The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, reduced metabolic support for oocytes, and the activation of regulated apoptotic pathways that end in follicular atresia. Ferroptosis, an emergent type of iron-dependent lipid peroxidation, has been identified as a crucial mechanism contributing to chemotherapy-induced ovarian insufficiency, polycystic ovary syndrome (PCOS), and granulosa cell death in aging ovaries, in addition to conventional apoptosis. The SIRT1-Nrf2 axis acts as a crucial anti-oxidative and anti-ferroptotic system that protects GC viability, maintains mitochondrial homeostasis, and upholds redox equilibrium. SIRT1 promotes mitochondrial biogenesis and metabolic resilience by deacetylating downstream proteins, including FOXO3 and PGC-1α. Nrf2 simultaneously controls the transcriptional activation of detoxifying and antioxidant enzymes, including HO-1, SOD2, NQO1, and GPX4, which are critical inhibitors of ferroptosis. Disruption of SIRT1-Nrf2 signalling accelerates GC senescence, follicular depletion, and reproductive aging. In contrast, pharmaceutical and nutraceutical therapies, including metformin, melatonin, resveratrol, and agents that increase NAD⁺ levels, may reverse ovarian deterioration and reactivate SIRT1-Nrf2 activity. This narrative review highlights innovative treatment prospects for ovarian aging, fertility preservation, and assisted reproduction by synthesising current evidence on ferroptotic pathways, SIRT1-Nrf2 interactions, and oxidative stress in granulosa cells. An understanding of these interrelated biological networks enables the development of tailored therapies that postpone ovarian ageing and enhance reproductive outcomes for women receiving fertility therapy.

Women of reproductive age, especially those with polycystic ovarian syndrome (PCOS), often use glucagon-like peptide-1 receptor agonists (GLP-1RAs) to improve their metabolic functions. A growing body of evidence suggests that GLP-1R signaling may directly affect ovarian physiology, influencing granulosa cell proliferation, survival pathways, and steroidogenic production, in addition to its systemic metabolic effects. Nonetheless, there is a limited comprehension of the molecular mechanisms that regulate these activities and their correlation with menstrual function, reproductive potential, and assisted reproduction. This comprehensive review focuses on ovarian biology, granulosa cell signaling networks, steroidogenesis, and translational fertility outcomes, integrating clinical, in vivo, and in vitro information to elucidate the effects of GLP-1 receptor agonists on reproductive health. We conducted a thorough search of PubMed, Scopus, and Web of Science for randomized trials, prospective studies, animal models, and cellular experiments evaluating the effects of GLP-1RA on reproductive or ovarian outcomes, in accordance with PRISMA criteria. The retrieved data included metabolic changes, androgen levels, monthly regularity, ovarian structure, granulosa cell growth and death, FOXO1 signaling, FSH-cAMP-BMP pathway activity, and fertility or IVF results. Clinical trials shown that GLP-1 receptor agonists improve menstrual regularity, decrease body weight and central adiposity, increase sex hormone-binding globulin levels, and lower free testosterone in overweight and obese women with PCOS. Liraglutide, when combined with metformin, significantly improved IVF pregnancy rates, whereas exenatide increased natural conception rates. Mechanistic studies demonstrate that GLP-1R activation affects FOXO1 phosphorylation, hence promoting granulosa cell proliferation and anti-apoptotic processes. Incretin signaling altered steroidogenesis by reducing the levels of StAR, P450scc, and 3β-HSD, so inhibiting FSH-induced progesterone synthesis, while simultaneously enhancing BMP-Smad signaling. Animal studies demonstrated both beneficial (enhanced follicular growth, anti-apoptotic effects) and detrimental results (oxidative stress, granulosa cell death, uterine inflammation), indicating a context- and dose-dependent response. GLP-1 receptor agonists influence female reproductive biology by altering overall physiological processes and specifically impacting the ovaries via FOXO1 regulation, steroidogenic enzyme expression, and BMP-mediated FSH signaling. Preliminary clinical data indicate improved reproductive function in PCOS, as seen by increased pregnancy rates in both natural and IVF cycles; nevertheless, animal studies reveal a potential risk of ovarian and endometrial damage. These results highlight the need for controlled human research to clarify reproductive safety, molecular pathways, and optimum therapy timing, particularly in non-PCOS patients and IVF settings.

Ferroptosis is a novel kind of regulated cell death that occurs when redox equilibrium is disrupted, leading to iron-dependent lipid peroxidation. Ferroptosis is defined by the buildup of deleterious lipid hydroperoxides, the inactivation of glutathione peroxidase 4 (GPX4), and mitochondrial shrinkage, setting it apart from apoptosis and necrosis. The relevance of this route to human reproduction remains unknown, despite its thorough investigation in neurodegeneration and cancer. Recent studies demonstrate that the ovarian follicular milieu is especially susceptible to ferroptosis owing to its high content of polyunsaturated fatty acids, iron-dependent metabolism, and the generation of reactive oxygen species. Dysregulation of ferroptosis may result in infertility by affecting granulosa cell survival, oocyte maturation, and embryonic competence. Ferroptotic activity correlates with oxidative stress indicators identified in clinical diseases including polycystic ovary syndrome, reduced ovarian reserve, and insufficient responsiveness to ovarian stimulation. Potential indicators include GPX4 expression, decreased glutathione levels, and the accumulation of lipid reactive oxygen species in granulosa cells and follicular fluid. Melatonin, which boosts antioxidant defences, and ferrostatin-1, a prototype inhibitor of ferroptosis that lowers lipid peroxidation, are two early candidates for treatment. For future evaluations, these agents should be used with standardised FF biomarker panels. Significantly, vitamin E, coenzyme Q10, and small-molecule ferroptosis inhibitors have shown efficacy in halting ferroptosis in experimental settings. These approaches have shown protective benefits in alternative systems and may signify viable treatment options for assisted reproduction. This narrative review encapsulates ferroptosis inside the ovarian follicle, its influence on oocyte quality, and the implications for in vitro fertilization results.

Endometriosis impairs fertility by interfering with ovarian function, embryonic development, and endometrial receptivity. Extracellular vesicles (EVs) are recognised as non-invasive biomarkers that may indicate biological processes based on their lipid, protein, and microRNA composition. This narrative review synthesises current data on extracellular vesicle (EV) signatures in serum/plasma, menstrual blood, follicular fluid, and uterine fluid in endometriosis patients using assisted reproductive technology (ART). We highlight critical EV-mediated processes, such as progesterone signalling, fibrosis, angiogenesis, inflammation, and metabolism, and their associations with oocyte competence, embryo development, and implantation. Certain EV-miRNA profiles, including miR-22-3p, miR-320a, the miR-200 family, and miR-145-5p, have shown use for diagnostic and prognostic purposes in various investigations. These characteristics are associated with live birth, implantation, and blastocyst quality. We propose a clinical framework that incorporates (i) menstrual-blood EVs for non-invasive endotyping, (ii) serum/plasma EV profiling for baseline risk stratification, and (iii) pre-transfer uterine-fluid EV evaluation to inform embryo-transfer decisions. Translation requires standardisation, cycle phase control, and prior validation. EVs may serve as a beneficial instrument for personalised in vitro fertilisation operations for ladies experiencing infertility due to endometriosis.

The reduction in oocyte competence and ovarian reserve coincides with reproductive ageing; nevertheless, the molecular mechanisms underlying this phenomenon remain poorly understood. Our testable mechanistic hypothesis is that the oxidative stress–telomere axis is a crucial regulatory mechanism controlling meiotic stability, mitochondrial resilience, and granulosa cell integrity. This notion posits that granulosa and cumulus cells have accelerated telomere attrition and impaired DNA-damage responses due to elevated amounts of reactive oxygen species, which also induce oxidative guanine lesions, inhibit telomerase function, and generate telomeric replication stress. This telomere-dependent vulnerability is anticipated to compromise developmental competence, disrupt meiotic spindle integrity, and diminish metabolic support to the oocyte, prior to observable declines in AMH or follicle count. Data from human IVF cohorts supports the model: Conditions such as PCOS, endometriosis, and POI have unique oxidative-telomeric profiles, whereas diminished telomere length in granulosa cells, reduced telomerase activity, and worse fertilisation, blastulation, and pregnancy outcomes are associated with increased follicular oxidative DNA damage. The findings suggest that oxidative DNA damage (8-OHdG), telomerase activity, and the structure of granulosa-cell telomeres may serve as preliminary indicators of preclinical ovarian ageing. This theory may be directly evaluated in forthcoming longitudinal studies and specific treatments related to telomerase regulation, mitochondrial medicines, or redox modulation. Consequently, the oxidative stress–telomere axis may represent a vital physiologic factor affecting reproductive lifespan and a prospective target for personalised ART techniques.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine and metabolic conditions affecting women of reproductive age. This condition affects around 20% of this demographic and is characterized by polycystic ovarian morphology, hyperandrogenism, and chronic anovulation. Obesity, impacting 40–85% of women with PCOS, exacerbates insulin resistance, increases insulin levels, and intensifies low-grade inflammation. This exacerbates the reproductive and metabolic complications associated with the condition. Recent advancements in molecular biology have underscored the significance of non-coding RNAs, including as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as crucial regulators of gene expression and prospective biomarkers for PCOS. Exosome-derived microRNAs (ex-miRNAs) have emerged as compelling candidates due to their stability in body fluids and their capacity to promote intercellular communication among adipose tissue, the ovary, and the endometrium. Research, encompassing both experimental and clinical studies, has shown that ex-miRNAs display differing expression levels in women with obesity-related PCOS. Several of these ex-miRNAs are associated with networks that govern inflammation, glucose metabolism, steroidogenesis, and folliculogenesis. Moreover, the encapsulation of these chemicals within exosomes safeguards them from enzymatic breakdown, hence augmenting their potential as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring. Despite the initial results being encouraging, challenges remain in standardising exosome separation, quantifying miRNA, and analyzing functional data within the complex pathophysiology of PCOS. This narrative review consolidates existing evidence regarding the molecular signatures of obesity-related infertility in PCOS, emphasising the growing significance of exosomal miRNAs and other non-coding RNAs, while examining their translational potential for early diagnosis and personalised therapeutic approaches.