Systems Biology in Reproductive Medicine最新文献

The use of assisted reproductive therapies, advances in embryo research, and developments in scientific fields such as gene editing and in vitro gametogenesis have attracted the attention of bioethicists for years. On one side, the 14-day rule has faced criticism from embryo researchers advocating for its extension. On the other side, the increasing number of cryopreserved embryos worldwide has raised practical and ethical concerns about their fate. While advancements in scientific research, especially gene editing and in-vitro gametogenesis (IVG), are not yet fully applicable, their potential future use appears to pose significant bioethical questions. In this review, we examine the evolving bioethics of embryo research, focusing on the 14-day rule, the challenges surrounding surplus cryopreserved embryos, and the future dilemmas posed by CRISPR-based gene editing, IVG, and preimplantation genetic testing for polygenic risk (PGT-P). We also highlight the critical role of multidisciplinary, patient-centered counseling in ART practice, to foster informed consent, realistic expectations, and psychosocial well-being. Finally, we underscore the need for anticipatory ethical frameworks and open-society engagement that integrate public deliberation with scientific progress to ensure that reproductive innovation proceeds responsibly, preserving both human dignity and social justice.

Female infertility is a multifactorial condition with complex biological and clinical underpinnings. Biologically, female-related infertility may stem from disruptions in the hypothalamic-pituitary-ovarian (HPO) axis, impaired folliculogenesis, oocyte maturation defects, uterine abnormalities, endometrial dysfunction, and fallopian tube abnormalities. This review highlights key genetic mechanisms contributing to reproductive dysfunction and their relevance to diagnosis and treatment. Chromosomal abnormalities, including Turner syndrome and X-autosome translocations, also contribute to infertility and recurrent pregnancy loss (RPL). Age-related declines in oocyte quality and quantity-due to increased aneuploidy significantly impact fertility after the mid-30s. Clinical causes such as polycystic ovary syndrome (PCOS), luteal phase defects, and endometriosis contribute to infertility through hormonal imbalance, inflammation, and impaired implantation. Environmental and lifestyle factors-like endocrine-disrupting chemicals, obesity, smoking, and stress-further influence reproductive function. Evaluation requires a multidisciplinary approach combining hormonal profiling, imaging, and genetic diagnostics. Ovarian reserve assessment using anti-Müllerian hormone (AMH) and antral follicle count (AFC), hormonal evaluation along with ultrasound and hysterosalpingography, are central to clinical workups. Next-generation sequencing is enhancing the role of genetic screening in unexplained infertility and specific conditions like POI and endometriosis. Treatment options-ranging from ovulation induction to surgery and assisted reproductive technologies (ART)-are increasingly personalized based on underlying causes and patient profiles. Despite advances, many cases remain idiopathic, highlighting the need for deeper molecular research and refined phenotyping. This review emphasizes the importance of precision medicine and an evidence-based, patient-centered approach to improve fertility outcomes across a broad spectrum of infertility etiologies.

Asthenoteratozoospermia is a major contributor to male infertility, with multiple morphological abnormalities of the flagellum (MMAF) representing a genetically heterogeneous disorder characterized by structural defects in sperm flagella. To identify the genetic determinants underlying MMAF-associated infertility, we conducted a comprehensive and systematic investigation involving Chinese infertile couples exhibiting the MMAF phenotype and undergoing assisted reproductive technology (ART). Our integrated approach combined whole-exome sequencing (WES) with Sanger sequencing for variant validation, complemented by scanning and transmission electron microscopy (SEM/TEM) to elucidate ultrastructural features. Molecular analyses included quantitative real-time PCR (qRT-PCR) and immunofluorescence (IF) to evaluate both transcriptional and translational alterations. We identified novel variants in six loci of dynein axonemal heavy chain 1 (DNAH1), including both missense and frameshift variants, across three unrelated families. Affected spermatozoa demonstrated characteristic morphological and ultrastructural abnormalities, while qRT-PCR and IF analyses revealed altered expression patterns of DNAH1. Personalized ART strategies enabled successful pregnancies in individuals harboring DNAH1 variants. While the limited sample size reflects the rarity of this genetic disorder, functional validation beyond expression analysis and structural prediction remains limited. Larger cohorts and in-depth biochemical assays will be required to generalize the findings. Nonetheless, our findings provide important insights into the genetic mechanisms of MMAF and its clinical management.

Refractile bodies (RBs) in human primordial oocytes may represent a lysosomal mechanism of cellular waste management independent of hormonal stimulation or age. This observational study investigated the ultrastructural features and molecular characteristics of refractile bodies (RBs) in human primordial oocytes, focusing on the involvement of lysosomes, autophagy, and mitochondria. Ovarian tissues were obtained from 34 individuals undergoing oophorectomy as part of female-to-male gender-affirming surgery, with no clinical interventions applied. Using fluorescence microscopy, immunocytochemistry, and transmission electron microscopy (TEM), we found large RBs (>5 μm) in all individuals, with no correlation to age. RBs exhibited strong LysoTracker fluorescence, indicating acidic content. LC3, but not RAB7, colocalized with RBs, suggesting incomplete autophagic processing. TEM revealed lysosomal vesicles, mitochondrial remnants, and lipid-rich structures within RBs, some partially enclosed by isolation membranes. These features support a model in which RBs transition from passive lipid accumulation to autophagy-driven remodeling in a size-dependent manner. RBs displayed lipofuscin-like characteristics and are likely formed through lysosomal and mitophagic pathways. Their formation appears to involve both canonical and non-canonical autophagic mechanisms, independent of age or hormonal stimulation. A limitation of this study is its observational nature without functional validation.

This review comprehensively discusses the innovative value and scientific mechanism of sequential embryo transfer (SET) technology in assisted reproduction. SET, by transferring embryos in stages, offers a novel approach to address clinical challenges in patients with recurrent implantation failure (RIF) and poor ovarian response (POR). The core mechanism involves bidirectional signal regulation between the embryo and endometrium. Extracellular vesicles (EVs) released by embryos during the initial transfer contain bioactive molecules like proteins, microRNA (miRNA), and mRNA. Through bidirectional molecular communication, these EVs interact with the maternal-fetal interface, promoting endometrial decidualization and establishing a molecular memory for 'embryo pre-adaptation,' thereby enhancing endometrial receptivity. Subsequent embryo transfers further optimize the pregnancy microenvironment through cumulative signaling effects, boosting embryo development and implantation success rates. Additionally, the synergistic impact of mechanical injury plays a role. Local micro-injuries induced by the transfer catheter operation trigger an inflammatory response, recruit immune cells, activate tissue repair pathways, stimulate regenerative cell and signaling molecule secretion, and enhance angiogenesis and endometrial remodeling. This 'microtrauma pre-activation' fosters favorable conditions for subsequent embryo implantation. Clinical evidence demonstrates that SET significantly elevates the clinical pregnancy and live birth rates in RIF patients without heightening the risk of multiple pregnancies. In POR patients, SET can reduce cycle cancelation rates. This review not only supports the clinical application of SET but also advances assisted reproduction from empirical to precision medicine guided by molecular mechanisms.

The multifaceted process of fertilization encompasses a precisely orchestrated cascade of molecular and morphological modifications of the participating male and female gametes. Fertilization culminates in the union of the maternal and paternal genomes and ultimately spark the development of a new individual. During the last decade, extensive new knowledge has been gained concerning the candidate cellular and molecular mechanisms that guide each step of the process from the sperm journey through the female reproductive tract to the gamete fusion and oocyte activation. In this review, we aim at summarizing the main molecular mechanisms of sperm and oocyte activation and fertilization from the moment sperm enters the female reproductive system up to zygote formation. Focusing on molecular determinants including but not limited to ligands, receptors, and signal transducers, we describe well established and novel molecular candidates that pave the way throughout this complex process and highlight the need for further investigation toward clinical application in assisted reproductive therapy.

The male gamete, the spermatozoon, is the carrier of paternal inheritance. Besides paternal genome, the spermatozoon contributes essential factors for successful fertilization, embryonic development, and continuation of species. A dynamic and extraordinarily complex process called spermatogenesis produces spermatozoa capable of maturing and acquiring full fertilizing capacity. Spermatogenesis proceeds through a series of events that involve cell division (proliferative phase assuring continuous restocking of spermatogenic stem cells), meiosis (recombination and haploidization of paternal genome), post-meiotic differentiation (spermiogenesis; hypercondensation of sperm DNA and generation of accessory sperm structures), and post-testicular maturation (including epididymal maturation, acquisition of seminal plasma components at ejaculation and spermatozoa capacitation within the female oviduct). In this chapter, we provide a concise overview of testis organization and spermatogenesis in different mammalian species and the details of the intricate structure of human/mammalian spermatozoa. Additionally, we explore the fascinating process of spermatogenesis and its regulation. We thus aim to offer insights into the fundamental process that drives male fertility and provides the foundation of reproductive success.

Macrozoospermia is a rare cause of male infertility characterized by a high proportion of sperm with large, irregular heads. In this study, we identified a novel homozygous Aurora kinase C (AURKC) missense variant (c.253G > A (p.Glu85Lys)) in a Chinese infertile man using whole-exome sequencing. Segregation of the AURKC c.253G > A variant within the family was confirmed by Sanger sequencing, and In silico prediction tools suggested that the variant is pathogenic. Sperm ultrastructural abnormalities in the patient were further examined using transmission electron microscopy. Our findings identify a novel pathogenic AURKC variant associated with macrozoospermia, providing potential value for genetic diagnosis and clinical management.

Male infertility accounts for approximately half of all infertility cases and is often linked to chromosomal abnormalities. While numerical and structural rearrangements are well recognized, the clinical significance of chromosomal polymorphisms remains unclear. To characterize the spectrum of cytogenetic alterations - including polymorphisms, structural rearrangements, and numerical changes - in men presenting with infertility and to assess their incidence on men with semen abnormalities. In this retrospective observational study, peripheral blood samples from 62 patients with detected cytogenetic alterations were collected at Genos Laboratory (Unimed Diagnostic Center) in Bauru, Brazil, between January 2015 and June 2020. Semen analysis reports for these patients were retrieved from the Fertility Clinic in Bauru, Brazil. Following specialist evaluation, a final cohort of 38 men diagnosed with infertility was analyzed. Results: Chromosomal polymorphisms were the most frequent alteration (77.4%), followed by structural rearrangements (17.7%) and numerical changes (4.8%). Among polymorphism carriers, 58% exhibited at least one abnormal semen parameter, most commonly asthenozoospermia (42%), teratozoospermia (38%), and oligozoospermia (33%). The 46,XYqh⁺ variant predominated (50%), with half of these cases demonstrating semen abnormalities. Double polymorphisms (46,XY9qh⁺ and 46,XY22ps⁺; n = 8) were uniformly associated with oligozoospermia and teratozoospermia. Structural alterations - pericentric inversion of chromosome 9 and Robertsonian translocation rob(13;14)(q10q10) - were found in 11 patients; 72% of these also had semen abnormalities. Numerical alterations were rare but associated with abnormal semen parameters in 66% of cases. Chromosomal polymorphisms, though traditionally viewed as benign, were frequently detected in compromised semen quality in this cohort. Structural and numerical rearrangements, while less common, were detected in a higher proportion of abnormal semen parameters. These findings underscore the value of comprehensive cytogenetic screening in the evaluation of male infertility.