Breast cancer (BC) is the most common malignancy among women of reproductive age. Improved survival has shifted clinical focus toward survivorship and fertility preservation. While the gonadotoxic effects of anticancer therapy are well recognized, the influence of patient age on fertility outcomes remains insufficiently integrated into clinical decision-making. This review synthesizes current evidence from clinical, molecular, and translational studies addressing the relationship between age, ovarian reserve, and reproductive outcomes in women with BC undergoing gonadotoxic treatments. It also examines how age interacts with BRCA mutations, endocrine therapy, and fertility preservation strategies. Age critically modulates the ovarian response to chemotherapy, the extent of oocyte depletion, and recovery of ovarian function. Younger patients show higher resilience and better success with fertility preservation methods such as oocyte, embryo, or ovarian tissue cryopreservation. Conversely, older women face accelerated follicular depletion, reduced AMH levels, and delayed conception due to prolonged adjuvant therapy. BRCA-related DNA repair defects further exacerbate age-related decline. Patient age represents the most decisive factor guiding fertility preservation in BC care. Incorporating age-specific counseling and early referral into multidisciplinary oncofertility practice is essential to optimize reproductive outcomes and align survivorship with future family planning goals.

Recent studies emphasize the role of neuroendocrine dysfunctions and sirtuins in polycystic ovarian syndrome (PCOS). We investigated whether altered SIRT1 and SIRT3 levels contribute to brain changes and oxidative stress, identifying these pathways as potential therapeutic targets for PCOS-related complications. Using a DHEA-induced PCOS mouse model, we examined brain expression of pathways related to SIRT1 and SIRT3 and to oxidative/glycative stress changes. SH-SY5Y cells treated with DHEA were used to confirm direct neuronal effects. We found decreased levels of Sirt1 and Sirt3 transcripts but increased protein expression and activity of both sirtuins in brains of DHEA-treated mice. The DHEA group showed elevated oxidative and glycative stress, including an overall increased lipid peroxidation and DNA damage, as well as accumulation of advanced glycation endproducts (AGEs) in isocortices. Differences in Cpt1 isoform expressions suggested disrupted metabolic processing in the PCOS brains. Neuronal degeneration was also observed, alongside unchanged Bdnf and TrkB mRNA levels in DHEA brains. Exposure of differentiated SH-SY5Y neuron-like cells to high concentrations (≥ 100 µM) led to increased oxidative stress, altered sirtuins expression, and ultimately cell toxicity. While low concentrations of DHEA (1 µM) did not elicit such responses. These findings reveal a complex interplay between oxidative stress, metabolic dysregulation, and neuronal health in PCOS brain, underscoring the need for further investigations into the underlying mechanisms, including research in genetic components. This research provides foundational insights into how PCOS may influence neurobiological processes and helps clarify some aspects of its pathogenesis.

Endometriosis, a common condition affecting 5–10

Abstract Study question Are nano-microplastics (NMPs) taken up into human granulosa cells causing redox alterations? Summary answer NMPs enter into human granulosa cells and influence viability, energy production and antioxidant response. What is known already In recent decades, anthropogenic activities have increased the production of global plastic with millions of tons produced every year. Under the action of different physical, chemical or biological agents, plastic waste breaks down into (NMP) particles that propagate in the environment posing threats for human health. NMPs translocate from digestive tract to circulatory systems reaching organs and cells, including female gonads. Nevertheless, there is insufficient knowledge of their effects on reproductive functions in mammals to allow for an accurate risk assessment to be conducted and any risks managed in animal and human being contexts. Study design, size, duration Human ovarian granulosa cells (KGN cell line) were exposed to NMPs of different sizes (40 nm, 70 nm, 100 nm, and 200 nm) at concentrations ranging from 5 to 1000 μg/ml for 24 h and then processed for cellular and biochemical analyses Participants/materials, setting, methods NMPs uptake by granulosa cells was tested by the employment of fluorescent NMPs and observation under confocal laser scanning microscopy. Cell viability was assed by Cell Counting Kit8. The effects of NMPs on mitochondrial bioenergetics was evaluated by MitoStress kit (Seahorse Xfe96, Agilent). ATP production was evaluated by Cell Titer-Glo ATP assay kit (Promega). Key enzymes of antioxidant response were analysed at transcript and protein level by using real-time Taqman PCR and Western blotting, respectively. Main results and the role of chance We demonstrated that NMPs are taken up by granulosa cells at all tested concentrions along with significant decrease of cell vitality with all sizes and concentrations. Seahorse analysis revealed an altered bioenergetic profiles. ATP levels increase at 70, 100 and 200 nm (one way ANOVA p = 0.001) at all tested concentrations (one way ANOVA p < 0.001). The gene and protein expression of catalase (CAT) superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) increased at 5 and 100 µg/ml with all sizes except 100 nm, whereas the level of sirtuins (SIRT1 and SIRT3) transcripts and protein decreased. Reduced levels of phosphorylated NRF2, the transcription factor that activates antioxidant responsive elements (ARE)-mediated gene expression were observed. Limitations, reasons for caution The use of human cell lines requires careful consideration when transferring to human testing. Wider implications of the findings Our results contribute to understanding the effects of NMPs on mammalian fertility in order to find possible protective approaches. Considering that the level of susceptibility of mammalian female germ cells to NMPs is still unknown, present results contribute to evidence-based strategies allowing living and working in a health promoting environment. Trial registration number Effects of combined exposure to nano/microplastics and plastic additives on mammalian female fertility (CUP E53D2301100006)

Polycystic ovarian syndrome (PCOS) is a heterogeneous condition characterized by hyperandrogenism (HA), polycystic ovaries, and dysfunctional ovulation, and it is associated with metabolic problems such as insulin resistance (IR) and obesity. After having investigated the morphological and antioxidant/antiglycative alterations on mouse ovaries and uteri, we here focus on PCOS oviducts, a tract of the reproductive system essential for the nourishment and transport of gametes and embryos. The modulating effects of L-carnitine (LC) and acetyl-L-carnitine (ALC) were also assessed. CD1 mice were administered or not with dehydroepiandrosterone (DHEA, 6 mg/100 g body weight) for 20 days, alone or with 0.40 mg of L-carnitine (LC) and 0.20 mg of acetyl-L-carnitine (ALC). Oviducts were then subjected to histology and immunohistochemistry to evaluate their morphology and collagen deposition, and steroidogenesis. Oxidative, mitochondrial, and methylglyoxal (MG)-dependent damage was also investigated. Transmission electron microscopy was used to detect ultrastructural alterations. The PCOS oviducts were affected by hyperfibrosis, hyperplasia, hypertrophy, and altered steroidogenesis, with oxidative alterations associated with MethylGlyoxal-Advanced Glycation End product (MG-AGE) accumulation. A reduced ciliary coverage and numerous dilated intercellular spaces were found in the epithelium. LC-ALC administration mitigated PCOS oviductal alterations. These results provide evidence for the detrimental action of oxidative and glycative stress in PCOS oviducts, confirming a protective role of carnitines on the PCOS phenotype.

Sperm cryopreservation is an efficient procedure for male fertility preservation, although the freeze-thaw procedure causes irreversible structural and functional changes in human spermatozoa. Indeed, the procedure is responsible for harmful changes that may affect sperm biology. In mammalian cells, cryopreservation induces a shift of redox homeostasis towards increasing generation of reactive oxygen species (ROS). The characteristics of ROS and the cellular outcomes depend on the cell type. Supra-physiological ROS levels during cryopreservation severely impact sperm survival, reproductive potential and DNA integrity, the latter a fundamental factor for fertilisation and transmission of paternal genetic information to offspring. The aim of this review is to summarise current knowledge of the main molecular mechanisms underlying ROS generation during sperm cryopreservation and its subsequent effects. In addition, we report current experimental approaches based on the supplementation of cryopreservation media with enzymatic and non-enzymatic antioxidants with the aim of minimising the harmful effects of ROS, and thus improving post-thaw sperm quality. Current data indicate that the potential use of antioxidants as constituents of the sperm freezing solution in clinical settings would require considerable attention. KEY WORDS: Spermatozoa, cryopreservation, ROS, oxidative stress, antioxidants.

Myo-inositol (MYO) and D-chiro-inositol (DCI) are the two most significant isomeric forms of inositol, playing a critical role in intracellular signaling. MYO is the most abundant form of inositol in nature; DCI is produced from MYO through epimerization by an insulin-dependent enzyme. Recently, it has been demonstrated that inositol may influence oocyte maturation and improve intracellular Ca2+ oscillation in the oocytes, and it has been proposed as a potential intervention for restoring spontaneous ovulation. The MYO concentration in human follicular fluid is considered a bioindicator of oocyte quality. In the ovary, DCI modulates the activity of aromatase, thus regulating androgen synthesis. Under physiological conditions, the MYO/DCI ratio is maintained at 40:1 in plasma. In women with PCOS, the MYO/DCI ratio is lowered to 0:2:1, contributing to elevated androgen production. By regulating FSH signaling, MYO administration increases the number of high-quality embryos available for transfer in poor responder patients. Finally, by acting downstream to insulin signaling, inositol administration during pregnancy may represent a novel strategy for counteracting gestational diabetes. These findings show that diet supplementation with inositol may be a promising strategy to address female infertility and sustain a healthy pregnancy.

While the use of follicle-stimulating hormone (FSH) in ovarian stimulation for in vitro fertilization (IVF) is an established practice, the use of luteinizing hormone (LH) remains debatable. MicroRNAs (miRNAs) are short, endogenous, non-coding transcripts that control a variety of cellular functions, such as gonadotrophin production and follicular development. The goal of this pilot study was to investigate whether the employment of recombinant LH (rLH) in ovarian stimulation protocols results in changes in the miRNA profiles in human oocytes. Patients were divided into two groups: seven received recombinant FSH (rFSH, 225 IU), and six received rFSH (150 IU) plus rLH (75 IU). MiRNA predesigned panels and real-time PCR technology were used to analyze the oocytes retrieved from the follicular ovarian retrieval. Among the miRNAs evaluated, a series of them evidenced upregulation or downregulation in their expression in the FSH plus LH group compared to the FSH group. Considering the results obtained from the functional and network analysis, the different maternal miRNA profiles in the two groups revealed a differential modulation of pathways involved in numerous biological functions. Overall, based on the pathways associated with most of these maternal miRNAs, the presence of LH may result in a different modulation of pathways regulating survival under the control of a Tp53-related mechanism. Interestingly, among the miRNAs differentially expressed in oocytes of the two groups, we have found miRNAs already investigated at ovarian, follicular, oocyte, and embryonic levels: hsa-miR-484, hsa-miR-222, hsa-miR-520d-5p, hsa-miRNA-17, hsa-miR-548, and hsa-miR-140. Thus, investigation into the role of these miRNAs in oocyte molecular pathways may help determine how LH affects oocyte competence and eventually leads to the clinical improvement of IVF.

Abstract Study question Can D-Chiro Inositol administration mitigate the phenotype of endometriosis in a mouse model? Summary answer Based on an endometriosis mouse model, we demonstrated that administration of D-Chiro Inositol can reduce development of endometriotic lesions. What is known already Endometriosis, a disease affecting 5-10% of women of reproductive age, is characterized by the spread of endometrial-like tissue outside the uterine cavity that produces ectopic endometriotic lesions causing pain and infertility. The sensitivity of endometriosis to estrogens is a characteristic that can be used for therapeutic purposes. D-Chiro Inositol (DCI), one of the nine isomers of Inositol, is known to decrease the CYP19A1 aromatase gene expression in granulosa cells. Based on these premises, it was suggested that treatment with DCI may have clinical application in conditions where decreased estrogen levels is required. Study design, size, duration To address the study question, a mouse model of endometriosis was generated. Out of 20 CD1 mice, 4 mice were randomly selected as donors of uterine fragments and the remaining 16 were recipient mice. The first day after transplantation, mice were randomly assigned to four experimental group which received for 28 days 2ml of water containing: none (CTRL); DCI 0.4mg (DCI 0.4); DCI 0.2mg and Dienogest 0.33ng (DCI 0.2+DG 0.33); DG 0.67ng (DG 0.67). Participants/materials, setting, methods Uterine horns were removed from donor mice at the diestrous stage of the reproductive cycle. The tissue cut into fragments was inoculated in recipient mice by intraperitoneal injection. Four weeks after induction, all mice were sacrificed. Their endometriotic lesions were excised, measured by number and size, and examined for the presence of blood vessels vascularization under stereomicroscope. Then, lesions were processed for histology examination by hematoxilin-eosin (H&E) and Azan Mallory staining. Main results and the role of chance Endometriotic lesions developed in recipient mice met all criteria for endometriosis, including the presence of endometrial epithelial and stromal cells, and encapsulation in neighboring tissues or organs. The lesions number was reduced in all the treatment groups when compared to control (p < 0.05, t-test), and no differences were observed among DCI 0.4, DCI 0.2+DG 0.33 and DG 0.67. Concomitantly the rate of vascularized lesions was lower in the treated groups, with more pronounced effect in the DCI 0.4 group where no vascularized lesions were observed (p < 0.05, t-test). The histological analysis revealed a marked reduction of endometriotic foci in all groups. These results provide evidence that DCI can reduce development and vascularization of endometriotic lesions in a mouse model, an effect that is not observed when it is employed at lower dose in association with DG. Although molecular mechanisms underlying DCI effects requires further investigation, present findings support the hypothesis that DCI could be more effective than DG in mitigating endometriosis phenotype. Limitations, reasons for caution Results from animal studies should be extrapolated to humans with caution. Wider implications of the findings Present findings may open new avenue in testing whether DCI may have clinical application in endometriosis therapy. Trial registration number Not Applicable

Carnitines play a key physiological role in oocyte metabolism and redox homeostasis. In clinical and animal studies, carnitine administration alleviated metabolic and reproductive dysfunction associated with polycystic ovarian syndrome (PCOS). Oxidative stress (OS) at systemic, intraovarian, and intrafollicular levels is one of the main factors involved in the pathogenesis of PCOS. We investigated the ability of different acyl-carnitines to act at the oocyte level by counteracting the effects of OS on carnitine shuttle system and mitochondrial activity in mouse oocytes. Germinal vesicle (GV) oocytes were exposed to hydrogen peroxide and propionyl-l-carnitine (PLC) alone or in association with l-carnitine (LC) and acetyl-l-carnitine (ALC) under different conditions. Expression of carnitine palmitoyltransferase-1 (Cpt1) was monitored by RT-PCR. In in vitro matured oocytes, metaphase II (MII) apparatus was assessed by immunofluorescence. Oocyte mitochondrial respiration was evaluated by Seahorse Cell Mito Stress Test. We found that Cpt1a and Cpt1c isoforms increased under prooxidant conditions. PLC alone significantly improved meiosis completion and oocyte quality with a synergistic effect when combined with LC + ALC. Acyl-carnitines prevented Cpt1c increased expression, modifications of oocyte respiration, and ATP production observed upon OS. Specific effects of PLC on spare respiratory capacity were observed. Therefore, carnitine supplementation modulated the intramitochondrial transfer of fatty acids with positive effects on mitochondrial activity under OS. This knowledge contributes to defining molecular mechanism underlying carnitine efficacy on PCOS.

(1) Background: Polycystic ovarian syndrome (PCOS) is a common and multifactorial disease affecting reproductive-age women. Although PCOS ovarian and metabolic features have received extensive research, uterine dysfunction has been poorly investigated. This research aims to investigate morphological and molecular alterations in the PCOS uterus and search for modulating effects of different carnitine formulations. (2) Methods: CD1 mice were administered or not with dehydroepiandrosterone (DHEA, 6 mg/100 g body weight) for 20 days, alone or with 0.40 mg L-carnitine (LC) and 0.20 mg acetyl-L-carnitine (ALC) in the presence or absence of 0.08 mg propionyl-L-carnitine (PLC). Uterine horns from the four groups were subjected to histology, immunohistochemistry and immunoblotting analyses to evaluate their morphology, collagen deposition, autophagy and steroidogenesis. Oxidative-/methylglyoxal (MG)-dependent damage was investigated along with the effects on the mitochondria, SIRT1, SOD2, RAGE and GLO1 proteins. (3) Results: The PCOS uterus suffers from tissue and oxidative alterations associated with MG-AGE accumulation. LC-ALC administration alleviated PCOS uterine tissue alterations and molecular damage. The presence of PLC prevented fibrosis and maintained mitochondria content. (4) Conclusions: The present results provide evidence for oxidative and glycative damage as the main factors contributing to PCOS uterine alterations and include the uterus in the spectrum of action of carnitines on the PCOS phenotype.

Wound healing is a complicated process, and the effective management of wounds is a major challenge. Natural herbal remedies have now become fundamental for the management of skin disorders and the treatment of skin infections due to the side effects of modern medicine and lower price for herbal products. The aim of the present study is to summarize the most recent in vitro, in vivo, and clinical studies on major herbal preparations, their phytochemical constituents, and new formulations for wound management. Research reveals that several herbal medicaments have marked activity in the management of wounds and that this activity is ascribed to flavonoids, alkaloids, saponins, and phenolic compounds. These phytochemicals can act at different stages of the process by means of various mechanisms, including anti-inflammatory, antimicrobial, antioxidant, collagen synthesis stimulating, cell proliferation, and angiogenic effects. The application of natural compounds using nanotechnology systems may provide significant improvement in the efficacy of wound treatments. Increasing the clinical use of these therapies would require safety assessment in clinical trials.

Purpose Although oncological advances have improved survival rates of female cancer patients, they often suffer a reduced fertility due to treatment side effects. In the present study, we evaluated the potential fertoprotective effects of the specific inhibitor of SIRT1, EX-527, on the gonadotoxic action exerted by cyclophosphamide (CPM) on loss of primordial follicles (PFs). Methods The effects of the CPM metabolite phosphoramide mustard (PM) on follicle activation, growth and viability and the protective action of EX-527 against PM effects were evaluated on bovine ovarian cortical strips in vitro cultured for 1 or 6 days. To understand whether PFs exposed to PM plus EX-527 were able to activate and grow to the secondary stage after suspension of the treatment, strips cultured for 3 days in PM plus EX-527 for 3 days were transferred to plain medium until day 6. Follicle growth and health were evaluated through histology and viability assay at a confocal microscope. In order to investigate the molecular pathways underlying the ovarian response to PM in the presence of EX-527, we analysed the protein level of SIRT1, HuR, PARP1 and SOD2 after 1 day of in vitro culture. Results We found that (1) PM, the main CPM active metabolite, promotes PF activation; (2) the ovarian stress response induced by PM includes a SIRT1-dependent pathway; and (3) EX-527 reduces PF activation and growth induced by PM. Conclusion SIRT1 can represent a candidate molecule to be targeted to protect ovarian follicles from alkylating agents and EX-527 could represent a potential fertoprotective agent for cancer patients.

Abstract Study question Can live real-time determination of mitochondrial bioenergetics represent a reliable assay of the mitochondrial activity and bioenergetic metabolism in mouse oocytes? Summary answer We demonstrated that real-time determination of mitochondrial oxidative phosphorylation is a feasible method for the characterization of mitochondrial activity and adaptation capacity of mammalian oocytes. What is known already Mammalian oocytes possess about 300.000 mitochondria and their alterations represent the main factors underlying reduced oocyte competence. Mitochondrial oxidative phosphorylation, measured as the oxygen consumption rate (OCR) is the largest contributor to cellular ATP demand. Fine-tuning mitochondrial activity is required to sustain bioenergetics homeostasis and maintain physiological levels of ROS production in the female gamete. Despite numerous techniques have been used to measure OCR, the application in oocytes have remained infeasible. Recently the development of a non-invasive, real-time assay has provided a more comprehensive picture of OCR in terms of the components of mitochondrial oxygen flux. Study design, size, duration Mitochondrial bioenergetic profile was determined in GV oocytes from young unprimed and primed mice; MII oocytes from young hCG-primed mice; oocytes from aged hCG-primed mice; young MII oocytes from IVM; aged MII oocytes from IVM; MII oocytes from IVM following oxidative stress in the presence or absence of the NAD+ booster p7C3 or propionyl-L-carnitine (PLC). Mean values of basal oxygen consumption rate, maximal capacity, reserve capacity and non-mitochondrial sources on oxygen consumption were evaluated. Participants/materials, setting, methods Young (4-8 weeks) and aged (36-40weeks) CD-1 mice were employed. GV oocytes were isolated from PMSG-primed and unprimed mice. MII oocytes were retrieved from hCG-primed mice. Oxidative stress was induced by exposure to 25-100µM H2O2 for 10-30’. IVM was performed in M2 medium with/out 1-5 mM P7C3 or 0.2mg/ml PLC. SeahorseXFp96 Agilent was employed to measure OCR (pmol/min/oocytes/wells) in pools of 8 oocytes after establishment of mitochondrial inhibitors concentrations. SigmaStat was used for statistical analysis. Main results and the role of chance From the analysis of the parameters above described, GV oocytes from primed and unprimed mice showed different bioenergetic profiles revealing lower basal OCR in unprimed GV. When exposed to oxidative stress, GV oocytes exhibited of redox state alteration evidenced by the response to the different inhibitors. These effects were prevented by exposure to P7C3 or PLC. A similar profile was present in GV oocytes from aged oocytes. All classes of MII displayed an OCR lower than GV. Ovulated MII oocytes showed an OCR lower than MII from IVM oocytes. Moreover, the latter displayed an increased non-mitochondrial respiration as evidence of oxidative stress. IVM oocytes exposed to oxidative insult revealed increased proton leak associated with reduced ATP levels. The presence of P7C3 in the IVM medium reduced non-mitochondrial respiration and proton leak with positive effects on ATP production and IVM rate. MII oocytes from aged mice when compared with the young group showed a different bioenergetic profile revealing lower OCR in the aged MII along with reduced spare respiratory capacity and increased proton leak. These changes suggest decreased mitochondrial mass and/or altered integrity of ETC components. The presence of P7C3 during IVM allowed a partial recovery of these dysfunctions. Limitations, reasons for caution Results from animal studies should be extrapolated to humans with caution. Wider implications of the findings Live real-time analysis of mitochondrial bioenergetics can be a reliable approach for the study of mitochondrial dysfunctions linked with reduced oocyte competence associated with aging and other oxidative stress conditions. Thus, it could be employed to set up specific recovery strategies based on metabolic boosters to improve human IVF. Trial registration number not applicable

Recently, the importance of bioenergetics in the reproductive process has emerged. For its energetic demand, the oocyte relies on numerous mitochondria, whose activity increases during embryo development under a fine regulation to limit ROS production. Healthy oocyte mitochondria require a balance of pyruvate and fatty acid oxidation. Transport of activated fatty acids into mitochondria requires carnitine. In this regard, the interest in the role of carnitines as mitochondrial modulators in oocyte and embryos is increasing. Carnitine pool includes the un-esterified l-carnitine (LC) and carnitine esters, such as acetyl-l-carnitine (ALC) and propionyl-l-carnitine (PLC). In this review, carnitine medium supplementation for counteracting energetic and redox unbalance during in vitro culture and cryopreservation is reported. Although most studies have focused on LC, there is new evidence that the addition of ALC and/or PLC may boost LC effects. Pathways activated by carnitines include antiapoptotic, antiglycative, antioxidant, and antiinflammatory signaling. Nevertheless, the potential of carnitine to improve energetic metabolism and oocyte and embryo competence remains poorly investigated. The importance of carnitine as a mitochondrial modulator may suggest that this molecule may exert a beneficial role in ovarian disfunctions associated with metabolic and mitochondrial alterations, including PCOS and reproductive aging.

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 μM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder in women in their reproductive age. In recent years, the role of advanced glycation end products (AGEs) in PCOS has gained great attention. AGEs are highly reactive molecules that can be assumed by diet or endogenously synthesized as by-products of metabolic processes. AGE deposition increases with aging, hyperglycemia, insulin resistance, and glycotoxin-rich diet. Therefore, it has become imperative to understand the underlying mechanism of AGEs actions and its downstream effects in PCOS pathophysiology. By integrating evidence from human studies and experimental models, the present review points out that altered AGE deposition is a common feature in all PCOS phenotypes. Searching for possible mechanisms involved in the adaptive response against glycation injury in oocytes and ovaries, the role of SIRT1, the main member of the mammalian sirtuin family, has also recently emerged. Therefore, further studies based on anti-AGE interventions could be helpful in creating innovative strategies for counteracting PCOS and its effects on fertility.