The placenta functions as a dynamic endocrine hub that translates maternal exposures into offspring developmental programming, consistent with the Developmental Origins of Health and Disease (DOHaD) framework. Beta-endorphin (β-EP), a placental POMC-derived opioid peptide, signals through MOR/DOR/KOR receptors to regulate angiogenesis, immune tolerance, oxidative stress, inflammation, and nutrient transport. Apigenin, a dietary flavone found in parsley, chamomile, and celery, modulates several pathways that overlap with this axis, including CREB/PKA signaling, DNA methyltransferase activity, Nrf2, NF-κB/NLRP3, and Foxp3[+] Treg differentiation, although most supporting evidence derives from non-placental systems such as cancer lines, keratinocytes, and macrophages. This review proposes that apigenin may amplify placental β-EP signaling across three conceptual tiers: a biosynthetic tier involving CREB/PKA-mediated POMC activation and 11β-HSD1 inhibition; a receptor-level tier involving DNMT1/3a inhibition and OPRM1 demethylation; and an effector-level tier involving Nrf2 activation, NF-κB/NLRP3 suppression, and Treg expansion, the last representing the strongest trophoblast-level evidence. Given reported β-EP dysregulation in preeclampsia, gestational diabetes, preterm birth, and intrauterine growth restriction, apigenin's relevance to these disorders remains an untested hypothesis rather than a validated therapeutic strategy, informed by a structured, non-systematic literature search (1986-2026).

Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder linked to infertility and adverse reproductive outcomes. Emerging evidence highlights immune dysregulation, particularly involving natural killer (NK) cells, as a key driver of PCOS-associated implantation failure. Successful embryo implantation requires precise dialogue between the embryo and maternal endometrium, mediated by immune cells. Uterine NK (uNK) cells, the dominant immune population at the maternal-fetal interface in early pregnancy, display low cytotoxicity and high immunoregulatory and angiogenic activity. These features support trophoblast invasion, spiral artery remodeling, and maternal-fetal tolerance. In PCOS, chronic low-grade inflammation, hyperandrogenism, and insulin resistance alter immune cell phenotypes, cytokine production, and NK cell function. Such disruptions compromise the immunological balance essential for endometrial receptivity, potentially triggering recurrent implantation failure and early pregnancy loss. This review analyzes the role of NK cells and immune factors in PCOS-related implantation failure. Clarifying the crosstalk between endocrine, metabolic, and immune pathways provides deeper insights into reproductive dysfunction in PCOS, offering potential therapeutic targets to enhance implantation rates and pregnancy outcomes.

Chronic endometritis (CE) represents an insidious and frequently underdiagnosed inflammatory condition of the endometrial stroma, increasingly recognized as a principal contributor to unexplained infertility, recurrent implantation failure and recurrent pregnancy loss. Historically relegated to a histological curiosity, CE has been reframed as a biologically complex disorder characterized by the convergence of endometrial microbial dysbiosis, immunological subversion, and, increasingly, antimicrobial resistance (AMR). This narrative review synthesizes contemporary evidence examining the mechanistic interplay between aberrant endometrial microbiota composition, disrupted innate and adaptive immune responses, and the emergence of antibiotic-resistant endometrial pathogens, collectively undermining endometrial receptivity and embryo implantation. We critically appraise the diagnostic limitations inherent to current histological and microbiological standards, and examine the translational implications of next-generation sequencing for the characterization of the endometrial microbiome. Furthermore, we interrogate the therapeutic paradox posed by AMR in clinical CE management, and delineate future research trajectories encompassing microbiome-targeted therapeutics, immunomodulatory strategies, and the ethical dimensions of emerging diagnostic and treatment frameworks. A convergent pathophysiological model is proposed in which microbial dysbiosis, immune dysregulation, and AMR form a self-reinforcing axis of reproductive failure, demanding integrated diagnostic and therapeutic paradigms.

This review synthesizes evidence on macrophage roles, polarization (M1/M2), and immunometabolic/signaling pathways in endometriosis, outlining therapeutic implications. We searched PubMed, Cochrane Library, ClinicalTrials.gov, Scopus, Embase, and Google Scholar. Available evidence demonstrates increased macrophage accumulation and substantial heterogeneity across the eutopic endometrium, peritoneal fluid, and established endometriotic lesions. Rather than undergoing a uniform shift from an M1 to an M2 phenotype, endometriosis-associated macrophages acquire overlapping inflammatory, immunoregulatory, angiogenic, phagocytic, metabolic, and profibrotic programs. Endometriotic epithelial and stromal cells regulate macrophage recruitment and activation through estrogen receptor β-NF-κB-CCL2 signaling, IL-17A- and TNF-α-dependent cytokine production, extracellular-vesicle-mediated microRNA transfer, and lactate-driven METTL3-Trib1-ERK/STAT3 signaling. The CCL2/MCP-1-CCR2 axis further links monocyte recruitment with inflammatory signaling and the invasive behavior of endometriotic cells, whereas TET3-mediated suppression of let-7 microRNAs sustains disease-associated macrophage activation. Functionally, macrophages contribute to defective clearance of displaced endometrial tissue, ectopic cell survival, angiogenesis, fibrosis, neuroimmune sensitization, pain, and impaired reproductive function. These findings support an immunometabolic model in which macrophage plasticity drives lesion establishment, progression, neuroangiogenesis, pain, and infertility. Therapeutically, targeting macrophage polarization and metabolism-via glycolytic and mitochondrial pathways, lactate signaling, or epitranscriptomic regulators-may restore immune homeostasis and limit disease progression. Further translational studies are needed to validate biomarkers and develop macrophage-directed interventions.

Endometriosis is characterized by pain symptoms, including dysmenorrhea, chronic pelvic pain, and dyspareunia, the severity of which does not necessarily correlate with the size or extent of lesions. Recent evidence suggests that, in addition to extracellular matrix (ECM) remodeling and tissue stiffening, neural remodeling and neuroimmune interactions may contribute to pain pathophysiology in endometriotic lesions. This review focuses on the relationship between fibrosis and mechanotransduction in endometriosis. We summarize their associations with inflammation, mechanical stimuli, intracellular signaling pathways, and pain, and examine the possibility that the biomechanical microenvironment of lesions may integrate these pathophysiological processes. Chronic inflammation may promote fibrotic responses, myofibroblast activation, and ECM accumulation. Subsequent ECM remodeling and tissue stiffening can alter cellular tension and activate mechanotransduction pathways. These mechanical signals may interact with inflammatory and neural pathways, potentially promoting neurotrophic factor signaling, sensory nerve remodeling, and nociceptor sensitization. Conversely, neuroimmune signaling may further modulate inflammatory and fibrotic responses, thereby establishing a self-reinforcing microenvironment. However, further investigation is required to determine how these pathophysiological processes differ according to lesion phenotype and anatomical location. In conclusion, pain associated with endometriosis may arise not simply from lesion burden but from dynamic interactions among endocrine, inflammatory, fibrotic, mechanical, and neural processes. The proposed "pain-fibrosis niche" model provides a conceptual framework for integrating these pathophysiological processes and may contribute to the development of mechanism-based and disease-modifying therapeutic strategies.