AGEs-related dysfunctions in PCOS: evidence from animal and clinical research. Tatone C et al. (2021) Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder in women in their reproductive age. In recent years, the role of AGEs (advanced glycation end products) 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.//////////////////
NCBI Summary:
The advanced glycosylation end product (AGE) receptor encoded by this gene is a member of the immunoglobulin superfamily of cell surface receptors. It is a multiligand receptor, and besides AGE, interacts with other molecules implicated in homeostasis, development, and inflammation, and certain diseases, such as diabetes and Alzheimer's disease. Many alternatively spliced transcript variants encoding different isoforms, as well as non-protein-coding variants, have been described for this gene (PMID:18089847). [provided by RefSeq, May 2011]
General function
Receptor
Comment
Correlation between follicular fluid levels of sRAGE and vitamin D in women with PCOS. Garg D et al. (2017) The pro-inflammatory advanced glycation end products (AGEs) and their anti-inflammatory soluble receptors, sRAGE, play a role in the pathogenesis of PCOS. There is a correlation between vitamin D (vit D) and sRAGE in the serum, whereby vit D replacement increases serum sRAGE levels in women with PCOS, thus incurring a protective anti-inflammatory role. This study aims to compare levels of sRAGE, N-carboxymethyl-lysine (CML; one of the AGEs), and 25-hydroxy-vit D in the follicular fluid (FF) of women with or without PCOS, and to evaluate the correlation between sRAGE and 25-hydroxy-vit D in the FF. Women with (n = 12) or without (n = 13) PCOS who underwent IVF were prospectively enrolled. Women with PCOS had significantly higher anti-Mullerian hormone levels, higher number of total retrieved and mature oocytes, and higher number of day 3 and day 5 embryos formed. Compared to women without PCOS, women with PCOS had significantly lower FF sRAGE levels. In women with PCOS, in women without PCOS, and in all participants together, there was a significant positive correlation between sRAGE and 25-hydroxy-vit D. sRAGE positively correlated with CML in women without PCOS but not in women with PCOS. In women with PCOS, the low ovarian levels of the anti-inflammatory sRAGE suggest that sRAGE could represent a biomarker and a potential therapeutic target for ovarian dysfunction in PCOS. Whether there is a direct causal relationship between sRAGE and vit D in the ovaries remains to be determined.//////////////////
Cellular localization
Plasma membrane
Comment
sRAGE downregulates the VEGF expression in OHSS ovarian granulosa cells. Wang B et al. (2021) Ovarian hyperstimulation syndrome (OHSS) is mainly caused by human chorionic gonadotropin (hCG) through vasoactive mediators such as vascular endothelial growth factor (VEGF) and various inflammatory factors. Our previous study showed that soluble receptor for advanced glycation end products (sRAGE) played a protective role in PCOS by inhibiting VEGF, so wanted to explore the role of sRAGE in OHSS. Two sets of experiments were performed in this study. In part one, sRAGE protein levels in follicular fluid (FF) samples from 60 patients with OHSS and 60 non-OHSS patients were measured by ELISA. In part two, ovarian granulosa cells were isolated from an additional 25 patients with OHSS and cultured. Then, ovarian granulosa cells were treated with different concentrations of sRAGE. Granulosa cells cultured without sRAGE stimulation were used as the control group. The levels of VEGF, amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG) mRNA were examined by quantitative RT-PCR. The protein levels of VEGF, AREG, BTC, and EREG were measured by ELISA. Compared with non-OHSS patients, patients with OHSS exhibited lower sRAGE levels in both serum and FF (p < .05). Treatment with sRAGE decreased the production of VEGF, and the effects were dependent on the concentration of sRAGE (p < .05). Simultaneously, the expression of the EGF-like growth factors AREG, BTC and EREG was decreased, and their expression was dependent on the concentration of sRAGE (p < .05). sRAGE downregulate VEGF expression in OHSS ovarian granulosa cells, in which EGF-like growth factor pathway may be involved, and sRAGE may play a potential protective role in OHSS.//////////////////An inverse association between serum soluble receptor of advanced glycation end products and hyperandrogenism and potential implication in polycystic ovary syndrome patients. Liao Y et al. (2017) Studies found that AGE-RAGE system is closely related to insulin resistance and hyperandrogenemia, which are two core pathophysiological processes in polycystic ovary syndrome (PCOS). This study is to investigate the relationship among advanced glycation end-products/soluble receptor of advanced glycation end-products (AGEs/sRAGE) and anthropometric evaluation, homeostatic model assessment-insulin resistance (HOMA-IR), free androgen index (FAI) in reproductive-aged PCOS patients. One hundred and forty-eight Chinese women with PCOS were enrolled in this study. Subgroups were divided according to body mass index (BMI), waist circumference (WC), quartile intervals of HOMA-IR and androgen levels. The relationships between AGEs/sRAGE and above clinical markers were assessed by Pearson's correlation analyses. Serum AGEs showed a gradually increased tendency with BMI and WC. It reached statistical significant between the normal weight group (BMI < 24 kg/m(2)) and the obesity group (BMI ≥ 28 kg/m(2)) . The sRAGE levels gradually decreased with increasing BMI, WC, HOMA-IR and FAI respectively. Furthermore, the differences between each group were statistical significant. The correlation analysis showed a positive correlation between BMI and serum AGEs levels. On the contrary, the sRAGE levels showed significantly inverse correlations with BMI, WC, HOMA-IR and FAI. The optimal point of sRAGE for the presence of insulin resistance was 704.097 pg/ml by ROC curve analysis. Along with the body fat accumulation, the serum levels of AGEs were increased, whereas, the serum levels of sRAGE were reduced in obese PCOS patients. The serum levels of sRAGE, which is a decoy receptor, dramatically decreased in the patients with more severe insulin resistant states and higher FAI, which might be a potential biomarker and a promising therapeutic target in the treatment of PCOS, especially in obese subjects.//////////////////
Decreased levels of sRAGE in follicular fluid from patients with PCOS. Wang B et al. (2016) This study aimed to explore the association between soluble receptor for advanced glycation endproducts (sRAGE) levels in follicular fluid and the number of oocytes retrieved and to evaluate the effect of sRAGE on vascular endothelial growth factor (VEGF) in granulosa cells in patients with polycystic ovarian syndrome (PCOS). Two sets of experiments were performed in this study. In part one, sRAGE and VEGF protein levels in follicular fluid samples from 39 patients with PCOS and 35 non-PCOS patients were measured by ELISA. In part two, ovarian granulosa cells were isolated from an additional 10 patients with PCOS and cultured. VEGF and SP1 mRNA and protein levels, as well as pAKT levels, were detected by real-time RT-PCR and Western blotting after cultured cells were treated with different concentrations of sRAGE. Compared with the non-PCOS patients, patients with PCOS had lower sRAGE levels in follicular fluid. Multi-adjusted regression analysis showed that high sRAGE levels in follicular fluid predicted a lower Gn dose, more oocytes retrieved and a better IVF outcome in the non-PCOS group. Logistic regression analysis showed that higher sRAGE levels predicted favorably IVF outcomes in the non-PCOS group. Multi-adjusted regression analysis also showed that high sRAGE levels in follicular fluid predicted a lower Gn dose in the PCOS group. Treating granulosa cells isolated from patients with PCOS with recombinant sRAGE decreased VEGF and SP1 mRNA and protein expression and pAKT levels in a dose-dependent manner.//////////////////
Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Diamanti-Kandarakis E et al. (2008) Nonenzymatic advanced glycation and oxidation end-products, advanced glycation end-products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. Clinical trial. One hundred and ninety-three age- and BMI-matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty-eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7.96 +/- 1.87 U/ml, P < 0.001) compared with those with isolated hyperandrogenaemia (5.61 +/- 0.61 U/ml), anovulation (5.53 +/- 1.06 U/ml), US-PCO morphology (5.26 +/- 0.25 U/ml) and controls (5.86 +/- 0.89 U/ml). In PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome.//////////////////
Ovarian function
Early embryo development
Comment
Intrafollicular soluble RAGE benefits embryo development and predicts clinical pregnancy in infertile patients of advanced maternal age undergoing in vitro fertilization. Li YJ et al. (2017) Soluble receptor for advanced glycation end products (sRAGE) can decoy the toxic AGEs and is considered to be a protective factor. This study aimed to evaluate the correlation between intrafollicular sRAGE levels and clinical outcomes in infertile women of young or advanced maternal age (AMA) undergoing in vitro fertilization (IVF). A total of 62 young women and 62 AMA women who would undergo IVF were included in this prospective study. The intrafollicular sRAGE concentration was measured to determine its association with the number of retrieved oocytes, fertilized oocytes, high-quality embryos or achievement of clinical pregnancy in young and AMA women, respectively. Besides, correlations between sRAGE and age or follicle-stimulating hormone (FSH) were examined. We found that the intrafollicular sRAGE levels were higher in young patients than those in AMA patients, suggesting that the sRAGE levels were inversely correlated with age. In young patients, sRAGE showed no correlation with the number of retrieved oocytes, fertilized oocytes, high-quality embryos or achievement of clinical pregnancy. But it was found that AMA patients with more retrieved oocytes, fertilized oocytes and high-quality embryos demonstrated higher sRAGE levels, which were a prognostic factor for getting clinical pregnancy independent of age or FSH level. In conclusion, the sRAGE levels decrease with age. Elevated intrafollicular sRAGE levels indicate good follicular growth, fertilization and embryonic development, and successful clinical pregnancy in AMA women, while in young women, the role of sRAGE may not be so predominant.//////////////////
Follicular fluid PlGF/sFlt-1 ratio and soluble receptor for advanced glycation end-products correlate with ovarian sensitivity index in women undergoing A.R.T. Nejabati HR et al. (2016) Considering potential roles of soluble receptor for advanced glycation end products (sRAGE) and placental growth factor (PlGF) in ovarian function and embryo implantation, in the present study we have evaluated the association of these factors and also PlGF/sFlt-1 ratio with the ovarian response and implantation rate by dividing patients according to the OSI. In a cross-sectional study, 90 infertile women who were undergoing ICSI cycle using long protocol were recruited. The patients were divided according to ovarian sensitivity index (OSI). ICSI cycle outcomes were evaluated for each patient and PlGF, sFlt-1 and sRAGE levels of follicular fluid were assayed using commercial ELISA kits. Follicular fluid (FF) sRAGE levels and PlGF/sFlt-1 ratio were statistically greater in high-responder women than other responders (p < 0.05). Positive correlations were obtained between sRAGE level with the number of oocytes, follicles and OSI level. sRAGE levels with cutoff value of 4.83 (ng/ml) for evaluating the pregnancy outcome showed 81.8 % sensitivity and 60.7 % specificity. Furthermore, there were positive associations between PlGF/sFlt-1 ratio with the number of oocytes, embryos and OSI level. In conclusion, the results of current study supported that good ovarian response is independent of pregnancy outcome. Our results showed that FF levels of sRAGE and PlGF/sFlt-1 ratio could be used as markers for determining the high-responder women. Also, FF sRAGE levels could be a good predictor for ART outcome.//////////////////
Follicular fluid soluble receptor for advanced glycation endproducts (sRAGE): a potential protective role in polycystic ovary syndrome. Wang B et al. (2016) To explore the relationships between the soluble receptor for advanced glycation endproducts (sRAGE) and the outcome parameters following in vitro fertilization-embryo transfer (IVF-ET) in patients with polycystic ovary syndrome (PCOS) and investigate the protective effect of sRAGE in PCOS development regarding inflammation. We conducted a prospective analysis of a subsample of 74 participants from the Reproductive Medical Center of the First Affiliated Hospital of Zhengzhou University. We quantified sRAGE, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF-α), interleukelin-6 (IL-6), and C-reactive protein (CPR) protein levels in the follicular fluid from 39 PCOS and 35 non-PCOS reproductive-age women. sRAGE and VEGF, TNF-α, IL-6, and CRP in follicular fluid aspirated without blood were measured by ELISA. sRAGE concentrations in the follicular fluid were significantly lower in the PCOS group compared to those in the control group, while VEGF, TNF-α, IL-6, and CRP concentrations were significantly higher in the PCOS group than in the control group (P < 0.05). sRAGE was significantly, inversely correlated with the total dose of gonadotropin (Gn) in the PCOS group undergoing IVF treatment (r = -0.451, P = 0.004). After adjusting for age and Gn dose (in international units used per cycle), sRAGE protein levels in the follicular fluid were significantly, inversely related to VEGF (r = -0.378, P = 0.018), TNF-α (r = -0.450, P = 0.004), IL-6 (r = -0.455, P = 0.004), and CRP (r = -0.375, P = 0.019). sRAGE in the follicular fluid might exert a protective effect against the inflammatory action of PCOS development.//////////////////
Follicular Fluid Soluble Receptor for Advanced Glycation End-Products (sRAGE): A Potential Indicator of Ovarian Reserve. Merhi Z 2013 et al.
Context:The interaction of advanced glycation end-products (AGEs) with their cellular receptor (RAGE) is implicated in the pathogenesis of abnormal ovarian follicular growth. RAGE has a circulating secretory receptor form, soluble RAGE (sRAGE), which neutralizes the action of AGEs and might exert a protective role on the follicular environment.Objective:To investigate whether serum or follicular fluid (FF) sRAGE levels are associated with markers of ovarian reserve.Design, setting and participants:Serum anti-Mullerian hormone (AMH) and sRAGE protein levels were correlated in 31 reproductive-aged women. Additional 33 women who underwent oocyte retrieval for IVF were enrolled. AMH and its receptor (AMHR-II) mRNA levels were quantified in cumulus granulosa cells and FF sRAGE and AMH protein levels were measured.Main outcome measures:Granulosa cell AMH and AMHR-II gene expression, serum and FF AMH and sRAGE protein concentration, and number of oocytes retrieved.Results:In the serum, sRAGE levels were negatively correlated with body mass index (BMI) (r=-0.5, p<0.001) but not with age or serum AMH. The higher the FF sRAGE, the lower the number of IUs of gonadotropin needed per cycle independent of age, BMI, or day 3 follicle-stimulating hormone (FSH) level (r=-0.4, p=0.04). After adjusting for age, BMI, day 3 FSH, and the total dose of gonadotropins, FF sRAGE predicted the number of oocytes retrieved (R(2)=0.27, p=0.045). FF sRAGE positively correlated with FF AMH levels (r=0.5, p=0.0085). RT-PCR results showed no correlation between FF sRAGE and AMH or AMHR-II mRNA levels.Conclusion:These data support a relationship between FF sRAGE and measures of ovarian reserve. The pathological significance of the harmful inflammatory AGEs in follicular health clearly requires further investigation. Targeting AGEs might offer potential therapeutic options for the treatment of diminished ovarian response.
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Advanced glycation end products and their relevance in female reproduction. Merhi Z 2013 et al.
STUDY QUESTION
Do advanced glycation end products (AGEs) and their receptors play a role in female reproduction?
SUMMARY ANSWER
AGEs might contribute to the etiology of polycystic ovary syndrome (PCOS) and infertility.
WHAT IS KNOWN ALREADY
The endogenous AGEs are produced in the body by chemical reactions. Exogenous sources of AGEs are diet and smoking. AGEs have been proposed to be among the main intermediaries involved in several diseases, such as metabolic syndrome, type 2 diabetes mellitus, cardiovascular disease, ovarian aging, inflammation, neurodegenerative disorders and PCOS.
STUDY DESIGN, SIZE, DURATION
A systematic review was performed for all available basic science and clinical peer-reviewed articles published in PubMed from 1987 to date. Abstracts of annual meetings of the Endocrine Society and American Society for Reproductive Medicine were also reviewed.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A total of 275 publications and scientific abstracts were identified from the initial search. Sixty-two papers and four published scientific abstracts were selected for full review. The main outcomes were the regulatory effects of AGEs on: (i) granulosa cells, adipocyte physiology, obesity and insulin resistance in women with PCOS and in polycystic ovary animal models and (ii) infertility and measures of ovarian reserve.
MAIN RESULTS AND THE ROLE OF CHANCE
There is an intricate relationship between the AGE-RAGE (receptor for AGEs) system and some aspects of PCOS, such as granulosa cell dysfunction, adipocyte pathophysiology, obesity and insulin resistance. Additionally, irregular ovarian AGE signaling might in part explain the abnormal ovarian histology observed in women with PCOS. The ovarian dysfunction due to AGEs in women without PCOS suggests a role for the AGE-RAGE system in the ovarian follicular environment, and might relate to assisted reproduction technology outcome and measures of ovarian reserve.
LIMITATIONS, REASONS FOR CAUTION
The body of literature currently available limits these findings. The results obtained from granulosa cell lines and animal models may not fully extrapolate to humans.
WIDER IMPLICATIONS OF THE FINDINGS
This review underscores a critical need to unveil the exact mechanistic actions of AGEs in reproductive physiology and more specifically the hypothalamic-pituitary-ovarian axis. AGE inhibitors might present an emerging therapeutic approach with significant applications in the context of PCOS and infertility.
STUDY FUNDING/COMPETING INTEREST(S)
American Society for Reproductive Medicine New Investigator Award and University of Vermont College of Medicine Internal Funds. No competing interests.
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Intrafollicular soluble receptor for advanced glycation end products (sRAGE) and embryo quality in assisted reproduction. Bonetti TC et al. The developmental potential of human embryos has important implications in assisted reproduction and depends, among other factors, on oocyte competency. The receptor for advanced glycation end products (RAGE) is a member of the superfamily of immunoglobulin cell-surface molecules that are constitutively expressed during embryonic development. RAGE is down-regulated in homeostasis in adult life. This study measured the concentration of soluble RAGE (sRAGE) in follicular fluid obtained from the leading follicle after ovarian stimulation of 54 women undergoing intracytoplasmic sperm injection. Corresponding embryos and sRAGE concentrations in follicular fluid were evaluated and correlations were investigated by multi-adjusted regression analysis. High intrafollicular sRAGE concentrations predicted poor-quality embryos (n=45, OR=0.986; P=0.026), adjusted for patient age, body mass index and oocyte quality, showing an inverse association between intrafollicular sRAGE concentrations and embryo development. The developmental potential of human embryos has important implications in assisted reproduction, and it depends, among other factors, on oocyte competency. The receptor for advanced glycation end products (RAGE) is a molecule constitutively expressed during embryonic development, but it is down-regulated in adult life. RAGE is frequently associated with pro-inflammatory responses, and it is implicated as an underlying condition in immune disorders, cardiovascular diseases, diabetes, Alzheimer's disease and cancer. In addition to activating the pro-inflammatory responses, RAGE down-regulates cellular defence mechanisms. The present study measured the concentrations of soluble RAGE (sRAGE) in follicular fluid samples obtained from leading follicles of women undergoing intracytoplasmic sperm injection (ICSI). This prospective cohort study included 54 patients undergoing ICSI, and follicular fluid samples were obtained from the leading follicle after ovarian stimulation. The corresponding embryos were evaluated and correlations with intrafollicular sRAGE concentrations were investigated using multi-adjusted regression analysis. We observed that high intrafollicular concentrations of sRAGE predicted poor embryo quality. Our findings suggest an association between high concentrations of intrafollicular sRAGE and poor embryo development following ovarian stimulation for ICSI.
Follicle stages
Comment
Expression pattern of RAGE and IGF-1 in the human fetal ovary and ovarian serous carcinoma. Poljicanin A et al. (2015) The expression pattern of RAGE and IGF-1 proteins in different ovarian cell lineages was histologically analyzed in six fetal, nine adult human ovaries, and nine serous ovarian carcinomas (OSC) using immunohistochemical methods. Mild expression of IGF-1 in ovarian surface epithelium (Ose) and oocytes in the 15-week human ovaries increased to moderate or strong in the stromal cells, oocytes and follicular cells in week 22. Occasional mild RAGE expression was observed in Ose during week 15, while strong expression characterized primordial follicles in week 22. In the reproductive human ovary, IGF-1 was mildly to moderately expressed in all ovarian cell lineages except in theca cells of the tertiary follicle where IGF-1 was negative. RAGE was strongly positive in the granulosa cells and some theca cells of the tertiary follicle, while negative to mildly positive in all cells of the secondary follicle. In the postmenopausal human ovary IGF-1 and RAGE were mildly expressed in Ose and stroma. In OSC, cells were strongly positive to IGF-1 and RAGE, except for some negative stromal cells. Different levels of IGF-1 and RAGE co-expression characterized fetal ovarian cells during development. In reproductive ovaries, IGF-1 and RAGE were co-localized in the granulosa and theca interna cells of tertiary follicles, while in postmenopausal ovaries and OSC, IGF-1 and RAGE were co-localized in Ose and OSC cells respectively. Our results indicate that intracellular levels of IGF-1 and RAGE protein might regulate the final destiny of the ovarian cell populations prior and during folliculogenesis, possibly controlling the metastatic potential of OSC as well.//////////////////