Systems Biology in Reproductive Medicine最新文献

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.

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 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.

MicroRNAs (miRNAs) have acquired an increased recognition to unravel the complex molecular mechanisms underlying Diminished Ovarian Reserve (DOR), one of the main responsible for infertility. To investigate the impact of miRNA profiles in granulosa cells and follicular fluid, crucial players in follicle development, this study employed a computational network theory approach to reconstruct potential pathways regulated by miRNAs in granulosa cells and follicular fluid of women suffering from DOR. Available data from published research were collected to create the FGC_MiRNome_MC, a representation of miRNA target genes and their interactions. 365 hubs were identified within the network, representing potential key regulators, and 210 nodes that act as both hubs and bottlenecks (H&BN nodes), suggesting that they may control the information flow within the network. GO enrichment analysis of the 210 H&BN nodes revealed their involvement in fundamental cellular processes relevant to ovarian function. In particular, the cluster analysis identified several shared pathways between cluster 1 and cluster 2 involved in the RAS/MAPK pathway, which plays a critical role in cell proliferation, differentiation and survival. These findings suggest that miRNAs play a significant role in DOR and highlight the potential of the RAS/MAPK pathway as a target for further investigation. Additionally, the genes identified as both hubs and bottlenecks revealed interesting connections to reproductive health in KO mice models. This in silico approach provides valuable insights into potential biomarkers and therapeutic targets for age-related reproductive disorders.

Assisted reproductive technologies (ART) have been widely and successfully used in both humans and livestock. However, only in humans and cattle have in vitro fertilization (IVF), in vitro embryo culture (IVC), and embryo transfer (ET) developed into large commercial sectors. The major differences between human and animal ART include the rationale of the treatment and the patient groups. While ART is used to treat infertility in humans, veterinary ART aims to maximize genetic gain and minimize generation intervals. Human ART is filled with societal, cultural, and emotional challenges, whereas veterinary ART aims to optimize economic success. While human ART deals with selected patients, including older individuals, veterinary ART focuses on young animals and a wide variety of species with different reproductive traits. Both human and veterinary ART face the shared challenge of establishing reliable tools to assess sperm fertilizing ability, evaluate oocyte developmental capacity, and support early embryo-maternal communication, which is pivotal for successful pregnancy. A holistic approach and comprehensive understanding of the underlying mechanisms and technologies across species could provide valuable insights for increasing ART success rates in both humans and animals.

The study focused on the spermicidal and anti-androgenic effects of aqueous-ethanolic (60:40) extract of Caesalpinia pulcherrima leaves (AEECPL) in human and rat samples from the viewpoint of its contraceptive efficacy through ex-vivo study. Six fertile adult males were selected randomly for semen collection. Parallelly sperm samples were collected by epididymal washing from six rats. Testes, epididymis, and liver were dissected from rats. Biological samples were divided into control, 1, 2, and 4 mg/ml of AEECPL exposed groups. Relevant spermiological, steroidogenic enzymes, oxidative stress, and metabolic toxicity sensors were evaluated. All the spermiological sensors were decreased significantly in dose and duration-dependent manners, and the number of comet positive spermatozoa were increased in dose-dependent mode in AEECPL exposed groups against the control both in human and rat. Activities of Δ5,3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD in testis, kinetics of superoxide dismutase both in testis and epididymis were significantly decreased along with the elevation in the level of thiobarbituric acid reactive substances in AEECPL exposed groups. Activities of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, acid phosphatase, and alkaline phosphatase in above mentioned tissues showed no significant difference among the control and AEECPL exposed groups, indicating its non-toxic effects on reproductive and metabolic tissues. The results presenting the prominent contraceptive preventing potentiality of the said extract both in human and rat. The optimal effect was noted at 2 mg/ml dose. In-depth investigations are required through in-vivo studies on animal model to know the genomic mode of action for the execution of male contraceptive activity.

Advancements in next generation sequencing technologies, including 16S rRNA amplicon sequencing, have vastly expanded our understanding of reproductive microbiota and its role in fertility. For example, in humans, the bacterial genus of Lactobacillus is the overwhelmingly dominant commensal bacterium within reproductive tissues and fluids, such as the vagina, and is an indicator of fertility in women. Shifts away from Lactobacillus allow for opportunistic pathogenic bacteria to inhabit the reproductive tract and result in dysbiosis and infertility. The goal of this review is to explore human reproductive microbiota including bacteria that commensally inhabit reproductive tissues and fluids as well as opportunistic pathogenic bacteria that can result in dysbiosis, infertility, and disease. Continued exploration of the microbiome and its association with reproductive health will aid in the development of targeted therapeutic strategies to positively modulate bacteria and improve fertility.