During the follicular phase of the menstrual cycle, a number of primordial follicles undergo development and maturation, and this process often results in one or more dominant mature follicles. These dominant follicles are the only ones destined for ovulation; other follicles that start to develop during the follicular phase will eventually undergo follicular atresia. Follicular atresia is influenced by three factors: loss of sensitivity to gonadotropic hormones (mainly FSH), loss of steroidogenic function and lastly mediation of ROS [2, 62].

Follicular angiogenesis is induced by hypoxia of the granulosa cells; a vital process for follicular growth and development [63]. ROS act as signal transducers or intracellular messengers of this angiogenic response [64]. The source of ROS in the follicular fluid is currently unknown, but it has been speculated that ROS might be generated by the oocyte itself, granulosa cells as well as endothelial and thecal cells. The theca interna is richly vascularized, thus providing a gateway for the passage of factors from the circulation into the follicular fluid [65]. Furthermore, follicular fluid is known to contain cytokines, neutrophils and macrophages, all prominent ROS sources [66]. The ovary initiates defensive mechanisms for detoxification and protection against ROS. These include enzymes such as catalase and superoxide dismutase, antioxidants such as vitamins C and E [67], carotenoid lutein [68] and the peroxidase cofactor reduced glutathione [69]. It has been suggested that a correlation between poor oocyte quality and abnormally low amounts of ROS in follicular fluid exists [66]. The free oxygen radical and related metabolites play essential roles in the cellular metabolism, prompting the breakdown of follicular walls for ovulation to occur [66].

Steroid hormones greatly influence the production of ROS in the uterus [70]. In the presence of estradiol, uterine weight increases along with a 200-fold increase in peroxidase activity [71]. This increase is largely due eosinophils present in the leukocyte infiltrate, which provide a substantial amount of peroxidase [2]. The function of peroxidase is to ensure to the uterus an antibacterial environment [72]. Peroxidase also regulates the levels of estrogen through a negative feedback mechanism [73].

The apical plasma membrane of the endometrial epithelium hosts NADPH oxidase, which is responsible for dismutation of superoxide anion. This, in turn, results in the production of hydrogen peroxide which is the major source of peroxidases [74]. Hydrogen peroxide plays a role in generating prostaglandins through enzymatic mechanisms, catalyzed by cyclooxygenase [75], as well as non-enzymatic pathways [76].

Arachidonic acid is an unsaturated fatty acid that serves as the main precursor of a family of lipid compounds called eicosanoids. Eicosanoids possess hormone-like properties and provide a very wide range of other compounds, such as prostaglandins. Once oxygen is added to arachidonic acid, cyclooxygenases produce different prostaglandins, including PGF_2α, which play essential roles in chemotaxis, implantation as well as degradation of the corpus luteum [2]. Phospholipase A2 is a calcium-dependent enzyme, which acts on the phospholipids in the membrane to produce arachidonic acid. Phospholipase A2 activity can be enhanced by lipid peroxidation and inhibited by antioxidants [77, 78].

Ovulation is frequently compared to an acute inflammation given it includes vascular swelling, a buildup of immune cells and the immediate production of prostaglandins [2]. Superoxide levels increase when ovulation takes place. Conversely, LH causes a temporary increase in SOD activity during ovulation [67]. Leukocytes located around pre-ovulatory follicles are a potential source of ROS during ovulation [79]. Interestingly, ovulation is significantly impaired in the presence of SOD [80]. It has been hypothesized that free radicals cause membrane damage which initiate the production of prostaglandins through the cyclooxygenase system by activation of phospholipases. These prostaglandins are essential for ovulation to occur.

Oxygen free radicals induce OS in the ovarian follicles, which elicit apoptosis of granulosa cells and instigates ovulation, whereas ROS scavengers have an inhibitory effect [81, 82]. Indomethacin inhibits cyclooxygenase activity, thus also inhibiting ovulation [2]. A rise in LH levels activates polymorphonuclear (PMN) cells, which leads to an increase in ROS production in the ovary. PMN cells exhibit LH receptors; these can facilitate oxygen production as soon as they are activated [83]. Oxygen plays various physiologic roles during ovulation.

Despite the fact that ROS are considered waste products of metabolic oxidations, small concentrations might in fact participate in physiological signaling pathways in the embryo [100]. ROS play a role in signal transduction and have the ability to exert vasoactive effects on the placenta [101]. Decidual macrophages are involved in the regulation of apoptosis during the process of implantation. This is necessary for invasion of the developing embryo during pregnancy [102]. When exposed to bacterial lipopolysaccharides, decidual macrophages produce superoxide anion and TNF-α -an inflammatory cytokine- and these actions are thought to play a role in protecting the fetus against intrauterine infections [103]. Recent studies have shown that oxidative stress and hypoxia trigger normal placental apoptosis of the trophoblast. These conditions are vital for growth and development of the embryo and placenta [5]. Conversely, a high level of oxidative stress has disastrous effects on pregnancy. During the early stages of placental development, a high level of oxidative stress has been linked to miscarriage, intrauterine growth restriction, pre-eclampsia and embryo resorption [101]. Early human pregnancy failure has been associated with defective placental antioxidant systems [104].

In conditions of high metabolic demand, ROS levels are known to increase remarkably in humans [1]. During parturition, neutrophils and monocytes invade uterine tissues as part of an inflammatory event which takes place in humans and animals [105]. When an increased expression of cytokines in the myometrium and cervix develops during labor, migration of leukocytes to the site of inflammation is actively enhanced [106]. These leukocytes are responsible for producing superoxide anion by combining hypoxanthine with xanthine oxidase, which triggers a rise in intracellular calcium thus leading to myometrial contraction [107]. H₂O₂ acts as a contractile agent on smooth muscles, participating in a number of mechanisms including the opening of Ca²⁺ release channels as well as the reuptake of Ca²⁺ in the sarcoplasmic reticulum, and modulating myofibrilar Ca²⁺ sensitivity [108]. Therefore, the process of labor can be thought of as a positive feedback system involving ROS and mediators of inflammation (prostaglandins and cytokines) [109, 110].

Before parturition can take place, serum concentrations of progesterone are reduced and levels of estrogen are elevated. Estrogen boosts ROS generation through pro-inflammatory actions, bringing about metabolic and enzymatic changes. Together, ROS and estrogen enhance myometrial contractions and uterine involution, which is essentially the shrinkage of the uterus after childbirth [110]. During the last phase of gestation, a tremendous increase in the enzymatic antioxidant reserve takes place in order to prepare for life in an oxygen-rich environment [111].