Konstantinos Dafopoulos

Background/Objectives: Nutritional exposures may influence female reproductive health through metabolic and epigenetic pathways, including DNA methylation, chromatin regulation, and non-coding RNAs. However, evidence for direct nutritional–epigenetic mediation of reproductive outcomes remains heterogeneous. This narrative review examines the evidence linking nutrition, epigenetic regulation, and female reproductive health across developmental programming, adult reproductive function, pregnancy, reproductive disorders, and reproductive aging. Methods: A comprehensive literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science to identify experimental, epidemiological, and clinical studies examining relationships among nutrition, metabolic status, epigenetic regulation, and female reproductive health. Evidence from molecular, animal, and human studies was critically synthesized, distinguishing epigenetic associations from evidence of mechanistic mediation. Results: Nutritional and metabolic exposures are associated with epigenetic pathways involved in ovarian and endometrial function, placental development, and reproductive aging. Experimental evidence supports nutrition-responsive epigenetic regulation, but evidence for epigenetic mediation of reproductive outcomes remains limited in humans. Similar limitations apply to major reproductive disorders and pregnancy complications. Conclusions: Nutritional epigenetics provides a biologically plausible framework linking diet, metabolism, and female reproductive health, but nutritional–epigenetic associations should not be interpreted as evidence of mediation without temporal and functional validation. Longitudinal and interventional studies integrating nutritional exposures with tissue-specific epigenomics and reproductive outcomes are needed before epigenetically informed biomarkers or personalized nutritional strategies can be translated into clinical practice.

Regulated cell death (RCD) has emerged as a fundamental determinant of cellular homeostasis and tissue remodeling, extending far beyond the classical concept of apoptosis. The identification of emerging RCD pathways, including ferroptosis, pyroptosis, necroptosis, cuproptosis, PANoptosis, and autophagy-dependent cell death, has expanded our understanding of reproductive physiology and disease. RCD mechanisms contribute to reproductive homeostasis and have been increasingly implicated in gametogenesis, folliculogenesis, embryonic development, implantation, placentation, and reproductive aging, while their dysregulation has been associated with infertility, recurrent implantation failure, recurrent pregnancy loss, pregnancy complications, endometriosis, polycystic ovary syndrome (PCOS), gynecological malignancies, and male reproductive disorders. This review provides a comprehensive overview of the molecular mechanisms governing RCD across reproductive physiology and disease, emphasizing the complex interplay between oxidative stress (OS), mitochondrial dysfunction, inflammation, immune regulation, metabolic reprogramming, and genetic and epigenetic networks. Particular attention is given to the contribution of emerging cell death pathways to reproductive disorders and their interactions with environmental and lifestyle factors, including endocrine-disrupting chemicals. In addition, current evidence regarding RCD-associated biomarkers, multi-omics approaches, and therapeutic strategies targeting specific cell death pathways is critically evaluated, with particular emphasis on distinguishing associative molecular signatures from functional evidence of RCD execution. By integrating recent advances from basic, translational, and clinical research, this review highlights the context-dependent role of RCD in reproductive biology and disease and identifies current limitations and future opportunities for RCD-informed diagnostics, patient stratification, and targeted therapeutic interventions in reproductive medicine.

Recurrent pregnancy loss (RPL), a multifactorial condition in reproductive medicine, affects approximately 1–3% of couples. Increasing evidence implicates endometrial dysfunction, immune dysregulation, impaired angiogenesis, and oxidative stress (OS) in its pathophysiology, highlighting the need for biologically targeted therapeutic strategies. In this context, platelet-rich plasma (PRP) has emerged as a regenerative approach with the potential to modulate these underlying mechanisms. This narrative review critically evaluates the biological rationale and current clinical evidence supporting PRP as an adjunctive treatment for RPL while proposing a precision medicine framework for biologically guided patient selection. A comprehensive narrative synthesis of the literature was performed, focusing on studies investigating PRP in RPL and related reproductive conditions, including thin endometrium and recurrent implantation failure (RIF). Mechanistically, PRP promotes angiogenesis through vascular endothelial growth factor (VEGF)-mediated pathways, enhances endometrial regeneration by stimulating stromal and epithelial cell proliferation, and modulates immune responses by promoting regulatory T-cell activity while attenuating pro-inflammatory signaling. In addition, PRP-derived extracellular vesicles (EVs) and microRNAs may contribute to the post-transcriptional and epigenetic regulation of implantation-related genes, including leukemia inhibitory factor (LIF) and HOXA10. Clinical studies in RIF and thin endometrium populations suggest that PRP may improve endometrial thickness, implantation, and clinical pregnancy outcomes; however, these findings constitute indirect evidence for RPL. Direct RPL-specific evidence remains very limited and is insufficient to establish a reduction in miscarriage or an improvement in live birth. These biological features instead provide a rationale for investigating PRP in defined patient subgroups characterized by impaired endometrial receptivity, defective angiogenesis, immune dysregulation, or unexplained RPL with suspected endometrial dysfunction. Accordingly, we propose that future clinical investigation of PRP should move beyond empirical use toward biomarker-informed, precision reproductive medicine strategies. Although PRP represents a biologically plausible and promising adjunctive therapy, robust randomized controlled trials incorporating standardized PRP protocols and biologically stratified patient populations are required before its routine clinical use can be recommended.

Primary lymphomas of the female genital tract (PLFGT) are extremely rare neoplasms, representing a minor fraction of both extranodal lymphomas and gynecologic malignancies. Due to their nonspecific clinical presentation and overlapping imaging features with more common gynecologic tumors, diagnosis is often delayed or missed. This narrative review aims to synthesize current evidence on the clinical characteristics, histologic subtypes, diagnostic approaches, treatment strategies, and prognostic factors of PLFGT, emphasizing recent developments that may influence clinical practice. A comprehensive literature review was conducted, incorporating data from institutional case series, population-based studies, and recent genomic investigations focusing on PLFGT across various anatomical sites: ovary, uterus, cervix, and vagina. PLFGT typically affects women aged 44–68 years, with the ovary being the most frequently involved organ. The most common subtype is diffuse large B-cell lymphoma (DLBCL), followed by Burkitt lymphoma and marginal zone lymphoma. Patients usually present with pelvic pain, mass, or abnormal bleeding, while B symptoms are infrequent. Image-guided core needle biopsy has emerged as a valuable diagnostic approach that may reduce unnecessary surgery. Characteristic sonographic findings, such as hypoechoic, well-defined lesions and homogeneous uterine echo reduction, should raise clinical suspicion, though primary and metastatic disease cannot be distinguished solely by imaging. Rituximab-containing regimens (R-CHOP) are the mainstay of treatment and have improved outcomes. Despite treatment, central nervous system (CNS) recurrence remains a concern, particularly in ovarian involvement. Additionally, mutations in MYD88 and CD79B, although not prognostic, offer potential for personalized therapy. Timely diagnosis and appropriate systemic therapy are critical for improving survival in PLFGT. Advances in imaging, biopsy techniques, and molecular profiling are reshaping the diagnostic and therapeutic landscape of this rare but clinically significant disease.

The hallmark feature of empty follicle syndrome (EFS) is failure to retrieve oocytes from apparently mature follicles despite adequate ovarian stimulation and appropriate ovulation triggering. Although considered uncommon, with a reported prevalence ranging from 0.2% to 7%, EFS may have a profound clinical and psychological impact and can recur in assisted reproductive technology (ART) cycles. Modern classification systems divide EFS into genuine and false forms. Genuine EFS is potentially associated with intrinsic abnormalities involving luteinizing hormone/choriogonadotropin receptor (LHCGR) signaling, oocyte competence, and cumulus–oocyte interaction, whereas false EFS is primarily attributed to pharmacokinetic or pharmacodynamic factors resulting in inadequate trigger exposure. Borderline EFS represents a third phenotype characterized by incomplete or partial impairment of final oocyte maturation. This review examines the pharmacodynamics of ovulation-triggering agents, including human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH) agonist protocols, and dual-trigger strategies, and their roles in regulating final oocyte maturation. The molecular aspects of periovulatory signal transduction and the mechanisms of LHCGR activation, epidermal growth factor (EGF)-like pathways, and meiotic resumption in relation to EFS etiopathogenesis will be described. The impact of patient-dependent conditions like obesity, poor ovarian reserve, polycystic ovary syndrome (PCOS), and pituitary response on trigger response will be assessed. New approaches like post-trigger monitoring of hormones and rescue treatment with gonadotropins represent a valuable method for avoiding cycle cancellation in patients at risk. Overall, EFS is increasingly regarded not as a single disorder but as a heterogeneous spectrum of periovulatory dysfunction arising from pharmacological, endocrine, and intrinsic ovarian factors that impair completion of final oocyte maturation.

The pineal gland regulates circadian physiology through the periodic production of melatonin (MLT). In addition to its established role as a chronobiotic agent, MLT regulates redox homeostasis and mitochondrial physiology. Mitochondria and redox-active molecules, particularly reactive oxygen species (ROS), play essential roles in reproduction, including gamete physiology, fertilization, and early embryonic development. Although excessive oxidative stress (OS) impairs fertility, controlled ROS signaling is necessary for normal reproductive function. This comprehensive review synthesizes current evidence regarding MLT as a key intermediary linking circadian signaling with mitochondrial physiology and redox homeostasis. We discuss molecular pathways through which MLT regulates mitochondrial function, including activation of the Nrf2 signaling pathway, modulation of mitochondrial permeability transition, regulation of electron transport chain (ETC) efficiency, and apoptotic signaling. Furthermore, this study investigates MLT’s ability to scavenge free radicals and activate antioxidant defense mechanisms. Moreover, we review novel findings regarding the effects of MLT in experimental animals and humans, assisted reproductive technologies (ART) such as in vitro fertilization (IVF), and consider the translational significance of the hormone as an enhancer of fertility. We also highlight gaps in the literature, including methodological inconsistencies, supraphysiologic doses, and insufficient data from large human cohorts. Lastly, we discuss an integrative model whereby MLT may function as an important regulator of mitochondrial redox balance, with potential implications for reproductive physiology and reproductive outcomes, and propose new avenues for investigation.

The large retrospective study of Wang et al. with 21,290 IVF/ICSI fresh embryo transfer cycles, addressed a significant surrogate marker of endometrial receptivity, i.e. the endometrial thickness (EMT) on the day of human chorionic gonadotropin (hCG) administration, in two different ovarian stimulation protocols: the early-follicular long-acting GnRH agonist protocol and the midluteal short-acting GnRH agonist long protocol, since the optimal thresholds in various ovarian stimulation protocols remain unclear. The researchers using advanced statistics with restricted cubic spline analysis, showed that with the early-follicular long-acting protocol, live birth rate increased with increasing EMT up to 10.6 mm, after which there was no benefit. However, regarding the midluteal short-acting protocol there was a continuous positive relationship between EMT and live birth rate. These important findings suggest that including the specific EMT evaluation in individualization of ovarian stimulation may optimize ART treatment and improve success rates.In modern ART treatment, the optimization of the outcome includes the accurate assessment of ovarian reserves and the prediction of the ovarian response to gonadotropin stimulation. The study by Melado et al. investigated whether evaluating novel high-specific AMH assays targeting distinct molecular isoforms may improve the limited predictive accuracy of conventional biomarkers, i.e. AMH and antral follicle count (AFC) in patients with low ovarian reserve. The authors showed that the combination of AFC with highly specific AMH assays using linear-epitope antibodies, had the highest predictive accuracy of the number of oocytes retrieved. This finding is of paramount importance for counselling patients and individualization of gonadotropin dosing in the challenging group of poor responders.Repeated embryo implantation failure (RIF) is an extremely frustrating condition for both patients and clinicians. Although some possible causes have been identified, in the great majority of cases the etiology is unknown. It is well known that insulin resistance (IR) plays a significant role in polycystic ovary syndrome (PCOS), but its impact on ART outcomes in non-PCOS women is not clear. The retrospective cohort study by Peng et al. investigated the possible role of IR in RIF patients undergoing frozen embryo transfer. The authors found that compared to women with no IR, the patients with IR showed significantly lower live birth rate and higher miscarriage rate. Furthermore, the patients with IR that were treated with metformin had higher clinical pregnancy, implantation and live birth rates and lower miscarriage rate, compared to the untreated patients. These findings suggest that systemic IR may negatively impact on ART outcomes and the improvement of insulin sensitivity via metformin seems to represent a beneficial adjunct in such patients.The retrospective study of Guan et al. including 1,981 GnRH-ant protocol cycles with fresh embryo transfer, investigated whether there was a significant effect of the ratio of serum progesterone (P) levels on the hCG trigger day to the levels on day 2 (PhCG/Pbasal) on pregnancy rates in patients with normal ovarian response. The authors showed that even a slight elevation in P levels on the day of hCG triggering reduced the live birth rate (LBR). Also, the PhCG/Pbasal ratio was found to be of important prognostic value since the cycles with a serum P level <1.06 ng/mL on the hCG trigger day combined with a PhCG/Pbasal ratio <1.2 had a significantly higher LBR. On the other hand, a PhCG/Pbasal ratio ≥1.2, was associated with lower LBR regardless of the P levels on the day of hCG triggering. The underlying mechanism of elevated P exposure on endometrium involves the advanced endometrial secretory transformation and finally the embryo-endometrial asynchrony that negatively impacts on pregnancy rates. The findings of this study suggest that the routine evaluation of the PhCG/Pbasal ratio may be included in the individualized clinical management as an additional means to optimize IVF treatment.One of the most difficult problems in ART is advanced maternal age (AMA), since many women delay childbearing globally, with inevitable negative consequences on ovarian reserve, oocyte quality, embryonic aneuploidy and finally low live birth rates. The study of Jin et al. in this Research Topic investigated whether a traditional Chinese medicine formulation, the Qiziyusi Decoction (QZYSD), had any effect on the IVF outcomes in women of AMA. The study found that compared to untreated AMA women, the group of AMA, that started oral administration of QZYSD from the day of pituitary downregulation until the day of oocyte retrieval, had significantly higher serum levels of E2, number of retrieved oocytes and number of high-quality embryos on day 3, and a trend for a higher cumulative clinical pregnancy rate. Furthermore, through an integrative multi-omics analysis of follicular fluid the authors showed that QZYSD treatment may modulate pathways associated with immune regulation and oxidative stress within the follicular fluid microenvironment, supporting that the integration of traditional medicine on modern infertility management may be beneficial on ART outcomes.In conclusion, the contributions in this Research Topic highlight the complexity and multifactorial determinants of a successful ART treatment. They also emphasize that the "one-size-fits-all" approach in reproductive medicine is outdated and replaced by personalized strategies that incorporate multiple data such as molecular biomarkers, clinical and metabolic parameters.

Background/Objectives: Traditional semen analysis techniques frequently result in incorrect male infertility diagnoses, despite advancements in assisted reproductive technology (ART). Reduced fertilization potential, decreased embryo development, and lower pregnancy success rates are associated with elevated DNA Fragmentation Index (DFI), which has been proposed as a diagnostic indicator of sperm DNA integrity. Improving reproductive outcomes requires incorporating DFI into predictive models due to its diagnostic importance. Methods: In this study, semen samples were stratified into low and high DFI groups across two datasets: the “Reference” dataset (162 samples) containing sperm motility (A, B, and C), total sperm count, and morphology percentage, and the “ORP” dataset (37 samples) with the same features plus oxidation-reduction potential (ORP). We trained and evaluated four machine learning (ML) models—Logistic Regression, Support Vector Machines (SVM), Bernoulli Naive Bayes (BNB), and Random Forest (RF)- using three feature subsets and three preprocessing techniques (Robust Scaling, Min-Max Scaling, and Standard Scaling). Results: Feature subset selection had a significant impact on model performance, with the full feature set (X_all) yielding the best results, and the combination of Robust and MinMax scaling forming the most effective preprocessing pipeline. Conclusions: ORP proved to be a critical feature, enhancing model generalization and prediction performance. These findings suggest that data enrichment, particularly with ORP, could enable the development of ML frameworks that improve prognostic precision and patient outcomes in ART.

The human gut microbiome is integral to maintaining systemic physiological balance, with accumulating evidence emphasizing its critical role in reproductive health. This review investigates the bidirectional interactions between the gut microbiota and the female reproductive system, mediated by neuroendocrine, immune, and metabolic pathways, constituting the gut–reproductive axis. Dysbiosis, characterized by microbial imbalance, has been linked to reproductive disorders such as polycystic ovary syndrome (PCOS), endometriosis, infertility, impaired spermatogenesis, and pregnancy complications. These associations can be explained by immunological dysregulation, systemic inflammation, altered sex hormone metabolism, and hypothalamic–pituitary–gonadal (HPG) axis disturbances. This review aims to clarify the molecular and cellular mechanisms underpinning gut–reproductive interactions and to evaluate the feasibility of microbiome-targeted therapies as clinical interventions for improving reproductive outcomes.

Background/Objectives: Infertility in both men and women can be significantly influenced by oxidative stress (OS), which occurs due to an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses. In women, OS disrupts oocyte maturation, implantation, and the viability of the embryo; in men, it impairs sperm quality, reduces motility, and damages DNA integrity. This review explores existing research on how dietary and lifestyle interventions can reduce OS and enhance reproductive health outcomes. Methods: We conducted a comprehensive review of clinical, translational, and molecular studies exploring the mechanisms by which OS affects fertility, as well as the efficacy of nutritional and behavioral strategies. The interventions evaluated include weight management, regular exercise, micronutrient supplementation, antioxidant-rich diets, smoking and alcohol cessation, and stress-reduction techniques. Results: Specific dietary components such as zinc, selenium, vitamins C and E, and polyphenols have been found to neutralize reactive oxygen species (ROS) and enhance gamete function. OS is additionally reduced through lifestyle modifications, including minimizing harmful exposures, managing stress, and participating in moderate physical activity. Biomarkers such as ROS levels, total antioxidant capacity, 8-OHdG, and DNA fragmentation index are essential for assessing the effectiveness of interventions. Conclusions: Fertility in both sexes can be improved, and oxidative stress significantly reduced, through a multimodal approach incorporating dietary and lifestyle changes. There are encouraging opportunities to improve reproductive health through customized approaches that are informed by biomarker profiles. To incorporate these treatments into regular fertility care, future studies should concentrate on standardized procedures and long-term results.