiotic germ cells have a high likelihood of sperm retrieval, whereas their absence on TPS indicates lower retrieval success, in which case histopathology remains a useful backup.