Reproductive Biology and Endocrinology最新文献

Endometriosis is one of the most common gynecological diseases in women and is still one of the most understudied diseases, affecting the daily lives of patients. Although the exact cause of this condition remains unclear, autophagy has been proposed as a potential biological process involved in the disease. Autophagy is a highly conserved catabolic process crucial for the degradation of lysosomes and several cellular components. In recent years, various studies have shown that this biological process could be crucial in endometriosis, with some evidence demonstrating its upregulation and others its downregulation in different study models. Due to this controversy and the potential implications of autophagy as a therapeutic target, this current review highlights significant findings on the involvement of autophagy in endometriosis and explores its potential as a therapeutic target.

Objective: This study aimed to investigate the microbiome profile in the cystic fluid of ovarian endometrioma and explore its association with the microbial communities present in the lower and upper reproductive tracts.

Design: A microbial analysis was conducted across multiple compartments of the reproductive tract in patients diagnosed with ovarian endometrioma.

Subjects: Sixteen female patients aged 25-43 years (mean age: 31.56 years) who underwent laparoscopic surgery for ovarian endometrioma at the First Hospital of Putian City between April 2023 and February 2024 were enrolled in this study.

Main outcome measures: 16S rDNA sequencing was employed to characterize the microbiome of ovarian endometrioma and assess its correlations with clinical symptoms, inflammatory markers, and serum CA125 levels RESULTS: Microbial communities were detected in the posterior vaginal fornix, endometrial fluid, peritoneal fluid, and cystic fluid, exhibiting distinct compositional profiles. Community diversity significantly increased along the anatomical gradient from the posterior vaginal fornix to endometrial fluid, peritoneal fluid, and cystic fluid, with the highest microbial diversity observed in the cystic fluid. Lactobacillus was the predominant genus in the posterior vaginal fornix, whereas Escherichia-Shigella was most abundant in endometrial fluid samples. Hydrogenophaga and Brevundimonas were the dominant taxa in both peritoneal and cystic fluids. Notably, the microbial composition of peritoneal fluid showed the greatest similarity to that of cystic fluid, and functional prediction analyses indicated largely overlapping biological functions between these two sites. Furthermore, Spearman correlation analysis revealed significant associations between specific microbial taxa and certain clinical manifestations or inflammatory factors.

Conclusion: This study demonstrates the presence of a unique and highly diverse microbiome within the cystic fluid of ovarian endometrioma. The site-specific microbial profiles and their correlations with clinical parameters suggest a potential role of microbiota in disease pathogenesis through inflammatory and metabolic mechanisms. These findings contribute novel insights that may inform future strategies for the prevention, diagnosis, and treatment of ovarian endometrioma.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to alleviate pain associated with endometriosis (EMS), yet the impact of their long-term use on disease progression remains unclear. This study investigates the dual role of NSAIDs in EMS pathogenesis using network toxicology and Mendelian randomization (MR).

Methods: The toxicity and ADMET profiles of nine NSAIDs were screened using ProTox 3.0 and ADMETlab 2.0. Potential drug targets were predicted using PharmMapper, STITCH, and SwissTargetPrediction, while EMS-related targets were retrieved from GeneCards, OMIM, and CTD databases. For the MR analysis, cis-eQTLs for whole blood tissue from GTEx v8 served as instrumental variables, based on the inflammatory nature of endometriosis. Outcome data were from an independent GWAS summary dataset (19,588 cases, 213,669 controls). Our analysis adhered to MR independence assumptions, ensuring no sample overlap between exposure and outcome data. Functional enrichment and molecular docking explored the underlying mechanisms.

Results: By integrating drug targets with disease genes, we first identified 463 overlapping targets. We revealed that EPHB4 is a core hub mediating the potential "risk-promoting" effects of nearly all NSAIDs, with its functions enriched in key pathological processes such as angiogenesis. Molecular docking confirmed that eight NSAIDs could stably bind to EPHB4. Crucially, we found that indomethacin exhibited a unique "dual-regulatory" pattern: it simultaneously targeted the protective target PTGER4 and the risk-associated target EPHB4. Molecular docking further substantiated, at the atomic level, that indomethacin possesses strong binding affinity for both targets, providing a structural biology explanation for its observed genetic effects.

Interpretation: This study provides, for the first time, robust causal evidence from both genetic and structural biology perspectives for the "double-edged sword" attribute of NSAIDs in EMS, and proposes a new paradigm of "target-oriented heterogeneous effects." We found that specific NSAIDs might inadvertently promote disease progression by activating the EPHB4 pathway, while indomethacin stands out as a key exception due to its unique dual-action mechanism. These findings not only offer a critical explanation for the current clinical controversy but also lay a solid scientific foundation for advancing EMS management from "empirical medication" towards "precision-based selection guided by molecular mechanisms."

Background: More than 500 patients have received cryopreserved ovarian tissue transplantation (OTT) worldwide, resulting in over 200 live births. Although guidelines recognize OTT as an effective fertility preservation method, there is no consensus on the optimal grafting site of OTT. This systematic review and meta-analysis aim to assess whether reproductive outcomes of OTT vary across different grafting sites.

Methods: A literature search was conducted through March, 2024, in PubMed, Embase and the Cochrane library, using the following terms: 'patient', 'fertility preservation', 'ovarian tissue transplantation' and 'live birth'. Studies including 5 or more subjects were included. Two reviewers independently selected the studies, collected the data and assessed the risk of bias. Heterogeneity and publication bias were evaluated using the I² statistic and Egger's test, respectively. A fixed-effect meta-analysis was performed only if I² was 0%, otherwise a random-effect model was applied. The primary outcome was the live birth rate (LBR). The secondary outcomes included the proportion of women who became pregnant, those who had at least one live birth, and those who underwent repeat OTT.

Results: Eighteen studies including 560 women were included. The estimated LBRs after transplantation to the remaining ovary and the pelvic peritoneum were 64% (20%-130%, I² = 74%) and 31% (15%-51%, I² = 21%), respectively. The LBRs after orthotopic transplantation (defined as transplantation to the remaining ovary, the pelvic peritoneum or both sites, which allowed spontaneous pregnancy), heterotopic transplantation and combined (orthotopic + heterotopic) transplantation were 44% (25%-69%, I² = 79%), 5% (0%-21%, I² = 0%) and 23% (4%-53%, I² = 19%), respectively. No publication bias was observed.

Conclusion: Reproductive outcomes of OTT vary across different grafting sites. The LBR of orthotopic transplantation is higher than that of heterotopic transplantation. Additionally, the LBR of OTT to the remaining ovary is higher than that to the pelvic peritoneum. The remaining ovary may therefore be a more suitable site for women undergoing OTT to preserve future fertility.

Registration number: CRD42023447618.

Non-obstructive azoospermia (NOA) is one of the most severe manifestations of male infertility, accounting for up to 70% of azoospermic cases and affecting approximately 1% of the male population. Advances in genomics and epigenetics have transformed our understanding of NOA from a primarily idiopathic condition into a biologically heterogeneous disorder driven by diverse molecular mechanisms. This review synthesizes the current knowledge of the genetic and epigenetic landscape of NOA, integrating chromosomal abnormalities, single-gene mutations, and non-coding RNA (ncRNA) dysregulation. First, we systematically examine classical and emerging chromosomal defects-including karyotype anomalies, Y-chromosome microdeletions, and structural rearrangements-that disrupt meiotic pairing and chromatin organization. Next, we explore syndromic and non-syndromic monogenic mutations affecting meiotic regulators, DNA repair factors, transcription regulators, and chromatin remodelers. Particular emphasis is placed on recently identified genes such as SYCP1, SYCE1 and HORMAD1, whose pathogenic variants are frequently linked to spermatogenic arrest. We then discuss the expanding role of ncRNAs-including microRNAs, PIWI-interacting RNAs, long non-coding RNAs, and circular RNAs-in regulating germ cell apoptosis, transposon silencing, and epigenetic reprogramming. Furthermore, we highlight the translational potential of these molecular insights (including gene variants, ncRNAs and protein) in clinical applications. Genotype-guided sperm retrieval, non-invasive biomarkers, and multi-omic approaches are discussed as promising tools to improve diagnosis and treatment. Moreover, we summarize current and emerging strategies for the treatment and fertility preservation of NOA. Finally, we identify persisting challenges, such as genotypic heterogeneity and incomplete functional validation, and emphasize the need to elucidate interactions between ncRNA and classical genetic pathways to uncover regulatory hierarchies underlying NOA. By integrating molecular genetics with testicular histopathology and clinical phenotypes, this review highlights emerging genetic and ncRNA biomarkers and underscores their potential applications in the clinical management of NOA. Ultimately, a comprehensive understanding of the genetic and epigenetic underpinnings of NOA will be essential for advancing precision diagnostics and improving reproductive outcomes in affected men.