Reactive oxygen species in ovarian physiology

NORIHIRO SUGINO

doi:10.1111/j.1447-0578.2005.00086.x

. 2005 Mar 7;4(1):31–44. doi: 10.1111/j.1447-0578.2005.00086.x

Reactive oxygen species in ovarian physiology

NORIHIRO SUGINO ^1,^✉

PMCID: PMC5904601 PMID: 29699208

Abstract

Cells living under aerobic conditions always face oxygen paradox. Oxygen is necessary for cells to maintain their lives. However, reactive oxygen species such as superoxide radical ( Inline graphic ), hydroxyl radical (OH⁻) and hydrogen peroxide (H₂O₂) are generated from oxygen and damage cells. Oxidative stress occurs as a consequence of excessive production of reactive oxygen species and impaired antioxidant defense systems. Antioxidant enzymes include: superoxide dismutase (SOD), which is a specific enzyme to scavenge superoxide radicals; copper‐zinc SOD, located in the cytosol; and manganese SOD, located in the mitochondria. Both types of SOD belong to the first enzymatic step to scavenge superoxide radicals.

It has been reported that a number of local factors such as cytokines, growth factors and eicosanoids are involved in the regulation of ovarian function, in addition to gonadotropins and ovarian steroid hormones. Since reactive oxygen species are generated and SOD is expressed in the ovary, there is a possibility that reactive oxygen species and SOD work as local regulators of ovarian function. The present review reports that reactive oxygen species and their scavenging systems play important roles in several processes of reproductive physiology, including follicular development, oocyte maturation, ovulation, corpus luteum function and follicular atresia. (Reprod Med Biol 2005; 4: 31– 45)

Keywords: corpus luteum, follicle, luteolysis, reactive oxygen species, SOD

INTRODUCTION

CELLS LIVING UNDER aerobic conditions always face oxygen paradox. Oxygen is necessary for cells to maintain their lives. However, reactive oxygen species such as superoxide radical ( Inline graphic ), hydroxyl radical (OH⁻) and hydrogen peroxide (H₂O₂) are generated from oxygen. Oxidative stress occurs as a consequence of excessive production of reactive oxygen species and impaired antioxidant defense systems. Reactive oxygen species have been reported to cause DNA damage, lipid peroxidation, which principally affects membrane structure and function, and protein damage. Furthermore, accumulating data have recently shown that reactive oxygen species can regulate cell function by controlling production or activation of substances that have biological activities.

However, cells under aerobic conditions have the defense system against reactive oxygen species. There are specific metallo‐enzymes to scavenge superoxide radicals: copper‐zinc superoxide dismutase (Cu,Zn‐SOD), located in the cytosol; and manganese SOD (Mn‐SOD), located in the mitochondria. Both SOD metabolize superoxide radicals to hydrogen peroxide, which is further detoxified to water and oxygen by catalase or glutathione peroxidase. Catalase is found primarily within peroxisomes of most cells; this iron metallo‐enzyme catalyzes the conversion of hydrogen peroxide into water and oxygen. Glutathione peroxidase is a selenium‐containing enzyme and catalyzes the degradation of lipid peroxides as well as hydrogen peroxide. In the defense system against reactive oxygen species, SOD is a first enzymatic step not only that protects cells from toxic reactive oxygen species, but also that regulates cell function by controlling the amount of superoxide radicals.

Reactive oxygen species are produced in the ovary. There are several potential sources of reactive oxygen species in the ovary. Macrophages and neutrophils, evident sources of reactive oxygen species, are well documented to reside in both follicles and corpora lutea. ¹ , ² , ³ , ⁴ , ⁵ Steroidogenic cells are also potential sources of reactive oxygen species because reactive oxygen species are generated as byproducts of normal metabolism. ⁶ Intracellular sources of reactive oxygen species include: mitochondrial electron transport, endoplasmic reticulum, nuclear membrane electron transport systems and plasma membranes. ⁶ This report reviews the physiological roles of reactive oxygen species and SOD in the ovary.

REACTIVE OXYGEN SPECIES AND FOLLICULAR DEVELOPMENT

BY IMMUNOHISTOCHEMICAL STUDY, Shiotani et al. showed in human follicles that Cu,Zn‐SOD did not express in preantral follicles, but began to express in theca interna cells in antral follicles, and there was no immunostaining in granulosa cells in any stages. ⁷ Ishikawa et al. also reported that Cu,Zn‐SOD expressed in theca interna cells, but not in granulosa cells in mature human follicle. ⁸ Furthermore, Suzuki et al. reported that Cu,Zn‐SOD was detected in theca interna cells of preantral, non‐dominant and dominant follicles, and in granulosa cells in only dominant follicles in human. ⁹ Interestingly, the expression pattern of Cu,Zn‐SOD seems identical to that of 3β‐hydroxysteroid dehydrogenase (3β‐HSD), which is an enzyme that converts pregnenolone to progesterone. Progesterone is formed by dehydrogenation of pregnenolone by 3β‐HSD, which requires oxidized nicotinamide adenine dinucleotide (NAD⁺) as the hydrogen acceptor. NAD⁺ is thought to be supplied by the oxidation of NADH by ascorbic radicals through a free radical mechanism. ¹⁰ SOD may be involved in this dehydrogenation process because SOD is one of the enzymes which generate hydrogen peroxide. The hydrogen peroxide generated by SOD may thus oxidize ascorbic acid into ascorbic acid radicals through the action of peroxidase. Therefore, Agrawal and Laloraya raised a hypothesis that Cu,Zn‐SOD plays a role in the synthesis of progesterone via reactive oxygen species. ¹⁰ It is of interest to note that Cu,Zn‐SOD strongly expresses in the corpus luteum formed after ovulation, ⁷ , ⁹ and the change in Cu,Zn‐SOD activities in the corpus luteum is similar to that in serum progesterone concentrations during the menstrual cycle in humans, and during pregnancy and pseudopregnancy in rats ¹¹ , ¹² , ¹³ as described later.

There is an alternative possibility that Cu,Zn‐SOD protects 3β‐HSD by scavenging toxic superoxide radicals in endoplasmic reticulum in the cytosol, because suppression of Cu,Zn‐SOD activity causes inhibition of progesterone production via increased superoxide radicals in rat luteal cells. ¹⁴ In addition, it has been reported that reactive oxygen species inhibit follicle‐stimulating hormone (FSH)‐sensitive cyclic adenosine monophosphate (cAMP) accumulation and progesterone production by rat granulosa cells ¹⁵ and 3β‐HSD in human granulosa cells. ¹⁶

However, Mn‐SOD expression is detected in both granulosa cells and theca interna cells in human follicles, ⁸ , ⁹ and strongly associated with the expression of Ad4‐binding protein (Ad4 bp) that has the potential to control the expression of steroidogenic enzymes in the human ovary. ¹⁷ It has been reported that superoxide radicals, generated in the mitochondria, inhibit cytochrome P450 side‐chain cleavage, which is an enzyme converting cholesterol to pregnenolone, and transport of cholesterol into mitochondria ¹⁶ , ¹⁸ , ¹⁹ and also can cause cell death if the amount of superoxide radicals is too much. Therefore, Mn‐SOD plays an important role in the protection of granulosa cells or theca interna cells from superoxide radicals generated in the mitochondria by the enhanced steroidogenesis during follicular development, because superoxide radicals are generated in the mitochondrial electron transport system as a consequence of normal metabolism and steroidogenesis.

In conclusion, superoxide radicals are generated in the cytosol and mitochondria by normal metabolism and steroidogenesis during follicular development. Reactive oxygen species, including superoxide radicals, have an inhibitory effect on steroidogenesis. Cu,Zn‐SOD and Mn‐SOD protect granulosa cells and theca interna cells by scavenging superoxide radicals for normal steroidogenesis and follicular development. However, there is a unique hypothesis that Cu,Zn‐SOD may play a role in progesterone production by theca interna cells via the synthesis of hydrogen peroxide.

REACTIVE OXYGEN SPECIES AND FOLLICULAR ATRESIA

MORE THAN 99% of ovarian follicles undergo a degenerative process called atresia during reproductive life. Several mechanisms involved in follicular atresia have been reported so far (reviewed in Hsueh et al. ²⁰ ). Recent studies have demonstrated that follicular atresia is caused by apoptosis of granulosa cells. ²⁰ There is a possibility that reactive oxygen species serve as a trigger for the initiation of atresia by causing granulosa cell death. ²¹ Reactive oxygen species are byproducts generated in cells through normal metabolic activity including steroidogenesis. If the level of SOD is not enough to scavenge the superoxide radical, the increased superoxide radical may cause a cell death.

Tilly and Tilly reported that granulosa cells within follicles incubated with medium alone, without survival factors such as FSH, exhibited extensive apoptosis, and this onset of apoptosis was blocked by treatment with SOD as well as FSH inhibited apoptosis. ²² In addition, in vivo priming of eCG, which prompts antral follicular growth and survival, caused a remarkable reduction in the number of apoptotic granulosa cells and atretic follicles, and this effect was associated with the increased Mn‐SOD expression, but not with Cu,Zn‐SOD. ²² Therefore, FSH‐mediated inhibition of follicular atresia involves enhanced expression of Mn‐SOD that functions to protect granulosa cells from the toxic effects of reactive oxygen species. Alternatively, inadequate response of the Mn‐SOD gene to FSH may cause follicular atresia through apoptosis of granulosa cells.

Estradiol is well known to serve as a survival factor against follicular atresia. ²⁰ It has also been reported that estradiol can serve as an antioxidant. ²³ Murdoch reported that estradiol inhibited oxidative stress‐induced apoptosis in pig follicles. ²⁴ It is also suggested that estradiol produced by granulosa cells contributes to inhibition of follicular atresia by preventing oxidative stress in ovine follicles. ²⁵ In other words, oxidative cellular damage due to inadequate estradiol production may be a putative cause of follicular apoptosis and atresia. In fact, lower estradiol levels in follicular fluids and higher percentages of apoptotic granulosa cells are observed in atretic follicles compared with those in mature follicles in humans. ²⁶

Ascorbic acid has long been associated with fertility. ²⁷ Among the more relevant biological actions of ascorbic acid is its essential role in the biosynthesis of collagen and other components of the extracellular matrix and its well known antioxidant properties. In fact, granulosa cells incubated with medium alone exhibited extensive apoptosis, and this induction of apoptosis was blocked by treatment with ascorbic acid, showing that one important antioxidant activity of ascorbic acid is the prevention of apoptosis. ²² Furthermore, culture of granulosa cells with FSH increases ascorbic acid uptake, suggesting that ascorbic acid accumulation in granulosa cells may be another essential process for prevention of follicular atresia and follicular development. ²⁸

REACTIVE OXYGEN SPECIES AND OVULATION

THE MECHANISM OF ovulation has been compared to an inflammatory reaction. ²⁹ Components of inflammation that are found in the process of ovulation include the increases in prostaglandin synthesis and cytokine production, the action of proteolytic enzyme, and increased vascular permeability. ³⁰ Reactive oxygen species could be important mediators of those inflammatory reactions and have therefore been reported to be involved in ovulation.

Sato et al. clearly showed in vivo that intravenous injection of SOD inhibited ovulation in pregnant mare serum gonadotropin–human chorionic gonadotropin (PMSG–HCG) rats. ³¹ Miyazaki et al. also reported, using an in vitro perfused ovary model, that SOD administration inhibited ovulation stimulated by HCG in rabbits. ³² In fact, the level of lipid peroxide, products of reactive oxygen species, increased in the ovary after HCG injection and reached the peak at 9 h after HCG injection in PMSG–HCG rats. ³³ Therefore, these findings strongly suggest that reactive oxygen species play an important role in the process of follicle rupture. Interestingly, the fact that SOD inhibited ovulation even in the in vitro perfused ovary ³² suggests that sources of reactive oxygen species are localized in the ovary. Possible sources of reactive oxygen species during the ovulatory process could be local leukocytes or endothelial cells. Leukocytes accumulate around preovulatory follicles and even infiltrate into the granulosa cell layer. ¹ , ² , ³⁴ Shirai et al. reported that peripheral blood polymorphonuclear leukocytes have luteinizing hormone (LH) receptors, and LH stimulates superoxide radical production by them. ³⁵ Furthermore, administration of a neutrophil‐depleting monoclonal antibody reduced the ovulation rate in the rat. ³⁶ Kodaman and Behrman also reported that reactive oxygen species generated from isolated follicles are originated in leukocytes. ³⁷

Regarding the species of reactive oxygen species involving in ovulation, simultaneous administration of catalase, catalyzing hydrogen peroxide, with SOD had no additive effect on the ovulation rate compared with SOD alone. ³² In addition, reactive oxygen species generation by follicular cells was completely suppressed by SOD, but not by catalase. ³⁷ These findings suggest that radical species involved in ovulation could be the superoxide radical.

However, newly formed blood vessels also infiltrate to the granulosa cell layer from the theca cell layer after HCG injection. Superoxide radicals can be generated in vascular endothelial cells via xanthine oxidase, which is an enzyme that produces superoxide radicals in the presence of hypoxanthine (xanthine) and oxygen. The potential role of endothelial cells, as a source of superoxide radicals involved in ovulation, may be supported by a previous report showing that administration of a xanthine oxidase inhibitor, allopurinol, inhibited ovulation in rabbits. ³⁸ In contrast, Margolin and Behrman reported, in rats, that the level of xanthine oxidase was unchanged in preovulatory follicles after ovulation induction by HCG and in follicles incubated with HCG, and that allopurinol did not inhibit ovulation. ³⁹ It seems controversial whether xanthine oxidase of vascular endothelial cells can be a source of superoxide radicals that are involved in ovulation.

Mechanisms by which superoxide radicals cause follicle rupture are not fully clarified yet. Superoxide radicals induce prostaglandins production, ⁴⁰ , ⁴¹ , ⁴² , ⁴³ activation of proteolytic enzymes such as matrix metalloproteinase, ⁴⁴ , ⁴⁵ and enhancement of vascular permeability. It is likely that superoxide radicals serve as mediators of those inflammatory reactions involved in follicle rupture.

Regarding the change and role of SOD in preovulatory follicles during the ovulatory process, Sato et al. and Sasaki et al. reported dynamic aspects of Mn‐SOD in follicles during the ovulatory process in PMSG‐HCG rats. ³¹ , ⁴⁶ Messenger ribonucleic acid (mRNA) levels of ovarian Mn‐SOD markedly increased and reached the peak 6 h after HCG injection, but its activities gradually decreased after HCG injection, whereas mRNA and activity levels of Cu,Zn‐SOD remained unchanged. The increase in Mn‐SOD mRNA levels was localized in theca interna cells by in situ hybridization. ⁴⁶ Sasaki et al. concluded that the high Mn‐SOD mRNA level and low Mn‐SOD activity level means rapid turnover of Mn‐SOD (increased rates of synthesis and consumption of Mn‐SOD), which indicates high levels of superoxide radical generation due to activated progesterone production and metabolism in theca interna cells during the ovulatory process. However, it is of special interest to note that such a pattern as increased Mn‐SOD expression without significant changes in Cu,Zn‐SOD expression is often seen in the inflammatory reaction or in the response to cytokines in a variety of cells. ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² In fact, Sugino et al. reported that lipopolysaccharide and several cytokines, interleikin‐1, interleukin‐6, and tumor necrosis factor‐α (TNFα) induced Mn‐SOD expression but not Cu,Zn‐SOD in rat luteal cells. ⁵¹ Cytokines have been reported to play important roles in ovulation. For example, interleukin‐1β enhances ovulation in the in vitro perfused ovary in rats, ⁵³ which is mediated by the increases in prostaglandin synthesis, proteolytic enzymes such as matrix metalloproteinase and plasminogen activating system, and vascular permeability in the preovulatory follicles. ³⁰ , ⁵⁴ Interestingly, interleukin‐1β mRNA expression is mainly detected in the theca cell layer, but not in the granulosa cell layer, and increases after HCG injection and reaches the peak at 6 h in PMSG–HCG rats. ⁵⁵ There seems to be strong relationship between Mn‐SOD mRNA expression and interleukin‐1β mRNA expression in theca interna cells. Therefore, it is likely that the increased Mn‐SOD expression in theca interna cells during the ovulatory process is due to the response to the cytokine rather than to the enhanced steroidogenesis described above. Mn‐SOD protects cells from cytokine‐induced oxidative stress. The detailed role of Mn‐SOD induced by cytokines will be discussed later, in the section ‘Reactive oxygen species and corpus luteum’.

Tamate et al. reported the change in Cu,Zn‐SOD expression in the rat ovary, which is different from the expression pattern of human. ⁵⁶ Cu,Zn‐SOD was localized in granulosa cells in preovulatory follicles, and especially, strong immunostaining was found in cumulus cells. Recent evidence has shown that Cu,Zn‐SOD is secreted out of the cell and exerts a protective role against superoxide radicals. ⁵⁷ , ⁵⁸ , ⁵⁹ Since superoxide radicals are generated in preovulatory follicles during the ovulatory process, Cu,Zn‐SOD derived from granulosa cells could protect not only granulosa cells themselves but also the oocyte against superoxide radicals. In fact, it is reported that cumulus cells have a critical role in protecting oocytes against oxidative stress in gilts. ⁶⁰

REACTIVE OXYGEN SPECIES AND OOCYTES

OOCYTES ARE SURROUNDED by cumulus cells in follicles. It has been reported that cumulus cells have a close connection with oocytes during maturation. Strong immunostaining of Cu,Zn‐SOD was found in cumulus cells. ⁵⁶ Interestingly, there is a report showing that cumulus cells protect oocytes against oxidative stress by increasing the glutathione content, an antioxidant, in the oocytes in gilts. ⁶⁰

Follicular fluids and tubal fluids surrounding the oocytes play a crucial role in fertilization and embryo development. The increase in oxidative stress and the decrease in defense systems in those fluids may have deleterious effects on the reproductive process. In fact, most studies have shown that reactive oxygen species inhibit oocyte development. ⁶¹ , ⁶² , ⁶³ Reactive oxygen species cause meiotic arrest and the increase of degenerated oocytes, ⁶⁰ and oxidative stress induces apoptosis in mouse zygotes. ⁶² In humans, elevated oxidative stress and apoptosis are detected in the fragmented embryos. ⁶⁴ Besides the cytotoxicity, reactive oxygen species possibly influence the embryo development. The in vitro development blockage of mouse embryos at the 2‐cell stage (mouse 2‐cell block) can be released by adding SOD to the culture medium, ⁶⁵ and also released by low oxygen culture, ⁶⁶ , ⁶⁷ suggesting that reactive oxygen species affect the development of embryos. The presence of Cu,Zn‐SOD activity in the human preovulatory follicular fluids has been reported, and the level of Cu,Zn‐SOD activities is equal to the concentration of the serum. ⁷ Antioxidant genes such as Cu,Zn‐SOD, catalase and glutathione peroxidase are expressed in the tube in humans, rats and cows, ⁸ , ⁵⁶ , ⁶⁸ and also tubal fluids have activities of those antioxidant enzymes. ⁶⁸ Therefore, SOD may play a crucial role in not only protection of oocytes but also embryonic development.

Controversially, there is a report suggesting a possibility that reactive oxygen species induce the resumption of meiosis. ⁶⁹ In the report, antioxidants inhibit germinal vesicle breakdown in oocyte‐cumulus complexes of the rat, and oocyte maturation induced by incubation of follicles with HCG is inhibited by antioxidants. ⁶⁹ However, it remains unknown whether reactive oxygen species actually work or the antioxidant works.

In addition to the external defense system by follicular and tubal fluids, internal defense systems against oxidative stress exist in oocytes. Genes encoding Cu,Zn‐SOD, Mn‐SOD and glutathione peroxidase are expressed in oocytes. ⁷⁰ , ⁷¹ Cu,Zn‐SOD is present in oocytes at all stages of maturation in humans and bovines. ⁷⁰ , ⁷¹ However, there are some reports that Mn‐SOD expression in oocytes is maturation‐specific, ⁷⁰ , ⁷² which is at present controversial.

REACTIVE OXYGEN SPECIES AND CORPUS LUTEUM

IN OVARIES, THE corpus luteum is formed after ovulation and produces progesterone, which is necessary for establishment and maintenance of pregnancy. When conception occurred, rescue of the corpus luteum and subsequent progesterone production are important for the maintenance of pregnancy. In contrast, when conception did not occur after ovulation, decline of progesterone production is important for the follicular development of the next reproductive cycle. To get a chance for conception as soon as possible is dependent on how rapidly progesterone production declines. Therefore, the strategy for reproduction in the ovary is the rapid rescue of the corpus luteum when conception occurred, and the rapid termination of the corpus luteum function when conception did not occur after ovulation. In this section, the roles of reactive oxygen species and SOD in the corpus luteum are reviewed.

Roles of reactive oxygen species and SOD in the corpus luteum regression

Corpus luteum regression is defined as that the corpus luteum declines in function, decreases in volume, and thereafter disappears from the ovary. Corpus luteum regression consists of two stages of regression, functional luteolysis and structural luteolysis. Structural luteolysis is defined as structural involution of the corpus luteum and is clearly distinguished from functional luteolysis, which is characterized by depletion of progesterone production without structural changes such as loss of luteal cells and blood vessels. Rapid decline in progesterone production is important for follicular growth in the next reproductive cycle. It is therefore of interest to study the mechanism of functional luteolysis. This part first focuses on the role of reactive oxygen species and SOD in functional luteolysis.

Figure 1 shows the change in serum progesterone concentrations, SOD activities and concentrations of lipid peroxide, products of reactive oxygen species, in the corpus luteum in pregnant rats and pseudopregnant rats. ¹¹ , ¹² In both rat models, the regression phase is caused by functional luteolysis. Cu,Zn‐SOD activities in the corpus luteum increase from the early to mid‐luteal phase and gradually decrease during the regression phase in both pregnant and pseudopregnant rats. The change in Cu,Zn‐SOD activities parallels the change in serum progesterone concentrations and there is a significant corelationship between Cu,Zn‐SOD activities and serum progesterone concentrations. In contrast, lipid peroxide levels increase in the corpus luteum during regression phase and show an opposite change against serum progesterone concentrations in both pregnant and pseudopregnant rats. Also, other studies on prostaglandin F_2α (PGF_2α)‐induced functional luteolysis showed that reactive oxygen species, including superoxide radicals and hydrogen peroxide, increase in the corpus luteum during the regression phase in pseudopregnant rats. ⁷³ , ⁷⁴ These findings suggest that the decrease in Cu,Zn‐SOD and the increase in reactive oxygen species in the corpus luteum are involved in functional luteolysis. In fact, Sugino et al. demonstrated that when Cu,Zn‐SOD activities were suppressed by incubation with Cu,Zn‐SOD antisense oligonucleotides in rat luteal cells (50% reduction), progesterone production was inhibited and this inhibitory effect was mediated by reactive oxygen species. ¹⁴ In addition, superoxide radicals inhibit progesterone production by rat luteal cells. ¹⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ Hydrogen peroxide or lipid peroxides also inhibit progesterone production by luteal cells in rats and humans. ¹¹ , ¹⁶ , ¹⁸ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² It is of interest to note that there was no significant change in cell viabilities in those treatments, suggesting that reactive oxygen species inhibited function of luteal cells, but did not caused cell death such as apoptosis. Reactive oxygen species have been reported to inhibit progesterone synthesis by inhibition of cytochrome P450 side‐chain cleavage, ¹⁶ , ¹⁹ 3β‐HSD ¹⁶ and intracellular transport of cholesterol to mitochondria. ¹⁸ , ⁷⁹ , ⁸¹ Sawada and Carlson, and Wu et al. reported that reactive oxygen species cause several changes that disrupt the plasma membrane of luteal cells, ⁸³ , ⁸⁴ which are often seen in the regressing corpus luteum. Taken together, reactive oxygen species play a crucial role in functional luteolysis by inhibiting progesterone production.

Changes in (a) serum progesterone concentrations, (b) copper‐zinc superoxide dismutase (Cu,Zn‐SOD), (c) manganese SOD activities in the corpus luteum, and (d) lipid peroxide concentrations in the corpus luteum throughout pseudopregnancy (psp) and pregnancy in rats.

Regarding the changes in SOD expression and reactive oxygen species in the corpus luteum throughout the menstrual cycle in humans, Cu,Zn‐SOD activities increase from the early to mid‐luteal phase, gradually decrease thereafter and are the lowest in the regression phase. ¹³ Cu,Zn‐SOD mRNA expression also decreases from the mid‐to‐late luteal phase to regression phase. ¹³ In contrast, the concentration of lipid peroxide is significantly higher in the regression phase compared with the other phases. ¹³ These changes suggest that Cu,Zn‐SOD expression and lipid peroxide levels are closely related with the corpus luteum function in humans as well as in rats.

Mechanisms for the increase in reactive oxygen species in the regressing corpus luteum

As described above, the increase in reactive oxygen species in the corpus luteum is involved in functional luteolysis. The decrease in Cu,Zn‐SOD expression could be one of the causes for the increase in reactive oxygen species in the regressing corpus luteum. There seems to be other possible mechanisms for the increase in reactive oxygen species as described below.

Prostaglandin F_2α

Prostaglandin F_2α (PGF_2α) has been well recognized as a luteolysin since it increases in the corpus luteum during the regression phase, ⁸⁵ and inhibits progesterone production by luteal cells. A number of reports have shown that the inhibitory effect of PGF_2α on progesterone production by the corpus luteum is, in part, mediated through the increase of reactive oxygen species. ⁷⁴ , ⁷⁶ , ⁸³ , ⁸⁶ , ⁸⁷ Injection of PGF_2α induces functional luteolysis accompanied by the increase in lipid peroxide levels in the corpus luteum in pseudopregnant rats. ¹² PGF_2α stimulates superoxide radical production not only by luteal cells, ⁷⁵ , ⁸³ , ⁸⁶ but also by phagocytic leukocytes such as macrophages or neutrophils in the corpus luteum in rats. ⁸⁸ , ⁸⁹ , ⁹⁰ Therefore, PGF_2α could be one of factors responsible for the increase in reactive oxygen species in the regressing corpus luteum.

It is of interest to note that reactive oxygen species can activate phospholipase A2 activity and cyclooxygenase‐2 expression in the corpus luteum, ⁸³ , ⁹¹ , ⁹² which are key enzymes for PGF_2α synthesis. Therefore, there seems to be a close interrelation in the generation of reactive oxygen species between PGF_2α and reactive oxygen species.

Macrophages

It is well known that macrophages are involved in the corpus luteum regression in rats and humans. Macrophages increase in number in the regressing corpus luteum, ³ , ⁴ , ⁹³ and produce cytokines such as TNFα, interleukin‐1 or interleukin‐6. These cytokines are expressed in the corpus luteum and inhibit progesterone production by luteal cells. ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ Macrophages also produce reactive oxygen species and damage cells when they are activated by some stimulation. Sugino et al. reported that the number of activated macrophages producing reactive oxygen species increases in the rat corpus luteum undergoing functional luteolysis, suggesting that reactive oxygen species by macrophages could affect progesterone production by luteal cells. ³ In fact, there is an interesting report showing that hydrogen peroxide produced by neutrophils enters the luteal cells and inhibits progesterone production. ¹⁰⁰ It is therefore likely that macrophages are, at least in part, involved in functional luteolysis through reactive oxygen species production. Thus, macrophages could be a factor for the increase in reactive oxygen species in the regressing corpus luteum. Interestingly, reactive oxygen species production by macrophages is inhibited by progesterone. ³ In other words, as serum progesterone levels decline during the regression phase, macrophages become activated to produce reactive oxygen species in the corpus luteum. Therefore, macrophages contribute to the acceleration of functional luteolysis.

Changes in ovarian blood flow

Changes in ovarian blood flow are closely related to the corpus luteum function. ¹⁰¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ A decrease in blood flow occurs in the ovary during the regression phase. ¹⁰⁶ , ¹⁰⁷ It is well known in a variety of organs that the decrease in blood flow causes tissue damage via reactive oxygen species generation by the mechanism of ischemia‐reperfusion injury. In fact, Sugino et al. demonstrated that experimentally induced ovarian ischemia‐reperfusion caused the decrease in serum progesterone levels accompanied by the increased reactive oxygen species in the corpus luteum in rats. ¹⁰⁸ Also, this inhibitory effect of ovarian ischemia‐reperfusion on progesterone production was blocked by simultaneous injection of SOD. Therefore, ovarian ischemia‐reperfusion inhibits progesterone production by the corpus luteum through reactive oxygen species generation. Thus, the decrease in ovarian blood flow could be responsible for the increase in reactive oxygen species in the regressing corpus luteum.

Roles of Cu,Zn‐SOD in the rescue of the corpus luteum

Ephemerality and prolongation of the corpus luteum have been a matter of great concern in reproduction for many years. The control mechanism is complicated, and it differs among mammalian species. In rats, the lifespan of the corpus luteum is too short (2–3 days) to prepare the uterus for implantation, but it can be prolonged for approximately 10 days by pituitary prolactin after mating or uterine cervical stimulation. The corpus luteum can be further maintained by placental luteotropins if pregnancy occurs (reviewed in Gibori ¹⁰⁹ ). The luteal phase in humans continues for 2 weeks, which is long enough for implantation to occur. After implantation, the corpus luteum function is prolonged by placental luteotropins, HCG. Therefore, rescue of the corpus luteum by placental luteotropins is essential for the maintenance of pregnancy. As described above, reactive oxygen species and Cu,Zn‐SOD play important roles in the regulation of corpus luteum function. It is therefore of interest to know how reactive oxygen species and Cu,Zn‐SOD expression change in the corpus luteum when rescued by placental luteotropins.

The lifespan of the rat corpus luteum is prolonged to 13 days by pituitary prolactin after uterine cervical stimulation, which is called pseudopregnancy. Changes in serum progesterone levels, Cu,Zn‐SOD activities and lipid peroxide concentrations in the corpus luteum from pseudopregnant rats and pregnant rats are shown in Figure 1. Cu,Zn‐SOD activities increase until day 9 and thereafter decrease in pseudopregnant rats, but in pregnant rats, they further increase until day 12 of pregnancy in a manner similar to serum progesterone concentrations, suggesting that the corpus luteum is rescued with the increased Cu,Zn‐SOD activity by placental luteotropins. In fact, rat placental lactogens, one of placental luteotropins, up‐regulate Cu,Zn‐SOD expression in rat luteal cells in vitro. ¹¹⁰ In addition, injection of placental luteotropins from day 9 to day 12 of pseudopregnancy can prolong the luteal function with the increased Cu,Zn‐SOD expression in the corpus luteum. ¹¹¹ Prolactin, a luteotropic hormone secreted by the pituitary gland and deciduas, also up‐regulates Cu,Zn‐SOD expression in rat luteal cells. ¹¹⁰ However, estradiol has an inhibitory effect and progesterone has no effect on Cu,Zn‐SOD expression in rat luteal cells in vitro. ¹¹⁰ Although serum progesterone concentrations parallel to Cu,Zn‐SOD expression in the corpus luteum, progesterone is unlikely to affect Cu,Zn‐SOD expression, and luteotropic hormones do not always up‐regulate Cu,Zn‐DOD expression in the corpus luteum. In humans, Cu,Zn‐SOD activities and mRNA levels in the corpus luteum of pregnancy are significantly higher than those in the mid‐luteal phase, whereas lipid peroxide concentrations are remarkably low in the corpus luteum of pregnancy. ¹³ Since Cu,Zn‐SOD expression was significantly increased by HCG when the corpus luteum from the mid‐luteal phase was incubated with HCG, ¹³ high expression of Cu,Zn‐SOD in the corpus luteum of pregnancy could be due to HCG stimulation. Therefore, the corpus luteum is rescued with increased Cu,Zn‐SOD expression by pregnancy and has a high ability to scavenge superoxide radicals.

Placental luteotropins are essential for the prolongation and maintenance of corpus luteum function to stimulate overall protein synthesis and steroidogenic capacity of luteal cells when pregnancy occurs. This increase in metabolism and steroidogenesis stimulates the generation of reactive oxygen species. ⁷⁶ Reactive oxygen species generated normally during steroidogenesis may restrict the capacity of the corpus luteum to produce progesterone. ¹⁹ As described above, the decrease in Cu,Zn‐SOD expression causes the inhibition of progesterone production via the increase in reactive oxygen species. Therefore, the increase in ability to scavenge reactive oxygen species may be associated with the maintenance of luteal cell integrity and prolonged lifespan of the corpus luteum. Also, in another animal such as bovines, antioxidant capacities including SOD and catalase have been reported to be correlated with progesterone production by the corpus luteum. ¹¹² Taken together, one facet of the luteotropic effect of placental luteotropins when pregnancy occurs, is to stimulate the expression of molecules that protect luteal cells from reactive oxygen species. It is concluded that the increase in Cu,Zn‐SOD by placental luteotropins is an important mechanism to rescue the corpus luteum and maintain progesterone production.

Roles of Mn‐SOD in the corpus luteum

The corpus luteum has mitochondrial Mn‐SOD besides cytosolic Cu,Zn‐SOD. Generally, it is thought that Cu,Zn‐SOD is a constitutive type and Mn‐SOD is an inducible type that can be responsive to inflammatory reaction or cytokines. The importance of eliminating superoxide radicals from the mitochondria is illustrated by the neonatal death due to oxidative mitochondrial injury in central nervous system neurons and cardiac myocytes in mice lacking Mn‐SOD expression. ¹¹³ , ¹¹⁴ This section briefly overviews the specific role of Mn‐SOD in the corpus luteum.

Mn‐SOD activities in the corpus luteum changes in a manner similar to Cu,Zn‐SOD and serum progesterone concentrations from the early phase to the mid‐luteal phase in pseudopregnant and pregnant rats as shown in Figure 1. Mn‐SOD is up‐regulated by prolactin and placental luteotropins, such as rat placental lactogens. ¹¹⁰ , ¹¹¹ One of the roles of Mn‐SOD is protection against reactive oxygen species generated in the mitochondria by the increase in metabolism and steroidogenesis induced by prolactin and placental luteotropins, which is a common role of Cu,Zn‐SOD.

It is of interest to note that Mn‐SOD is, in part, differently expressed and regulated from Cu,Zn‐SOD in the corpus luteum in humans and rats. In contrast to Cu,Zn‐SOD, Mn‐SOD expression is low in the mid‐luteal phase and increases during the late‐to‐regression phase of the human menstrual cycle. ¹³ Also, as shown in Figure 1, the level of Mn‐SOD activities in the rat corpus luteum remains unchanged after day 15 of pregnancy, whereas Cu,Zn‐SOD activities decline. The mRNA level of Mn‐SOD does not decline during the regression phase in pregnant rats, whereas the Cu,Zn‐SOD mRNA level declines. ⁵¹ These different expressions of Mn‐SOD from Cu,Zn‐SOD can be explained by the selective induction of Mn‐SOD caused by inflammatory reaction or cytokines. ⁵¹ Macrophages increase in number in the corpus luteum during the regression phase and produce cytokines. ³ , ⁴ , ⁹³ In fact, several cytokines such as interleukin‐6 or TNFα have been demonstrated to be expressed in the corpus luteum, and the levels of those cytokines increase in the corpus luteum during the regression phase. ⁹⁴ , ⁹⁵ , ⁹⁷ , ⁹⁸ , ⁹⁹ Mn‐SOD, but not Cu,Zn‐SOD, is induced in the corpus luteum by inflammatory reaction such as lipopolysaccharide injection in pregnant rats. ⁵¹ In addition, selective induction of Mn‐SOD is shown in the corpus luteum or luteal cells treated with interleukin‐1, interleukin‐6, and TNFα in pregnant rats. ⁵¹ Therefore, the high expression of Mn‐SOD in the corpus luteum undergoing regression could be due to inflammatory reactions and cytokines.

Cytokines cause reactive oxygen species generation and damage cells. ¹¹⁵ , ¹¹⁶ , ¹¹⁷ For example, cytotoxic effects of cytokines can be reduced by increased levels of Mn‐SOD. ¹¹⁷ , ¹¹⁸ Interestingly, it is reported that cytokine‐resistant cells produce Mn‐SOD to protect themselves from the cytokine‐induced oxidative stress. ⁴⁷ , ⁴⁸ The constant Mn‐SOD expression in the corpus luteum undergoing regression may contribute to scavenging large amounts of reactive oxygen species generated in the mitochondria by cytokines. This response is necessary and important for luteal cells to survive and complete functional luteolysis, because the corpus luteum undergoing regression is under a cytokine‐rich environment. Therefore, luteal cells can respond to the cytokine‐rich environment with increased Mn‐SOD expression until the structural integrity of the corpus luteum is disrupted, after which Mn‐SOD expression is remarkably low in the regressed corpus luteum and cell death is inevitable. ⁹ , ¹¹⁹

Specific roles of Cu,Zn‐SOD and Mn‐SOD in the corpus luteum have not been clarified so far. It is now clear that Cu,Zn‐SOD is closely related with progesterone production by luteal cells, while Mn‐SOD protects luteal cells from inflammation‐ and cytokine‐mediated oxidative stress.

Reactive oxygen species and luteal cell apoptosis

A number of evidences have shown that apoptotic luteal cell death is involved in structural luteolysis. ¹²⁰ , ¹²¹ , ¹²² , ¹²³ , ¹²⁴ , ¹²⁵ , ¹²⁶ It has also been reported that accumulation of reactive oxygen species and a decrease in SOD levels are involved in apoptotic cell death in a variety of cells. ⁹² , ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³² , ¹³³ Especially, excessive reactive oxygen species in mitochondria causes cell death. Mitochondria are involved in apoptosis by releasing cytochrome c to the cytoplasm in which it activates caspases by interacting with some cytosolic factors including Apaf‐1. Antioxidant function of Bcl‐2, an antiapoptotic factor, prevents superoxide production and then blocks cytochrome c release and apoptosis. ¹³⁴ Daramajaran et al. reported the increased expression of Mn‐SOD and the decreased expression of Bax, a apoptotic factor, in the corpus luteum rescued by HCG in rabbits, ¹²² suggesting that Mn‐SOD is involved in the survival of luteal cells. The importance of eliminating superoxide radicals from the mitochondria is illustrated by the neonatal death of mice lacking Mn‐SOD expression as described above. ¹¹³ , ¹¹⁴ For example, if luteal cells are exposed to the cytokine‐rich environment and Mn‐SOD is not induced, rapidly increased reactive oxygen species in the mitochondria may cause apoptotic cell death.

In the natural cycle, such as pregnancy or pseudopregnancy of rats, despite the increase in reactive oxygen species in the corpus luteum during the regression phase (functional luteolysis), few apoptosis is detected in the corpus luteum. ¹²⁶ It may be due to that Mn‐SOD levels are maintained in the corpus luteum undergoing functional luteolysis, suggesting the corpus luteum still has the protective ability against oxidative stress. ¹¹ , ¹² , ⁵¹ Tanaka et al. reported that PGF2α, which induces functional luteolysis in rats, caused apoptosis via reactive oxygen species in rat luteal cells in vitro. ⁸⁶ However, this effect was only 5% reduction of cell viability and seems negligible. Therefore, this report rather supports the data of Takiguchi et al. ¹²⁶ that few apoptosis are detected in the corpus luteum during the functional luteolysis, although reactive oxygen species are increased.

In the human menstrual cycle, apoptosis is detected in the regressed corpus luteum with the increased level of reactive oxygen species and decreased Cu,Zn‐SOD expression, but Mn‐SOD expression is still high, suggesting that luteal cells have a protective ability against mitochondrial oxidative stress. ¹³ , ¹²⁰ , ¹²⁴ This finding may raise a possibility that the increase in reactive oxygen species in the cytosol caused by the decrease in cytosolic Cu,Zn‐SOD induces luteal cell apoptosis in the human corpus luteum. As described above in rats, the decrease in Cu,Zn‐SOD within a physiological range, such as the decline during the regression phase in pregnant or pseudopregnant rats, or 50% reduction by Cu,Zn‐SOD antisense oligonucleotides, had no significant effect on apoptotic cell death. Such a small decrease in Cu,Zn‐SOD activities may have been insufficient to cause apoptosis. However, in the human menstrual cycle, the level of Cu,Zn‐SOD activities in the regressed corpus luteum is less than 30% of the mid‐luteal phase level. ¹³ There may be a possibility that such a large decrease in Cu,Zn‐SOD activities causes luteal cell apoptosis in the human corpus luteum, because Rothstein et al. reported that a 40% decrease in Cu,Zn‐SOD activities did not cause apoptosis, but a 60% decrease caused apoptosis in nerve cells. ¹³⁰ Apoptosis may depend on the level of reactive oxygen species generated by the decrease in Cu,Zn‐SOD. There are several reports supporting that the decrease in cytosolic Cu,Zn‐SOD activities can cause apoptosis via reactive oxygen species. ¹³⁰ , ¹³¹ , ¹³⁵ For example, Fujiyama et al. reported that Cu,Zn‐SOD blocked cytosolic release of cytochrome c and could thereby inhibit apoptosis in mouse brain. ¹³⁵ In addition, there are some evidences showing a close relation between reactive oxygen species and luteal cell apoptosis in other animals (e.g. bovines or pigs). ⁹² , ¹³³

ACKNOWLEDGMENTS

THIS WORK WAS supported in part by Grant‐in‐Aid for Scientific Research 11671623, 13671721 and 15591753 from the Ministry of Education, Science, and Culture, Japan.

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PERMALINK

Reactive oxygen species in ovarian physiology

NORIHIRO SUGINO

Abstract

INTRODUCTION

REACTIVE OXYGEN SPECIES AND FOLLICULAR DEVELOPMENT

REACTIVE OXYGEN SPECIES AND FOLLICULAR ATRESIA

REACTIVE OXYGEN SPECIES AND OVULATION

REACTIVE OXYGEN SPECIES AND OOCYTES

REACTIVE OXYGEN SPECIES AND CORPUS LUTEUM

Roles of reactive oxygen species and SOD in the corpus luteum regression

Figure 1.

Mechanisms for the increase in reactive oxygen species in the regressing corpus luteum

Prostaglandin F_2α

Macrophages

Changes in ovarian blood flow

Roles of Cu,Zn‐SOD in the rescue of the corpus luteum

Roles of Mn‐SOD in the corpus luteum

Reactive oxygen species and luteal cell apoptosis

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Cite

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PERMALINK

Reactive oxygen species in ovarian physiology

NORIHIRO SUGINO

Abstract

INTRODUCTION

REACTIVE OXYGEN SPECIES AND FOLLICULAR DEVELOPMENT

REACTIVE OXYGEN SPECIES AND FOLLICULAR ATRESIA

REACTIVE OXYGEN SPECIES AND OVULATION

REACTIVE OXYGEN SPECIES AND OOCYTES

REACTIVE OXYGEN SPECIES AND CORPUS LUTEUM

Roles of reactive oxygen species and SOD in the corpus luteum regression

Figure 1.

Mechanisms for the increase in reactive oxygen species in the regressing corpus luteum

Prostaglandin F2α

Macrophages

Changes in ovarian blood flow

Roles of Cu,Zn‐SOD in the rescue of the corpus luteum

Roles of Mn‐SOD in the corpus luteum

Reactive oxygen species and luteal cell apoptosis

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

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Prostaglandin F_2α