Review 10.1586/17474108.3.4.539 © 2008 Expert Reviews Ltd ISSN 1747-4108 539 www.expert-reviews.com Impact of oxidative stress on IVF Expert Rev. Obstet. Gynecol. 3(4), 539–554 (2008) Stefan S du Plessis, Kartikeya Makker, Nisarg R Desai and Ashok Agarwal † † Author for correspondence Center for Reproductive Medicine, Glickman Urological and Kidney Institute and Ob–Gyn and Women’s Health Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk A19.1, Cleveland, OH 44195, USA Tel.: +1 216 444 9485 Fax: +1 216 445 6049 agarwaa@ccf.org Gametes and embryos are natural sources of free radicals. When manipulated in vitro during assisted reproductive techniques, these cells run the risk of generating and being exposed to supraphysiological levels of reactive oxygen species. It is therefore clear that free radicals and oxidative stress can have a significant impact on IVF outcome. This review summarizes the role of oxidative stress in the etiology and pathophysiology of human IVF, as well as considering different strategies and approaches to be followed to prevent the harmful effects of oxidative stress on IVF. KEYWORDS: antioxidant • assisted reproductive technology • embryo • free radical • IVF • oocyte • oxidative stress • reactive oxygen species • spermatozoa The term oxidative stress (OS) is generally applied when oxidants outnumber anti- oxidants [1], when peroxidation products develop [2] and when these phenomena cause pathological effects [3,4]. The imbalance between the production of reactive oxygen species (ROS) and a biological system’s ability to readily detoxify the reactive intermediates or easily repair the resulting damage is known as OS [5]. All forms of life maintain a reducing environment within their cells. This reducing environment is preserved by enzymes that maintain the reduced state through a constant input of metabolic energy. Disturbances in this normal redox state can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids and DNA [6]. The effects of OS depend upon the size of these changes, with a cell being able to over- come small perturbations and regain its origi- nal state. However, more severe OS can cause cell death, and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis [7]. A particularly destruc- tive aspect of OS is the production of ROS, which include free radicals and peroxides [8]. Various ROS play an important role in many physiologic functions, such as phago- cytosis. Free radicals are also known as a nec- essary evil for intracellular signaling involved in the normal processes of cell proliferation, differentiation and migration [9–11]. In the reproductive tract, free radicals also play a dual role and can modulate various reproductive functions. Physiological levels of ROS influence and mediate the gametes [12–14] and crucial reproductive processes, such as sperm–oocyte interaction [15], implantation and early embryo development [16]. An imbalance in the redox state can thus cause OS to develop, ultimately affecting successful pregnancy outcome [17–19]. Since the birth of the first IVF baby [20], assisted reproductive techniques (ART) have become the treatment of choice in many cases of male and female infertility [17]. These methods inevitably require manipulation of gametes and embryos in vitro, exposing these cells to additional OS [21]. Various factors, for example, the absence of cytokines/growth fac- tors, pH shock, osmotic shock, temperature fluctuations, UV light damage and nutrient imbalance can influence the outcome of ART; however, OS has recently emerged as one of the most important factors negatively affect- ing ART outcome [5,22–24]. It has been hypoth- esized that this is predominantly due to a lack of in vitro gamete and embryo protection by oxygen radical scavengers [21,23,25]. The goal of this review is to discuss the pos- sible sources of ROS that can lead to OS dur- ing ART, as well as the effects of OS on IVF outcome. Suggestions and possible solutions to curtail this necessary ROS evil to prevent OS in the IVF setting will also be presented.