Advanced glycation end products and their relevance in female reproduction

Human Reproduction, Vol.29, No.1 pp. 135– 145, 2014 Advanced Access publication on October 30, 2013 doi:10.1093/humrep/det383 REVIEW ARTICLE Reproductive biology Advanced glycation end products and their relevance in female reproduction Z. Merhi* Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Endocrinology and Infertility, University of Vermont College of Medicine, 111 Colchester Avenue, Burlington VT 05401, USA *Correspondence address. Tel: +1-802-847-3450; Fax: +1-802-847-9243; E-mail: Submitted on July 10, 2013; resubmitted on September 18, 2013; accepted on September 23, 2013 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. Key words: advanced glycation end products / polycystic ovary syndrome / infertility / obesity / insulin resistance Introduction Advanced glycation end products (AGEs) are the end products of a chemical procedure called the Maillard reaction in which the carbonyl group of carbohydrates reacts non-enzymatically with primary amino groups of proteins (Brownlee et al., 1988; Unoki and Yamagishi, 2008). This glycation reaction involves the formation of chemically reversible early glycosylation products with proteins, so-called Schiff bases and Amadori adducts, for example HbA1C (Brownlee, 1991). It was not until around 1980 that researchers began recognizing the significance of the complex, late-stage Maillard processes as mediators of the complications of diabetes and aging (Monnier et al., 1981). Subsequently, proteins bearing Amadori product have come to be referred to as glycated proteins (distinguishing them from enzymatically glycosylated proteins), & The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 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 136 and used as markers of AGE accumulation in various tissues (DiamantiKandarakis et al., 2007c). AGEs are usually formed slowly under physiological conditions. Hyperglycemia, insulin resistance, obesity, aging, oxidative stress and hypoxia accelerate the generation of AGE precursors (Yamagishi et al., 2005). The accumulation of AGEs is associated with variable pathologies such as T2DM, MetS, CVD, aging (including ovarian aging), inflammation, neurodegenerative disorders, obesity and even PCOS (Yamagishi et al., 2005; Diamanti-Kandarakis et al., 2007d; Tatone and Amicarelli, 2013). The action of AGEs is classified as receptor independent (such as cross links with ECM) or receptor dependent (Piperi et al., 2012). AGEs circulate and act on cell surface receptors, such as the receptor for AGE (RAGE) which is a member of the immunoglobulin superfamily of receptors (Kalea et al., 2009). The AGE-RAGE interaction leads to activation of secondary messenger activating nuclear factor-kappa B leading to the development of a proinflammatory state, cellular toxicity and damage (Fig. 2) (Kalea et al., 2009). RAGE Methods Search strategy and data extraction A systematic review was performed for all available basic science (in vitro and in vivo) and clinical peer-reviewed articles (prospective, retrospective and review articles) published in English from 1987 to date in PubMed. Additionally, references from all relevant articles were checked and hand searches of the abstracts of annual meetings of the Endocrine Society and American Society for Reproductive Medicine were performed. In addition to using ‘advanced glycation end-products’ as a keyword search in PubMed, the following keywords were used: ‘receptor’, ‘inhibitor’, ‘obesity’, ‘insulin resistance, ‘hyperandrogenism’, ‘PCOS’, ‘granulosa cell’, ‘infertility’, ‘assisted reproductive technology’, ‘in vitro fertilization’, ‘ovarian reserve’, and ‘antiMullerian hormone’. Data were extracted from the text, tables and graphs in the manuscripts. RAGE has transmembrane, cytosolic and extracellular domains (Basta, 2008). RAGE is expressed in many tissues including ovaries and is most abundant in the heart, lung, skeletal muscle, vessel wall and ovaries (Basta, 2008). It is also present in monocytes, macrophages and lymphocytes (Basta, 2008). RAGE is down-regulated in most organs during normal life. With aging, RAGE expression increases again, possibly due to the accumulation of RAGE ligands, which in turn up-regulate receptor expression (Yan et al. (...truncated)