Cellular senescence, mitochondrial dysfunction, and cumulative oxidative stress (OS) are the main causes of the progressive decreases in oocyte and sperm quality that define reproductive age. There is growing evidence that these processes are controlled by systemic variables, such as metabolites produced from the gut microbiome and extracellular vesicle (EV)-mediated intercellular communication, rather than being exclusively regulated at the tissue level. Antioxidant enzymes, regulatory microRNAs, and bioactive lipids that regulate mitochondrial redox balance, mitophagy, and inflammatory signaling are transported by EVs derived from reproductive organs, stem cells, immune cells, and the gut microbiota. Concurrently, microbiome-derived metabolites such as urolithin A, short-chain fatty acids, and polyphenol derivatives enhance mitochondrial quality control, activate antioxidant pathways, and suppress senescence-associated secretory phenotypes. This narrative review integrates the most recent research on the relationship between redox homeostasis, mitochondrial function, gut microbiota activity, and EV signaling in the context of male and female reproductive aging. We propose an emerging gut–EV–mitochondria axis as a unified framework through which systemic metabolic and antioxidant signals affect gamete competence, reproductive tissue function, and fertility longevity. Finally, we discuss therapeutic implications, including microbiome modulation, EV-based interventions, and senotherapeutic strategies, highlighting key knowledge gaps and future research directions necessary for clinical translation.

Preliminary data have shown that it is possible to attempt in vitro fertilization (IVF) treatment in fresh cycles without the use of a gonadotropin-releasing hormone (GnRH) antagonist or any other medication to prevent the luteinizing hormone (LH) surge during ovarian stimulation. To date, there is no information on this topic in the context of a prospective controlled trial. However, as prevention of the LH surge is an established procedure in fresh cycles, the question is whether such a study can be performed in frozen cycles. We aim to perform a pilot study in order to compare the efficacy of a protocol using FSH alone with that of a protocol using follicle-stimulating hormone (FSH) plus a GnRH antagonist for controlled ovarian hyperstimulation (COH) in cycles of elective freezing in the context of a donor/recipient program. This is a seven-center, two-arm prospective pilot cohort study conducted at the respective Assisted Reproductive Units in Greece. The hypothesis to be tested is that an ovarian stimulation protocol that includes FSH alone without any LH surge prevention regimens is not inferior to a protocol including FSH plus a GnRH antagonist in terms of the clinical outcome in a donor/recipient model. The results of the present study are expected to show whether the addition of the GnRH antagonist is necessary in terms of the frequency of LH secretory peaks and progesterone elevations >1 ng/mL during the administration of the GnRH antagonist according to the adopted frequency of blood sampling in all Units.

In the human reproductive system, extracellular vesicles (EVs) have been recognized as playing a vital role in mediating cell–cell communication. They are considered critical for embryo development, implantation, gamete interaction, and fertilization. The various cargoes carried by EVs, depending on the physiological and pathological state of the cell, include proteins, lipids, nucleic acids, and mitochondrial components. EVs are recognized as critical carriers of redox-related signals and mitochondrial components, linking oxidative stress (OS) to reproductive failure and influencing gamete quality and embryo competence. Although considerable progress has been made, research remains poorly integrated, despite individual omics technologies providing valuable molecular insights. The use of multi-omics technologies, including transcriptomics, proteomics, metabolomics, and microbiome analysis, has been proposed as a global approach to understanding the complexities associated with EVs and discovering new biomarkers associated with infertility. ML and AI have been proposed to identify predictive signatures linked to ART effectiveness and reproductive outcomes, with a strong capacity to handle high-dimensional data. The review aims to provide an overview of current knowledge on EV-mediated redox–mitochondrial signaling in human reproduction, while highlighting the importance of emerging multi-omics and AI technologies for EV-mediated biomarker development. The review discusses the promise of EVs in the development of minimally invasive diagnostic approaches and therapeutic interventions, as well as the challenges in the standardization, integration, and clinical translation of EV-mediated research. In addition, the review proposes integrating computational approaches to better understand molecular pathways involved in the development of next-generation precision medicine in human reproduction.