Female Infertility and Assisted Reproduction: Impact of Oxidative Stress-- an Update

Send Orders of Reprints at [email protected] Current Women’s Health Reviews, 2012, 8, 183-207 183 Female Infertility and Assisted Reproduction: Impact of Oxidative Stress-- An Update Beena J. Premkumar and Ashok Agarwal* Center for Reproductive Medicine, Cleveland Clinic, Cleveland, USA Abstract: Augmented levels of reactive oxygen species (ROS) that overpower the body’s antioxidant defenses result in oxidative stress (OS). Physiologically balanced levels of ROS and antioxidants maintain homeostasis in the body and allow for normal physiological processes to proceed. Physiological processes that involve oxygen consumption inevitably produce ROS. However, an overabundance of ROS leads to widespread injury to cells, and can damage DNA, lipid membranes, and proteins. An unfavorable reproductive environment hinders normal physiology secondary to this disruption of homeostasis. Infertility may be attributed to reproductive pathologies, leading to OS. Infertile couples often turn to assisted reproductive techniques (ART) to improve their chances for a successful pregnancy. In vitro techniques create an unfavorable environment for gametes and embryos by exposing them to a surplus of ROS in the absence of enzymatic antioxidant protection that normally exists in vivo. This article will review the currently available literature on the effects of ROS and OS on ART outcomes. The role of antioxidant supplementation of ART culture media continues to be a subject of interest to increase the likelihood for ART success. Keywords: Antioxidants, assisted reproduction, female infertility, oxidative stress. BACKGROUND INFORMATION the role of OS in female infertility and its impact on gametes and embryos in the ART setting. Close to 10% of reproductive aged couples fail to conceive through natural means. Associated pathologies and Reactive Oxygen Species and Oxidative Stress causative factors of infertility may be identified in either partner, however, the cause of subfertility remains unknown Oxidative stress occurs in the midst of an unbalanced in about 30% of these cases [1]. Female factors include ratio of pro-oxidants to antioxidants in favor of the former endometriosis, polycystic ovary syndrome (PCOS) [2], tubal [10]. This ratio can be disrupted by an abundance of reactive factors, premature ovarian failure, oocyte aging, and oxygen species (ROS) and/or by weakened antioxidant unexplained infertility (Fig. 1). In males, conditions affecting defenses [11, 12]. Normal physiological functions including the sperm, including azoospermia, asthenospermia, damaged processes of cell signaling, proliferation, and differentiation, sperm DNA, and varicocele, may contribute to infertility, as depend on the presence of a certain amount of ROS well as unexplained and idiopathic causes [3]. Women with [13, 14]. In the reproductive environment, physiological high body mass index (BMI) [4] and those who smoke levels of ROS are necessary not only for ovulation [15, 16], cigarettes [5] have been documented to be at an increased but also for sperm-oocyte interactions, fertilization [17], risk for infertility. Irrespective of the etiology of infertility, implantation, and early embryo development. However, the infertile couples often turn to assisted reproductive overproduction of ROS can overwhelm the body’s natural techniques (ART) to improve their chances of conception. antioxidant defenses, disturbing the female reproductive However, even those who seek the help of ART to conceive environment and disrupting normal female physiological have still been shown to have lower pregnancy success [6-8] reactions [10]. Growing literature suggests that OS may rates than normal weight and non-smoking women. be paramount to determining successful outcomes with Over the years, oxidative stress (OS) has been ART. The methods used in ART are known to over-expose increasingly thought to exert adverse effects on the sperm, oocytes, and embryos to unnecessary levels of ROS, reproductive abilities of both men and women [3]. The which likely contributes to the reportedly low fertility contributions of OS to the pathogenesis of infertility have outcomes. been more extensively studied in the realm of male infertility Reactive oxygen species have been implicated as an [9], specifically in terms of its ability to affect various important contributor to embryonic arrest and apoptosis in in aspects of sperm quality. This review however, will focus on vitro culture, as they can inflict serious damage to proteins, lipids, DNA, enzyme functions, and mitochondria [9]. Both radical and non-radical derivatives of O2 are known as *Address correspondence to this author at the Center for Reproductive Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk A19.1, Cleveland, ROS. Unpaired electron(s) in the atom’s outer shell account Ohio 44195, USA; Tel: (216) 444-9485; Fax: (216) 445-6049; for the high reactivity of free radicals [18]. During oxidative E-mail: [email protected] phosphorylation and ATP production, electron leakage from 1875-6581/12 $58.00+.00 © 2012 Bentham Science Publishers 184 Current Women’s Health Reviews, 2012, Vol. 8, No. 3 Premkumar and Agarwal Hydrosalpinx Endometriosis Polycystic Ovary Syndrome Oxidative Stress Ovarian aging High BMI Cigarette smoking Cell Membrane Fig. (1). Factors influencing OS in female infertility. the mitochondrial electron transport chain (ETC) forms the associated with the production of superoxide from NADPH majority of ROS [19, 20]. Redox reactions occurring in [27], which likely leads to the induction of LH. In addition biological systems mainly involve the superoxide anion, to regulating steroid production within cells, ROS may also hydrogen peroxide (H2O2), and nitric oxide (NO) [21]. aid in stimulating corpus luteum release of progesterone. Reactions involving oxygenase and electron transfers use O2 Controlled amounts of oxidation are also important for the as a substrate to produce ROS, of which the superoxide formation of disulfide bonds during ovulation in females and anion is the most common [22]. In the ovary and other in sperm nuclei in males. Carbonyl production is stimulated steroidogenic tissues, ROS are also generated by cytochrome by ROS; levels of carbonyl compounds increase during cell P450 enzymes [23]. proliferation, steroid hormone generation, and ovulation [20]. Thus, the utilization of ROS by the reproductive system The Haber-Weiss reaction, catalyzed by transition is essential for certain vital reproductive processes. metals, produces the hydroxyl radical, which is considered the most toxic inflictor of oxidative damage due to its ability Throughout various developmental stages, oocytes and to modify purines and pyrimidines, thereby causing DNA embryos are exposed to fluctuating levels of the superoxide damage [24]. The highly reactive hydroxyl radical and the anion and H2O2; however, in high amounts, these ROS can reactive nitrogen species (RNS), peroxynitrite, are formed cause apoptosis of oocytes and embryos by damaging from exogenous non-detoxified H2O2 [25]. Technically, mitochondria [28], DNA, lipids, and proteins [29, 30]. The H2O2 is not a free radical, but is often considered in the process of ovulation is stimulated by NO, an RNS produced same category because of its involvement in free radical from nitric oxide synthase (NOS) III. Similarly, in vitro production and breakdown [24]. In the presence of metal embryo development heavily relies on a critical concentration ions such as iron, accumulated H2O2 stimulates the production of NO, in the culture medium. When NO is present in of H2O and O2 through the Fenton and Haber-Weiss reactions excess, however, embryos have been shown to exhibit [26]. developmental arrest as well as apoptosis [31]. Reactions between ROS or RNS with lipids, proteins, and nucleic acids A conservative elevation of ROS can stimulate the can damage cells [29, 30]. Intracellular lipid peroxidation growth and proliferation of cells. In fact, a baseline level of secondary to ROS results from increased production of fatty ROS is necessary for cell signaling processes. In endocrine acid peroxides [32], and weakens cell membranes [33]. organs including the ovary and testes, ROS produced by the When levels of ROS are high enough to disturb processes P450-mediated monooxygenase reaction plays an important mediated by cellular redox status, shifting of the oxidant/ role in the synthesis of steroid hormones from cholesterol. antioxidant balance occurs, and OS results [34, 35]. Fig. (2) During regression of the corpus luteum, levels of ROS summarizes ROS/RNS and the main antioxidants and increase. In murine ovaries, the pre-ovulatory phase in antioxidant enzymes. cycling females and the luteal phase in pregnant mice are Effects of Oxidative Stress in Female Infertility and Artificial Reproduction Current Women’s Health Reviews, 2012, Vol. 8, No. 3 185 2 H2O 2 H20 + O2 Xanthine oxidase Catalase NADPH oxidase Fe2+ Fe3+ Mitochondria Superoxide dismutase O2 O2∙ˉ H2O2 ∙OH R‐SH Myeloperoxidase RNOS Clˉ ∙NO GPx ONOOˉ Nitric oxide synthase HOCl Tyrosine Nitrotyrosine 2 GSH GSSG L‐arginine Peroxiredoxin GR 2 Trx‐SH Thioredoxin disulfide Thioredoxin reductase Fig. (2). ROS/RNS and the major antioxidant enzymes and antioxidants. Inflammation Antioxidants Inflammatory processes have generally been associated A delicate balance between levels of ROS and with increased generation of ROS. However, recently, some antioxidant defenses exists to regulate physiological research groups have proposed a protective

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