Menopause: The Journal of The North American Menopause Society Vol. 24, No. 3, pp. 345-351 DOI: 10.1097/GME.0000000000000755 ß 2016 by The North American Menopause Society
REVIEW ARTICLE Aging ovary and the role for advanced glycation end products Magdalena Pertynska-Marczewska, MD, PhD,1 and Evanthia Diamanti-Kandarakis, MD, PhD 2 Abstract Objective: The hypothalamic gonadotropin-releasing hormone pulse generator, the pituitary gonadotropes, the ovaries, and the uterus play a crucial role in female fertility. A decline in reproductive performance represents a complex interplay of actions at all levels of the hypothalamic-pituitary-ovarian axis. Recently, in the field of female reproductive aging attention is drawn to the carbonyl stress theory. Advanced glycation end products (AGEs) contribute directly to protein damage, induce a chain of oxidative stress (OS) reactions, and increase inflammatory reactions. Here, we highlight some of the mechanisms underlying glycation damage in the ovary. Methods: Searches of electronic databases were performed. Articles relevant to possible role of OS, AGEs, and receptor for AGE (RAGE) in aging ovary were summarized in this interpretive literature review. Results: Follicular microenvironment undergoes an increase in OS with aging. Data support the role of OS in ovulatory dysfunction because AGEs are well-recognized mediators of increased OS. RAGE and AGE-modified proteins with activated nuclear factor-kappa B are expressed in human ovarian tissue. It was suggested that accumulation of AGEs products at the level of the ovarian follicle might trigger early ovarian aging or could be responsible for reduced glucose uptake by granulosa cells, potentially altering follicular growth. Moreover, impaired methylglyoxal detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive aging. Conclusions: Further investigation of the role for the AGE-RAGE axis in the ovarian follicular environment is needed, and results could relate to assisted reproduction technology outcomes and new measures of ovarian reserve. Key Words: Advanced glycation end products – Aging – Menopause – Ovary – Oxidative stress.
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ver the last century a progressive increase in the female lifespan has been observed; however, neither the end of reproductive capacity nor the onset of menopause have changed.1 The loss of functional follicles/ oocytes, leading to menopause, plays a crucial role in declining fertility. Such gradual loss of fertility increases in the late 30s, despite ovulatory cycles, finally ending in menopause at a mean age of 50 to 51 years.2 Such observations have been confirmed in assisted reproduction treatments, where the age of the woman is probably the most important factor influencing clinical outcome. Pregnancy rate has been shown to decrease from 43.6% at age 25 years and younger to 21.0% at 41 years and older (P < 0.001).3 During fetal life, due to rapid cell proliferation female fetus ovaries are supplied with approximately 6 million oocytes surrounded by somatic granulosa cells.2 The pool of Received May 16, 2016; revised and accepted July 27, 2016. From the 1Independent Consultant in Obstetrics and Gynecology, New Malden, UK; and 2Department of Endocrinology and Diabetes Center of Excellence, Medical School of Athens, Athens, Greece. Funding/support: None. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Magdalena Pertynska-Marczewska, MD, PhD, 44 Traps Lane, KT3 4SA New Malden, UK. E-mail: [email protected]
primordial follicles is gradually depleted by atresia and only approximately 1 million follicles remain at birth, approximately 300,000 at menarche, and during reproductive life an average of 1,000 follicles are lost each month2,4-6 and menopause commences when the remaining follicles are fewer than 1,000.2,7 Theories of aging share the concept that age-associated malfunction results from physiological accumulation of irreparable damage to biomolecules as an unavoidable side effect of normal metabolism and underline the importance of the capability of defensive repair.8 Hence, the theory of ovarian aging, first proposed by Tarin,9 implied a reduced ability of oocytes and granulosa cells to counteract reactive oxygen species (ROS), which are among the most important physiological inducers of cellular injury associated with aging.10 At every new cycle only a limited number of follicles is, however, recruited from the cohort of small growing follicles.11 Therefore, the majority of follicles that start to grow will not reach the preovulatory stage and are intended to undergo atresia,12 probably the default developmental pathway for follicles, especially follicles of the preantral and early antral stage.13 These taken together result in ovarian aging. Glucose and other reducing sugars can react nonenzymatically with the amino groups of proteins, nucleotides, and lipids. These early glycation products undergo further Menopause, Vol. 24, No. 3, 2017
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complex reactions to become irreversibly cross-linked, heterogeneous derivatives termed advanced glycation end products (AGE).14 The formation and accumulation of AGEs are known to progress during normal aging, and at an accelerated rate in diabetes.15 Most of AGEs’ biological effects are mediated through specific receptors (receptor for AGE [RAGE]) presented on cell surface throughout the body,16 and their interaction triggers oxidative stress (OS) and inflammation. A hypothesis of the involvement of AGEs in the ovarian aging has been proposed, and it has been suggested that the potential intraovarian accumulation of AGE compounds compromises the vascular supply of the ovary and induces an OS response through interaction with RAGE.17 Moreover, Stensen et al3 suggested that accumulation of aging-related molecular damage in ovarian somatic cells stimulates innate immune responses and contributes to a decline in ovarian function. This review will focus on the possible role of AGEs and RAGE in aging ovary. AGEs-RAGE AXIS Formation of AGEs AGEs are prooxidant metabolic derivatives of nonenzymatic reactions between reducing sugars and free amines of proteins as well as of aminolipids and nucleic acids.18-20 Extracellular and intracellular reactive carbonyl precursors (ie, glyoxal) generate AGEs or glycoxidants (ie, Ne-carboxymethyl-lysine [CML]).20 During the forming of AGEs, many intermediates are unstable and spontaneously degrade or undergo redox cyclization reactions, releasing ROS that can modify proteins, lipids, or nucleic acids either in the extracellular or extracellular spaces.20 The formation of the AGE accelerating intermediates methylglyoxal (MG) and glyoxal seems to occur through sugar fragmentation. Such sugar fragmentation and protein conformational changes observed are dependent on hydroxyl radicals produced by glucose autoxidation.21 In general, oxidized proteins are degraded by the 20S proteasome of the Ubiquitin-Proteasome System (UPS)22,23; however, formation of cross-linked proteins can cause inhibition of the Ubiquitin-Proteasome System by blocking the entry of the proteasomal core.22 This in turn results in a decrease in proteolytic activity leading to an increase in oxidized and damaged proteins,24 which can encourage further protein modification. Moreover, elevated levels of oxidants promote the oxidation of lipids and glucose, resulting in the accelerated formation of AGEs.22 Therefore, excessive ROS levels result in a decline of antioxidative and repair potential of the cells. Hence, increasing levels of AGEs support the formations of reactive oxygen and nitrogen species which in turn induce further formation of AGEs.22,25 One needs to be also aware that AGEs could be introduced into the circulation together with nutrients processed by common methods such as dry heat26 or other food processing methods, for example ionization26 or during tobacco
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smoking.27 Human and animal studies demonstrated that approximately 10% of AGEs embedded in a meal can be absorbed into circulation, of which two-thirds remain in the body for 72 hours.28,29 It seems long enough to promote OS, produce more AGEs, and potentially cause tissue injury.27 Therefore, AGEs have a range of chemical, cellular, and tissue effects.27 AGEs receptor RAGE RAGE It belongs to the group of prooxidant receptors and as a multiligand receptor is a progression factor amplifying immune and inflammatory responses.20,30,31 RAGE initiates the intracellular signaling that disrupts cellular function through its recognition and binding of AGEs.15 Interaction of AGEs with RAGE on vascular cells induces a proinflammatory state and accelerated OS, causing atherogenesis.32,33 Engagement of RAGE in intracellular signaling leads to ROS production via activation of the proinflammatory transcription factor nuclear factor-kappa B (NF-kB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This leads to the production of proinflammatory cytokines, chemokines, adhesion molecules, and to the OS causing inflammation, macrophage and platelet activation, and thrombosis, resulting in vascular damage.33 Moreover, increased superoxide production causes an increased formation of AGEs and up-regulation of RAGE,34 thus inactivating two critical antiatherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways increased intracellular ROS activate a number of proinflammatory pathways35,36 (Fig. 1). sRAGE The soluble form of RAGE (sRAGE) is a product of both splicing of the gene for RAGE and cleavage of membranebound RAGE. sRAGE acts as a decoy by binding the circulating AGEs, and thus competitively inhibiting AGE-RAGE interaction and its downstream proinflammatory signalling.37,38 The extracellular effect of AGEs includes modification of the structural integrity of the vessel wall and underlying basement membranes by inducing cross-linking of matrix proteins.2 Such action leads to reduced elasticity, increased stiffness and vessel rigidity, and together implicating AGEs’ role in atherosclerosis.16 AGING OVARY AND OS OS is defined as an unbalance between oxidant and antioxidant systems, and it effects the entire reproductive span of women’s life and extends even later (menopause).39 ROS play a role in the modulation of an entire spectrum of physiological reproductive functions such as oocyte maturation, ovarian steroidogenesis, corpus luteal functions, and luteolysis.39 Only recently studies in humans and animal models have provided evidence for correlation of dicarbonyl stress with ovarian dysfunction, for example, ovarian aging and ß 2016 The North American Menopause Society
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AGING OVARY AND AGES Cell membrane
AGEs sRAGE
RAGE
NADPH oxidase
ROS
ENDOTHELIAL DYSFUNCTION
NF-κB Translocation to the nucleus
TARGET GENE EXPRESSION
INFLAMMATION CYTOKINES ADHESION MOLECULES
FIG. 1. A schematic diagram of AGE-RAGE signaling cascade. Intracellular effects are mediated through binding of AGEs to specific cellular receptors RAGE. Engagement of RAGE in intracellular signaling leads to ROS production via activation of NADPH oxidase with subsequent nuclear translocation of NF-kB which targets several genes involved in inflammation, immune response, and apoptosis. In addition, increased superoxide production causes an increased formation of AGEs and overexpression of RAGE, acting as positive-feedback loop thus worsening the inflammatory response. The circulating receptor for AGEs-soluble RAGE (sRAGE) acts as a decoy for ligands, thus competitively inhibiting AGE-RAGE interaction and its downstream proinflammatory signaling. AGEs, advanced glycation end products; NADPH, nicotinamide adenine dinucleotide phosphate; NF-kB, nuclear factor kappa B; RAGE, receptor for AGE; ROS, reactive oxygen species.
polycystic ovary syndrome (PCOS).40 Numerous studies have demonstrated the presence of ROS in ovaries.41-45 It has been suggested that the age-related decline in fertility is modulated by OS46 because ovulation is regulated by ROS.47 Many studies demonstrated that ROS levels rise and antioxidant levels fall in response to the preovulatory gonadotropin surges, and treatment with antioxidants inhibits ovulation.48-50 Also, ROS levels in follicular fluid (FF) seem to play a significant role in embryo formation and quality.51,52 Over a decade ago, Carbone et al53 demonstrated that FF from older women exhibited a reduced level of glutathione transferase and catalase activities and a higher level of superoxide dismutase activity. Immunoblot analysis revealed that aging was associated with decreased protein expression of glutathione S-transferase Pi isoform and did not affect superoxide dismutase and catalase protein expression. Although population size of the study was limited, the investigators demonstrated that significant amounts of antioxidant enzymes were present in human FF and that FF from older women displays a different pattern of antioxidant enzymatic defenses. Taken together, the results indicated that reproductive aging is accompanied by a change in the antioxidant enzymatic pattern that could impair ROS-scavenging efficiency in the follicular environment.53 Because the increase in ROS production during aging may lead to oxidized protein accumulation, such accumulation is thought to represent a valid marker of the OS status of biological samples.54 Tatone et al17 labeled free protein-SH groups with biotin by using 3-N-maleimidopropionyl biocytin and then analyzed them by two-dimensional gel
electrophoresis. They demonstrated a marked quantitative and qualitative reduction in labeled proteins from FF of older women. In the context of oxidative damage in an aging ovary, the evidence that (approximately 56 kDa) protein is strongly labeled in FF samples from young women, whereas it was practically absent in older women, makes this data worth consideration. Such reduction in free-SH groups with age strongly suggests that the follicular microenvironment undergoes an increase in OS with aging. The microtubular cytoskeleton of mammalian metaphase II oocytes changes during aging in vivo and in vitro. The spindle migrates toward the center of the oocyte, shortens, and finally breaks down55; therefore, a gradual and slow increase in intracellular OS of oocytes with maternal age may moderately affect the dynamic instability of microtubules and/or the spindle microtubule motion forces.56 Also, de Bruin et al46 suggested that age-related changes observed in ovarian mitochondria, smooth endoplasmic reticulum, and Golgi complex imply a role for oxidative damage. Moreover, increased soluble receptor for AGEs and vascular endothelial growth factor levels in FF of endometriosis patients suggest that a key mechanism in the pathogenesis of endometriosis may involve signaling pathways activated by RAGE.57 AGEs IN OVARIAN AGING The binding of AGEs with RAGE results in ROS production via activation of the proinflammatory transcription factor NF-kB and NADPH oxidase.58 The first evidence suggesting the involvement of AGE in ovarian dysfunction came from studies by the group of Diamanti-Kandarakis Menopause, Vol. 24, No. 3, 2017
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et al,59,60 demonstrating increased levels of AGEs in the serum and ovary of PCOS. The same group demonstrated for the first time that RAGE and AGE-modified proteins with activated NF-kB are expressed in human ovarian tissue.59 RAGE was highly expressed in normal and PCOS tissues in PCOS ovaries, but granulosa cells displayed stronger RAGE expression than theca interna cells in comparison with controls. The authors also showed that NF-kB was expressed in the cytoplasm of theca interna and granulosa cells of both normal and PCOS ovaries, whereas the NF-kB p65 subunit was only observed in granulosa cells nuclei in PCOS tissue.59 The only limitation of this study was the population size (six women with PCOS and six healthy women of similar age). The investigators, however, demonstrated for the first time a differential qualitative distribution of AGE, RAGE, and NF-kB p65 subunit in women with PCOS compared with healthy controls, and a stronger localization of both AGE and RAGE in the granulosa cell layer of PCOS ovaries. It was suggested that accumulation of AGEs products at the level of the ovarian follicle might trigger early ovarian aging17 or could be responsible for reduced glucose uptake by granulosa cells, potentially altering follicular growth.16 Diamanti-Kandaraki et al61 also investigated the potential interaction of AGEs with insulin signaling pathways and glucose transport in human granulosa KGN cells. KGN cells were cultured with variable concentrations of human glycated albumin (50-200 mg/mL) or insulin (100 ng/mL). Combined treatments of KGN cells with insulin (100 ng/mL) and human glycated albumin (200 mg/mL) were also performed. The investigators demonstrated that AGEs interfere with insulin signaling in granulosa cells and prevent glucose transporter type 4 membrane translocation, suggesting that intraovarian AGEs accumulation, from endogenous or exogenous sources, may contribute to the pathophysiology of states characterized by anovulation and insulin resistance such as PCOS. Also, separation of ovarian proteins by two-dimensional gels and Western blotting revealed an approximate 30-fold increase in the extent of protein glycation in aged ovaries.62 Moreover, the biochemical activity of glyoxalase I (GLO-I), the main component of the MG-scavenging system, was significantly decreased in ovaries from reproductively aged mice in comparison with the young group.62 Such results showed that impaired MG detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive aging.62 Also, Kandaraki et al63 presented data showing the potential of a diet rich in AGEs and androgen excess to impair the activity of ovarian GLO-I in rats, possibly contributing to reduced detoxification and associated ovarian dysfunction observed in modified dietary and hyper-androgenic states. This was a well-designed study with satisfactory sample size, and the investigators demonstrated that high AGEs diet may promote a high ROS environment, on the basis of elevated serum AGEs, which could negatively influence GLO-I activity. Moreover, the high-AGE diet-fed rats exhibited increased glucose, insulin, and testosterone levels as well
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as decreased estradiol and progesterone levels compared with the low-AGE diet-fed ones, thus indicating a metabolic and hormonal dysregulation attributed to high-AGE dietary exposure. Also, decreased monocytic expression of scavenger receptors such as RAGE and scavenger receptor class A (SRA) noticed in the high-AGE diet-fed rats may result in a higher deposition of AGEs in peripheral endocrine tissues, hence promoting endocrine-related abnormalities and diseases.64 Again, serum levels of AGEs, testosterone, OS, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) index were significantly increased on the high AGEs diet compared with the ad libitum AGEs content diet and subsequently decreased on the low AGEs diet (compared with high AGEs) in women with PCOS.65 AGEs had also been shown to stimulate the extracellular matrix (ECM) production and was involved in abnormal collagen cross-linking in ovarian tissue.59 Papachroni et al demonstrated that the deposition of excess collagen in PCO tissue could be due to AGE-mediated stimulation of lysyl oxidase activity,66 which is a key enzyme in the ovary responsible for collagen and elastin cross-linking in the organization of ECM during follicular development.67 The mechanism causing anovulation is still under investigation, but the defective selection mechanism results in accumulation of small antral follicles, which contributes to the production of antimu¨llerian hormone (AMH).68 AMH is a member of transforming growth factor b family, which is synthesized by granulosa cells of primary follicles and expressed in preantral and small antral follicles.68 Diamanti-Kandarakis et al69 in a cross-sectional study with a study group consisting of 60 women with PCOS (37 anovulatory and 23 regularly ovulating) demonstrated that serum levels of AGEs, as mediators of OS immunolocalized in the granulosa cells of polycystic ovarian tissue, as well as AMH were higher in the group of anovulatory women with PCOS than non-PCOS anovulatory women. Such data support the role of OS in ovulatory dysfunction because AGEs are well-recognized mediators of increased OS.69 AGEs have also been found to be involved in the impaired folliculogenesis leading to impaired follicle maturation.70 The activity of sRAGE in the FF is still unclear, but it may reflect the activity of the AGE-RAGE axis in ovarian follicles.40 Malickova´ et al71 for a preliminary study recruited a total of 33 women undergoing in vitro fertilization (IVF) treatment. To support the hypothesis that ovulation can be compared with an inflammatory event investigators decided to study inflammatory processes during ovarian hyperstimulation.71 They reported that the FF concentration of sRAGE is severalfold higher than serum and other biological fluids.71 The authors also suggested that a significant negative correlation of serum sRAGE with the yield of follicles and oocytes, together with the high follicular sRAGE levels, in women with a positive IVF outcome, could be explained by the essential outflow of sRAGE to the follicular compartment. Bonetti et al72 in a prospective cohort study measured the concentration of sRAGE in FF obtained from the leading ß 2016 The North American Menopause Society
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AGING OVARY AND AGES
follicle after ovarian stimulation of 54 women undergoing intracytoplasmic sperm injection. High intrafollicular sRAGE concentrations predicted poor-quality embryos (n ¼ 45, odds ratio ¼ 0.986; P ¼ 0.026), adjusted for participant age, body mass index, and oocyte quality, showing an inverse correlation between intrafolliculars RAGE concentrations and embryo development. Therefore, FF sRAGE concentration in healthy women may represent a marker of oocyte competence useful in the selection of oocytes to be fertilized to improve reproductive outcome.73 Also, a relevant study in a clinical setting reported that serum and FF concentrations of some AGEs, namely pentosidine, CML (Ne-carboxymethyllysine) correlated negatively and significantly with follicular growth, fertilization, and embryonic development.74 The authors indicated that lower concentrations of pentosidine in FF and glyceraldehyde-derived AGE in serum were the most significant novel predictors for achievement of ongoing pregnancy, acting independently of conventional determinants like age and day-3 follicle-stimulating hormone.74 This first direct clinical evidence based on human IVF/intra-cytoplasmic sperm injection (ICSI) therapy for an important role of AGE accumulation in ovarian dysfunction and diminished fertility is the strength of this study.74 Fuji and Nakayama75 in a clinical preliminary study examined AGEs, sRAGE, and vascular endothelial growth factor (VEGF) concentrations in plasma and FF from reproductive-age women. Plasma concentration of sRAGE was significantly higher in the group less than 35 years old; VEGF in FF was significantly higher in the group of more than 35 years old. The authors concluded that the results suggest a possibility that RAGE-VEGF regulation may be related to reproductive dysfunction in aging women. Indeed, VEGF signaling is deregulated in the follicular microenvironment of aged women and may account for alterations in follicular vasculature.76 Fuji and Nakayama’s study demonstrated for the first time that sRAGE and VEGF secretion in reproductive women have correlation with age, and sRAGE may relate to the condition of reproductive environment. To find out whether sRAGE or VEGF could work as markers of the follicular environment and egg quality, further studies are, however, needed. Becausre AGE and RAGE are expressed in granulosa and theca cells,76 as well as in luteinized cells derived from the ovary, Stensen et al6 looked how AGE and RAGE affect the cells of the human ovarian follicle. They demonstrated that AGE-modified proteins are present on the surface of freshly isolated human granulosa lutein cells and intrafollicular monocytes, suggesting that ovarian cells may be exposed to AGE-related damage in vivo. They also observed that granulosa cells and ovarian monocytes bind AGE-modified albumin in vitro and that specific RAGE receptors are present on the surface of these cells. These data imply that AGEs, which are involved in the structural and functional modification of cellular proteins, the formation of cross-links between molecules in the basement membrane and the ECM, and activation of the RAGE receptor that leads to
production of ROS,18 may also be involved in the decline of ovarian function. Stensen et al6 also noticed that with ligandinduced up-regulation, the expression of RAGE by granulosa lutein cells was increased in older women. Because in this prospective cohort study, human follicle fluid-derived cells were isolated from aspirates of ovarian follicles of women who underwent assisted reproduction treatment, the impact of AGE and RAGE in the ovary shown here in cells in culture remains to be further validated in clinical settings. Also, engagement of RAGE in intracellular signaling through binding with AGEs leads to induction of inflammatory reactions and could affect the aging process. On the contrary, inflammation itself may suppress ovarian function or indicate immune challenges that lead to ovarian suppression.77 In general, the sources of ovarian AGEs are currently unknown. They could result from a local ovarian production, but they could also be coming from an exogenous source. For example, Diamanti-Kandarakis et al78 demonstrated that in rats ingested AGEs led to increased serum AGE levels and higher expression of AGE and RAGE in the ovary. Also, tobacco smoking that increases in vivo concentrations of AGE21 may possibly increase AGE levels also in the ovary. Aging may result in the accumulation of reactive carbonyl compounds leading to AGE formation in organs including the ovary.63 In a very interesting, well-designed and very detailed study, using young and old mice, Tatone et al demonstrated that the sensitivity to carbonyl stress by MG seems to increase with maternal age.79 MG exposure induces DNA damage, meiotic delay, spindle aberrations, anaphase I lagging, and epimutation, hence aged oocytes are particularly at risk for such disturbances in the absence of efficient protection by cumulus. Furthermore, the authors also suggested that disturbances in mitochondrial distribution and redox regulation may be especially critical for fertilization and developmental competence of oocytes exposed to MG and carbonyl stress before or during maturation, for instance, in aged women, or in PCOS or diabetic patients. This is in line with suggestions of correlations between poor follicular and embryonic development, lower pregnancy rate, and the presence of toxic AGEs in serum, irrespective of age.74 All the above observations indicate that the accumulation of AGEs in aging ovary is a marked event that may account for compromised vascularization as well as activation of oxidative response through RAGE interaction.80,81 CONCLUSIONS Recently, the concept of carbonyl stress theory in ovarian aging gained a lot of attention from professionals in the field of female reproductive aging. In this review, we focused on the mechanisms underlying glycation damage in the ovary. AGEs contribute directly to protein damage, induce a chain of reactions of OS, and increase inflammatory reactions. Further investigation of the role for the AGE-RAGE system in the ovarian follicular environment is required, and human Menopause, Vol. 24, No. 3, 2017
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granulosa cells obtained from IVF patients could provide a model for investigating age-related dysfunction in the ovarian microenvironment. The results could relate to assisted reproduction technology outcomes and measures of ovarian reserve. REFERENCES 1. Cedars MI. Biomarkers of ovarian reserve—do they predict somatic aging? Semin Reprod Med 2013;31:443-451. 2. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002;8:141-154. 3. Stensen MH, Tanbo T, Storeng R, Byholm T, Fe`dorcsak P. Routine morphological scoring systems in assisted reproduction treatment fail to reflect age-related impairment of oocyte and embryo quality. Reprod Biomed Online 2010;21:118-125. 4. Byskov AG. Differentiation of mammalian embryonic gonad. Physiol Rev 1986;66:71-117. 5. Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 1996;11: 1484-1486. 6. Stensen MH, Tanbo T, Storeng R, Fedorcsak P. Advanced glycation end products and their receptor contribute to ovarian ageing. Hum Reprod 2014;29:125-134. 7. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342-1346. 8. Yin D, Chen K. The essential mechanisms of aging: irreparable damage accumulation of biochemical side-reactions. Exp Gerontol 2005;40: 455-465. 9. Tarin JJ. Aetiology of age-associated aneuploidy: a mechanism based on the ‘free radical theory of ageing. Hum Reprod 1995;10:1563-1565. 10. Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci 2006;1067:10-21. 11. Visser JA, Durlinger AL, Peters IJ, et al. Increased oocyte degeneration and follicular atresia during the estrous cycle in anti-Mu¨llerian hormone null mice. Endocrinology 2007;148:2301-2308. 12. Hsueh AJ, Billig H, Tsafriri A. Ovarian follicle atresia: a hormonally controlled apoptotic process. Endocr Rev 1994;15:707-724. 13. Kaipia A, Hsueh AJ. Regulation of ovarian follicle atresia. Annu Rev Physiol 1997;59:349-363. 14. Singh R, Barden A, Mori T, Beilin L. Advanced glycation endproducts: a review. Diabetologia 2001;44:129-146. 15. Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med 2002;251:87-101. 16. Piperi C, Adamopoulos C, Dalagiorgou G, Diamanti-Kandarakis E, Papavassiliou AG. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. J Clin Endocrinol Metab 2012;97:2231-2242. 17. Tatone C, Amicarelli F, Carbone MC, et al. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update 2008;14:131-142. 18. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-820. 19. Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci U S A 1993;90:6434-6438. 20. Vlassara H, Striker GE. Advanced glycation endproducts in diabetes and diabetic complications. Endocrinol Metab Clin North Am 2013;42: 697-719. 21. Poulsen MW, Hedegaard RV, Andersen JM, et al. Advanced glycation endproducts in food and their effects on health. Food Chem Toxicol 2013;60:10-37. 22. Grimm S, Ott C, Horlacher M, Weber D, Hohn A, Grune T. Advancedglycation-end-product-induced formation of immunoproteasomes: involvement of RAGE and Jak2/STAT1. Biochem J 2012;448: 127-139. 23. Jung T, Catalgol B, Grune T. The proteasomal system. Mol Asp Med 2009;30:191-296. 24. Valencia JV, Weldon SC, Quinn D, et al. Advanced glycation end product ligands for the receptor for advanced glycation end products: biochemical characterization and formation kinetics. Anal Biochem 2004;324:68-78.
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25. Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol 2014;2:411-429. 26. Koschinsky T, He CJ, Mitsuhashi T, et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci U S A 1997;94:6474-6479. 27. Cerami C, Founds H, Nicholl I, et al. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci U S A 1997;94: 13915-13920. 28. Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr Diab Rep 2014;14:453-466. 29. He C, Sabol J, Mitsuhashi T, Vlassara H. Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes 1999;48:1308-1315. 30. Vlassara H, Palace MR. Diabetes and advanced glycation endproducts. J Intern Med 2002;251:87-101. 31. Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001;108:949-955. 32. Bodiga VL, Eda SR, Bodiga S. Advanced glycation end products: role in pathology of diabetic cardiomyopathy. Heart Fail Rev 2013;19:49-63. 33. Ramasamy R, Schmidt AM. Receptor for advanced glycation end products (RAGE) and implications for the pathophysiology of heart failure. Curr Heart Fail Rep 2012;9:107-116. 34. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107:1058-1070. 35. Ramasamy R, Yan SF, Schmidt AM. Advanced glycation endproducts: from precursors to RAGE: round and round we go. Amino Acids 2012;42:1151-1161. 36. Yan SF, Ramasamy R, Schmidt AM. Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response. J Mol Med (Berl) 2009;87:235-247. 37. Falcone C, Bozzini S, Guasti L, et al. Soluble RAGE plasma levels in patients with coronary artery disease and peripheral artery disease. ScientificWorldJournal 2013;2013:584504. 38. Haitoglou CS, Tsilibary EC, Brownlee M, Charonis AS. Altered cellular interactions between endothelial cells and nonenzymatically glycosylated laminin/type IV collagen. J Biol Chem 1992;267:12404-12407. 39. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol 2005;3:28-35. 40. Tatone C, Di Emidio G, Vitti M, et al. Sirtuin functions in female fertility: possible role in oxidative stress and aging. Oxid Med Cell Longev 2015;2015:659687-659692. 41. Behrman HR, Kodaman PH, Preston SL, Gao S. Oxidative stress and the ovary. J Soc Gynecol Investig 2001;8:S40-S42. 42. Sabatini L, Wilson C, Lower A, Al-Shawaf T, Grudzinskas JG. Superoxide dismutase activity in human follicular fluid after controlled ovarian hyperstimulation in women undergoing in vitro fertilization. Fertil Steril 1999;72:1027-1034. 43. Shiotani M, Noda Y, Narimoto K, et al. Immunohistochemical localization of superoxide dismutase in the human ovary. Hum Reprod 1991;6:1349-1353. 44. Suzuki T, Sugino N, Fukaya T, et al. Superoxide dismutase in normal cycling human ovaries: immunohistochemical localization and characterization. Fertil Steril 1999;72:720-726. 45. Jozwik M, Wolczynski S, Szamatowicz M. Oxidative stress markers in preovulatory follicular fluid in humans. Mol Hum Reprod 1999;5:409413. 46. de Bruin JP, Dorland M, Spek ER, et al. Ultrastructure of the resting ovarian follicle pool in healthy young women. Biol Reprod 2002;66: 1151-1160. 47. Luderer U. Ovarian toxicity from reactive oxygen species. Vitam Horm 2014;94:99-127. 48. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci U S A 2011;108:1462-1467. 49. Sato EF, Kobuchi H, Edashige K, et al. Dynamic aspects of ovarian superoxide dismutase isozymes during the ovulatory process in the rat. FEBS Lett 1992;303:121-125. 50. Miyazaki T, Sueoka K, Dharmarajan AM, Atlas SJ, Bulkley GB, Wallach EE. Effect of inhibition of oxygen free radical on ovulation and progesterone production by the in-vitro perfused rabbit ovary. J Reprod Fertil 1991;91:207-212.
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AGING OVARY AND AGES 51. Das S, Chattopadhyay R, Ghosh S, et al. Reactive oxygen species level in follicular fluid—embryo quality marker in IVF? Hum Reprod 2006;21:2403-2407. 52. Wiener-Megnazi Z, Vardi L, Lissak A, et al. Oxidative stress indices in follicular fluid as measured by the thermochemiluminescence assay correlate with outcome parameters in vitro fertilization. Fertil Steril 2004;82:1171-1176. 53. Carbone MC, Tatone C, Delle Monache S, et al. Antioxidant enzymatic defences in human follicular fluid: characterization and age-dependent changes. Mol Hum Reprod 2003;9:639-643. 54. Davies MJ, Fu S, Wang H, Dean RT. Stable markers of oxidant damage to proteins and their application in the study of human disease. Free Rad Biol Med 1999;27:1151-1163. 55. Eichenlaub-Ritter U, Chandley AC, Gosden RG. Alterations to the microtubular cytoskeleton and increased disorder of chromosome alignment in spontaneously ovulated mouse oocytes aged in vivo: an immunofluorescence study. Chromosoma 1986;94:337-345. 56. Tarı´n JJ. Aetiology of age-associated aneuploidy: a mechanism based on the ‘‘free radical theory of ageing.’’ Hum Reprod 1995;10:1563-1565. 57. Fujii EY, Nakayama M, Nakagawa A. Concentrations of receptor for advanced glycation end products, VEGF and CML in plasma, follicular fluid, and peritoneal fluid in women with and without endometriosis. Reprod Sci 2008;15:1066-1074. 58. Schmidt AM, Yan SD, Yan SF, Stern DM. The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 2000;1498:99-111. 59. Diamanti-Kandarakis E, Piperi C, Patsouris E, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol 2007;127:581-589. 60. Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2008;69: 634-641. 61. Diamanti-Kandarakis E, Chatzigeorgiou A, Papageorgiou E, Koundouras D, Koutsilieris M. Advanced glycation end-products and insulin signaling in granulosa cells. Exp Biol Med (Maywood) 2016;241:1438-1445. 62. Tatone C, Carbone MC, Campanella G, et al. Female reproductive dysfunction during ageing: role of methylglyoxal in the formation of advanced glycation endproducts in ovaries of reproductively-aged mice. J Biol Regul Homeost Agents 2010;24:63-72. 63. Kandaraki E, Chatzigeorgiou A, Piperi C, et al. Reduced ovarian glyoxalase-I activity by dietary glycotoxins and androgen excess: a causative link to polycystic ovarian syndrome. Mol Med 2012;18:1183-1189. 64. Chatzigeorgiou A, Kandaraki E, Piperi C, et al. Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats. J Endocrinol 2013;218:331-337. 65. Tantalaki E, Piperi C, Livadas S, et al. Impact of dietary modification of advanced glycation end products (AGEs) on the hormonal and metabolic profile of women with polycystic ovary syndrome (PCOS). Hormones (Athens) 2014;13:65-73.
66. Papachroni KK, Piperi C, Levidou G, et al. Lysyl oxidase interacts with AGE signalling to modulate collagen synthesis in polycystic ovarian tissue. J Cell Mol Med 2010;14:2460-2469. 67. Harlow CR, Rae M, Davidson L, Trackman PC, Hillier SG. Lysyl oxidase gene expression and enzyme activity in the rat ovary: regulation by follicle-stimulating hormone, androgen, and transforming growth factor-beta superfamily members in vitro. Endocrinology 2003;144: 154-162. 68. Weenen C, Laven JS, Von Bergh AR, et al. Anti-Mu¨llerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 2004;10:77-83. 69. Diamanti-Kandarakis E, Piouka A, Livadas S, et al. Anti-mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome. Eur J Endocrinol 2009;160: 847-853. 70. Devangelio E, Santilli F, Formoso G, et al. Soluble RAGE in type 2 diabetes: association with oxidative stress. Free Radic Biol Med 2007;43:511-518. 71. Malickova´ K, Jarosova´ R, Reza´bek K, et al. Concentrations of sRAGE in serum and follicular fluid in assisted reproductive cycles: a preliminary study. Clin Lab 2010;56:377-384. 72. Bonetti TC, Borges E Jr, Braga DP, et al. Intrafollicular soluble receptor for advanced glycation end products (sRAGE) and embryo quality in assisted reproduction. Reprod Biomed Online 2013;26:62-67. 73. Tatone C, Eichenlaub-Ritter U, Amicarelli F. Dicarbonyl stress and glyoxalases in ovarian function. Biochem Soc Trans 2014;42:433-438. 74. Jinno M, Takeuchi M, Watanabe A, et al. Advanced glycation end products accumulation compromises embryonic development and achievement of pregnancy by assisted reproductive technology. Hum Reprod 2011;26:604-610. 75. Fujii EY, Nakayama M. The measurements of RAGE, VEGF, and AGEs in the plasma and follicular fluid of reproductive women: the influence of aging. Fertil Steril 2010;94:694-700. 76. Yeh J, Kim BS, Peresie J. Ovarian vascular endothelial growth factor and vascular endothelial growth factor receptor patterns in reproductive aging. Fertil Steril 2008;89:1546-1556. 77. Clancy KB, Klein LD, Ziomkiewicz A, Nenko I, Jasienska G, Bribiescas RG. Relationships between biomarkers of inflammation, ovarian steroids, and age at menarche in a rural Polish sample. Am J Hum Biol 2013;25: 389-398. 78. Diamanti-Kandarakis E, Piperi C, Korkolopoulou P. Accumulation of dietary glycotoxins in the reproductive system of normal female rats. J Mol Med (Berl) 2007;85:1413-1420. 79. Tatone C, Heizenrieder T, Di Emidio G, et al. Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. Hum Reprod 2011;26:1843-1859. 80. Li Q, Geng X, Zheng W, Tang J, Xu B, Shi Q. Current understanding of ovarian aging. Sci China Life Sci 2012;55:659-669. 81. Tatone C, Amicarelli F, Carbone MC, et al. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update 2008;14:131-142.
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REVIEW ARTICLE Aging ovary and the role for advanced glycation end products Magdalena Pertynska-Marczewska, MD, PhD,1 and Evanthia Diamanti-Kandarakis, MD, PhD 2 Abstract Objective: The hypothalamic gonadotropin-releasing hormone pulse generator, the pituitary gonadotropes, the ovaries, and the uterus play a crucial role in female fertility. A decline in reproductive performance represents a complex interplay of actions at all levels of the hypothalamic-pituitary-ovarian axis. Recently, in the field of female reproductive aging attention is drawn to the carbonyl stress theory. Advanced glycation end products (AGEs) contribute directly to protein damage, induce a chain of oxidative stress (OS) reactions, and increase inflammatory reactions. Here, we highlight some of the mechanisms underlying glycation damage in the ovary. Methods: Searches of electronic databases were performed. Articles relevant to possible role of OS, AGEs, and receptor for AGE (RAGE) in aging ovary were summarized in this interpretive literature review. Results: Follicular microenvironment undergoes an increase in OS with aging. Data support the role of OS in ovulatory dysfunction because AGEs are well-recognized mediators of increased OS. RAGE and AGE-modified proteins with activated nuclear factor-kappa B are expressed in human ovarian tissue. It was suggested that accumulation of AGEs products at the level of the ovarian follicle might trigger early ovarian aging or could be responsible for reduced glucose uptake by granulosa cells, potentially altering follicular growth. Moreover, impaired methylglyoxal detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive aging. Conclusions: Further investigation of the role for the AGE-RAGE axis in the ovarian follicular environment is needed, and results could relate to assisted reproduction technology outcomes and new measures of ovarian reserve. Key Words: Advanced glycation end products – Aging – Menopause – Ovary – Oxidative stress.
O
ver the last century a progressive increase in the female lifespan has been observed; however, neither the end of reproductive capacity nor the onset of menopause have changed.1 The loss of functional follicles/ oocytes, leading to menopause, plays a crucial role in declining fertility. Such gradual loss of fertility increases in the late 30s, despite ovulatory cycles, finally ending in menopause at a mean age of 50 to 51 years.2 Such observations have been confirmed in assisted reproduction treatments, where the age of the woman is probably the most important factor influencing clinical outcome. Pregnancy rate has been shown to decrease from 43.6% at age 25 years and younger to 21.0% at 41 years and older (P < 0.001).3 During fetal life, due to rapid cell proliferation female fetus ovaries are supplied with approximately 6 million oocytes surrounded by somatic granulosa cells.2 The pool of Received May 16, 2016; revised and accepted July 27, 2016. From the 1Independent Consultant in Obstetrics and Gynecology, New Malden, UK; and 2Department of Endocrinology and Diabetes Center of Excellence, Medical School of Athens, Athens, Greece. Funding/support: None. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Magdalena Pertynska-Marczewska, MD, PhD, 44 Traps Lane, KT3 4SA New Malden, UK. E-mail: [email protected]
primordial follicles is gradually depleted by atresia and only approximately 1 million follicles remain at birth, approximately 300,000 at menarche, and during reproductive life an average of 1,000 follicles are lost each month2,4-6 and menopause commences when the remaining follicles are fewer than 1,000.2,7 Theories of aging share the concept that age-associated malfunction results from physiological accumulation of irreparable damage to biomolecules as an unavoidable side effect of normal metabolism and underline the importance of the capability of defensive repair.8 Hence, the theory of ovarian aging, first proposed by Tarin,9 implied a reduced ability of oocytes and granulosa cells to counteract reactive oxygen species (ROS), which are among the most important physiological inducers of cellular injury associated with aging.10 At every new cycle only a limited number of follicles is, however, recruited from the cohort of small growing follicles.11 Therefore, the majority of follicles that start to grow will not reach the preovulatory stage and are intended to undergo atresia,12 probably the default developmental pathway for follicles, especially follicles of the preantral and early antral stage.13 These taken together result in ovarian aging. Glucose and other reducing sugars can react nonenzymatically with the amino groups of proteins, nucleotides, and lipids. These early glycation products undergo further Menopause, Vol. 24, No. 3, 2017
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complex reactions to become irreversibly cross-linked, heterogeneous derivatives termed advanced glycation end products (AGE).14 The formation and accumulation of AGEs are known to progress during normal aging, and at an accelerated rate in diabetes.15 Most of AGEs’ biological effects are mediated through specific receptors (receptor for AGE [RAGE]) presented on cell surface throughout the body,16 and their interaction triggers oxidative stress (OS) and inflammation. A hypothesis of the involvement of AGEs in the ovarian aging has been proposed, and it has been suggested that the potential intraovarian accumulation of AGE compounds compromises the vascular supply of the ovary and induces an OS response through interaction with RAGE.17 Moreover, Stensen et al3 suggested that accumulation of aging-related molecular damage in ovarian somatic cells stimulates innate immune responses and contributes to a decline in ovarian function. This review will focus on the possible role of AGEs and RAGE in aging ovary. AGEs-RAGE AXIS Formation of AGEs AGEs are prooxidant metabolic derivatives of nonenzymatic reactions between reducing sugars and free amines of proteins as well as of aminolipids and nucleic acids.18-20 Extracellular and intracellular reactive carbonyl precursors (ie, glyoxal) generate AGEs or glycoxidants (ie, Ne-carboxymethyl-lysine [CML]).20 During the forming of AGEs, many intermediates are unstable and spontaneously degrade or undergo redox cyclization reactions, releasing ROS that can modify proteins, lipids, or nucleic acids either in the extracellular or extracellular spaces.20 The formation of the AGE accelerating intermediates methylglyoxal (MG) and glyoxal seems to occur through sugar fragmentation. Such sugar fragmentation and protein conformational changes observed are dependent on hydroxyl radicals produced by glucose autoxidation.21 In general, oxidized proteins are degraded by the 20S proteasome of the Ubiquitin-Proteasome System (UPS)22,23; however, formation of cross-linked proteins can cause inhibition of the Ubiquitin-Proteasome System by blocking the entry of the proteasomal core.22 This in turn results in a decrease in proteolytic activity leading to an increase in oxidized and damaged proteins,24 which can encourage further protein modification. Moreover, elevated levels of oxidants promote the oxidation of lipids and glucose, resulting in the accelerated formation of AGEs.22 Therefore, excessive ROS levels result in a decline of antioxidative and repair potential of the cells. Hence, increasing levels of AGEs support the formations of reactive oxygen and nitrogen species which in turn induce further formation of AGEs.22,25 One needs to be also aware that AGEs could be introduced into the circulation together with nutrients processed by common methods such as dry heat26 or other food processing methods, for example ionization26 or during tobacco
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smoking.27 Human and animal studies demonstrated that approximately 10% of AGEs embedded in a meal can be absorbed into circulation, of which two-thirds remain in the body for 72 hours.28,29 It seems long enough to promote OS, produce more AGEs, and potentially cause tissue injury.27 Therefore, AGEs have a range of chemical, cellular, and tissue effects.27 AGEs receptor RAGE RAGE It belongs to the group of prooxidant receptors and as a multiligand receptor is a progression factor amplifying immune and inflammatory responses.20,30,31 RAGE initiates the intracellular signaling that disrupts cellular function through its recognition and binding of AGEs.15 Interaction of AGEs with RAGE on vascular cells induces a proinflammatory state and accelerated OS, causing atherogenesis.32,33 Engagement of RAGE in intracellular signaling leads to ROS production via activation of the proinflammatory transcription factor nuclear factor-kappa B (NF-kB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This leads to the production of proinflammatory cytokines, chemokines, adhesion molecules, and to the OS causing inflammation, macrophage and platelet activation, and thrombosis, resulting in vascular damage.33 Moreover, increased superoxide production causes an increased formation of AGEs and up-regulation of RAGE,34 thus inactivating two critical antiatherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways increased intracellular ROS activate a number of proinflammatory pathways35,36 (Fig. 1). sRAGE The soluble form of RAGE (sRAGE) is a product of both splicing of the gene for RAGE and cleavage of membranebound RAGE. sRAGE acts as a decoy by binding the circulating AGEs, and thus competitively inhibiting AGE-RAGE interaction and its downstream proinflammatory signalling.37,38 The extracellular effect of AGEs includes modification of the structural integrity of the vessel wall and underlying basement membranes by inducing cross-linking of matrix proteins.2 Such action leads to reduced elasticity, increased stiffness and vessel rigidity, and together implicating AGEs’ role in atherosclerosis.16 AGING OVARY AND OS OS is defined as an unbalance between oxidant and antioxidant systems, and it effects the entire reproductive span of women’s life and extends even later (menopause).39 ROS play a role in the modulation of an entire spectrum of physiological reproductive functions such as oocyte maturation, ovarian steroidogenesis, corpus luteal functions, and luteolysis.39 Only recently studies in humans and animal models have provided evidence for correlation of dicarbonyl stress with ovarian dysfunction, for example, ovarian aging and ß 2016 The North American Menopause Society
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AGING OVARY AND AGES Cell membrane
AGEs sRAGE
RAGE
NADPH oxidase
ROS
ENDOTHELIAL DYSFUNCTION
NF-κB Translocation to the nucleus
TARGET GENE EXPRESSION
INFLAMMATION CYTOKINES ADHESION MOLECULES
FIG. 1. A schematic diagram of AGE-RAGE signaling cascade. Intracellular effects are mediated through binding of AGEs to specific cellular receptors RAGE. Engagement of RAGE in intracellular signaling leads to ROS production via activation of NADPH oxidase with subsequent nuclear translocation of NF-kB which targets several genes involved in inflammation, immune response, and apoptosis. In addition, increased superoxide production causes an increased formation of AGEs and overexpression of RAGE, acting as positive-feedback loop thus worsening the inflammatory response. The circulating receptor for AGEs-soluble RAGE (sRAGE) acts as a decoy for ligands, thus competitively inhibiting AGE-RAGE interaction and its downstream proinflammatory signaling. AGEs, advanced glycation end products; NADPH, nicotinamide adenine dinucleotide phosphate; NF-kB, nuclear factor kappa B; RAGE, receptor for AGE; ROS, reactive oxygen species.
polycystic ovary syndrome (PCOS).40 Numerous studies have demonstrated the presence of ROS in ovaries.41-45 It has been suggested that the age-related decline in fertility is modulated by OS46 because ovulation is regulated by ROS.47 Many studies demonstrated that ROS levels rise and antioxidant levels fall in response to the preovulatory gonadotropin surges, and treatment with antioxidants inhibits ovulation.48-50 Also, ROS levels in follicular fluid (FF) seem to play a significant role in embryo formation and quality.51,52 Over a decade ago, Carbone et al53 demonstrated that FF from older women exhibited a reduced level of glutathione transferase and catalase activities and a higher level of superoxide dismutase activity. Immunoblot analysis revealed that aging was associated with decreased protein expression of glutathione S-transferase Pi isoform and did not affect superoxide dismutase and catalase protein expression. Although population size of the study was limited, the investigators demonstrated that significant amounts of antioxidant enzymes were present in human FF and that FF from older women displays a different pattern of antioxidant enzymatic defenses. Taken together, the results indicated that reproductive aging is accompanied by a change in the antioxidant enzymatic pattern that could impair ROS-scavenging efficiency in the follicular environment.53 Because the increase in ROS production during aging may lead to oxidized protein accumulation, such accumulation is thought to represent a valid marker of the OS status of biological samples.54 Tatone et al17 labeled free protein-SH groups with biotin by using 3-N-maleimidopropionyl biocytin and then analyzed them by two-dimensional gel
electrophoresis. They demonstrated a marked quantitative and qualitative reduction in labeled proteins from FF of older women. In the context of oxidative damage in an aging ovary, the evidence that (approximately 56 kDa) protein is strongly labeled in FF samples from young women, whereas it was practically absent in older women, makes this data worth consideration. Such reduction in free-SH groups with age strongly suggests that the follicular microenvironment undergoes an increase in OS with aging. The microtubular cytoskeleton of mammalian metaphase II oocytes changes during aging in vivo and in vitro. The spindle migrates toward the center of the oocyte, shortens, and finally breaks down55; therefore, a gradual and slow increase in intracellular OS of oocytes with maternal age may moderately affect the dynamic instability of microtubules and/or the spindle microtubule motion forces.56 Also, de Bruin et al46 suggested that age-related changes observed in ovarian mitochondria, smooth endoplasmic reticulum, and Golgi complex imply a role for oxidative damage. Moreover, increased soluble receptor for AGEs and vascular endothelial growth factor levels in FF of endometriosis patients suggest that a key mechanism in the pathogenesis of endometriosis may involve signaling pathways activated by RAGE.57 AGEs IN OVARIAN AGING The binding of AGEs with RAGE results in ROS production via activation of the proinflammatory transcription factor NF-kB and NADPH oxidase.58 The first evidence suggesting the involvement of AGE in ovarian dysfunction came from studies by the group of Diamanti-Kandarakis Menopause, Vol. 24, No. 3, 2017
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et al,59,60 demonstrating increased levels of AGEs in the serum and ovary of PCOS. The same group demonstrated for the first time that RAGE and AGE-modified proteins with activated NF-kB are expressed in human ovarian tissue.59 RAGE was highly expressed in normal and PCOS tissues in PCOS ovaries, but granulosa cells displayed stronger RAGE expression than theca interna cells in comparison with controls. The authors also showed that NF-kB was expressed in the cytoplasm of theca interna and granulosa cells of both normal and PCOS ovaries, whereas the NF-kB p65 subunit was only observed in granulosa cells nuclei in PCOS tissue.59 The only limitation of this study was the population size (six women with PCOS and six healthy women of similar age). The investigators, however, demonstrated for the first time a differential qualitative distribution of AGE, RAGE, and NF-kB p65 subunit in women with PCOS compared with healthy controls, and a stronger localization of both AGE and RAGE in the granulosa cell layer of PCOS ovaries. It was suggested that accumulation of AGEs products at the level of the ovarian follicle might trigger early ovarian aging17 or could be responsible for reduced glucose uptake by granulosa cells, potentially altering follicular growth.16 Diamanti-Kandaraki et al61 also investigated the potential interaction of AGEs with insulin signaling pathways and glucose transport in human granulosa KGN cells. KGN cells were cultured with variable concentrations of human glycated albumin (50-200 mg/mL) or insulin (100 ng/mL). Combined treatments of KGN cells with insulin (100 ng/mL) and human glycated albumin (200 mg/mL) were also performed. The investigators demonstrated that AGEs interfere with insulin signaling in granulosa cells and prevent glucose transporter type 4 membrane translocation, suggesting that intraovarian AGEs accumulation, from endogenous or exogenous sources, may contribute to the pathophysiology of states characterized by anovulation and insulin resistance such as PCOS. Also, separation of ovarian proteins by two-dimensional gels and Western blotting revealed an approximate 30-fold increase in the extent of protein glycation in aged ovaries.62 Moreover, the biochemical activity of glyoxalase I (GLO-I), the main component of the MG-scavenging system, was significantly decreased in ovaries from reproductively aged mice in comparison with the young group.62 Such results showed that impaired MG detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive aging.62 Also, Kandaraki et al63 presented data showing the potential of a diet rich in AGEs and androgen excess to impair the activity of ovarian GLO-I in rats, possibly contributing to reduced detoxification and associated ovarian dysfunction observed in modified dietary and hyper-androgenic states. This was a well-designed study with satisfactory sample size, and the investigators demonstrated that high AGEs diet may promote a high ROS environment, on the basis of elevated serum AGEs, which could negatively influence GLO-I activity. Moreover, the high-AGE diet-fed rats exhibited increased glucose, insulin, and testosterone levels as well
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as decreased estradiol and progesterone levels compared with the low-AGE diet-fed ones, thus indicating a metabolic and hormonal dysregulation attributed to high-AGE dietary exposure. Also, decreased monocytic expression of scavenger receptors such as RAGE and scavenger receptor class A (SRA) noticed in the high-AGE diet-fed rats may result in a higher deposition of AGEs in peripheral endocrine tissues, hence promoting endocrine-related abnormalities and diseases.64 Again, serum levels of AGEs, testosterone, OS, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) index were significantly increased on the high AGEs diet compared with the ad libitum AGEs content diet and subsequently decreased on the low AGEs diet (compared with high AGEs) in women with PCOS.65 AGEs had also been shown to stimulate the extracellular matrix (ECM) production and was involved in abnormal collagen cross-linking in ovarian tissue.59 Papachroni et al demonstrated that the deposition of excess collagen in PCO tissue could be due to AGE-mediated stimulation of lysyl oxidase activity,66 which is a key enzyme in the ovary responsible for collagen and elastin cross-linking in the organization of ECM during follicular development.67 The mechanism causing anovulation is still under investigation, but the defective selection mechanism results in accumulation of small antral follicles, which contributes to the production of antimu¨llerian hormone (AMH).68 AMH is a member of transforming growth factor b family, which is synthesized by granulosa cells of primary follicles and expressed in preantral and small antral follicles.68 Diamanti-Kandarakis et al69 in a cross-sectional study with a study group consisting of 60 women with PCOS (37 anovulatory and 23 regularly ovulating) demonstrated that serum levels of AGEs, as mediators of OS immunolocalized in the granulosa cells of polycystic ovarian tissue, as well as AMH were higher in the group of anovulatory women with PCOS than non-PCOS anovulatory women. Such data support the role of OS in ovulatory dysfunction because AGEs are well-recognized mediators of increased OS.69 AGEs have also been found to be involved in the impaired folliculogenesis leading to impaired follicle maturation.70 The activity of sRAGE in the FF is still unclear, but it may reflect the activity of the AGE-RAGE axis in ovarian follicles.40 Malickova´ et al71 for a preliminary study recruited a total of 33 women undergoing in vitro fertilization (IVF) treatment. To support the hypothesis that ovulation can be compared with an inflammatory event investigators decided to study inflammatory processes during ovarian hyperstimulation.71 They reported that the FF concentration of sRAGE is severalfold higher than serum and other biological fluids.71 The authors also suggested that a significant negative correlation of serum sRAGE with the yield of follicles and oocytes, together with the high follicular sRAGE levels, in women with a positive IVF outcome, could be explained by the essential outflow of sRAGE to the follicular compartment. Bonetti et al72 in a prospective cohort study measured the concentration of sRAGE in FF obtained from the leading ß 2016 The North American Menopause Society
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AGING OVARY AND AGES
follicle after ovarian stimulation of 54 women undergoing intracytoplasmic sperm injection. High intrafollicular sRAGE concentrations predicted poor-quality embryos (n ¼ 45, odds ratio ¼ 0.986; P ¼ 0.026), adjusted for participant age, body mass index, and oocyte quality, showing an inverse correlation between intrafolliculars RAGE concentrations and embryo development. Therefore, FF sRAGE concentration in healthy women may represent a marker of oocyte competence useful in the selection of oocytes to be fertilized to improve reproductive outcome.73 Also, a relevant study in a clinical setting reported that serum and FF concentrations of some AGEs, namely pentosidine, CML (Ne-carboxymethyllysine) correlated negatively and significantly with follicular growth, fertilization, and embryonic development.74 The authors indicated that lower concentrations of pentosidine in FF and glyceraldehyde-derived AGE in serum were the most significant novel predictors for achievement of ongoing pregnancy, acting independently of conventional determinants like age and day-3 follicle-stimulating hormone.74 This first direct clinical evidence based on human IVF/intra-cytoplasmic sperm injection (ICSI) therapy for an important role of AGE accumulation in ovarian dysfunction and diminished fertility is the strength of this study.74 Fuji and Nakayama75 in a clinical preliminary study examined AGEs, sRAGE, and vascular endothelial growth factor (VEGF) concentrations in plasma and FF from reproductive-age women. Plasma concentration of sRAGE was significantly higher in the group less than 35 years old; VEGF in FF was significantly higher in the group of more than 35 years old. The authors concluded that the results suggest a possibility that RAGE-VEGF regulation may be related to reproductive dysfunction in aging women. Indeed, VEGF signaling is deregulated in the follicular microenvironment of aged women and may account for alterations in follicular vasculature.76 Fuji and Nakayama’s study demonstrated for the first time that sRAGE and VEGF secretion in reproductive women have correlation with age, and sRAGE may relate to the condition of reproductive environment. To find out whether sRAGE or VEGF could work as markers of the follicular environment and egg quality, further studies are, however, needed. Becausre AGE and RAGE are expressed in granulosa and theca cells,76 as well as in luteinized cells derived from the ovary, Stensen et al6 looked how AGE and RAGE affect the cells of the human ovarian follicle. They demonstrated that AGE-modified proteins are present on the surface of freshly isolated human granulosa lutein cells and intrafollicular monocytes, suggesting that ovarian cells may be exposed to AGE-related damage in vivo. They also observed that granulosa cells and ovarian monocytes bind AGE-modified albumin in vitro and that specific RAGE receptors are present on the surface of these cells. These data imply that AGEs, which are involved in the structural and functional modification of cellular proteins, the formation of cross-links between molecules in the basement membrane and the ECM, and activation of the RAGE receptor that leads to
production of ROS,18 may also be involved in the decline of ovarian function. Stensen et al6 also noticed that with ligandinduced up-regulation, the expression of RAGE by granulosa lutein cells was increased in older women. Because in this prospective cohort study, human follicle fluid-derived cells were isolated from aspirates of ovarian follicles of women who underwent assisted reproduction treatment, the impact of AGE and RAGE in the ovary shown here in cells in culture remains to be further validated in clinical settings. Also, engagement of RAGE in intracellular signaling through binding with AGEs leads to induction of inflammatory reactions and could affect the aging process. On the contrary, inflammation itself may suppress ovarian function or indicate immune challenges that lead to ovarian suppression.77 In general, the sources of ovarian AGEs are currently unknown. They could result from a local ovarian production, but they could also be coming from an exogenous source. For example, Diamanti-Kandarakis et al78 demonstrated that in rats ingested AGEs led to increased serum AGE levels and higher expression of AGE and RAGE in the ovary. Also, tobacco smoking that increases in vivo concentrations of AGE21 may possibly increase AGE levels also in the ovary. Aging may result in the accumulation of reactive carbonyl compounds leading to AGE formation in organs including the ovary.63 In a very interesting, well-designed and very detailed study, using young and old mice, Tatone et al demonstrated that the sensitivity to carbonyl stress by MG seems to increase with maternal age.79 MG exposure induces DNA damage, meiotic delay, spindle aberrations, anaphase I lagging, and epimutation, hence aged oocytes are particularly at risk for such disturbances in the absence of efficient protection by cumulus. Furthermore, the authors also suggested that disturbances in mitochondrial distribution and redox regulation may be especially critical for fertilization and developmental competence of oocytes exposed to MG and carbonyl stress before or during maturation, for instance, in aged women, or in PCOS or diabetic patients. This is in line with suggestions of correlations between poor follicular and embryonic development, lower pregnancy rate, and the presence of toxic AGEs in serum, irrespective of age.74 All the above observations indicate that the accumulation of AGEs in aging ovary is a marked event that may account for compromised vascularization as well as activation of oxidative response through RAGE interaction.80,81 CONCLUSIONS Recently, the concept of carbonyl stress theory in ovarian aging gained a lot of attention from professionals in the field of female reproductive aging. In this review, we focused on the mechanisms underlying glycation damage in the ovary. AGEs contribute directly to protein damage, induce a chain of reactions of OS, and increase inflammatory reactions. Further investigation of the role for the AGE-RAGE system in the ovarian follicular environment is required, and human Menopause, Vol. 24, No. 3, 2017
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PERTYNSKA-MARCZEWSKA AND DIAMANTI-KANDARAKIS
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