Reproductive Biology and Endocrinology最新文献

Background: Recent research in male infertility genetics has identified numerous candidate genes, some of which were also involved in DNA repair. Mismatch repair (MMR) genes, such as MSH4 and MSH5, have been linked to male infertility due to their role in meiosis, suggesting that other MMR genes may also contribute to impaired spermatogenesis. To investigate the role of MMR genes in male infertility, we first conducted a systematic review focusing on their involvement in impaired spermatogenesis, which was followed by a multicenter cohort study assessing the occurrence of rare deleterious variants in MMR genes among men with severely impaired fertility. The present study aimed to assess the contribution of MMR genes to male infertility and to evaluate their potential clinical utility in the diagnostic workup of men with severely impaired fertility.

Methods: A systematic review was conducted through a PubMed database search with a focus on the role of MMR genes in spermatogenesis. We additionally prepared a cohort study, including whole-exome sequencing data from 244 infertile men presenting azoospermia or severe oligozoospermia (< 5 million spermatozoa/ml). Rare, deleterious variants in MMR genes were classified using the ACGS Guidelines for Variant Classification 2020.

Results: Following a systematic review of the literature, we gathered robust evidence supporting the strong involvement of MSH4 and MSH5 variants in male infertility, moderate evidence for MLH3, and limited evidence for other MMR genes. From our cohort, we identified likely pathogenic or pathogenic variants in two individuals: one with two MSH4 variants and another with a PMS2 variant.

Conclusions: The present study identifies MSH4 and MSH5 as strong candidate genes for male infertility, supporting the integration of their testing into the clinical diagnosis of infertile men, particularly those exhibiting non-obstructive azoospermia. Although current evidence suggests that genetic variants in most MMR genes do not cause infertility, genetic defects in MMR genes can still impair spermatogenesis due to their critical role in sperm DNA repair and maintenance of genome integrity.

Background: Almost half of patients with functional hypothalamic amenorrhea (FHA) show polycystic ovarian morphology (PCOM) on the ultrasound, which leads to a diagnostic confusion. Although FHA and polycystic ovarian syndrome (PCOS) have been thought to co-exist and some FHA-patients seem to have had PCOS before developing FHA, respectively, once hypothalamic inhibition proceeds, the FHA phenotype predominates over the PCOS features, except from PCOM. This connection has never been shown longitudinally. Furthermore, it is still not clear if FHA-PCOM is actually related to preexisting PCOS or if these women constitute their very own heterogeneous subgroup. Thus, the aims of this study were to evaluate changes in hormonal parameters and PCOM after remission and to provide further insight into pathophysiological processes of PCOM in FHA.

Methods: Monocentric retrospective cohort study. Sixty women with FHA in remission were included. While anti-mullerian hormone (AMH) was the main outcome parameter, we also analyzed total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), sex hormone-binding globulin (SHBG) and dehydroepiandrosterone sulfate (DHEAS). PCOM was diagnosed using ultrasound.

Results: At baseline, FHA-PCOM patients revealed higher baseline prolactin (p = 0.029) and AMH levels (p < 0.001). At follow-up, compared to women without PCOM, these women had higher PCOM prevalence (48.1% versus 0%, p < 0.001), higher AMH levels (median 6.49 ng/mL, IQR 4.74-7.95 versus median 2.25 ng/mL, IQR 2.0-2.71; p < 0.001) and higher PCOS prevalence (22.2% versus 0%, p = 0.006). While overall median AMH levels increased significantly, FHA-PCOM patients revealed a significant median decrease in AMH levels (median AMH dynamics - 0.82 ng/mL, IQR - 2.30 - -0.16; p < 0.001).

Conclusions: Our data support the hypothesis that relative FSH deficiency in hypothalamic dysfunction can lead to lower AMH levels. In contrast, the decline in AMH levels and the resolution of PCOM in the FHA-PCOM group may indicate a reversible state of ovarian hyperactivation during FHA.

Trial registration: Not applicable.

Preeclampsia (PE) is a relatively common pregnancy complication that results in significant morbidity and mortality among mothers and children worldwide. It is critical to identify women who are at high risk of developing PE to provide timely treatment, in line with the general shift in medicine towards precision health, with an emphasis on disease prediction and prevention. However, independent and reliable predictors for PE are lacking, and clinical symptoms are typically resolved through delivery. Notably, there have been significant breakthroughs in the use of non-invasive approaches to predict PE, particularly the detection of cell-free RNAs (cfRNAs) in maternal peripheral blood, which are correlated with tissue-specific gene expression and provide a view of prenatal health throughout gestation. Unlike established protein markers such as sFlt-1/PlGF, which primarily reflect angiogenic imbalance and are most informative near the time of clinical presentation, cfRNAs provide a dynamic, tissue-resolved readout of gene expression programs throughout gestation from the placenta, fetus, and maternal organs. Their levels directly correlate with the current state of pregnancy, and cfRNA-based prediction models have demonstrated robust performance, with AUC values ranging from 0.70 to 0.99 and an average sensitivity exceeding 70%. We review recent research on circulating cfRNAs in PE as well as their innovative applications and associated challenges in diagnosing and predicting PE. This review is expected to prompt further research aimed at expanding the clinical applicability of cfRNAs as non-invasive and reliable biomarkers for PE.

Objective: To explore the potential the role of miR-151a-5p in sperm dysfunction and its association with DNA fragmentation, mitochondrial dysfunction, and male infertility.

Methods: Sperm samples with high DNA fragmentation were collected, and miR-151a-5p expression was measured using quantitative polymerase chain reaction. GC-2 cells were transfected with miR-151a-5p mimics to assess its effects on DNA damage, apoptosis, mitochondrial function, and reactive oxygen species levels. RNA sequencing, RNA pull-down, and bioinformatics analyses were used to identify the direct target genes of miR-151a-5p. Dual-luciferase reporter assays confirmed the binding of miR-151a-5p to the 3' untranslated regions of INPP4B and VAMP1. Knockdown of these genes was performed to validate their roles in miR-151a-5p-induced effects. In vivo experiments were conducted by injecting miR-151a-5p mimics into mouse zygotes to examine the impact on embryo development.

Results: miR-151a-5p was significantly upregulated in sperm with high DNA fragmentation and negatively correlated with sperm motility and viability. Overexpression of miR-151a-5p in GC-2 cells was associated with increased DNA damage, apoptosis, mitochondrial dysfunction, and elevated reactive oxygen species. RNA sequencing and bioinformatics analyses suggested INPP4B and VAMP1 as direct targets of miR-151a-5p. Dual-luciferase assays confirmed that miR-151a-5p binds to their 3' untranslated regions, inhibiting their expression at both the messenger RNA and protein levels. Knockdown of INPP4B or VAMP1 partially reproduced the cellular changes observed with miR-151a-5p overexpression. In vivo, microinjection of miR-151a-5p mimics into mouse zygotes exerted only mild effects on embryo development, indicating a possible contribution of miR-151a-5p primarily through sperm dysfunction.

Conclusions: miR-151a-5p may contributes to sperm dysfunction by targeting INPP4B and VAMP1, linking DNA fragmentation with mitochondrial and genomic instability. This study offers additional insights into the molecular mechanisms underlying male infertility.

Background: Chronic endometritis (CE) is frequently diagnosed in women with repeated implantation failure (RIF) and recurrent pregnancy loss (RPL), yet the lack of standardized diagnostic criteria and uncertainty about the timing of assessment and optimal treatment lead to open questions regarding its clinical relevance. This study aims to identify clinical risk factors that may guide targeted CE testing and to evaluate an ideal time point in the diagnostic pathway to offer CE assessment in women with RIF and RPL.

Methods: In this retrospective cohort study, 392 women with RIF (no pregnancy after two or more transfers of good quality blastocysts) and 119 women with RPL (two or more subsequent miscarriages) who underwent endometrial biopsy with CD138 immunohistochemistry between 2016 and 2024 were analyzed. Odds ratios for presumed CE risk factors were calculated and CE prevalence and reproductive outcomes were assessed.

Results: Women in the RPL group had a higher prevalence of CE compared to the RIF group (39.5 vs. 25.0%, p = 0.004). A history of cesarean delivery was associated with increased CE risk in the RPL group (OR 2.5, 95% CI 1.14-7.84). CE prevalence did not increase with the number of failed embryo transfers in RIF (32.2% after two, 21.3% after three, 24.7% after ≥ 4 transfers; p = 0.349) or miscarriages in RPL (44.2% after two, 51.4% after three, 57.1% after ≥ 4 miscarriages; p = 0.518). When RIF patients treated for CE were compared with those with normal biopsy after both two and three previous embryo transfers, we found no differences in pregnancy outcomes.

Conclusions: Our data did not confirm a significant increase in CE prevalence with an increasing number of failed embryo transfers or miscarriages. No relevant differences in the reproductive outcomes of RIF patients with normal biopsies compared with treated CE were found. While prior cesarean delivery may identify a subgroup of RPL patients who could benefit from targeted screening, the overall utility of routine CE testing and treatment remains limited. Standardized diagnostic criteria and further prospective studies are needed to clarify the role of CE in reproductive outcomes, with cautious consideration of uncritical antibiotic treatment.